Revisiting the Concept of Subjective Tolerability to Antipsychotic Medications in Schizophrenia and its Clinical and Research Implications: 30 Years Later.

Schizophrenia is a long-term psychiatric disorder that impacts important mental functions and requires indefinite treatment, as well as psychosocial and economic support. The introduction of chlorpromazine, the first antipsychotic, and the subsequent development of a long list of similar dopamine-blocking antipsychotic medications, has changed the treatment of schizophrenia as medications have become the cornerstone of clinical management. The enthusiasm that greeted the introduction of antipsychotics was soon tempered by the realisation that they induced significant side effects, such as extrapyramidal and autonomic symptoms. A less-recognized side effect at the time was the emergence of subtle subjective side effects that led patients to dislike medications and eventually discontinue them, with serious consequences of frequent relapses requiring hospitalization, poor outcomes and more health costs. The development of our dedicated programme for research into subjective tolerability to medications over the past 30 years has allowed us to establish the validity of the construct of 'subjective tolerability' to antipsychotics, applying research methodologies that are required for any scientific inquiry. We clarified definitions, developed reliable measuring tools, and constructed psychosocial and neurobiological conceptual models. We also documented the serious consequences of negative subjective tolerability to antipsychotics: poor medication adherence behaviour, impaired quality of life, and worse clinical and functional outcomes. More recently, using neuroimaging techniques, we and other international research groups were able to clearly elucidate the neurobiology of dysphoric negative subjective responses, linking it to low dopamine functioning in the striatal region of the brain. Such a discovery for the first time allowed us to also link the development of comorbid drug abuse in schizophrenia, which is a common occurrence, to the development of neuroleptic dysphoria, since both relate to the low dopamine function in the striatum. As an already validated scientific concept that has serious consequences, subjective tolerability to antipsychotics can serve as a model for patient-centered outcomes that really matter. Our long-serving research programme also illustrates the value of clinical observations to the development of important clinical research studies, i.e. from the bedside to the research bench, and back to the bedside.

'The patient': at the center of patient-reported outcomes.

The recent emphasis of including patient reports in their own care management is reviewed in terms of the factors that contributed to its popularity. The role change of patients as being active participants in their own care as a result of the rising consumerism and advocacy has led to increased pressures for including patients in the therapeutic decision-making process. As consumers of clinical services, their perspectives and attitudes towards health and illness acquired more importance. The rising cost of healthcare has added another dimension in cost containment by empowering patients and sharing responsibility in their recovery, which hopefully can improve outcomes. Challenges in the development and implementation of patient-reported outcomes in psychiatry are reviewed and include the still unresolved subjective/objective dichotomy, identification of the most appropriate and relevant patient-reported outcomes. Few outcomes are identified and include: subjective tolerability of medication, self-reported health-related quality of life, preferences, patients' attitudes towards health and illness, satisfaction with medication and overall satisfaction of quality of care, and functional state, with particular focus on social functioning.

Revisiting the 'self-medication' hypothesis in light of the new data linking low striatal dopamine to comorbid addictive behavior.

Persons with schizophrenia are at a high risk, almost 4.6 times more likely, of having drug abuse problems than persons without psychiatric illness. Among the influential proposals to explain such a high comorbidity rate, the 'self-medication hypothesis' proposed that persons with schizophrenia take to drugs in an effort to cope with the illness and medication side effects. In support of the self-medication hypothesis, data from our earlier clinical study confirmed the strong association between neuroleptic dysphoria and negative subjective responses and comorbid drug abuse. Though dopamine has been consistently suspected as one of the major culprits for the development of neuroleptic dysphoria, it is only recently our neuroimaging studies correlated the emergence of neuroleptic dysphoria to the low level of striatal dopamine functioning. Similarly, more evidence has recently emerged linking low striatal dopamine with the development of vulnerability for drug addictive states in schizophrenia. The convergence of evidence from both the dysphoria and comorbidity research, implicating the role of low striatal dopamine in both conditions, has led us to propose that the person with schizophrenia who develops dysphoria and comorbid addictive disorder is likely to be one and the same.

The impact of newer atypical antipsychotics on patient-reported outcomes in schizophrenia.

Over the past two decades there has been increasing interest in including patients' self-reports in the management of their illness. Among the many reasons for such recent interest has been a rising consumer movement over the past few decades, which has led patients, their caregivers and their families to press for more meaningful sharing with physicians in the clinical decision-making process, with the clear expectations of better therapies and improved outcomes. Patients as consumers of services, their views, attitudes towards healthcare, as well as their level of satisfaction with care, have become increasingly recognized. The recent interest by the US Food and Drug Administration (FDA), as well as other regulatory agencies, in patient-reported outcomes (PROs) in the process of developing and testing new antipsychotics, has also added more impetus. It is clear that including patients in the decision-making process about the management of their psychiatric conditions also broadens the concept of 'recovery', by empowering patients to be active participants and gives a clear message that successful treatment in schizophrenia is more than a symptomatic improvement, but also includes improved functional status. Additionally, the recent interest in personalized medicine puts the patient in the centre of such development. Since 2004, when we published our review about the impact of new antipsychotics on quality of life in CNS Drugs, a number of newer antipsychotics have been introduced and include ziprasidone, aripiprazole, paliperidone, asenapine, iloperidone and lurasidone. The current review is based on 31 selected publications that cover the years 2004-2012, and deals with the impact of such newer antipsychotics on specific domains of PROs, such as subjective tolerability, quality of life, medication preference, satisfaction and social functioning. Most of the available data deal with ziprasidone, aripiprazole and paliperidone. Though the great majority of the studies indicate the newer antipsychotics have favourably impacted on aspects of PROs, such a conclusion can only be considered a trend due to the many design and methodological limitations of many of these studies. It is interesting to note, as the field awaits more rigorous studies, that there seems to be a unifying core that exists among the various subjective outcomes and that tends to generalize from one subjective outcome to other subjective outcomes. The patient who experiences good subjective tolerability to medications tends generally to be more satisfied and has a strong medication preference. The identification of such a unifying core can prove helpful, not only in the development of appropriate scales, but also in informing and guiding the process of development of new antipsychotics.

Validation of a patient interview for assessing reasons for antipsychotic discontinuation and continuation.

INTRODUCTION: The Reasons for Antipsychotic Discontinuation Interview (RAD-I) was developed to assess patients' perceptions of reasons for discontinuing or continuing an antipsychotic. The current study examined reliability and validity of domain scores representing three factors contributing to these treatment decisions: treatment benefits, adverse events, and distal reasons other than direct effects of the medication. METHODS: Data were collected from patients with schizophrenia or schizoaffective disorder and their treating clinicians. For approximately 25% of patients, a second rater completed the RAD-I for assessment of inter-rater reliability. RESULTS: All patients (n = 121; 81 discontinuation, 40 continuation) reported at least one reason for discontinuation or continuation (mean = 2.8 reasons for discontinuation; 3.4 for continuation). Inter-rater reliability was supported (kappas = 0.63-1.0). Validity of the discontinuation domain scores was supported by associations with symptom measures (the Positive and Negative Syndrome Scale for Schizophrenia, the Clinical Global Impression - Schizophrenia Scale; r = 0.30 to 0.51; all P < 0.01), patients' primary reasons for discontinuation, and adverse events. However, the continuation domain scores were not significantly associated with these other indicators. DISCUSSION: Results support the reliability, convergent validity, and known-groups validity of the RAD-I for assessing patients' reasons for antipsychotic discontinuation. Further research is needed to examine validity of the RAD-I continuation section.

Measuring quality of life in patients with schizophrenia: an update.

In 1997, we published a review in PharmacoEconomics about quality of life (QOL) measurement in patients with schizophrenia. The objective of this article is to provide an update, as well as to revisit the development of the construct of QOL and its measurement as applied to schizophrenia. Since our previous article, there has been significant growth in the number of publications about QOL in schizophrenia. Unfortunately, alongside this significant increase in research interest, a number of concerns have also risen about the limitations and lack of impact the concept of QOL has on clinical care and health-policy decision making. A number of concerns previously outlined (such as lack of consensus on a uniform definition of QOL) continue to be an issue. However, we believe that a uniform definition may not be possible, and instead, it may be preferable to have several definitions, which may enrich the concept and broaden its usefulness. Some of the scales we reviewed in 1997 continue to be in use, while others are now rarely or never used. New scales with better psychometrics have been introduced, but most are without theoretical or conceptual foundation. On the other hand, the field of scaling in general has been changing over the past few years and is moving towards a new approach for scale development, based on item response theory, item banks and computer adaptive testing. Unfortunately, this has not extended to QOL in schizophrenia. There continues to be a dearth of theoretical and conceptual models for QOL in schizophrenia, which seems to create the perception that the construct lacks a good theoretical and scientific foundation. One of the major gaps identified in this review is the recognized lack of impact of QOL measurements on clinical management or policy decision making. The majority of publications continue to focus on measurement rather than what to do with the data. The lack of strategies to integrate QOL data in clinical care, as well as the failure to contribute to policy decisions, particularly in cost analysis or resource allocations, has created the perception that the construct of QOL in schizophrenia is not that useful. It is evident that, for QOL in schizophrenia to regain its promise, researchers must take the ultimate next step beyond measurement: to develop credible strategies for integrating QOL data in clinical practice. Additionally, more focused research is needed to demonstrate the role of QOL, not only as an outcome in itself but also as a contributor to other outcomes, such as adherence to medications, more satisfaction, less resource utilization and so on. Since self-appraisal of QOL does not happen in a vacuum but relates to the total human experience in all its biological, psychosocial and environmental aspects, particular attention must also be focused on important neurobiological dimensions such as affect and cognition. Both are significantly affected by the illness itself and its treatment.

Is it time to consider comorbid substance abuse as a new indication for antipsychotic drug development?

Comorbid drug abuse in schizophrenia has been consistently reported as high, with estimates ranging between 10-70%. Comorbid addictive states in schizophrenia are possibly multifactorial, yet recent research assigns a significant neurobiological role in its genesis. Abnormalities in hippocampal/cortical function in schizophrenia which mediate reward and reinforcement behavior are identified as central to the development and maintenance of comorbid addictive states. Preliminary data suggest that the vulnerability of patients with schizophrenia to substance use disorders may be a primary disease symptom. The management of comorbid substance abuse in schizophrenia relies on the use of antipsychotic medications. Recent data raise the concern about whether first-generation antipsychotics in long-term use can conversely lead to enhancement of the abused substance's reinforcing properties. Some recent reports have assigned a favorable outcome to clozapine and second-generation antipsychotics, pointing to a possible differential role for various antipsychotics. In view of the high prevalence of comorbid drug abuse in schizophrenia, its impact on outcome of treatment and the recent emerging neurobiological information, it is my contention that comorbid drug abuse constitutes a dimension by itself and deserves to receive an indication in the development of new antipsychotics similar to negative symptoms or cognitive deficits.

Methodological issues in negative symptom trials.

Individuals from academia, the pharmaceutical industry, and the US Food and Drug Administration used a workshop format to discuss important methodological issues in the design of trials of pharmacological agents for improving negative symptoms in schizophrenia. The issues addressed included the need for a coprimary functional measure for registration trials; the characteristics of individuals who should enter negative symptom trials; the optimal duration for a proof-of-concept or registration trial; the optimal design of a study of a broad-spectrum agent that treats both positive and negative symptoms or a co-medication that is added to an antipsychotic; the relative strengths and weaknesses of available instruments for measuring negative symptoms; the definition of clinically meaningful improvement for these trials; and whether drugs can be approved for a subdomain of negative symptoms.

Reasons for discontinuation and continuation of antipsychotics in the treatment of schizophrenia from patient and clinician perspectives.

OBJECTIVE: To identify reasons for discontinuation and continuation of antipsychotic medications in the treatment of schizophrenia from the patients' and their clinicians' perspectives. RESEARCH DESIGN AND METHODS: Two measures were previously developed to assess the Reasons for Antipsychotic Discontinuation/Continuation (RAD), one from the patient's perspective and another from the clinician's perspective. These measures were administered to acutely ill schizophrenia patients enrolled in a 12-week study of antipsychotic medications (N = 596) and to their clinicians. The RAD was assessed at baseline and at endpoint. Reasons were rated on a 5-point scale from 'primary reason' to 'not a reason.' The single most important reason was also identified. The 'single most important reason' and the 'primary reasons' for discontinuing the drug used prior to enrollment, and for discontinuing or continuing the study drug were identified. Levels of concordance between patients' and clinicians' reasons were assessed. CLINICAL TRIAL REGISTRATION: The data source for this study is a clinical trial registered at www.clinicaltrials.gov (NCT00337662). MAIN OUTCOME MEASURES: Reasons for Antipsychotic Discontinuation/Continuation (RAD). RESULTS: Patients and clinicians identified several reasons for medication discontinuation and continuation (2.3 to 6.3 reasons, on average). The top 'single most important' reason for discontinuing the drug used prior to enrollment and for discontinuing the study drug was 'positive symptoms not sufficiently improved or made worse,' followed by 'medication-related adverse events.' The most frequent 'single most important' reason for medication continuation was 'improved positive symptoms,' followed by 'patient's perception of improvement,' and 'functional improvement.' A high level of concordance was observed between patients' and clinicians' ratings. CONCLUSIONS: Medication efficacy appears to be the core driver of medication discontinuation and continuation, especially with regard to positive symptoms. There was a high level of concordance between patients' and clinicians' perspectives. Limitations include the study requirement that patients be at least moderately ill and experiencing acute psychotic exacerbation, a potential selection bias in the readiness to respond to measures, and small sample sizes for some analyses. Further research is needed to replicate findings in patients who are not acutely ill.

Psychometric evaluation of the Medication Satisfaction Questionnaire (MSQ) to assess satisfaction with antipsychotic medication among schizophrenia patients.

The Medication Satisfaction Questionnaire (MSQ) is a single-item questionnaire which evaluates satisfaction with antipsychotic medication in schizophrenia patients. This study evaluated the reliability and validity for its use in research and clinical settings. Data pooled across treatment groups (control vs. Paliperidone ER) from a randomized 6-week study were used to conduct four psychometric assessments of the MSQ: (1) test-retest reliability, (2) convergent validity, (3) known-groups validity, and (4) minimally important difference (MID). This analysis included 191 randomized subjects. Test-retest reliability was evaluated for patients with no change in satisfaction from weeks 2 to 4 and weeks 4 to 6 (ICC=0.80; 0.83, respectively). Convergent validity was demonstrated through large correlations with Treatment Satisfaction Questionnaire for Medication (TSQM) global score (r=0.72-0.77), and through small correlations with variables measuring clinical symptoms and functioning (e.g., Positive and Negative Syndrome Scale (PANSS) total score [r=-0.30 to -0.17], CGI-S [r=-0.35 to -0.27], SF-36 Physical Functioning Score [r=0.18] and side effects and extrapiramidal measures (including UKU, ESRS-A, SAS). Mean MSQ scores were significantly different between those who completed and discontinued the study, and between different satisfaction groups based on TSQM, demonstrating good known-groups validity. MID estimates for the MSQ ranged from 0.47 (standard error of measurement) to 0.58 (anchor-based method). Results suggest that the MSQ has acceptable reliability and validity, making this single-item questionnaire appropriate and easy to use in clinical research and potentially in clinical practice. A 1-point change on the MSQ may be considered clinically meaningful.

New generation antipsychotic drugs and compliance behaviour.

PURPOSE OF REVIEW: Antipsychotic therapy has been eclipsed by high rates of noncompliance; the problem was attributed to a lack of efficacy and the burden of side effects of neuroleptics. This review sought to examine whether the arrival of second generation (atypical) antipsychotic drugs with low side-effect liability and improved efficacy has helped to positively reinforce compliance behaviour among people treated for schizophrenia. RECENT FINDINGS: The number of studies that systematically examined compliance behaviour and its determinants during antipsychotic drug therapy is disappointingly low. A review of relevant clinical trials, drug dispensation databases and observational studies yielded equivocal results. The data have failed to substantiate the notion that novel antipsychotic drug use leads to improved medication compliance and favourable clinical outcomes. SUMMARY: A decade of clinical experience and research indicates that compliance behaviour has only marginally improved since the introduction of second generation antipsychotic drugs. Noncompliance in schizophrenia is a complex maladaptive pattern of behaviour determined by personal beliefs, illness-related factors, social attributes and health system variables. The reinforcing value of antipsychotic drugs may be less relevant in enhancing treatment compliance and influencing the natural history of schizophrenia.

The burden of schizophrenia on caregivers: a review.

Schizophrenia is a disabling, chronic psychiatric disorder that poses numerous challenges in its management and consequences. It extols a significant cost to the patient in terms of personal suffering, on the caregiver as a result of the shift of burden of care from hospital to families, and on society at large in terms of significant direct and indirect costs that include frequent hospitalizations and the need for long-term psychosocial and economic support, as well as life-time lost productivity. 'Burden of care' is a complex construct that challenges simple definition, and is frequently criticized for being broad and generally negative. Frequently, burden of care is more defined by its impacts and consequences on caregivers. In addition to the emotional, psychological, physical and economic impact, the concept of 'burden of care' involves subtle but distressing notions such as shame, embarrassment, feelings of guilt and self-blame. The early conceptualization of 'burden of care' into two distinct components (objective and subjective) has guided research efforts until the present time. Objective burden of care is meant to indicate its effects on the household such as taking care of daily tasks, whereas subjective burden indicates the extent to which the caregivers perceive the burden of care. Research contributions in later years (1980s to the present) have added more depth to understanding of the construct of burden of care by exploring important determinants and factors that likely contribute or mediate the caregiver's perception of burden of care. Several studies examined the role of gender, and reported that relatives of male patients with schizophrenia frequently experience more social dysfunction and disabilities than those of female patients. Similarly, a number of other studies documented the contribution of ethnicity and cultural issues to subjective burden of care. Although there is no complete agreement on whether a specific cluster of psychotic symptoms has the most impact on a caregiver's burden of care, there is agreement that the severity of symptoms increases it. An extensive literature concerning family interventions in schizophrenia has demonstrated the positive impact of various family interventions in improving family environment, reducing relapse and easing the burden of care. Although the evidence of such positive impact of family interventions in schizophrenia is well documented, such interventions are neither widely used nor appropriately integrated in care plans, and are frequently underfunded. Although the cost of caregiving is considered to be significant, there are no reliable estimates of the costs associated with such care. The majority of available literature categorized the cost of burden of care among the indirect costs of schizophrenia in general. In recent years, attempts to compare the costs of caregiving in several countries have been reported in the evolving literature on this topic. 'Burden of care' as a complex construct certainly requires the development of appropriate methodology for its costing. In achieving a balance between the patients' and caregivers' perspectives, caregivers have to be included in the care plan and adequate information and support extended to the family and caregivers. Access to better treatment for patients, including medications, psychosocial interventions and rehabilitation services, are important basic elements in easing the burden on caregivers. Other measures such as availability of crisis management, provision of legally mandated community treatment to avert hospitalization, and well informed and balanced advocacy are also important. Although research efforts have been expanded in the last 3 decades, an urgent need exists for enhancing such efforts, particularly in the development and evaluation of effective family interventions strategies. There is also a need for continued improvement in the delivery of psychiatric services to the severely psychiatrically ill and their families. As there is a lack of reliable cost information about the family burden of care specific to schizophrenia, there is an urgent need to develop reliable approaches that can generate data that can inform in policy making and organization of services.

Quality of life among bipolar disorder patients misdiagnosed with major depressive disorder.

OBJECTIVE: Bipolar disorder is frequently misdiagnosed as major depressive disorder (MDD). We aim to quantify the prevalence of misdiagnosed bipolar disorder among the depression population and evaluate the quality-of-life (QOL) impact of misdiagnoses. METHOD: Data were collected from 2 self-administered, cross-sectional studies in 2003. Patients participating in The Bipolar Disorder Misdiagnosis Study (N = 1156) were previously diagnosed with depression, experienced a depressive episode within the past year, and had no previous diagnosis of bipolar disorder or schizophrenia. Patients who experienced a manic episode in the past year, based on DSM-IV criteria, were classified as misdiagnosed. Patients participating in The Bipolar Disorder Project (N = 1214) self-reported a diagnosis of bipolar disorder and were recruited through community mental health centers and support groups. Quality of life was assessed via the Psychological General Well-Being (PGWB) Index and Medical Outcomes Study 8-Item Short-Form Health Survey (SF-8). Demographic differences between groups were controlled using linear regression models. RESULTS: Of the diagnosed MDD sample, 14.3% met criteria for misdiagnosed bipolar disorder. When controlling for demographic differences, the PGWB overall score for the misdiag-nosed averaged 12.77 (p < .001) points lower than that of MDD patients and 9.55 (p < .001) points lower than that of diagnosed bipolar disorder patients. The average SF-8 mental component summary score for the misdiagnosed was 5.85 (p < .001) points lower than that of MDD patients and 3.18 (p = .002) points lower than that of diagnosed bipolar disorder patients. CONCLUSION: Misdiagnosis is associated with poorer QOL than MDD or diagnosed bipolar disorder, which are recognized as having a considerable impact on QOL.

Reduction in psychotic symptoms as a predictor of patient satisfaction with antipsychotic medication in schizophrenia: data from a randomized double-blind trial.

BACKGROUND: Patient satisfaction with antipsychotic treatment is important. Limited evidence suggests that satisfaction is associated with symptom improvement and compliance. Predictors of patient satisfaction with antipsychotic medication were examined in a study of patients with a recent exacerbation of schizophrenia. METHODS: Data are from a randomized, double-blind trial comparing risperidone (n = 152), quetiapine (n = 156), and placebo (n = 73). Medication Satisfaction Questionnaire (MSQ) was completed after 14 days of treatment and after 6 weeks at last study visit. RESULTS: Medication satisfaction at both time points was significantly associated in multiple regression analysis with improvement on 3 Positive and Negative Syndrome Scale (PANSS) factor scores (positive symptoms p < .01; uncontrolled hostility/excitement, p < .0005; anxiety/depression, p < .04) and treatment with risperidone (p < .03); at day 14, significant association was also found with older age (p = .01). At both time points, predictor variables explained over 30% of the variance in medication satisfaction. Change in Hamilton Depression Scale, prolactin levels, sex, and reported adverse events of extrapyramidal symptoms, sedation, and movement disorders were not significant predictors of satisfaction. Lower level of medication satisfaction at day 14 was associated with earlier discontinuation in the trial at week 6 end point. A focused principal components analysis of PANSS factors and MSQ suggested that medication satisfaction relates to 3 groups of factors in descending order of magnitude: lower levels of (a) uncontrolled hostility/excitement, (b) positive symptoms, and (c) negative symptoms, disorganized thoughts, and anxiety/depression. CONCLUSION: Results give further support that treatment satisfaction is positively associated with symptom improvement, particularly psychotic symptoms, and suggest that satisfaction may also be related to compliance, as those who were more satisfied remained in the trial for a longer period of time.

Subjective and behavioural consequences of striatal dopamine depletion in schizophrenia--findings from an in vivo SPECT study.

Dysphoria is an integral part of the symptomatology of a variety of clinical states, though there is little empirical data available on the qualitative and quantitative aspects of this phenomenon. The purpose of the study was to administer alphamethyl paratyrosine (AMPT), a catecholamine depleting agent as a chemical probe to induce dysphoria, and document the ensuing changes in mental status. AMPT (4-5 g/day) was administered to a group of medication-free schizophrenic patients (n=13) over a 48 hour period, and changes in their mental status were monitored at 12 hour intervals with the Profile of Mood States (POMS), Addiction Research Center Inventory (ARCI), Drug Attitude Inventory (DAI) and other standardized rating scales. All of the subjects experienced dysphoric responses of variable severity. The profile of changes included blunted pleasure responsivity, clouded thinking, loss of motivation and lowered vigilance. Subtle subjective changes were experienced soon after the first dose of AMPT and the dysphoria steadily worsened, resulting in social withdrawal and personal distress. Subjective responses were the earliest to manifest, followed by akathisia, akinesia and rigidity. We conclude that AMPT induced dopamine depletion is a safe, rapid, reliable and reversible method of studying dysphoric states in humans. The technique is helpful in examining the phenomenology of dysphoria, the temporal relationship between subjective and behavioural consequences of dopamine depletion, and the role of dopamine in mediating subtle aspects of pleasure responsivity, which is in turn crucial to the understanding of treatment non-adherence in schizophrenia and the origins of comorbid substance abuse.

Chlorpromazine for schizophrenia: a Cochrane systematic review of 50 years of randomised controlled trials.

BACKGROUND: Chlorpromazine (CPZ) remains one of the most common drugs used for people with schizophrenia worldwide, and a benchmark against which other treatments can be evaluated. Quantitative reviews are rare; this one evaluates the effects of chlorpromazine in the treatment of schizophrenia in comparison with placebo. METHODS: We sought all relevant randomised controlled trials (RCT) comparing chlorpromazine to placebo by electronic and reference searching, and by contacting trial authors and the pharmaceutical industry. Data were extracted from selected trials and, where possible, synthesised and random effects relative risk (RR), the number needed to treat (NNT) and their 95% confidence intervals (CI) calculated. RESULTS: Fifty RCTs from 1955-2000 were included with 5276 people randomised to CPZ or placebo. They constitute 2008 person-years spent in trials. Meta-analysis of these trials showed that chlorpromazine promotes a global improvement (n = 1121, 13 RCTs, RR 0.76 CI 0.7 to 0.9, NNT 7 CI 5 to 10), although a considerable placebo response is also seen. People allocated to chlorpromazine tended not to leave trials early in both the short (n = 945, 16 RCTs, RR 0.74 CI 0.5 to 1.1) and medium term (n = 1861, 25 RCTs, RR 0.79 CI 0.6 to 1.1). There were, however, many adverse effects. Chlorpromazine is sedating (n = 1242, 18 RCTs, RR 2.3 CI 1.7 to 3.1, NNH 6 CI 5 to 8), increases a person's chances of experiencing acute movement disorders, Parkinsonism and causes low blood pressure with dizziness and dry mouth. CONCLUSION: It is understandable why the World Health Organization (WHO) have endorsed and included chlorpromazine in their list of essential drugs for use in schizophrenia. Low- and middle-income countries may have more complete evidence upon which to base their practice compared with richer nations using recent innovations.