are psychological treatments of panic disorder...

UNIVERSITY FRIBOURG, CH| Department of Psychology | Chair of Clinical Psychology and Psychotherapy| PD Dr. Peter Wilhelm, Spring 2018 1

Are psychological treatments of panic

disorder efficacious?

Peter Wilhelm

7.3 and 14.3.2018


Efficacy of Behavioral Treatment of Panic Disorder

First randomised controlled trial

Barlow and colleagues

Barlow, D. H., Craske, M. G., Cerny, J. A. & Klosko, J. S. (1989). Behavioral treatment of panic disorder. Behavior Therapy,

20, 261-282.

Craske, M. G., Brown, T. A. & Barlow, D. H. (1991). Behavioral treatment of panic disorder: A two-year follow-up. Behavior

Therapy, 22, 289-304.


Individual experiences recurrent unexpected panic attacks,

and is persistently concerned or worried about having more panic attacks,

or changes his or her behavior in maladaptive ways because of the panic attacks (e.g., avoidance of exercise or of unfamiliar locations).

Panic attacks are abrupt surges of intense fear or intense discomfort that reach a peak within minutes, accompanied by physical and/or cognitive symptoms:

• e.g. accelerated heart rate, sweating, trembling or shaking, shortness of breath, chest pain or discomfort.., fear of loosing control, fear of dying.

12 month prevalence: 2-3%, women vs men: 2:1

High comorbidity


Background: Panic Disorder, DSM 5 (p. 190)


State of the art treatment for panic disorder, in the1980s,

when the study was conducted:

• Panic attacks can effectively be treated with

psychoactive drugs (Benzodiazipines)

Behavioral therapy is effective in treating avoidance behavior

(via in vivo confrontation)

• Implicit assumption: Behavioral therapy is not an efficacious

treatment for panic disorder without agoraphobic avoidance


Background


Is cognitive behavioral therapy (CBT) efficacious for the

treatment of panic disorder without agoraphobic

avoidance?

State of research

• Several case studies in which CBT led to an improvement

(e.g. Gitlin et al., 1985; Clark, Salkovskis & Chalkley, 1985)

• 1 controlled pilot study (Biofeedback, PMR & cognitive Therapy

vs. waiting list control group), with 11 patients (Barlow, Cohen et

al., 1984)


Background


Objective:

Evaluating the efficacy of a newly developed CBT for the

treatment of panic disorder


Aim of the studie


Exposition & cognitive Therapy (E&C)

Cognitive restructuring: Acquiring skills for re-evaluating beliefs and appraisals about environmental and internal physiological cues

• analysis of faulty logic, reattribution, decatastrophizing, self instruction

Interoceptive exposure after the 5th session: • Anxiety hierarchy.

• Cognitive skills were applied to anxiety provocing situations through visualisation of anxiety scences and overbreathing.

Progressive Muscle Relaxation (R)

2x exercises per day. After 5th session: exercising the use of relaxation as a coping skill

Relaxation combined with exposition und cognitive therapy (Comb)

Wait list control group


Treatment conditions


Single Therapy: 1 x per week, 15 weeks

Treatment manuals: detailed description for evry session

Therapist: 10 doctoral students and psychologists, who were trained for all interventions

Weekly supervision

Treatment Integrity • All sessions were audiotaped

• 35 tapes were randomly selected: Two 5 min segments were selected and therapist behavior was rated

• Patients rated credibility and Logic of treatment (after 1. and last session, follow up)


Application of treatments


Patients of „Phobia and Anxiety Disorder Clinic“,

State University of New York

Panic Disorder without or only slight Agoraphobia


Participants


Inclusion Criteria

DSM III-R: Panic disorder, no or slight agoraphobic avoidance

Therapist Rating: Severity of disorder > 4 (Scale 0 to 8) (Anxiety Disorder Interview Schedule-Revised; ADIS-R)

At least 1 attack within the last 2 weeks (diary, 4 times daily)

Patients who already got other treatments not related to anxiety

Stable medication

Exclusion Criteria

Age 18 to 65;

Alcohol- or substance abuse

Major depression, psychosis, organic brain syndrome

Other therapies of anxiety /

Begin of Psychopharmacological treatment • less than 3 Mon. benzodiazepines,

• less than 6 Mon. MAO-Hemmer, tricyclic antidepressants)


Sample: Inclusion and exclusion criteria


Standardized Interviews (blind judges)

Hamilton Anxiety and Depression Scales

Standardized Self-Reports

State-Trait Anxiety Inventory (Spielberger, Gorusch, & Lushene, 1970)

Cognitive Somatic Anxiety Questionnaire, (Marks & Mathews, 1979),

Fear Questionnaire (Marks & Mathews, 1979)

Beck Depression Inventory (Beck et al., 1961)

Psychosomatic Rating Scale (Cox, Freundlich & Meyer, 1975)

Subjective Symptom Scale (Modification, Hafner & Marks, 1978)

Self-Observation: Structured diary (4 times daily) Anxiety Rating from 0 to 8; Panic yes/no; stressful events?


Meassurements


Treatment responder

20% Improvement in three of four measures:

Clinical rating of severity (> 2 points)

Fear Questionnaire (> 2 points)

Number of panic attacks per week

Subjective Symptom Scale Total score (> 8 points)

Treatment non-responder

Deterioration of 20% (Pre-Post) in any of the measures (independent of improvement in other variables)

End state functioning

absolute level of functioning at Post-Assessment(only completers) • low end state (LES) vs high end state (HES)


Composite measures of clinically significant change


Patients were randomly assigned to 4 conditions

Assessment : Pre – Post – Follow up: 3, 6, 12, 24 months


Research Design



Sample size and drop-outs (in %)

Comparison drop-outs vs. completers (ANOVAS)

Drop-outs: lower severity at pre treatment

Higher consumption of anxiolytics

Pre Post 6-Month 24-Month

Wait-list 16 15 (6%) - -

Exposition (E) &

Cognitive Therapie (C)

16 15 (6%) 8 15

Relaxation (R) 15 10 (33%*) 9 9

Combined (E & C & R) 20 16 (17%) 6 10

* signifikant



Change in sample size over time



„Treatment Responders“ at Post-Assessment

significant

N = 54; lacking information for n = 13



„High End-State Functioning“ at Post-assessment

significant

N = 53; lacking information for n = 14



Comparison: Pre-Post Assessment

Reduction in clinical rating of severity

• All treatment groups significantly improved but not CG

• All treatment groups were significantly better than CG

Reduction in Hamilton Anxiety Score

• All treatment groups significantly improved but not CG

• R and Combined G were significantly better than control

group

Psychosomatic Symptoms

• Only relaxation group significantly improved

• Only R was significantly better than CG

No significant differences in the other measures



Patients without panic attacks. Post-Assessment

(Study completers)



Patients without panic attacks. Post-Assessment

(Intent to treat analysis with total sample)



24 Month Follow-Up: Summary

Maintainance of therapy success

Decrease of trait-anxiety and somatic symptoms

(Post vs. 24 months)

BDI-Scores

• Increase in R-group

• Decrease in E & C-group



Participants with high end state and without panic

(Excluding drop outs)



Participants with high end state and without panic

(Including drop outs)

significant for „Panic-Free“



24 months Follow-Up:

Other Psychological Treatments

Alternative Psychotherapy:

R 83%, E&C 33%, COMB 40%

Psychopharmaca

R 71%, E&C 17%, COMB 43%



Summary of results

Post Assessment: (R, E&C, E&C&R) > Wait list

In relaxation group, less patients were panic free,

However anxiety and psychosomatic symptoms were reduced.

Follow up: Maintenance of therapy success over 2 years

For patients with interoceptive exposer and cognitive restructuring

Patients in relaxation group less stable patterns

• Highest drop out rate

• Highest rate of additional treatment

Cognitive behavioral therapy with relaxation (E&C&R) was not more efficacious than E&C



Conclusions

Panic disorder without agoraphobic avoidance can be efficaciously treated with a combination of interoceptive exposer + cognitive restructuring

Directly after treatment, relaxation is as efficacious as interoceptive exposer + cognitive restructuring, but in the long run it is less efficacious.

Relaxation is not a necessary component of an efficacious treatment of panic disorder. Interoceptive exposer + cognitive restructuring is sufficient.

Compared to results in the literature, long term effects of interoceptive exposer and cognitive restructuring seem to better than pharmacological treatment


Cognitive-behavioral therapy, pharmacotherapy, or their combination for

treating panic disorder (PD): A randomized controlled trial (RCT)

(Barlow, Gorman, Shear, & Woods, 2000)

Barlow, D. H., Gorman, J. M., Shear, M. K., & Woods, S. W. (2000). Cognitive behavioral therapy, imipramine, or their

combination for panic disorder: A randomized controlled trial. Journal of the American Medical Association, 283,

2529–2536.


CBT, pharmacotherapy, or their combination? (Barlow et al., 2000)

Background

Background: Well established efficacy for two PD treatments

Psychological treatment: CBT

Pharmacological treatment with Imipramine (Tofranil)

• First tricyclic antidepressant, discovered 1951 by Ciba Geigy (today Novartis)

• increases the extracellular level of neurotransmitters (serotonin, norepinephrine ) by limiting their reabsorption (reuptake) into the presynaptic cells

• Broad range of effects

Improves mood, reduces symptoms of agitation and anxiety

side effects: dry mouth, drowsiness, dizziness, blurred vision, low blood pressure, rapid heart rate, increased sweating, diarrhea, stomach cramps, increase of appetite, weight gain



Objectives

Relative and combined efficacies of drug and PT treatment for PD have not been evaluated

Objectives: To evaluate, whether

• drug and PT for PD are each more efficacious than placebo

• one treatment is more efficacious than the other

• combined therapy is more efficacious than either therapy alone?



Study design

312 panic disorder patients were randomly assigned to five groups (double blind)

CBT

Imipramine

Drug placebo

CBT + Imipramine

CBT + Drug placebo



Treatments (acute phase)

Treatments were manualized for each condition

Acute treatment phase: 11 sessions during 12 weeks for each condition

CBT • individual 50-minute sessions

Interoceptive exposure, cognitive restructuring, and breathing training

Psychopharmacotherapy (Imipramine or Placebo) + Clinical Management • individual 30-minute contacts

monitor adverse effects, clinical state, and physical/mental condition

maximize compliance

proscribe specific interventions included in CBT (cognitive restructuring of anxiety and panic symptoms)

Imipramine treatment was slowly titrated up to a maximum of 300 mg/day

Blood levels were assessed at 6 and 12 weeks

Combined Treatment (Imipramine or Placebo + CBT) • individual contacts with 2 therapists for about 75 minutes per week.

Benzodiazepine screening of urine samples



Treatments (maintenance phase)

Responders to acute treatment entered a 6-month maintenance phase without breaking the study blind.

6 monthly appointments in which treatment similar to the acute treatment was continued

After maintenance phase treatment was stopped



Therapists

Therapists providing CBT were doctoral level clinicians who underwent extensive training

Pharmacotherapists were experienced psychiatrists who underwent additional training

Ongoing supervision, biweekly

Adherence and competence ratings were collected after listening to a sample of audiotaped sessions



Assessment

at baseline

after acute phase (3 months after baseline)

after maintenance phase (9 months after baseline)

after follow-up phase (15 months after baseline)

Trained evaluators (blind to treatment assignment) judged patients on

• Panic Disorder Severity Scale (PDSS)

clinician-rated scale of PD severity

Response was defined > 40% reduction of PD symptoms

• Clinical Global Impression Scale (CGI),

7-point ratings on 2 items: overall improvement and severity

Definition of responders:

• CGI much improved (≤ 2) while being rated as mild or less (≤ 3) on CGI severity

• Patients who received nonstudy treatment for anxiety = nonresponders



Patients

Inclusion criteria:

Potential participants met DSM-III-R or DSM-IV criteria for PD with no more than mild agoraphobia (ADIS-R avoidance scale ≤ 18)

Panic attack(s) in the 2 weeks before treatment

Patients with comorbid unipolar depression were not excluded

Patients were permitted to take benzodiazepines until end of acute phase

Exclusion criteria

psychotic, bipolar, or significant medical illnesses,

suicidality, significant substance abuse,

contraindications to either treatment,

prior nonresponse to similar treatments,

concurrent competing treatment or pending disability claims



Allocation of Patients



Drop outs during acute phase


0

10

20

30

40

50

60

70

80

90

100

Placebo CBT IPT CBT + Placebo CBT + Imipramine

Per

cent

Response was defined > 40% reduction in symptoms on Panic Disorder Severity Scale (PDSS) rated by trained evaluators


Responders (%) at the end of acute phase (3 months) (Intent to treat, N = 312)

*

Imipramine


0

10

20

30

40

50

60

70

80

90

100


Per

cent



Responders (%) at the end of acute phase (3 months) (intent to treat)

*

*

Imipramine


0

10

20

30

40

50

60

70

80

90

100


Per

cent


n.s.



*

*

Imipramine


0

10

20

30

40

50

60

70

80

90

100


Per

cent


n.s.

n.s.



*

*

Imipramine


0

10

20

30

40

50

60

70

80

90

100


Per

cent


n.s.

n.s.

n.s.



*

*

Imipramine


0

10

20

30

40

50

60

70

80

90

100


Per

cent


n.s.

n.s. n.s.

n.s.



*

*

Imipramine



Responders (%) at the end of acute phase (3 months) (completers N = 213)

*

#

#

n.s.

n.s. n.s.

0

10

20

30

40

50

60

70

80

90

100

Placebo CBT Imipramine CBT + Placebo CBT + Imipramine

Per

cent



Responders in maintenance phase and follow up

Only Responders entered maintenance phase



Responders (%) at the end of 6-month maintenance phase (Intention to continue maintenance N = 170)

*

#

#

n.s.

n.s. n.s.

0

10

20

30

40

50

60

70

80

90

100


Per

cent



Responders (%) at the end of 6-month maintenance phase (Intent to treat, N = 312)

0

10

20

30

40

50

60

70

80

90

100


Per

cent

Imipramine

*

*

*

*

After 6-month maintenance phase: responders continued medication or monthly CBT



Responders in maintenance phase and follow up

Only Responders entered maintenance phase

Maintenance responders were assessed at follow up; except 17, who were randomly selected for a pilot study.



Responders (%) at the end of 6-month follow up phase (Intention to continue follow up: N = 116)

n.s.

n.s.

**

n.s.

* #

0

10

20

30

40

50

60

70

80

90

100


Per

cent


0

10

20

30

40

50

60

70

80

90

100


Per

cent

#

Imipramine


Responders (%) at follow up 6 months after maintenance (Intent to treat, N = 295; 17 were randomly excluded after

maintenance phase)

* #

After 6-month follow up without treatment



Summary and conclusions of the authors

Both imipramine and CBT are better than pill placebo for treatment of PD (post acute, post maintenance)

High attrition in placebo group; weak and non durable response

Imipramine produced a superior quality of response until end of maintenance

CBT had more durability and was somewhat better tolerated

• Relapse 4% for CBT, 25% for Imipramine

Coadministration of Imipramine and CBT resulted in limited benefit over monotherapy

• Improvement after maintenance

• addition of imipramine appeared to reduce long-term durability of CBT

Potential underestimation of benefits of medication by using a tricyclic antidepressant instead of an SSRI



What are limitations and problems of this study?




Design is in favor of pharmacotherapy

• Pharmacotherapy = drug (placebo) + clinical management Imipramine and Placebo condition: Every week 30-minute contact with psychiatrist; recommendations and prescription

of exposure (not typical for usual psychiatric drug treatment) Combined treatment (Imipramine or Placebo + CBT), individual contacts with 2 therapists for about 75 minutes per week

(higher dosage of treatment than CBT alone)

• Assessment only based on external interviewer ratings of current symptoms and improvement. Patients perspective was not assessed, which shows usually less difference to placebo No adverse effects of treatment were assessed (side effects)

Pharmacotherapists were experienced psychiatrists; CBT therapists were doctoral level clinicians, prior

experience was not required

Placebo effect was probably underestimated • Blinding did probably not work for many patients because placebo did neither produce positive effects nor

side effects • Blinding did probably not work for doctors -> lower positive expectations

High and selective drop out rates impair interpretation of results

• Drop outs in placebo group: post = 58%, maintenance and follow up = 88% • Drop outs imipramine: post = 39%, maintenance = 52%, follow up = 68% • Drop outs CBT: post = 27%, maintenance = 47%, follow up = 62%

• -> underestimation of placebo effect in ITT analyses




Selected patients who accept drug treatment

Many patients who were eligible refused participation in the study

• unwilling to start treatment with imipramine (30.6% and 47.4%), or

discontinue their current medication (22.6% and 35.1%).

“Results from comparative treatment outcome studies are limited

not only to people who meet the study criteria but also to those who

are willing to begin a medication treatment and discontinue their

current medication.” (Hofmann et al., 1998, p. 43)




Design is in favor of pharmacotherapy

• Pharmacotherapy = drug (placebo) + clinical management

Imipramine and Placebo condition: Every week 30-minute contact with psychiatrist; recommendations and prescription of exposure

Combined treatment (Imipramine or Placebo + CBT), individual contacts with 2 therapists for about 75 minutes per week (higher dosage of treatment than CBT alone)

• Blinding did probably not work for many patients because Placebo did neither produce positive effects nor side effects

• Blinding did probably not work for doctors

• Assessment is only based on external interviewer ratings of current symptoms and improvement. Patients perspective was not assessed

• No adverse effects of treatment were assessed (side effects)

High drop out rates



Conclusion drawn from the Barlow et al. (2000) study (APA practice guidelines, 2009, p. 52)

This study provided evidence for the short- and long-term efficacy of CBT

CBT is largely equivalent in short-term efficacy to imipramine and combination treatments,

CBT may produce more durable effects than imipramine or the combination of CBT and imipramine


Conclusions about efficacy of CBT treatments for panic disorder (APA practice guidelines, 2009, p. 51)

There are numerous controlled trials demonstrating the efficacy of CBT for panic disorder

Meta-analyses of clinical trials support the conclusion that effects of CBT for panic disorder are robust and durable.


Take home message

With an RCT Barlow & colleagues (1989) could show that • Relaxation is not a necessary component for treating panic disorder, relaxation is sufficient • Cognitive restructuring and interoceptive exposer is an efficacious treatment for panic

disorder and an alternative to pharmacotherapy

With another RCT Barlow et al. (2000) could show

• that CBT is as efficacious as Imipramine for the treatment of panic disorder directly after treatment

• After treatment has been stopped CBT is more efficacious than imipramine.

CBT is recommended as a first line treatment for panic disorder in national guidelines:

• American Psychiatric Association (APA) (2009). https://www.psychiatry.org/psychiatrists/practice/clinical-practice-guidelines

• National Institute for Health and Care Excellence (NICE) (2011, 2015). https://www.nice.org.uk/guidance/cg113

• Arbeitsgemeinschaft der Wissenschaftlichen Medizinischen Fachgesellschaften e.V. (AWMF) http://www.awmf.org/leitlinien/detail/ll/051-028.html

• Compare guidelines with critical Cochrane review (Imai, Tajika, Chen, Pompoli, & Furukawa, 2016).

https://www.psychiatry.org/psychiatrists/practice/clinical-practice-guidelines





https://www.nice.org.uk/guidance/cg113

https://www.nice.org.uk/guidance/cg113

http://www.awmf.org/leitlinien/detail/ll/051-028.html





Take home message: Methodological issues

Drop outs are a common problem in therapy outcome studies

“Intent to treat analysis” (ITT) (e.g. last value carried forward) is a method to deal with drop outs

• ITT might change the pattern of results suggested by completer analyses

• When drop out rates are different for different conditions, ITT may lead to biased results

Long term follow up assessments are essential to demonstrate the sustainability of treatment effects

There might be problems with the generalization of results

• Treatments are not applied as in clinical practice

• Patients are highly selected


References

American Psychiatric Association (2009). Practice guideline for the treatment of patients With panic disorder (2nd ed.). American Psychiatric Association. Retrieved 20.3.2018 from https://psychiatryonline.org/pb/assets/raw/sitewide/practice_guidelines/guidelines/panicdisorder.pdf

American Psychiatric Association [APA] (2013). Diagnostic and statistical manual of mental disorders (5th ed.). Washington, DC: American Psychiatric Association.

Bandelow, B., Wiltink, J., Alpers, G. W., Benecke, C., Deckert, J., Eckhardt-Henn, A., ... Beutel, M. E. (2014). Deutsche S3-Leitlinie Behandlung von Angststörungen. Retrieved 20.3.2018 from http://www.awmf.org/uploads/tx_szleitlinien/051-028l_S3_Angstst%C3%B6rungen_2014-05_2.pdf

Barlow, D. H., Craske, M. G., Cerny, J. A. & Klosko, J. S. (1989). Behavioral treatment of panic disorder. Behavior Therapy, 20, 261-282.

Barlow, D. H., Gorman, J. M., Shear, M. K., & Woods, S. W. (2000). Cognitive-behavioral therapy, imipramine, or their combination for panic disorder: A randomized controlled trial. Journal of the American Medical Association, 283, 2529–2536.

Craske, M. G., Brown, T. A. & Barlow, D. H. (1991). Behavioral treatment of panic disorder: A two-year follow-up. Behavior Therapy, 22, 289-304.

Hofmann, S. G., Barlow, D. H., Papp, L. A., Detweiler, M. F., Ray, S. E., Shear, M. K., ... Gorman, J. K. (1998). Pretreatment attrition in a comparative treatment outcome study on panic disorder. American Journal of Psychiatry, 155 (1), 43-47.

Imai, H., Tajika, A., Chen, P., Pompoli, A., & Furukawa T. A. (2016). Psychological therapies versus pharmacological interventions for panic disorder with or without agoraphobia in adults. Cochrane Database of Systematic Reviews, 10, Art. No.: CD011170. DOI: 10.1002/14651858.CD011170.pub2.

National Institute for Health and Care Excellence [NICE] (2011). Generalised anxiety disorder and panic disorder in adults: management. Clinical guideline. Retrieved 20.3.2018 from https://www.nice.org.uk/guidance/cg113/resources/generalised-anxiety-disorder-and-panic-disorder-in-adults-management-pdf-35109387756997

National Institute for Health and Care Excellence [NICE] (2015). Generalised anxiety disorder and panic disorder (with or without agoraphobia) in adults: Management in primary, secondary and community care. Recommendation for Guidance Executive. Retrieved 20.3.2018 from https://www.nice.org.uk/guidance/cg113/evidence/surveillance-review-decision-july-2015-pdf-2482902685

http://www.awmf.org/uploads/tx_szleitlinien/051-028l_S3_Angstst%C3%B6rungen_2014-05_2.pdf






https://www.nice.org.uk/guidance/cg113/resources/generalised-anxiety-disorder-and-panic-disorder-in-adults-management-pdf-35109387756997






















https://www.nice.org.uk/guidance/cg113/evidence/surveillance-review-decision-july-2015-pdf-2482902685















Links to Practice Guidelines

United States • American Psychiatric Association (APA)


United Kingdom • National Institute for Health and Care Excellence (NICE)

https://www.nice.org.uk/

Germany • Arbeitsgemeinschaft der Wissenschaftlichen Medizinischen Fachgesellschaften e.V.

(AWMF) http://www.awmf.org/leitlinien/leitlinien-suche.html

Cochrane Society • “Global independent network of researchers, professionals, patients, carers, and

people interested in health” • “Cochrane contributors - 37,000 from more than 130 countries - work together to

produce credible, accessible health information that is free from ccommercial sponsorship and other conflicts of interest.” Retrieved 21.3.2018 from http://www.cochrane.org/about-us

• http://www.cochrane.org/








https://www.nice.org.uk/

http://www.awmf.org/leitlinien/leitlinien-suche.html





http://www.cochrane.org/about-us



http://www.cochrane.org/

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