Treatment Resistant Schizophrenia

WHAT IS SCHIZOPHRENIA?

Schizophrenia comprises a group of disorder with heterogeneous etiologies, and it includes patients whose clinical presentation, treatment response and course of illness vary. Sign and symptoms are variable and include change in perception, emotion, cognition, thinking and behavior.

This disorder usually begins before 25years,persists throughout the life and affect the person of all social classes

Prevalence of Schizophrenia in Specific Populations

Population Prevalence (%)

General population 1%

Non-twin sibling of a schizophrenia patient 8%

Child with one parent with schizophrenia 12%

Dizygotic twin of a schizophrenia patient 12%

Child of two parents with schizophrenia 40%

Monozygotic twin of a schizophrenia patient 47%

COURSE AND PROGNOSIS Each relapse leads to further deterioration of baseline functioning

POSITIVE SYMPTOMS NEGATIVE SYMPTOMS

10-20% patients have a good outcome

> 50% patients have a poor outcome

Remission rate is 10 – 60%

COURSE AND PROGNOSIS

20-30% patients can lead a somewhat normal life 20-30% patients continue to experience moderate

symptoms 40-60% patients have significant lifetime impairment

Features Weighting Toward Good to Poor Prognosis in Schizophrenia

Good Prognosis Poor Prognosis

Late onset Young onset

Obvious precipitating factors No precipitating factors

Acute onset Insidious onset

Good premorbid social, sexual, and work histories Poor premorbid social, sexual, and

work histories Mood disorder symptoms (especially depressive disorders) Withdrawn, autistic behavior

Married Single, divorced, or widowed

Family history of mood disorders Family history of schizophrenia

Good support systems Poor support systems

Positive symptoms Negative symptoms

History of perinatal trauma No remissions in 3 years Many relapses History of assaultiveness

WHAT IS TREATMENT RESISTANT SCHIZOPHRENIA

Treatment resistant” schizophrenia (TRS) is defined by an inadequate response to a succession of treatments” (Taylor and Duncan-McConnell, 2000).

It can be applied even if a patient has not had a trial of ECT. The concept of treatment resistance should not be confused with: “ chronic schizophrenia” as chronicity and “resistance” are different concepts.

Chronic patients can respond to standard treatments and treatment resistance may be as high as 15% even in first episode patients(McGorry et al., 2003).

The prevalence of TRS is estimated to be 30-50% of patients with the diagnosis of schizophrenia.

Two forms of treatment resistant schizophrenia are: 1) Kraepelinean schizophrenia which refers to patients with severe,

persistent cognitive deterioration; and 2) “negative” or “deficit” schizophrenia: schizophrenia patients with

prominent and persistent primary negative symptoms, including very flat affect.

Criteria of TRS: TRS is present if the patient fulfills the following criteria which are modified from those of Kane et al (1988) to be useful in everyday clinical practice

1) prior non-response to at least 2 antipsychotic drugs of two different chemical classes for at least 4-6 weeks each at doses ≥ 400 mg equivalents of chlorpromazine or 5 mg/day Risperidone in the last 5 years without significant clinical improvement.

2) moderate to severe psychopathology, especially positive symptoms: conceptual disorganization, suspiciousness, delusions or hallucinatory behavior.

3) Reduction of at least 20% on the BPRS scale, score > 35 points on the BPRS scale after treatment, CGI score > 3 after treatment with 60 mg/day of haloperidol for 6 weeks

Brenner’s criteria for treatment-resistant schizophrenia

LEVEL 1- Clinical remission - No need for a formal rehabilitation program, Rapid response to antipsychotics at recommended doses. Patient may show anhedonia or another negative symptom. CGI normal and score < 2 on BPRS. Good functional level without supervision.

Level 2- Partial remission- No need for a formal rehabilitation program ,Rapid reduction of psychotic symptoms. Mild signs of residual psychotic symptoms. CGI 2. None of the BPRS scale items are > 3.

Level 3- Light resistance - Need for a rehabilitation program, Slight or incomplete reduction of symptoms with positive and negative residual symptoms. Alteration of social or personal functioning in at least two areas and requiring occasional supervision. No more than one item with a score > 4 on the BPRS.

Level 4 - Moderate resistance- Need for a rehabilitation program, Reduction of symptoms but with a clear persistence of them, affecting six or more areas of social and personal functioning and requiring frequent supervision. CGI 4. A score of 4 on 2 BPRS items. A BPRS score 45 on the 18-item version and 60 on the 24 item version.

Level 5- Severe resistance - Need for a continuous strategy, with atypical antipsychotics and adjuvant treatment, Reduction of symptoms but with a clear persistence of them, affecting six or more areas of social and personal functioning and requiring frequent supervision. CGI 5. A score of 5 on 1 BPRS item or >4 on 3 items. A total BPRS > 50 on the 18-item version and 67 on the 24-item version.

Level 6- Refractoriness - Longer-term hospitalization with pharmacological and psychosocial attempts, Reduction of mild or non-demonstrable symptoms and persistence of positive and negative symptoms with marked alteration in all areas of social and personal functioning. CGI 6. A score of 6 on 1 BPRS item or of > 5 on 2 items. Total BPRS score of >5 per level.

Level 7 - Severe refractoriness - Longer-term hospitalization with pharmacological and psychosocial attempts .No reduction of symptoms with many positive and negative symptoms associated with behavioral alterations. All areas of social and personal functioning have deteriorated, requiring constant supervision. CGI 7. A score of 7 on 1 BPRS item. Total score of > 5 per level

PREDICTORS OF TRS

Early age of onset Male gender Higher number of hospitalizations No. of episodes of illness History of obstetric complications Long duration of untreated psychosis History of substance abuse

FACTORS RELATED TO TREATMENT RESISTANT SCHIZOPHRENIABIOLOGICAL FACTORS

• Structural brain abnormalities• Family history

• Neurochemichal abnormalities

NON PHARMACOLOGICAL PREDICTORS

• Delay of psychosocial intervention

• Insufficient quality of treatment and rehabilitation

• Poor therapeutic alliance

PSYCHOSOCIAL FAMILY FACTORS

• Situational stress, aggression• Reluctance against treatment

• Cultural background

SYMPTOMATIC FACTORS• Severity of

symptoms(especially positive and/or negative symptoms)•Marked cognitive impairment• Poor early course pattern

TREATMENT RESISTANT SCHIZOPHRENIA

PHARMACOLOGICAL PREDICTORS

•Delay in initiating pharmacological treatment

• Incorrect choice , dose , and duration of psychotropic treatment

• Appearance of EPS/TD• Psychotropic drug-drug

interactions

OTHER ILLNESS FACTORS

• Poor premorbid adjustment• Childhood onset

schizophrenia• Comorbidity(e.g. substance

abuse)• Learning disability

ENVIRONMENTAL FACTORS

• Lack of social network(e.g. homelessness,lack of family

support)• Migration

PSYCHOLOGICAL PATIENT FACTORS

• Lack of insight• Negative attitude towards

treatment• Adverse life events

OTHER FACTORS• Male gender

• Non adherence with medication

• Disengagement from treatment

NEUROIMAGING AND TRS

TWO TYPES OF STUDIES

Retrospective/cohort Prospective/case controlBrain abnormalities Treatment response

are related to treatment is related to brain outcomes. abnormalities.

RETROSPECTIVE STUDIES Ventricular enlargement is related to poor

outcome

PROSPECTIVE STUDIES Ventricular enlargement is associated with

response to conventional antipsychotics Cortical atrophy mediates the effect of atypical

neuroleptics

OTHER PSYCHOBIOLOGIC CORELATES

Altered T cell functions

Alteration of interleukins mediated inflammatory process

Oral doses for an SGA for treatment-responsive schizophrenia and eventually in some cases of TRS:

Risperidone: 4 to 6 mg/dayOlanzapine: 10 to 20 mg/dayQuetiapine: 300 to 600 mg/dayAripiprazole: 15 to 30 mg/dayClozapine : 300 to 600 mg/day

Treatment approaches to TRSCarefully evaluate whether the patient has had an adequate trial of an antipsychotic,including whether the dose was adequate and whether the patient was taking the medication as prescribed.

Consider a trial of clozapine for a patient who has had what is considered a clinically inadequate response to 2 antipsychotics and for a patient with persistent suicidal ideation that has not respond to other treatments.

Depending on the type of residual symptom(positive,negative,cognitive or mood symptoms,aggressive behavior)augmentation strategies include adding another antipsychotic,anticonvulsants or BZD

ECT has demonstrated benefits in patients with treatment resistant symptoms

CBT may have value in improving positive symptoms with low risk of side effects.

Clozapine has two FDA indications

The treatment-resistant schizophrenia

Risk reduction of recurrent suicidal behavior

Clozapine A meta-analysis of 12 randomized controlled trials of atypical antipsychotic

drugs found that clozapine was the treatment of choice for TRS. (Chakos et al: 2001)

clozapine was introduced in the United States in 1990, although it had been available in some countries in Europe since the early 1970s.The atypical antipsychotic agent clozapine is associated with a lower propensity for extrapyramidal symptoms than classical antipsychotic agents.

Clozapine is a five-membered heterocyclic compound, 8-chloro-11-(4-methyl-1-piperazinyl)-5H-dibenzo-[1,4-] diazepine.

clozapine does interfere with the binding of dopamine at D1,D2,D3 and D5, receptors, and has a high affinity for the D4 receptor.

Clozapine is preferentially more active at limbic dopamine receptor, may explain the relative freedom of clozapine from EPS.

Clozapine also acts as an antagonist at adrenergic,cholinergic,histaminergic and serotonergic receptors.

Metabolism is exensive and occurs mainly in liver. Clozapine is efficacious in the treatment of both positive and negative

symptoms,it improves cognition and reduce suicidality.

Precautions and Adverse Reactions The only contraindications to the use of clozapine are a WBC count below 3,500

cells per mm3, a previous bone marrow disorder, a history of agranulocytosis during clozapine treatment, or the concomitant use of another bone marrow suppressant drug such as carbamazepine . Although the mechanism of action is unknown, there is a slight risk of respiratory depression or collapse if treatment is initiated while patients are taking benzodiazepines.

SIDE EFFECTS Sedation Dizziness Syncope Tachycardia most common side effects Hypotension ECG changes Nausea Vomiting Fatigue Weight gain Constipation Hypersalivation anticholinergic side effects

Drug Interactions

fluvoxamine , will elevate clozapine concentrations, whereas fluoxetine administration may only lead to changes in higher dosage ranges.

selective serotonin reuptake inhibitors (SSRIs), tricyclic drugs, and valproic acid decrease clearance, whereas phenytoin and carbamazepine may decrease concentrations of clozapine (50 percent or less).

Dosage and duration Clozapine treatment should begin with 12.5 to 25.0 mg per day and

increased to 25 or 50 mg per day on the second day. The daily dose, which should be administered at least twice daily, can usually be increased by 25 mg every 1 or 2 days until a target dose of 300 to 450 mg per day is reached.

Patients who fail to respond to respond in the 300 to 450 mg per day range and who do not have serious side effects can be increased gradually to doses as high as 900 mg per day.

clozapine will continue to improve over a 3- to 6-month period. If there are concerns that patients are experiencing excessive side effects or an inadequate response, measurement of plasma concentration may be helpful. Levels above 350 ng/mL are an indication that patients are receiving adequate dosages of clozapin

TREATMENT OVERVIEW

Reviews of controlled trials of the effectiveness of second-generation antipsychotics versus first-generation antipsychotics or second generation antipsychotics in patients who have treatment resistant schizophreniaAuthor, Year Controlled Trials Number of Subjects Results/Conclusions

Wahlbeck et al , 1999 Clozapine versus FGA: 30 studies ,12 versus chlorpromazine13 versus haloperidol1 versus trifluoperazine1 versus thioridazine1 versus clopenthixol2 various

2530 Patients treated with clozapine showed more clinical improvement and less relapses in long term than in short term studies

Taylor and Duncan- McConnell, 2000 Clozapine: 8 studies3 versus chlorpromazine1 versus fluphenazine3 versus haloperidol1 versus zotepineRisperidone: 4 studies2 versus haloperidol2 versus clozapineOlanzapine: 2 studies1 versus chlorpromazine1 versus haloperidol

1664 Clozapine is effective in TRS.Data on others SGAs are inconclusive

Tunainer et al ,2002/2006 Clozapine versus SGA: 8 studies2 versus olanzapine1 versus remoxipride/risperidone/zotepine1 versus remoxipride4 versus risperidone

795 Almost no differences between groups in terms of global improvement andRelapses. Clozapine showed a trend for being more effective for positivesymptoms. SGAs showed a trend for being moreeffective in cognitive functions.

CLOZAPINE AUGMENTATION

A narrow definition of partial or incomplete response to clozapine is the persistence of psychotic symptoms despite a trial of clozapine with adequate doses (i.e., 300-900 mg/d) for a minimum of 8 weeks and for up to 6 months with plasma levels reaching 350 ng/ml. Thus the improvement of psychotic symptoms is considered the main treatment target, and, as an apparent logical consequence, the addition of high-potency antipsychotic medications to clozapine has been proposed for the treatment of these symptoms.

CLOZAPINE AUGMENTATION A study of sulpiride augmentation in 28 patients partially

responsive to clozapine by Shiloh et al in 1997 noted a mean reduction of 40-50% in various clinical response scores ( Brief psychiatric rating scale and scale for the assesment of positive symptoms)

A case series by Zink et al in 2004 showed improvement in previously treatment resistant symptoms following a combined treatment strategy of clozapine and amisulpiride.

Munro et al in 2004 carried out a 52 week long study of amisulpiride augmentation in which significant improvement was seen in 50% of the patients , with no additional side effects

A randomised placebo controlled cross over study of 34 patients by Tilhonen et al in 2003 revealed that lamotrigine treatment also improved positive symptoms and general psychopathological symptoms but had no effect on negative symptoms

Some studies have shown that Lamotrigine in doses of(25- 300 mg/day) may be useful in partial or non responders.

ADJUNCTIVE TREATMENT LITHIUM Studies by Shiloh et al found that as an adjunct lithium

may enhance the efficacy of antipsychotic medication Also effective in affective symptoms ,impulsivity ,

violent behavior ANTICONVULSANTS Addition of valproic acid helps in resolving manic ,

impulsive or violent behavior ANTIDEPRESSANTS Adjuvation with antidepressants such as SSRI’s can

help in resolving residual negative symptoms , obssesive compulsive symptoms , and other anxiety symptoms besides depression.

BETA BLOCKERS High dose propranolol (upto 1200mg/day)

augments antipsychotic efficacy in treatment refractory schizophrenia

It can treat akathesia Increases antipsychotic serum levels Decreases anxiety symptoms

GLYCINE AND D CYCLOSERINE High doses of glycine (30-60 mg/day) show

improvement in negative symptoms in combination with antipsychotic medication

OTHER ATYPICAL ANTIPSYCHOTICS RISPERIDONE

In a 10 week open label trial of risperidone v/s clozapine by Wahlbeck et al in 2000 using 20% decrease in the PANSS score as sign of clinical improvement , it was found that there was not much significant difference between the two drugs.however there was an unusual dropout rate of patients taking clozapine (5 out of 10) which significantly reduced the power of the study.

OLANZAPINE Conley et al in 1998 concluded that olanzapine was no

better than chlorpromazine in treatment resistance Lindenmayer et al in 2002 showed that olanzapine lead

to improvement in symptoms related to cognitive functions

In an 8 week open and double blind trial by Conley et al in 1999 treatment resistant patients were first administered olanzapine and then subsequent olanzapine resistant patients were treated with clozapine. only 5% of the patients responded to olanzapine ,rest of the patients who were switched over to clozapine 41% patients reported improvement

Open label studies of olanzapine by Martin et al.(1997) and Dursun et al(1999)., have shown that olanzapine at moderate to high doses 25-40 mg/day is effective for a significant proportion of treatment resistant patients

QUETIAPINE Case reports by ,I Reznik (1996) suggest that

some treatment resistant patients respond to quetiapine

ARIPIPRAZOLE Studies by M Kutol (2003) showed that moderate

effect of aripiprazole (15-30 mg/day) has been seen in patients resistant to risperidone or olanzapine

Chang et al.(2008) studied augmentation of clozapine with aripiprazole and found significant improvement in the negative symptoms, and significantly lower level of prolactin and triglycerides in the patients treated with the combination.

Nonpharmacologic augmentation strategies

ELECTROCONVULSIVE THERAPY

ECT can augment the response to clozapine

The efficacy of this combination treatment is based on the mechanisms such as clozapine induced lowering of the seizure threshold and ECT compromising the blood brain barrier so that greater amounts of clozapine penetrate into the brain.

A review study of 36 published cases by M Kupchik of clozapine treatment combined with ECT showed that 67% of the patients benefitted from this treatment

TRANSCRANIAL MAGNETIC STIMULATION

TMS has been used in controlled studies to treat medication-resistant auditory hallucinations

Rosa and colleagues (2007) did a controlled study of the use of TMS to treat persistent hallucinations in clozapine nonresponders which showed that TMS can be administered safely to patients taking clozapine.These patients showed improvement in the severity of their persistent hallucinations

Psychosocial treatments

Individual Psychotherapy

Individual psychotherapy involves regularly scheduled talks between the patient and a mental health professional

The sessions may focus on current or past problems, experiences, thoughts, feelings or relationships.

By sharing experiences with a trained empathic person (talking about their world with someone outside it) individuals with schizophrenia may gradually come to understand more about themselves and their problems.

Recent studies indicate that supportive, reality-oriented, individual psychotherapy, can be beneficial for outpatients with schizophrenia.

Family education

It is important that family members learn all they can about schizophrenia and understand the difficulties and problems associated with the illness.

It is also helpful for family members to learn ways to minimize the patient’s chance of relapse — for example, by using different treatment adherence strategies — and to be aware of the various kinds of outpatient and family services available in the period after hospitalization.

Family “psychoeducation,” which includes teaching various coping strategies and problem-solving skills, may help families deal more effectively with their ill relative and may contribute to an improved outcome for the patient.

Self help groups Although not led by a professional therapist, these groups may be

therapeutic because members provide continuing mutual support as well as comfort in knowing that they are not alone in the problems they face.

Self-help groups may also serve other important functions.

Patients acting as a group rather than individually may be better able to dispel stigma and draw public attention to such abuses as discrimination against the mentally ill.

Family and peer support and advocacy groups are very active and provide useful information and assistance for patients and families of patients with schizophrenia.

Social Skills Training Social skills are those "…specific response capabilities necessary for

effective social performance“ .

Social skills training uses learning theory principles to improve social functioning by working with patients to remediate problems in activities of daily living, employment, leisure, and relationships.

It is hoped that the improved skills (primary outcome) will generalize to better community functioning and have a downstream effect on relapse and psychopathology.

There are three forms of social skills training: the basic model, the social problem-solving model, and the cognitive remediation model.

Cognitive Behavior Therapy Over the past decade, there has been a growing interest in applying

cognitive behavior therapy techniques to persons with schizophrenia, particularly those who continue to experience psychotic symptoms despite optimal pharmacological treatment.

The principal aims of cognitive behavior therapy for medication-resistant psychosis are to reduce the intensity of delusions and hallucinations (and the related distress) and promote active participation of the individual in reducing the risk of relapse and levels of social disability.

Interventions focus on rationally exploring the subjective nature of the psychotic symptoms, challenging the evidence for these, and subjecting such beliefs and experiences to reality testing.

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