GUIDELINES FOR THE TREATMENT OF SCHIZOPHRENIA

Document prepared by:

P. Kulhara, S. Chakrabarti

Department of Psychiatry, PGIMER, Chandigarh

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GUIDELINES FOR THE TREATMENT OF SCHIZOPHRENIA

INTRODUCTION

Schizophrenia is one of the major mental health problems of our time. It is prevalent worldwide and rates of 2-3 per 1000 reported from India (Murthy et al., 1997) are in line with other countries. The illness has substantial short-term and long-term consequences for the individuals affected, their families, and the society. The symptoms can cause immense distress to patients, and are often associated with a variety of social and occupational impairments. There is also an increased incidence of several medicaldisorders and mortality, especially from suicide. The condition usually disrupts the family life of afflictedpersons, and has considerable adverse impact on relatives or caregivers. The social and economic burdenit poses for the community makes it one of the most serious health problems faced by the society.

Cross-cultural studies have shown that culture has an important effect on the natural history of the disorder. (Jablensky et al., 1992; WHO, 1973) The socio-cultural milieu of developing countries like India seem to augur for a more favourable course and outcome, though the reasons for this are not quite clear. Over the years there have been many new advancesin the understanding and management of schizophrenia. Not surprisingly, these developments have had a positive impact on the way the condition is managed in India. Despite this the lot of a majority of the Indian

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patients does not seem to have improved. This is partlybecause the lack of sustained efforts to adapt existingtreatments to suit the specific requirements of Indian patients and their families. Part of the difficulty also lies in the mental health services presently existing in the country. Treatment facilities vary widely but a shortage of trained personnel and sparse community resources are common to all. Lack of awareness about mental illness, stigma encountered by sufferers and their kin, belief in supernatural causation and traditional methods of care often compound these problems. Poverty, lack of education, and inadequate access to health care facilities also place severe constraints on what can be offered. In this situation simple replication of Western treatment models and strategies is clearly neither possible, nor appropriate. The need to develop treatments tailored tomeet the requirements of our patients and appropriatelymatch the existing resources has been voiced time and again. However, very little has been achieved.

The current document is a small step towards meeting this need by formulating certain principles to guide the treatment of schizophrenia in the Indian context. The aim is to set down certain minimum standards that need to be taken into account while caring for our patients and their families.

Scope of this document

These guidelines seek to summarize data available on major treatments available for people with schizophrenia, with the hope that this knowledge will help ensure uniform standards of care. They are neithercomprehensive nor definitive. Psychiatrists caring for a patient should consider, but not be limited to the recommendations made. Patients of schizophrenia are cared for in a number of different settings in our country. In their present form these guidelines are particularly applicable to general hospital psychiatricunits on the assumption that such units cater to a

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majority of these patients.4 They might not be wholly suitable for other treatment settings. They are also meant principally for adult patients. Finally, they must be regarded only as a preliminary effort, especially given the paucity of previous work in this area in India. It is expected that several modifications and revisions will be required to improvetheir usefulness. Inputs from all mental health professionals in the country in this regard will thus be more than welcome.

GUIDELINES REVIEWED

1. American Psychiatric Association. Practice Guideline for the Treatment of Patients With Schizophrenia (APA, 1997).

2. National Institute for Clinical Excellence (NICE). Schizophrenia guidelines (NICE, 2002).

3. CRAG/SCOTMEG Working Group on Mental Illness (1995). Services for people affected by schizophrenia. A good practice statement. The Scottish Office. National Health Service in Scotland.

4. Pharmacotherapy algorithms. Japanese Psychopharmacology Algorithm Project (Hayashida & Nakane, 1999; Koshino, 1999; Tsutumi & Uchimura, 1999; Kusumi & Koyama, 1999; Saito & Saijo, 1999).

5. Texas Medication Algorithm Project (TMAP). Schizophrenia algorithms (Miller et al., 1999).

6. Expert Consensus Guideline Series. Treatment of Schizophrenia (Expert Consensus Guidelines, LLC., 1999)

7. Task Force of the World Psychiatric Association (WPA). The usefulness and use of second-generation antipsychotic medications – an update(Sartorius et al., 2002; 2003).

8. The Royal College of Psychiatrists’ consensus statement on the use of high-dose antipsychotic medication (Thompson 1994).

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9. World Health Organization consensus statement onprophylactic use of anticholinergics in patientson long-term neuroleptic treatment (1990).

10. Management of schizophrenia. Guidelines for minimum standards of care (Kulhara et al., 1999;2000).

11. American Psychiatric Association. Practice Guideline for the Treatment of Patients With Schizophrenia, Second Edition (APA, 2004).

REVIEW OF TREATMENT MODALITIES

General issues

Consideration has to be given to several factors while treating a patient with schizophrenia. Among others these would include clinical issues (both cross-sectional and longitudinal), socio-cultural variables such as attitudes to and beliefs about the illness or its treatment, service parameters e.g. thetype of treatment facilities available, and so on. Despite considerable differences in such factors for individual patients, certain elements of care are common to all. Many patients with the condition will require comprehensive and continuous treatment for prolonged periods. Wherever possible an integrated, bio-psychosocial approach to care will need to be adopted. An active collaboration with the family while planning and delivering treatment is almost always required. Management should be sensitive to the patient’s needs and empirically titrated to the patient’s response and progress.Since there is no cure for the condition, treatment seeks to decrease the morbidity and mortality associated with the disorder. The general goals of treatment are to decrease the frequency, severity andconsequences of episodes (exacerbations) and maximizefunctioning between episodes. Specific goals depend on the specific phases of illness.

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Phases of illness/treatment

Acute phase

This is the florid psychotic phase during which patients exhibit symptoms such as delusions or hallucinations, disorganized thinking, behavioural disturbances e.g. extreme agitation or retardation etc. Their functioning is severely impaired, they areunable to care for themselves, and can be at risk of harming themselves or others. The principal tasks of treatment are reduction of symptoms and risk of harm,and improvement of functioning. (APA, 1997; NICE, 2002; CRAG/SCOTMEG, 1995).

Post-acute phase/ Stabilization phase/ Continuation-treatment phase

This phase begins once the acute symptoms reduce in severity or remit. Consolidation of remission, continued reduction in symptoms and prevention of early relapses are the usual treatment objectives during this phase, which lasts about 6 months (APA, 1997; NICE, 2002;).

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Important considerations in treatment

Comprehensive and continuous treatment for prolonged periods for most

Integrated, bio-psychosocial approach to care

Active collaboration with the family while planning and delivering treatment

Stable phase / Maintenance treatment phase

Symptoms are stable and usually less severe than in the acute stage. Negative symptoms may predominate and deficits in social and occupational functioning become more apparent. Maintaining or improving level of functioning and prevention of recurrences are the major aims of treatment (APA, 1997; NICE, 2002; Saito& Saijo, 1999).

Basic ingredients of treatment

Whatever be the phase of illness, goals of treatment,or social and cultural circumstances, certain basic principles of treatment are applicable to most, if not all patients. These include:

1. Comprehensive assessment – A systematic and comprehensive assessment of the patient’s problems, which include an evaluation of psychiatric, physical, psychosocial and cultural aspects, is the essential first step of implementing treatment. Assessments and reassessments have to be continuous and ongoing.

2. Evolving a treatment plan / regular updating – Every patient should have a well thought out treatment plan which should preferably be documented. This plan should be prepared in consultation with, and be agreed upon by relatives/carers, the patient (whenever appropriate) and other professionals involved in treatment. Since needs of patients arelikely to vary with time, this plan will need to be revised and updated regularly depending on the demands of the situation.

3. Monitoring – Continuous monitoring of clinical status, response to treatment, adverse effects etc. is necessary to pre-empt relapses and preventsetbacks.

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Treatment-phases and goals

Acute phase Reduction of symptoms and risk of

harm, improvement of functioning

Post-acute phase Consolidation of remission,

continued reduction in symptoms, prevention of early relapses

4. Forming a therapeutic alliance – A supportive therapeutic alliance with the patient forms the foundation on which treatment is carried out. Mutual trust, respect and continuity of care greatly aid this process.

5. Collaborating with the family – A similar alliance with the family also furthers treatment. Relatives are invaluable sources of information; they can help by endorsing treatment decisions, ensuring compliance with treatment, closely monitoring the patient’s condition and providing support for the patient. To enable them to act effectively in thisrole they need to be involved, educated, as well as helped and supported themselves.

6. Ensuring adherence to treatment – A large percentage of patients do not comply with treatment or drop out at various stages. Their reasons for doing so may vary from mistaken beliefs to the experiencing of unpleasant side effects. Being aware of the phenomenon of non-adherence, creating an atmosphere where such problems can be freely discussed by patients, being sensitive to their needs, and modifying treatment to deal with such situations can often help in minimizing non-compliance and its consequences.

Pharmacological treatment

Medications are used for the treatment of acute episodes, prevention of relapses and recurrences, andimprovement of symptoms in the interim. Antipsychoticagents are the mainstay of treatment with antidepressants, mood stabilizers or benzodiazepines being useful adjuncts.

Antipsychotics The modern era of drug treatment of psychotic disorders began with the discovery of antipsychotic properties of chlorpromazine in the early 1950s. Tillabout the 1990s conventional antipsychotics of this kind were the only drugs available for treatment of

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schizophrenia. Though highly effective these drugs have several limitations. They cause acute and chronic extrapyramidal side effects (EPSEs), some of which can be serious or irreversible. They do not alleviate all symptoms of schizophrenia, are partially effective in a substantial proportion of patients, and largely ineffective for some signs and symptoms. NICE, 2002; Marder & van Kammen, 2000; van Kammen & Marder, 2000). These deficiencies were sought to be overcome with the introduction of a newer group of agents such as clozapine, risperidone and olanzapine. These drugs appear to have a better risk/benefit ratio and several other advantages. Thenagain, much of the claims regarding their usefulness are still under scrutiny (Sartorius et al., 2002; 2003; van Kammen & Marder, 2000).

Terminology Drugs useful in treatment of psychosis have been referred to as neuroleptics or major tranquillisers, but the term antipsychotic is considered more appropriate. Similarly, the older group goes by the name of traditional, conventional or typical antipsychotics. The more acceptable term, however, isfirst-generation antipsychotic medications (FGAMs), as opposed to second-generation antipsychotic medications (SGAMs), a term that refers to drugs suchas clozapine, risperidone, olanzapine etc (Sartorius et al., 2002; 2003; Lohr & Braf, 2003).

First-Generation Antipsychotic Medications

Types

Members include agents from diverse pharmacological groups such as phenothiazines (chlorpromazine, thioridazine, trifluoperazine, fluphenazine etc.),

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butyrophenones (haloperidol, droperidol, trifluoperidol etc.), thioxanthexenes (thiothixene, zuclopenthixol, flupenthixol etc.), diphenylbutylpiperidines (pimozide, penfluridol etc.), dihydroindolones (molindone), dibenzoxazepines(loxapine), substituted benzamides (sulpiride) and other drugs e.g. oxypertine. The therapeutic responseto these drugs is thought to be related to their ability to block D2 receptors. FGAMs are also traditionally divided into high potency drugs (classically haloperidol), which have higher likelihood of causing EPSEs. Low potency agents (typically chlorpromazine) have greater propensity tocause anticholinergic and cardiovascular side effects(APA, 1997; NICE, 2002; van Kammen & Marder, 2000).

Efficacy

Acute phase

Randomised controlled trials/systematic reviews/ meta-analyses – The evidence for acute phase efficacyof FGAMs comes from numerous double-blind randomised controlled trials (RCTs), starting with studies from the National Institute of Mental Health, U.S.A. (NIMHPsychopharmacology Service Centre Collaborative StudyGroup, 1964) and replicated by several other researchers. In addition there are several reviews and meta-analytic studies of their effectiveness. Allthese trials have provided compelling evidence for the efficacy of these drugs in every subtype and subgroup of schizophrenia (Marder & van Kammen, 2000;Klein & Davis, 1969; Janiacak et al., 1993; Lehman etal., 1998).Although these drugs are effective in diminishing most symptoms of schizophrenia, their effect is most marked on positive symptoms. Early appraisals of the usefulness of these drugs noted that approximately 60% of patients treated for 6 weeks achieve complete,or near complete remission, 40% have moderate to severe symptoms, while 8% do not improve at all. A

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more recent review confirmed the efficacy of these drugs in reducing positive symptoms during acute psychotic episodes with remissions of positive symptoms being achieved in 70% of the cases. Efficacyis relatively less in case of other symptom-groups e.g. negative symptoms or disorganization, but even these symptoms improve to some degree. However, response patterns are complex and complicated by the frequent emergence of side effects such as EPSEs. AllFGAMs are equally effective, and the proposal that low potency agents are more effective for agitated, and high potency agents for withdrawn patients, has never been substantiated by controlled trials. As a group, female patients respond better and require smaller doses, but the only reliable predictor of response is the patient's prior response (Marder & van Kammen, 2000; NIMH Psychopharmacology Service Centre Collaborative Study Group, 1964; Klein & Davis, 1969; Janiacak et al., 1993; Lehman et al., 1998).

Maintenance phase

A large number of RCTs, reviews and some meta-analytic studies have also consistently documented the usefulness of FGAMs in prevention of relapses. Many more patients (53%-75%) who come off drugs or are switched to placebo tend to relapse, than those who continue with their medication (16%-24%) Marder &van Kammen, 2000; Davis, 1975) Hogarty, 1976; Kane, 1990; Davis et al., 1993).

Maintenance medication is also useful in preventing relapse among first-episode patients, although relapse rates tend to be lower in this population.Other studies have found that patients who relapsed while on drugs had less severe episodes with less likelihood of violence, self-harm and antisocial acts. Patients not taking treatment were more likely

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to be admitted involuntarily, and ended up requiring a higher total dose of medication.Nevertheless, maintenance treatment with FGAMs has its limitations. Many patients become non-compliant, and relapse rates are still very high in those who carry on with their drug-treatment. There are often considerable socio-occupational deficits in those whorespond, and adverse outcomes such as permanent institutionalisation or suicide are not uncommon (Marder & van Kammen, 2000).

Side effects

Sedation

Sedation is the single most common side effect of these drugs. It is more common with low potency agents. It is more evident during the initial phases,but some tolerance develops with continued treatment.Sedation can be beneficial for agitated patients; however, daytime drowsiness often causes problems. Insuch situations reducing doses, administering medication as a single bedtime dose, or switching to a less sedating drug can be helpful (APA, 1997; Marder & van Kammen, 2000; Arana, 2000).

Anticholinergic effects

These include problems such as constipation, dry mouth, blurred vision, urinary retention, tachycardiaetc. They occur in about 10%-50% of treated patients,and are more common with low potency agents. Such adverse effects are usually mild but can occasionallylead to serious complications like paralytic ileus. Elderly patients, those with prostatic hypertrophy, or narrow-angle glaucoma are particularly at risk. The more rare syndrome of central anticholinergic toxicity can impair cognitive functions, or even leadto delirium. It normally occurs in those taking drugswith high anticholinergic activity (e.g. chlorpromazine or thioridazine), along with

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antiparkinsonian medication, in the elderly, debilitated or the physically ill. Cessation of drugsusually leads to complete reversal of symptoms, although parenteral physostigmine may occasionally berequired (APA, 1997; Marder & van Kammen, 2000; Arana, 2000).

Postural hypotension

This is due to antiadrenergic effects of FGAMs and commoner among low potency agents. Patients usually complain of mild giddiness while getting up. It can lead to falls especially in the elderly with serious consequences such as fractured hips. More severe hypotension can cause syncopal episodes. Patients areadvised to be careful while getting up, increase saltand fluid intake and use elastic stockings. Corticosteroids such as fludrocortisone may need to be used in very severe cases of hypotension (APA, 1997; Marder & van Kammen, 2000; Arana, 2000).

Neurological side effects

Extrapyramidal side effects (EPSEs)

Up to 60% of patients on treatment with first-generation drugs, particularly those on high potency agents such as haloperidol can develop EPSEs. From the patient’s perspective EPSEs are often more distressing than the symptoms of the disorder and a major cause of non-compliance. EPSEs can be acute with onset within days to weeks of starting treatment; these are dose dependent and usually reversible. Chronic EPSEs occur after months or yearsof treatment, are not clearly dose dependent, and canpersist even after the offending drugs have been withdrawn (APA, 1997; Marder & van Kammen, 2000; Arana, 2000).

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Acute EPSEs

Dystonia

Acute dystonias occur in about 10% of those starting treatment. Onset is often after the first few doses and 90% of the dystonic reactions occur within 3 daysof treatment. Young men, on high doses of high potency medication and intramuscular preparations areparticularly at risk. Symptoms include intermittent, sustained spasms of discrete muscle groups of head, neck and trunk. Dystonias appear quite suddenly, are very frightening for the patient, and in some situations (e.g. laryngeal dystonias) even life threatening. They respond very well to parenteral administration of anticholinergics, benzodiazepines or antihistamines. Recurrences can be prevented by administration of oral anticholinergics (APA, 1997; Marder & van Kammen, 2000; Arana, 2000; King, 1995).

Medication-induced Parkinsonism

This side effect is found in 20%-30% of patients receiving treatment. Onset is within the fist few days to weeks of treatment and is dose dependent. Symptoms resolve on drug withdrawal, but can occasionally persist, especially in the elderly. Riskfactors include old age, female sex, a prior history of similar symptoms, and basal ganglia disease. Clinical features include bradykinesia, rigidity and tremor. A milder form (akinesia) occurs in about halfof the treated patients and is associated with depressive symptoms (akinetic depression) and cognitive impairment. It is often difficult to distinguish from negative symptoms. Parkinsonian symptoms can be effectively treated withanticholinergic/ antiparkinsonian medications such astrihexyphenidyl, procyclidine, orphenadrine,

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benzhexol, benztropine and biperiden, but these should be used cautiously. Antihistaminics (diphenhydramine) and amantadine are useful second line alternatives. Symptoms also respond to reductions in antipsychotic dose (when this is possible), or on changing to an alternative drug, preferably a second-generation one (APA, 1997; Marder& van Kammen, 2000; Arana, 2000; King, 1995).

Akathisia

Akathisia is a peculiar state of somatic restlessnessmanifesting both subjectively and objectively in about 25%-50% patients on antipsychotics. Patients complain of inability to sit still and are commonly seen fidgeting or pacing. It usually appears by the fifth day of treatment or earlier. It is one of the most distressing and difficult to treat side effect. It is associated with poor outcome and suicide attempts. Chronic and tardive forms have also been reported. Akathisia is commoner among women, in patients on high doses of mostly (but not always) high potency drugs. Beta-blockers such as propranolol are the most established form of treatment. Benzodiazepines are also helpful, but not anticholinergic drugs unless there is coexisting Parkinsonism (APA, 1997; Marder &van Kammen, 2000; Arana, 2000; King, 1995). More recently, serotonin (5HT2a) antagonists such as mianserin, ritanserin and cyproheptidane have been found to be efficacious in the treatment of akathisia(Poyurovsky et al., 2001). Reducing the dose of the antipsychotic or switching to a second-generation drug are reasonable alternatives.

The role of prophylactic anticholinergic treatment

The role of prophylactic anticholinergic medication is still controversial. Some studies have shown the

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benefit of this approach in lowering the rates of EPSEs, particularly acute dystonias. However, tolerance usually develops to EPSEs and anticholinergics are unnecessary after 3-6 months in all but 10% of patients (King, 1995). Moreover, anticholinergics have troublesome side effects of their own, can interact adversely with antipsychotics, can be abused, and have the potentialto precipitate tardive dyskinesia. These considerations led a WHO statement on this issue to recommend against prophylaxis (WHO, 1990). However others believe that prophylactic treatment is necessary when there is a high risk of EPSEs (e.g. young men on high potency agents), a predisposition to EPSEs (e.g. a prior history), or likely detrimental consequences of EPSEs, e.g. non-compliance (Casey & Keepers, 1985).

Neuroleptic malignant syndrome (NMS)

This is a rare (prevalence 1%-2%), but potentially fatal adverse effect of antipsychotic treatment. It is characterized by severe rigidity, hyperthermia, clouding of consciousness and autonomic instability such as hypertension or tachycardia. Elevations of creatinine phosphokinase and liver transaminases, leukocytosis, myoglobinemia and myoglobinuria are also reported. Mortality rates are high, up to 20%, though with recent improvements in detection and management these rates are likely to have fallen. NMS is commoner among young males on high doses of high potency medications, particularly parenteral forms, who have had rapid escalation of their doses. Haloperidol is often the culprit, and combinations with lithium are particularly neurotoxic. Physical illness, neurological disability and dehydration are the other risk factors. Early detection, immediate discontinuation of antipsychotics, prompt institution of supportive treatment measures and intensive monitoring are the principal steps of management. Drugs such as

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dantrolene, bromocriptine or amantadine can accelerate the reversal of the process and should always be tried. After several weeks of recovery antipsychotics can be cautiously resumed with a lowerpotency drug (APA, 1997; Marder & van Kammen, 2000; Arana, 2000; King, 1995).

Acute/paradoxical dyskinesias

Acute onset dyskinetic movements resembling tardive dyskinesia may also occur with antipsychotic treatment. These respond well to anticholinergic medication (King, 1995; Casey & Keepers, 1985).

Chronic EPSEs

Tardive dyskinesia

Tardive dyskinesia (TD) is an involuntary movement disorder that follows long-term treatment with antipsychotics. The mean reported prevalence is 15%-20% worldwide, with an annual incidence of 4%-5% in the first few years of treatment. The classical picture is one of orofacial and bucco-lingual movements, but a range of other movements such as choreoathetoid movements of limbs, tics, abnormal postures, hemiballismus, grunting vocalizations and disturbances of respiration can also occur. Risk factors include old age, female gender coupled with postmenopausal status, diagnosis of affective disorder (especially major depression), concurrent physical disorders such as diabetes, higher doses of medication and longer durations of treatment, prior history of EPSEs, alcohol abuse etc. In most patients, particularly the young and those with recent onset TD, the disorder is mild and non-progressive. TD might become irreversible if antipsychotics are continued, but even in these cases

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some improvement does occur. If drugs are stopped theoutcome is better. TD can be prevented to a great extent by using minimum effective doses of antipsychotics during long-term treatment, by regular monitoring and early detection. When TD is suspected other potential causes of dystonias (e.g. Huntington’s or Wilson’s disease) need to be ruled out. Discontinuation of theantipsychotic may be considered, but only in stable and remitted patients. Gradual dose reduction is the other alternative. These manoeuvres might lead to a temporary worsening of movements (withdrawal dyskinesias), which usually diminish with time. If reduction in dose is not possible because of the riskof relapse, a trial of Vitamin E (1600 IU/day) is recommended by some authors. The more common advice, however, is to switch to a second-generation agent which have lower propensity to cause TD. The final option is to treat with clozapine. Though there are very few RCTs of treatment of TD with clozapine, the available evidence indicates that some patients benefit from this drug (APA, 1997; Marder & van Kammen, 2000; Arana, 2000; King, 1995; Glazer, 2000; Simpson, 2000).

Perioral tremor (Rabbit syndrome)

A rapid perioral tremor which can occur at any point during antipsychotic treatment, but which usually arises after several months, has been occasionally reported. The tremor responds well to anticholinergics (Marder & van Kammen, 2000; Casey & Keepers, 1985).

Cardiovascular effects

Low potency agents such as chlorpromazine or thioridazine can cause ECG abnormalities such as prolongation of PR and QTc intervals, T-wave bluntingor inversion, and ST segment depression. Malignant arrhythmias such as torsae de pointes that are

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potentially lethal have also been reported (APA, 1997; Marder & van Kammen, 2000; Arana, 2000). There is now increasing awareness of the risk of sudden deaths with antipsychotics. Although a causal link is as yet unclear, studies suggest that the association with thioridazine is particularly strong.Unexpected deaths have also occurred in a number of young patients without pre-existing cardiac disease who have been treated with high doses of pimozide (Thompson, 1994). A recent review of this area concluded that although, pimozide, sertindole, droperidol and haloperidol have been documented to cause torsae de pointes and sudden death, the most markedrisk was with thioridazine (Glassman et al., 2001). Another naturalistic study also found prolonged QTc intervals were strongly associated with thioridazine and droperidol (Reilly et al., 2002). Following this, restrictions have been placed on the use of thioridazine and pimozide, and droperidol has been withdrawn. Then again similar side effects have been reported with a number of other antipsychotics. Indeed, some authors feel that until further evidenceis available it will be prudent to assume that all antipsychotics have the potential to increase the risk of serious arrhythmias and cause sudden death (Ray, & Meador, 2002). Sudden deaths could also result from drug-induced seizures, hypotension, asphyxiation, aspiration, paralytic ileus, hyperthermia, NMS etc. Old age, pre-existing disease,dehydration, stress, agitation and exhaustion are thepotential risk factors. Proper screening, judicious use of antipsychotics, adequate medical and nursing care, and regular monitoring are required to prevent such unfortunate events (APA, 1997; Thompson, 1994). Drugs such as thioridazine should not be used as first line treatments. High doses of pimozide should not be used and regular ECG monitoring is required during treatment (Thompson, 1994).

Seizures

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All FGAMs can lower seizure threshold and precipitateseizures. The risk is below 1% at conventional dose ranges, those with pre-existing seizure disorders areat higher risk. If a seizure happens, antipsychotic medication should be withdrawn or dose reduced by half till further evaluation is possible (APA, 1997; Marder & van Kammen, 2000).

Endocrine effects

All first generation drugs block D2 receptors and cause elevation of prolactin levels. Prospective studies have shown that 3-9 weeks of treatment at therapeutic doses increases mean baseline levels of prolactin by up to ten-fold. Hyperprolactinemia is more common in women than men, and women also have significantly greater elevations of prolactin. In them it commonly results in amenorrhoea with or without galactorrhoea; existing data reveal that thismay affect 17%-78% of women on long-term antipsychotic treatment. Hyperprolactinemia can also cause breast enlargement, ovarian dysfunction, sexualdysfunctions, premature bone loss and several other adverse effects (Wieck, & Haddad, 2003). Dose reduction helps, but when not feasible addition of low doses of bromocriptine or amantadine is recommended (APA, 1997).

Weight gain

Weight gain occurs in about 40% of patients on first generation agents, with all drugs apart from molindone (APA, 1997). Thioridazine seems to be associated with the maximum weight gain although the magnitude of the problem seems to be lesser than somesecond generation drugs Allison et al, 1999; Allison & Casey, 2001). Weight gain has a number of physical consequences and can also lead to non-compliance. Periodic monitoring and recommendations for changes in diet and exercise can be used to control weight. The role of weight reducing drugs in such situations

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such as sibutramine, topiramate or orlistat is still not entirely clear (Allison & Casey, 2001; Blackburn,2000).

Sexual dysfunction

Virtually all FGAMs are associated with sexual problems including ejaculatory disturbances, impotence, decreased libido and changes in quality oforgasm in men, and lowered libido and orgasmic dysfunction in women. The prevalence is about 45%, and thioridazine is again one of the worst culprits (Smith et al., 2002). Dose reductions or discontinuation usually results in improvement or elimination of symptoms. Although adjunctive medications have been used there is still little evidence of their effectiveness (APA, 1997).

Cutaneuos effects

These occur infrequently with antipsychotics. Stopping treatment or adding an antihistamine is usually effective (APA, 1997; Marder & van Kammen, 2000).

Jaundice

Cholestatic jaundice occurs in less than 0.5% of patients treated with chlorpromazine and requires discontinuation of treatment (APA, 1997; Marder & vanKammen, 2000).

Ophthalmologic effects

Pigmentary retinopathies and corneal opacities are known to occur with low potency agents such as chlorpromazine or thioridazine, at high doses. Routine eye checks can detect these problems. High doses should be avoided (APA, 1997; Marder & van Kammen, 2000).

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Blood dyscrasias

A benign leucopenia is seen in 10% of patients on treatment with chlorpromazine, agranulocytosis is rare and reported in 0.32% of these patients (APA, 1997; Marder & van Kammen, 2000).

Choice of drug/doses

Since all FGAMs are equally effective the only guidesto choice of a particular drug are past response and side effect profiles. In practice high potency agentsare used more often probably because they are comparatively safer, can be increased rapidly, and can be administered parenterally with relative ease (APA, 1997).

Then again, low potency agents have the advantage of being more sedative, an effect that is particularly useful in acutely ill agitated patients. Accordingly,they are preferred by many clinicians (King, 1995).Although doses have to be titrated for each patient, in general moderate doses (500-900mg/day of chlorpromazine or its equivalent) are better than high (above 800 mg/day) or low doses (less than 250 mg/day) (Marder & van Kammen, 2000; Baldessarini et al., 1988). High doses of medication are neither moreeffective, nor faster acting. Instead they are associated with a number of side effects, some of which (NMS, sudden death etc.) are potentially lethal. For these reasons a Royal College of Psychiatrists (U.K.) Consensus Panel has expressly recommended against use of high dose medication even in emergency situations, during acute treatment, or for patients resistant to treatment (Thompson, 1994).Dosing strategies are different for the maintenance phase of treatment.

Route of Administration

Tablets are the most common form of administration. Rapidly dissolving formulations or liquid

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preparations are also available for some drugs. They might be absorbed more rapidly, and could be of some use in patients who spit their tablets out when not observed. Intramuscular (i.m.) or intravenous (i.v.) preparations are faster acting and useful in acute emergencies. Long-acting depot preparations are better at ensuring compliance and are used in maintenance treatment.

Interactions

There are a number of clinically significant interactions with other psychotropics and central nervous system depressants, antihypertensives, cimetidine, anticonvulsants, chloroquine etc.

Blood levels

Earlier studies were unable to find a reliable relation between plasma levels of first- generation drugs and clinical response. More recently such a relationship has been demonstrated for haloperidol insome studies. Even then routine monitoring of plasma levels is not supported by current empirical evidence, except in cases of inexplicable non-response or side effects (Marder & van Kammen, 2000).

Second-Generation Antipsychotic Medications

Types

These medications include clozapine, risperidone, olanzapine, ziprasidone, quetiapine, aripiprazole, sertindole, zotepine and amisulpiride. Most of these drugs have action on serotonin and dopamine receptors, hence are referred to as serotonin-dopamine antagonists (SDAs). However, there is great variability in the pharmacological profile of these agents. For example, amisulpiride is a selective D2/D3

antagonist and aripiprazole has actions on both presynaptic and postsynaptic DA receptors. Clozapine

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is unique in its actions at multiple receptors, limbic selectivity, and low D2 activity (Sartorius etal., 2002; 2003).

Efficacy

Clozapine

Although the efficacy of clozapine had been demonstrated earlier, the landmark trial by Kane et al. (1988) proved to be a turning point for this drug. In this 6-week RCT of treatment-refractory patients, those treated with clozapine did substantially betterthan those with chlorpromazine on a number of measures. Subsequent trials confirmed this efficacy. More recently, the role of clozapine has been examined in other situations such as moderately refractory schizophrenia and first-episode patients. In a 29-week RCT of moderately refractory patients clozapine was found to be superior to haloperidol on various measures such as response rates, number of drop outs, positive symptom efficacy etc. (Kane et al., 2001). Volavka et al. (2002) compared the efficacy of clozapine, olanzapine, risperidone and haloperidol in a 14-week RCT. Clozapine and olanzapine (but not risperidone) were significantly more efficacious than haloperidol, although clinical differences were modest. Several meta-analyses have also been performed to determine the treatment-efficacy of clozapine in schizophrenia. A Cochrane review of comparative RCTs concluded that clozapine was more effective than FGAMs in all types of schizophrenia, but the comparative advantage of clozapine was greater in treatment-resistant patients(Wahlbeck et al., 1999). Results of a meta-analysis by Chakos et al. (2001) also indicated that clozapinewas superior to FGAMs, both in terms of efficacy and safety, in patients with treatment-resistance, although the magnitude of treatment effects was not consistently robust. Efficacy data for other SGAMs intreatment-refractory schizophrenia was inconclusive.

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This notion of clozapine’s superiority has, however, been challenged by a recent meta-analysis of 10 trials by Moncrieff (2003) that failed to reveal a substantial advantage for clozapine in terms of a clinically relevant effect, when compared with FGAMs in treatment-refractory patients. The relative effectiveness of clozapine compared to other SGAMs seems to be more uncertain. A Cochrane review on the subject found no difference between the efficacy of clozapine and other SGAMs in patients with treatment-refractory schizophrenia (Tuunainen et al., 2002). Results of another meta-analysis performed for the NICE arrived at similar conclusions; clozapine was consistently superior to FGAMs in treatment-resistantpatients in this analysis, but inconsistently so compared to olanzapine and risperidone (NICE, 2002).

Risperidone

The efficacy of risperidone in treatment of chronic schizophrenia was compared with placebo and haloperidol in a number of large multi-centric RCTs employing variable-dose and fixed-dose designs (van Kammen & Marder, 2000; Chouinard et al., 1993; Marder& Meibach, 1994; Peuskens et al., 1995). Risperidone in the doses of 6mg/day or in the dose range of 4-8 mg/day was superior to haloperidol on a number of measures and caused fewer EPSEs. Subsequent trials with first-episode patients have suggested that dosesin the range of 2-4 mg/day lead to better outcomes than haloperidol, and no clinically significant EPSEs(Kopala et al., 1997; Emsley et al., 1999). Meta-analytic studies have also concluded that risperidoneis superior to placebo, and at least as effective as,or superior to FGAMs such as haloperidol (van Kammen & Marder, 2000). Another meta-analysis of risperidonein treatment of negative symptoms found that risperidone was superior to first-generation agents in this regard as well (Carman et al., 1995). Finally, at least 2 RCTs have shown risperidone to bebetter than haloperidol in patients with treatment-

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refractory schizophrenia (Bondolfi et al., 1998; Wirshing et al., 1999).

Olanzapine

Four pivotal clinical trials established the efficacyof olanzapine in treatment of schizophrenia (Tollefson & Kuntz, 1999; Stephenson & Pilowsky 1999). These RCTs compared the drug with either haloperidol or placebo, or both. Both olanzapine and haloperidol were superior to placebo in treating positive symptoms. Olanzapine proved to be better than haloperidol in one of the trials, but both drugswere comparable in the other two studies. Combined results of these trials also demonstrated that olanzapine was significantly more effective against negative symptoms than haloperidol. A post-hoc analysisof the data from one of these trials also concluded that olanzapine was more effective than haloperidol in treating a varied spectrum of patients with schizophrenia with positive, negative or mixed symptom profiles, and a chronic or subchronic course of illness (Gomez & Crawford, 2001). In addition Davis and Chen (2001) carried out a meta-analysis of the data from all four trials. They found that olanzapine produced a greater improvement than haloperidol on a large number of items or factors. EPSEs during olanzapine treatment were indistinguishable from effects seen with placebo. Twostudies comparing olanzapine with haloperidol in first-episode psychosis found that although low dosesof both drugs were effective olanzapine had a risk benefit profile significantly superior to haloperidol(Sanger et al., 1999; Lieberman et al., 2003). Olanzapine has been found to be efficacious in situations of treatment-resistance compared to haloperidol or chlorpromazine, but results of other studies have been equivocal (Stephenson & Pilowsky 1999).

Ziprasidone

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Results from 4-6 week fixed dose RCTs have shown ziprasidone to be superior to placebo and comparable to haloperidol in the treatment of positive, negative, depressive and anxiety symptoms of schizophrenia and schizoaffective disorder (Sartoriuset al., 2002; van Kammen & Marder, 2000).

Quetiapine

In randomised controlled trials quetiapine has provedto be consistently superior to placebo and effective against both positive and negative symptoms of schizophrenia. Quetiapine was also as effective as chlorpromazine or haloperidol in improving symptoms of acute schizophrenia. The consistent, placebo-levelEPSEs associated with quetiapine were not seen with haloperidol. A meta-analysis of data from 4 RCTs has also confirmed the superior efficacy of quetiapine versus haloperidol (Kasper et al., 2001).

Aripiprazole

Phase II and phase III trials have shown aripiprazoleto be superior to placebo in improving positive and negative symptoms of schizophrenia. The drug was either comparable or somewhat superior to haloperidolin the same studies (Bowles et al., 2003). A meta-analysis of 5 RCTs confirmed the favourable safety and tolerability profile of aripiprazole compared to haloperidol (McQuade et al., 2002).

Amisulpiride

In patients with positive symptoms high doses of amisulpiride produced improvement comparable to haloperidol or flupenthixol. In acutely ill patients it was better than haloperidol or flupenthixol in reducing affective symptoms. Low doses have been shown to be better than placebo or FGAMs in improvingnegative symptoms (Sartorius et al., 2002). A recent

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meta-analysis of 18 RCTs found amisulpiride to be better than placebo or FGAMs in treatment of global schizophrenic symptoms and negative symptoms, with fewer dropouts and adverse events (Leucht et al., 2002).

Zotepine

Several RCTs have documented the antipsychotic efficacy of zotepine. It has been better than chlorpromazine in treating psychotic symptoms and hasproduced less EPSEs than haloperidol (Sartorius et al., 2002; 2003).

Sertindole

Antipsychotic efficacy of sertindole was found to be similar to other SGAMs but it was temporarily withdrawn following concerns about its cardiovascularside effects. The suspension has been lifted and post-marketing surveillance trials have been initiated (Sartorius et al., 2003).

Meta-analytic studies

Meta-analyses aggregate the results of individual studies to increase the statistical power, which helps in establishing consistency of treatment effects as well as comparative effectiveness of different drugs. Cochrane reviews that have compared SGAMs with placebo or FGAMs have found that SGAMS are clearly superior to placebo and mostly equivalent to FGAMs (Sartorius et al., 2003).Meta-analytic studies focusing on the efficacy of clozapine have found it to be effective in treatment-resistant schizophrenia but the effects are modest and contrary results have also been reported (Wahlbeck et al., 1999; Chakos et al., 2001; Moncrieff, 2003; Tuunainen et al., 2002).

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Leucht et al. (1999) conducted a meta-analytic study of efficacy and tolerability of second-generation versus first-generation drugs in treatment of schizophrenia. They found that risperidone, olanzapine, quetiapine and sertindole were all superior to placebo. Sertindole and quetiapine were as effective as haloperidol, whereas olanzapine and risperidone were slightly more effective against global schizophrenic pathology. All SGAMs were superior to placebo in the treatment of negative symptoms, but so was haloperidol. Olanzapine and risperidone were slightly superior, sertindole comparable, and quetiapine less effective than haloperidol in this regard. All SGAMs were associatedwith fewer EPSEs than haloperidol.Geddes et al. (2000) carried out a meta- analysis of 52 RCTs comparing SGAMs (amisulpiride, clozapine, risperidone, olanzapine, quetiapine and sertindole) with FGAMs (haloperidol and chlorpromazine). They found substantial heterogeneity in the results partlyaccounted for by the dose of the comparator FGAM. If the dose of the FGAM was less than 12 mg/day of haloperidol equivalents, SGAMs and FGAMs were comparable in efficacy, although the former still caused fewer EPSEs. They concluded that there were nodifferences inefficacy and tolerability between the two groups. They proposed that FGAMs should not be used as initial treatments except in cases of previous poor response or unacceptable EPSEs.Leucht et al. (2002) in a more recent meta-analysis of 18 RCTs comparing amisulpiride with placebo or FGAMs found amisulpiride to be superior to placebo inall aspects. Amisulpiride was more effective against positive symptoms and equally effective against negative symptoms, compared to FGAMs. There were fewer adverse effects and dropouts with amisulpiride.Another meta-analytic comparison of SGAMs and FGAMs as well as comparison between different SGAMs has been reported recently. RCTs of 10 SGAMs including clozapine, amisulpiride, risperidone, olanzapine, quetiapine, sertindole, zotepine, ziprasidone,

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remoxipride and aripiprazole, were considered. Only four second-generation drugs clozapine, risperidone, olanzapine and amisulpiride were superior to FGAMs. No differences were found between different second-generation agents. The authors also ruled effects of haloperidol dose as a confounder (Davis et al., 2003).

Head-to-head comparisons

Risperidone and olanzapine have been compared in 2 large RCTs one lasting 8 weeks (Conley & Mahmoud, 2001) and the other 28 weeks (Tran et al., 1997). Onefound olanzapine to be significantly better in controlling negative symptoms (Tran et al., 1997),

the other showed risperidone to be significantly moreeffective against positive, anxiety and depressive symptoms (Conley & Mahmoud, 2001). In a 4-month open-label comparison of risperidone with quetiapine the only difference that emerged was that patients on quetiapine required less anticholinergic medication (Kasper et al., 2001). A 12-week RCT of clozapine andrisperidone in severe, chronic schizophrenia revealedclozapine to be superior to risperidone, and associated with fewer EPSEs (Azorin et al., 2001). This was similar to the results of an earlier open trial (Flynn et al., 1998) but differed from those ofa randomised trial, which found no difference betweenrisperidone and clozapine in treatment-resistant patients (Bondolfi et al., 1998). However the latter trial had several methodological problems. Overall, there is insufficient evidence to demonstrate the superior efficacy of any second-generation agent compared to others.

Negative symptoms

The efficacy of SGAMs against negative symptoms of schizophrenia has been demonstrated for a number of drugs including clozapine, olanzapine, ziprasidone, quetiapine, aripiprazole and sertindole (Thomas &

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Lewis, 1998). These have been supported by meta-analytic data on others such as risperidone or amisulpiride (Carman et al., 1995; Leucht et al., 2002). However, differences compared to first-generation agents are often marginal, and some studies have provided contradictory results. Moreover, it remains unclear whether this effect of SGAMs is a primary one or mediated through improvements in positive symptoms and lack of EPSEs. Carpenter et al. (1995) have distinguished between ‘primary’ negative symptoms of blunted affect and poverty of speech, from qualitatively similar ‘secondary’ negative symptoms, which may be the result of severe positive symptoms, depression, or EPSEs. They contend that efficacy against primary negative symptoms are not supported by the current evidence. Some trials (e.g. with olanzapine) have, however, demonstrated otherwise (Tollefson & Kuntz, 1999; Stephenson & Pilowsky 1999).

Depressive symptoms and suicide

Results of RCTs and several reviews of the subject have suggested that SGAMs have particular efficacy against depressive symptoms that occur as a part of schizophrenia (Levinson et al., 1999; Siris, 2000). Several studies have shown the efficacy of clozapine in reducing suicidality, suicide attempts and mortality from suicide. A recent study attempting to model the impact of increased clozapine prescription on lives saved estimated that if all treatment-resistant patients in the UK received clozapine fifty-three suicides could be avoided each year (Duggan et al., 2003). In another international multi-centric RCT of 980 patients at high risk for suicide (Meltzer et al., 2003), clozapine proved to be superior to olanzapine in preventing suicidal attempts. However, olanzapine has also been shown to significantly decrease suicide risk compared to haloperidol (Tollefson & Kuntz, 1999) and risperidone(Tran et al., 1997).

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Cognitive symptoms

Several studies with different second generation agents have shown that as a group SGAMs are more effective than first-generation drugs in improving cognitive function (Sharma, 1999; Bilder et al., 2002), yet again it is unclear whether the improved cognitive profile is a direct effect or secondary to lower treatment-emergent EPSEs with SGAMs (Sartorius et al., 2003).

Maintenance treatment

Trials with several SGAMs including risperidone, olanzapine, ziprasidone, quetiapine, aripiprazole andsertindole have provided evidence for their effectiveness in the long-term treatment of schizophrenia (Sartorius et al., 2002; 2003).

However, the number of such studies is still small, some are open-label or extension trials, and others have only considered rehospitalisation rates. Differences compared to FGAMs are inconsistent and marginal. Results of meta-analytic studies have also been contradictory. One recent meta-analysis of 17 relapse-prevention studies of amisulpiride, clozapine, olanzapine, risperidone, ziprasidone, sertindole and zotepine found that SGAMs were superior to placebo in this regard. Further, rates ofrelapse and overall treatment failure (but not drop outs) were modestly but significantly lower with SGAMs when compared with FGAMs. The evidence was particularly strong for risperidone, olanzapine and sertindole (Leucht et al., 2003). In contrast, another meta-analysis concluded that in the absence of head-to-head trials of appropriate duration the relative efficacy for relapse prevention of SGAMs against FGAMs remains uncertain (NICE, 2002).

First-episode patients

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Randomised controlled trials of clozapine (Lieberman et al., 2003; Woerner et al., 2003) risperidone (Kopala et al., 1997; Emsley et al; 1999) and olanzapine (Sanger et al., 1999; Lieberman et al., 2003) have demonstrated the efficacy of these drugs in first-episode psychosis. However, these are only marginally superior to FGAMs in these situations. Most of these studies suggest that low doses of both first and second-generation agents are effective in first-episode patients. Nevertheless, because of their superior safety in terms of neurological side effects, SGAMS (except clozapine) are recommended foruse as first-line treatments and preferred drugs in the treatment of first-episode psychosis (Sartorius et al., 2002; 2003).

Treatment-refractory patients

Although there is some suggestion of efficacy of risperidone and olanzapine in this condition, and despite recent doubts about the effectiveness of clozapine, it still is the drug of choice in these situations (Sartorius et al., 2002).

Adverse effect profile

The available evidence strongly demonstrates that SGAMs have a lower side effect risks in terms of EPSEs, TD and in most cases elevation of prolactin and consequent endocrine effects, than FGAMs. However, this advantage can often be offset by troublesome side effects such as weight gain, and potentially serious metabolic, cardiovascular and haematological effects (Sartorius et al., 2002; 2003).

Compliance/patient preference/quality of life

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It is probably because of this favourable side effectprofile that differences are seen between first and second-generation agents in terms of improved compliance, increased patient preference and better quality of life (Sartorius et al., 2003; Dolder et al., 2002).

Cost-effectiveness

The evidence regarding cost-effectiveness of SGAMs (or the lack of it) is still a matter of some debate.Although the cost per-tablet basis of second-generation drugs is substantially higher, the total costs of treatment appear to be lower than FGAMs. Thelower risks of EPSEs and improved quality of life with SGAMs may prove advantageous in cost-effectiveness terms, but these parameters are often not entered into cost-benefit analyses (Sartorius et al, 2003).

Side effects

Sedation

Sedation is the most common adverse effect of clozapine and is also observed with a number of otherdrugs including olanzapine, risperidone, ziprasidone and quetiapine (Barnes & McPhillips, 1999).

Postural hypotension

Postural hypotension and giddiness is often reported by patients on clozapine, and is also commonly associated with risperidone, olanzapine, quetiapine and sertindole (Barnes & McPhillips, 1999).

Sialorrhoea

Hypersalivation during sleep and other times is a particularly troublesome side effect of clozapine. It

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can be treated with low doses of amitriptyline or clonidine (APA, 1997; Barnes & McPhillips, 1999).

Seizures

This is a serious side effect of clozapine. The incidence is dose related with maximum risk (4.4%) atdoses greater than 600mg/day. Most patients who experience a seizure are, however, able to continue clozapine after dose reduction, gradual re-challenge,or addition of an anticonvulsant. Though any of the other drugs can also induce seizures risperidone, olanzapine, quetiapine and sertindole have shown no increase in risk compared to haloperidol or placebo (Barnes & McPhillips, 1999).

Neutropenia/agranulocytosis

A potentially fatal side effect seen with clozapine is agranulocytosis (reduction of absolute neutrophil counts below 500 mm3). The risk is about 0.8% worldwide and greatest during the first 3 months of treatment. Risk factors include increasing age, female gender, Asian origin, and low neutrophil counts before treatment (Barnes & McPhillips, 1999).

Detailed guidelines regarding monitoring for and management of clozapine-related agranulocytosis are available (APA, 1997 van Kammen & Marder, 2000). Several cases of olanzapine-related neutropenia/ agranulocytosis have been reported recently. This hasoften been seen in patients who had a prior history of clozapine-related neutropenia. It is now recommended that white blood cell counts be monitoredin patients on SGAMs who have a history of drug-induced white cell disorders, or are on drugs, which could cause such disorders (Sartorius et al., 2003).

Weight gain

Weight gain is seen with almost all second-generationdrugs with the exception of ziprasidone. In one of

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the most detailed meta-analytic reviews of the subject Allison et al. (1999) showed that the magnitude of weight gain was greater among SGAMs. Clozapine and olanzapine were associated with the highest gain in weight, and ziprasidone the least. Though patients gain weight early in treatment, some amount of weight gain continues throughout treatment.Weight gain is not dose dependent. Gain in weight is often associated with a number of adverse physical and psychosocial outcomes. Treatment is recommended if a patient gains 2.3 kgs or more. Periodic monitoring, recommendations regarding diet and exercise form the basis of such treatment. The role of weight reducing drugs such as sibutramine is uncertain (Allison et al., 1999; Allison & Casey, 2001, Blackburn, 2000).

Hyperprolactinemia

Most SGAMs do elevate prolactin levels, although not to the same extent as first-generation drugs. The elevations are significantly above baseline in case of risperidone and amisulpiride, but minimal with clozapine, olanzapine, quetiapine and aripiprazole (Sartorius et al., 2002; 2003). Hyperprolactinemia can be associated with amenorrhoea, galactorrhoea, and sexual dysfunction (Wieck & Haddad, 2003).

Sexual dysfunction

Although the extent of the problem is not clearly known, SGAMs do cause all manner of male and female sexual dysfunctions. Whether the rates of these side effects are similar for both first and second-generation drugs, as some studies seem to suggest, isalso not clear (Sartorius et al., 2002; 2003).

Diabetes mellitus/hyperlipidemia

Based on several reports there has been growing concern about the risks of new-onset diabetes and

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disturbances in lipid metabolism associated with second-generation agents. Some studies have reportedthe risk of diabetes to be greater among patients receiving SGAMs, while others have been unable to find significant differences between FGAMs and SGAMs.Among the SGAMs clozapine and olanzapine carry the highest risk of new-onset diabetes. The risk appearsto be greater in younger patients below 40 years of age. The data suggests that SGAMs like clozapine or olanzapine rather than causing diabetes/hyperlipidemia independently, may induce these disorders in susceptible persons (Henderson et al., 2000; Lund et al., 2001; Sernyak et al., 2002; Koro et al., 2002). The medical consequences of theseeffects are not clear. Monitoring of these parametersin those at risk is required during treatment (NICE, 2002; APA, 2004).

EPSEs

As a group second-generation antipsychotics are much less likely to cause EPSEs than FGAMs. However, SGAMsvary considerably in their propensity to cause various EPSEs. A dose dependent effect has been observed with risperidone, with doses more than 6 mg/day more likely to cause EPSEs. High doses of amisulpiride are also known to cause similar effects.On the other hand drugs like quetiapine, aripiprazole, olanzapine and clozapine carry almost no risk of causing EPSEs. The risks of TD are also considerably less among all SGAMs. Then again there are several case reports of TD with all SGAMs and akathisia with clozapine (Sartorius et al., 2002; 2003). A recent review also identified several instances of NMS occurring with clozapine and risperidone (Hasan & Buckley, 1998).

Cardiovascular side effects

Tachycardia is a common side effect of clozapine and sertindole and has been reported with quetiapine.

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Cohen et al. (2001) reported that clozapine was significantly more likely than haloperidol to cause higher heart rate, lower heart rate variability and other indicators of autonomic dysregulation and impaired cardiac repolarisation. There are also recent reports of clozapine-related myocarditis and cardiomyopathy in physically healthy young adults started on treatment.16 All SGAMs prolong the QTc interval and this effect has raised some concerns in case of ziprasidone and sertindole (Sartorius et al.,2003; Barnes & McPhillips, 1999). The latter was briefly withdrawn because of concerns regarding its cardiovascular safety profile.

Other side effects

Other side effects of SGAMs include nasal congestion with risperidone and sertindole, raised liver transaminases with olanzapine, urinary incontinence with clozapine and risperidone etc. (Barnes & McPhillips, 1999).

Maintenance treatment with antipsychotics

FGAMs

Efficacy

Several RCTs and systematic reviews have provided strong support for the efficacy of first-generation antipsychotics in relapse prevention. In the most comprehensive study of this subject Gilbert et al. (1995) analysed the results of 66 studies involving 4365 patients of schizophrenia. The mean cumulative relapse rate was 53% in patients withdrawn from treatment and 16% in those maintained on drugs over amean follow-up period of 9.7 months. The only consistent predictor of relapse was the length of follow-up. Others have found that relapse in patientswithdrawn from antipsychotics occurs relatively early, usually within the first 3 months after

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stopping drugs. Relapse rates are higher in those patients whose drugs are withdrawn rapidly (Baldessarini & Viguera, 1995). The review by Gilbertet al. (1995) also highlights the dilemmas in maintenance treatment. About half of the patients in their review managed to remain relapse free even after their drugs were withdrawn, although others have argued that this was due to the short length of follow-up and almost all such patients relapse when followed up for 2 years or more (Greden & Tandon, 1995). There is, however, the problem of a significant minority of patients (16% in Gilbert’s review) who relapse despite continuing with treatment. Further, there are no reliable ways to predict this relapse. On the other hand, continued treatment with FGAMs takes its toll in terms of side effects and increases the risk of producing TD (Gilbert et al., 1995).

Dosing strategies

Studies have looked at the differential efficacy of high, standard, low and very low doses of antipsychotics during maintenance treatment. Another strategy that has received some attention is that of targeted or intermittent therapy.

High dose therapyA review of 33 RCTs in which high doses (mean of 5200mg of chlorpromazine equivalents) were compared with low dose (mean of 400 mg chlorpromazine equivalents) found that lower doses had superior efficacy as well as tolerability Baldessarini et al., 1988).

Standard doses

This essentially refers to the doses normally used totreat patients during acute phases. In most trials this would be about 25-50 mg of fluphenazine decanoate or 40 mg of flupenthixol decanoate every 2 weeks, or 100 mg of haloperidol decanoate every

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month. The efficacy of these doses in relapse prevention is beyond doubt. However, the burden of side effects, the risk of TD, expectations of patients and relatives regarding dose reduction have prompted the examination of other dosing strategies which utilize lower doses (Johnson, 1985; Schooler, 1993; Kane, 1995; Kane, 1999).

Low doses (or continuous low-dose treatment)

In the various trials conducted low doses have been of the order of 2.5-5 mg of fluphenazine decanoate or20 mg of flupenthixol decanoate every 2 weeks, or 50 mg of haloperidol decanoate every month. The results of some of these studies suggest that dose reduction is feasible. Short-term (up to about a year) relapse rates are not significantly different between the lowdose and standard dose groups. Positive effects of dose reduction are evident in the diminution of side effects, particularly EPSEs, and reduction in anxietyand depressive symptoms. Family members are more satisfied with the outcome of dose reduction and family burden is less with low doses. However, reduction in risk of TD is not consistently or clearly evident. On the other hand the risk of psychotic relapses can be greater with lower doses. The proportion of patients relapsing increases with lower doses and longer periods of follow-up. The moreunstable the patients are initially, the greater the risk may be. Apart from this it is difficult to predict which patient will, or will not benefit from dose reduction (Johnson, 1985; Schooler, 1993; Kane, 1995; Kane, 1999). This has led several authors to conclude that dose reduction, even in clinically stable patients, is problematic and difficult to justify (Schooler et al., 1997; Kane et al., 2002).

Very low doses

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Very low doses of antipsychotics (less than 5 mg of fluphenazine decanoate or 25 mg of haloperidol decanoate) have been used in some studies for maintenance treatment. Very low doses lead to a significantly higher relapse rate in the first year of follow-up (Kane et al., 1983; 2002).

Targeted or intermittent treatment

Targeted or intermittent strategies involve discontinuation of medication followed by intensive monitoring to identify the earliest signs of exacerbation or relapse, at which point treatment is immediately reinstituted. Studies show that such strategies are feasible and can be implemented in outpatient settings. They result in reduced cumulative antipsychotic exposure and reduction in side effects. However, the high rates of relapse and rehospitalisation make this an unacceptable option. This strategy is only recommended for patients who refuse continuous medication and might comply with anintermittent regimen if properly educated (Johnson, 1985; Schooler, 1993; Kane, 1995; Kane, 1999).

Duration of treatment

Studies suggest that the duration of treatment in patients who have had multiple exacerbations or relapses should be five years or longer (Johnson, 1985). For first-episode patients medications need tobe continued for at least one year (Johnson, 1985),

although some studies suggest that maintenance treatment needs to continue beyond this period (Gitlin et al., 2001).

SGAMs

The need to reduce doses of FGAMs during maintenance was felt in order to avoid distressing side effects, especially TD. This is less of a problem with second-generation drugs. Thus continuous maintenance

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treatment with a SGAM may be the best option for preventing relapse. Although, controlled trials have indicated that these drugs can be used in maintenancetreatment, the evidence is limited and conflicting (NICE, 2002; Sartorius et al., 2003).

Depot antipsychotic treatment

The introduction of depot antipsychotics in the 1960swas heralded as a major advance in the treatment of chronic schizophrenia. Depot antipsychotics generallyconsist of an ester of the drug in an oily solution, which is administered by deep intramuscular injection. Following injection, the drug is slowly released from the injection site allowing relatively stable plasma drug levels to be achieved over long periods, while injections only need to be given once every few weeks. Depot injections guarantee consistent drug delivery, overcome the bioavailability problems that occur with oral preparations, and eliminate the risk of deliberate orinadvertent overdoses. There is less inter-individualvariability and patients can be treated with lower doses. However, the main practical advantage is the avoidance of covert non-adherence with drug treatment. People on depots need to attend a clinic regularly to receive their injection and can be closely supervised during this process. Any drop outsare immediately identified and steps taken to intervene early. The disadvantage of depot preparations is the comparative lack of flexibility of administration, with adjustment to the optimal dosage being a protracted and uncertain process. They have the potential to cause more adverse effects such as EPSEsincluding TD and can be associated with uncomfortablereactions at the site of injection. Patients sometimes resent this form of treatment. Finally, their use does not always guarantee good treatment adherence, with around a third of those prescribed

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depots failing to become established on the injections (Johnson, 1985; Kane, 1995).Over the years a substantial body of literature has accumulated examining the efficacy and safety of depot injections versus oral drugs. Initial trials, reviews and meta-analyses concluded that patients maintained on depots had a significantly lower rate of relapse than those on oral medication. The risk ofadverse effects was no greater when comparisons were made with equivalent doses of oral antipsychotics. The number of refusals was small and rates of non-compliance a fraction of those defaulting on oral drugs (Johnson, 1985; Kane, 1995). More recently, larger and more comprehensive meta-analytic reviews have suggested otherwise. Depots appear to be safe and effective modes of treatment, not associated withany greater risks of treatment-emergent side effects.However, they confer only a small benefit over oral medication in terms of global improvement. There are no differences between depot and oral antipsychotics in terms of relapse rates or dropouts. Comparison between different depots revealed a small advantage for zuclopenthixol decanoate in terms of lower relapse rates, but this could be due to the fact thatit is a comparatively newer compound. Similarly, fluphenazine preparations were associated with a higher risk of EPSEs, probably as a result of the larger number of trials with these injections. Evidence in favour of cost-effectiveness of depots was little and of uncertain value (NICE, 2002; Adams et al., 2001). Then again, another systematic review of patient attitudes found that patients were happy with their depot treatment and preferred it to oral medication (Walburn et al, 2001).Until recently there were no depot preparations of second-generation antipsychotics, which was a major disadvantage of these drugs. A long acting form of risperidone has now become available. Moreover, a 12-week multicentric double-blind randomised placebo controlled study of 554 patients has shown that 25 mg. of depot risperidone administered every 2 weeks

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is a safe and efficacious means of treatment (Kane etal 2003).

Rapid Tranquillisation

Acute behavioural disturbances in the context of schizophrenia may require urgent treatment. A personmay be agitated, aggressive or violent towards othersas a result of persecutory delusions, command hallucinations, or high levels of anxiety. Rapid tranquillisation means the use of drug treatments to achieve rapid, short-term behavioural control of extreme agitation, aggression and potentially violentbehaviour that places the individual or those around them at risk of physical harm. The aim of drug treatment in such circumstances is to calm the person, and reduce the risk of violence and harm, rather than treat the underlying psychiatric condition. An optimal response would be a reduction in agitation or aggression without sedation (NICE, 2002; McAllister-Williams & Ferrier, 2002).Parenteral preparations useful in rapid tranquillisation are i.m. injections of lorazepam, haloperidol, olanzapine or ziprasidone, and i.v. preparations of lorazepam, diazepam or haloperidol. Intramuscular chlorpromazine is not recommended because of potentially serious cardiovascular side effects, i.m. droperidol has been withdrawn because of similar concerns, and i.m. diazepam is not used due to its erratic absorption (McAllister-Williams & Ferrier, 2002).Data on comparative effectiveness of these drugs is limited, and there appear to be no clinically significant differences between benzodiazepines and antipsychotics. However, recent reviews have suggested that a combination of i.m. haloperidol andi.m. lorazepam may produce a faster response than i.m. haloperidol alone (NICE, 2002). Three RCTs have also shown i.m. olanzapine to be as effective as, and have a better side effect profile than i.m. haloperidol. Some studies have also found i.m.

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ziprasidone to be rapidly effective and well tolerated at therapeutic doses with minimal EPSEs (Sartorius et al., 2003; McAllister-Williams & Ferrier, 2002). In practical terms steps should be taken to anticipate possible violence and to de-escalate the situation at the earliest opportunity. Physical means of restraint or seclusion should be resorted to only after the failure such of attempts. When drugs have to be used low doses of single agentsare preferred. Oral medication (tablets, rapidly dissolving formulations and liquids) should be offered before parenteral medication. If parenteral treatment proves necessary, the i.m route is to be preferred over the i.v. one from a safety point of view. Intravenous administration should only be used in exceptional circumstances. When rapid tranquillisation is urgently needed, a combination ofi.m haloperidol and i.m lorazepam can be considered. Regular monitoring for adverse consequences is essential. Staff should be trained in this method, and there should be adequate access to facilities forresuscitation (NICE, 2002; King, 1995; McAllister-Williams & Ferrier, 2002).

Adjunctive medication

Lithium carbonate

Most trials of lithium in schizophrenia have been carried in the acute phase of the illness, and controlled data is scarce. Studies of lithium as monotherapy in schizophrenia show only modest improvements, sometimes even worsening of symptoms, and early relapses with the drug. Lithium is less efficacious than FGAMs in this situation. However, when added to antipsychotic medications lithium augments the response in general, and appears to specifically improve negative symptoms. Such improvement is greatest in the areas of psychotic symptoms, agitation and excitement, irritability, and

45

behavioural and functional disturbances. Such improvement can be seen in up to half of the patients, so a trial of adjunctive lithium needs to be considered in patients who show poor response to antipsychotics (APA, 1997; Siris, 1993; Morrison, 1996; Barnes et al., 1996; Williams et al., 2002). Lithium has also been shown to have specific benefitsfor patients of schizophrenia with affective symptoms. Lithium either alone or added to FGAMs shows greater ability to reduce depression/anxiety and thought disorders scores in patients of schizophrenia with depression. Such effects are not seen in patients who are not depressed. Indirect evidence for efficacy of lithium in schizophrenia with affective symptoms comes from trials showing theusefulness of lithium-antipsychotic combinations in schizoaffective disorder (APA, 1997; Siris, 1993; Morrison, 1996; Barnes et al., 1996; Williams et al.,2002). However, a recent review concluded that adjunctive use of lithium for depressive symptoms in schizophrenia is inadequate and inconsistent, and there is no empirical basis for its use in such conditions (Levinson et al., 1999).There has been some concern about adverse effects of lithium-antipsychotic combinations, particularly neurotoxicity. Though estimates vary, neurotoxic effects are generally uncommon under ordinary therapeutic conditions. Nevertheless, monitoring for such side effects and regular serum-level estimationsare recommended. A trial of 4-12 weeks is required to determine the response to lithium when added to anantipsychotic. Predictors of a favourable response include excitement, overactivity, affective symptoms,especially depression, episodic course and past or family history of affective symptoms (APA, 1997; Siris, 1993; Morrison, 1996; Barnes et al., 1996; Williams et al., 2002).

Antidepressants

46

It is generally recognized that a substantial proportion of patients with schizophrenia suffer fromeither depressive symptoms or clinically significant depressive episodes, during various phases of their illness. However, the treatment of depression in schizophrenia is complicated by difficulties in distinguishing symptoms from syndromes, depressive symptoms from negative symptoms and EPSEs, and concerns about exacerbations of psychosis with antidepressants. The large majority of studies examining adjunctive antidepressant treatment in schizophrenia have involved addition of tricyclic drugs or monoamine oxidase inhibitors to FGAMs. Thesehave often, but not always, indicated that the addition of such drugs to ongoing antipsychotic treatment produces substantial benefits. Two recent reviews have also concluded that there is substantialevidence to indicate that adjunctive antidepressants are useful in treatment of depressive syndromes, but not depressive symptoms, in the post-psychotic phase.At the same time they have cautioned against the use of additional antidepressants during acute exacerbations of schizophrenia because of the lack ofefficacy, and potential for worsening psychotic symptoms (Levinson et al., 1999; Siris, 2000).The evidence for efficacy of antidepressants in treatment of other syndromes such as negative symptoms or anxiety syndromes is sparse, mostly inconsistent, and generally inconclusive (APA, 1997; Siris, 1993; Morrison, 1996; Barnes et al., 1996; Williams et al., 2002).

Benzodiazepines

A meta-analytic review of double-blind trials of adjunctive benzodiazepine treatment in schizophrenia showed that addition of benzodiazepines to antipsychotics had positive effects on anxiety, agitation and positive symptoms. Responses are seen in about half of the treated patients. This strategy appears to be particularly useful in the management

47

of acute psychotic agitation, because of the sedativeeffects of benzodiazepines, and rapid onset of beneficial effects. Benzodiazepine use has the added advantage of reduction in antipsychotic doses and consequent relief from antipsychotic-related side effects. However, other studies have indicated that effectiveness of benzodiazepines does not last beyondthe first few weeks. Limited evidence also suggests that adjunctive benzodiazepine treatment may be specifically useful in patients with either prominent anxiety symptoms orcomorbid anxiety syndromes. The evidence for efficacy of adjunctive benzodiazepines in the management of negative or depressive symptoms is limited and contradictory. Benzodiazepines as monotherapy in schizophrenia have only mild antipsychotic efficacy, and are inferior toFGAMs in this regard, Paradoxical disinhibition, worsening of symptoms on benzodiazepine discontinuation, and instances of abuse/dependence have been reported (APA, 1997; Siris, 1993; Morrison,1996; Barnes et al., 1996; Williams et al., 2002).

Anticonvulsants

Double-blind studies of adjunctive carbamazepine in acute phase of schizophrenia have shown significant positive effects. Such treatment appears to produce improvements in patients who are agitated or violent,and those who have EEG abnormalities suggestive of seizure activity. The number of such studies is, however, still very small and most studies have a number of methodological problems. Studies with otheranticonvulsants are still fewer. A review of five studies of valproate in schizophrenia concluded that there is little evidence for its efficacy. When treating patients with additional carbamazepine or valproate, the dose of the antipsychotic might need

48

to be adjusted because these drugs can reduce blood levels of antipsychotics (APA, 1997; Siris, 1993; Morrison, 1996; Barnes et al., 1996; Williams et al.,2002).

Electroconvulsive therapy

In the acute phase of schizophrenia some studies of first-admission patients have found ECT alone to be as effective as first-generation antipsychotics. However, one RCT of first-admission patients found that while ECT alone was superior to psychological therapies, it was not as effective as antipsychotics alone. On the other hand, when ECT is combined with antipsychotics the combination has been consistently more effective than either treatment used alone. Combinations of ECT and antipsychotics also result inmore rapid resolution of symptoms. It is equally effective in ameliorating both affective and psychotic symptoms. If used during the initial part of the illness ECT can reduce risks of chronicity andfurther personality deterioration. A short duration of illness predicts better response. ECT is also useful in treatment of patients with catatonic or depressive presentations and those at risk for suicide. However, the acute efficacy of ECT/antipsychotic combinations is not maintained for long, and advantages disappear within a matter of weeks (APA, 1997).In chronic schizophrenia ECT is much less effective and response rates in patients continuously ill for more than a year are 20% or less. There are very few controlled studies of the role of ECT in treatment-refractory patients. Uncontrolled data have shown some benefits of ECT when used alone in patients withpoor response to drugs, or in combination with FGAMs and clozapine in patients resistant to treatment (APA, 1997).

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Psychosocial treatments

Although the causes of the schizophrenic syndrome remain unclear, most workers in this field view it from stress-diathesis or bio-psychosocial perspective. Apart from emphasising the underlying biological vulnerabilities, this model also stresses their interaction with psychological and social factors in the onset and course of the disorder (Zubin, 1986). Research over the years has delineateda number of these psychosocial factors such as stressful life events, expressed emotion, and social support. Specific interventions designed to target some or all of these parameters have proved useful inimproving the outcome of schizophrenia.The need for psychosocial therapies is being increasingly acknowledged for several reasons. Although pharmacotherapy is effective in treating acute symptoms and reducing the risk of relapse, it is not always effective, neither does it guarantee good outcome all the time. Drugs do not address the problem of residual social and cognitive deficits to the same extent as symptom relief. Drugs cannot teacha patient the skills required to cope with the demands of daily living. Nor can they wholly alleviate the distress of relatives or reduce the burden of caring for an ill family member. Drug compliance is a major problem, as is relapse, which can be precipitated by family/environmental factors.

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Modalities of treatment – Somatic

1. Antipsychotic medications First-generation antipsychotic medications Second-generation antipsychotic

medications

► Oral/parenteral/depot - preparations

2. Adjunctive medications Lithium carbonate Antidepressants Benzodiazepines Anticonvulsants

3. Other medications Antiparkinsonian medications Beta-blockers

In contrast, psychosocial treatments extend beyond symptoms of the illness and encompass the pervasive deficits in social, cognitive, and affective domains;as well deficits in daily functioning that are characteristic of schizophrenia. They help prepare patients and their families to cope with the illness,help patients strive for greater self-sufficiency andachieve a better quality of life. In addition, these therapies seek to enhance treatment adherence, to decrease distress and disability, to minimise symptoms, and to reduce risk of relapse in patients. . Finally, such treatments also endeavour to reduce distress and burden among family members (Penn, & Mueser, 1996; Stillo et al., 2001; Garety, 2003).The term ' psychosocial treatments ' refers to all those procedures, psychological or social, used to intervene on behalf of the patient. Specifically, it excludes somatic treatments (Lehman, 1995). Psychosocial interventions can be classified according to their focus, modus, or locus, as well astheir goals and objectives. The focus may be the individual, his family, groups, or the whole milieu. The modality of treatment varies from psychodynamic to behavioural, or a combination of several strategies. The locus can be an inpatient facility, aday hospital, a social club etc. Each intervention often has different goals or objectives. For example,some may maintain the individual at a marginal level of functioning with minimal stress or relapse, while others may aim to teach him social and independent living skills. However, these interventions are not substitutes for somatic treatments. Rather, they complement and add to the benefits obtained by drugs.Sufficient evidence exists to suggest that best results are obtained by using a combination of pharmacotherapy and psychosocial measures. (Lehman, 1995; Penn, & Mueser, 1996).

Family Intervention

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This includes all family intervention programmes, which involve a combination of didactic materials about schizophrenia for patients and their relatives,and therapeutic strategies designed to improve stressmanagement by all family members through enhanced communication and problem solving skills. These programmes evolved from research originating in Britain about the concept of expressed emotions (EE),which has been subsequently replicated in other countries. The common goals of all these programmes include decreasing patient relapses, decreasing family burden, and improving both the patient's and family's functioning. All approaches emphasise the value of family participation in treatment and stressthe importance of working together in a collaborativeprocess. Common elements of such interventions include positive and early engagement, ongoing contact, education about aetiology, treatment, and prognosis of schizophrenia, teaching coping with stress, increasing problem-solving and communication skills, and crisis intervention. Other components often incorporated are identification of stressors associated with relapse, setting of realistic expectations, expanding social networks etc. (Penn, &Mueser, 1996; Stillo et al., 2001; Garety, 2003). There are several systematic reviews of controlled trials comparing family intervention with other formsof care, mainly standard outpatient care and also supportive psychotherapy, psychoeducation etc. The more recent meta-analyses have included up to 18 suchRCTs (NICE, 2002). There is strong evidence from thisdata that family treatment improves the outcomes for people with schizophrenia living with, or having close contact with, their family, most notably in reducing the rate of psychotic relapses both during treatment and for up to 15- 24 months after treatmenthas ended. Family interventions are also effective inreducing relapse rates in those who have recently relapsed, and in those who remain symptomatic after resolution of an acute episode. The benefits are most

52

marked if treatment is provided over a period of morethan 6-9 months and/or for more than 10 planned sessions, and if the patient is included in the family sessions. Family interventions also decrease family-burden and improve treatment adherence. Their effects on social functioning are less clear. They donot seem to influence symptoms, suicide rates, or rehospitalisation rates. All modes of delivering treatment are equally efficacious though patients seem to prefer single-family rather than multiple-family interventions. Limited evidence also suggests that providing family interventions may represent good ‘value for money’ (NICE, 2002; Penn, & Mueser, 1996; Stillo et al., 2001; Garety, 2003; Pilling et al., 2002).However, despite consistent results across diverse interventions, the components critical to the successof family interventions have not yet been identified.Little is known about the characteristics of patientsor families who do, or do not respond to such treatments. Research is also needed to clarify the relative cost-effectiveness of different models of family treatment for differing patient groups and types of problems (Lehman, 1995).

Cognitive behavioural therapy

Cognitive behavioural therapy (CBT) was originally developed in the 1970s for the treatment of depression, and has since been applied to a large number of different clinical conditions. CBT for psychotic disorders was a later development, informedby new cognitive psychological models of positive psychotic symptoms. Its initial focus was on patientswith persistent psychotic symptoms, but its use has been extended later to other groups of patients with schizophrenia. Controlled trials have also tried to address outcomes other than symptom reduction. In themanagement of schizophrenia, CBT has been applied in a variety of different ways with a number of different aims; common to all are attempts to modify

53

psychotic experiences/ symptoms or their effects upona person’s thoughts, feelings and/or behaviour. CBT bases itself on a collaborative effort with the patient to make sense of his/her psychotic experiences. This involves identifying key beliefs, and thoughts, reviewing the evidence for these, becoming aware of thinking biases, and relating thoughts to mood and behaviour. Patients are encouraged to try out new ways of behaving or thinking in ‘homework’ sessions. Although CBT is delivered in a structured and time-limited way, the standard cognitive therapy approach is modified to meet needs of people with psychosis. Modifications include longer duration during the early part of treatment and flexibility regarding sessions, to allow engagement and prevent therapy from becoming too stressful (Garety, 2003). Several reviews of efficacy of CBT have been carried out including a recent meta-analysis of 13 RCTs (NICE, 2002). All participants in these trials were also receiving antipsychotic drugs, and most often CBT was targeted at individuals with long-standing ortreatment-resistant psychosis. Control groups received ‘standard care’, recreational activities, befriending or supportive counselling. Overall, therewas strong evidence to suggest that CBT reduces symptoms for people with schizophrenia during treatment and at 9-12 month follow-up, compared to ‘standard care’ and other treatments. The evidence was stronger when CBT was used for the treatment of persisting psychotic symptoms rather than for acute symptoms. The evidence for the use of CBT in the acute phase of a first episode of schizophrenia was unclear. CBT can also improve insight and adherence with drug treatment and may have a positive effect upon social functioning. The benefits of CBT are mostmarked when treatment is continued for more than 6 months and involves more than 10 treatment sessions. Shorter-term treatment with CBT may produce modest improvements in depressive symptoms, but is unlikely to have an impact upon psychotic symptoms. Moreover,

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when CBT is continued for longer than 3 months, thereis stronger evidence that relapse rates are reduced. The available evidence suggests that CBT may be more cost effective than other control treatments, but is not conclusive. At the same time the quality of RCTs has been criticized, and the better-designed trials have been unable to demonstrate superiority of CBT over other control treatments. Since CBT is a relatively newly developed treatment option in the management of schizophrenia, further research into the use and effects of CBT in the treatment of peoplewith schizophrenia is needed to clarify the differentroles and potential value of this treatment (NICE, 2002; Stillo et al., 2001; Garety, 2003; Pilling et al., 2002).

Social skills training

This is a highly structured approach, which uses behavioural and learning techniques to target the social disabilities accompanying schizophrenia. The goal is to remedy specific deficits in the patient's role functioning by helping him to acquire skills required to meet interpersonal, self care and other coping demands of community life. Social skills training programmes begin with a very detailed assessment andbehavioural analysis of individual social skills. Skills are then taught through a combination of positive reinforcement, goal setting, modelling, role-playing, rehearsal, coaching, reinforcement, shaping etc. The type of skills vary widely and usually include communication, assertiveness and problem-solving skills, or skills related to certain activities of daily living such as managing medication, shopping, transport, cooking etc. The training can be imparted in either individual or group settings with patients and / or their families.Initially smaller social tasks, such as responses to non-verbal social cues, are worked-on, and gradually new behaviours are then built-up into more complex

55

social skills such as conducting a meaningful conversation. There is a strong emphasis on homework assignments to help generalise newly learnt behaviouraway from the treatment setting (Penn, & Mueser, 1996; Stillo et al., 2001).Several reviews and meta-analytic studies have demonstrated that skills training has an effect on improving the specific social skills targeted during treatment, and that this learning can be maintained for up to 12 months. However, there is little evidence that this learning translates into improved social outcomes in terms of improvement in social functioning, competence or adjustment. This lack of generalization of skills from treatment settings to community settings is a major limitation of this treatment. There is also very little evidence to suggest that social skills training benefits symptomsor reduces relapse rates (NICE, 2002; Penn, & Mueser,1996; Stillo et al., 2001; Pilling et al., 2002).

Cognitive remediation

Cognitive remediation techniques for schizophrenia have been based upon comparable methods of treatment in people with neurological disorders. The major methods concentrate on repeating laboratory-based cognitive tests or repeated practice of procedures designed to specifically address a particular cognitive deficit. The theory behind this approach asserts that cognitive deficits contribute to a person’s vulnerability to schizophrenia (either directly or through increasing a person’s susceptibility to stress), and therefore correcting these deficits should, at least in theory, render a person less vulnerable (NICE, 2002; Penn, & Mueser, 1996; Stillo et al., 2001).Although initial studies demonstrated that certain cognitive processes such as attention/concentration or executive functions might be amenable to such

56

treatment, recent meta-analytic evidence is disappointing. This shows no consistent evidence thatcognitive remediation is effective in improving outcomes for people with schizophrenia, either in terms of specially targeted cognitive functions, or in terms of core outcomes such as symptom reduction (NICE, 2002; Penn, & Mueser, 1996; Stillo et al., 2001; Pilling et al., 2002).

Individual therapy

Exploratory insight oriented psychotherapy has not proved very useful in treatment of schizophrenia. Supportive therapy or supportive counselling is thus the most widely accepted and practiced form of psychotherapy. It usually consists of empathic listening, active problem solving, education about the illness and its treatment, and developing a supportive relationship. The major problem with the technique is that its use in schizophrenia remains undefined, and research evidence for its efficacy is scant (APA, 1997; Penn, & Mueser, 1996; Stillo et al., 2001). The only meta-analysis of this area defined supportive therapy very clearly and examined the results of 14 RCTs comparing it with other types of treatment (NICE, 2002). There was no evidence to suggest that supportive psychotherapy was superior to‘standard care’ or ‘other active treatments’ in the treatment of people with schizophrenia. Nevertheless,certain potential benefits of such therapy such as reducing distress, enhancing compliance, and gaining a better understanding of the patient are, however, quite evident in routine practice. Moreover, the roleof a supportive empathic relationship between a person with schizophrenia and a professional, in which good listening plays a central role in the therapeutic alliance is an essential part of good practice (APA, 1997; NICE, 2002).

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Group therapy

Apart from social skills training and family psychoeducation groups, a variety of other group therapies ranging from psychotherapeutic to educational and supportive, have been used in the treatment of schizophrenia. The goals of group therapy are similar to individual supportive treatment, such as improving social functioning or learning to deal with the illness. As with individualtherapy, evidence for the efficacy of group treatments is at best modest. Moreover, a number of these studies are plagued by serious methodological flaws (APA, 1997; Penn, & Mueser, 1996).

Specific programmes for early intervention

Specific programmes that target prodromal symptoms can be useful in preventing relapse. A few RCTs have shown specific attempts to educate patients/relativesabout prodromal symptoms and early intervention can reduce relapse rates (APA, 1997).

Vocational rehabilitation

Unemployment rates among severely mentally persons are extremely high mainly because of the associated disability, and partly due to factors such as stigma,discrimination, and the low priority given to employment status by mental health services. Nevertheless, work and employment schemes (or vocational rehabilitation) have been developed motivated by the belief that work can itself be therapeutic, and can help patients develop skills andgain the confidence to re-enter competitive employment. Two models of vocational rehabilitation have emerged over recent years, each using differing methods and principles, both aiming to improve employment outcomes. These are:

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Pre-vocational Training: - in which participants are expected to undergo a period of preparation before being encouraged to seek competitive employment. Thispreparation phase could involve either work in a sheltered environment (such as a workshop or work unit), or some form of pre-employment training (e.g. job support or job clubs), or transitional employment. Supported Employment: - which is an approach to vocational rehabilitation that attempts to place clients immediately in competitive employment. Supported employment can begin with a short period ofpreparation, but this does not usually involve work placement in a sheltered setting, or training, or transitional employment. There is evidence from several (mostly US) studies tosuggest that supported employment is superior to pre-vocational training programmes in helping people withserious mental health problems gain competitive employment (NICE, 2002; Stillo et al., 2001).

Community interventions

Case management

Patients of schizophrenia are often ill prepared to find and maintain links with multiple services they need to function in community. Case management is theattempt by one person (the case manager) or a team ofprofessionals (outreach teams) to ensure that such patients receive coordinated, comprehensive and continuous care. There are several models of case management. In the ‘brokerage’ model the primary roleof the case manager is to help the patient establish contact with various services, and coordinate betweendifferent service providers. In the clinical case management model managers are clinicians who apart from brokering, act as clinicians and provide direct services. Assertive Community Treatment (ACT) is a

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model of service delivery with clearly defined aims of keeping people with serious mental health problemsin contact with services, reducing the extent of hospital admissions, and improving quality of life and social functioning of patients. ACT is delivered by a multidisciplinary team, in the community, often using the ‘assertive outreach’ principle of offering treatment assertively to uncooperative or reluctant patients. Team members share responsibility for each patient, and attempt to provide all the psychiatric and social care for them, rather than referring them on to other agencies. Staff to patient ratios is low.The intensive case management model (ICM) is a variant of the ACT meant for the most seriously ill patients. The evidence for the efficacy of the various types of case management models is variable because of differing definitions of the various models used and other methodological problems. Meta-analytic studies have concluded case management services to be either highly effective, or highly ineffective. However, consistent evidence suggests that, ACT, compared to standard care, is more likely to improve contact and satisfaction with services, decrease the use of hospital services, improve quality of life, as well as improve work and housing stability. This is especially so among patients who are high service users. The evidence regarding ICM isinconsistent with some reports findings gains similarto ACT, while others suggest that it is no better than ordinary case management (NICE, 2002; Stillo et al., 2001; Mueser et al., 1998; Ziguras et al., 2002).

Community mental health teams

Community mental health teams are multidisciplinary teams that focus assessment and care away from hospital settings and offer a range of interventions tailored to the patient’s specific needs. Despite thefact that community mental health teams remain the

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mainstay of community mental health care, there is surprisingly little evidence to show they are an effective way of organising services. One systematic review concluded that community mental health team management was superior to standard care in promotingtreatment acceptance, reducing hospitalisations, and preventing suicide (Simmonds et al., 2001). However, the concept is perhaps still too ill defined to standsuch examination (NICE, 2002).

Crisis resolution teams

Crisis resolution treatment teams aremultidisciplinary teams that aim to avoid admittingacutely ill people to hospital by providing intensivehome-based support, with a specific remit to dealwith such situations, in and beyond ‘office hours.’Controlled evidence shows that for people withschizophrenia and other serious mental healthproblems in an acute crisis, such teams are superiorto standard hospital-based care in reducingadmissions and shortening stay in hospital. Theyappear to be more acceptable than hospital-based carefor acute crises, and are more successful inmaintaining contact with patients. Crisis resolutionteams may also have a marginally better effect onsome clinical outcomes (NICE, 2002).

INDIAN RESEARCH

Antipsychotics

Clinical trials

Tables 1 to 4 are an attempt to summarise results ofIndian clinical trials with first and second-generationantipsychotics. It was not possible to include allstudies because of considerations of space andunavailability of data. However, the studies includedare a reasonable representation of the research in thisarea.

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Modalities of treatment – Psychosocial

1. Family intervention

2. Cognitive behavioural therapy

3. Social Skills training

4. Cognitive remediation

5. Individual therapy

6. Group therapy

7. Early-intervention programmes

8. Vocational rehabilitation

9. Case management

Table – 1 Representative Indian Trials First Generation Antipsychotic Medications: Short-Term

Trials

Author(s) Drug Comparisons Design

OpDx

Std.Assmt

N Duratn.(weeks)

Dose(mg/d)

Results

Kothari, 1962

Ffz(oral)

None Open No No 15 4 2.5-5 Poor response

Chatterjee &Bhusan, 1963

Tdz none Open No No 26 4- 16 300 50%improved

Thomas & Narayanan, 1965

Tfz Unicpz Open No No 10 12 5 -15 TFZ = Unicpz

Teja, 1967 Thio-pro

None Open No Yes 25 6 15 56% improved

Mokashi & Chandorkar, 1967

Thio-pro(im)

Cpz, Placebo

DB, RCT

No No 60 5 days 15 (Thio-pro)

Thiopro> Cpz

Menon & Badsha, 1968

Thio-thx

Tfz, Placebo

DB, RCT, Cross-over

No Yes 30 16 15-30 (both drugs)

Thiothx> Tfz

Kishore et al, 1970

Thio-thx

Tfz, Thiopro, Procpz, Cpz, Triflpz

DB, RCT

No Yes 60 12 10 -30(Thio-thx)

Procpz>Thiothx>Triflpz>Thiopro>Tfz, Cpz

Bagadia et al, 1970

Cpz Tfz TrifluoFlupen

ECTICT

Open No No 300

4 Cpz –600-2400Tfz –15-60Trifluo -2-6Flupen

ECT > Tfz, Cpz, Trifluo> Flupen > ICT

62

-3-15Ramachandran& Menon, 1972

Trifluo

Placebo DB, RCT

No Yes 50 6 1.5 Trifluo>Placebo

Bagadia et al, 1972

Flupen None Open No Yes 116

2-4 1.5-9 46.5%improved

Bagadia et al, 1972

Trifluo

None Open No Yes 76 4 1-4 65.8%improved

Bagadia et al, 1972

Trifluo

None Open No Yes 53 4-10 2-6 45%improved

Kishore et al, 1972

Trifluo

ThiothxProcpz

DB, RCT

No Yes 60 12 6 (Trifluo)

All equal

Sharma & Dutta, 1976

Pmz Placebo DB, RCT

No Yes 34 4 1-5 Pmz > placebo

Channabasavanna et al, 1976

Trifluo

None Open No Yes 36 3 1.5 69%improved

Basu et al, 1996

Loxap None Open Yes

Yes 50 6 50-125 Loxapine effective

Emanuel et al, 1997 * Loxap None Open Ye

sYes 66 6 50-150

Loxapine effective

* Other studies of loxapine are by Dube & Kumar, (1976); Sethet al., (1979)

Table – 2 Representative Indian Trials First Generation Antipsychotic Medications: Long-Term/Maintenance Trials

Author(s) Drug Comparisons

Design Op. Dx

Std.Assmt.

N Duration

Dose Results

Davis et al, 1965

Tfz Insulin coma Rx (ICT)

Retrospective comparison

No No 306

1 year 15-60 mg/d

Tfz = ICT

Dube & Mathur, 1966

Tdz None Open No No 35 Few wksto

100-300

7.2%improve

63

months mg/d dNarayanan et al 1967

Pro-cpz

Cpz Open No No 20 20 weeks

100 mg/d (both drugs)

Procpz> Cpz

Bagadia et al, 1973

Pmz None Open No No 50 12 weeks

1-2 mg/d

88% benefited

Mahal & Janakiramaiah, 1975

Pmz Placebo DB, RCT No Yes 62 6 months

2- 4 mg/d

Pmz > placebo

Bagadia et al, 1976

Pmz Tfz DB CTCrossover

No Yes 50 6 months

Pmz -2 mg/dTfz-5 mg/d

Pmz = Tfz

Channabasavanna & Michael,1987

Penflu

Hpl, Placebo

RCT Yes

Yes 30 12 weeks

20-60 mg/wk.

Penflu = Hpl >placebo

Sharma, 1988 Penflu

Tfz Open Yes

Yes 29 6 months

20-40mg/wk

Penflu > Tfz

Table – 3 Representative Indian Trials First Generation Antipsychotic Medications: Depot

preparations

Author(s)

Drug Comparisons

Design Op. Dx

Std.Assmt.

N Duration

Dose Results

Iyer etal, 1968

Ffz ethanate

None Open No Yes 30 2 weeks 1.5-62.5 mg(single dose)

62.5%improved

Gehlot et al, 1977

Ffzdecanoate

None Open No No 30 20 weeks

25 mg/2-3 wks

60% improved

Bagadiaet al, 1979*

Ffzdecanoate

None Open, retrospective

No Yes 83 4 months

6.25 mg/2 wks

Clinical, social, occupational improvement; high

64

EPSE, 46% drop-outs

Bagadiaet al, 1979

Piportil

None Open No No 27 4 weeks 50 mg/wk

76% improved

Shukla,1981

Ffz decanoate

None Open No No 40 6 months

25 mg/3 wks

63% improved,39% dropouts

Verma &Kulhara, 1989

Hpl decanoate

None Open Yes

Yes 30 4 weeks 50-300 mg/4 wks

Improvement in positive& negativesymptoms, few side effects

Fernandes et al, 1999

Zuclopen acetate

None Open Yes

Yes 120

3 days 50 mg(2 doses)

Zuclopenacetate effective, EPSE mild

Fernandes et al, 1999

Zuclopen decanoate

None Open Yes

Yes 120

8 weeks 100 -200 mg/ 2wks

Zuclopendecanoate effective, EPSE mild

* Other trials with fluphenazine ethanate by Shah et al., (1971) & Bagadia et al., (1972) found it effective

Table – 4 Representative Indian Trials Second-Generation Antipsychotic Medications

Author(s)

Drug Comparison(s)

Design

Op. Dx Std.Assmt.

N Duration(weeks)

Dose(mg/d)

Results

Sharma & Bhardwa

Risp None Open Yes Yes 25 8 4-10 Efficacious in positive

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j, 1997 & negativesymptoms

Agarwalet al, 1997

Cloz None Open Yes (TreatmentResistant)

Yes 29 16 50- 450

Effect by 9-16 weeks, no leucopenia

Agarwalet al, 1998

Risp None Open Yes Yes 165

6 6-8 Efficacious in positive& negativesymptoms, EPSEs in 40%

Agashe et al.,1999

Risp None Open Yes Yes 30 24 6-8 Risp safe, effective, mild side effects

Bajaj et al.,1999

Risp None Open Yes(moderately refractory)

Yes 30 > 2 years

2-10 Improvement in negativesymptoms, 25% re-emergence of positivesymptoms

Desai et al.,1999

Cloz None Open Yes (Treatmentresistant)

Yes 28 12 241(mean)

Significant improvement, no leucopenia

Singh et al.,1999

Centb

Hpl DB RCT

Yes Yes 44 6 Centb- 1.5-4.5Hpl- 5-15

Centb = Hpl

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Srivastava & Gopa, 2000

Risp Hpl Open Yes Yes 50 1 year Risp-2 Hpl- 5-15

Risp = Hpl on symptomsRisp > Hpl on social measures, suicidality, readmission

Table – 4 Representative Indian Trials (continued) Second Generation Antipsychotic

Medications

Author(s)

Drug Comparison(s)

Design Op. Dx

Std.Assmt.

N Duration(weeks)

Dose(mg/d)

Results

Srivastava et al., 2001

Risp None

Post-marketing survey

- - 67 psychiatrists

- - 3-4 mg/d effective & preferred

Suresh Kumar et al.,2001

Risp None Open Yes

Yes 24 12 6-8 Improvement inpositive, negative & depressive symptoms, highrates of EPSEs

Agarwal& Chadda,2001

Risp OD vs. BD dose

Open Yes

Yes 44 8 4-8 79-82% response, OD =BD dose

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Avasthiet al.,2001

Olanz

Hpl Open Yes

Yes 27 12 5-20 Improvement inpositive, negative & depressive symptoms

Chandraet al.,2002

Centb

Risp DB RCT Yes

Yes 44 8 Centb- 3-4.5Risp-4-6

Centb =Risp

Abbreviations: Op Dx- operationalized diagnosis using standard criteria; Std. assmt – structured assessments using reliable measures; Duratn/Duration. – duration of trial; DB RCT- double-blind randomised controlled trial; N- number of patients; Ffz-fluphenazine; Tdz-thioridazine; Tfz- trifluoperazine; Unicpz- unichlorpromazine; ICT- insulin comatherapy Thiopro- thioproperazine; Cpz- chlorpromazine; Thiothx- Thiothexene; Procpz- prochlorpromazine; Triflpz- trifluopromazine; Trifluo- trifluoperidol; Flupen- flupenthixol; Pmz- pimozide; Loxap-loxapine; Penflu- penfluperidol; Hpl- haloperidol; Zuclopen- zuclopenthixol; Risp- risperidone; Cloz- clozapine; Centb- centbutindole; Olanz- olanzapine; CBZ- carbamazepine

FGAMs

Clinical trials of first-generation medications began in the 1960s in India, and since then a large number ofdrugs have been examined for their effectiveness in indigenous patient populations. Almost every aspect of treatment with FGAMs including acute (short-term) treatment, maintenance (long-term) treatment, and treatment with depot injections has been assessed. Drugs have been compared with placebo, with each other,with ECT, and even with insulin coma therapy. All, but one trial has found the different FGAMs to be effectiveand well tolerated. Drugs have consistently proved to be better than placebos, better than insulin coma

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therapy, and more or less comparable to ECT. Minor differences in efficacy between two drugs have been reported in some studies, but overall no drug has been shown to be clearly superior to others. Efficacy in thelong-term, and efficacy as well as safety of depot preparations have also been demonstrated. Therefore, these findings are broadly similar to what has been reported in Western patient populations. However, several methodological limitations make it difficult to interpret the results of these drug trials. Randomised controlled trials are few. Many studies have not used standardized diagnoses, and/or structured assessments to rate change. Samples have often been too small and heterogeneous. Follow-up periods have sometimes been inadequate. Nevertheless, there is no doubt that these drugs are safe and efficacious under Indian conditions.

SGAMs

Trials involving SGAMs are understandably fewer and have begun appearing only in the past few years. Methodology is variable, but the number of RCTs is still low. These drugs have been shown to be effective against positive, negative and depressive symptoms, as well as other parameters e.g. functioning, readmission etc. Efficacy has been demonstrated in short-term, and (less often) in long-term treatment of schizophrenia. SGAMs are generally well tolerated. Of particular interest is the drug centbutindole, which has been developed indigenously. It appears to have an atypical profile, and efficacy is comparable to other second-generation drugs.

Adjunctive medications

Studies of adjunctive medications in the treatment of schizophrenia are included in table-5. The number of trials is too few to make any reasonable conclusions about the usefulness of these agents.

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Table – 5 Representative Indian Trials Adjunctive medications in the treatment of

schizophrenia

Author(s) Comparison(s)

Design Diagnoses No.

Duration

Results

Mood stabilisersDube et al.,1981

Lithium vs. Cpz, placebo

DB RCTcrossover

ICD 9 60 4 weeks Lithium reduced overactivity, excitement, hostility,withdrawal

Raju, 1984 CBZ & CBZ + antipsychotics

Open RDC (unresponsive to FGAMs)

9 variable

7 improved

AntidepressantsDua et al., 1990

Imipramine 75 mg +Cpz 800 mg vs. Cpz + placebo

DB RCT RDC 18 6 weeks Adjunctiveimipramine– no benefit

Agarwal & Agarwal, 2000

Fluoxetine up to 80 mg + antipsychotics

Open DSM IV comorbid OCD

7 12 weeks

5 showed improvement in OC symptoms

AnticholinergicsBehere & Ramakrishna,1983

Anticholinergics + Antipsychotics vs. Antipsychotics alone

Open Psychosis mainly schizophrenia

70 4 weeks No differencein EPSEs between both groups

L-dopaSethi et al., 1990

L-dopa Open Schizophrenia with TD

30 14 weeks

80% showed> 50% reduction in TD

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Abbreviations: CBZ- carbamazepine; Cpz= chlorpromazine; DB RCT- double-blind randomised controlled trials

Other drug trials

Trials have also been carried out with other drugs including experimental compounds, ayurvedic preparations, and drugs such as propanolol or naloxone.

Issues relating to dose

It is widely believed that there are ethnic differencesin pharmacokinetic characteristics of psychotropic drugs. Studies suggest that Asian patients often need lower doses of antipsychotics than non-Asian patients. Asian patients also tend to have higher serum levels with equivalent doses of antipsychotics, though this might not be true for all antipsychotic medications (Kuruvilla, 1996). The immediate implications for practicing clinicians are that relying on Western guidelines for dose requirements may not be appropriatefor Indian patients. Beyond this, the evidence is too meagre and conflicting to serve as a guide to suit the requirements of our patients. Clinical experience suggests that the doses should be lower than recommended in standard (Western) texts. At the same time the doses used in drug trials have been within therange used in Western patients, and the drugs still seem to be well tolerated. Then again, in the case of some drugs such as risperidone, the need for lower doses has been recognized (Basu et al., 2000; Suresh Kumar et al., 2001).

Side effects

Clinical experience and pharmacokinetic data suggest that Indian patients should be more sensitive to side effects. However, the few studies (table-6) that specifically address this issue have only been able to find a marginally higher prevalence of side effects such as EPSEs. Data from drug trials yield higher

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rates, but could be biased because they rely heavily onhigh potency FGAMs. Further studies are needed to either confirm or refute clinical suspicions.

Table – 6 Representative Indian Trials Side effects of antipsychotics

Author(s) Methodology Results

Ray et al., 1992

25 inpatients, 14 withRDC schizophrenia, exposed to Hpl, Tfz, Ffz, structured ratings for akathisia

28% had akathisia few patients complained

Dutta et al., 1994

Structured assessmentsfor TD in 350 patientson antipsychotics for 3 months

25.5% had persistent TD, higher age, higher total doses, longer duration of treatment correlated with TD

Suresh Kumar& Manoj Kumar, 1997

Retrospective comparison of 42 patients with DSMIIIR schizophrenia vs. 42 patients with mood disorders

EPSEs –

dystonia- 17%; parkinsonism- 60%;akathisia- 30%TD- 6.7%

Basu et al.,2000

Retrospective review of 43 patients, predominantly schizophrenia, on risperidone, mean dose6.26 mg/d

67.4% had EPSEs, most patients developed EPSEs at doses of 5-7 mg/d

Chopra & Raghuram, 2001

Retrospective review of 13 cases of NMS, treated with bromocriptine or amantadine

Re-challenge with high potency drugs led to partial recurrence; treatment with single agent better

Gupta et al., 2003

Prospective 4-year study, 15 cases of NMS

Risk factors –male sex, new exposure, parenteral drugs, rapid dose increases, combination of antipsychotics, concomitant lithium, agitation, dehydration, infections

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Abbreviations: Tfz-trifluoperazine, Ffz-fluphenazine, Hpl- haloperidol.

Plasma-levels

Determination of plasma levels is only recommended for inexplicable non-response or side effects. However for reasons of cost, cultural differences, doubtful utilityof and lack of facilities for such tests, therapeutic drug monitoring has been discouraged (Kala, 1997).

Cost of treatment/Availability

Although the situation has changed, not all antipsychotic preparations are available in India. The acquisition costs of some FGAMs (e.g. trifluoperazine) are lower than SGAMs (Indian Drugs Review, 2003). Then again, studies have also shown that the cost of SGAMs is similar to FGAMs in India (Girish et al., 1999). In general, there is a lack of comprehensive Indian data on cost effectiveness of antipsychotic drugs. Cost of illness studies have shown that drugs constitute a muchhigher proportion of total costs of treatment, comparedto Western data. Further, even if drugs are available they might be out of reach of the average patient. The prohibitive costs of some drugs can deter patients fromcomplying with treatment. Hospitals may supply one or two preparations, but the supply is often unreliable.

Monitoring

Monitoring for response, side effects and compliance are essential components of drug treatment. Several professionals are often involved in this process, especially during the maintenance phase when such monitoring may have to be done in the community. The lack of such facilities in India means that standards requirements for drug delivery and monitoring are not met. Practices have to be modified, and family members are often relied upon to fill this gap.

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Cultural beliefs

There is also growing awareness that cultural beliefs might affect drug compliance by influencing attitudes to taking drugs, expectations from drug treatment, and the labelling or reporting of therapeutic/adverse events. Beliefs of patients and their families about causes of illness determine several key issues such as treatment seeking, expectations from treatment, adherence to treatment etc. Belief in supernatural causes is common and families have a lot of faith in traditional methods of treatment. Allopathic drugs are considered too strong, believed to produce excessive ‘heat’, and in general be detrimental to health. Certain side effects can be especially distressing for some e.g. amenorrhoea for young unmarried women, or sexual dysfunction for men. Expectations of quick relief often clash with the long duration of treatment needed. Families often expect clinicians to take all decisions themselves. An awareness of socio-cultural factors is thus essential for effective pharmacotherapy(Kuruvilla, 1996).

ECT

ECT though not favoured in the West for treating schizophrenia is often used in India for this purpose. Table- 7 lists the Indian studies that have focused on the role of ECT in the treatment of schizophrenia. The evidence, particularly for acute efficacy of ECT is quite impressive. The consistent finding across severalstudies is that the combination of ECT and antipsychotics is superior to antipsychotics alone. It leads to a much faster resolution of symptoms during the first few weeks of treatment. However, some studiessuggest that this advantage is lost if adequate doses of comparator antipsychotics are used. Further, almost all studies show that the enhanced efficacy only persists for the first few weeks following which ECT and antipsychotics have similar effects. Reviews of thesubject have also that ECT has an edge over

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antipsychotics in the early part of treatment, which disappears after 8-12 weeks. Predictors of good response include acute onset, shorter duration of illness, stable premorbid adjustment, and the presence of psychotic, catatonic or affective symptoms. ECT is not useful in chronic schizophrenia, in those with negative symptoms and in relapse prevention. Some authors have proposed that there are other advantages of ECT that make it a useful treatment option in developing settings. These include low costs of treatment, the relative lack off long-term side effects, the need for lower doses of antipsychotics when used with ECT, and the shortened duration of hospital stay that results from rapid recovery. However, there is a lot of stigma among patients and relatives regarding ECT, although studies about patientacceptance are equivocal in this regard (Goswami et al., 2003). Such negative attitudes are often not helped by the varying standards in the delivery of thistreatment, across different settings.

Table – 7 Representative Indian Trials Electroconvulsive Therapy

Author(s) Design Comparison(s) Op. Dx

Std.Assmt.

N Duration

Results

Shah & Bagadia, 1962

Prospective, open

None No No 398

3 years

Best results inthose ill for < 6 months

Dutta-Ray & Kapoor, 1963

Open ECT vs. Cpz No No 200

1 year Best results inacute onset illness of< 1 year

Bagadia etal., 1970

Open ICT, Cpz, Tfz, Trifluo,Flupen

No No 300

4 weeks

ECT > drugs > ICT

Desmukh etal., 1980 1

Open Daily vs. 3 ECTs/week

No Yes 60 3 weeks

Daily = 3 ECTs per

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weekJanakiramiah & Subbakrishna, 1981

Single-blind RCT

ECT + Cpz vs.Cpz alone

Yes

Yes 44 6 weeks

ECT > Cpz by wk 2; ECT = Cpz by wk 6

Janakiramiah et al.,1982

Single-blind RCT

Cpz 300 mg vs. Cpz 300 mg + ECT vs. Cpz 500 mg vs. Cpz 500 mg + ECT

Yes

Yes 60 6 weeks

ECT faster, augments low, not high dose Cpz

Bagadia etal., 1983

DB RCT Real ECT + placebo vs. Simulated ECT+ Cpz,

Yes

Yes 38 3 weeks

ECT = Cpz

Natani et al., 1983

RCT ECT vs. Hpl 15 mg vs. ECT+ Hpl 15 mg

Yes

Yes 90 3 weeks

Wks 1 &2 ECT +Hpl best; Wk 3all equal

Agarwal & Winny, 1985

DB RCT Cpz 800-1200 mg + real ECTvs. Cpz + simulated ECT

Yes

Yes 28 4 weeks

Both conditionsequal

Abraham & Kulhara, 1987

DB RCT Tfz 20 mg + real ECT vs. Tfz + simulated ECT

Yes

Yes 22 26 weeks

Up to 8 weeks realECT superior; 12 & 26 weeks bothgroups same

Sarkar et al., 1994

DB RCT Hpl 15 mg + true ECT vs. Hpl + sham ECT

Yes

Yes 30 6 months

Both groups equal

Goswami etal., 2003

DB RCT oftreatmentresistantpatients

Cpz 1000 mg +real ECT vs. Cpz + sham ECT

Yes

Yes 25 4 weeks

True ECT >Sham ECT

Abbreviations: Op Dx- operationalized diagnosis using standard criteria; Std. assmt – structured assessments using reliable measures; Duratn/Duration. – duration of trial; DB RCT- double-blind randomized controlled trial; N- number of patients; Tfz- trifluoperazine; ICT- insulin coma therapy;

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Cpz- chlorpromazine; Thiothx- Thiothexene; Trifluo- trifluoperidol; Flupen- flupenthixol; Hpl- haloperidol

Psychosocial interventions

There are major differences in the mental health services and the socio-cultural milieu between developing and developed countries. There is a glaring lack of infrastructure, funds and political support formental heath care in developing countries. This is compounded by a severe shortage of adequately trained and motivated staff. Services are mostly urban-based and therefore relatively inaccessible for a majority ofpatients who reside in rural areas. In such a situationfamilies have become caregivers of the first and last resort. Cultural beliefs, norms and attitudes to mentalillness, as well as expectations from treatment also differ greatly. Given these fundamental differences psychosocial treatments often used so successfully in the West, cannot be directly transposed to developing settings. Instead it has been proposed that these countries need to develop their own theory of rehabilitation and test models of intervention based onthis theory (Philips & Pearson, 1994). Although some progress has been made, tables 8 a, b and c indicate that this area still remains relatively neglected in India. There seems to be adequate amount of research onpsychosocial aspects such as family burden and distress, coping styles of patients and carers, role oflife events and social support, disability, quality of life, work performance, rehabilitation needs etc. However, interventions studies are sorely lacking John,1997).

Family treatment (Table 8a): In India there has been a long tradition of involving families in the treatment of mentally ill relatives. However, few efforts had been made to develop structured programmes suited to the cultural context, and still fewer efforts to test them. Pioneering work with the families of mentally ill patients was done by

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Dr. Vidyasagar in Amritsar. Family wards exist in hospitals like CMC, Vellore and NIMHANS, Bangalore, andinvolvement of families in patient care is a routine practice in many other centres. However, the hospital-based, and resource-intensive and infrastructure-dependent nature of such programmes means that they might not be the most appropriate models to adopt (Shankar & Menon, 1993). Of late there have been effortsto develop a framework for family interventions suitable for both community and institution-based treatment. Sadly, there are no controlled studies of family interventions from India.

Table – 8a Representative Indian Trials Psychosocial Therapies: Family Treatment

Author(s) Description Sample ResultsNarayanan et al., 1972

Descriptive study oftreatment in a family ward

104 patients, 76 with schizophrenia

“gratifying results”with family treatment

Chacko et al, 1967

Descriptive study oftreatment in a family ward

Mixed group; mainly with schizophrenia

Benefits from family treatment

Verghese et al.,1988

Assessment of knowledge & attitudes of carers

94 caregivers attending afamily participation programme

Positive change in knowledge & attitudes following attendance

Shankar & Menon,1993

Description of a family intervention module

Case reports Intervention useful

Sovani, 1993 Descriptive study ofa one- day family-psycho educational programme

Caregivers Caregiversexpressed need for such programmes

Home-care (Table-8b):

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Efforts to develop and study an alternative to hospital-based care, particularly those by Pai and her colleagues, were reasonably successful, but have not been followed-up. Some studies have also indicated the useful role community psychiatric nurses can play (Murthy et al., 1997; John, 1997).

Table – 8b Representative Indian Trials Psychosocial Therapies: Home Treatment

Author(s) Description Sample/Assessments ResultsSuman et al., 1980

Descriptive study ofan intervention consisting of home visits, counselling & social casework

30 patients with psychosis

Interventions beneficial

Pai & Kapur, 1982; 1983

Home treatment by trained nurse vs. hospital treatment

54 patients with ICD 9 diagnosis of schizophrenia, first episodes assessed for symptoms, social functioning, family burden

After 6 months home treatment group significantly improved on symptoms, functioning, family burden

Pai & Roberts, 1983

Home treatment by trained nurse vs. hospital treatment

37 patients with ICD 9 diagnosis of schizophrenia, first episodes assessed for symptoms, social functioning, family burden

At 2 year follow-up home treatment group significantly improved on symptoms only, hospitalised less often

Pai et al., 1985 Home treatment by 25 chronically mentally At 2-year

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trained nurse vs. hospital treatment

ill patients with schizophrenia, psychosis,epilepsy with > 2 years illness assessed for symptoms, social functioning, family burden

follow-up home treatment group lesslikely to have been hospitalised; no differenceon symptoms, functioning, family burden

Rehabilitation: Culture-specific characteristics that rehabilitation programmes need to adopt in order to be successful in developing country settings have been mentioned (Gopinath & Rao, 1994). These include:

shifting the locus of care from the hospital to the community

focusing primarily on families of patients, supporting them, helping them cope and easing their burden

developing a network of services from the periphery to the centre

placing a particular emphasis on vocational rehabilitation, given the centrality of work in these cultures

adopting techniques which are culturally based and, hence, more acceptable

mobilising both private and public resources motivating and training more number of mental

health professionalsHowever, apart from the studies mentioned in table 8c, and a handful of reports on the utility of industrial and occupational therapy, there is limited Indian research in this area (Sarada Menon et al., 1985). Moreover, setting up of rehabilitation services and facilities as envisaged by the National Mental Health Plan (Ministry of Health and Family Welfare, Govt. of

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India, 1982) has never achieved fruition (Murthy et al., 1997; John, 1997).

Table – 8c Representative Indian Trials Psychosocial Therapies: Other Interventions

Author(s) Description Sample/Assessments ResultsThara & Srinivasan, 1998

Intervention packageincluding psychoeducation, social skills training, occupational therapy& medication management vs. antipsychotic medications alone; open trial of 1-year

135 patients with DSMIIIRschizophrenia assessed for negative symptoms, disability, psychologicalimpairments

Both treatmentgroups improved, onlyminor differences between both

Chatterjee et al, 2003

Community-based rehabilitation (CBR)vs. outpatient care;longitudinal trial of 1 year

207 patients with chronicschizophrenia as per ICD 10; assessed for symptomsand disability

CBR better in reducing disability, improving outcome and treatment-adherence

CLINICAL PRACTICE RECOMMENDATIONS

Treatment during the acute phase

Goals of treatment

The goals of treatment during the acute phase are reduction in symptoms and improvement in role functioning. Establishing contact with the family with a view to involve them in the treatment process,and establishing an alliance which can continue throughout this process, is another important objective. Formulating a plan for further short or long-term treatment is the final goal of this phase.

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Assessment

Before proceeding on to treatment all patients need adetailed and comprehensive assessment, which considers the psychiatric, physical/medical, as well as social/familial aspects of the situation.

Psychiatric assessment

Psychiatric evaluation during the acute phase is needed-

to establish the diagnosis to assess the severity of illness particularly

in terms of risk of harm to self and others to detect comorbid conditions such as substance

abuse

A diagnosis of schizophrenia should be made according to structured diagnostic criteria, wherever possible. Such a diagnosis is more reliable, facilitates communication between clinicians, and allows for betterapplicability of research recommendations regarding treatment.A definitive diagnosis may need time. Further, because of the enormous psychosocial consequences a diagnosis of schizophrenia needs to be made with great caution and sensitivity. A medication-free observation period in the hospital has been recommended in doubtful cases,but needs to be balanced against the risks of delaying treatment or the potential for harm in acutely ill patients. Efforts should be made to obtain information from all sources, particularly the family. If a second opinion is asked for by the family, or feltnecessary by the treatment team, this should always be sought.The list of conditions mimicking schizophrenia is long.Those that need to be commonly considered are organic brain disorders, substance-induced psychotic disorders,

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acute psychotic conditions, and mood disorders with psychotic symptoms. Careful history taking physical andmental state assessments will help in ruling out most of these conditions. Investigations such as drug screens, EEG, neuroimaging etc. can be used whenever required.The risk of harm to self and others secondary to delusions and hallucinations or suicidal ideas needs tobe particularly looked into. If present, appropriate precautions will need to be taken. Standardized rating scales are reliable and accurate ways of assessing severity. Wherever possible, unstructured assessments need to be supplemented by ratings on such scales.A high index of suspicion coupled with thorough assessment will be able to detect most patients with comorbid substance abuse/dependence. Urine or blood screens (with prior consent) can be used to confirm theexistence of comorbid substance abuse/dependence, wherever such facilities are available.

Physical assessment

Patients with schizophrenia are more likely than the general population to have lifestyle risk factors for cardiovascular disease and mortality. People with schizophrenia are also less likely to exercise or take a proper diet, and more likely to neglect heath problems (McCreadie et al., 2003). The higher physical morbidity and mortality of patients with schizophrenia must be considered in all assessments. Particular attention should be paid to the risk of metabolic and cardiovascular disease. An effort should also be made to establish the state of the patient’s physical condition through detailed examinations, routine investigations, and special tests wherever required. The physical status of the patient needs to be reviewedfrom time to time.

Assessment of family parameters

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Much of this will be a part of the psychiatric assessment. Economic and living conditions, needs and expectations from treatment, knowledge about illness, attitudes towards patient etc., also need to be focusedon.

Choice of treatment setting

Although the decision to admit the patient may hinge onseveral clinical and social factors the principal reasons for hospitalisation are

risk of harm to self/others inability to care for self presence of comorbid physical or psychiatric

conditions requirement for more intensive treatment

Alternatives to hospitalisation are outpatient treatment and a range of intermediate facilities or modalities such as day hospitalisation, home-care, ACT etc. These are feasible and efficacious alternatives asdemonstrated by research data from the West, and to a lesser extent from India. However the virtual absence of such facilities in India means that the only practical alternative to hospitalisation in this country is outpatient care.

Antipsychotic treatment

Antipsychotic medications are indicated for nearly all patients with acute episodes of schizophrenia. Antipsychotic therapy should be initiated as part of a comprehensive package of care that addresses the patient’s clinical, emotional and social needs, as wellas the needs of his/her family.

Choice of drug

In general the choice of an antipsychotic is guided by the side-effect profile of the drug, prior response

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patterns, patient preferences and the preferred route of administration (oral versus parenteral).SGAMs have several advantages in the treatment of schizophrenia. These drugs have significant effects in reducing positive symptoms, in which aspect they are equal, if not superior to FGAMs. The evidence for theirefficacy against negative, cognitive and affective symptoms though less firm, is still compelling. They are efficacious in patients with aggressive or suicidalimpulses, and have proved useful in relapse prevention.Their greatest advantage, however, is the lower risk ofEPSEs, particularly TD. They seem to be more acceptableto patients, and lead to improved adherence and qualityof life. They are, therefore. universally recommended as first-line treatments in schizophrenia, and should be used preferentially in first-episode patients (except clozapine). They are also the preferred choice in treatment of patients with parkinsonism, EPSE sensitivity, and those with TD. They should also be considered in patients who develop unacceptable side effects with first-generation drugs. However, patients who are well controlled on FGAMs and are not experiencing significant side effects should not be switched to second-generation antipsychotics. FGAMs canalso be useful in the management of acute agitation andfloridly psychotic patients (Sartorius et al., 2003).

Dose

The recommended dose of FGAMs is in the range of 300 - 1000 mg chlorpromazine equivalents per day (APA, 1997; 2004; NICE, 2002). Standard recommendations for SGAMs are also available.Lower than recommended doses are usually recommended for first-episode patients. The use of high or mega doses of antipsychotics, if required, may be used with caution in exceptional circumstances. It is likely that Indian patients require lower doses of antipsychotic drugs. Although this is suggested by clinical experience and pharmacokinetic studies of

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Asian patients, there is little evidence for, or against this supposition from clinical trials.

Route of administration

Parenteral administration is often required in acutely agitated patients to achieve rapid control of behavioural disturbance. Liquid or mouth-dissolving formulations are helpful in non-compliant patients. Depot preparations are generally not used during the acute phase. The use of one drug by one route is recommended in order to minimise drug interactions and simplify clinical observations.

Duration of treatment

The minimum recommended duration of treatment for all drugs is 4- 6 weeks, with the exception of clozapine, where the minimum period of treatment should be 3 months (APA, 1997; 2004; NICE, 2002).

Response.

Antipsychotics are known to produce a significant remission of positive symptoms. This could thus be a reasonable goal of treatment. Effects on negative symptoms are less impressive, therefore a mild to moderate reduction in negative symptoms is often acceptable. Response indicators for other aspects of the illness (e.g. cognitive symptoms) are not clear (Miller et al., 1999). Regular monitoring is required for determining the degree of response and the emergence of side effects.

Non-response

In case of non-response, non-compliance, which is highly prevalent among patients, should be suspected first. If this is confirmed the causes should be lookedfor, and appropriate steps taken to handle the problem.Clozapine is recommended after failure of sequential

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trials of 2 antipsychotics (at least one of which is a SGAM), in patients who are violent/at risk for suicide and not responding to their current medication, or in patients who have intolerable side effects with two different classes of antipsychotics (APA, 1997; 2004; NICE, 2002).

Combining antipsychotics

The evidence for the efficacy of combining antipsychotics is limited and anecdotal. Combinations of antipsychotics should be normally avoided, except inpatients not responding to clozapine (NICE, 2002). 6

Cost of treatment

Whether patients can actually afford the drugs being prescribed should always be enquired about. In certainsituations the cost of the drug could be an important determinant of the choice of the antipsychotic to be used.

Adjunctive medications

Lithium and other mood stabilizers can be added in agitated, overactive patients or those with affective symptoms responding poorly to their current drug. Adjunctive benzodiazepines can be useful in controllingagitation and in those with sleep disturbance. The roleof antidepressants in treating depressive symptoms during the acute psychotic phase, as opposed to the post-psychotic phase, is not clear. Prophylactic anticholinergic treatment is generally required in situations of high risk for EPSEs, predisposition to EPSEs, or possible detrimental effects of EPSEs on compliance (APA, 1997; 2004; NICE, 2002; Kusumi & Koyama, 1999).

ECT

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ECT can be used for patients with catatonic or affective symptoms and in certain situations where rapid control of symptoms is required.

Psychosocial interventions

In the acute phase psychosocial treatments with the patient are aimed at reducing over stimulating or stressful conditions, while providing a safe and structured environment. The interventions are kept relatively simple. Information about the nature and treatment of illness can be provided depending on the patient’s ability to handle such information. There should be opportunities for recreational and simple therapeutic activities. Input from social workers, nurses and psychologists may be required to deal with non-psychotic symptoms or difficult behaviours.An effort is also made to involve and engage the familyin the process of treatment. Relatives need to be seen regularly for this purpose. The aim is to educate the family in understanding the illness. Simple and brief explanations about the nature of the patient’s illness,treatments, likely side effects, likely length of treatment etc. can be offered. Relatives also need to be given time to confront the painful fact of the illness, and what it entails for the patient and the family as a whole. It is important that professionals are careful and considerate, but clear and thorough in their use of clinical language and in the explanations they provide. No blame should be attached to the family. Treatment adherence will be another main objective at this stage; family members will need assistance in dealing with various problems it presentse.g. continued use of medication to control symptoms,issues of non-compliance, dealing with distressing sideeffects etc.

Planning for further treatment

At the end of the acute phase the treating team, familymembers and the patient whenever possible, should

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jointly decide on a plan for further treatment. Issues such as follow-up, medication management, preventing psychosocial stress etc. could be discussed. To ensure continuity of care it is preferable for the same team member(s) to be involved in the future care of the patient.

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Aspects of treatment during the acute phase

Determining goals

Assessment (psychiatric/ physical/ psychosocial)

Choice of treatment setting

Antipsychotic treatment

1. Choice of drug2. Dose3. Route of administration4. Duration of treatment5. Determining response or non-

response6. Combining antipsychotics

Use of adjunctive medications

Post-acute phase / Stabilization phase/ Continuation-treatment phase

Goals of treatment

Goals of treatment during this phase include facilitation of continued symptom reduction and decreasing the likelihood of relapse. Stress on patients needs to be minimized, support needs to continue, and patient’s adaptation to life in the community enhanced.

Assessment

Assessments for further help to minimise disability, reduce risk of relapse and improve quality of life should be routinely undertaken during recovery from theacute phase.

Antipsychotic drug treatment

Though studies have not specifically examined the issueof efficacy of drugs during this phase, the data on maintenance phase efficacy of antipsychotics provide important clues. This suggests that if the patient has improved with a particular drug during the acute phase he/she should continue with the same drug at the same dose for the next 6-12 months. Failure to do so may result in a relapse relatively early.

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Psychosocial interventions

Psychosocial treatments remain supportive. Engagement with family continues with further psychoeducation and support. The importance of treatment compliance is reemphasised. Patients when they are willing and able can also be taught how to manage their medication, although the family members should also supervise drug intake. A few basic skills that will help prepare the patient for life in the community can also be taught. It is important to ensure continuity of care and prevent early dropouts. Frequent outpatient appointments, ensuring that patients have ready access to treatment facilities, dealing with any emergencies that might arise, all help in this process. Home visitscan also be arranged if required and when feasible.

Stable phase / Maintenance treatment phase

Goals of treatment

The goals of treatment during this phase are to maintain or improve functioning and quality of life. Prodromal symptoms or psychotic exacerbations should beeffectively treated. Adverse effects should be detectedand managed.

Assessments and monitoring

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Aspects of treatment during the post-acute phase

Determining goals

Further assessment

Antipsychotic treatment

Further assessments may be required during this period especially if psychosocial treatments are being planned. Monitoring is required for assessing response and for side effects that may emerge. Information should be obtained both from the patients, family members, and other available sources. Whenever possible, objective ratings should be used to gauge theprogress of therapy more effectively. Standardised instruments improve reliability and enhance communication. Reassessment on several parameters may need to be carried out from time to time. Frequency of contact will depend on several factors such as clinicalstate, the distance of the hospital from the patient’s home, social support available for the patient, the type of treatment being administered etc.

Assessments for drug treatment

Ongoing assessments and monitoring are required to determine response to antipsychotics and the need for change if any, to detect side effects, and to identify the early signs of a relapse.

Suggested assessments and monitoring *

Parameter Baseline assessment

Follow-up monitoring

Vital signs (pulse, B.P., temperature etc.)

Required As required

Height/weight/body massindex (BMI)

Required BMI every visit for 6 months & every 3 months thereafter

Haemogram Required Repeated as required, particularly for those on clozapine

Biochemistry (electrolytes, renal, liver and thyroid functions etc.)

Required Annually and as clinically indicated

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Screening for infections (syphilis, HIV etc.)

Required if clinically indicated

-

Screening for substanceabuse

Required if clinically indicated

-

Neuroimaging/EEG Required if clinically indicated

-

Screening for diabetes(history, examination, fasting blood sugars)

Required especially in those with risk factors and those on drugs with known predisposition

Fasting blood sugar or Haemoglobin A1c after 4 months of treatment & annually thereafter

Hyperlipidemia (lipid profile)

Required especially in those with risk factors and those on drugs with known predisposition

At least every 5 years

Screening for cardiovascular disorders (history, examination, ECG etc.)

Required especially in those with risk factors and those on drugs with known predisposition

ECG with every dose change or addition of new drugs & as required

Hyperprolactinemia (history & examination;prolactin level only ifindicated and feasible)

Required especially in those on drugswith known predisposition

Screening for signs/symptoms of hyperprolactinemia - at each visit until on stable doses, yearly thereafter for those on drugs with known predisposition. Prolactin level only if indicated and feasible

Clinical assessment for (Acute) EPSEs

Required afterstarting drugs

Clinical assessment at least weekly until on

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stable doses, at every follow-up thereafter

Clinical assessment forTardive dyskinesia

Required after3 months of treatment

At least every 6 months for FGAMs & every 12 months for SGAMs

* Extent of baseline assessments and frequency of monitoring are principally determined by the clinical situation

Psychosocial evaluation

The following areas need to be looked into:

1. Knowledge about illness - Both the patient's and relatives' knowledge about the disorder, its manifestations and treatment should be inquired into.

2. Attitudes towards illness - Attitudes towards the illness as well as perceptions of the persons involved need to be explored. Special emphasis should be placed on cultural beliefs and attributions e.g. diet or supernatural causes.

3. Family background / social support - A more detailed assessment of the family is required at this stage. Primary carers of the patient need to be identified. The social network and supports available for the family are to be assessed.

4. Physical factors - Factors such as accommodation, sources of income and financial situation, access to medical facilities, opportunities for leisure etc., are expected to have important bearing on subsequent treatment efforts. A clear idea of these is thus essential for planning any family based intervention.

5. Family burden - Various areas that need to be looked into are those of financial burden, disruption of routine family activities, disruption of family leisure, effect of patient's illness on physical and mental health of carers, and subjective burden. A list of symptoms or

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behaviours that the relatives find particularly burdensome can be made. An attempt should be made to differentiate those behaviours which the carersfeel are due to the illness from those which they feel to be a part of the patient's ‘personality.’

6. Coping - Coping strategies, resources, previous efforts, and coping in different situations by both the patient and the family as a whole should be evaluated.

7. Involvement with / satisfaction from treatment agencies - Families may have been to several doctors, hospitals, and traditional healers beforeseeking treatment at a psychiatric facility. This involvement with various treatment agencies reveals a lot about the family, their beliefs about the illness, their expectation from treatment etc. Their level of satisfaction with the current treatment also needs to be examined. Family’s expectations from treatment should be assessed.

8. Family interactions - At each session with family members it would be useful to observe the pattern of family interactions. Although a structured assessment of EE might not be possible, it is important nevertheless, to ascertain whether the elements of hostility, criticism and over-involvement are a part of the interactions betweenthe family and the patient.

9. Occupation - If the patient is employed the statusof his/her occupational functioning, including housework, need to be evaluated. After obtaining permission from the patient and family, a visit tothe work place (distance permitting) can be planned. If the patient is unemployed his suitability for work and opportunities available might be explored.

10. Other assessments - Specialised assessments such as behaviour analysis, evaluation of risks such as risk for suicide or violence etc. will need to be carried out as required.

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Antipsychotic treatment

Dose

The dose of the antipsychotic needs to be individualized. A balance has to be struck between the need to reduce side effects and the need to prevent relapse. Stable patients who do not have positive symptoms may be candidates for reduction in doses. Doses need to be reduced gradually at the rate of about 20% every 6 months till a minimum effective dose is reached. Minimum doses would be in the range of 2.5 mg of oral haloperidol, or 6.25 -12.5 mg of fluphenazine decanoate, or 50 mg of haloperidol decanoate, or their equivalents (APA, 1997; 2004; NICE, 2002). Targeted or intermittent dosage maintenance strategies should not be used routinely. This strategy is only recommended for patients who refuse continuous medication and might comply with an intermittent regimen if properly educated (APA, 1997; 2004; NICE, 2002). Reduction of dose/ withdrawal of antipsychotic medication should be undertaken gradually whilst regularly monitoring signs and symptoms for evidence ofpotential relapse. Following withdrawal from antipsychotic medication, monitoring for signs and symptoms of potential relapse should continue for at least 2 years after the last acute episode (APA, 1997; 2004; NICE, 2002). Any re-emergence of symptoms should be immediately treated.

Depot preparations

Depots are helpful in ensuring compliance and should beused in all situations where non-compliance is a problem. They should also be used if patients/relativesindicate a preference for this kind of treatment. SinceSGAMs are not widely available in long-acting forms, first generation preparations need to be used in patients requiring treatment with depot injections. For

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optimum effectiveness in preventing relapse, depot preparations should be prescribed within the standard recommended dosage and interval range. Test doses should normally be administered at the start of treatment. People receiving depots should be maintainedunder regular clinical review, particularly in relationto the risks and benefits of the drug regimen (NICE, 2002).

Duration of treatment

Duration of treatment depends on a number of factors and will need to be individualized. The suggested guidelines are as follows:

first-episode patients should receive 1-2 years ofmaintenance treatment

patients with several episodes or exacerbations should receive maintenance treatment for 5 years or longer

patients with history of aggression or suicide attempts should receive treatment for an indefinite period, even lifelong.

Psychosocial intervention

Interventions with the family

Standardised treatment packages which have been tested under controlled conditions in India, are not available. However, modules for use in outpatient and community settings have been described (Shankar & Menon, 1993). The following guidelines are partly based on these.

General principles

The focus of any psychosocial treatment is expected to include both the patient and the family. It might not always be possible either to meet all the family members, or include all of them in each and every

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session. So, it would be worthwhile to identify and focus on 'key members' while involving the others as often as possible.One of the principal tasks of any family based intervention is to form a supportive and trusting relationship with the patient as well as the family. This allows gathering of important information about them and lays the foundations on which treatment can beimplemented. Often a substantial portion of the initialsessions is needed to foster a trusting relationship.It is essential to consider the family members as allies, not as targets of treatment. Otherwise it mightbe difficult to get them to cooperate fully. It is alsoimportant to tell the relatives at the very outset thatthey are not to blame for the patient's condition. Relatives often fear this and feel guilty. Allaying their anxieties in this regard might make them more willing to cooperate with any treatment plan.The patient may be seen individually or with the familydepending on the circumstances. It is advisable to holdsome sessions jointly, and some separately with the patient. Natal as well as marital families may need to be involved in this process.As with the family, a member of the treating team can be designated as a ‘key-worker ' or as a sort of a 'case manager'. The patient and his family should have ready access to this person. In addition the key-workershould be in a position to coordinate treatment effortsby different team members, so that they provide maximumbenefit to the patient and the family.In most instances the locus of treatment will either bethe inpatient ward, the outpatient clinic, or rarely the patient’s home.The frequency of sessions will vary, but a minimum of once monthly is recommended. Contact should be maintained for as long as possible, preferably for a year.Involvement of nurses, social workers, psychologists, occupational therapists, rehabilitation professionals and other paramedical professionals is highly

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desirable. Every effort should be made to solicit theirhelp.Treating teams would often have to be flexible and innovative in their approach. They need not rigidly adhere to Western models of psychosocial interventions with the family. Approaches can be simple and goal oriented as long as they are acceptable to the family and feasible in the context of limited treatment resources that are usually available.

Phases and tasks

1. Engagement This is the phase when therapists introduce themselves.They explain the nature of treatment and what it will entail.

2. Intervention phase proper This can be held in the form of monthly sessions of 45-60 minutes each. The location could be the outpatient clinic or the patient’s home if this is possible. This phase is expected to last anywhere between 6-9 months.

Content of sessions will include:

Informing about diagnosis

Both the patient and relatives need to be told about the diagnosis. If the patient is acutely ill informing him about the diagnosis may be postponed till he is in a receptive frame of mind. A realistic picture of the illness should be presented, emphasizing positive aspects such as treatments available, but without detracting from the implications of the condition. The patient and the family need to be assured that more detailed information would be provided subsequently, and that they should feel free to clarify any doubts they may have.

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Education

Information booklets about schizophrenia can be distributed to those who can read. After the booklet has been read, various aspects of the illness such as aetiology, symptoms, treatment and prognosis should be discussed. The information imparted should cover the disorder in general, but should be made relevant by focusing on areas concerning the individual patient. The explanations should be in simple terms, professional jargon should be avoided. The patient's and relative’s level of education and understanding need to be considered while trying to educate them about the illness. Questions should be encouraged and doubts clarified. The ability to understand might vary among the different family members. The patient's understanding might be particularly affected by the illness. Relatives will need time to absorb the facts. Thus, education needs to be an ongoing process. It is not necessary or possible to cover all aspects of the illness in the initial few sessions; some areas e.g. early recognition of relapses could be discussed later.For an educational programme to be successful it is imperative to justify the need for education and stressthe advantages of learning skills to have more control over treatment. Expectations of the family may be different from the treating team. Setting common educational objectives at the very outset, is thus, very helpful. Imparting of information should never be one sided, the family and the patient (wherever possible) need to be actively involved in the process. One or more sessions should be set aside to discuss issues that the family wants to bring up. The carers commonly want to discuss issues such as marriage, work,care of children and other relevant issues. These mustbe, therefore, given due importance. The areas covered could include

aetiology symptoms prognosis treatment methods

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common myths and beliefsWhile discussing aetiology of schizophrenia, it is important to emphasise both the biological and psychosocial aspects of the disorder. Stating that schizophrenia is a brain disorder worsened by stress ofany kind is perhaps a good way to start this part of the discussion. Both positive and negative symptoms need to be discussed. The differentiation of symptoms from ‘personality traits’ needs to be emphasized. Variations in prognosis and risks of relapse need to behighlighted. Different treatment methods and the rationale for theiruse should be mentioned Belief in supernatural causation of mental illnesses iscommonly prevalent in our country. The relatives need to be told that there is no scientific evidence for this. Similarly, the myths about the effect of certain diets in influencing the patient's mental state need tobe dispelled. Some families hold that marriage has a curative role in mental illnesses. Such families frequently want to get the patients married and seek advice regarding this. Although, what is to be told will differ depending on the individual patient's circumstances, some aspects will be applicable to all. It needs to be stressed that marriage can be stressful for a patient hence it should not be planned till the patient has been stable for a considerable period of time. Informing the prospective husbands/ brides and in-laws that the patient suffers from a mental illness and is undergoing treatment is necessary, though it makes the task of finding a suitable partner more difficult. The risk of offspring's developing the illness also needs to be addressed at some point.At the end of the initial sessions a feedback needs to be obtained. Areas in which information has not been retained may need to be covered again.

Treatment adherence

Enhancing compliance with the treatment regimen is one of the main objectives of any educational programme.

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Long-term treatment is required for most patients. However, missing appointments, not taking medicines as prescribed, or not reporting essential information is far too common. Frequent causes of non-compliance are denial of illness, cultural beliefs, failing to appreciate the need for medication in a relatively asymptomatic state, and expectation of, or actually experiencing distressing side effects (Kuruvilla, 1996;Kulhara et al., 1999; 2000). The following areas thus need to be addressed:

information about available treatment modalities. an explanation of treatment for acute as well as

more stable phases of the illness; the need to continue treatment even when relatively free of symptoms to reduce risks of relapse should be stressed.

information about medication actually being administered, the role of each drug, doses, frequency of administration; written material can supplement verbal instructions if felt appropriate.

explanation of therapeutic effects e.g. how long is the drug expected to take to act, which symptoms will respond and which might not respond so well, what if one drug fails.

information about side effects; patient and relatives should be encouraged to report side effects rather than stopping treatment.

enquiry about whether they can actually afford thedrug being prescribed; exploring alternatives whenever this is not possible.

re-emphasizing the risks of discontinuing treatment.

discussion of the pros- and cons of traditional methods of treatment since they form a common partof the belief system.

certain treatment modalities such as ECT or clozapine may need more detailed explanations.

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As far as possible the patient should be persuaded to take medications by self. In addition, it is often helpful to nominate a family member to supervise the patient's drug intake. However, care should be taken toensure that this does not become a source of conflict between the patient and family members. The aim is to create an atmosphere in which the patient feels free todiscuss his negative feelings about a particular drug or treatment. Attempts should always be made to modifythe treatment plan (whenever possible), according to the patient's and family’s needs and preferences.

Reducing family distress

After confirming the diagnosis the family members should be allowed every opportunity to express how theyfeel about being told that one of them has schizophrenia. Help can also be sought from the primarycare physician in this regard. It must be ensured that they do not blame themselves or the patient in any way for what has occurred. More often than not, the relatives have high expectations of the affected individual. That the illness severely compromises the person's capabilities must thus be explained. The family should be helped to tone down their expectationsand have a realistic appreciation of what the patient can achieve now that the person has developed the illness. During the course of the illness families alsoneed continued advice and information on such matters as dealing with problem behaviours, managing medication, avoiding exposure to stressful situations etc. These should be readily discussed, and if possible, the relatives need assistance to arrive at some sort of solutions to these common problems.

Enhancing coping

Individuals and families use a number of different strategies to cope with the effects of the illness. Broadly coping mechanisms can be divided into problem solving and emotion focussed ones. Problem solving

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techniques aim at reducing stressful life situations. Emotion focussed strategies are meant for dealing with emotional turmoil. It is important to remember all these aspects while trying to improve the individual's or family's coping skills. Some of the ways in which the family is already coping with the illness may be quite appropriate and effective. These need to be reinforced rather than suggesting alternative strategies, which they might find alien and unhelpful. Families often seek advice on how to cope with distressing symptoms e.g. suspiciousness, aggressive behaviour, suicidal threats or refusal to take medications, disinihibited sexual behaviours. So particular attention needs to be paid to these problems. Patients might need help in dealing with persistent positive symptoms like delusions and hallucinations. Practical measures such as using distraction or masking techniques can be suggested. Cognitive techniques can also be tried.

Reducing burden / increasing support

All measures that the family can adopt to reduce the burden of care and increase the amount of social support available to them have to be considered. It would be useful to remember the various functions of social support including emotional support, instrumental support, motivational support and social companionship (Champion & Goodall, 1994). Instrumental support includes all those measures, which provide practical, tangible and material help. Therefore, some of the measures that can be taken in this regard are enlisting help of voluntary and corporate organisationsto fund the costs of treatment if needed; rail or bus passes can be arranged to reduce the costs of transportation. . Assistance should be offered in getting disability benefits under the Persons with Disability Act. Sharing of certain principal tasks in the family e.g. looking after the children could be suggested. Making use of community resources such as neighbours, local clubs, religious groups or family

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doctors can be encouraged. Informational support i.e. the provision of information, education and guidance has already been considered. Emotional support consistsof providing reassurance, attempting to boost self-esteem etc. Support that consistently helps to maintainhope in chronically difficult circumstances is referredto as motivational support. It does not need to be reiterated that providing emotional and motivational support are the key aspects of working with patients and their families.

Improving family functioning

Both during the initial assessments and subsequent sessions it would be possible to form an idea of the family functioning in terms of specific problems, interactions, assets and resources etc. This information needs to be used now in an attempt to enhance communication and improve problem-solving skills. Enhancing communication would entail teaching family members to listen to, and consider each other's views on a particular issue. Positive feelings need to be expressed and positive communications acknowledged. Requests can be made in a non-confrontational manner and as calmly as possible. Similarly, negative feelingscan be expressed in constructive ways. Teaching the family a problem-solving approach is another major objective. They should be able to discuss a problem objectively, generate alternatives to deal with it, choose a reasonable alternative and try and implement it. For both the above learning tasks it is best to apply them to issues or problems that arise during the sessions. This makes the concepts more relevant and understandable for the family members. Homework assignments are essential. Some families might need more structured and extended treatment based on the same principles.

3. Maintenance phase

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During this phase, contacts can be made once every 2-3 months and more frequently in times of crises, or if desired by the family. Feedback needs to be taken from the family. Any new issues that arise are discussed. Some of the previous points may need reemphasis.

Other forms of intervention

Imparting social skillsIt might not always be possible to implement a structured social skills training programme. Nevertheless, every attempt should be made to teach thepatient skills of daily living e.g. self care, managingmedications, looking after money matters, shopping or cooking, using public transport and interacting with others in social situations. Encouraging the patient touse these skills in real life settings, offering praisefor any successes will all be important components of this effort.

Individual treatment

Apart from providing education, support and guidance tothe patient certain situations might need more structured approaches e.g. behaviour therapy for negative symptoms or treatment for social anxiety. Simple measures such as time structuring or attempting to increase social contacts are also of help to the patient.

Vocational rehabilitation

Facilities for vocational rehabilitation are scarce. However, if the patient is already working efforts can be made to help out in any problems at the work place, which could be due to the effects of the illness. If the patient is unemployed, his suitability for work needs to be assessed. If he is ready for work, he should be encouraged to seek appropriate jobs.

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Re-evaluating / modifying the treatment plan

As time elapses the nature of the illness, problems faced by the relatives, needs of the patient and the family and previously determined targets are all expected to change. Regular contact, awareness and monitoring are needed to detect these changes. Ongoing assessment is thus essential. It allows those modifications to be made in the treatment plan, which are required to accommodate any new problems or demandsthat may have arisen.

Early intervention for relapses

The treatment programme should be organised to respond as quickly as possible to any relapses in the patient'scondition. Patients and relatives need to be educated to recognise prodromal symptoms of a relapse. They should be told about the need for early intervention inimpending cases of relapse. They should have easy access to treatment facilities such as emergency services or inpatient settings, which will cater to theneeds of a patient on the verge of a relapse. Contact should be increased during the prodromal phase. Crisis intervention measures such as brief admissions or frequent home visits need to be adopted, whenever feasible. All these are important steps in efficient detection and treatment of relapses.

Other interventions

Based on the available evidence it would be reasonable to expect that other psychosocial treatments e.g. cognitive behavioural therapy could also be effective. However, there are no studies on the usefulness of suchinterventions under Indian conditions. It is, therefore, unclear how such treatments should be implemented.

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Aspects of treatment during the stable phase

Determining goals

Assessments

1. For drug treatment2. Psychosocial evaluation

Regular monitoring

1. Mental state2. Drug side effects

Antipsychotic treatment

1. Dose2. Duration of treatment3. Use of depot preparations

Psychosocial interventions

SPECIAL SITUATIONS

Treatment-resistance/difficult to treat patients

Although the introduction of antipsychotic medication was the first specific treatment proven to be efficacious, a sizeable number of individuals receivingthese drugs failed to respond adequately. Treatment-resistant schizophrenia is relatively common, in that between a fifth and a third of patients show a disappointing response to adequate trials of first-generation antipsychotic drugs (NICE, 2002).

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The pharmacological treatment options for treatment-resistance include increasing the dose of the antipsychotic or decreasing the dose if poor treatment adherence is the result of adverse drug. Switching to another class of FGAMs is another option though the evidence for the possible value of such a strategy is inconsistent. The use of adjunctive medications such asmood stabilizers, antidepressants or benzodiazepines has also been considered, but the role of such drugs isprobably limited. With the advent of clozapine it has been proposed that its unusual mode of action may be ofvalue for those with treatment-resistance. Other second-generation drugs have also been suggested as possible alternatives in the treatment of refractory patients (Morrison, 1996; APA, 1997; NICE, 2002; Koshino, 1999; Miller et al., 1999).Most of the research in this area shows that clozapine has superior efficacy when compared with first-generation antipsychotics in situations of treatment-resistance (Wahlbeck et al., 1999; Chakos et al., 2001). However, some recent evidence seems to indicate otherwise, and that differences from other SGAMs may only be modest. For example a meta-analysis of 5 controlled comparisons of risperidone with clozapine intreatment-resistance concluded that it was not clear whether or not the two drugs were equally effective, orwhether one was actually superior (NICE, 2002; Tuunainen et al., 2002; Moncrieff, 2003).There are several definitions of treatment-resistance from the very strict to less restrictive ones. A consensus definition proposes that schizophrenia be considered treatment-resistant when there is a lack of a satisfactory clinical improvement despite the sequential use at least of two antipsychotics, one of which is a SGAM, at recommended doses for a minimum of 6 to 8 weeks. This definition reflects a broadening of the group of individuals who were viewed as clinically eligible for treatment with clozapine (APA, 1997; NICE,2002).The first step in the management of treatment-resistance is to establish that the disorder has failed

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to respond to adequate trials of first-generation antipsychotic drugs in terms of dosage, duration and adherence. Other causes of non-response should be considered such as, non-compliance, adverse effects, comorbid conditions such as substance misuse, before actually diagnosing treatment refractoriness.If the symptoms of schizophrenia are unresponsive to FGAMs, a trial of a second-generation agent such as risperidone or olanzapine may be considered prior to making a diagnosis of treatment-resistant schizophreniaand a trial of clozapine is initiated. In individuals with clear evidence of treatment-resistance clozapine should be introduced at the earliest opportunity. Clozapine should be gradually titrated to effective doses.There is growing evidence that monitoring plasma clozapine concentration may be helpful in establishing the optimum dose of clozapine in terms of risk-benefit ratio particularly for patients showing a poor therapeutic response and/or significant side effects despite appropriate dosage. However, there is considerable disagreement regarding the critical levels. Routine monitoring is thus not recommended. Response to clozapine is comparatively slow and an adequate trial should be of 3-6 months. Monitoring for side effects (especially leucopenia/agranulocytosis) needs to be maintained, although there is some variability in the recommended parameters of such monitoring (Morrison, 1996; APA, 1997; NICE, 2002; Koshino, 1999; Miller et al., 1999). The role of ECT in such situations has not been examined, although one Indian study suggests it could be useful (Goswami et al., 2003). Psychosocial interventions such as cognitive therapy, family treatment, assertive outreach or crisis intervention are also beneficial in refractory or difficult to treatpatients.Treatment options in patients unresponsive to clozapineare limited, but could include addition of antipsychotics, antidepressants, mood stabilizers, ECT

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and psychosocial treatments (Barnes et al., 1996; Williams et al., 2002).

Depression

Despite differing definitions of the term a substantialrate of depression has consistently been found in patients of schizophrenia. Available reports indicate that the modal rate of depression in schizophrenia is around 25%; the prevalence of depressive symptoms may be higher. Depression appears to occur during all phases of schizophrenia with the period 6-12 months after resolution of acute psychotic symptoms (post-psychotic phase) being a particular period of risk. Post-psychotic depression is also associated with a higher risk of suicide. A rational approach to treating depression in schizophrenia first needs to consider and rule out possible differential diagnoses for the condition. These include organic conditions, negative symptoms, antipsychotic associated side effects (dysphoria, akinesia and akathisia), schizoaffective depression, stress-related reactions, and an impending psychotic episode. Controlled trials with SGAMs have shown that they are superior to first-generation antipsychotics in their antidepressant efficacy. In addition clozapine may be particularly effective in patients at high risk for suicide. Therefore switching to a second-generation drug followed by minimization of EPSEs and optimisationof treatment with FGAMs are the initial options in treating depression during the acute psychotic phase. Antidepressants are generally ineffective during the acute phase. They may even worsen the psychosis, and are best avoided. On the other hand, results of controlled trials have demonstrated the efficacy of adjunctive antidepressant therapy in post-psychotic depression. Although the data mainly concerns addition of tricyclic drugs to FGAMs, a few studies of specific serotonergic reuptake inhibitors and SGAMs have found this combination to be effective as well. Thus, a trial

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of antidepressants in patients with post-psychotic depression may be a worthwhile strategy. The evidence for the usefulness of other treatments such as lithium,valproate or carbamazepine is limited (Levinson et al.,1999; Siris, 2000). Clinical experiences suggest ECT may be helpful.

First-episode psychosis and early intervention

The early phase of psychosis including a period of untreated psychosis is a critical period with regard tothe future course of the illness. Studies of first-episode of psychotic disorders including schizophrenia show that the average time from onset of psychotic symptoms to initiation of treatment is often a year or more. Longer durations of untreated psychosis are powerful predictors of subsequent poor outcome. The evidence from such studies also suggests that when deterioration occurs, it does so in the first 2-3 yearsof the illness. Moreover, research evidence also indicates that comprehensive programmes of drug and psychosocial interventions with adults who show early signs of psychosis may contribute to a lowered incidence of major episodes of schizophrenia. Field trials of early intervention strategies also demonstrate that they are effective and can be routinely applied in clinical situations (Birchwood et al., 1998; Falloon et al., 1998). Critics of this approach while agreeing on the need for early intervention argue that there are substantial ethical, practical and economic problems in implementing such strategies (Pelosi/Birchwood, 2003). Nevertheless, there appears to be some consensus regarding general principles of treatment of first-episode psychosis or first-episode schizophrenia (Birchwood et al., 2001).The aims of such treatment are to reduce the duration of untreated psychosis, to promote remission through effective pharmacological and psychosocial interventions, to maximize functioning, and to prevent relapse and other adverse outcomes. Early detection, comprehensive assessment, emphasis on continued

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engagement, and flexible treatment enable early intervention services to meet these goals. Recommendations for pharmacotherapy include a short antipsychotic-free observation period to determine diagnosis, use of SGAMs as first-line treatments to achieve remission, and early assessment and intervention in situations of treatment resistance. Controlled trials have demonstrated the efficacy of several second-generation antipsychotics in the treatment of first-episode psychosis. Though they are not unequivocally superior to FGAMs in such patients, they are preferred because of their better side-effect profile. Trials of antipsychotics have also underlined the necessity for using low doses of drugs while treating patients with first episodes of psychosis. Doses as low as 2-3 mg/day of haloperidol or 2-4 mg/dayof risperidone have shown to be the optimal in treatingpositive symptoms without inducing too many side effects. It is still not clear for how long patients with first-episode psychosis should continue maintenance antipsychotic medication. A 1-2 year periodis usually recommended (APA, 19997; 2004), though many patients may require longer periods, and some shorter periods of treatment than this (Johnson, 1985; Gitlin et al., 2001).

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