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DENISE MEULDIJK

DOINGMOREWITHLESSConcise and standard treatment for depressive and anxiety

disorders compared in clinical practice

DOINGMOREW

ITHLESS Concise and standard treatmeepressive and anxiety disorders com

pared in clinical practice DENISE MEULDIJK

4063 Meuldijk COVER.indd 1 15-05-16 20:46

Doing more with lessConcise and standard treatment for depressive and

anxiety disorders compared in clinical practice

Denise Meuldijk

40637 Meuldijk THESIS-Final F+D.indd 1 17-05-16 09:57

Doing more with less - Concise and standard treatment for depressive and anxiety disorders compared in clinical practice. D. Meuldijk. Thesis, Leiden University Medical Centre (LUMC), the Netherlands, 2016

ISBN: 978-94-6332-036-8

Cover design and layout: Denise Meuldijk & Ivan Prsa (www.ivansmechanisedart.com.au)Printed by: GVO drukkers & vormgevers B.V. | Ponsen & Looijen

This PhD project was supported by Regional Mental Healthcare Provider Rivierduinen, which is gratefully acknowledged.

© 2016 D. Meuldijk, Leiden, the Netherlands.No part of this thesis may be reproduced or distributed in any form or by any means without prior permission of the author or, when appropriate, the copyright owning journals.


Doing more with lessConcise and standard treatment for depressive and

anxiety disorders compared in clinical practice

Proefschrift

ter verkrijging van de graad van Doctor aan de Universiteit Leiden,

op gezag van Rector Magnificus prof. mr. C.J.J.M Stolker,

volgens besluit van het College voor Promoties

ter verdediging op donderdag 23 Juni 2016

klokke 10.00 uur

door

Denise Meuldijk

geboren te Breda

11 Maart 1983


Promotores: Prof. dr. F.G. Zitman

Prof. dr. A.M. van Hemert

Copromotores: Dr. I.M. van Vliet

Dr. I.V.E. Carlier

Promotiecommissie: Prof. dr. N.J.A. van der Wee

Prof. dr. E. de Beurs

Prof. dr. C.M. van der Feltz-Cornelis, Tilburg University

Dr. L. Hakkaart-van Roijen, Erasmus University Rotterdam


voor de allerliefste, Cris †


Table of Contents

Chapter 1 General Introduction 9

Chapter 2 A randomised controlled trial of the efficacy and cost- 31 effectiveness of a brief intensified cognitive behavioural therapy and/or pharmacotherapy for depressive and anxiety disorders: design and methods Contemporary Clinical Trials 2012;33:983-92.

Chapter 3 The clinical effectiveness of concise cognitive behavioural 53 therapy with or without or pharmacotherapy for depressive and anxiety disorders; a pragmatic randomised controlled equivalence trial in clinical practice Contemporary Clinical Trials 2016;47:131-138.

Chapter 4 Economic evaluation of concise cognitive behavioural 75 therapy and/or pharmacotherapy for depressive and anxiety disorders Journal of Mental Health Policy and Economics 2015;18:4:175-183.

Chapter 5 Subgroup analyses of a concise care trial of depressive 91 and/or anxiety disorders Submitted

Chapter 6 A validation study of the Web Screening Questionnaire 107 (WSQ) compared to the Mini-International Neuropsychiatric Interview Plus (MINI-Plus) Submitted

Chapter 7 Summary and General Discussion 121

Chapter 8 Summary in Dutch/Nederlandse samenvatting 135 Curriculum Vitae List of publications Acknowledgements/Dankwoord


Chapter 1General Introduction


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1BACKGROUND Depressive and anxiety disorders are the most prevalent psychiatric disorders (de Graaf et al. 2012; Wang et al. 2007). They are associated with highly negative consequences for both the patient and society (Alonso et al. 2004; Buist-Bouwman et al. 2006; Ferrari et al. 2013; Murray et al. 2012; Murray & Lopez, 1997). Fortunately, in the last decennia many effective treatments for these disorders have become available. Which treatments and in what order to apply them has been described in guidelines. In general, it is advised to start with the simplest, less invasive (often shortest) and cheapest treatment option as a first step. Only patients unable to profit from this first step treatment will be offered more complicated, invasive (often longer) and more expensive treatments. This is called ‘the stepped care approach’ (Bower & Gilbody, 2005; Haaga, 2000; Kessler et al. 1996). During the last years the number of patients presenting with depressive and anxiety disorders has grown substantially, and society is worried about the significant costs associated with the treatment of these patients (Bijl & Ravelli, 2000a; de Graaf et al. 2012; Smit et al. 2006). Therefore, there is a strong incentive to make the treatments, especially the important first step, as concise as possible, without compromising effectiveness. In this thesis, we describe a study on the effectiveness of concise formats of the first step in the treatment of depressive and anxiety disorders compared with the longer standard delivery of this first step in a real-world clinical practice secondary mental healthcare setting. This chapter starts with an overview of the signs and symptoms of depressive and anxiety disorders, their prevalence and the disease burden and the costs associated with these disorders. Next, it addresses the evidence-based treatment guidelines for depressive and anxiety disorders and gives an introduction to concise, time-limited therapies. In addition, the importance of identifying predictors of successful treatment outcome is discussed. Then, we discuss the screening of mental disorders in general practice as a first step towards implementing concise therapies in clinical practice. Next, the trial that is the subject of this thesis and the specific research questions will be presented. Finally, an outline will be given of the remaining chapters of this thesis.

SIGNS AND SYMPTOMS OF DEPRESSIVE, ANXIETY AND ADJUSTMENT DISORDER Depressive disorders are characterized by one or more depressive episodes, which are, according to the Diagnostic Statistical Manual, fourth edition, text revision (DSM-IV-TR) (American Psychiatric Association, 1994) characterised by the presence of depressed mood or loss of interest or pleasure over a consecutive period of two weeks, accompanied by other symptoms (SEE BOX 1.1). Another type of mood disorder is the dysthymic disorder1. This dysthymic disorder is characterized `by a depressed mood nearly always present during at least two years. This mood is accompanied by at least two of the following: 1) poor appetite or overeating, 2) insomnia or hypersomnia, 3) low energy or fatigue, 4) low self-esteem, 5) poor concentration or difficulty making decisions. Those affected may experience some periods of normal, non-depressed mood of up to a maximum of two months.

1Note that in the newest edition of the Diagnostic and Statistical Manual of Mental Disorders, fifth edition (DSM-5) released in 2013, what was referred to as dysthymia (300.4) in DSM-IV, now falls under the category of persistent depressive disorder, which includes both chronic major depressive disorder and the previous dysthymic disorder (American Psychiatric Association, 2013).


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BOX 1.1. DSM-IV-TR CRITERIA FOR DEPRESSIVE EPISODE

Five (or more) of the following symptoms have to be present during the same 2-week period and represent a change from previous functioning; at least one of the symptoms is either (1) depressed mood, or (2) loss of interest or pleasure.

1 Depressed mood2 Markedly diminished interest or pleasure in activities3 Significant weight loss or weight gain4 Insomnia or hypersomnia5 Psychomotor agitation or retardation6 Fatigue or loss of energy 7 Feelings of worthlessness or excessive or inappropriate guilt8 Diminished ability to think or concentrate, or indecisiveness9 Recurrent suicidal ideation or suicide attempt

Source: Based on American Psychiatric Association. The Diagnostic Statistical Manual, fourth edition, text revision (DSM-IV-TR). Washington, DC: American Psychiatric Association: 1994 (American Psychiatric Association, 1994)

Anxiety disorders are characterized by feelings of apprehension, fearfulness or distress and an inherent recognition that the fear is excessive or unreasonable. These anxious feelings are usually associated with various physical symptoms such as fatigue, palpitations, sweating, shortness of breath, dizziness, chest pain or nausea. The DSM-IV-TR (American Psychiatric Association, 1994) defines several types of anxiety disorders, each with their own distinct symptom profile. In the study described in this thesis, the most common anxiety disorders to be seen in clinical practice are included: e.g. agoraphobia, panic disorder (with or without agoraphobia), specific phobias, social phobia (social anxiety disorder), obsessive compulsive disorder (OCD) , post-traumatic stress disorder (PTSD)2, generalized anxiety disorder (GAD) and anxiety disorder Not Otherwise Specified (NOS). Acute stress disorders and anxiety disorder due to medical condition or substance use are less prevalent in secondary mental healthcare and therefore not subject of this thesis. BOX 1.2. describes the different types of anxiety disorders in this thesis, and their symptoms.

Adjustment disorders3 In psychiatric outpatient clinics, many patients present with mood and/or anxiety symptoms without having the full syndrome of a depressive of anxiety disorder. The majority of these patients have an adjustment disorder with depressed mood and/or anxiety (Carta et al. 2009; Strain et al. 1998). Adjustment disorders are characterized by emotional symptoms such as sadness, anxiety and worry, or behavioural symptoms such as fighting and poor school or work performance, in response to an identifiable psychosocial stressor or stressors. The symptoms must have occurred within three months of the onset of the stressor (American Psychiatric Association, 1994). In clinical practice, adjustment disorders with depressed mood and/or anxiety are difficult to differentiate from mood and anxiety disorders and are frequently treated in the same way (Carta et al. 2009).

2The DSM-5 chapter on anxiety disorders no longer includes obsessive compulsive disorder (OCD, 300.3) or post-traumatic stress disorder (PTSD, 309.81) (and acute stress disorder (308.3)). OCD and PTSD have been moved to separate chapters on Obsessive-Compulsive and Related Disorders and Trauma- and Stressor-Related Disorders, respectively (American Psychiatric Association, 2013).3Note that in DSM-5, adjustment disorders are re-conceptualized as a heterogeneous array of stress-response syndromes that occur after exposure to a distressing (traumatic or non-traumatic) event, rather than as a residual category for individuals who exhibit clinically significant distress without meeting criteria for a more discrete disorder (as in DSM-IV) and are categorized as Trauma- and Stressor-Related Disorders (American Psychiatric Association, 2013).


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1Diagnostic criteria for AgoraphobiaA Fear of being in places or situations

from which escape might be difficult (or embarrassing) or in which help might not be available in the event of having unexpected panic-like symptoms.

B The situations are typically avoided or require the presence of a companion.

C The condition is not better accounted for by another mental disorder.

Diagnostic criteria for Panic Disorder With (1) or Without (2) AgoraphobiaA Both 1 and 2: 1 Recurrent unexpected Panic Attacks 2 At least one of the attacks has been

followed by 1 month (or more) of one of the following:

a Persistent concern about having additional panic attacksb Worry about the implications of the attack or its consequencesc A significant change in behaviour related to the attacks

B Presence or absence of agoraphobiaC The panic attacks are not due to the

direct physiologic effects of a substance (e.g., a drug of abuse, a medication) or a general medical condition (e.g., hyperthyroidism).

D The panic attacks are not better accounted for by another mental disorder.

Diagnostic criteria for Specific PhobiaA Persistent fear that is excessive or

unreasonable, cued by the presence or anticipation of a specific object or situation.

B Exposure provokes immediate anxiety, which can take the form of a situational predisposed panic attack.

C Patients recognize that the fear is excessive or unreasonable.

D Patients avoid the phobic situation or else endure it with intense anxiety or distress.

E The distress in the feared situation interferes significantly with the person’s normal routine, occupational functioning, or social activities or relationships.

F In persons younger than 18 years, the duration is at least 6 months.

G The fear is not better accounted for by another mental disorder.

Diagnostic criteria for Social Phobia A A fear of one or more social or

performance situations in which the person is exposed to unfamiliar people or to possible scrutiny by others and feels he or she will act in an embarrassing manner.

B Exposure to the feared social situation provokes anxiety, which can take the form of a panic attack.

C The person recognizes that the fear is excessive or unreasonable.

D The feared social or performance situations are avoided or are endured with distress.

E The avoidance, anxious anticipation, or distress in the feared situation interferes significantly with the person’s normal routine, occupational functioning, or social activities or relationships.

F The condition is not better accounted for by another mental disorder, substance use, or general medical condition

G If a general medical condition or another mental disorder is present, the fear is unrelated to it.

H The phobia may be considered generalized if fears include most social situations.

Diagnostic criteria for Obsessive– Compulsive DisorderA Either obsessions or compulsions: Obsessions as defined by 1, 2, 3, and 4: 1 Recurrent and persistent thoughts, impulses, or images that are experienced as intrusive and inappropriate, causing anxiety or distress. 2 The thoughts, impulses, or images are not simply excessive worries about real-life problems. 3 The person attempts to ignore or suppress such thoughts, impulses, or images or to neutralize them with some other thought or action. 4 The person recognizes that the obsessional thoughts, impulses, or images are a product of his or her own mind.

Compulsions as defined by 1, 2, and 3: 1 Repetitive behaviours or mental acts

that the person feels driven to perform in response to an obsession or according

to rules that must be applied rigidly.2 The behaviours or mental acts are aimed

at preventing or reducing distress or preventing some dreaded event or situation.

3 These behaviours or mental acts either are not connected in a realistic way with what they are designed to neutralize or prevent, or they are clearly excessive.

B At some point during the course of the disorder, the person has recognized that the obsessions or compulsions are excessive or unreasonable.

C The obsessions or compulsions cause marked distress, take up more than 1 hour a day, or significantly interfere with the person’s normal routine, occupation, or usual social activities.

D If another Axis I disorder, substance use, or general medical condition is present, the content of the obsessions or compulsions is not restricted to it.

Specify if: With Poor Insight: if, for most of the time during the current episode, the person does not recognize that the obsessions and compulsions are excessive or unreasonable.

Diagnostic Criteria for Posttraumatic Stress Disorder A The person has been exposed to a

traumatic event in which both the following were present:

1 The person experienced, witnessed, or was confronted with an event or events that involved actual or threatened death or serious injury, or a threat to the physical integrity of self or others 2 The person’s response involved intense fear, helplessness, or horror. B The traumatic event is persistently

re-experienced in at least one of the following ways:

1 Recurrent and intrusive distressing recollections of the event, including images, thoughts, or perceptions. 2 Recurrent distressing dreams of the event.

Continues on next page

BOX 1.2. DSM-IV-TR DIAGNOSTIC CRITERIA FOR ANXIETY DISORDERS


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THE PREVALENCE OF DEPRESSIVE AND ANXIETY DISORDERSDepressive and anxiety disorders are the most common mental disorders in the general population (Bijl et al. 1998; Kessler et al. 2009; Wittchen et al. 2011). In the Netherlands, the lifetime prevalence for both depressive and anxiety disorders found in the second NEMESIS study, a representative survey of 6.646 adults in the Netherlands conducted between 2007 and 2009, were 20.2% and 19.6%, respectively (de Graaf et al. 2012). Another way of looking at the prevalence of depressive and anxiety disorders is to study how many people suffered from these disorders during one year, the so-called one-year prevalence. Lifetime as well as one-year prevalence of depressive and anxiety disorders in the Netherlands remain fairly stable (Bijl et al. 1998; de Graaf et al. 2012). BOX 1.3. shows the one-year prevalence of depressive and anxiety disorders found in the second Nemesis study (de Graaf et al. 2012). High rates of comorbidity between anxiety and depressive disorders have frequently been described in epidemiological and clinical studies (Kessler et al. 1994; Kessler et al. 2005; Lamers et al. 2011). Approximately 85% of patients with a depressive disorder also experience significant symptoms of anxiety, as part of their depressive disorder and/or as comorbid anxiety disorder. Similarly, comorbid depressive disorders occur in up to 90% of patients with anxiety disorders (Brown et al. 2001; Gorman, 1996; Kessler et al. 1996; Kessler et al. 2005). Also, treatment of depressive and anxiety disorders is to a large extent comparable (see later in this chapter under treatment guidelines for more details). The considerable overlap between these disorders is believed to stem from the same biological vulnerability (Barlow, 2002; Clark et al. 1994).

3 Acting or feeling as if the traumatic event were recurring, including a sense of reliving the experience, illusions, hallucinations, and flashback episodes.

4 Intense psychological distress at exposure to cues that symbolize an aspect of the traumatic event.

5 Physiologic reactivity on exposure to cues that symbolize or resemble an aspect of the traumatic event.

C The person persistently avoids stimuli associated with the trauma and has numbing of general responsiveness including at least three of the following:

1 Efforts to avoid thoughts, feelings, or conversations associated with the trauma 2 Efforts to avoid activities, places, or people that arouse recollections of the trauma 3 Inability to recall an important aspect of the trauma 4 Markedly diminished interest or participation in significant activities 5 Feeling of detachment or

estrangement from others 6 Restricted range of affectD Persistent symptoms of increased

arousal are indicated by at least two of the following:

E Difficulty falling or staying asleepF Irritability or outbursts of anger 1 Difficulty concentrating 2 Hyper vigilance 3 Exaggerated startle responseG Duration of the disturbance is more than

1 month.H The disturbance causes clinically

significant distress or impairment in social, occupational, or other important areas of functioning

Diagnostic Criteria for Generalized Anxiety DisorderA Excessive anxiety about a number of

events or activities, occurring more days than not, for at least 6 months.

B The person finds it difficult to control the worry.

C The anxiety and worry are associated

with at least three of the following six symptoms (with at least some symptoms present for more days than not, for the past 6 months):

1 Restlessness or feeling keyed up or on edge 2 Being easily fatigued 3 Difficulty concentrating or mind going blank 4 Irritability 5 Muscle tension 6 Sleep disturbance

Diagnostic Criteria for Anxiety Disorder Not Otherwise specifiedA This diagnosis occurs when someone

experiences symptoms of an anxiety disorder without any clear cause, and it may include some depressive disorders. Those with this diagnosis often have anxiety that manifests in many of the physical and emotional symptoms of anxiety, but doesn’t appear to qualify for a specific diagnosis.

BOX 1.2. DSM-IV-TR DIAGNOSTIC CRITERIA FOR ANXIETY DISORDERS (CONTINUED)

Source: Based on American Psychiatric Association. The Diagnostic Statistical Manual, fourth edition, text revision (DSM-IV-TR). Washington, DC: American Psychiatric Association: 1994 (American Psychiatric Association, 1994)


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1

BURDEN OF DISEASE Depressive and anxiety disorders are imposing a large burden on the patient and his significant others, and can be associated with significant long-term disability (Bijl & Ravelli, 2000b; Ormel et al. 1994; von Korff et al. 1992). The World Health Organization (WHO) Collaborative Study on Psychological Problems in General Healthcare (Ormel et al. 1994) reported that more than one-half of the patients with an anxiety disorder experience moderate to severe occupational dysfunction and physical disability. The severity and disability reported for depressive disorders was similar (Kessler et al. 1999). In addition, the clinical symptoms of depressive and anxiety disorders cause significant emotional distress and those affected experience poorer levels of general health (Mendlowicz & Stein, 2000; Rapaport et al. 2005; Saarni et al. 2007). In terms of burden of disease, depression is estimated to be the second greatest contributor to disability-adjusted life years (DALYs)4 throughout the developed world, whereas anxiety disorders were found to be the sixth leading cause of disability (Baxter et al. 2014; Ferrari et al. 2013; Murray et al. 2012). Moreover, depressive and anxiety disorders are also associated with high levels of morbidity and mortality (Mathers & Loncar, 2006). In fact, depressive disorders are the most common disorders contributing to suicide (Cuijpers & Smit, 2002). The high burden of disease is furthermore reflected in the high costs associated with depressive and anxiety disorders due to the increased use of mental health services, and productivity losses (Cuijpers et al. 2007; Gustavsson et al. 2011; Hu, 2006; Nutt, 2011; Simon et al. 1995; Sobocki et al. 2006). The 1998 report of the World Health Organization stated that “more working days are lost as a result of mental disorders than of physical conditions” (WHO, 1998). In the Netherlands, Smit and colleagues (2006) calculated the annual direct and indirect economic costs5 of depressive and anxiety disorders per capita on respectively 5,009 and 3,587 Euros per year (Smit et al. 2006). The US National Advisory Mental Health Council (NAMHC) estimated the 1990 total cost for depressive and anxiety disorders each at nearly $45 billion [http://www.eu-wmh.org].

4The disability-adjusted life year (DALY) is a measure of overall disease burden, expressed as the number of years lost due to ill-health, disability or early death. One DALY is thus one lost year of healthy life. It was developed in the 1990s as a way of comparing the overall health and life expectancy of different countries (Murray, 1994).5Direct costs are mainly the costs of health service resource and fall into the categories: a) direct healthcare costs (i.e. all goods and services related to the prevention, diagnosis and treatment of a disorder; for example physician visits, hospitalizations and pharmaceuticals); b) direct non-medical costs (i.e. other goods and services related to the disorder; e.g. social services, special accommodation and informal care). Indirect costs have been defined as all the costs and negative effects that are related to health problems but not directly to the treatment (i.e. lost production due to work absence or early retirement).

BOX 1.3. ONE-YEAR PREVALENCE (%, SE) OF COMMON DEPRESSIVE AND ANXIETY DISORDERS ACROSS POPULATION STUDIES IN THE NETHERLANDS

NEMESIS- 2aDepressive disorders Major depressive disorder 5.2 (0.3) Dysthymic disorder 0.9 (0.1)

Anxiety disorders Panic disorder 1.2 (0.2) Agoraphobia 0.4 (0.1) Social phobia 3.8 (0.3) Specific phobia 5.0 (0.4) Generalized anxiety disorder 1.7 (0.2)

Abbreviations: NEMESIS: Netherlands Mental Health Survey and Incidence Study; DSM-IV: Diagnostic and Statistical Manual of Disorders, fourth edition; (WMH-)CIDI: (World Mental Health-) Composite International Diagnostic InterviewaDSM-IV disorders measured with the WMH- CIDI


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TREATMENT GUIDELINES Treatment guidelines describe evidence-based and best-practice recommendations concerning assessment and treatment of psychiatric disorders. By offering practical suggestions and instructions for professionals and patients concerning preventive, diagnostic, therapeutic and organizational procedures, the guidelines help to decide which therapies are most appropriate in the management of these disorders. Examples are the guidelines of the American Psychiatric Association (APA) and, in the United Kingdom (UK), the National Institute of Clinical Excellence (NICE) guidelines. In the Netherlands, the National Guideline Steering Group for Multidisciplinary Guideline Development in Mental Health (NGSMH) and the Trimbos Institute formulated multidisciplinary clinical guidelines for the treatment of depressive and anxiety disorders (Mental health guidelines (in Dutch) [http://www.ggzrichtlijnen.nl]). In both Dutch and international guidelines, the use of either psychotherapy or pharmacotherapy is widely recommended as first treatment step for depressive and anxiety disorders in clinical practice (Cuijpers et al. 2013). With respect to psychotherapy, cognitive behavioural therapy (CBT) is the treatment of first choice for both depressive and anxiety disorders (see (Butler et al. 2006; Compton et al. 2004; Hollon et al. 2006; March et al. 2004). Other interventions (e.g. psycho-education, self-help interventions (individual or group courses), problem solving treatment (PST)), are also allowed, as well as more disorder-specific forms of treatment (e.g. Eye Movement Desensitization Reprocessing (EMDR) for posttraumatic stress disorder). In pharmacotherapy for both depressive and anxiety disorders the first step is selective serotonin reuptake inhibitors (SSRIs) (Bandelow et al. 2012; Bauer et al. 2007; Mental health guidelines (in Dutch) [http://www.ggzrichtlijnen.nl], 2015; National Institute for Health and Clinical Excellence (NICE), 2009). Besides, the guidelines provide information on the duration of each treatment step and when to switch to the next step. For example, the effectiveness of pharmacotherapy should be evaluated after six weeks of treatment and of psychotherapy after twelve weeks. A frequency of one session every week is recommended. However, it is generally accepted that treatment duration depends on the nature and severity of the complaints, the characteristics of the individual patient, and the professional experience of the therapist. In clinical practice, the frequency of psychotherapy sessions do not take place weekly, and evaluation in most cases does not take place on a fixed moment after treatment starts and mostly occurs later.

CONCISE THERAPIES Healthcare systems in secondary care are currently facing tremendous budget constraints (Lokkerbol & Smit, 2011). Given the increasing care demands and the limited time available for therapists, it is important for mental healthcare centres and healthcare in general to optimize the use of resources without compromising effectiveness (Beekman et al. 2002; de Beurs et al. 1999; Smit et al. 2006). Concise therapies, by medication or brief psychotherapy, or both combined, in which treatment is condensed in a shorter time period and with fewer sessions, are suggested to meet these requirements and have gained interest in clinical practice (Jarrett & Rush, 1994; Marks, 2002; Newman, 2000). Besides, concise therapies are regarded as main candidate for the first step (i.e. after psycho-education and self-help), in a stepped care model (Bower & Gilbody, 2005; Meeuwissen et al. 2008; Scott et al. 1997; van Straten et al. 2015). Time-limited treatments do also


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1meet patient preferences for brief psychological interventions as has been described repeatedly (Jarrett & Rush, 1994; Roth & Fonagy, 2005). The question remains whether it is possible to provide a more concise treatment that is at the same time at least as effective as standard treatment and also less costly. And, preferably, can be carried out in clinical practice. Under the assumption that the new intervention and the standard treatment are equally effective in terms of outcomes, identifying the least costly treatment option is important to inform clinical and health system decision making and policy.

THE EFFECTIVENESS OF CONCISE THERAPIES Several studies have addressed the effectiveness of concise therapies versus longer therapies in the treatment of depressive and anxiety disorders in a variety of treatment settings. They showed comparable effectiveness, independently of the duration of the intervention (Bressi et al. 2010; Cape et al. 2010; Churchill et al. 2001; Knekt, 2004; Lang et al. 2006; Nieuwsma et al. 2012). In general practice (i.e. referred to as primary care), a comprehensive review by Cape and colleagues (2010) confirmed the effectiveness of different forms of brief psychotherapy (i.e., various types of CBT, IPT, short-term psychodynamic therapy, and non-directive supportive therapy either or not as an adjuvant to pharmacotherapy), compared to longer standard therapy in more sessions and over a longer time period (Cape et al. 2010). However, generalizability of these findings to patients seen in everyday clinical practice is limited. First, effectiveness of concise therapies has been examined through RCTs performed on selected subjects under more controlled conditions than is usual in clinical practice (Bower & Gilbody, 2005). Only a few studies have evaluated a standardized stepped care protocol in clinical outpatient practice (Meeuwissen et al. 2008; Muntingh et al. 2014; Muntingh et al. 2009; Oosterbaan et al. 2013; van Straten et al. 2006). Second, RCTs are carried out with a selected group of patients, not representative for the clinical population. For instance, patients with adjustment disorders are excluded, although in clinical practice they are often treated as patients with full mood or anxiety disorders (Carta et al. 2009). Third, research on brief psychological therapies has mainly focussed on patients with either depressive (Bockting et al. 2011; Higgins & Hecker, 2008; Nieuwsma et al. 2011) or anxiety disorders (Clark et al. 1999; Marchand et al. 2009; Muntingh et al. 2014; Muntingh et al. 2009) with a diagnosis based on a structured interview, whilst in clinical practice diagnoses are mostly based on the unstructured interview of the clinician. In those interviews, clinicians seldom screen systematically for all symptoms of all likely disorders. They seldom diagnose comorbidity, but instead choose for a mood or an anxiety disorder, even if a patient does not meet full diagnostic criteria for either disorder (Wardenaar & de Jonge, 2013). Add to this that in clinical practice also adjustment disorders are treated and it will be clear that the patient samples in the studies carried out thus far, are not representative for the practice of psychiatric outpatient clinics. In order to determine whether concise care is effective in clinical practice, it should be evaluated in the patients treated in real-world clinical practice. Besides, it should not be assessed for a single type of treatment, for instance pharmacotherapy, but for the whole group of treatments that are employed in the first step of treatment for depressive and anxiety disorders. The patients and therapists should be able to choose for a therapy just as they would do in clinical practice.


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OUTCOME PREDICTORS Determining subgroups of patients who are most likely to benefit from a specific treatment, may improve cost-effectiveness and appropriate delivery of healthcare (Cortese, 2007; Cuijpers et al. 2013). Moreover, the identification of potential variables associated with treatment success of concise care contributes to the development of clinical staging and profiling as it enables clinicians to match care with the needs of the individual patient, facilitating the development of more effective and tailor-made treatments (McGorry et al. 2006; van Balkom et al. 2012; Zitman, 2012). To this end, prior research in clinical practice has examined the relationship between treatment outcomes of usual psycho- and/or pharmacotherapy in anxiety and depressive disorders, on the one hand (Cuijpers et al. 2008) and several socio-demographic patient characteristics and clinical factors, on the other hand (Schat et al. 2013; van Noorden et al. 2012). Different studies have shown that several variables influence outcome of traditional psycho- and pharmacotherapy in the treatment of depressive and anxiety disorders: e.g. female sex, being unmarried, younger age at the start of treatment, and higher education (college/university) are associated with more successful treatment responses (Fournier et al. 2009; Frank et al. 2002; Ramsawh et al. 2011; Weinberger et al. 2008). Moreover, the presence of comorbid disorders and having concomitant symptoms of either anxiety or depressive disorder were associated with poorer outcome (Brent et al. 1998; Bruce et al. 2005; Penninx et al. 2011; van Noorden et al. 2012). In addition, differential effects on treatment outcome were found for depressive versus anxiety disorders. Some studies have found a more favourable course for depressive disorders compared to anxiety disorders (Ormel et al. 1993; Penninx et al. 2011; Spijker et al. 2002). Other meta-analyses have found that treatment of anxiety disorders generally lead to better outcomes as perceived by patients (Butler et al. 2006; Hofmann et al. 2012). However, as stated before, in clinical practice patients are treated with various types of pharmaco- and psychotherapy based on the diagnosis made by the clinician. No strict in- and exclusion criteria are used and there also is much more freedom to apply psycho- and pharmacotherapy than in RCTs, even in concise care. Therefore, the predictors of a successful response to concise care cannot be extrapolated simply from the predictor studies discussed above.

TREATMENT EVALUATIONIn order to provide systematic monitoring of patients’ treatment progress, in the Leiden area in the Netherlands, Routine Outcome Monitoring (ROM) has been developed and integrated in daily clinical practice since 2002 by a collaboration of the Regional Mental Health Provider (RMPH) Rivierduinen (RD) and the Department of Psychiatry of the Leiden University Medical Centre (LUMC) (Carlier et al. 2012; de Beurs et al. 2011). It is used now in standard care in all mental healthcare centres in the Netherlands, but it can also be applied, preferably in an abridged form, in the evaluation of concise care. The ROM method used, at the time of our study, is described in more detail in BOX 1.4.

CONCISE CARE IN GENERAL PRACTICE?An important incentive for concise care is cost reduction. If it is possible to attain the same treatment results as in standard clinical practice in a shorter time period, than this will probably imply a more cost-effective treatment. Moreover, an even higher cost-reduction could be attained


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1

if concise care could be carried out in general practice, for instance by specially trained nurses. Transferring concise care to general practice requires adequate screening of patients in general practice who may be eligible for concise treatment, and can be a key in successful treatment outcomes of concise care. With the limited time available for therapists, it is furthermore important that this screening is as brief as possible. Various standardized diagnostic interviews for mental health have been developed, such as the Structured Clinical Interview for DSM-III-R (SCID) (Spitzer et al. 1992) and the Mini-International Neuropsychiatric Interview Plus (MINI-Plus) (Sheehan et al. 1998; van Vliet & de Beurs, 2007). However, these diagnostic screening instruments are not designed as a brief screening instrument, they are time-consuming, costly, and require a well-trained interviewer to conduct. Therefore, these interviews are impractical, as a screener, for routine use in busy mental healthcare centres, and even more so, in general practice. Hence, a reliable and valid, brief self-rating screening questionnaire that could adjust or replace these laborious diagnostic interviews would be welcome. Such an instrument has been developed in the Netherlands: the Web Screening Questionnaire (WSQ) (Donker et al. 2009; Gega et al. 2005). The WSQ is a self-report questionnaire consisting of only 15 items to screen for the most common mental disorders, and it has proven to be a reliable and valid screener (Donker et al. 2009). Whereas the few other screening instruments that are both short and practical for use in clinical practice, such as the PRIME-MD Patient Health Questionnaire (Spitzer et al. 1999), the Panic Disorder Screener (PADIS) (Batterham et al. 2015) and more recently, for the primary care settings,

BOX 1.4. ROM IN THE LEIDEN UNIVERSITY MEDICAL CENTRE AND RIVIERDUINEN

In spring 2002, the Regional Mental Healthcare Provider (RMHP) Rivierduinen (an institute serving a region with more than 1 million inhabitants) and the Department of Psychiatry of the Leiden University Medical Centre (LUMC) started collaboration for routine assessment of Diagnostic Statistical Manual of Mental Disorders fourth edition, text revision (DSM-IV-TR) diagnoses as well as symptom severity, wellbeing, and generic health status at intake and follow-up. This project is known as Routine Outcome Monitoring (ROM). Initially, ROM was restricted to patients who were referred for treatment of mood, anxiety, and/or somatoform (MAS) disorders. These patients form a relatively homogenous group with substantial mutual comorbidity (American Psychiatric Association, 1994) who mainly receive outpatient care. To be eligible, patients must have sufficient mastery of the Dutch language, and have to be able to complete self-report questionnaires. Patients who are considered (by their clinician) to be too ill to complete questionnaires or refuse assessment, are excluded from ROM. Patients are assessed by psychiatric research nurses who have been extensively trained and supervised. Assessments are scheduled at intake, at three- to four-month intervals during follow-up, at the start of a new treatment step, and at the end of treatment. During the first session, a standardised diagnostic interview (the Mini-International Neuropsychiatric Interview-plus, MINI-Plus) (Sheehan et al. 1998) is administered to determine DSM-IV-TR axis-I diagnoses. In addition, socio-demographic characteristics are assessed and maladaptive personality traits are identified with the Dimensional Assessment of Personality Pathology Short Form (DAPP-SF) (Livesley & Jackson, 2006). At baseline and at follow-up, a number of self-report as well as observer-rated generic and disorders specific symptom severity scales are administered in order to monitor change in symptom reduction, wellbeing, and general functioning (Sperry et al. 1996). All instruments are commonly used in treatment-outcome research and have good psychometric properties as demonstrated by national and international publications. An overview of instruments used is available at https://www.lumc.nl/sub/3010/att/1211140330002029.pdf. To date, treatment information has not been documented in ROM. Results are summarised in a report which is discussed with the patient by the clinician and which is used to evaluate treatment. In addition, data are anonymised and used for scientific research. As data collection is integrated in standard care and data are anonymised, patients are not required to provide informed consent. The use of the anonymised data for scientific purposes has been approved by the Medical Ethical Committee of the LUMC.

Source: Based on Van Noorden, 2012, On real-world patients and real-world outcomes: The Leiden Routine outcome Monitoring Study in patients with mood, anxiety and somatoform disorders; p22. With permission of the author.


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the M.I.N.I. Screen (Sheehan et al. 1998), focus on a single disorder (i.e. depressive disorder; panic disorder), the WSQ broadly screens for several psychiatric disorders. Thus far, the WSQ has only been studied in a general Dutch population sample with a rather low prevalence of psychiatric disorders (Donker et al. 2009). It has not been investigated in a general practice population in which the prevalence of psychiatric disorders is higher.

AIMS AND RESEARCH QUESTIONSIn the paragraphs above, we have discussed that in clinical practice diagnoses are not made so reliable as happens with a structured diagnostic interview and that, as a consequence, the diagnoses of the patients are more diverse than in RCTs performed up to now. Also, the patients and therapists are free to choose between the various treatments that are described in the guidelines as the first step (after psycho-education and self-help). In order to apply and evaluate a more concise treatment in clinical practice, this should be taken into account. Otherwise, a RCT is carried out that evaluates the effects of concise treatment for only a small group of the patients that are normally treated in clinical practice. Therefore, the main object of this study was to evaluate the effects of concise versions of psycho- and/or pharmacotherapy (hereinafter referred to as ‘concise care’) in a group of clinical outpatients with depressive, anxiety and adjustment disorders, in which patients and therapists were free to select the type of treatment, thus approaching the real-world situation as much as possible. As comorbidity is high and treatment options are highly comparable for depressive and anxiety disorders, we included patients with both these disorders. We aimed at detecting equivalence of concise care with standard care. Therefore we carried out a pragmatic, randomised controlled equivalence trial evaluating whether concise care is as effective as standard care delivered in a secondary outpatient setting. For this study, we developed concise formats of evidence based psycho- and/or pharmacotherapy. Treatment protocols in concise care were confined to a maximum of 7 weekly, 45 minutes sessions and consist of the following evidence based interventions: [1] cognitive behavioural therapy, [2] pharmacotherapy and [3] Eye Movement Desensitization and Reprocessing-therapy (EMDR), in case of a posttraumatic stress disorder (see the website awp.rivierduinenlumc.nl for an overview of the concise treatment protocols [in Dutch]). The secondary aim was to evaluate the cost-effectiveness of concise care compared to standard care. In addition, the identification of potential intake variables associated with treatment success of concise care, was a further objective of this thesis. Moreover, the feasibility of a brief screening questionnaire, the Web Screening Questionnaire (WSQ), was investigated. The study was carried out in five outpatient mental health centres of the Regional Mental Health Provider Rivierduinen.


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1OUTLINE CHAPTER 2 describes the protocol of this study. The rationale and design of the pragmatic RCT of equivalence are described. The recruitment, the sample, the procedures, the primary and secondary outcome measures and the planned statistical analyses are described.

CHAPTER 3 presents the findings regarding the clinical effectiveness of both concise care and standard care. This study focuses on the primary outcomes and main secondary outcomes in terms of equivalence and anxiety and depressive symptom reduction, as well as improvement of general health and quality of life.

CHAPTER 4 contains an economic evaluation in which the cost-utility of concise care compared to standard care over the total study period is assessed.

CHAPTER 5 discusses the potential demographic and clinical predictors of treatment outcome of concise care. The limited information available for clinicians before start of treatment was used to guide clinical decision making in the allocation of adequate care.

CHAPTER 6 investigates the feasibility of the WSQ to identify DSM-IV diagnosis of anxiety and depression according to the MINI-Plus. The WSQ and the MINI-Plus were administered in our study on concise care as well as in a study on reference values for several questionnaires, carried out among others in the general population (Schulte-van Maaren et al. 2012) We used the data of both studies for this investigation.

Finally, CHAPTER 7 summarizes the main findings of the studies included in this thesis, and put them in broader view in the general discussion, including a description of clinical implications and directions for future research.


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Zitman FG. [Staging, profiling and routine outcome monitoring]. Tijdschr Psychiatr 2012; 54:979-984.


Chapter 2A Randomised Controlled Trial of the Efficacy and Cost-effectiveness of a Brief Intensified Cognitive Behavioural therapy and/or Pharmacotherapy for

Mood and Anxiety Disorders: Design and Methods

Previously published as:Meuldijk D, Carlier IVE, van Vliet IM, van den Akker- van Marle ME, Zitman FG.

A randomised controlled trial of the efficacy and cost-effectiveness of a brief intensified cognitive behavioural therapy and/or pharmacotherapy for mood and anxiety disorders: Design and methods.

Contemp Clin Trials 2012;33:983-992


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ABSTRACTBACKGROUNDAnxiety and mood disorders involve a high disease burden and are associated with high economic costs. A stepped care approach intervention and abbreviated diagnostic method are assumed to increase effectiveness and efficiency of the mental healthcare and are expected to reduce economic costs.

METHODSPresented are the rationale, design, and methods of a two-armed randomised controlled trial comparing ‘treatment as usual’ (TAU) with a brief intensified cognitive behavioural therapy (CBT) and/or pharmacotherapy. Eligible participants (n = 500) of five Dutch outpatient Mental Healthcare Centres are randomly assigned to either TAU or to the experimental condition (brief CBT and/or pharmacotherapy). Data on patients’ progress and clinical effectiveness of treatment are assessed at baseline, post-treatment (3 months after baseline), and at 6 and 12 months post-treatment by Routine Outcome Monitoring (ROM). Cost analysis is performed on the obtained data.

DISCUSSIONSince few studies have investigated both the clinical and cost effectiveness of a stepped care approach intervention and a shortened diagnostic ROM method in both anxiety and/or mood disorders within secondary mental health care, the results of this study might contribute to the improvement of (cost)-effective treatment options and diagnostic methods for these disorders.


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INTRODUCTIONAnxiety and mood disorders belong to the most common mental disorders. Several epidemiological surveys found anxiety and mood disorders to be the most prevalent class of mental disorders in the general population (Bijl et al. 1998; Kessler et al. 2009). The World Health Organization surveys estimated their global lifetime prevalence to be 14.3% and 10.6%, respectively (Kessler et al. 2009; Wittchen et al. 2011). These disorders frequently start early in life and tend to have a chronic or relapsing course (Landelijke Stuurgroep Multidisciplinaire Richtlijn ontwikkeling in de GGZ, 2015); moreover, their presence contributes to a high disease burden for both the patient and their family (Wittchen et al. 2011). They also have a substantial impact on daily functioning at home/work and on quality of life (Bijl & Ravelli, 2000; Buist-Bouwman et al. 2006; Mathers et al. 2008; Ormel et al. 1994), comparable to the impact and effects of major chronic illnesses (Buist-Bouwman et al. 2006; Kessler et al. 2001; Murray & Lopez, 1997). Consequently, the economic costs of these disorders for healthcare systems and society are high (Smit et al. 2006). It is estimated that in 2010 the direct and indirect costs of anxiety and mood disorders in Europe were 74.4 + 113.4 billion euros, respectively (Gustavsson et al. 2011). Earlier studies in the USA and UK reported even higher estimates (Hu, 2006). In the last decades, evidence-based treatments for anxiety and mood disorders have become available, i.e. cognitive behavioural therapy (CBT) and interpersonal therapy specifically developed for these disorders, as well as pharmacotherapy (mainly antidepressants) (Bandelow et al. 2002; Bandelow et al. 2008). As important differences in effectiveness between the treatments are absent (Hu, 2006) guidelines were developed advocating a stepped care model (Davison, 2000; Haaga, 2000). Moreover, to enhance effectiveness, for each of these treatments protocols and guidelines became available based on those used in randomised controlled trials (RCT) (Andrews et al. 2004; Carlier et al. 2012; de Beurs et al. 2011; Landelijke Stuurgroep Multidisciplinaire Richtlijnontwikkeling in de GGZ, 2015). Recently, we added Routine Outcome Monitoring (ROM) to the stepped care approach to help the diagnostic process and treatment evaluation (Carlier et al. 2012; de Beurs et al. 2011. It is clear that guidelines, protocols and ROM have the potential to improve treatment efficacy. However, these improvements may not yet be fully realized as adherence to the guidelines and protocols remains questionable (Bower & Gilbody, 2005; Davison, 2000; Meeuwissen et al. 2008; Shafran et al. 2009), even when ROM is added (Carlier et al. 2012; de Beurs et al. 2011). This implies that treatments last longer, consist of too many sessions and, thus, unnecessarily prolong suffering and increase related costs (Bower & Gilbody, 2005; Davison, 2000; Meeuwissen et al. 2008). Moreover, the current economic situation offers a strong incentive to make treatments as cost-effective as possible. This applies not only to the treatments as such, but also to ROM; from an economic point of view ROM should be as concise as possible. As most patients are treated in the first phase of the stepped care model, it is in this phase that cost reduction is most profitable. Brief therapy is suggested to be suitable as a first step in a stepped care model (Bower & Gilbody, 2005; van Straten et al. 2006). This paper describes an RCT designed to evaluate the effects and costs of a shortened first treatment in the stepped care protocol for anxiety and mood disorders in secondary care, an area where there is a paucity of research. It consists of time-limited (brief ) CBT and/or medication treatment using a protocol following the multidisciplinary guidelines, but confined to a 7-week


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period and a maximum of 7 sessions. Also examined is the feasibility of a shorter, less labour-intensive ROM. In addition, the cost-effectiveness of the treatment and the adapted ROM are compared to ‘treatment as usual’ (TAU).

DESIGN AND METHODSTUDY GOALSPrimary aim of this study is to evaluate the efficacy and effectiveness of a newly developed time-limited (brief ) therapy intervention compared with TAU. Secondary aim is to evaluate the cost-effectiveness of the experimental intervention as compared with TAU. Additionally, the feasibility of a shortened, less work intensive and time-consuming ROM is evaluated. Patient and therapist satisfaction with the new intervention is also explored.

STUDY DESIGNThe study is a pragmatic, two-armed RCT using a parallel group design. Five Dutch mental health clinics are projected to enrol a total of 500 participants over an 18-month period of active recruitment. Eligible participants who provide informed consent are randomly assigned to one of two groups: the control group (TAU), or the experimental group. Patients in both groups are assessed by ROM at baseline and after 3 months (post-treatment). Follow-up assessments are conducted in all patients at 6 and 12 months post-treatment. Primary and secondary outcomes are assessed by ROM. Primary outcomes are the scores on the Web Screening Questionnaire (WSQ) and Brief Symptom Inventory (BSI). Secondary outcomes are the scores on the other instruments assessed by ROM (SEE SECTION ROUTINE OUTCOME MEASURES AND FEEDBACK AND TABLE 1). The design and methodology of this study allows to assess analysis of equivalency (non-inferiority), since we do not expect to find the introduced intervention to be superior to TAU.

CONTROL GROUP (TAU)Individuals assigned to the control group receive standard psychiatric treatment called; Treatment As Usual (TAU). TAU varies across centres depending on the current activities at the participating MHCs. In MHCs, TAU is not strictly formalized; a multidisciplinary team is free to assign a therapy from a wide range of evidence-based therapeutic options (including: pharmacotherapy and psychological treatment, psychosocial interventions, contact with a psychiatric test nurse) according to the stepped care approach. The treatment decision is based on professional experience, taking into account the specific problems and characteristics of the individual patient. The number of sessions depends on the therapy that is offered and can be weekly or (almost always) at a lower frequency of sessions, and are not confined to a maximum of sessions.

EXPERIMENTAL GROUPThe experimental group receives a brief, intensified cognitive CBT and/or pharmacotherapy confined to a fixed time period (7 weeks) and a limited number of weekly sessions (maximum 7 sessions within 7 weeks). The offered CBT and pharmacotherapy are described in more detail in Section Treatment. An intake and outtake session are also involved when in the experimental group (described in Section Intake and outtake).


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STUDY SETTINGThe study is conducted at five outpatient mental health clinics from the Dutch Regional Mental Health Provider (RMHP) Rivierduinen (RD). RD provides secondary mental health care for an area with over one million inhabitants. In the Netherlands access to mental health care is easy and is not limited by insurance or the financial means of the individual patient. Health insurance is compulsory for all citizens and regulated by the government (van Fenema et al. 2012; van der Lem et al. 2011). The Dutch mental healthcare system is organized in a stepped care manner and uses evidence-based treatment guidelines. According to a stepped care approach a brief but intensive first step is offered and patients who are insufficiently helped by the initial intervention are allowed to ‘step up’ to subsequent treatment (Haaga, 2000). The therapeutic principles within the treatment protocols of the intervention are referred to as a ‘first step’ of a stepped care approach. PARTICIPANTSEligible participants are males and females aged 18 to 65 years, currently diagnosed with an anxiety and/or depressive disorder as main diagnosis. Patients with current psychotic or bipolar traits, homicidal or suicidal risk or severe social dysfunction, as diagnosed by their general practitioner (GP), psychiatrist, or as assessed in a diagnostic interview, are excluded. All eligible subjects need to have adequate understanding of the Dutch language. Patients with the following DSM-IV (American Psychiatric Association, 1994) diagnoses are therefore included: minor or major depressive disorder (single episode or recurrent), depressive disorder NAO, dysthymia, panic disorder (with or without agoraphobia), panic disorder NAO, social phobia, simple phobia, generalized anxiety disorder, obsessive compulsive disorder, posttraumatic stress disorder (type I or single trauma), adjustment disorder (with anxiety and/or depressive mood). Co-morbidity associated with other psychiatric diagnoses (with the exception of psychotic or bipolar disorder) is allowed in order to establish a clinically relevant, broadly representative sample.

SAMPLE SIZEThe sample size was calculated using the method of Cohen (Cohen, 1992) and based on review of the available literature of earlier comparable studies. We aimed at detecting an equivalence with an acceptable difference of 5% on the primary outcome measures WSQ and BSI (SEE SECTION ROUTINE OUTCOME MEASURES AND FEEDBACK AND TABLE 1) and a 15% maximal difference in outcome scores between TAU and the intervention under the usual assumptions of an α = 0.05 and power of 80%. This results in an intended total sample size of 500 participants.

RECRUITMENT, SCREENING AND ENROLMENT PROCEDURESAll patients referred by their GP to one of the participating MHCs for the treatment of anxiety and/or mood disorders are, initially, eligible to participate in the study. We adopted the following steps in recruitment: first, all referred patients are globally screened by an experienced psychiatrist for the presence of depression and/or anxiety disorders as current, main problem. This global screening is based on written information provided by the GP containing an interpretation of the patient’s current health status and referral for further mental health care; this step does not require face-to-face contact with the patient. Subsequently, the potentially eligible patients are invited for a first ROM assessment. Prior to this first ROM assessment, the psychiatric


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research nurse conducting the ROM assessment invites the patients to participate in the study. Those who agree to participate are asked to provide written informed consent. When informed consent is given, the baseline ROM assessment (T1) according to the study design is conducted. After completion of this assessment, participants’ randomisation by the research team takes place (see Section Randomisation and blinding). Depending on the randomised treatment condition, final eligibility is assessed during the subsequent intake session by means of the inclusion and exclusion criteria of the study. Patient enrolment began March 1, 2010 and will end December 31, 2011. Follow-up assessment is ongoing and is projected to continue until December 31, 2012.

RANDOMISATION AND BLINDINGAfter successful screening, provision of written informed consent and completion of the baseline measurement (T1) (SEE SECTION RECRUITMENT, SCREENING AND ENROLMENT PROCEDURES); all eligible participants in this RCT are randomly assigned to one of two groups: the experimental group or the control group (TAU). Random allocation was generated by using a variable blocked design developed by an independent researcher from the Department of Medical Statistics & BioInformatics, LUMC and derived by computer. Randomisation takes place on the individual level by clinical centre (n = 5) and gender. This procedure is used to increase the likelihood that the distribution between groups is balanced on the two potentially important confounding variables and to conceal random allocation sequence. Participants and clinicians are informed about the outcome of the randomisation; the psychiatric test nurses (assessors) involved in the ROM assessment in the study, are kept blinded to the randomisation condition throughout the entire study. Randomisation and the subsequent assignment of participants to the intervention will be performed by the researcher (D.M.), whom is not an assessor.

ASSESSMENTFor both treatment conditions assessment information is obtained in two-fold, as shown in FIGURE 1. First, patients participating in this study are assessed by ROM (SEE ROUTINE OUTCOME MEASURES AND FEEDBACK) at four time intervals: 1) T1 at baseline (start of study), 2) T2 immediately post treatment (3 months after baseline measurement), 3) T3 6 months post-treatment (first follow-up measurement), and 4) T4 12 months post-treatment (second follow-up measurement). The second assessment method is provided by an intake and outtake evaluation (see also Intake and outtake). The timetable of assessments is shown in FIGURE 1.


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FIGURE 1. TIMETABLE OF ASSESSMENTS DURING THE STUDY. Note: T1 : baseline assessment; T2: post treatment assessment; T3: first follow-up assessment; T4: second follow- up assessment.

ROUTINE OUTCOME MEASURES AND FEEDBACKThis study is conducted on data collected using ROM (de Beurs et al. 2011). ROM is a monitoring system for patient care, implemented in 2002 in the outpatient clinics of RD and the Department of Psychiatry of the LUMC. All outpatients referred to these clinics by their GP for treatment of a mood, anxiety and/or somatoform disorder, are assessed by ROM. ROM periodically measures the presence and severity of psychiatric symptoms in patients and thereby monitors patients’ progress/changes during treatment by conducting an extensive battery of psychometric instruments. An overview of the instruments used in ROM is available at http://www.lumc.nl/psychiatry/ROM-instruments. These instruments are routinely assessed at baseline and during treatment at several time points (de Beurs et al. 2011; de Beurs, 2007). The baseline assessment also comprises a standardized diagnostic interview (Dutch version of the Mini-International Neuropsychiatric Interview Plus, version 5.0.0) (Sheehan, 1998; van Vliet & de Beurs, 2007), the collection of socio-demographic and socio-economic data, and the administration of general measures of health and disease-specific severity scales. Instruments are both self-report and interviewer based. All interviewer- based instruments are carried out by a psychiatric research nurse and the self-report questionnaires are completed using a touch-screen computer. A web-based software QuestManager (http://www.psyquestmanager.nl) was developed to assist the ROM method and is also used in the current study. Data collected by ROM are provided to the clinician and patient as written feedback (a brief report) by the psychiatric research nurse. This written feedback consists of an overview of the main measurement results. Furthermore, a summary of the diagnostic interview and a summary of the main questionnaires is given (one or two pages). The clinician shares and discusses these results with the patient. The assessment outcomes are used to support decision-making for the future course of the treatment (de Beurs et al. 2011; de Beurs, 2007). For the present study, all eligible patients are routinely assessed by ROM. TABLE 1 lists the instruments used to assess the disorders of interest for the current study. To further test the hypotheses of the present study, five additional questionnaires are added to the regular ROM and are indicated (in bold print) in TABLE 1. Similar to the regular ROM, the baseline assessment comprises the standardized diagnostic interview, MINI-Plus 5.0.0, and the collection of socio-demographic and socio-economic data.


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For the present study, the written ROM feedback depends on the randomised treatment condition. Clinicians in the experimental group are provided with minimal information about the results of the questionnaires, i.e. an overview of the results of the patient’s performance on the two primary outcome measures: the Web Screening Questionnaire (WSQ) (Donker et al. 2009) and the Brief Symptom Inventory (BSI) (Derogatis, 1975). The summary of the diagnostic interview and information about the other measures is left out. Clinicians in the TAU group are provided with the regular, extensive, feedback about all measurement results.

INTAKE AND OUTTAKEIn addition, to examine the progress of patients’ wellbeing and the effectiveness of the treatment, an intake and outtake session is included in the study design (FIG. 1). Both intake and outtake session are semi- structured and conducted by the same experienced psychiatrist (SEE SECTION THERAPIST SELECTION, TRAINING AND SUPERVISION), during one 45 minute (approximately) session.The intake takes place before the start of the treatment, after the ROM baseline measurement. A semi-structured clinical interview, especially designed for this study, is administered. Compared to a regular intake, this intake session is protocolised, shorter and more structured. Moreover, the intake aims to ensure that the patient is eligible to participate in this study by means of the in- and exclusion criteria (Section Participants). Personal data, including demographics and the current clinical picture, are also obtained during this intake session. The outtake evaluation takes place within (maximally) 2 weeks post-treatment (FIG. 1) and is part of a stepped care approach. The aim of this semi- structured outtake session is to evaluate if patients are sufficiently helped by the offered initial intervention or ‘stepping up’ to subsequent (additional) treatment is necessary. The ‘stepping-up’ is according to clinical experience and the local and national guidelines as handled by the involved MHC. During the outtake the progress of the patient’s symptoms and his/her current clinical status will be assessed. Furthermore, it evaluates the patient’s wellbeing and an ‘end diagnosis’ is formulated. A possible subsequent treatment plan can be discussed by patient and clinician. When the outtake session demonstrates that the achieved treatment effect is insufficient, the patient is offered to ‘step up’ to additional treatment according to the treatment guidelines in the same MHC, or elsewhere.

TREATMENTFor the current study the following treatment protocols are formulated by the research team:1 Pharmacotherapy protocol for mood and/or anxiety disorders (maximum 4 sessions within 7 weeks)2 Brief Cognitive Behavioural Therapy protocol for depression (minimal 5, maximum 7 weekly sessions)3 Brief Cognitive Behavioural Therapy protocol for anxiety (minimal 5, maximum 7 weekly sessions)4 Eye Movement Desensitization and Reprocessing (EMDR) therapy protocol for post-traumatic stress disorder (PTSD) (maximum 6 sessions within 7 weeks)

The treatment decision was made by the patient and therapist, based on the professional experience of the therapist and taking into account the specific disorder and characteristics of


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the individual patient, thereby acknowledging the patient’s preferences as is good practice and according to the common accepted principles of shared-decision making (Hamann et al. 2003; Joosten et al. 2008). The treatment protocols are based on the existing treatment guidelines described in the (multidisciplinary) guidelines in Dutch mental healthcare (Kerngroep Multidisciplinaire Richtlijn Angststoornissen, 2009; Kerngroep Multidisciplinaire Richtlijnontwikkeling, 2009; Landelijke Stuurgroep Multidisciplinaire Richtlijnontwikkeling in de GGZ., 2015) and on acknowledged evidence-based literature (Beck, 1995; Butler et al. 2006; Clark & Salkovskis, 1987; Landelijke Stuurgroep Multidisciplinaire Richtlijnontwikkeling in de GGZ, 2015; Shapiro, 1995). All treatment protocols are evaluated during an outtake session (SEE SECTION INTAKE AND OUTTAKE). Delivering treatment by combining the described protocols is also possible.

PHARMACOTHERAPY FOR MOOD AND/OR ANXIETY DISORDERS

In the current study the pharmacotherapy protocol for mood disorders and/or anxiety is characterized by a quick onset and aims to reach an optimal clinical effect of the used medication, involving rapid stepping up to the most optimal dose and minimizing the side-effects for patients as much as possible. Patients are treated with a selective serotonin reuptake inhibitor (SSRI) in 4 sessions within a 7-week period. Medication use is evaluated after this fixed period and continued when necessary. The protocol provides a scenario for patients when not using an SSRI (SSRI 1 condition) or, on the other hand, a scenario for patients with a history of (sufficient and adequate) SSRI use and now starting with a new different SSRI (SSRI 2 condition). When patients are currently using an SSRI (as prescribed by their GP), medication is continued and when necessary adapted according to the pharmacotherapy protocol.

BRIEF CBT FOR DEPRESSION

The brief CBT for depression protocol is focusing on decreasing the depressive mood of the client and maintain this improvement and based on the cognitive behavioural therapy manuals/protocols for depression (Beck, 1995; Boelens, 2009). For the current study this protocol is confined to a maximum of 7 weekly sessions (minimal 5 sessions) within a 7 week time period. The first 3 sessions of this brief CBT protocol are dedicated to activation-enhancement and training of social skills. The last 4 sessions emphasizes tracing and altering irrational cognitions by challenging them (Beck, 1995; Boelens, 2009). Each treatment session consists of a 45-min face-to-face contact and is characterized by a quick onset (no waiting list).

BRIEF CBT FOR ANXIETY

The brief CBT protocol for anxiety disorder is also characterized by a quick onset (no waiting list) and a maximum number of sessions (minimal 5, maximum 7 weekly sessions within a 7-week period). Each treatment session consists of a 45-min face-to-face contact. The main focus of the brief CBT for anxiety protocol is on the core CBT techniques for the treatment of anxiety disorders: anxiety/tension- reducing techniques, cognitive techniques and exposure techniques (used when adequate) (Clark and Salkovskis, 1987). If dys-functional worrying is interfering, anti-worrying techniques are offered.


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EYE MOVEMENT DESENSITIZATION AND REPROCESSING THERAPY

The EMDR therapy for the PTSD protocol is characterized by a quick onset (no waiting list) and a limited number of sessions (a maximum of 6 sessions within 7 weeks). Furthermore, all EMDR sessions comprise a 45-min face-to-face contact. The EMDR protocol of this study is based on the Dutch Manual EMDR (de Jongh & ten Broeke, 2003) and approved principles described in the literature (Shapiro, 1995), or the treatment of PTSD for patients suffering from a Type I trauma or single trauma.

THERAPIST SELECTION, TRAINING AND SUPERVISIONThe treatment protocols are performed by experienced clinicians: psychiatrists and psychologists working at the participating MHCs. Clinicians working at RD provide treatment in accordance with the multidisciplinary guidelines of the National Steering Committee describing evidenced-based treatments for mood and anxiety disorders. The participating clinicians are all professionally educated and trained in CBT. Years of experience ranged between 1 and 7 years. They were especially trained to work with the brief treatment protocols within this study. The participating clinicians were initially instructed by the research team. Two hours of instructions were provided for participating clinicians on two consecutive days. On the first day, a 2-hour instruction was provided for clinicians involved in the CBT condition. During this instruction, the EMDR protocol was also introduced. On the subsequent day, a 2-hour instruction was provided for clinicians involved in providing the pharmacotherapy within this study. During these instruction meetings, consensus was achieved on a number of core elements of the t reatments. Furthermore, the content of future supervision session for all involved clinicians was discussed. Clinicians in the TAU group received no specific training from the research team. They provide the usual treatment to the patients; globally following the available multidisciplinary treatment guidelines, since adherence is questionable. Furthermore, six certified psychiatric test nurses were trained by the research team to assess the ROM measurements according to the guidelines of the study. The research nurses are all trained and certified to assess ROM measurements. Instruction was given on the administration and reporting of the ROM measurements designed for this study. The psychiatric test nurses were informed about the logistics of the study and how to apply the blinding method used in the present study. Once every 3 months supervision sessions were organized by the research team for the clinicians and the psychiatric test nurses. Interview techniques, how to avoid protocol violations and other challenges were discussed and evaluated. In addition, unrestricted support is provided to all study clinicians and psychiatric test nurses via email and through visits made by the research team.

FIDELITY MONITORINGAll treatment sessions within the brief CBT protocols will be audio-taped, using a digital voice recorder to ensure treatment protocol fidelity. The taped treatment sessions will be randomly checked and scored on protocol consistency and reliability by the research team. Furthermore, therapist adherence and satisfaction will be monitored using an evaluation questionnaire. This evaluation questionnaire furthermore monitors the delivery and compliance of the different


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treatment protocols since it questions how many sessions were involved and if treatment was successfully delivered. This evaluation questionnaire, and the list of the criteria for protocol consistency and reliability, can be obtained from the corresponding author.

STATISTICAL ANALYSESDescriptive statistics will be used to describe the characteristics of the two groups, and the outcome variables, at the four measurement points. To evaluate potential group differences at baseline, post-treatment and at the 6 and 12- month follow-up measurements, repeated measures analysis will be conducted to analyse the short and long-term effects between the experimental and control group. All analyses will be conducted according to the intention-to-treat (ITT) approach. Additionally, analysis per protocol will be conducted. Chi-square analyses and t-tests for independent samples will be used for data measured on one occasion (e.g. patient satisfaction, therapist satisfaction, baseline demographic features) to detect possible differences between the two groups. Differences are considered statistically significant at p<0.05. Missing values will be imputed with regression imputation techniques. Generalized Estimating Equation (GEE) analyses will additionally be performed on the dataset with missing data and when missing values are imputed. Analyses adjusting for cluster effects will be performed when analysing the data. All analysis will be done using SPSS (version 17,Windows).

HEALTH ECONOMICS ANALYSISCost-effectiveness will be also calculated. An economic evaluation based on the TIC-P questionnaire (see TABLE 1) examines the costs and other aspects of the study protocol.Direct costs per patient in the experimental condition versus the costs per patient in the control condition will be compared. Costs are validated by reference; if these references are not available, costs will be estimated by costs research. Cost or product losses are verified by the ‘friction cost method’ (Koopmanschap et al. 1995).The friction cost method estimates the indirect costs of disease, which explicitly considers economic circumstances that limit production loss due to disease. According to this method, these indirect costs mainly occur during the time it takes to replace a worker, i.e. the friction period (Johannesson & Karlsson, 1997).

APPROVALS AND DATA/SAFETY MONITORINGThe study protocol was approved by the Medical Ethical Committee (MEC) of the Leiden University Medical Centre (LUMC). After full verbal and written information about the study, written informed consent was obtained from all participants at the start of baseline assessment. To safeguard the anonymity of the patients and to ensure proper handling of the data, processing of all data is in accordance with a comprehensive protocol: the Psychiatric University Network Registration Leiden (PAREL-regulations). The MEC of the LUMC approved the regulations of this protocol and agreed with this policy (de Beurs et al. 2011). Confidentiality of data is maintained by using a unique research identification (ID) number for each participant, which enables to identify individuals without using names. Only a limited number of persons (researcher) have access to the record that links the ID number to identifiable information.


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CURRENT STATUS AND DEMOGRAPHICS OF SAMPLEData will be collected until at least December 31, 2012. At the time of completion of this paper, the inclusion period of the study is still ongoing. A total of 161 patients have completed the baseline measurement. Their preliminary sociodemographic and clinical characteristics are presented in TABLE 2. These 161 participants are evenly distributed across both groups; 79 in the TAU group and 82 in the experimental group. Demographic data (educational and employment status, and ethnic background) are missing for 4 patients. Moreover, for 12 patients the MINI-Plus diagnostic interview did not lead to a DSM-IV classification in ROM; therefore, only a clinical diagnosis is available for these patients. At baseline there were no significant differences in demographic data between the two groups. The mean age of the patients is 37.2 (SD 11.5; range 18–65) years, and there is a similar distribution for gender (61.5% female and 38.5% male) in both groups. Furthermore, the participants comprise a relatively homogeneous group with common mental disorders, i.e. mainly mood and anxiety disorders. The majority of the included patients have more than one clinical diagnosis. At baseline, of all patients 45.3% had an anxiety disorder only, and 37.9% were diagnosed with depression only. In total, 15.5% of the patients were diagnosed with both an anxiety and mood disorder. This distribution was similar in both treatment arms (TABLE 2).

TABLE 2. SOCIO-DEMOGRAPHIC AND CLINICAL CHARACTERISTICS OF THE ELIGIBLE PATIENTS AT BASELINE.

Randomised condition Total p-value

Control group Experimental group

TAUa CBTb and/or Pharmacotherapy

(n = 79) (n = 82) (n = 161)

N % N %

Age in years: mean (SD) 37.2 (11.5) 36.0 (12.8) 36.6 (12.1)

Gender .609

Male 32 40.5 30 36.6 62

Female 47 59.5 52 63.4 99

Ethnic backgroundc .967

Dutch 74 93.7 72 93.6 146

Other ethnicity 5 6.3 5 6.4 10

Educational statuscd .968

Lower education 30 38.0 29 37.7 59

Higher education 49 62.0 48 62.3 97

Employment statusc .546

Employed 45 52.0 36 46.8 81

Unemployed/retired 13 16.5 16 20.8 29

Work-related disability 17 21.5 18 23.4 35

Other 4 5.1 7 9.1 11

Marital statusc .226

Married/Cohabitating 38 48.1 45 58.4 83

Divorced/separated/widow 11 13.9 5 6.5 16

Single 30 38.0 27 35.1 57

DSM-IV-TRe diagnosis (n, %)

Any Depression 32 19.9 29 18.0 61 .501

Any Anxiety disorder 31 19.3 42 26.1 73 .127

Mood and Anxiety disorder 11 6.8 14 8.7 25 .581

Adjustment disorder (with anxious and/or depressive symptoms) 2 1.2 2 1.2 4 .970

Post-Traumatic Stress Disorder 8 5.0 7 4.3 15 .729

Other 26 16.1 21 13.0 47 .308

Note: patients may have more than one diagnosis

aTAU=Treatment As Usual. bCBT=Cognitive Behavioural Therapy cDemographic data; ethnic background, educational status and employment status are missing for 4 participants.

dLower education= basic education, primary education, no education at all. Higher education= Higher education, university. eDSM-IV-TR= The Diagnostic Statistical Manual,

fourth edition, text revision.


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DISCUSSIONEvidence-based clinical guidelines advocating a stepped care approach are available in mental healthcare and have demonstrated success in the treatment of mood and anxiety disorders (Smits, 2010). Progress within these stepped care approaches is carefully monitored and patients are able to ‘step up’ when no subsequent improvement occurs (Haaga, 2000). However, initiation of and adherence to these recommended and effective treatments within these guidelines is usually poor (Andrews et al. 2004). The optimal content and organization of how to provide this stepped care is unclear, and implementation and acceptability of stepped care as a method of delivering psychological/ psychiatric services has not yet been adopted (Bower and Gilbody, 2005; Meeuwissen et al. 2008). Little information is available about how stepped care should be effectively implemented (Bower & Gilbody, 2005) and only a few randomised trials present convincing evidence and evaluations of both the cost and clinical effectiveness of this stepped care model. Most studies investigated either the cost-effectiveness (van Roijen et al. 2006; van ‘t Veer- Tazelaar et al. 2006) or the clinical effectiveness (Cape et al. 2010; Seekles et al. 2009; Seekles et al. 2011; van ‘t Veer- Tazelaar et al. 2006) of stepped care. When simultaneously investigated, the studies examined the effectiveness of a stepped care model for patients with either a mood disorder (de Graaf et al. 2008) or an anxiety disorder (Muntingh et al. 2009), and only in primary care. The present study aims to examine the clinical effectiveness and cost effectiveness of an innovative stepped care intervention for patients (aged 18–65 years) with anxiety and/or mood disorders in secondary care. To carefully monitor the patient’s progress, the ROM method is added. To our knowledge this is the first long-term study to simultaneously analyse the clinical and cost effectiveness of a stepped care approach in the treatment of both mood and anxiety disorders in a secondary care setting. The ROM method, monitoring patients’ progress at fixed time intervals with a follow-up period of 1 year, allows to establish the long-term efficiency expectations of treatment success and effects on health status and economic costs. Moreover, for the current study, ROM is shortened and evaluated in terms of feasibility. Since the baseline characteristics of the participants in both the experimental and the control group show no significant differences, the study outcomes are expected to be highly generalizable. The findings of the present study will have potential implications for provision of the most convenient form of mental healthcare in the Netherlands. The offered time-limited, brief intervention could provide valuable information to help the development of an optimal treatment protocol for patients with anxiety and/or mood disorders. The limited number of sessions reduces the average amount of therapist input per patient and, moreover, is an adequate response to patient preferences for brief psychological interventions (Jarrett & Rush, 1994). Since the intervention has not only fewer sessions but also an earlier start after intake, it is expected to reduce waiting lists; this is a common problem in the provision of mental healthcare. Results of the analyses will allow to compare both the clinical (patient improvement) and cost effectiveness (economic costs of the intervention) between the experimental intervention and TAU. Besides answering our primary question (‘is the experimental intervention at least as effective as providing regular care, i.e. treatment as usual’) these analyses are expected to provide insight into how to increase the quality and efficiency of care. The experimental intervention is expected to reduce costs and increase efficiency on (at least) the short term. The study design will also provide insight into long-term effects, possibly encouraging the implementation of an effective stepped care model in mental healthcare.


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Apart from evaluation of the effectiveness of the intervention, the study also examines what works best for the individual patient. The broad inclusion criteria allow the recruitment of patients with a wide range of mood and/or anxiety disorders. The resulting sample is then broadly representative of the patient population commonly referred to outpatient mental healthcare centres in the Netherlands. No indication of a selection bias is expected and, since the ROM method outlines patient characteristics, the advantages of the experimental intervention for the individual patient can be clearly assessed. A major strength of this study is that it is a pragmatic randomised trial. In such trials, patients and therapist are the same as those encountered in daily practice. Care is provided by healthcare professionals from the field and, since the sample of patients is the same as those seen in daily practice, this enhances the external validity of the study. Moreover, since the stepped care algorithm used covers the whole continuum from enrolment, diagnostics, assessments and treatment, this study reflects the ‘real’ effects of daily practice thereby allowing generalization and implementation of any beneficial logistical and organizational effects in (clinical) practice. However, this advantage also carries some risks. Besides the logistic difficulties of implementing a pragmatic randomised trial, it is difficult to maintain treatment integrity when conducting a study in daily practice. We aim to minimize this limitation by means of our instruction meetings and supervision sessions for all clinicians and psychiatric test nurses involved. Moreover, since all treatment sessions within the brief CBT protocols are audiotaped, treatment protocol fidelity is closely examined and, hopefully, achieved. Moreover, since conducting a study in daily practice involves the possibility of combining CBT and medication therapy and enhances the possibilities of non-specific effects in therapy, the potential therapeutic benefit of the intervention can only be formulated with caution. While the design of the current study addresses many of the limitations of previous research, a preliminary reflection on further limitations and strengths of our design is required. Although homogeneous patient groups are expected in both treatment arms, the control group may have some nonspecific effects on the expected outcomes. For example, no control is made regarding the number of visits made by persons in the TAU group to their physicians. Therefore, it is possible that patients in the control group make fewer visits to their physician or, in some cases, no visits at all if they are still on a waiting list. Although this does reflect daily practice, we cannot rule out the nonspecific effects of an increased number of visits and/or attention from physicians as an explanation for the (possible) better outcomes in the experimental group. Another limitation concerns the expected dropout rates at the four ROM measurement assessments, which may affect the results of the study. Although compliance with the ROM procedure is relatively successful, a 20% dropout rate is expected at reassessments. In response to these high attrition rates, the aggregated data are also analyzed according to the intention-to-treat analysis. This might yield a more valid reflection of the results and conclusions about the effectiveness of the experimental intervention. We have described the rationale and design of an RCT examining the clinical and cost effectiveness of a time-limited, stepped care based intervention in the treatment of mood and anxiety disorders. This study is collecting a substantial amount of data which will improve our understanding of how to develop effective strategies to adequately diagnose and treat patients with mood and/or anxiety disorders in secondary care. If the experimental intervention proves


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to be as effective as regular care, this type of intervention could facilitate the growing need of providing the most optimal and (cost)-efficient mental healthcare. This study will hopefully elucidate how we can provide the most convenient and adequate mental healthcare for our patients.

CONFLICT OF INTERESTNo disclosures to report.

FUNDINGSee details in the Acknowledgments section.Trial registration: Netherlands Trial Register NTR2590.

ACKNOWLEDGMENTSThis is a collaborative study between Leiden University Medical Centre and Rivierduinen (a regional mental healthcare provider) and is funded entirely by Rivierduinen. The authors thank the staff at Rivierduinen for their contribution to this research, as well as all the patients participating in this study.


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Chapter 3The Clinical Effectiveness of Concise Cognitive

Behavioural Therapy With or Without Pharmacotherapy for Depressive and Anxiety

disorders; a Pragmatic Randomised Controlled Equivalence Trial in Clinical Practice

Previously published as:Meuldijk D, Carlier IVE, van Vliet IM, van Veen T, Wolterbeek R, van Hemert AM, Zitman FG.

The Clinical effectiveness of concise cognitive behavioural therapy with or without pharmacotherapy for depressive and anxiety disorders; a pragmatic randomised controlled equivalence trial in clinical practice.

Contemp Clin Trials 2016;47:131-138.


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ABSTRACTBACKGROUND Depressive and anxiety disorders contribute to a high disease burden. This paper investigates whether concise formats of cognitive behavioural- and/or pharmacotherapy are equivalent with longer standard care in the treatment of depressive and/or anxiety disorders in secondary mental health care.

METHODS A pragmatic randomised controlled equivalence trial was conducted at five Dutch outpatient Mental Healthcare Centres (MHCs) of the Regional Mental Health Provider (RMHP) ‘Rivierduinen’. Patients (aged 18-65 years) with a mild to moderate anxiety and/or depressive disorder, were randomly allocated to concise or standard care. Data were collected at baseline, 3, 6 and 12 months by Routine Outcome Monitoring (ROM). Primary outcomes were the Brief Symptom Inventory (BSI) and the Web Screening Questionnaire (WSQ). We used Generalized Estimating Equations (GEE) to assess outcomes.

RESULTS Between March 2010 and December 2012, 182 patients, were enrolled (n = 89 standard care; n = 93 concise care). Both intention-to-treat and per-protocol analyses demonstrated equivalence of concise care and standard care at all-time points. Severity of illness reduced, and both treatments improved patients general health status and subdomains of quality of life. Moreover, in concise care, the beneficial effects started earlier.

DISCUSSION Concise care has the potential to be a feasible and promising alternative to longer standard secondary mental health care in the treatment of outpatients with a mild to moderate depressive and/or anxiety disorder. For future research, we recommend adhering more strictly to the concise treatment protocols to further explore the beneficial effects of the concise treatment.


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INTRODUCTIONDepression and anxiety disorders are highly prevalent, cause great suffering and disability, and have a large impact on society (Buist-Bouwman et al. 2006; Murphy et al. 2004; Murray & Lopez, 1997a; Murray & Lopez, 1997b; Wittchen et al. 2011). Fortunately, several effective psycho- and pharmacotherapeutic treatments are widely applied for these disorders (Cuijpers et al. 2013). However, they place a high demand on healthcare services (Gustavsson et al. 2011; Nutt, 2011; Smit et al. 2006). Offering these treatments in a more concise form without compromising effectiveness might mitigate this problem (Cape et al. 2010). In this paper, we report the clinical results of a pragmatic, randomized controlled equivalence trial. This entails comparing concise and standard care. We tested the hypothesis that concise care is ‘as effective as’ standard care delivered in a secondary outpatient setting. We focused on patients with mild to moderate illness severity because we assumed that since in most cases their illness is less complicated, they would react more favourable to a concise approach. In both conditions, patients are treated with psycho- and/or pharmacotherapy delivered in routine practice. However, in concise care the treatments are limited in time and in number of (weekly) sessions (maximum 7) and offered as first (brief ) step in a stepped care model (Haaga, 2000; Davison, 2000). Standard care is not confined to a maximum number of sessions or limited time period (van Fenema et al. 2012). Patient characteristics and treatment effectiveness are assessed with Routine Outcome Monitoring (ROM) (de Beurs et al. 2011), a standard monitoring procedure already in use in the participating outpatient clinics. We hypothesized that concise care is equally effective as (equivalent to) standard care 3, 6 and 12 months after baseline assessment.

METHODS The methods were published previously (Meuldijk et al. 2012) and are summarized briefly here. The Medical Ethics Committee (MEC) of the Leiden University Medical Centre (LUMC) approved the study. It involved a comprehensive protocol (titled “Psychiatric Academic Registration Leiden database”) which safeguarded the anonymity of patients and participants and ensured proper handling of the data. We followed consolidated standards for reporting randomised controlled equivalence trials (Hopewell et al. 2008; Moher et al. 2010; Piaggio et al. 2012). All participants provided written informed consent before study entry.

STUDY DESIGN AND PARTICIPANTSA two-armed pragmatic randomised controlled equivalence trial was conducted at five outpatient Mental Health Clinics (MHCs). These clinics were part of Rivierduinen (RD), a secondary Regional Mental Health Provider (RHMP) in the province of South-Holland, the Netherlands. Eligible participants were patients referred to the MHCs by their general practitioners (GP), aged 18-65 years, and meeting the DSM IV-TR criteria for a primary current diagnosis of anxiety disorder and/or depression, established using the Mini-International Neuropsychiatric Interview-Plus, version 5.0.0 (MINI-Plus) (Sheehan et al. 1998; van Vliet & de Beurs, 2007). For a list of included diagnoses see SUPPLEMENTARY MATERIAL, TABLE S1. Excluded were patients with suicidal or homicidal risk, severe social dysfunction, delusions, hallucinations and/or suffering from bipolar or psychotic disorders. Other co-morbidity with psychiatric disorders was allowed. The inclusion (and exclusion) criteria for enrolling subjects in this study induced a study sample of patients suffering from mild


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to moderate anxiety and/or depressive disorders (APA, 1994). Insufficient mastery of Dutch was a reason for exclusion. Experienced psychiatrists at the MHCs determined study eligibility (Meuldijk et al. 2012). Eligible participants were randomly assigned to concise or standard care and assessed by ROM at baseline (T1), 3 (T2), 6 (T3) and 12 (T4) months thereafter.

RANDOMISATION AND MASKINGA block randomisation scheme, stratified by MHC (n = 5) and gender was used. Randomisation was carried out by one of the researchers (D.M.). Patients and therapists were informed about the outcome; the psychiatric test nurses responsible for the ROM assessments were not (Meuldijk et al. 2012).

TREATMENTThe treatment protocols in both conditions followed the Dutch and international guidelines for the evidence-based treatment of depressive and anxiety disorders. In both concise and standard care, a choice could be made between pharmacotherapy with a selective serotonin reuptake inhibitor (SSRI) (Guy, 1976), Cognitive Behavioural Therapy (CBT) (Beck, 1995; Clark & Salkovskis, 1987) and, in case of a posttraumatic stress disorder, Eye Movement Desensitization and Reprocessing- therapy (EMDR) (Shapiro, 1995). A combination of pharmaco- and psychotherapy was also possible. In standard care the number of sessions, start and duration of treatment is variable and treatment could continue during the entire study period of 1 year. On average, psychotherapy is provided in 3-6 months on a weekly basis, but in practice once every 2 to 3 weeks, pharmacotherapy for 1 year or longer (van Fenema et al. 2012). In contrast, concise care started within one week after the baseline measurement and had to be given within 7 weeks thereafter. Concise care was initially described as 4 to maximum 7 individual 45-minute psychotherapy sessions, depending on the treatment protocol (see also Meuldijk et al. 2012). The pharmacotherapy protocol for depressive and/anxiety disorders in concise care was confined to a maximum of 4 sessions within 7 weeks. Moreover, therapists’ treatment choice in both standard and concise care followed the principles of shared decision-making (Hamann et al. 2003; Joosten et al. 2008). Contrary to standard care, treatment goals and procedures in concise care are clearly established and mutually agreed on, prior to initiating treatment. In addition, treatment success of concise care was evaluated at the end of treatment. When either the patient or therapist is convinced that the clinical effects are insufficient or patients are insufficiently helped by the initial treatments in concise care, ‘stepping up’ or continuation of (additional) standard treatment, in line with stepped care principles, was possible (Davison, 2000; Haaga, 2000). Pharmacotherapy in concise care was also evaluated after 7 weeks, and continued when necessary according to the (inter) national clinical guidelines. After implementation changes to the treatment protocols were made at the recommendation of the MHCs; these included extending the treatment duration of concise care to a maximum of 7 sessions in 7-9 weeks. This was to allow treatment continuation of concise care in case of cancelled or missed sessions by therapists or patients. Therapists providing concise care received a 2 hours instruction in the core elements of the intensified psychotherapy and/or pharmacotherapy, as described in the protocols. Therapists in the standard condition did not get additional training (Meuldijk et al. 2012). The same therapists were responsible for delivering standard and concise care. All sessions in concise care were


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audiotaped for post-hoc assessment of treatment fidelity. Sufficient treatment protocol-adherence (>75%) was demonstrated in a random sample of 20 patients with a satisfactory overall agreement between two independent raters (Cohen’s Kappa: 0.74).

MEASURESROUTINE OUTCOME MONITORING (ROM)ROM is a computer-based system to routinely assess symptom severity and functioning with an extensive battery of psychometric instruments. ROM is administered as part of the intake procedure (at baseline) and repeatedly during and after treatment (de Beurs et al. 2011). In the present trial, measures of participants characteristics were collected at baseline, while symptom measures were administered at each time point (see also Meuldijk et al. 2012). An overview of ROM instruments at the different time points, is given in TABLE S2, SUPPLEMENTARY MATERIAL.

OUTCOMESThe Brief Symptom Inventory (BSI) (Derogatis, 1975) and the Web Screening Questionnaire (WSQ) (Donker et al. 2009) constituted the primary outcome measures in this study. The secondary measures used were the Clinical Global Impression (CGI) (Guy, 1976) and the Short- Form-36 Health Survey (SF-36) (Aaronson et al. 1998; Ware et al. 1993). Additionally, patients satisfaction with their care was explored by The Dutch Mental Healthcare Thermometer of Appreciation by Clients (Kok & van Wijngaarden, 2003).

PRIMARY OUTCOMES

BRIEF SYMPTOM INVENTORY (BSI) (Derogatis, 1975). This patient-rated, 53 item questionnaire which is based on the Symptom Checklist (SCL-90) (Derogatis & Melisaratos, 1983) assesses psychopathological symptom severity on a 5-point Likert scale (from 0 ‘not at all’ to 4 ‘extremely’). The BSI total score, most indicative of general psychopathology, was computed as the mean score of all individual items (range 0-4). WEB SCREENING QUESTIONNAIRE (WSQ) (Donker et al. 2009). This is a self-rated, 15 item questionnaire which is based on the screening questionnaire (SQ) of Marks and colleagues. It is used as a quick tool to screen patients for most common mental disorders (Gega et al. 2005). The WSQ has 8 ‘yes’ or ‘no’ answers, the other 7 are Likert-type scales. Response was defined as a score above the pre-specified threshold for being diagnosed with any particular WSQ diagnosis (Donker et al. 2009).

SECONDARY OUTCOMES

CLINICAL GLOBAL IMPRESSION (CGI) (Guy, 1976) This is a clinician rated scale that assesses illness severity. The main item ‘severity of illness’ measured on a 7-point Likert scale (from 1 ‘normal, not at all ill’ to 7 ‘among the most extremely ill patients’) is used in the present analyses.THE SHORT FORM-36 HEALTH SURVEY (SF-36) (Aaronson et al. 1998; Ware et al. 1993). This self-report questionnaire assesses current general health status and quality of life in eight domains (36 items). Measurement scales vary per subscale, ranging from yes/no to answers on 3-, 5-, or 6-point Likert scale. All raw scores are linearly converted to a 0-100 subscale, with higher scores representing better functioning/quality of life. In this paper, we report the changes in scores on the three SF-36 subscales which are primarily indicative of physical and mental health (Ware et al. 1994, 2000): physical functioning, social functioning and general health.


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THE DUTCH MENTAL HEALTHCARE THERMOMETER OF APPRECIATION BY CLIENTS (Kok & van Wijngaarden, 2003). The thermometer contains 18 items; 17 items with ‘yes’ or ‘no’ answers, and one question on ‘overall satisfaction with care’, (scores from 1 to 5, higher scores indicating more satisfaction). Two additional items with an open answer format were not included here. EQUIVALENCE MARGINSThe study was designed to demonstrate therapeutical equivalence between concise and standard care and follows study procedures already published in Meuldijk et al. 2012. The sample size calculation (see Meuldijk et al. 2012) indicated that 500 patients (alpha=0·05, 1 – β=0·80, two-sided) were required to demonstrate equivalence (Jones et al. 1996). Concise care will be deemed equivalent to standard care, if the 95% confidence interval (CI) for the observed difference in the proportions of treatment success (defined as a 50% reduction in BSI score compared to baseline BSI score) do not cross these predefined clinical margins of equivalence (∆) of -15% and + 15% including an acceptable difference of 5% (Jones et al. 1996; Meuldijk et al. 2012; Wiens, 2002). The equivalence margins are specified a priori on the basis of a clinical notion of detection, a minimally clinically important difference in effect (see Meuldijk et al. 2012). If the treatment effects of concise and standard care differ by more than this equivalence margin in either direction, then equivalence does not hold. Although not powered for, we similarly evaluated equivalence for WSQ remission (defined as a score below the pre-specified threshold for being diagnosed with any WSQ diagnosis) at 6 and 12 months’ measurements.We performed both intention-to-treat analyses and sensitivity analyses on the per protocol population (patients who completed both the baseline and the subsequent measurement) to test therapeutic equivalence.

STATISTICAL ANALYSISWe used descriptive statistics for the comparison of the baseline demographic and clinical variables between the groups that completed the treatment (completer group) and the group as randomised; t-tests were used for continuous measures and chi-square tests for categorical data. The margins of the 95% CIs on the basis of the observed difference in the proportions of treatment success of the primary outcomes were compared with the pre-determined equivalence margins. Equivalence was tested in both the intention-to-treat and per protocol population. Additionally, Generalized Estimating Equation (GEE) models (Twisk, 2004; Zeger & Liang, 1986) were used to estimate the mean differences between treatment groups and the confidence intervals (CIs) at each assessment point for both primary and secondary continuous outcomes; odds ratios with 95% CIs were given for dichotomous outcomes and differences in means for continuous outcomes. Since our GEE models yields odds ratios as the effect measure instead of risk ratios, effect-sizes are not presented. For all GEE analyses, the predictor variables were: time (baseline (T1) as reference, versus 3 (T2), 6 (T3) and 12 month (T4) measurement); treatment group (concise care versus standard care), and interaction between time and treatment group. An unstructured correlation matrix was specified in the GEE model to account for the within-patient correlation (repeated, longitudinal observations). To investigate if results were overly optimistic due to drop-out of those with less favourable outcome, GEE analyses were repeated with imputation of missing data, by carrying the last


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observation forward method. Patient satisfaction was explored by between-group comparisons of two sample t-tests for continuous variables.. GEE analyses for both primary and secondary outcomes were on an intention-to-treat basis using IBM SPSS version 20 (Windows). Significance for all statistical tests was set at a p-value < 0.05 (two-sided).

RESULTSRandomisation and treatment allocation took place between March, 2010 and December, 2011. Follow-up assessments were completed for all patients in January, 2013. The passage of the participants through the study is depicted in the CONSORT Flow diagram in FIGURE 1. A total of 182 eligible participants provided informed consent and completed the baseline

Patients referred to Mental Health Care Center of

‘R ivierduinen’ Psychiatric I nstitute

S creening for eligibility

Patients com pleted T 1

( n = 1 8 2 )

R andom isation( n = 1 8 2 )

R easons for exclus ion: * - not m eeting inclus ion criteria - refused to participate - other reasons

Allocated to C on cis e ca r e( n = 9 3 )

Allocated to S ta n da r d ca r e( n = 8 9 )

Patients com pleted T 2 ( n = 5 2 ) Patients com pleted T 2 ( n = 5 2 )


I ntake

Outtake


I ntake

Patients referred to Mental Health Care Center of

‘R ivierduinen’ Psychiatric I nstitute

S creening for eligibility

Patients com pleted T 1

( n = 1 8 2 )

R andom isation( n = 1 8 2 )

R easons for exclus ion: * - not m eeting inclus ion criteria - refused to participate - other reasons

Allocated to C on cis e ca r e( n = 9 3 )

Allocated to S ta n da r d ca r e( n = 8 9 )



I ntake

Outtake


I ntake

FIGURE 1. CONSORT FLOW DIAGRAM.

T1: baseline assessment; T2: 3 month assessment; T3: 6 month assessment; T4: 12 month assessment.

*Reasons for post-randomisation drop-out after study entry are not known.

Patients referred to Mental Health Care

Center of ‘Rivierduinen’

Psychiatric Institute

Screening for eligibility

Patients completed T1(n = 182)

Randomisation(n = 182)

Reasons for exclusion:* - not meeting inclusion criteria- refused to participate- other reasons

Allocated to Concise care(n = 93)

Allocated to Standard care(n = 89)

Patients completed T2 (n = 52) Patients completed T2 (n = 52)


Intake

Outtake


Intake


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assessment; 93 were randomised to concise care and 89 to receive standard care. 57% of the participants completed the 3-month assessment (n = 104). At assessments T3 and T4, (see FIGURE 1), respectively n = 65 and n = 42 had outcome data.

DESCRIPTIVE STATISTICS The socio-demographic and clinical characteristics of the randomised sample and patients who completed both the baseline and the 3-month measurement (completer sample) are summarized in TABLE 1. Demographic data were available for 178 patients (98%). The MINI-Plus was administered in 181 patients (99%).

TABLE 1. SOCIO-DEMOGRAPHIC AND CLINICAL CHARACTERISTICS OF THE TWO TREATMENT GROUPS AT BASELINE

MEASUREMENT.

Total Randomised Sample Completer sample

Standard care Concise care Standard care Concise care

Baseline characteristics n = 182 n = 89 n = 93 n = 52 n = 52 p - valuea

Socio-demographicsb

Age (years): mean [SD] 36.5 (12.3) 37.0 (11.98) 36.0 (12.0) 37.8 (11.8) 38.3 (13.1) 0.83

Gender

Female 111 (61%) 53 (60%) 58 (62%) 29 (56%) 31 (60%) 0.84

Ethnical backgroundc

Dutch 167 (94%) 84 (94%) 83 (94%) 50 (96%) 47 (94%) 0.96

Other 10 (6%) 5 (6%) 5 (6%) 2 (4%) 3 (6%)

Education leveld

Lower education 68 (38%) 34 (38%) 34 (39%) 19 (37%) 16 (32%) 0.78

Higher education 109 (62%) 55 (62%) 54 (61%) 33 (64%) 34 (68%)

Employment status

Employed 90 (51%) 49 (55%) 41 (47%) 25 (49%) 24 (48%) 0.99

Unemployed/retired 87 (49%) 40 (45%) 47 (53%) 27 (52%) 26 (52%)

Marital status

Married/Cohabitating 93 (53%) 42 (47%) 51 (58%) 24 (46%) 37 (74%) 0.01

Clinical characteristics/MINI-Plus Diagnosise

Any Depressive disorder 70 (39%) 36 (20%) 34 (19%) 22 (21%) 18 (18%) 0.49

Any Anxiety disorder 82 (45%) 36 (20%) 46 (25%) 23 (22%) 29 (28%) 0.38

Panic disorder (without agoraphobia) 25 (14%) 11 (6%) 14 (8%) 9 (17%) 8 (15%) 0.56

Agoraphobia (without panic disorder) 38 (21%) 17 (9%) 21 (12%) 12 (23%) 13 (25%) 0.81

Panic disorder with agoraphobia 19 (10%) 8 (4%) 11 (6%) 6 (12%) 6 (12%) 0.90

Social phobia 9 (5%) 3 (2%) 6 (3%) 1 (2%) 3 (6%) 0.78

Specific phobia 3 (2%) 1 (1%) 2 (1%) 1 (2%) 2 (4%) 0.99

Generalized anxiety disorder 23 (13%) 11 (6%) 12 (7%) 5 (10%) 7 (14%) 0.99

Posttraumatic stress disorder 15 (8%) 7 (4%) 8 (4%) 2 (4%) 6 (12%) 0.42

Obsessive compulsive disorder 3 (2%) 2 (1%) 1 (1%) 1 (3%) 0 (0%) 0.91

Depressive and anxiety disorder 31 (17%) 14 (8%) 17 (9%) 7 (14%) 10 (19%) 0.99

No current DSM IV- TR diagnosis 34 (19%) 19 (22%) 15 (16%) 5 (5%) 7 (7%) 0.79

Results are presented as numbers (percentages) for categorical variables and means ± (standard deviation [SD]) for continues variables.

DSM- IV-TR: Diagnostic and Statistical Manual of Mental Disorders; 4th edition. MINI-Plus: mini-international neuropsychiatric interview-plus.

aP-values denotes the differences between standard vs. concise care in the completers sample. bDemographic data; ethnic background, educational status and employment

status are missing for 5 participants. cDutch ethnic background was assumed when the patient and both parents were born in the Netherlands. dLower education= having

completed elementary school, lower general primary education or no education at all; higher education= more than lower education (includes university). eClinical

characteristics/diagnosis was missing for 1 participant.

Note. Patients may have more than one MINI-Plus diagnosis, comorbidity was allowed.


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Randomisation reasonably balanced the treatment groups with respect to the baseline characteristics. No statistical differences in baseline clinical or demographic characteristics were found between patients who entered the trial and those who dropped out after baseline assessment. These p-values ranged from p = 0.061 to p = 0.892. In addition, we found no evidence of selective attrition on baseline measures (i.e. primary outcomes) between completers and dropouts (data not shown). According to the MINI-Plus interview, 39% (n = 70) of the total sample suffered from depressive (with or without anxiety) disorder and 31% (n = 82) from anxiety (with or without depressive) disorder(s). Comorbidity between anxiety and depression was found in 17% (31 patients). 34 patients (19%) did not pass the threshold for having any current Axis- I DSM-IV-TR diagnosis according to the MINI-Plus interview. These patients did seek professional help for their (subthreshold) depressive and/or anxiety complaints or symptoms.

TREATMENT RECEIVED During the entire study-period, 47 (25%) of all 182 patients, did not enter treatment (concise care, n = 24 of 93; standard care, n = 23 of 89). The majority of patients (61%) started treatment within 3 months after the baseline assessment (concise care, n = 63 (91%); standard care n = 48 (73%)). The majority of these patients were offered psychotherapy (concise care, n = 49 (78%); standard care n = 37 (77%)). Only a small number of patients were offered pharmacotherapy (concise care, n = 4 (6%); standard care, n = 6 (13%)) or a combination of both therapies (concise care n = 10 (16%); standard care n = 5 (10%)). In addition, with concise care, the number of therapy sessions (i.e. face to face contacts) was on average as prescribed. in the treatment protocols: six sessions for psychotherapy and one for pharmacotherapy. Compared with standard care, the number of therapy sessions did not differ significantly (all P values > 0.05). Patients in the standard care group had on average three psychotherapy and one pharmacotherapy sessions (face to face contacts), within the first 3 months after baseline assessment. After the initial 3 months, 18 (27%) of the patients in standard care and 7 (10%) of the patients allocated to concise care actually started treatment. The number of patients who remitted or continued treatment after 12 months is unknown. No adverse events were reported.

EQUIVALENCE: BSI AND WSQTABLE 2 presents the mean differences in the proportions of treatment success of BSI and WSQ and 95% CIs for both treatment groups over time for the intention-to-treat and the per protocol analysis. The results of TABLE 2 are visualized in FIGURE 2. In the intention-to-treat analysis, equivalence of concise and standard care could be demonstrated at T3 and T4 for the primary outcome measures BSI and WSQ. At assessments T3 and T4, the two-sided 95% CI’s for the difference in the proportions of treatment success for BSI and WSQ scores are within the predetermined equivalence margins (∆) of -15% and +15%. Furthermore, at T2, the right margin of the 95% CI of the difference in BSI improvement crosses the ∆ margin (> +15%) in favour of concise care. In the per protocol analysis, equivalence of concise and standard care for BSI improvement and WSQ remission has been neither proved nor disproved. At T2, T3 and T4, the right margins of the 95% CI’s for the difference in the proportions of treatment success of the BSI outcome measure cross the ∆ margins (> +15%) in the per protocol analysis in favour of concise care. In addition, at T3 and T4 both left and right margins of the 95% CI of WSQ remission cross the ∆ margins, not establishing equivalence.


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GEE ANALYSES: PRIMARY AND SECONDARY OUTCOMESPRIMARY OUTCOMES

FIGURE 3 presents the mean BSI scores and percentage of patients with a psychiatric disorder according to the WSQ at the different assessment points; severity of psychopathology in both treatment groups decreased over time. Furthermore, GEE analyses showed that the difference in BSI scores between groups was the largest 3 months after baseline and in favour of concise care (SEE SUPPLEMENTARY MATERIAL, TABLE S3).

SECONDARY OUTCOMES

Mean secondary outcomes scores during treatment for both groups are presented in FIGURE 4. The Clinical Global Impression scores reduced over time. Likewise, general health and quality of life improved in both treatment groups. GEE analyses showed statistically significant differences in effectiveness 3 and 12 months after baseline assessment in favour of concise care (SEE SUPPLEMENTARY MATERIAL, TABLE S4) All analyses using imputation with last observation carried forward for the missing data yielded similar results. Since randomization had been successful, we did not explore all possible confounders. Adjusting for age and gender did not influence the differences between the concise and standard care group for any of the primary or secondary outcomes (data not shown).

SATISFACTION WITH TREATMENT. Patient satisfaction with treatment was measured 3 months after baseline in 81 patients (missing data in 23 patients). On average, patients in the concise treatment group (n = 41) were more satisfied with overall treatment than patients in standard care (mean item difference 1.04; p = 0.024). Satisfaction with the therapist did not differ significantly between groups (p = 0.205).

TABLE 2. OBSERVED DIFFERENCES IN THE PERCENTAGES OF TREATMENT SUCCESS OVER 12 MONTHS IN THE

INTENTION-TO-TREAT AND PER-PROTOCOL ANALYSIS.

Intention-to-treat

Standard care Concise care Difference in proportions 95% CI

BSI improvement T2 0.10 0.23 0.13 0.02 to 0.23

T3 0.15 0.18 0.04 -0.07 to 0.15

T4 0.11 0.16 0.05 -0.05 to 0.15

WSQ remission T3 0.05 0.03 0.01 -0.05 to 0.08

T4 0.06 0.05 0.00 -0.08 to 0.08

Per-protocol

Standard care Concise care Mean difference 95% CI

BSI improvement T2 0.18 0.42 0.24 0.06 to 0.40

T3 0.38 0.63 0.25 -0.00 to 0.46

T4 0.46 0.75 0.30 -0.00 to 0.53

WSQ remission T3 0.15 0.16 0.01 -0.20 to 0.25

T4 0.23 0.29 0.07 -0.20 to 0.34

Estimated differences in proportions and 95% CI are presented

BSI: Brief Symptom Inventory; WSQ: Web Screening Questionnaire. T2: 3 month assessment; T3: 6 month assessment; T4: 12 month assessment.


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Concise care better

Concise care worse

+∆ -∆

T4

-20 -15 -10 -5 0 5 10 15 20 30 40 50

Concise care worse

Percentage difference and 95% CI

T3

T2

FIGURE 2. EQUIVALENCE FIGURE BSI AND WSQ; INTENTION-TO-TREAT ANALYSES VS. PER PROTOCOL ANALYSES.

Horizontal bars indicate two-sided 95% confidence interval (CI) of the percentage difference in proportions success between concise care and standard care. The zone between

the vertical dashed lines at x = - ∆/+∆ indicates the equivalence margin. BSI: Brief Symptom Inventory; WSQ: Web Screening Questionnaire. T2: 3 month assessment; T3: 6 month

assessment; T4: 12 month assessment.

WSQBSI

WSQBSI

-15 -10 -5 0 5 10 15 25

Concise care better

+∆ -∆

Concise care worse

Percentage difference and 95% CI

T2

T3

T4


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DISCUSSIONIn this study we demonstrated that a novel 7-sessions concise version of cognitive behavioural therapy and/or pharmacotherapy led to comparable clinical outcomes as the longer standard care in the treatment of depressive and/or anxiety disorders in secondary care outpatients. This was true at the end of concise care at 3 months, but also later at 6 and 12 months and for all effect parameters. In fact, in concise care, the clinical effects are obtained earlier, in the first phase of treatment. Moreover, patients were more satisfied with treatment in concise care. These results are in line with other studies on the effectiveness of brief treatments for depressive and anxiety disorders (Cape et al. 2010; Ehlers et al. 2014; Nieuwsma et al. 2011; van Straten et al. 2006). Although we cannot state with certainty what underlies the beneficial effect of concise care compared to standard care, we can hypothesize it. Therapists and patients had a central role in treatment. They were asked to strictly following the treatment protocols and actively participate in the study. Besides, prior to starting therapy, treatment goals were formulated and mutually agreed on by both the patient and therapist. These facts, could have also impacted the treatment outcome of concise care. Clinicians and patients could be highly motivated, contributing to this positive treatment effect. Our study is one of the first to demonstrate these effects in secondary mental health care. Treatment was provided in a regular ‘real life’ psychiatric outpatient sample by qualified therapists already working in the participating MHCs, reflecting day-to-day clinical practice. This increases external validity, thereby enhancing the generalizability of the results to clinical practice. Moreover, our study has good internal validity as is demonstrated by the successful randomization of the treatment groups, the sufficient treatment fidelity and delivery of treatment according to protocols. However, several potential methodological concerns have to be noted. Firstly, the desired sample size of 500 patients was not achieved. An investigation of the inclusion during a 2 month period showed that the majority of patients seeking treatment at the MHCs did not meet the trial inclusion criteria of our study because of the higher severity and burden of disease. Secondly, a substantial number of patients did not complete treatment or were lost to assessment, a common problem in long-term studies in naturalistic out-patient settings (Rush et al. 2006; van Noorden et al. 2012; van Straten et al. 2006). However, although we did not achieve the intended sample size of 500 patients we did find concise care to be at least as effective as concise care. Contrary to our initial expectations and assumptions of a real difference in percentages success between the treatments of 5% in either direction, the observed difference between the two treatments was larger than expected; e.g. 13% in favour of concise care in the intention-to-treat population at three months for the primary outcome measure BSI. The observed differences in success percentages at the three time points all being in favour of concise turned out to be sufficient to compensate for the loss to follow-up of patients. Another limitation is that because of the pragmatic study design, patient’s suitability to participate in the trial during the course of the study was assessed by the therapists involved. Unfortunately, the reasons for excluding patients from care during the trial were not adequately reported. Due to this lack of knowledge, we cannot make any statements about post-randomisation drop-out and reasons for loss to follow-up after study entry. However, concise care, as such, did not increase dropout rates significantly when compared to standard care. In both groups a comparable


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number of patients had to be excluded, dropped out or did not visit the clinic as scheduled. We found no evidence for selective attrition on baseline characteristics, and our conservative handling of missing data, with last observations carried forward, did not alter the patterns of outcomes. An additional limitation, associated with the pragmatic study design, was that in practice, treatment and therapist adherence to the protocols in concise care was not optimal; not all patients were offered concise care as prescribed in the treatment protocols. Moreover, the design of the study as a RCT in a pragmatic setting resulted in considerable differences in follow-up periods between patients and groups. Although the majority of patients were offered concise care within the first 3 months after study entry, the duration of concise care was prolonged and continued during the entire study period (i.e. therapy sessions in concise care were delivered in 7-9 weeks). However, it appears that concise care did a better job of engaging patients in treatment in a more timely manner. This is reflected in the higher patient satisfaction rating for concise care reported at 3 months. In conclusion, we found that concise care is equally effective as standard care in the secondary outpatient treatment of depressive- and/or anxiety disorders. The early start of concise care, the strict scheduling of weekly patient-therapist contacts and the ongoing monitoring of treatment outcome are important for the beneficial effects of the concise treatment. Since concise care is likely to provide significant health gain, and most beneficial effects are obtained within the first phase of treatment, concise care is recommended as first step in a stepped care delivery of care. Moreover, in contrast to other studies, concise care examined here follows a stratified stepped care approach taking into account patients’ needs and preferences which may be clinically more adequate than the more stringent model of stepped care which begins with the least intensive treatment for each patient regardless of the patients’ needs and circumstances. Because the study was carried out in a naturalistic setting, the generalizability of the results is good. The study population reflects the subgroup of lighter cases referred to secondary care, therefore the findings of our study are generalizable to a broader patient population. However, the problems with the inclusion of patients and the high drop-out rate may decrease the generalizability, but these problems are also very difficult to avoid in a naturalistic setting. We hope that future studies with a larger sample size, longer follow-up and more strict adherence to the study protocol, will confirm our promising findings.

ROLE OF FUNDING SOURCEThis is a collaborative study between RD and the department of Psychiatry of the LUMC and is funded entirely by RD. RD is a secondary Regional Mental Health Provider (RHMP) in the province of South-Holland, the Netherlands. The funding source contributed to the study design and enrolment of participants but had no role in data collection, data analysis, data interpretation or writing of the report. The corresponding author had full access to all study data and had final responsibility for the decision to submit for publication.

CONFLICT OF INTERESTNone of the authors have a conflict of interest related to the findings within the submitted manuscript.


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CONTRIBUTORS’ STATEMENTThe funding source, in close collaboration with the LUMC, contributed to the design of the study. Further trial development was carried out by the trial project managers: DM (principal investigator and main author), IVEC (project adviser and co-promotor), IMV (project adviser and co-promotor), AMH (promotor) and FGZ (project adviser and promotor). Data collection was done by DM, who monitored data collection and integrity of randomisation. The statistical analyses were done by DM. TV and RW provided statistical advice. All authors contributed to the interpretation of the data and drafting of the report, DM was responsible for writing the manuscript. All authors commented on drafts of the manuscript and all approved the final report.

ACKNOWLEDGMENTSWe gratefully acknowledge the funding source Rivierduinen (RD). The authors thank all the patients participating in this study and the staff at RD: psychiatrists, psychologists, psychiatric test nurses, secretary and all others for their contribution to this research.


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SUPPLEMENTARY MATERIAL CHAPTER 3SUPPLEMENTARY TABLE S1. DSM IV-TR DIAGNOSES INCLUDED WITHIN STUDY.

Included DSM IV-TR diagnoses

minor or major depressive disorder (single episode or recurrent)

depressive disorder NOS

dysthymia

panic disorder (with or without agoraphobia)

panic disorder NOS

social phobia

simple phobia

generalized anxiety disorder

obsessive compulsive disorder

posttraumatic stress disorder (type I or single trauma),

adjustment disorder (with anxiety and/or depressive mood).

Note: Co-morbidity associated with other psychiatric diagnosis (with the exception of psychotic or bipolar disorder) is allowed. NOS: Not Otherwise Specified

SUPPLEMENTARY TABLE S2. ROM STUDY MEASURES BY TIME INTERVAL, IN ALPHABETICAL ORDER.

Instrument Full Name Domain Clustera Typeb Time interval

T1 T2 T3 T4

BSI Brief Symptom Inventory Psychopathology Gen SR X X X X

CGI Clinical Global Impression Psychopathology Gen OS X X X X

DEMOG Demographic Inventory Social Demographics Gen SR X

Mental Healthcare Thermometerc Dutch Mental Healthcare Thermometer of Appreciation by Clients Consumer Satisfaction Gen SR X

MINI-Plus Mini- International Neuropsychiatric Interview Plus Psychopathology Gen OS X

SF- 36 Short Form Health Survey 36 Psychosocial Functioning Gen SR X X X X

WSQ Web Screening Questionnaire for common mental disorders Psychopathology Gen SR X X X

Note: For a list of the complete set of questionnaires used within the study see Meuldijk et al. 2012. In bold: primary and secondary outcome measures.

T1: baseline assessment; T2: 3 month assessment; T3: 6 month assessment; T4: 12 month assessment.

BSI: Brief Symptom Inventory; CGI: Global Clinical Impression; Demog: Demographics; MINI-Plus: mini-international neuropsychiatric interview-plus; SF-36: Short-Form Health

Survey ; WSQ: Web Screening Questionnaire.aGen: Generic cluster. bSR: Self Report, OS: Observer Scale. cMental Healthcare Thermometer (in Dutch: GGZ Thermometer).

SUPPLEMENTARY TABLE S3. ESTIMATED MEAN DIFFERENCES FOR THE PRIMARY OUTCOME MEASURES AT BASELINE, 3 MONTHS, 8 MONTHS, AND 12 MONTHS, BASED ON INTENTION-TO-TREAT GEE ANALYSIS.

Measure Time Mean difference 95% CI Sig

Primary outcomes

BSI Total score Baseline 0.05

3 months -0.30 -0.54 to -0.06 0.01*

6 months -0.10 -0.39 to 0.20 0.53

12 months -0.18 -0.52 to 0.17 0.32

ORc 95% CI

WSQ score Baseline 0.78

6 months 0.76 0.16 to 3.65 0.73

12 months 0.78 0.17 to 3.71 0.80

Estimated mean differences are expressed as β (95% CI) or as OR (95% CI). Standard care is reference category. BSI: Brief Symptom Inventory; WSQ: Web Screening Questionnaire.*Significant as p <0.05.


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SUPPLEMENTARY TABLE S4. ESTIMATED MEAN DIFFERENCES FOR SECONDARY OUTCOMES AT BASELINE,

3 MONTHS, 8 MONTHS, AND 12 MONTHS, BASED ON INTENTION-TO-TREAT GEE ANALYSIS.

Measure Time Mean difference 95% CI Sig

Secondary Outcomes

Severity of Illness (CGI score) Baseline 0.01

3 months -0.57 -0.94 to -0.20 0.003*

6 months -0.20 -0.74 to 0.34 0.47

12 months -0.35 -0.98 to 0.28 0.28

Social Functioning (SF-36 score) Baseline 1.62

3 months 13.35 4.28 to 22.42 0.004*

6 months -3.23 -14.76 to 8.29 0.58

12 months 3.29 -9.66 to 16.24 0.62

Physical Functioning (SF-36 score) Baseline -0.56

3 months 0.12 -5.64 to 5.88 0.97

6 months 4.07 -3.53 to 11.67 0.29

12 months 5.01 -3.87 to 13.89 0.27

General Health (SF-36 score) Baseline 1.50

3 months 4.21 -3.54 to 11.96 0.29

6 months 5.40 -3.66 to 14.46 0.24

12 months -31.60 -60.53 to -2.67 0.03**

CGI: Clinical Global Impression SF-36: Short-Form Health Survey. Standard care is reference category.*Significant at p <0.01.**Significant at p <0.05.


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weekly cognitive therapy for PTSD and emotion-focused supportive therapy. Am J Psychiatry 2014;171:294-304.

Gega L, Kenwright M, Mataix-Cols D, Cameron R, Marks IM. Screening people with anxiety/depression for suitability for guided self-help. Cogn Behav Ther 2005;34:16-21.

Gustavsson A, Svensson M, Jacobi F et al. Cost of disorders of the brain in Europe 2010. Eur Neuropsychopharmacol 2011;21:718-779.

Guy W. ECDEU Assessment Manual for Psychopharmacology. National Institue of Mental Health, Rockville, MD., 1976.

Haaga DAF. Introduction to the special section on stepped care models in psychotherapy. J Consult Clin Psychol 2000;68:547-548.

Hamann J, Leucht S, Kissling W. Shared decision making in psychiatry. Acta Psychiatr Scand 2003;107:403-409.

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Joosten EA, DeFuentes-Merillas L, de Weert GH, Sensky T, van der Staak CP, de Jong CA. Systematic review of the effects of shared decision-making on patient satisfaction, treatment adherence and health status. Psychother Psychosom 2008;77:219-226.


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Kok I, van Wijngaarden B. Client Appreciation in Mental Health Care: Manual of the Dutch Mental Healthcare Thermometer of Appreciation by Clients [in Dutch]. Utrecht, Trimbos-instituut/GGZ Nederland, 2003.

Meuldijk D, Carlier IV, van Vliet IM, van den Akker-Marle ME, Zitman FG. A randomized controlled trial of the efficacy and cost-effectiveness of a brief intensified cognitive behavioral therapy and/or pharmacotherapy for mood and anxiety disorders: design and methods. Contemp Clin Trials 2012;33:983-992.

Moher D, Hopewell S, Schulz KF et al. CONSORT 2010 explanation and elaboration: updated guidelines for reporting parallel group randomised trials. BMJ 2010;340:c869.

Murphy JM, Horton NJ, Laird NM, Monson RR, Sobol AM, Leighton AH. Anxiety and depression: a 40-year perspective on relationships regarding prevalence, distribution, and comorbidity. Acta Psychiatr Scand 2004;109:355-375.

Murray CJ, Lopez AD. Alternative projections of mortality and disability by cause 1990-2020: Global Burden of Disease Study. Lancet 1997;349:1498-1504.


Nieuwsma JA, Trivedi RB, McDuffie J, Kronish I, Benjamin D, Williams JW. 2011. Brief Psychotherapy for Depression in Primary Care: A Systematic Review of the Evidence [Internet]. Washington (DC): VA Evidence-based Synthesis Program Reports; January 2011.


Piaggio G, Elbourne DR, Pocock SJ, Evans SJ, Altman DG. Reporting of noninferiority and equivalence randomized trials: extension of the CONSORT 2010 statement. JAMA 2012;308:2594-2604.

Rush AJ, Trivedi MH, Wisniewski SR et al. Acute and longer-term outcomes in depressed outpatients requiring one or several treatment steps: a STAR*D report. Am J Psychiatry 2006;163:1905-1917.


Sheehan DV, Lecrubier Y, Sheehan KH et al. The Mini-International Neuropsychiatric Interview (M.I.N.I.): the development and validation of a structured diagnostic psychiatric interview for DSM-IV and ICD-10. J Clin Psychiatry 1998;59 Suppl 20:22-33

Smit F, Cuijpers P, Oostenbrink J, Batelaan N, de GR, Beekman A. Costs of nine common mental disorders: implications for curative and preventive psychiatry. J Ment Health Policy Econ 2006;9:193-200.

Twisk JW. Longitudinal data analysis. A comparison between generalized estimating equations and random coefficient analysis. Eur J Epidemiol 2004;19:769-776.

van Fenema, van der Wee NJ, Bauer M, Witte CJ, Zitman FG. Assessing adherence to guidelines for common mental disorders in routine clinical practice. Int J Qual Health Care 2012;24:72-79.

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Ware, JE. SF-36 Health Survey Update. Spine 2000; 25(24): 3130-3139.Wiens BL. Choosing an equivalence limit for noninferiority or equivalence studies. Control Clin Trials

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the brain in Europe 2010. Eur Neuropsychopharmacol 2011;21:655-679.Zeger SL, Liang KY. Longitudinal data analysis for discrete and continuous outcomes. Biometrics

1986;42:121-130.


Chapter 4Economic Evaluation of Concise Cognitive Behavioural

Therapy and/or Pharmacotherapy for Depressive and Anxiety Disorders

Previously published as:Meuldijk D, Carlier IVE, van Vliet IM, van Hemert AM, Zitman FG, van den Akker- van Marle ME.

Economic Evaluation of Concise Cognitive Behavioural Therapy and/or Pharmacotherapy for Depressive and Anxiety Disorders.

J Ment Health Policy Econ 2015;18:3175-183.


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ABSTRACTBACKGROUND Depressive and anxiety disorders cause great suffering and disability and are associated with high health care costs. In a previous conducted pragmatic randomised controlled trial, we have shown that a concise format of cognitive behavioural and/or pharmacotherapy is as effective as standard care in reducing depressive and anxiety symptoms and in improving subdomains of general health and quality of life in secondary care psychiatric outpatients. Aims of the Study: In this economic evaluation, we examined whether a favourable cost-utility of concise care compared to standard care was attained.

METHODS The economic evaluation was performed alongside a pragmatic randomised controlled trial. Health-related quality of life was measured using the Short-Form (SF-36) questionnaire. Cost of healthcare utilization and productivity loss (absenteeism and presenteeism) were assessed using the Trimbos/iMTA questionnaire for Costs associated with Psychiatric Illness (TiC-P). A cost-utility analysis, using cost-effectiveness acceptability curves, comparing differences in societal costs and Quality-Adjusted Life Years (QALYs) at 1 year was performed.

RESULTS One year after study entry, the difference in mean cost per patient of the two primary treatments was not significant between both groups. No significant differences in other healthcare and non-healthcare costs could be detected between patients receiving concise care and standard care. Also, QALYs were not statistically different between the groups during the study period. From both the societal and healthcare perspective, the probability that concise care is more cost-effective compared to standard care remains below the turning point of 0.5 for all acceptable values of the willingness to pay for a QALY. The economic evaluation suggests that concise care is unlikely to be cost-effective compared to standard care in the treatment for depressive- and anxiety disorders in secondary mental healthcare during a one year follow up period.

DISCUSSION Total costs and QALYs were not significantly different between standard and concise care, with no evidence for cost-effectiveness of concise care in the first year. The longer impact of concise care for patients with mild to moderate symptoms of depressive- and/or anxiety disorders compared to standard care in secondary care needs to be further studied.

IMPLICATIONSThis economic evaluation failed to find significant differences in cost between concise and standard care over the study period of one year. Replication of our economic evaluation might benefit from an extended follow-up period and strict adherence to the study protocol. If concise care will be found to be cost-effective in the long term, this would have major implications for recommendations how to optimize secondary mental health care in the treatment of depressive – and anxiety disorders.


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INTRODUCTIONDepressive and anxiety disorders are highly prevalent in clinical practice, causing great suffering and disability, and having a considerable impact on individuals, health services and society (Kessler et al. 2009; Murray & Lopez, 1997a; Murray & Lopez, 1997b). Several psycho- and pharmacotherapeutic treatments are widely applied and have been shown to provide adequate treatment for these disorders. However, they place an increased demand on health and social care resources, causing a considerable economic burden (Gustavsson et al. 2011; Nutt, 2011; Smit et al. 2006). Offering these treatments in a more concise form, in which treatments are confined to a maximum number of sessions within a fixed time-period, can yield savings in both healthcare and societal costs. As a result, costs of treatment could be lowered while maintaining clinical effectiveness, resulting in a favourable cost-effectiveness of concise care compared to standard care. In a recent pragmatic randomised controlled trial (Meuldijk et al. 2012), we compared a concise, time restricted approach of psycho- and/or pharmacotherapy with standard routine care in the treatment of secondary care outpatients with an anxiety- and/or depressive disorder. Both standard and concise care equally succeeded in reducing depressive- and anxiety complaints and improved current general health status and subdomains of quality of life (e.g. functional status and physical functioning) during the first year after study entry. We concluded that a concise format of psycho- and/or pharmacotherapy is as effective as standard care in the treatment of outpatients with a mild to moderate depressive- and/or anxiety disorders (see Meuldijk et al. in press). In addition, since health care budgets are shrinking, an economic evaluation of this effect is desired to inform decisions which health care services to offer. This paper reports about the cost-effectiveness (cost-utility) of concise care versus standard care. We performed an economic evaluation based on the data of our randomised controlled trial (Meuldijk et al. 2012) to determine whether, given the similar clinical effectiveness, a favourable cost-effectiveness for concise care is attained, one year after study entry.

METHODSSTUDY DESIGNAn economic evaluation was embedded in a pragmatic, randomised controlled trial of equivalence examining the effectiveness of concise care in patients with a mild to moderate anxiety- and/or depressive disorder (Meuldijk et al. 2012). The study was approved by the Medical Ethical Committee (MEC) of the Leiden University Medical Centre (LUMC) and adhered to the consolidated standards for reporting randomised controlled equivalence trials (Hopewell et al. 2008; Moher et al. 2010; Piaggo et al. 2012). The trial was conducted at five Dutch outpatient Mental Healthcare Centres (MHCs) of the Regional Mental Health Provider (RMHP) Rivierduinen. In short, between March 2010 and December 2012, 182 patients were enrolled. These patients (aged 18-65 years) with a mild to moderate anxiety- and/or depressive disorder were randomly allocated to concise or standard care. Patients with suicidal or homicidal risk, severe social dysfunction, delusions, hallucinations and/or suffering from bipolar or psychotic disorders were excluded from the trial. Co-morbidity with other psychiatric disorders was allowed. Patients’ progress and clinical effectiveness of treatment were assessed by touch-screen Routine Outcome Monitoring (ROM), and planned at baseline (T1), 3 months (T2), 6 (T3) and 12 (T4) months after baseline. Written informed consent was obtained from all participants before study entry. The baseline


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characteristics of both groups were similar (Meuldijk et al. 2012). Details on the methodology and design of this randomised clinical trial and the clinical effectiveness results are reported elsewhere (Meuldijk et al. 2012; Meuldijk et al. in press).

TREATMENTSIn both concise and standard care, a choice could be made between pharmacotherapy with a selective serotonin reuptake inhibitor (SSRI) (Guy, 1976) or psychotherapy with Cognitive Behavioural Therapy (CBT) (Beck, 1995; Clark & Salkovskis, 1987) or, in case of a posttraumatic stress disorder, Eye Movement Desensitization and Reprocessing-therapy (EMDR) (Shapiro, 1995). CONCISE CARE is characterized by a quick onset, a fixed number of weekly sessions (maximum of 7 sessions) within a 7-week fixed time period after which concise care ends. If insufficiently helped by this initial treatment, continuation of (additional) treatment, according to the stepped-care principles (van Fenema et al. 2012), was possible. STANDARD CARE is not confined to a maximum number of sessions or within a fixed time-period and could continue during the entire study period of 1 year. The treatment protocols in concise and standard care followed the Dutch guidelines for the evidence-based treatment of depressive and anxiety disorders (van Fenema et al. 2012), thereby advocating a stepped-care approach (Davison, 2000; Haaga et al. 2000). Details of the treatment can be found elsewhere (Meuldijk et al. 2012).

MEASURESThe information for the economic evaluation was captured during the entire study period of one year. Generic health-related quality of life was assessed with the Short Form-36 Health Survey (SF-36) (Aaronson et al. 1998; Ware et al. 1993) at baseline and at the subsequent follow-up measurements. Use of medical resources and productivity loss were assessed with the Trimbos/iMTA questionnaire for Costs associated with Psychiatric Illness (TiC-P), (Hakkaart- van Roijen et al. 2002; Bouwmans et al. 2013) 3, 6 and 12 months after baseline.

QUALITY OF LIFE The SF-36 (Aaronson et al. 1998; Ware et al. 1993) is a 36-item self-report questionnaire that measures health status in eight domains: physical functioning, social functioning, physical problems, emotional problems, mental health, vitality, bodily pain and general health. The SF-36 has good psychometric properties and is proven useful in differentiating the health benefits produced by a wide range of different treatments. The SF-36 scores were used to calculate utilities (Brazier et al. 2002). These represent the societal valuation of the health-related quality of life of the patients on a scale from ‘0’ (‘as bad as death’) to ‘1’ (‘perfect health’). Quality-adjusted life-years (QALYs) were estimated by applying the area-under-the-curve method. QALYs take into account both the quantity and quality of life generated by health care interventions and offer the possibility of comparison of the impact with other medical interventions, which is preferred for economic evaluations (Brazier et al. 2012; McDonough & Tosteson, 2007)

HEALTHCARE AND NON-HEALTHCARE COSTSThe economic evaluation was undertaken from a societal perspective, and included costs due to health care resource utilisation (healthcare costs) and costs attributable to production losses (non-healthcare cost). Data on costs of primary treatment (either standard or concise care) were


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assessed from case-record forms in which type of contact (face-to-face, telephone, e-mail), type of visit (psychologist, psychiatrist, psychotherapists, and other) and time per contact was collected, directly from the participating centres. Costs of crisis therapy/contacts were also included. Other healthcare and non-healthcare costs from the patients were collected using the TiC-P questionnaire (Bouwmans et al. 2013; Hakkaart- van Roijen et al. 2002). The first part of the TiC-P measures medical resource utilization by asking for the number of contacts with different (para)medical and psychological health-care providers (e.g. general practitioner (GP), psychiatrist, medical specialist, physiotherapist, alternative health practitioner, day care/hospital length of stay) during the past 4 weeks (Hakkaart- van Roijen et al. 2002). When calculating the costs, it was assumed that the number of contacts and/or days in those 4 weeks to be representative for the total period between assessments (i.e.: 3 months between T1 – T2, 3 months between T2- T3, 6 months between T3- T4). To estimate health service use over the total period, we interpolated the frequencies of contacts within these four weeks, to the total observed period between assessments. The number of medical contacts were multiplied by reference unit costs of the corresponding health care services. All costs were adjusted to the year 2013 according to the consumer price index (Statistics Netherlands, 2010) and are presented in euros. The TiC-P questionnaire was adjusted for the current study: open-ended questions were categorized to be suitable using the touch screen ROM method (e.g. ‘How often did you visit the GP in the past 4 weeks?’: 1 time, 2 to 5 times, 5 to 10 times, 10 times or more). Absence from work, reduced efficiency at work, difficulties with job performance (absenteeism from paid work), and production losses without absenteeism from paid work (e.g. presenteeism) are measured in the second part of the TiC-P. Work absenteeism is measured by two questions related to short- and long-term absence (< 2 weeks and > 2 weeks) from work. For the current study, only data on short-term absence was available. Again, we interpolated the short-term absence to the total time period between two assessments. Costs of absenteeism from paid work were calculated according to the Friction Cost (FC) method (Koopmanschap et al. 1995). With this method, the number of hours patients were absent from their job is multiplied with the actual gross wage per hour for the duration of the friction period, i.e. the timespan organisations need to restore the initial production level. In the Netherlands, the friction period is set at 23 weeks (Hakkaart- van Roijen et al. 2010). Presenteeism is measured by asking patients how many days at work their health problems hinders their performance while at work and their efficiency on these days, scored on a scale ranging from ‘0’ (could not do anything) to ‘10’ (able to do as much as normally). Presenteeism costs were calculated by weighing the number of working days impaired by the efficiency score and interpolating these estimates of productivity loss due to presenteeism in the past 2 weeks to the total time period between two assessments (assuming 240 eligible work days/year).

DATA ANALYTIC PROCEDURES

All analyses followed the intention-to-treat principle. A total of 182 patients participated in the randomized controlled trial and were randomised to either standard care (n = 89) or concise care (n = 93). Full economic and outcome data were available at T2, T3, and T4 for respectively 57%, 36% and 23% of the total patients (CONSORT Flow of participants diagram see Meuldijk (in press) and colleagues (Meuldijk et al. in press). To impute missing cost and effect data, Multiple Imputation


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(MI) according to the Multivariate Imputation by Chained Equations (MICE) algorithm with 10 iterations for the switching regression model was done (van Buuren et al. 1999; van der Heijden et al. 2006). Differences in (societal) costs were compared between both groups for the total number of 182 patients. In the cost-utility analysis societal costs and QALYs based on the SF-36 from the start of the study until the end of the first year were compared. Subsequently, cost-effectiveness acceptability curves (CEACs) were constructed. They represent the probability that, given a certain threshold for the willingness to pay for a QALY, concise care is cost-effective in comparison with standard care. Cost-effectiveness is plausible, when the probability that concise care is effective exceeds 0.5 for a given willingness-to-pay. The Dutch economic threshold for willingness to pay is assumed to be between €20,000 and €80,000 per QALY (Council for Public Health and Health Care, 2006; Smulders & Thijs, 2006) Cost analyses were conducted with Stata 9.2 (Stata Corp, College Station, Texas, USA) and IBM SPSS version 20 for Windows (SPSS Inc., Chicago, IL, USA).

RESULTSThe study design planned assessments to be performed at baseline, 3, 6, and 12-months post-baseline, referred to as respectively T1, T2, T3 and T4. Due to the pragmatic nature of our study design, patients had large differences in follow-up periods between assessments. To enhance comparability, the time horizon to assess QALYs and costs, was set at one year after the baseline measurement (T1) for each individual patient.

HEALTHCARE AND NON-HEALTHCARE COSTS TABLE 1 shows the estimated total mean healthcare and non-healthcare costs per patient over the study period. Direct costs associated with the primary treatments (including psycho- and pharmacotherapy contacts) and crisis contacts were €759 in the concise care group compared to €655 in the standard care group. This difference was non-significant (Table 1). Moreover, the non-significant differences in mean number of contacts between groups are presented in SUPPLEMENTARY MATERIAL, TABLE S1. Combined with other hospital costs (including hospital admission, specialist contacts) and healthcare costs outside the hospital (i.e. physiotherapy, general practitioner care, alternative medicine, home care) mean total healthcare costs per patient are €14,761 for concise care and €12,881 for standard care, which results in a non-significant difference of €1,180 (95% CI -5006 to 1246) between the two treatment groups. Cost due to outpatient visits (see Table 1) were the greatest contributor to mean total costs. Productivity loss due to absenteeism and presenteeism moreover resulted in a non-significant difference (€2915, 95% CI -12453 to 6622) in non-healthcare costs. Societal costs (sum of healthcare + non-healthcare costs) over the total study period were approximately €44,366 for concise and €39,570 for standard care, which is a non-significant difference (TABLE 1).


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TABLE 1. MEAN COSTS PER PATIENT AFTER CONCISE AND STANDARD CARE FOR A FOLLOW-UP PERIOD OF ONE YEAR.

Concise care (n = 93) Standard care (n = 89) Difference (95% CI)

%1 Costs, Euro (€) (±SD) %1 Costs, Euro (€) (±SD) Costs, Euro (€) P-value

Primary treatment2 80.7 759 (1498) 75.3 655 (954) 104 (-260 to 468) 0.58

Cognitive Behavioural Therapy 76.3 679 (1365) 71.9 586 (934) 93 (- 246 to 432) 0.59

Pharmacotherapy 29.0 64 (156) 30.3 54 (120) 10 (-31 to 50) 0.64

Crisis contacts 8.6 17 (82) 5.6 15 (116) 1 (-28 to 31) 0.93

General Practitioner (GP) 72.8 790 (946) 71.9 617 (789) 173 (-153 to 499) 0.29

Ambulatory mental health services 75.7 2010 (2282) 82.7 1943 (2028) 68 (-832 to 967) 0.88

Psychiatrist/psychologist/psychotherapist 52.8 1277 (1809) 39.2 1079 (1872) 198 (-636 to 1032) 0.62

Company physician 65.1 486 (665) 60.2 409 (633) 77 (- 203 to 356) 0.58

Outpatient visits 88.2 4327 (3275) 83.0 3657 (3271) 670 (- 377 to 1716) 0.21

Day care (hospital) 26.7 141 (279) 22.1 111 (223) 31 (-93 to 154) 0.60

Hospital days 31.0 865 (1451) 29.4 888 (1793) 24 (-823 to 776) 0.95

Physical therapist 69.9 743 (708) 71.5 688 (653) 55 (-218 to 328) 0.68

Social worker 33.3 411 (841) 35.1 389 (783) 22 (-475 to 519) 0.92

Centre for Drugs and Alcohol Addiction 30.8 344 (593) 28.2 289 (541) 55 (-242 to 352) 0.70

Paid domestic care 16.9 267 (564) 16.9 276 (637) -9 (-255 to 237) 0.94

Alternative care 79.7 2341 (2189) 70.1 1880 (2039) 461 (-265 to 1187) 0.21

Total Healthcare costs (sd) 100.0 14761 (9431) 100.0 12881 (8715) 1880 (-1246 to 5006) 0.23

Self-help 66.3 2123 (3069) 61.4 1650 (2541) 474 (-973 to 1920) 0.49

Absenteeism 66.2 17806 (21217) 60.0 16466 (20736) 1340 (-5690 to 8369) 0.71

Presenteeism 78.6 9675 (10664) 84.4 8573 (9022) 1102 (-2479 to 4682) 0.54

Total non-healthcare costs (sd) 91.4 29605 (26619) 93.2 26689 (24404) 2915 (-6622 to 12453) 0.54

Total societal cost (sd) 100.0 44366 (32427) 100.0 39570 (29739) 4795 (-6384 to 15975) 0.30

Note: Mean costs are presented as mean (±standard deviation [SD]).

1Percentages of patients who made costs for that item unless stated otherwise; t test for unequal variance corrected for nonresponse with multiple imputation.

CI=Confidence Interval.2Face to Face, No Show, Telephone and/or email contacts primary treatment.

QUALITY OF LIFEUtility scores were comparable between both conditions during the study period (FIGURE 1). As a result, total QALYs [SD] over the study period were 0.633 (0.077) for concise care and 0.628 (0.074) for standard care. The difference in QALYs between concise and standard care was not statistically different (difference: -0.005; 95% confidence interval -0.032 to 0.022, p = 0.73).

COST UTILITY ANALYSISThe cost-effectiveness acceptability curves (CEAC) indicates the probability of concise care being cost-effective. Analyses indicate that for varying levels of the willingness-to-pay (WTP) threshold, the probability that concise care is more cost-effective compared to standard care remains below the turning point of 0.5 (see FIGURE 2). The CEACs show a probability below 25% that concise care will be considered cost effective for all values of the willingness to pay considered acceptable for the Dutch situation (National Council for Public Health and Health Care, 2006; Smulders & Thijs, 2006).


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FIGURE 1. UTILITIES WITH 95%

CONFIDENCE INTERVALS ACCORDING FOR

CONCISE CARE AND STANDARD CARE.

Note: T1: baseline assessment; T2: 3 month assessment; T3: 6

month assessment; T4: 12 month assessment.

FIGURE 2. COST-EFFECTIVENESS ACCEPTABILITY CURVES FOR CONCISE CARE COMPARED WITH STANDARD CARE

FOR A FOLLOW-UP PERIOD OF ONE YEAR.


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DISCUSSIONMAIN FINDINGS Cost comparisons between concise care and standard care, in the treatment of mild to moderate depressive and anxiety disorders in secondary mental health care, did not reveal any significant differences in mean healthcare and societal costs over a study period of one year. The mean cost of the primary treatments were estimated at €759 and €655 (difference €104; 95% CI - €260 to €468) for concise and standard care respectively. Also, after considering other healthcare- and non-healthcare cost over the study period, no significant differences between treatment groups could be detected. In both groups, most of the healthcare costs were caused by non-psychiatric outpatient visits, supporting the frequent observation that persons with depressive or anxiety disorders have many other health problems (Simon et al. 1995). The QALYs based on the SF36 did not differ significantly either. Our results demonstrate that the reduction of depression and anxiety symptoms and improved subdomains of health related quality of life associated with concise care compared to standard care (see Meuldijk (in press) and colleagues (Meuldijk et al. in press) were not reflected in the utility scores and achieved without significant differences in costs. Therefore, this study failed to demonstrate a favourable cost-utility for concise care in comparison with standard care. Our results are in line with earlier studies examining cost-effectiveness of brief psychological treatments (Churchill et al. 2001; Hakkaart- van Roijen et al. 2006; Maljanen et al. 2012). In most of these studies the differences in total healthcare costs between brief therapy and standard care were very small and not statistically significant.

LIMITATIONSThere are certain methodological considerations about our study that need to be addressed as well. Firstly, the relatively small sample size and the substantial number of patients who did not complete treatment or were lost to assessment (see Meuldijk (in press) and colleagues (Meuldijk et al. in press), for which we accounted by Multiple Imputation (MI), is worth noticing. Although MI is a sophisticated imputation technique, even this method of dealing with missing data is precarious because of the large amount of missing data in this trial especially at the final follow up moments (Carpenter et al. 2008; Sterne et al. 2009). Secondly, our study was underpowered to detect relevant cost differences, which is reflected in the wide confidence intervals around the cost estimates. Unfortunately, this is a common problem in economic evaluations alongside clinical trials in a natural setting (Briggs, 2000). Moreover, the design of the study as a RCT in a pragmatic setting resulted in considerable differences in follow-up periods between patients and groups. Therefore, the time horizon for the economic evaluation was set at one year after baseline measurement. However, this time period of one year might not be long enough to capture the full costs and the long term effects of concise care and standard care, and may turn out to be a limitation of this trial. One might speculate that concise care is completed by the end of the follow-up period while patients in the standard care group could still be provided with healthcare. It is therefore possible that the potential savings in concise care were not fully visible after one year and may need a longer follow-up period. An additional methodological limitation was that in practice, not all patients were offered concise care as planned in the study protocol. Although the majority of patients was offered concise care within the first 3 months, the duration of concise care was prolonged and continued during the entire study period, resulting in non-significant higher


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costs of primary treatment in concise care compared to standard care in the first year. More strictly adhering the treatment protocol, whereby the number of sessions is realized as planned in the protocol and within the scheduled time-period, could lead to lower costs of concise care. In this situation concise care may help to reduce waiting lists by the earlier completion of treatment and could be also more successful in meeting the preferences of the patients (Furukawa et al. 2014; van Schaik et al. 2004). Finally, study outcomes were assessed by Routine Outcome Monitoring (ROM), a procedure already in use in the participating outpatient clinics (van Noorden et al. 2012). Since ROM is computer-based (touch-screen) and therefore does not allow open answer format questions, some items of the TiC-P questionnaire were categorized. Respondents had to choose an answer from a given number of options, which might have resulted in less exact answers. Moreover, data related to medication use costs were not available for the economic evaluation because of the open answer format of computer-based measuring.

IMPLICATIONSHowever, the pragmatic study design, is also an important strength of this economic evaluation. It offers an opportunity to evaluate the cost-effectiveness of concise care under real world conditions, this increases external validity, and greatly enhances the generalizability of the findings to clinical practice (Rush et al. 2006; van Straten et al. 2006). We conducted this large-scale multicentre RCT in the naturalistic clinical setting of routine mental health care services for secondary care in The Netherlands, reflecting normal day-to-day clinical practice in a regular ‘real life’ psychiatric outpatient population. To our knowledge, this is one of the first studies to assess the cost-utility of concise care alongside a clinical effectiveness trial in a secondary care setting. According to our results, symptoms of depressive and anxiety disorders were reduced to a similar extent and concise and standard care are comparable in terms of costs, no statistically significant differences in total costs and/or QALYs were found between both groups. This may be due to inadequate sample sizes for the economic evaluation6. More research overcoming the limitations of the current study and a sufficiently long follow-up period are needed before definite conclusions about the cost-effectiveness of concise care, can be made. Future studies may give insight how to optimize clinical and cost effectiveness and increase the quality of secondary mental healthcare. ACKNOWLEDGMENTSThis is a collaborative study between Rivierduinen (RD) and the department of Psychiatry of the LUMC. The authors thank all the patients participating in this study and the staff at RD: psychiatrists, psychologists, psychiatric test nurses, secretary and all others for their contribution to this research.

6Based on the observed standard deviations of the costs per patient in this study, a sample size of more than n=500 patients per condition (power of 80% under the assumption of alpha=0.05) would be needed to show a significant difference in societal costs between both conditions.


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SUPPLEMENTARY MATERIAL CHAPTER 4.SUPPLEMENTARY TABLE S1. MEAN NUMBER OF SESSIONS OF PRIMARY TREATMENT FOR A FOLLOW-UP PERIOD

OF ONE YEAR.

Concise care (n = 93) Standard care (n = 89)

Number of sessions Primary Treatmenta Mean ( ±SD) IQR Median Range Mean ( ±SD) IQR Median Range P-value

At 3 months assessment(T2)

Number of sessions Primary Treatmenta 10 (20) 2-9 6 0-177 5 (9) 0-7 2 0-47 0.081

Cognitive Behavioural Therapy 8 (17) 1-8 5 0-145 4 (7) 0-6 1 0-37 0.061

Pharmacotherapy 1 (4) 0-0 0 0-26 1 (3) 0-0 0 0-18 0.283

Crisis contacts 0 (2) 0-0 0 0-18 0 (3) 0-0 0 0-31 0.969

At 6 months assessment (T3)



Pharmacotherapy 2 (4) 0-1 0 0-26 1 (3) 0-1 0 0-18 0.363

Crisis contacts 0 (0) 0-0 0 0-18 0 (0) 0-0 0 0-31 0.987

At 12 months assessments (T4)



Pharmacotherapy 2 (5) 0 -1 0 0-26 1 (3) 0-1 0 0-18 0.372

Crisis contacts 0 (3) 0 -0 0 0-18 0 (2) 0-0 0 0-31 0.987

Note: Number of sessions are presented as mean (±standard deviation [SD]), interquartile range (IQR), median, range).

aTotal number of Face to Face, No Show, Telephone and/or email contacts primary treatment.


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Smit F, Cuijpers P, Oostenbrink J, Batelaan N, de Graaf R, Beekman A. Costs of nine common mental disorders: implications for curative and preventive psychiatry. J Ment Health Policy Econ 2006;9:193-200.

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van Noorden MS, Van Fenema EM, van der Wee NJ, van Rood YR, Carlier IV, Zitman FG, Giltay EJ. Predicting outcomes of mood, anxiety and somatoform disorders: the Leiden routine outcome monitoring study. J Affect Disord 2012;142:122-31.

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Chapter 5Subgroup Analyses of a Concise care trial of Depressive

and/or Anxiety disorders

Submitted as:Meuldijk D, Giltay EJ, Carlier IVE, van Vliet IM, van Hemert AM, Zitman FG.

Subgroup analyses of a concise care trial of depressive and/or anxiety disorders


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ABSTRACTBACKGROUNDConcise forms of psycho- and pharmacotherapy have shown effectiveness, Identifying the factors that predict who is most likely to benefit from such treatment may help to deliver the most adequate one for the individual.

METHODSSecondary care outpatients aged 18-65 years with mild to moderate DSM-IV depressive and/or anxiety disorders, participated in a pragmatic randomised controlled equivalence trial comparing a concise format of cognitive behavioural- and/or pharmacotherapy (i.e., concise care) to standard care. A range of putative factors associated with treatment outcome –socio-demographic characteristics (i.e., age, gender, level of education, employment status, and marital status) and clinical characteristics (psychiatric disorders)– were assessed at baseline. Subgroup analyses were conducted using multilevel regression analysis (i.e. Mixed Models) analysing the effects of interaction terms on changes over time in the Brief Symptom Inventory (BSI) scores as the outcome.

RESULTSA total of 182 participants were included and randomised to concise care (n = 93) and to standard care (n = 89), participants were on average 36.5 (SD 12.3) years old, and 61% were women. Patients suffering from any ‘anxiety (without depressive) disorder’ benefited significantly less from concise care than standard care (p = 0.012). No other clinical or socio-demographic factor was associated with differential effects.

LIMITATIONSThe overall sizes of the subgroups were relatively small. We evaluated the predictors of a relatively short-term outcome to concise treatment.

CONCLUSIONSThe benefit of a concise form of psycho- and pharmacotherapy was independent from demographic and clinical characteristics. Only patients with anxiety (without depressive) disorders benefitted less from this concise treatment.


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INTRODUCTIONConcise forms of psycho- and/or pharmacotherapy have shown efficacy in the treatment of outpatients with depressive and/or anxiety disorders in secondary mental health care (Driessen et al. 2013; Knekt & Lindfors, 2004; Knekt et al. 2008; van Straten et al. 2006). A recent pragmatic randomised controlled equivalence trial demonstrated that concise care, in which treatments where confined to a maximum number of sessions (7 or fewer) within a fixed time period (7 weeks), was as effective as standard care in reducing depressive and anxiety symptoms, while concise care engaged patients in treatment in a more timely manner (Meuldijk et al. 2016). Until now, little is known about which patient benefits from concise care. Potentially, patient characteristics may influence treatment-decision making, thereby improving health care delivery and quality, reducing health care costs, and improving patient outcomes. Although no previous study systematically examined both socio-demographic patient characteristics and clinical factors as potential predictors of outcome to concise care (Frank et al. 2002; Joutsenniemi et al. 2012), several studies have focused on traditional/standard psychotherapy and pharmacotherapy in the treatment of depressive and anxiety disorders in routine secondary care (Meyers et al. 2002; Nilsen et al. 2013; Penninx et al. 2011; Schat et al. 2013; van Noorden et al. 2012; Weinberger et al. 2008; Yonkers et al. 2000). These studies demonstrated that younger age, being married, being employed, and a higher level of education were associated with a positive treatment response. Moreover, the presence of comorbid disorders and having concomitant symptoms of either anxiety or depressive disorder were associated with poorer recovery (Brent et al. 1998; Bruce et al. 2005; Penninx et al. 2011; van Noorden et al. 2012). In addition, some differential effects on treatment outcome were found regarding the type of disorder (i.e., depressive versus anxiety disorders). In some cohorts, treatment of depressive disorders was associated with a more favourable course (Ormel et al. 1993; Penninx et al. 2011), whereas other studies reported larger beneficial effects of treatment of patients with anxiety disorders (Butler et al. 2006; Hofmann et al. 2012; Spek et al. 2007;). Concerning concise forms of psychotherapy and/or pharmacotherapy in routine clinical practice, it is relatively unknown which kinds of patients may respond best. The aim of the present study was to examine possible socio-demographic and clinical patient characteristics as predictors of positive response to concise formats of psychotherapy and/or pharmacotherapy among a naturalistic cohort of outpatients with mild to moderate anxiety and/or depressive disorders recruited from a pragmatic randomised controlled trial on the equivalence of effectiveness of concise care compared to standard care (Meuldijk et al. 2012). Given time constraints in clinical practice and the importance of identifying these variables in the short time window prior to treatment assignment, we investigated the predictive value of demographic (i.e., age, gender, level of education, employment status, and marital status) and clinical characteristics (the presence of one or more disorders) as these variables are easily available to front-line clinicians. In addition, they are assessed by screening and assessment instruments, which can be routinely administered before treatment initiation.

METHODSSTUDY DESIGN AND PROCEDURESData were used from a pragmatic RCT comparing the effectiveness of concise forms of psycho and/or pharmacotherapy (concise care) in addition to standard care in the treatment of patients


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with a mild to moderate depressive and/or anxiety disorder. This trial was conducted in five outpatient Mental Health Clinics (MHCs) of Rivierduinen (RD), a secondary Regional Mental Healthcare Provider (RMHP) in the province of South-Holland, the Netherlands. Study outcomes were assessed by using self-report measures and observer-rated scales that were completed by touch-screen Routine Outcome Monitoring (ROM): at baseline measurement (T1), 3 months after baseline (T2), and at the subsequent follow-up measurements: 6 months (T3) and one year (T4) after baseline. The study aimed to determine if concise care was as effective in reducing clinical symptoms and enhancing general health outcomes as standard care. The study protocol and all procedures were approved by the local ethics committee and followed consolidated standards for reporting pragmatic trials (CONSORT- guidelines; Campbell et al. 2004; Hopewell et al. 2008; Moher et al. 2010; Zwarenstein et al. 2008). Design and results of the trial have been described in more detail elsewhere (Meuldijk et al. 2012; 2015; 2016).

PARTICIPANTS Between March 2010 and December 2012, a total of 182 patients were included in the trial. Patients, referred to the participating MHCs by their general practitioner, were considered eligible if they were aged 18-65 years and met the DSM-IV-TR criteria for a current mild to moderate depressive and/or anxiety disorder as main diagnosis (APA, 1994). Patients with suicidal or homicidal risk, severe social dysfunction, delusions, hallucinations and/or those suffering from bipolar or psychotic disorders were excluded from the trial. Insufficient knowledge of the Dutch language was another reason for exclusion. Eligible participants were randomly assigned to receive concise or standard care (control group) using an allocation ratio of 1:1. A block randomisation scheme, stratified by MHC (n = 5) and gender was used. All patients provided written informed consent before participation.

TREATMENT PROTOCOLSTreatment protocols for concise care and standard care have been described in detail elsewhere (Meuldijk et al. 2012). In brief, both concise and standard care treatment options could be augmented by choice with a selective serotonin reuptake inhibitor (SSRI) (Guy, 1976), Cognitive Behavioural Therapy (CBT) (Beck, 1995; Clark & Salkovskis, 1987) and, in case of a posttraumatic stress disorder, with Eye Movement Desensitization and Reprocessing- therapy (EMDR) (Shapiro, 1995). Combinations of the additional SSRI and EMDR treatments was also possible. The treatment protocols in both concise care and standard care followed the Dutch and international guidelines for the evidence-based treatment of depression and anxiety disorders and are presented within a stepped care framework (Davison, 2000; Haaga, 2000). Treatment protocols in concise care were confined to a maximum of 7 weekly session, within a 4-7 week time-period. ‘Stepping up’ or continuation of (standard) treatment was possible for those patients insufficiently helped by the initial treatments in concise care. In contrast, patients in standard care had unstructured access to outpatient mental health care as typically provided by the MHCs. The number of sessions, frequency, and treatment duration were kept variable. Treatment was delivered by experienced therapists working at the participating MHCs, therapists delivering concise care received additional training by the research team in the core elements of concise care (see Meuldijk et al. 2012).


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TREATMENT EFFECTIVENESSEquivalence tests demonstrated that both standard and concise care were equally successful in reducing anxiety- and depression complaints. Both intention-to-treat and per protocol analyses showed a reduction in total BSI scores at 3 months after baseline and subsequent follow-up measurements for both standard and concise care. However, a stronger (or faster) reduction in BSI scores in patients receiving concise care (vs. standard care) was demonstrated at 3 months after baseline (see Meuldijk et al. 2016) for a full description on the effectiveness of concise care compared to standard care).

MEASURESSELF- REPORT DEMOGRAPHIC AND CLINICAL PREDICTORS Prior to treatment assignment the following SOCIO-DEMOGRAPHIC VARIABLES were ascertained at the baseline ROM assessment using a self-report questionnaire: gender, age, level of education, ethnical background, employment status, and marital status. Dutch ethnic background was assumed when the patient was born in the Netherlands. Education was dichotomized into two levels: ‘low education ‘(i.e. completed only elementary school, lower general primary education, or no education at all) and ‘high education’. Marital status was dichotomized into ‘married or cohabiting’ and ‘being unmarried and living without a partner’. Employment situation was dichotomized into ‘employed’ (i.e. employed full-time or part-time, receiving education) and ‘unemployed’ (i.e. unemployed, sick leave, or retired). The predictor variable age, was dichotomized at the median (35 years) into age 18 – 35 and 36 – 65 years. The demographic variable: ‘ethnical background’ was excluded from analysis due to the small number of patients within this subgroup (n = 10). In addition, the self-report CLINICAL PATIENT CHARACTERISTICS at baseline were determined using the Web Screening Questionnaire (WSQ) (Donker et al. 2009) scores. The WSQ is a 15 item self-report questionnaire that screens for the presence of the most common mental disorders in the general population: depressive disorder, generalized anxiety disorder (GAD), panic disorder (PD) with and without agoraphobia, social phobia, specific phobia, obsessive compulsive disorder (OCD), post-traumatic stress disorder (PTSD), agoraphobia and alcohol abuse/dependence. The WSQ is a brief questionnaire (<5 min), that has proven to be reliable for screening (Donker et al. 2009). Since the number of patients being screened with any single disorder according to the WSQ was too low to run proper statistical analyses (n = 8), the number of comorbid positive screeners was dichotomized over the median of 4 positive screeners: ‘Zero to three positive screeners’ versus ‘Four or more positive screeners’.

OBSERVER-RATED CLINICAL PREDICTORSDSM-IV-TR diagnostic information was assessed at baseline by trained psychiatric nurses using the Dutch version of the MINI International Neuropsychiatric Interview-Plus (MINI-Plus 5.0.0.) (Sheehan et al. 1998; van Vliet & de Beurs, 2007). The MINI-Plus 5.0.0. has been demonstrated to have good psychometric properties, with good sensitivity and specificity (Lecrubier et al. 1997). For this study, the association between the current (i.e. within the past month) DSM-IV-TR diagnosis of mild to moderate depressive and anxiety disorders and treatment outcome was evaluated between treatment groups (concise vs. standard care). The MINI-Plus 5.0.0 DSM-IV-TR diagnoses were subcategorized into ‘depressive disorders (no anxiety)’ vs. ‘other disorders’ and any


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‘anxiety disorders (without depression)’ vs. ‘other disorders’. Mixed depressive and anxiety disorder was furthermore categorized defining patients suffering from a ‘comorbid depressive and anxiety disorder’. TABLE 1 shows the distribution of depressive and anxiety disorders in our total sample. Furthermore, the number of MINI-Plus 5.0.0 DSM-IV-TR diagnoses was dichotomized into ‘single disorder’ versus ‘multiple (i.e. two or more) disorders’.

OUTCOME MEASUREThe continuous outcome variable was the Brief Symptom Inventory (BSI; Derogatis, 1975), a patient-rated, 53-item self-report measure that assesses psychological symptoms of anxiety and depressive disorders on a 5-point Likert scale (from 0 ‘not at all’ to 4 ‘extremely’). The BSI total score was computed as the mean score of all individual items (range 0-4) and generates an overall measure of psychopathological symptom severity. Lower BSI scores correspond to less symptoms and a more beneficial outcome. The BSI has shown good internal consistency and convergent validity (de Beurs et al. 2011; Derogatis & Melisaratos, 1983).

STATISTICAL ANALYSESThe data were analysed using all 182 randomised patients, consistent with our study design (Meuldijk et al. 2012) and the overall approach of ‘intention to treat (ITT)’. Socio-demographics and clinical characteristics at baseline in patients were examined using χ2 test for categorical variables and two-sample t-tests for continuous variables. To examine the association between the demographics and clinical characteristics with changes in treatment outcome (i.e., total BSI score) during the one year study period, the between-group differences (concise vs. standard care) were assessed using multilevel regression analysis (i.e. Mixed models). To test for differential effects between each of the two subgroups, we performed linear mixed models using an unstructured covariance model, with changes in BSI scores as outcome variable and resulting effect sizes (Cohen, 1992) as the magnitude of the difference between groups. The multilevel model had an upper level (i.e., patient) and lower level (i.e., BSI values assessed at up to 4 time points; i.e., baseline, 3, months, 6 months and 1 year). The interaction terms between each subgroup characteristic × time (as a continuous variable) were tested. All models were adjusted for baseline BSI scores. Only patient samples of n > 25 were considered large enough to detect clinically relevant differences among subgroups. All p-values were considered statistical significant at the level of p-value < 0.05. Data analyses were performed using SPSS for Windows, Version 20.

RESULTS BASELINE CHARACTERISTICS AND DROP-OUTDemographics for randomised patients are presented in TABLE 1. In general, the randomised sample was mainly of Dutch origin (n = 167; 94%), female (n = 111; 61%), higher educated (n = 109; 62%), and employed (n = 90; 51%). Age was on average 36.5 years (SD 12.3), and 53% of the participants were married at the time of the baseline measurement. The mean BSI baseline scores (total BSI score) between groups (concise care: 1.29 (SD: 0.76); standard care: 1.24 (SD:0.24)) were all higher than the cut-off value (95th percentile) of 0.68 (Schulte-van Maaren et al. 2012). There were no significant differences between the randomised groups at baseline with respect to clinical


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or demographic characteristics (all p’s > 0.05; see Table 1). Of the 182 subjects randomised, 102 (57%) completed the 3-month (T2) assessment, 65 (36%) completed the 6 month (T3) assessment and 42 (23%) completed the one year (T4) follow-up assessment. A complete analysis of attrition/missing data in these patients demonstrated no significant differences between subject characteristics for the randomised sample and those who did not provide data after the baseline measurement. These results have been presented previously in the report on the effectiveness trial (Meuldijk et al. 2016).

TABLE 1. SOCIO-DEMOGRAPHIC AND CLINICAL CHARACTERISTICS OF THE STUDY SAMPLE AT BASELINE

MEASUREMENT.

Total Intention-to-Treat/Randomised Sample

Standard care Concise care

Baseline characteristics n = 182 n = 89 n = 93 p - value

Socio-demographic characteristicsa

Age group (years): mean [SD], IQR 36.5 (12.3) 25- 46 37.0 (12.0) 26-48 36.0 (12.7) 25-45 0.59

Gender

Female 111 (61%) 53 (60%) 58 (62%) 0.81

Educational status

Lower education 68 (38%) 34 (38%) 34 (39%) 0.99

Higher education 109 (62%) 55 (62%) 54 (61%

Employment status

Employed 90 (51%) 49 (55%) 41 (47%) 0.33

Unemployed/retired 87 (49%) 40 (45%) 47 (53%)

Marital status

Married/Cohabitating 93 (53%) 42 (47%) 51 (58%) 0.20

Clinical characteristicsb

Depression (without anxiety)c 39 (22%) 22 (25%) 17 (18%) 0.36

Anxiety (without depression)c 51 (28%) 22 (25%) 29 (16%) 0.45

Comorbid depression and anxietyc 31 (17%) 14 (16%) 17 (18%) 0.82

Other DSM-IV-TR diagnosisd 26 (14%) 11 (12%) 15 (16%) 0.61

No current DSM-IV- TR diagnosise 34 (19%) 19 (22%) 15 (16%) 0.45

Number of positive WSQ screens

Zero to three screens 101 (57%) 48 (55%) 53 (58%) 0.79

Four or more screens 77 (43%) 39 (45%) 38 (42%)

Number of MINI-Plus diagnosisf

Single diagnoses 125 (69%) 62 (34%) 63 (35%) 0.82

Two or more diagnoses 56 (31%) 26 (14%) 30 (17%)

BSI total score: mean [SD], IQR 1.27 (0.69) 0.74-1.64 1.24 (0.60) 0.81-1.55 1.29 (0.76) 0.68-1.89 0.59

Categorical variables are presented as n (percentage), continuous variables are presented as mean (±standard deviation [SD]), interquartile range (IQR). The MINI International

Neuropsychiatric Interview-Plus 5.0.0. (MINI-Plus) was used to collect diagnostic information. DSM- IV-TR=Diagnostic and Statistical Manual of Mental Disorders, fourth edition –

text revision; WSQ=Web Screening Questionnaire 15 item version; BSI=Brief Symptom Inventory 53 item version.

aDemographic data are missing for 5 participants. bClinical characteristics/DSM-IV-TR diagnosis was missing for 1 participant. cComorbidity with other than anxiety and/or

depressive DSM-IV-TR diagnoses was allowed. dOther DSM-IV-TR diagnosis indicates patient with no diagnosis of anxiety or depressive disorders (i.e. somatoform , adjustment

disorders, alcohol dependence and/or substance abuse). eDenotes patients who did not pass the threshold for having a current Axis- I DSM-IV-TR diagnosis according to the

MINI-Plus interview. However, these patients did seek professional help for their (subthreshold) depressive and/or anxiety complaints or symptoms. fNumber of current MINI-Plus

diagnosis irrespective of what disorder.


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DEMOGRAPHIC VARIABLESThe difference in BSI outcome scores of concise versus standard care for demographic variables, examined independently, are demonstrated in Table 2. No significant differences were found for any of the demographic characteristics for the observed between group differences in reduction in BSI scores (concise versus standard care) from baseline to one year follow-up (all p’s > 0.05).

TABLE 2. SELF- REPORT DEMOGRAPHIC PREDICTORS.

Difference in BSI scores per year for concise versus standard treatment (range -0.5 to 1.5). Effect sizes represents the standardized mean differences in BSI scores for patients in

concise care compared to standard care (i.e. standard care is reference category). Negative scores represents reduction of psychopathological symptoms; -0.5 is a 50% reduction

in total BSI scores. *Significant as p <0.05.aDemographic data are missing for 5 participants.

CLINICAL VARIABLES TABLE 3 demonstrates the interactions between the independent clinical variables and treatment group for the outcome measure BSI. No significant interaction terms with treatment allocation were found for the subgroups with any ‘depression (without anxiety)’ (p = 0.43) and with ‘comorbid depression and anxiety’ (p = 0.33). In addition, the presence of any ‘anxiety (without depression)’, showed a statistically significant interaction term with treatment allocation (p = 0.01). These findings indicate that patients with any anxiety disorder without depressive disorder showed significantly less improvement when receiving concise care compared to standard care (ES = 0.142, CI:-0.259 - 0.543 vs. ES = -0.632, CI:-0.982 - 0.283). Furthermore, no significant interaction terms with treatment allocation were found for any of the other subgroups based on WSQ (p = 0.81) or MINI-Plus variables (p = 0.26).


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TABLE 3. CLINICAL SELF-REPORT AND OBSERVER-RATED PREDICTORS.

Difference in BSI scores per year for concise versus standard treatment (range -0.5 to 1.5). Effect sizes represents the standardized mean differences in BSI scores for patients in

concise care compared to standard care (i.e. standard care is reference category). Negative scores represent reduction of psychopathological symptoms; -0.5 is a 50% reduction in

total BSI scores. *Significant as p < 0.05.

aClinical characteristics/DSM-IV-TR diagnosis was missing for 1 participant. bComorbidity with other than anxiety and/or depressive DSM-IV-TR diagnoses was allowed. cNumber

of current MINI-Plus diagnosis irrespective of what disorder

DISCUSSIONThis study aimed to identify potential predictors of positive response to concise forms of psycho- and/or pharmacotherapy (so called ‘concise care’) versus standard care among a group of psychiatric outpatients with mild to moderate anxiety and/or depressive disorders referred to secondary mental health care. In contrast to the socio-demographic characteristics that did not have differentiating power, the clinical characteristics of anxiety disorders were associated with a less favourable treatment outcome of concise care as compared to depressive disorders with or without anxiety disorders. As far as we know our study is unique in the type of comparison we made. We did not compare one specific treatment with another; neither did we restrict the evaluation to a single disorder. We compared a mix of patients with depressive and/or anxiety disorders who could be treated with various types of psycho- and pharmacotherapy, just as the patient and their therapist preferred. The only difference was that one group got the treatments in a more concise form than is usual provided, while the other group, the standard group, received treatment in the usual way. Therefore it is inapplicable to compare the predictors we found directly with those of previous studies. The sparse literature on the prediction to outcome to short-term therapies has mainly assessed the prediction of socio-demographic factors (Joutsenniemi et al. 2012; Lindfors et al. 2014) in study samples with either a depressive (Frank et al. 2002; Sotsky et al. 1991) or anxiety disorder (Crits-Christoph et al. 2004; Ehlers et al. 2005) among RCTs. Besides, the large variation in


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methodology limits the comparability of these previous studies (Jakubovski et al. 2013; Laaksonen et al. 2013; Laaksonen et al. 2014; Lindfors et al. 2014). Nevertheless, previous study findings can be used to place our findings in perspective. Our finding that anxiety (without depressive) disorders were associated with a less favourable (or less rapid) treatment outcome are in line with findings from studies examining the course trajectory of anxiety disorders in primary care (Ormel et al. 1993; Penninx et al. 2011), as anxiety disorders showed a more chronic course and a longer mean time to remission, as compared to depressive disorders. Other clinical trials and naturalistic cohort studies similarly revealed that a chronic clinical course of anxiety disorders is common (Keller & Hanks, 1993; Keller, 2003; 2006; Pollack & Otto, 1997; Tiemens et al. 1996). According to the literature, patients with anxiety disorders exhibited greater overall psychopathology (Angst & Vollrath, 1991; Bruce et al. 2005, Rhebergen et al. 2011; Yonkers et al. 2000) and require a more comprehensive treatment approach; with a longer duration (Cuijpers et al. 2013; Lewis et al. 2008; Penninx et al. 2011). In addition, our findings are also consistent with studies that reported larger beneficial effects in depressed patients when briefer forms of psychotherapy were compared to standard care of longer duration (Abbass et al. 2014; Bressi et al. 2010; Driessen et al. 2013; Leichsenring et al. 2004). However, more large, high-quality, pragmatic RCTs, are necessary to assess the effectiveness of the short-term variants of psychotherapy as first-step in the stepped care treatment in secondary mental health care, and whether its effects differ between patients with depressive and anxiety disorders. There are several strengths in this study. Data was collected in a naturalistic setting and has more accuracy in reflecting ‘real-world’ daily clinical practice in contrast to clinical trials, as only patients with severe disorders were excluded. The pragmatic design maximizes external validity and generalizability of the study results. In addition, as opposed to most previous studies, we were able to assess both socio-demographic and clinical factors in one study in a sample of patients with depressive and anxiety disorders. Several limitations of this study need to be noted. We studied a relatively short-term outcome of treatment (1-year follow-up), meaning that the identified predictors are not per se also predictors of long-term treatment outcome of concise care. Another limitation of this study was that the overall sizes of the subgroups were relatively small, which may have hindered the observation of some differences. The high percentages of drop-out should be noticed and one must be cautious in drawing firm conclusions from subgroups. Further analysis in larger subgroups might yield different results. Besides, since we limited our subgroup analysis to socio-demographic and clinical patient characteristics, further study on the issue of how personality factors modifies the effects on the outcome to concise care is needed. Furthermore, selection in the process of referral to the trial and the relatively large attrition, may also have introduced bias. However, despite the small sample size, we were able to identify a clinical predictor in this study sample.

CONCLUSIONThis study produced further evidence on the importance of taking into account the clinical patient characteristics in the selection of patients for concise format of psycho- and/or pharmacotherapy. While further research overcoming the limitations of the current study with a sufficiently long follow-up, are necessary to confirm our the results described here, the identification of clinical


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patient characteristics as predictor of patients most likely to benefit from concise care represents an important first step in improving the concise treatment for depressive and/or anxiety disorders in secondary mental health care. More research is, however, still needed to increase the current understanding of the extent to which socio-demographic and clinical factors predict the results for different types of psycho- and pharmacotherapy of different lengths.

ROLE OF FUNDING SOURCEThis research was funded by Rivierduinen (RD), who had no role in conducting the research or in writing and submitting the report.

CONFLICT OF INTERESTNone of the authors have a conflict of interest related to the findings within the submitted manuscript.

CONTRIBUTORSAll authors were actively involved in the design of the study, the analytical method of the study, the selection and review of all scientific content. The statistical analyses were done by DM and EG. All authors contributed to the interpretation of the data and drafting of the report, DM was responsible for writing the manuscript. All authors have approved the final report.

ACKNOWLEDGMENTSThe authors thank all the patients participating in this study and the staff at RD, which includes psychiatrists, psychologists, psychiatric test nurses and secretary for their help in recruiting them and for their contribution to this research. This study was a collaboration between RD and the department of Psychiatry of the LUMC and is funded entirely by RD.


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Chapter 6A Validation Study of the Web Screening Questionnaire

(WSQ) compared to the Mini- International Neuropsychiatric Interview Plus (MINI-Plus)

Submitted as:Meuldijk D, Giltay EJ, Carlier IVE, van Vliet IM, van Hemert AM, Zitman FG. A validation study of the Web Screening Questionnaire (WSQ) compared

to the Mini- International Neuropsychiatric Interview Plus (MINI-Plus)


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ABSTRACT BACKGROUNDThere is a need for brief screening methods for psychiatric disorders in clinical practice. Therefore, we assessed the accuracy of a brief self-report screening questionnaire, the Web Screening Questionnaire (WSQ), in detecting psychiatric disorders in a group composed of the general population and psychiatric outpatients.

OBJECTIVETo investigate whether the Web Screening Questionnaire (WSQ) is an adequate test to screen for the presence of depressive and anxiety disorders in clinical practice.

METHODSParticipants were 1292 adults (1117 subjects from the general population and 175 psychiatric outpatients), aged 18 to 65 years. The discriminant characteristics of the WSQ were examined in relation to ‘gold standard’ Mini-International Neuropsychiatric Interview-Plus (MINI-Plus) disorders, using sensitivity, specificity, area under the curve (AUC), positive and negative predictive values.

RESULTSThe specificity of the WSQ to detect depressive disorders, anxiety disorders and alcohol abuse/dependence individually ranged from 0.89 to 0.97 for most disorders, with the exception of posttraumatic stress disorder (0.52) and specific phobia (0.73). The sensitivity values ranged from 0.67 to 1.00, with the exception of depressive disorder (0.56) and alcohol abuse/dependence (0.56). Given the low prevalence of separate disorders in the general population, negative predictive values were extremely high across the disorders (≥ 0.97) whereas positive predictive values were variable and low (range 0.02 to 0.47).

CONCLUSIONS The findings demonstrate that the WSQ is reliable screening tool to identify patients without a depressive and anxiety disorders in clinical practice, as it accurately identified those unlikely to suffer from these disorders (except for post-traumatic stress disorders and specific phobias). In case of a positive WSQ screening result, further diagnostic procedures are required.


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INTRODUCTIONStructured Diagnostic interviews like the Composite International Diagnostic Interview (CIDI) (World Health Organization, 1990) and the Structured Clinical Interview for DSM-III-R (SCID) (Spitzer et al. 1992) are gold standards to diagnose psychiatric disorders in research (Basco et al. 2000; Robins et al. 1988; World Health Organization, 1990). They are less suitable for clinical practice because their administration is time-consuming and they can only be administered by well-trained interviewers (Kessler & Ustun, 2004). The Mini-International Neuropsychiatric Interview-Plus (MINI-Plus) (Sheehan et al. 1998) is a much shorter diagnostic interview with diagnostic properties that are to a large extent similar to de CIDI (Lecrubier et al. 1997; Sheehan et al. 1998). However, the MINI-Plus also requires trained interviewers and takes up to 30 minutes to complete, which may make it costly for routine use in clinical practice. The Web Screening Questionnaire (WSQ) (Donker et al. 2009) has been developed to quickly screen for common psychiatric disorders (i.e. anxiety and depressive disorders, alcohol abuse/dependence). This self-report screening questionnaire consists of only 15 items and requires less than 5 minutes to complete. The WSQ has proven to be a valid screener for social phobia, panic disorder with agoraphobia, agoraphobia (without panic disorder), obsessive compulsive disorder (OCD) and alcohol abuse/dependence (sensitivity ranges from 0.72 to 1.00; and specificity ranges from 0.63 to 0.80) (Donker et al. 2009). Slightly more modest psychometric properties were reported for depressive disorder, generalised anxiety disorder (GAD), post-traumatic stress disorder (PTSD), specific phobia and panic disorder (without agoraphobia). I.e. sensitivity ranged from 0.80 to 0.93 and specificity ranged from 0.44 to 0.51 (Donker et al. 2009). These data reflect the validation of the WSQ compared to CIDI diagnoses ascertained in the general population with 6- month prevalence rates of DSM-IV-TR diagnoses (The Diagnostic and Statistical Manual, 4th edition, text revision) (American Psychiatric Association, 1994). Since the WSQ screens for current symptoms (Donker et al. 2009) it is relevant to test the WSQ against current DSM-IV diagnoses. In this paper we report the usefulness of the WSQ as screener against 1-month prevalence MINI-Plus disorders covered by the WSQ. The study was carried out in a large general population sample recruited from primary care registrations. We enriched the general population sample with a smaller sample of psychiatric outpatients to increase the prevalence of psychiatric disorders.

METHODSSAMPLEFor the analyses we combined a general population and a clinical sample. The participants from the general population were recruited between November 2009 and January 2011 from the administration of eight university-affiliated general practices in the vicinity of Leiden, the Netherlands. As in the Netherlands nearly 100% of the population is registered with a general practitioner, the primary care sample is equivalent to a general population sample (Boerma et al. 1997; Schafer et al. 2010). Exclusion criteria were: 1) treatment in a secondary psychiatric care centre in the last six months for psychiatric problems and/or dependence on alcohol or drugs; 2) hearing impairment, limited cognitive abilities such as aphasia, severe dyslexia or dementia; 3) illiteracy or insufficient mastery of the Dutch language and 4) a terminal disease. The initial study was designed to generate reference values in primary care for questionnaires used in the assessment of psychopathology. This study is described in detail by Schulte-van Maaren and


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colleagues (2013) (Schulte-van Maaren et al. 2013). Here we focus on the main aspects relevant for the current study. The general population sample was enriched with a sample of 182 secondary care outpatients, who had originally been recruited for a pragmatic randomised controlled trial (RCT) of equivalence, in which also the WSQ and the MINI-Plus were assessed at baseline. This study is described in more detail by Meuldijk and colleagues (2012) (Meuldijk et al. 2012). The trial was conducted at five outpatient Mental Health Clinics (MHCs) in and around Leiden of Rivierduinen (RD), a secondary Regional Mental Health Provider (RHMP) in the province of South-Holland, the Netherlands, between March 2010 and December 2012. Eligible participants were patients aged 18 through 65 years, referred to the MHCs by their general practitioner (GP) for the treatment of a current mild to moderate anxiety- and/or depressive disorder, including depressive disorder, dysthymia, panic disorder (with or without agoraphobia), social phobia, specific phobia, generalized anxiety disorder, obsessive compulsive disorder and posttraumatic stress disorder. Exclusion criteria were 1) suicidal or homicidal risk, 2) delusions, hallucinations, bipolar or psychotic disorder, 3) severe social dysfunction and/or 4) insufficient knowledge of the Dutch language. The study protocol for both samples was approved by the Medical Ethical Committee of the Leiden University Medical Centre (LUMC). In both samples the assessment included among others, the MINI-Plus and the WSQ. Of the initial population sample of 1302 participants, 185 had incomplete WSQ data, leaving 1117 participants for inclusion in the analysis. Of the outpatient sample of 182 patients 6 had incomplete WSQ data and 1 MINI-Plus interview was incomplete, leaving 175 outpatients. The combined sample for the current study consisted 1292 subjects.

WEB SCREENING QUESTIONNAIRE (WSQ)The Web Screening Questionnaire (WSQ) (Donker et al. 2009) is a 15 item self-report instrument that screens for depressive disorder, generalized anxiety disorder (GAD), panic disorder with and without agoraphobia, social phobia, specific phobia, obsessive compulsive disorder (OCD), post-traumatic stress disorder (PTSD), agoraphobia and alcohol abuse/dependence (Donker et al. 2009). The WSQ is based on the screening questionnaire (SQ) of Marks and colleagues (Gega et al. 2005). Compared to 6-months CIDI diagnoses, the WSQ has moderate to good screening properties (sensitivity 0.72 to 1.00; specificity 0.44 to 0.80) in the general population (Donker et al. 2009). See SUPPLEMENTARY MATERIAL for full questionnaire.

MINI-INTERNATIONAL NEUROPSYCHIATRIC INTERVIEW-PLUS The Mini-International Neuropsychiatric Interview-Plus (MINI-Plus) 5.0.0, Dutch version (Sheehan et al. 1998), was used as the ‘gold standard’ reference. The MINI-Plus is a structured diagnostic interview used to determine most common psychiatric disorders according to axis 1 DSM-IV-TR (American Psychiatric Association, 1994) and the International Classification of Diseases and Related Health Problems (ICD-10) (Sheehan et al. 1998). In the current study, we used the diagnoses of the mood disorders (depression and dysthymia) and anxiety disorders (panic disorder with or without agoraphobia, agoraphobia, social phobia, specific phobia, GAD, PTSD (type I or single trauma) and OCD) and alcohol abuse/dependence. The MINI-Plus has good psychometric properties and is widely used to support diagnostics in psychiatry. The MINI-Plus


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was conducted by trained research nurses. Since the WSQ screens for current diagnoses we only used 1-month MINI-Plus.

STATISTICAL ANALYSESThe discriminant function of the WSQ was assessed for each of the MINI-Plus Axis 1 DSM-IV-TR disorder for which it screens, using sensitivity, specificity, Receiver Operating Characteristics (ROC) curve (AUC) (Hanley & Lippman-Hand, 1983) and positive (PPV) and negative (NPV) predictive values (PPV). Specificity was calculated as the proportion of patients who did not have the MINI-plus diagnosis who had a negative WSQ screen. Sensitivity as the proportion of patients with a MINI-Plus psychiatric diagnosis who had a positive WSQ screen for the same disorder. The AUC, interpreted as the probability that a randomly selected clinical case will score higher on the test than a non-case, is not sensitive to prevalence and has been proposed to correct this problem (Cohen, 1960). It can range from 0.50 (worthless test) to 1.00 (perfect test). Following Agresti (2002) (Agresti, 2002) we considered the AUC to be of excellent evidence of concordance if ≥ 0.90, good evidence of concordance if between 0.80 and 0.90, acceptable although only average if between 0.70 and 0.80 and poor if below 0.70. Positive predictive value (PPV) was calculated as the percentage of patients with a positive test on the WSQ who actually had the disorder according to the MINI-Plus diagnosis, while the negative predictive value (NPV) was calculated as the percentage of patients with a negative test who did not have the disorder, according to the MINI-Plus. Since the PPV and the NPV strongly depend on the prevalence of the disorder, we calculated these indices on general population sample, without the enrichment. Otherwise, findings would be artificially inflated. Further, WSQ cut-off scores were chosen as originally recommended by Donker and colleagues (Donker et al. 2009) and slightly adapted to fit within Routine Outcome Monitoring (ROM), a monitoring system for psychiatric patient care (de Beurs et al. 2011). All analyses were conducted using IBM SPSS version 20.0 for Windows.

RESULTSDEMOGRAPHICS AND PREVALENCE OF DSM-IV-TR DIAGNOSESCharacteristics of the two samples included in the study are presented in TABLE 1. The mean age of the total sample was 39.6 (range 18- 65, SD 12.6) years, and the 61% of patients were female. Most participants were of Dutch origin (95%) and higher educated (76%). The majority (78%) of the participants was employed and 67% were married at the time of the baseline measurement. The demographics were similar for the sample from the general population and from secondary care. In the combined study sample, 79 patients (6%) met DSM-IV-TR MINI-Plus criteria for a current (i.e. within the past month) depressive (with or without anxiety) disorder. Of the sample, 139 patients (11%) met the criteria for an anxiety with or without depressive disorder. These patients were diagnosed according to the common subtypes of anxiety as indicated in TABLE 2. Fifty-five patients (4%) met the criteria for current alcohol abuse/dependence disorder. The majority of the study sample (n = 934, 72%) did not pass the threshold for a current MINI-Plus diagnosis.


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TABLE 1. SOCIO-DEMOGRAPHIC AND CLINICAL CHARACTERISTICS OF THE STUDY SAMPLE (N = 1292) AT BASELINE MEASUREMENT.

General population sample Outpatient sample Total Study sample

Baseline characteristics n = 1117 n = 175 n = 1292

Socio-demographicsa

Age (years): mean (SD) 40.04 (12.53) 36.67 (12.40) 39.6 (12.56)

Gender

Female 712 64% 70 40% 782 61%

Ethnical backgroundb

Dutch 1116 95% 160 91% 1223 95%

Other 53 5% 10 6% 63 5%

Educational statusc

Lower education 250 22% 64 37% 314 24%

Higher education 866 78% 106 61% 972 76%

Employment status

Employed 914 82% 85 49%% 999 78%

Unemployed/retired 202 18% 85 49% 287 22%

Marital status

Married/Cohabitating 766 69% 89 51% 855 67%

Clinical characteristics/MINI-Plus Diagnosisd

Depressive (with or without anxiety) disorder 12 1% 67 39% 79 6%

Anxiety (with or without depressive) disorder 60 5% 79 45% 139 11%

Panic disorder (without agoraphobia) 4 0.4% 24 14% 28 2%

Agoraphobia 27 2% 37 21% 64 5%

Panic disorder with agoraphobia 2 0.2% 18 10% 20 2%

Social phobia 10 1% 9 5% 19 2%

Specific phobia 9 1% 3 2% 12 1%

Generalized anxiety disorder 13 1% 22 13% 35 3%

Posttraumatic stress disorder 5 0.4% 14 8% 19 2%

Obsessive compulsive disorder 6 0.5% 3 2% 9 1%

Alcohol abuse/dependence 51 5% 4 2% 55 4%

No current DSM-IV- TR diagnosise 902 81% 32 18% 934 72%

Categorical variables are presented as n (percentage), continuous variables are presented as mean (±standard deviation [SD]). The MINI International Neuropsychiatric Interview-

Plus 5.0.0. (MINI-Plus) was used to collect diagnostic information. DSM-IV-TR=Diagnostic and Statistical Manual of Mental Disorders, fourth edition – text revision.

aDemographic data; ethnic background, educational status and employment status are missing for respectively 6 participants (one participant from the general population

sample; 5 outpatients). bDutch ethnic background was assumed when the participant was born in the Netherlands. cLower education= having completed elementary school,

lower general primary education or no education at all; higher education= more than lower education (includes university). dClinical characteristics/diagnosis were missing for 1

participant. e Denotes participants who did not pass the threshold for having a current Axis- I DSM-IV-TR diagnosis according to the MINI-Plus interview.

Note: Participants may have more than one diagnosis, comorbidity was allowed.


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TABLE 2 AGREEMENT BETWEEN THE MINI-PLUS AND THE WSQ FOR INDIVIDUAL DISORDERS IN THE STUDY SAMPLE

(N = 1292)

DSM-IV-TR diagnosis MINI prev. (%) WSQ prev. (%) True Pos. False Pos. False Neg. True Neg. Specificity Sensitivity AUC (95% CI)

Depressive disorder 6.1% 8.9% 46 69 33 1144 0.94 0.58 0.83 (0.68 – 0.98)

Panic disorder 2.2% 13.2% 28 142 0 1122 0.89 1.00 0.98 (0.96 – 1.00)

Agoraphobia 5.0% 8.6% 52 59 12 1169 0.95 0.81 0.80 (0.69 – 0.91)

Panic disorder with agoraphobia 1.5% 4.7% 18 43 2 1229 0.97 0.90 0.99 (0.98 – 1.00)

Social phobia 1.5% 7.8% 15 86 4 1187 0.93 0.79 0.95 (0.92 – 0.99)

Specific phobia 0.9% 28.1% 12 351 0 929 0.73 1.00 0.93 (0.89 – 0.97)

Generalized anxiety disorder 2.7% 11.2% 23 122 12 1135 0.90 0.66 0.89 (0.79 – 0.99)

Posttraumatic stress disorder 1.5% 48.1% 15 606 4 667 0.52 0.79 0.86 (0.74 – 0.98)

Obsessive compulsive disorder 0.7% 9.3% 6 114 3 1169 0.91 0.67 0.82 (0.59 – 1.00)

Alcohol abuse/dependence 4.3% 9.4% 31 90 24 1147 0.93 0.56 0.82 (0.75 – 0.88)

DSM- IV-TR=Diagnostic and Statistical Manual of Mental Disorders, fourth edition – text revision. MINI-Plus=The MINI International Neuropsychiatric Interview-Plus 5.0.0.

WSQ=Web Screening Questionnaire. AUC=Area Under the Curve; CI=Confidence Interval

Note: Numbers in the table reflect the use of each screening subscale to detect any diagnosis, rather than only the diagnosis associated with the subscale. WSQ cut-off scores

were derived from the original cut-offs recommended by Donker and colleagues (2009). WSQ cut-off scores: Depression: Q1≥ 5 & Q2=1; Panic disorder: Q4 ≥1; Agoraphobia:Q5=1;

Panic disorder with Agoraphobia Q4 ≥1 & Q5=1; Social phobia: Q8=1 & Q9=1; Q5=1; Specific phobia: Q6 or Q7=1; GAD: Q3≥2; Social phobia: Q8=1 & Q9=1; PTSD: Q10=1 or

Q11=1; OCD: Q12≥1; Alcohol Abuse Dependence : Q13≥2 & Q14≥3.

CONCORDANCE BETWEEN MINI-PLUS AND WSQ Concordances between each diagnosis classified according to the DSM-IV-TR with the MINI-Plus and the WSQ questionnaire are presented in TABLE 2. Specificity was high (range 0.89 to 0.97) for most individual disorders, with the exception of specific phobia (0.73) and post-traumatic stress disorder (0.52). Sensitivity was substantial to high (0.67 to 1.00) for the majority of disorders. The exceptions were depressive disorder (0.58) and alcohol abuse/dependence (0.56). All AUC values were good to excellent (≥ 0.82) for individual disorders. The best discriminating subscale was panic disorder with agoraphobia (AUC = 0.99), followed by panic disorder (AUC = 0.98) and social phobia (AUC = 0.95). In FIGURE 1 the discriminative power of each subscale of the WSQ is depicted graphically. Positive and negative predictive values are given in TABLE 3. These indices were calculated for the general population sample only, because of the strong relation to the prevalence of the disorders. Despite generally strong discriminative power, the positive predictive value was poor and varied from 0.01 (PTSD) to 0.33 (agoraphobia). Negative predictive values were uniformly high (≥ 0.97) for all scales.


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FIGURE 1. DISTRIBUTION OF THE MINI-PLUS DIAGNOSIS FOR THE CORRESPONDING WSQ SUBSCALES IN THE STUDY

SAMPLE (N = 1292).

MINI-Plus=The MINI International Neuropsychiatric Interview-Plus 5.0.0. WSQ=Web Screening Questionnaire. Note: WSQ cut-off scores were derived from the original cut-offs

recommended by Donker and colleagues (2009). WSQ cut-off scores: Depression: Q1≥ 5 & Q2=1; Panic disorder: Q4 ≥1; Agoraphobia:Q5=1; Panic disorder with Agoraphobia

Q4 ≥1 & Q5=1; Social phobia: Q8=1 & Q9=1; Q5=1; Specific phobia: Q6 or Q7=1; GAD: Q3≥2; Social phobia: Q8=1 & Q9=1; PTSD: Q10=1 or Q11=1; OCD: Q12≥1; Alcohol Abuse/

Dependence : Q13≥2 & Q14≥3.

TABLE 3. PREDICTIVE VALUE OF THE WSQ FOR INDIVIDUAL DISORDERS ACCORDING TO THE MINI-PLUS IN THE

GENERAL POPULATION (N = 1117).

DSM-IV-TR diagnosis MINI prev. (%) WSQ prev. (%) True Pos. False Pos. False Neg. True Neg. PPV NPV

Depressive disorder 1.1% 2.5% 6 22 6 1083 0.21 0.99

Panic disorder 0.4% 5.7% 4 60 0 1053 0.06 1.00

Agoraphobia 2.4% 4.7% 17 35 10 1055 0.33 0.99

Panic disorder with agoraphobia 0.2% 1.0% 2 9 0 1106 0.18 1.00

Social phobia 0.9% 4.2% 7 40 3 1067 0.15 1.00

Specific phobia 0.8% 25.2% 9 272 0 836 0.03 1.00

Generalized anxiety disorder 1.2% 4.1% 8 38 5 1066 0.17 1.00

Posttraumatic stress disorder 0.4% 45.7% 5 506 0 606 0.01 1.00

Obsessive compulsive disorder 0.5% 4.9% 4 51 2 1060 0.07 1.00

Alcohol abuse/dependence 4.6% 9.8% 28 82 23 984 0.25 0.98

DSM- IV-TR=Diagnostic and Statistical Manual of Mental Disorders, fourth edition – text revision. MINI-Plus=The MINI International Neuropsychiatric Interview-Plus 5.0.0.

WSQ=Web Screening Questionnaire. PPV=positive predictive value; NPV=negative predictive value.

Note: Numbers in the table reflect the use of each screening subscale to detect any diagnosis, rather than only the diagnosis associated with the subscale. WSQ cut-off scores

were derived from the original cut-offs recommended by Donker and colleagues (2009). WSQ cut-off scores: Depression: Q1≥ 5 & Q2=1; Panic disorder: Q4 ≥1; Agoraphobia:Q5=1;

Panic disorder with Agoraphobia Q4 ≥1 & Q5=1; Social phobia: Q8=1 & Q9=1; Q5=1; Specific phobia: Q6 or Q7=1; GAD: Q3≥2; Social phobia: Q8=1 & Q9=1; PTSD: Q10=1 or

Q11=1; OCD: Q12≥1; Alcohol Abuse/Dependence : Q13≥2 & Q14≥3.

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DISCUSSIONIn this study we evaluated the feasibility of the WSQ to screen for DSM-IV-TR diagnoses of depressive disorder, anxiety disorders and alcohol abuse/dependence. Overall, the results showed that for the majority of the WSQ subscales, it correctly identified patients who are unlikely to have a diagnosis according to the MINI-Plus. However, if the WSQ indicates that a disorder might be present further examination is warranted. The findings regarding sensitivity and specificity demonstrated that the WSQ measures what it is supposed to measure, as it has high accuracy. Sensitivity and specificity were mostly in the excellent range and good to excellent AUC values were observed. The high specificity of the WSQ suggests that is a desirable screening for confirmatory diagnoses. Its high sensitivity suggests that the WSQ may be a tool to confirm the absence of most of these diagnoses, i.e. ruling out disorders. Exceptions are depressive disorder, specific phobia, PTSD and alcohol abuse/dependence, for which the agreement was lower. Overall, the WSQ successfully distinguishes between patients with a MINI-Plus diagnosis and patients without such a diagnosis. When we examined the PPV and NPVs in our general population sample, NPVs were high, PPVs were rather low relative to the MINI-Plus. However, positive and negative predictive values are directly related to the prevalence of the disease in the population. Assuming all other factors remain constant, PPV will increase with increasing prevalence; and NPV decreases with increase in prevalence. Together with the results reported by Donker and colleagues (Donker et al. 2009) who found AUCs from 0.65 to 0.83 in their validation of the WSQ against DSM-IV-TR diagnoses made with the CIDI in the general population, these results indicate that the WSQ can be useful as screener. Our findings are in line with previous validation studies of brief screening tools against longer ones also showing the feasibility of these short screening instruments. This applies, for example, for the Psychiatric Diagnostic Screening Questionnaire (PDSQ) in outpatients (Zimmerman and Mattia, 2001) and the Mental Health Inventory 5 (MHI-5) and the Anxiety and Depression Detector (ADD) for primary care study populations (Cuijpers et al. 2009; Means-Christensen et al. 2006; Rumpf et al. 2001).

STRENGTHS AND LIMITATIONSThe most obvious strength of this study was the large number of patients included. A further strength is that our MINI-Plus data allowed the determination of WSQ concordance against last month DSM-IV-TR diagnoses, whereas a previous study by Donker and colleagues (2009) (Donker et al. 2009) used 6-month prevalence rates. A limitation of our study is that the GP practices included were affiliated with a university hospital. As those practices in general are more focused on research and training than non-affiliated practices, this may have introduced a bias in the study population. It is likely that we selected an overly healthy normal population, since the prevalence of psychiatric disorders in our general population sample was substantially lower than expected from population-based surveys in the Netherlands (Bijl et al. 1998; de Graaf et al. 2012). As a result the NPV estimates may have been too high and the PPV too low. Our findings with regard to predictive value must be considered as extremes, given a very low prevalence of disorders. Our estimates of the sensitivity, specificity and AUC are not affected by this limitation.


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A final limitation to be considered is that our sample was limited to Dutch speaking people able to write. Illiterate or non-Dutch speaking people were excluded from the study. This may have limited the generalizability of our results, especially across different immigrant groups.

CONCLUSIONSThe WSQ is a short questionnaire to screen for depression, GAD, panic disorder with and without agoraphobia, social phobia, specific phobia, OCD, PTSD, and alcohol abuse/dependence. In earlier studies it proved useful in the general population to screen for the 6-months prevalence for these disorders with the CIDI as gold standard (Donker et al. 2009). In our study we showed the same with the 1-month prevalence of these disorders in the MINI-Plus in a general practice population, enriched with psychiatric outpatients. Taken together, the results indicate that the WSQ could be useful in situations in which the prevalence of these disorders is low. It appears to have potential as a tool in a two-step diagnostic approach, for example in primary care. It could assist health care providers in screening their patients prior to consultation. Patient screening positive should be included for more extensive diagnostic procedures, whereas a negative screen indicates that it highly unlikely that further evaluation will be useful. With such an approach diagnostic accuracy could be increased, while costly diagnostic procedures can be limited.

ACKNOWLEDGEMENTSThis is a collaborative study between Rivierduinen (RD) and the department of Psychiatry of the Leiden University Medical Centre (LUMC) and is funded entirely by RD.

CONFLICTS OF INTERESTNone declared.


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SUPPLEMENTARY MATERIAL CHAPTER 6. WEB SCREENING QUESTIONNAIRE (WSQ)

Q Web Screening Questionnaire for common mental disorders (WSQ) Subscale from

1 Circle a number from the scale below to show how much you are troubled by feeling miserable or depressed: Depres. SQ Hardly at Slightly disturbing/ Definitely disturbing/ Markedly d is tu rb ing / Very severely

all not really/disabling disabling disabling disturbing/d isab l ing

(0) (1) (2) (3) (4) (5) (6) (7) (8)

2 Do you experience a loss of interest and/or pleasure in most things, like work, hobbies and Yes (1) No (0) Depres. CIDI

other things you usually enjoy? other things you usually enjoy? 3 During the past two weeks, how often have you been bothered by the following problem: Having trouble relaxing? GAD GAD-7

Not at all Several days More than half the days Nearly every day

(0) (1) (2) (3)

(0) (1) (2) (3)

4 A panic attack is a sudden rush of fear or discomfort accompanied by at least 4 of the symptoms listed below. Panic PDSS-SR

In order to qualify as a sudden rush, the symptoms must peak within 10 minutes. Symptoms are: rapid or pounding heartbeat, sweating, trembling/shaking, breathlessness, feeling of choking, chest pain/discomfort, nausea, dizziness/faintness, feelings or unreality, numbness/tingling, chills or hot flashes, fear of losing control or going crazy, fear of dying. If you have had any panic attacks during the past week, how distressing (uncomfortable, frightening) were they while they were happening? If you did not have any panic attacks but did have limited symptoms attacks, answer for the limited symptom attacks.

Not at all distressing, or no panic Mildly Moderately Severely Extremely

or limited symptom attacks distressing distressing (intense, distressing distressing

during the past week (not too intense) but still manageable) (very intense) (extreme distress during all attacks) (0) (1) (2) (3) (4)

5 Do you avoid public places from which a quick escape may be difficult or do you endure this Yes (1) No (0) AGO SQ with clear suffering or anxiety? (e.g. public transport, shops/town centres, queues, cinema,

unfamiliar buildings, distance from home).

6 Are you either extremely anxious or do you avoid specific objects or situations? Yes (1) No (0) Specific SQ Phobia

7 Are you scared of: animals (e.g. dogs, spiders, snakes, cats, birds, mice, insects) or Yes (1) No (0) Specific VU

medical issues (e.g. blood, dentist, injection, surgery, hospital, doctor) or Phobia

specific situations (e.g. bus, crowded shop, tunnel elevator, airplane, bridge or car driving)

medical issues (e.g. blood, dentist, injection, surgery, hospital, doctor) or Phobia specific situations (e.g. bus, crowded shop, tunnel elevator, airplane, bridge or car driving)

8 Have you avoided social situations for fear that attention might be on you? Yes (1) No (0) Social MINI Phobia

9 Are you fearful or embarrassed being watched, being the focus of attention, or fearful of being Yes (1) No (0) Social MINI

humiliated? (This includes situations like speaking in public, eating in public with others, Phobia

writing while someone watches, or being in social situations).

10 Did your symptoms start after having experienced, witnessed or had to deal with an extremely Yes (1) No (0) PTSD MINI traumatic event that included actual or threatened death or serious injury to you or someone else? (e.g. serious accident, sexual or physical assault, a terrorist attack, being held hostage, kidnapping, hold-up, fire, discovering a body, unexpected death, war, natural disaster)

11 Have you ever experienced a traumatic event? Yes (1) No (0) PTSD SQ 12 Obsessions are recurrent thoughts, impulses or images that are unwanted, distasteful, inappropriate, OCD ybocs intrusive or distressing (e.g. the idea of hurting your children although you know you never want to do that). How much time did you spend on obsessions in the past week?

0 hr/day or no obsessions 0-1 hr/day 1-3 hr/day 3-8 hr/day >8 hr/day

(0) (1) (2) (3) (4)

13 How many drinks containing alcohol do you have on a typical day when you are drinking? Alcohol audit None 1-2 3-4 5-6 7-9 10 or more

(0) (1) (2) (3) (4) (5)

14 How often do you have six or more drinks on one occasion? Alcohol audit Never Less than monthly Monthly Weekly Daily or nearly daily

(0) (1) (2) (3) (4)

15 Has the idea of harming yourself or taking your own life, recently come into your mind? Suicide SQ Definitely not Has crossed my mind but I would I seriously considered it but I I would do it given the not do it stopped myself opportunity

(0) (1) (2) (3)

*WSQ cut-off scores: Depression: Q1≥ 5 & Q2=1; GAD: Q3≥2; Panic: Q4 ≥1; Panic with Ago Q4 ≥1 & Q5=1; Ago: Q5=1; Specific phobia: Q6 or Q7=1; Social phobia: Q8=1 & Q9=1; PTSD: Q10=1 or Q11=1; OCD: Q12≥1; Alcohol Abuse/Dependence : Q13≥2 & Q14≥3 ; Suicide : Q15=3 (exclusion)


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de Graaf R, ten Have M, van Gool C, van Dorsselaer S. Prevalence of mental disorders and trends from 1996 to 2009. Results from the Netherlands Mental Health Survey and Incidence Study-2. Soc Psychiatry Psychiatr Epidemiol 2012;47:203-213.

Donker T, van Straten A, Marks I, Cuijpers P. A brief Web-based screening questionnaire for common mental disorders: development and validation. J Med Internet Res 2009;11:e19.

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Hanley JA, Lippman-Hand A. If nothing goes wrong, is everything all right? Interpreting zero numerators. JAMA 1983;249:1743-1745.

Kessler RC, Ustun TB. The World Mental Health (WMH) Survey Initiative Version of the World Health Organization (WHO) Composite International Diagnostic Interview (CIDI). Int J Methods Psychiatr Res 2004;13:93-121.

Lecrubier Y, Sheehan DV, Weiller E et al. The Mini International Neuropsychiatric Interview (MINI). A short diagnostic structured interview: reliability and validity according to the CIDI. European Psychiatry 1997;12:224-231.

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Meuldijk D, Carlier IV, Van Vliet IM, van den Akker-Marle ME, Zitman FG. A randomized controlled trial of the efficacy and cost-effectiveness of a brief intensified cognitive behavioral therapy and/or pharmacotherapy for mood and anxiety disorders: design and methods. Contemp Clin Trials 2012;33:983-992.


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Chapter 7Summary and General Discussion


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INTRODUCTIONThe general goal of the study described in this thesis was to evaluate the effectiveness of concise formats of psycho- and/or pharmacotherapy (concise care) in patients suffering from mild to moderate depressive and anxiety disorders in secondary mental health care. Therefore, a pragmatic randomised controlled trial was set up and carried out as much as possible as part of clinical practice in five outpatient Mental Health Clinics (MHCs) of Rivierduinen, a secondary Regional Mental Health Provider (RHMP) in The Netherlands. The primary aim of this equivalence trial was to evaluate the clinical effectiveness of concise care compared with standard care. Secondary aim was the evaluation of the cost-effectiveness of concise care compared with standard care. Studied topics in the subsequent chapters are the clinical effectiveness, the cost-effectiveness, and the determination of subgroups of patients who are most likely to benefit from concise care versus standard care. Next, to help optimize and economise mental health care delivery in clinical practice, we also investigated the feasibility of a brief screening method for depressive and anxiety disorders, the Web Screening Questionnaire (WSQ). This chapter will summarize the main findings of these studies. Next, we will discuss these findings within the context of prior research. In addition, methodological issues as well as implications of our findings for clinical practice will be addressed. Lastly, recommendations for future research will be suggested.

SUMMARYCHAPTER 1 offers the general introduction to the contents of this thesis. This chapter sets out the prevalence of depressive and anxiety disorders and their contribution to the total burden and costs of disease. Also the discrepancy between diagnoses made by a clinician and by structured interviews is discussed. Although evidence-based stepped-care clinical guidelines are available for the treatment of anxiety and depressive disorders, there is a lack of concise treatment options for these disorders with proven effectiveness. Concise formats, in which treatments are confined to a maximum number of sessions within a fixed time period, might reduce healthcare costs without compromising effectiveness. In line with this, the importance of determining subgroups of patients who are most likely to benefit from concise treatment, and the need for brief screening methods for psychiatric disorders are introduced. As the data of our study were collected with Routine Outcome Monitoring (ROM), this method is furthermore described in chapter one. CHAPTER 2 describes the rationale, design and methodology of the pragmatic, randomised controlled equivalence trial in which we evaluate whether concise care is as effective as standard care in the treatment of depressive and/or anxiety disorders in secondary mental health care. The primary aim of this trial is to evaluate the clinical effectiveness of concise care compared to standard care. Secondary aim is the evaluation of the cost-effectiveness of both treatments. Treatment protocols in concise care were confined to a maximum of 7 weekly sessions and consist of the following evidence based interventions: [1] cognitive behavioural therapy, [2] pharmacotherapy and [3] Eye Movement Desensitization and Reprocessing-therapy (EMDR), in case of a posttraumatic stress disorder (i.e. see the website awp.rivierduinenlumc.nl for an overview of the concise treatment protocols [in Dutch]). The number of sessions and treatment duration of standard care was not determined in advance, and thus expected to be variable. Recruitment of participants was planned to take place in five mental healthcare centres of the


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secondary mental health care provider Rivierduinen (RD) in the Netherlands. To be included in the study, secondary care outpatients (aged 18-65 years) needed to meet the DSM-IV-TR criteria for a current primary diagnosis of a depressive disorder, agoraphobia, panic disorder (with or without agoraphobia), specific phobias, social phobia (social anxiety disorder), obsessive compulsive disorder, post-traumatic stress disorder (type I or single trauma), generalized anxiety disorder, anxiety disorder Not Otherwise Specified (NOS) or adjustment disorder (with anxiety and/or depressive mood). Both treatment conditions were monitored at baseline, 3, 6 and 12 months after baseline and administered by Routine Outcome Monitoring (ROM). Primary outcomes were the reduction in symptoms of depressive and anxiety disorders as measured with the Brief Symptom Inventory (BSI) and the Web Screening Questionnaire (WSQ). Secondary outcomes (i.e. quality of life, general health status, patient satisfaction with care, use of health care and work productivity) are the scores on the other instruments assessed by ROM. Analyses were performed according to the intention-to-treat principle. Strengths and limitations of this study are discussed. Note that in this chapter concise care is called ‘shortened (brief ) first treatment’ and standard care ‘treatment as usual’. Concise and standard care are names we gave the treatments in a later phase of the study, being more suitable translations of the Dutch name of the interventions used in the study (i.e. Kort & Krachtig [in Dutch]). In CHAPTER 3 the main findings with respect to effectiveness from our pragmatic randomised controlled equivalence trial are described. A total of 182 outpatients (aged 18-65 years) with a primary current mild to moderate DSM-IV-TR diagnosis of depressive and (or) anxiety disorder, were randomised to concise care (n = 93) and standard care (n = 89). We found evidence for equivalence of concise care compared with standard care during the first year of follow-up. In both conditions, severity of illness was reduced and general health status and subdomains of quality of life improved. Moreover, in concise care, the beneficial effects started earlier and patients were more satisfied with overall treatment than patients in standard care within the first 3 months after study entry. The economic evaluation is described in CHAPTER 4. No significant differences in healthcare costs and QALYs between both treatments were found. From both the societal and healthcare perspective, a favourable cost-effectiveness of concise care compared to standard care, could not be demonstrated. Apart from evaluation of the clinical- and cost-effectiveness of the intervention, the study also examines what works best for what type of patient. CHAPTER 5 examines the possible predictors associated with treatment outcome of concise care. In subgroup- analyses of our cohort of patients with mild to moderate depressive and/or anxiety disorders, it was shown that only patients suffering from any anxiety disorder (without comorbid depressive disorder) benefitted less from concise care than from standard care. No other clinical or demographic factors were associated with differential treatment effects. In CHAPTER 6 the concordance between a brief screening questionnaire the Web Screening Questionnaire (WSQ), and the gold standard diagnostic interview MINI-Plus was examined. This separate study was carried out to evaluate the feasibility of the WSQ for the rapid screening of mental disorders in a study sample composed of the general population (see thesis Y. Schulte-van Maaren, 2014), which was enriched with psychiatric outpatients from our pragmatic trial. Exploring the agreement between both instruments, reveals that the WSQ is a good screening tool for


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depressive and anxiety disorders (except for post-traumatic stress disorder and specific phobia) in clinical practice and it might be a further step in the economization and optimization of mental healthcare. However, in case of a low prevalence rate, the probability of detecting a disorder in a positive screened individual is in fact variable when using the WSQ.

DISCUSSION OF MAIN FINDINGS AND PRIOR RESEARCHCLINICAL EFFECTS AND ECONOMIC EVALUATIONIn the introduction we stated that there is a need to develop treatments that are at least as effective as the treatments available now, but less time-consuming and at lower costs. Concise treatment formats, in which treatments are confined to a maximum number of sessions within a fixed time period, might answer these needs. In this discussion, we will first focus on treatment effectivity of concise formats of cognitive behavioural- and/or pharmacotherapy (concise care) compared to standard care during the first year of follow-up. Subsequently, we will focus on cost-effectiveness. As we hypothesized, we found that concise care was as equally effective as standard care (Chapter 3). This finding is in agreement with previous studies on the effectiveness of brief treatments for depressive and anxiety disorders (Muntingh et al. 2014; Nieuwsma et al. 2011; Oosterbaan et al. 2013). In primary care, a meta-analytical study by Cape et al. (2010) indicated that several forms of brief (i.e. 6-7 sessions) psychotherapies administered within primary care, across and between anxiety, depressive and mixed disorders, have shown effectiveness compared to control conditions with treatments of longer duration (Cape et al. 2010). In addition, Nieuwsma et al. (2012) conducted a systematic review and meta-analysis evaluating the efficacy of brief forms (i.e. ≤ 8 sessions) of CBT, problem solving therapy and mindfulness-based cognitive therapy for the treatment of depressive disorders in primary care (Nieuwsma et al. 2012). Larger effect sizes of these brief psychotherapies as compared to control treatment (i.e. up to 20 sessions) were reported, suggesting that these brief psychotherapies might be an attractive treatment alternative for implementation in primary care. Besides, in secondary care, a controlled trial by van Straten et al. (2006) demonstrated that brief therapy (on average 8 sessions) and brief CBT (on average 10 sessions) were suitable as a first treatment step, as significantly fewer sessions were needed to obtain similar treatment results, as in matched care. However, our study differs in several aspects from the studies reported in the literature. First of all, we tried to approach ‘real life’ as much as possible. Therapists and patients were free to choose among the concise treatment options available (see the website awp.rivierduinenlumc.nl for an overview of concise treatment protocols [in Dutch]). Secondly, we included as much as possible ‘real-world’ patients as they present themselves in clinical practice with a minimum of exclusion criteria. This improves the generalizability of our results. However, the extent to which the findings can be generalized to other settings depends on the comparability of patients groups. Thirdly, our study is one of the few studies carried out in secondary mental health care. The literature regarding the evaluation of concise treatment in clinical practice settings is scarce. However, this is not surprising as concise care might be more suitable for primary care. In fact, as mentioned in Chapter 1, it was our aim to ‘export’ our concise care model to primary care. The finding that the beneficial clinical effects of concise care were obtained earlier, during the first phase of treatment (within the first 3 months), suggests that concise care did a better job of ‘engaging’ patients in treatment in a more timely manner. Patients were more satisfied with treatment in concise care. Although, this was a post-hoc result requiring further study.


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The economic evaluation described in Chapter 4 failed to demonstrate a favourable cost-effectiveness of concise care compared to standard care. No significant differences were found in mean healthcare and societal costs between concise and standard care, nor were there any significant differences in utility scores between the groups. The healthcare costs in the concise care group were somewhat higher than the costs in the standard care group, although not statistically significant. These findings correspond with the lack of significant differences found in earlier studies examining cost-effectiveness of brief psychological treatments (Churchill et al. 2001; Maljanen et al. 2012; Maljanen et al. 2014; Maljanen et al. 2015; van Roijen et al. 2006). In most of these studies the differences in total healthcare costs between brief therapy and standard care were small. However, in our study, certain methodological problems, such as a lack of power and a smaller sample size, impeded detection of relevant cost differences. Moreover, acting in antithesis of the concise treatment protocols, the duration of concise care was prolonged and continued during the entire study period, blurring the difference in mean number of contacts with standard care. These differences might emerge over time, when the follow-up period is extended, and the cost savings of concise care will likely be more notable. In Chapter 1 we wrote about the strong incentive to develop treatments, especially the first step, as concise and cost-effective as possible. Do our results mean that the format of concise care we developed is suited to function as a new, first step of the stepped-care approach? Of course, the results of one single study are not sufficient to mandate this conclusion. Moreover, we could not demonstrate that concise care was more cost-effective compared to standard care. Replication of our study in larger patient groups and in different settings is needed to answer this question. Replication of the study will also benefit from therapists more strictly adhering to the concise treatment protocols: i.e. restrict treatment to the small number of sessions and short time, as was prescribed in the protocol.

WORKING MECHANISMS AND PREDICTORS There is a growing awareness that one no longer should evaluate treatment effects only for the whole group of patients with, for instance, depressive or anxiety disorders, but instead analyse whether specific subgroups of these patients might be helped with a new type of treatment or a new way of applying existing treatments, in order to tailor treatment to the individual patient characteristics. This ‘personalized treatment’ could offer possibilities to make treatment more cost-effective (Alda, 2013; Cortese, 2007). Besides, knowledge about subgroups of patients who are most likely to benefit from treatment, enables the clinician to make proper treatment adjustments in an early stage of treatment, a further refinement of clinical staging and profiling (McGorry et al. 2006; van Balkom et al. 2012; Zitman, 2012). Therefore, in Chapter 5 we examined whether positive treatment outcome to concise care was associated with certain patient variables available at intake. We found that the benefit of concise care was largely independent from the socio-demographic and clinical characteristics we studied. Only the treatment outcome of patients with pure anxiety was less favourable with concise care compared to standard care. One possible explanation for this finding is that anxiety disorders have a longer mean time to remission and therefore may need long-term treatments (Ormel et al. 1993; Penninx et al. 2011). Of course, we cannot make any definite conclusions based on our small sample.


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QUICK DIAGNOSTIC SCREENING While clinician-administered diagnostic interviews are generally considered the ‘gold standard’ for diagnosing mental disorders in mental health care, these interviews generally are neither financially nor logistically feasible in clinical practice. Most of the diagnostic screens in clinical practice are time-consuming, costly and require a well-trained interviewer to conduct (Haro et al. 2006; Kessler et al. 2004; Kessler & Ustun, 2004). Contrary to the above, the Web Screening Questionnaire (WSQ) for common mental disorders (i.e. depression, GAD, panic disorder with and without agoraphobia, social phobia, specific phobia, OCD, PTSD, and alcohol abuse/dependence), is a brief questionnaire (taking about 5 minutes to complete) that can be completed by the patients themselves (i.e. self-report) (Donker et al. 2009). In a previous study by Donker et al. 2009, the WSQ has shown good concordance with lifetime DSM-IV diagnoses based on the fully-structured lay-administered Composite International Diagnostic Interview Version 3.0 (CIDI) in a general population study sample. In Chapter 6, we were able to show the same results with the last month prevalence of these disorders derived from the ‘gold standard’ Mini-International Neuropsychiatric Interview Plus (MINI-Plus) (Sheehan et al. 1998; van Vliet & de Beurs, 2007), in a general population sample enriched with psychiatric outpatients from our pragmatic trial. For the majority of WSQ subscales the specificity and sensitivity relative to the MINI- Plus were good. Exceptions are depressive disorder, specific phobia, PTSD and alcohol abuse/dependence, for which the agreement was lower. In addition, the Areas Under the Curve (AUCs) of most WSQ’s subscales were comparable to AUCs of longer questionnaires. Despite the good test-characteristics, the positive predictive value remained disappointingly low for all disorders due to a low prevalence of disorders. This is a general obstacle when screening for disorders with low prevalence. The high negative predictive and efficiency values of the WSQ suggest that most subscales of the tool can be effectively used to exclude the presence of a disorder in populations where the prevalence of these disorders is modest. In case of a positive WSQ screening result, further diagnostic procedures are required.

STRENGTHS AND LIMITATIONSTo our knowledge, the study described in this thesis, is one of the first to evaluate the effects of concise versions of psycho- and pharmacotherapy in a group of outpatients with depressive, anxiety and adjustment disorders in secondary mental health care. As stated before, we included patients who are representative of those seen in day-to-day outpatient clinical practice in the Netherlands. There were almost no exclusion criteria, only patients with severe disorders were excluded. Moreover, treatment is provided by qualified therapists already working in the participating MHCs, reflecting day-to-day clinical practice. Besides, therapists and patients were able to choose among the available concise treatments for depressive and anxiety disorders, just as the patient and their therapist preferred. The pragmatic design of our study enhances generalizability and external validity of our results. Several methodological issues have already been addressed in the previous chapters. In this section, we will discuss the most important limitations of our studies. While the study was powered on 500 patients, finally 182 patients could be included. Besides, a total of 140 patients (76.9 percent) dropped out during treatment and follow-up. Although we did not achieve the intended sample size of 500 patients, we found concise care to be at least as


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effective as concise care. The sample size calculation showed that approximately 250 patients in each treatment group would be needed to detect equivalence with an acceptable difference of 5% and a maximal difference of 15% (in either direction) in success rate, which was assumed to be clinically relevant (see Chapter 2). Contrary to our initial expectations and assumptions, the observed differences between the two treatments were higher as expected, in favour of concise care. Therefore, we could conclude that concise care was at least as effective as standard care. In many studies the influx of patients is smaller and slower than was estimated beforehand (van der Wouden et al. 2007). A review by Mc Donald et al. (2006) showed that only a third (31%) of the 114 randomised controlled trials examined, were able to reach their original patient recruitment target, and in 47 trials (41%) the start of recruitment was delayed (McDonald et al. 2006). In this respect our study is no exception. From the start, recruitment to the study was slower and more difficult than anticipated. Important factors, which might have contributed to these findings, were without doubt the ‘usual suspects’: referring patients to the trial was not part of the daily practice and required a time-consuming and logistically complicated informed consent procedure. Moreover, an interim evaluation of the inclusion process showed that the majority of patients seeking treatments at the MHCs did not meet the inclusion criteria of our study, because the severity and burden of their disease were too high. This finding surprised us as an important impetus to start this study were the observations and worries of therapists that a growing number of patients only had mild problems, demanding too much time of experts trained to treat more complicated cases. This also may be an example of the ‘usual suspects’: before a study begins, a large number of relevant patients seems to be available to the investigator. As soon as the study actually starts, these patients seem to have disappeared and the supply of suitable patients becomes a fraction of what it was assumed to be before the trial began (Gorringe, 1970). This is a well-recognized phenomenon that has been described as ‘Lasagna’s law’ (Lasagna, 1979). Another, less common, factor is the rapid change of the organization of mental health care in the Netherlands. Because of the need to control rising health care expenditure in the Netherlands in January 2012 (24 months after patient inclusion started in our study), the government made it obligatory for patients in secondary mental health care to pay a substantial amount of money (€ 200,-) themselves, an amount that could not be refunded by the insurance company, the so-called ‘eigen bijdrage’. This caused a lot of publicity and many patients cancelled referrals to secondary mental health care. Specifically patients with less severe problems decided to abstain from secondary care (Koopmans and Verhaak, 2012; Lokkerbol and Smit, 2011). Another limitation has to do with protocol adherence. Therapists were free in the choice of concise treatment option. There were only restrictions in the number of sessions (7) and treatment duration (7 weeks). As is shown in Chapter 3, many patients allocated to concise care were treated for a longer period of time or with more sessions than was written in the protocol. In fact, one of the possible explanations that no differences were found in cost-effectiveness (Chapter 4) might be that in many cases of concise care therapists treated the patients with more sessions and/or during a longer time period, in that way blurring the difference with standard care. With respect to standard care no such restrictions were made, however it is known from other studies and from clinical practice that in everyday clinical practice, pharmacotherapy as well as psychotherapy in the outpatient treatment of anxiety and depressive disorders take more sessions than is suggested by the guidelines (Bauer, 2002; van Fenema et al. 2012). Besides, whereas the study protocol


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prescribed a fixed time schedule for the monitoring of treatment over time, in practice, the time between ROM assessments turned out to be variable in time between patients and groups. On the other hand, the heavy workload of the therapists and the professional demands upon them, had a further impact upon protocol adherence. Numerous logistic difficulties were faced by the therapists and MHCs participating in this study, in order to meet the study infrastructure of weekly sessions within a fixed period of time. We performed longitudinal data analyses to make optimal use of the available data. Multiple imputation techniques were used to make statements about the intention-to-treat sample. Results could be biased as a result of estimating data, although we did not find evidence for his. Patients who dropped out after baseline assessment did not differ from those who continued in demographic and baseline variables. However, comparison of findings from models in which missing data are imputed differently would provide more reassurance with regards to the robustness of our findings. In addition, we did not yet carry out all the analyses planned originally, as described in Chapter 2. We will discuss here the most important deviations from the protocol as far as they have not been discussed above. In Chapter 2, Table 1, we listed a large number of questionnaires also used in Routine Outcome Monitoring at that time. We planned to use them all as secondary outcomes, but did not carry out that plan because of the small number of participants. In addition, our exploratory research aims: evaluation of [1] the feasibility of a shortened, less time-consuming ROM and [2] therapist satisfaction with concise care, could not be fully answered and were not described in one of the chapters, because the steps to fidelity monitoring could not be fully executed. Although we were able to obtain sufficient treatment protocol-adherence (>75%) and we did succeed in the monitoring of patient satisfaction (see Chapter 3), the monitoring of therapist satisfaction with concise care, proved to be unattainable. While an evaluation questionnaire assessing the delivery and compliance of the different treatments was available and therapist were repeatedly invited to complete this questionnaire, in practice only few therapists have filled in this questionnaire and returned it to the research team (only 60 forms were returned, a response rate of 32%). Since 2014, it is mandatory in the Netherlands (EU) for RCTs with (psychotropic) drugs to submit the trial protocol to a trial register (i.e. European (EU) Clinical Trials Register) (European Parliament, 2014a; European Parliament, 2014b). This policy requires investigators of all clinical trials to deposit information about their randomised controlled trial design into this clinical trial registry prior to participant enrolment, as a precondition for publication of the trial’s findings in member journals. The EU Clinical Trials Register is a publically available, and aims to ensure a greater level of harmonisation of the rules of conducting and reporting of clinical trials (European Parliament, 2014a; European Parliament, 2014b; Peat et al. 2014). For trials in which psychotherapy is included, this is not yet necessary. We suggest making trial registration obligatory also for RCTs involving psychotherapy. By publishing Chapter 2 we made our plans and the extent in which we succeeded as transparent as possible. When looking back, the discrepancies illustrate how difficult it is to implement a new treatment approach in clinical practice.


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CLINICAL IMPLICATIONS AND FUTURE DIRECTIONS In this study, we were able to demonstrate that concise care does not compromise treatment effectivity. In this respect it could be applied in clinical practice. Unfortunately, the hope that concise care is more cost-effective than standard care did not materialize. However, the sample we were able to study was small. Therefore, additional studies are necessary in other, larger samples in different clinical settings. Concise care is especially developed for patients with less severe disorders. As discussed above, the therapists felt at the time the study started, that these patients were a part of their caseload for which they felt themselves overqualified. Therefore, we first planned to evaluate concise care in outpatient clinics but later on to ‘export’ them to general practice, to be used by general practitioners for pharmacotherapy and for psychotherapy by psychologists or specially trained nurses (i.e. Practical Supporter General Practitioner Mental Healthcare (Dutch abbreviation: POH-GGZ). The POH-GGZ is a mental health specialist within the GP practice and supports the GP in diagnosing, treating and referring patients with mental health problems. The reader of this thesis will expect now a recommendation to repeat the study in primary care, as suggested above. However, to a large extent due to reforms in mental health care to control rising expenditure in the Netherlands, much has changed in mental health care since the study started in 2009. First, throughout the course of the study, referrals to secondary mental health care were much lower than they were before because of the temporary ‘eigen bijdrage’ (see paragraph 7.2.): the patients had to pay a substantial amount of money (€ 200,-) when referred to secondary mental health care. If this policy had been continued, it would have changed the ‘flow’ of patients from primary to secondary health care. Fortunately, this measure (‘eigen bijdrage’) was withdrawn in 2013. Secondly, secondary mental health care was forced to economize to a large extent7, also due to the rising costs. This will without doubt also influence the referral pattern of patients with depressive and/or anxiety disorders to secondary care and thus the patients remaining for treatment in primary care. Thus, it is even uncertain whether we should have the same results if we repeated the study nowadays. But also other changes have occurred in mental health care, which may influence the results. The treatment guidelines for depressive and anxiety disorders have been modified in 2013, including which are the treatments of first choice. This implies that a replication of our study today, would include other preferable treatments as first step (i.e. psycho-education and self-help) and that concise care ‘new style’ possibly also will yield other results. Besides, in 2013 a new version of the DSM, the DSM 5 (American Psychiatric Association, 2013), was introduced, as already mentioned in Chapter 1. Because of the changes in inclusion criteria for the diagnoses included in our study, this may change the ‘mix’ of patients that will be included in the study and treated with concise care ‘new style’. Finally, also Routine Outcome Monitoring has changed a lot since the start of the study. While Rivierduinen had an extensive set of questionnaires in 2009, including the MINI-Plus as diagnostic instrument. Unfortunately, nowadays the MINI-Plus is no longer used. In fact, no

7Since January 1st 2014, the former two types of mental healthcare (first line and second line) are divided in three echelons: GP and POH-GGZ, Generalistic Basic mental healthcare (GB GGZ) and Specialised mental healthcare (G GGZ). Care provided by your GP and POH-GGZ is reimbursed by the basic healthcare insurance. Care provided in GB GGZ en G GGZ is reimbursed by your basic health insurance if there is a DSM-disorder, plus a reference from the GP and the psychologist is on the list of 'head practitionwers' (hoofd behandelaars), as appointed by the minister. On this list are, for example, psychologists and psychotherapists with a registration under the Individual Health Care Professions Act (BIG), Child- and Youth Psychologists NIP and Remedial Educationalist (NVO).


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diagnostic instrument is applied any more. Given all the budget restraints it became too costly to use the MINI-plus in routine practice. Besides, due to requirements made by a new policy in the Netherlands requiring all mental health centres to send at least one questionnaire, the SQ-48 is (Carlier et al. 2015; Carlier et al. 2012) assessed repeatedly in all patients, and send to a central organization, the ‘Stichting Benchmark GGZ (SBG)’, Rivierduinen had to direct all resources to the attainment of that goal and had to drop other questionnaires. To conclude, we think that, notwithstanding the recent changes in mental health care, our study is valuable as it demonstrates that it is worthwhile to aim for the delivery of treatments in a concise format, more structured and within a shorter period of time, than is normally the case in secondary mental healthcare. Besides, concise care, might become a valuable approach in Generalistic Basic mental healthcare. In this respect, our study is a proof of principle, a promising proof of principle. In addition, although much has changed in mental health care in the Netherlands during the last 5 years, and some new treatment modalities were introduced, the concise treatments for which we developed protocols, are still applicable. To facilitate their use, the protocols are available on the website awp.rivierduinenlumc.nl.


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Chapter 8Summary in Dutch/Nederlandse samenvatting

Curriculum VitaeList of publications

Acknowledgements/Dankwoord


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SUMMARY IN DUTCHIn dit proefschrift worden de resultaten beschreven van een onderzoek naar de klinische en kosteneffectiviteit van beknopte formats van psycho- en / of farmacotherapie (beknopte zorg) bij patiënten die lijden aan lichte tot matige depressieve en angststoornissen in de tweedelijns geestelijke gezondheidszorg (GGZ). Een pragmatische gerandomiseerde gecontroleerde equivalentie trial werd uitgevoerd als onderdeel van de klinische praktijk, in vijf ambulante vestigingen van Rivierduinen, een tweedelijns geestelijke gezondheidszorg instelling in Leiden en omgeving (Nederland). Het primaire doel van deze trial was onderzoeken of de klinische effectiviteit van deze beknopte zorg tenminste even groot was als die van standaard zorg. Het secundaire doel was de evaluatie van de kosteneffectiviteit van beknopte zorg in vergelijking met standaard zorg. Naast de klinische en kosteneffectiviteit, werd tevens gekeken of er subgroepen van patiënten waren die de meer kans dan anderen hadden om te profiteren van beknopte zorg. Tenslotte onderzochten we de haalbaarheid van een korte screeningsmethode voor depressieve en angststoornissen, de Web Screening Questionnaire (WSQ), in onze studiepopulatie aangevuld met patiënten uit huisartsenpraktijken. De introductie (HOOFDSTUK 1) biedt een algemene inleiding op de de stoornissen waar dit proefschrift betrekking op heeft en op de vraagstellingen van dit proefschrift. Dit hoofdstuk beschrijft de prevalentie van depressieve en angststoornissen en hun bijdrage aan de totale lasten en kosten voor de individuele patiënt en de maatschappij. Ook wordt de discrepantie tussen diagnosen opgesteld door een clinicus versus diagnosen n.a.v. gestructureerde interviews besproken. Alhoewel evidence-based klinische richtlijnen volgens het stepped care principe (getrapte zorg) beschikbaar zijn voor de behandeling van patiënten met angst en depressieve stoornissen, is er een gebrek aan beknopte opties met bewezen effectiviteit voor de behandeling van deze aandoeningen. Beknopte zorg (beknopte formats van psycho- en / of farmacotherapie), waarin behandelingen worden beperkt tot een maximum aantal sessies binnen een bepaalde periode, kunnen de kosten voor gezondheidszorg verminderen zonder afbreuk te doen aan de effectiviteit. In lijn hiermee, wordt het belang van het identificeren van subgroepen van patiënten met de meeste kans om te profiteren van deze beknopte zorg, en de noodzaak van korte screeningsmethoden voor psychiatrische stoornissen geïntroduceerd. Aangezien de gegevens van dit onderzoek werden verzameld met behulp van Routine Outcome Monitoring (ROM), wordt ook deze werkwijze verder beschreven in hoofdstuk één. HOOFDSTUK 2 beschrijft de rationale, het design en de methodologie van deze pragmatische, gerandomiseerde gecontroleerde equivalentie trial waarbij we beoordelen of beknopte formats van psycho- en / of farmacotherapie (beknopte zorg) even effectief zijn als standaard zorg in de behandeling van patiënten met depressieve en/of angststoornissen in de tweedelijns GGZ. Het primaire doel van deze studie is om de klinische effectiviteit van beknopte zorg in vergelijking met standaard zorg te evalueren. Secundair doel is de evaluatie van de kosteneffectiviteit van beide behandelingen. Behandelprotocollen in beknopte zorg werden beperkt tot een maximum van 7 wekelijkse sessies en bestaat uit de volgende evidence based interventies: [1] cognitieve gedragstherapie, [2] farmacotherapie en [3] Eye Movement Desensitization and Reprocessing-therapie (EMDR), in geval van een posttraumatische stress-stoornis. N.b. Zie de website awp.rivierduinenlumc.nl voor een overzicht van de beknopte behandelprotocollen ontworpen voor


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deze studie. Het aantal sessies en de duur van de behandeling van de standaard zorg werd niet vooraf vastgesteld, en werd naar verwachting verwacht variabel te zijn in therapieduur en aantal therapiesessies. Werving van de deelnemers was gepland plaats te vinden in vijf geestelijke gezondheidszorg centra van de tweedelijns gezondheidszorg instelling Rivierduinen. Om te worden geincludeerd in de studie, moesten tweede lijns poliklinische patiënten (18-65 jaar) voldoen aan 1 van de volgende DSM-IV-TR criteria: primaire diagnose van een depressieve stoornis, agorafobie, paniekstoornis (met of zonder agorafobie), specifieke fobieën, sociale fobie (sociale angststoornis), obsessief-compulsieve stoornis, post-traumatische stress stoornis (type I of enkele trauma), gegeneraliseerde angststoornis, angststoornis niet anders gespecificeerd (NOS) en/of aanpassingstoornis (met angst en / of depressieve stemming). Beide behandelmethoden werden geëvalueerd op baseline (nul-meting), 3, 6 en 12 maanden na de baseline meting door middel van Routine Outcome Monitoring (ROM). ROM is het routinematig in kaart brengen van de (ernst van de) psychische klachten en het sociaal functioneren van de patiënt en de vooruitgang in therapie met behulp van gestandaardiseerde meetinstrumenten. Primaire uitkomsten in deze studie waren de vermindering van de symptomen van depressie en angst zoals gemeten met de Brief Symptom Inventory (BSI) en de Web Screening Questionnaire (WSQ). Secundaire studie-uitkomsten zijn de scores op de andere instrumenten afgenomen met behulp van ROM (onder andere kwaliteit van leven, de algemene gezondheidstoestand, de patiënt tevredenheid met de zorg; evaluatie van het gebruik van de gezondheidszorg en de gemeten productiviteit op werk). Analyses werden uitgevoerd volgens het intention-to-treat principe (methode waarbij onderzoeksresultaten van personen worden geanalyseerd in de groepen waaraan zij door randomisatie zijn toebedeeld, onafhankelijk van de interventie die zij daadwerkelijk ondergingen). Sterke punten en beperkingen van deze studie worden besproken in dit hoofdstuk. In HOOFDSTUK 3 worden de voornaamste bevindingen met betrekking tot de klinische effectiviteit van onze studie beschreven. Een totaal van 182 poliklinische patiënten (18-65 jaar) met een primaire milde tot matige DSM-IV-TR diagnose van depressie en (of ) angststoornis, werden gerandomiseerd naar beknopte zorg (n = 93) en standaard zorg (n = 89). We vonden bewijs voor equivalentie van beknopte zorg in vergelijking met standaard zorg in het eerste jaar na begin van de studie. Beide behandelmethoden verminderden de ernst van de symptomen van depressie en/of angst en verbeterden de algemene gezondheidstoestand en subdomeinen van de kwaliteit van leven. Bovendien begonnen, in beknopte zorg, de gunstige effecten eerder en waren de patiënten over het algemeen meer tevreden over de behandeling vergeleken met patiënten in de standaard zorg binnen de eerste 3 maanden na studieaanvang. De economische evaluatie van beide behandelingen wordt beschreven in HOOFDSTUK 4. Er werden geen significante verschillen in de kosten voor gezondheidszorg en QALY’s (levenskwaliteit) tussen beide behandelingen gevonden. Vanuit zowel maatschappelijk en gezondheidszorg perspectief, kon een gunstige kosteneffectiviteit van beknopte zorg in vergelijking met standaard zorg, niet worden aangetoond. Wellicht zou het verlengen van de studieduur en het strikter volgen van studieprotocollen in beknopte zorg tot een gunstiger effect van beknopte zorg kunnen lijden. HOOFDSTUK 5 gaat in op de mogelijke voorspellers in verband met de behandelingsuitkomst van beknopte zorg. In subgroup-analyses van ons cohort van patiënten met milde tot matige depressieve en/of angststoornissen, werd aangetoond dat alleen patiënten die lijden aan een


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angststoornis (zonder comorbide depressieve stoornis) minder profiteren van beknopte zorg vergeleken met standaard zorg. Geen enkele andere klinische of demografische factor bleek geassocieerd met een verschil in effect van behandelmethoden. In HOOFDSTUK 6 wordt de overeenkomst tussen een korte screening vragenlijst: de Web Screening Questionnaire (WSQ), en de gouden standaard het diagnostische interview: MINI-Plus onderzocht. Deze studie werd uitgevoerd om de haalbaarheid van de WSQ als korte screeningsmethode voor psychische stoornissen in een studiepopulatie samengesteld uit de algemene bevolking (zie proefschrift Y. Schulte-van Maaren, 2014), verrijkt met psychiatrische patiënten afkomstig uit onze pragmatische trial te evalueren. Bij het verkennen van de overeenkomst tussen beide instrumenten, blijkt dat de WSQ een goede screening tool voor de meeste depressieve en angststoornissen is in de klinische praktijk (met uitzondering van de post-traumatische stress stoornis en specifieke fobie) en dat het een verdere stap in de optimalisering en economisering van de geestelijke gezondheidszorg zou kunnen zijn. In het geval van een lage prevalentie van psychische stoornissen, is de waarschijnlijkheid dat een stoornis juist gedetecteerd wordt variabeler bij het gebruik van de WSQ. De slotbeschouwing wordt gepresenteerd in HOOFDSTUK 7 (Discussie). Samengevat kunnen we concluderen dat het aanbieden van beknopte formaten van psycho- en / of farmacotherapie als eerste behandelstap een veelbelovend alternatief is voor de standaard zorg in de poliklinische behandeling van patiënten met mild tot matige depressieve- en / of angststoornissen. Als onze klinische effectiviteit resultaten kunnen worden gerepliceerd en beknopte zorg kosten-effectief bevonden zal worden op de lange termijn, kan beknopte zorg van grote waarde zijn voor de klinische praktijk. Bovendien, de implementatie en het gebruik van beknopte formats van psycho- en / of farmacotherapie in POH GGZ geestelijke gezondheidszorg zou kansen bieden voor de verdere verhoging van de kwaliteit van de zorg en het verlagen van de gezondheidszorgkosten.


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CURRICULUM VITAE Denise Meuldijk was born on March 11th, 1983 in Breda, the Netherlands. After completing her pre-university education in 2001, she studied psychology at the University of Maastricht. After a research internship at the Concordia University in Montreal, Quebec, Canada, where she examined the effects of temporary deactivation of the hippocampus on contextual influences on object recognition memory, she completed her Master’s in Biological Psychology, sub-specialisation Neuropsychology, end- 2006. In 2007 she shifted her focus from biological psychology to clinical psychology and obtained her Master’s in Clinical Psychology at the Leiden University in 2008. In the meantime, she became involved in clinical research, and worked as a research assistant for the Dutch Study of Depression and Anxiety (NESDA) at the department of Psychiatry of the Leiden University Medical Centre (LUMC). In 2009, Denise started her PhD (Kort & Krachtig study) [in Dutch] on the clinical and cost-effectiveness of concise formats of psycho- and pharmacotherapy in the treatment of psychiatric outpatients of the Dutch regional mental health care provider GGZ Rivierduinen, at the department of Psychiatry of the LUMC and in close collaboration with GGZ Rivierduinen. Between the period May 2014 and January 2015, she combined the completion of her PhD with the position of senior policy officer at the Dutch Knowledge Centre for Child and Adolescent Psychiatry. She supported the Knowledge Centre by the actualisation and development of diagnostic and treatment protocols by making scientific research accessible to professionals, parents and young people. Moreover, she was involved in several projects as part of the E-Knowledge centre, which aims at formulating policy with respect to online efforts. From February 2016, Denise started working as a postdoctoral researcher at the University of Wollongong, Australia, where she conducts research on new models of care for the treatment of personality disorders, and provides consultation and training to health professionals in evidence-based care for these disorders within the Australian public mental health system.


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LIST OF PUBLICATIONSTHIS THESISMeuldijk D, Carlier IVE, van Vliet IM, van den Akker- van Marle ME, Zitman FG. A randomized controlled trial of the efficacy and cost-effectiveness of a brief intensified cognitive behavioral therapy and/or pharmacotherapy for mood and anxiety disorders: design and methods. Contemp Clin Trials 2012;33:983-92.

Meuldijk D, Carlier IVE, van Vliet IM, van Veen T, Wolterbeek R, van Hemert AM, Zitman FG. The clinical effectiveness of concise cognitive behavioural therapy with or without pharmacotherapy for depression and anxiety disorders; a pragmatic randomised controlled equivalence trial in routine care. Contemp Clin Trials 2016;47:131-138.

Meuldijk D, Carlier IVE, van Vliet IM, van Hemert AM, Zitman FG, van den Akker- van Marle ME. Economic evaluation of concise cognitive behavioural therapy and/or pharmacotherapy for depressive and anxiety disorders. J Ment Health Policy Econ 2015;18:3:175-183.

Meuldijk D, Giltay EJ, Carlier IVE, van Vliet IM, van Hemert AM, Zitman FG. Subgroup analyses of a concise care trial of depressive and/or anxiety disorders. Submitted.

Meuldijk D, Giltay EJ, Carlier IVE, van Vliet IM, van Hemert AM, Zitman FG. A validation study of the Web Screening Questionnaire (WSQ) compared to the Mini-International Neuropsychiatric Interview Plus (MINI-Plus). Submitted.

OTHER PAPERSCarlier IVE, Meuldijk D, van Vliet IM, van Fenema E, van der Wee NJ, Zitman FG. Routine outcome monitoring and feedback on physical or mental health status: evidence and theory. J Eval Clin Pract 2012;18:104-110.

Carlier IVE, Meuldijk D, van Vliet IM, van Fenema EM, van der Wee NJA, Zitmam FG. [Empirical evidence for the effectiveness of Routine Outcome Monitoring. A study of the literature]. [Article in Dutch]. Tijdschr Psychiatr 2012;54(2):121-8.


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ACKNOWLEDGEMENTS/DANKWOORD En dan is het af. De afgelopen jaren hebben in het teken gestaan van het afronden van dit boekje. Het schrijven van dit dankwoord betekent dat de verdediging van mijn proefschrift en daarmee het begin van een leven zonder proefschrift dichtbij is. Wat heb ik hier voor geknokt en naar verlangd. Tegelijkertijd symboliseert het voor mij een afsluiting van een niet altijd makkelijke periode. Zonder de stimulans en hulp van velen op werk èn daarbuiten was dit mij echter niet gelukt. Graag wil ik diegenen die hebben bijgedragen, bedanken. Allereerst alle patiënten van GGZ Rivierduinen, die bereid waren deel te nemen aan dit onderzoek. Zonder hen was dit proefschrift er nu niet geweest. Veel dank is ook verschuldigd aan alle betrokken medewerkers van GGZ locaties binnen GGZ Rivierduinen waar dit onderzoek heeft plaatsgevonden (GGZ Duin- en Bollenstreek, GGZ Haagstreek, GGZ Midden- Holland, GGZ Rijnstreek, GGZ Zoetermeer); behandelaren, logistiek medewerkers, ROM verpleegkundigen, teamleiders van Rivierduinen. Hartelijk dank dat jullie mee wilden werken aan het onderzoek ‘Kort & Krachtig’. In het LUMC dank ik alle (oud) collega’s en psychiaters, de verpleging van C8 en alle (oud) mede-kantoortuinbewoners: Anke, Annette, Arianne, Cesare, Floriana, Jessica, Justine, Klaas, Leonie, Luisa, Margien, Marieke, Marloes, Marie-Jose, Marion, Martijn, Nathaly, Nienke, Steven, Sumayah, Viktòria, Yvonne en alle anderen. Lieve Nathaly en Nienke, mijn paranimfen, dank dat ons collegialiteit uitgegroeid is tot een hechte vriendschap. Ik ben ontzettend blij en trots om jullie vandaag naast mijn zijde te hebben mogen staan. Floor en Margien dank voor jullie stimulans om ‘the Bigger Picture’ te blijven zien. Marieke en Marion bedankt voor jullie betrokkenheid bij de opzet van Kort & Krachtig maar ook daarna, tijdens de schrijffase van mijn promotietraject. Last but certainly not least; lieve Anke, Jessica en Marloes, jullie waren onmisbaar in mijn laatste eindsprint! Mijn promotieteam. Mijn promotoren, hoogleraar Emeritus Professor Frans Zitman, Professor Bert van Hemert, mijn copromotoren Dr. Irene van Vliet en Dr. Ingrid Carlier, dank voor jullie vertrouwen in mij. Dit promotietraject was er één met veel hobbels en tegenslagen maar uiteindelijk is de finish gehaald. Beste professor Zitman, beste Frans, ik ben erg dankbaar dat jij je ook na je emeritaat in de laatste fase van mijn promotietraject hebt opgeworpen als directe begeleider. Dank voor onze leerzame overleggen en je inhoudelijk zeer waardevolle feedback. Collega’s die een bijdrage hebben geleverd aan één of meerdere projecten binnen mijn promotietraject, wil ik ook graag bedanken. Dr. Giltay, Erik, Dr. van Veen, Tineke, Dr. van den Akker- van Marle, Elske en MD. Wolterbeek, Ron, dank voor het delen van jullie expertise. Dr. Hakkaart- van Roijen, Professor van der Feltz- Cornelis, Professor de Beurs en Professor van der Wee wil ik bedanken voor hun bereidheid hun tijd en expertise ter beschikking te stellen en zitting te nemen in de leescommissie. I would like to extend my sincerest thanks to Professor Grenyer, from the University of Wollongong in Australia. I am grateful for the opportunity to be part of the Project Air Research Team and to work in the beautiful Australia. Veel motivatie heb ik ook geput uit alle nevenactiviteiten die het leven naast een promotie heel leuk maakte. Lieve vrienden en familie(s) graag maak ik van deze gelegenheid gebruik om te zeggen hoe blij ik met jullie ben. Ik begrijp dat dit traject soms onnavolgbaar was voor jullie, maar zonder jullie was mijn promotietraject een stuk minder aangenaam en succesvol geweest.


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Dank jullie wel voor jullie betrokkenheid en warmte. Ik kan de vraag ‘Is het nu nog niet af?’ nu eindelijk met een volmondig ‘JA’ beantwoorden. Lieve Cris, de start van mijn promotietraject hebben we samen gevierd, wat was je trots. Helaas ben je er niet om dit moment samen met mij te vieren. Mijn promotietraject stond in het kader van jouw plotselinge overlijden. Verdriet, chaos, loskomen en uiteindelijk aanvaarding. Voor altijd in mijn hart. Ik ben je dankbaar voor alles wat je mij gegeven hebt, dit proefschrift draag ik op aan jou.


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