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Editorial
Looking Back, Moving Forward
Quentin Rae-Grant
(PDF)

Original Research
Intramuscular Olanzapine and Intramuscular Haloperidol in Acute Schizophrenia: Antipsychotic Efficacy and Extrapyramidal Safety During the First 24 Hours of Treatment
Padraig Wright, Stacy R Lindborg, Martin Birkett, Karena Meehan, Barry Jones, Karla Alaka, Iris Ferchland-Howe, Anne Pickard, Cindy C Taylor, John Roth, John Battaglia, István Bitter, Guy Chouinard, Philip LP Morris, Alan Breier
(PDF)

EEG Abnormalities and Outcome in First-Episode Psychosis
Rahul Manchanda, Ashok Malla, Rajendra Harricharan, Leonardo Cortese, Jatinder Takhar
(PDF)

Impact of Antidepressant Side Effects on Adolescent Quality of Life
Amy H Cheung, Anthony J Levitt, John P Szalai
(PDF)

Violence by Psychiatric Patients: The Impact of Archival Measurement Source on Violence Base Rates and Risk Assessment Accuracy
Kevin S Douglas, James R Ogloff
(PDF)

Medicated Anxious Children: Characteristics and Cognitive-Behavioural Treatment Response
Vitaly Liashko, Katharina Manassis
(PDF)

Review Paper
From Chlorpromazine to Clozapine—Antipsychotic Adverse Effects and the Clinician’s Dilemma
Sabina Abidi, Sreenivasa M Bhaskara
(PDF)

Research Methods in Psychiatry
Unicorns Do Exist: A Tutorial on “Proving” the Null Hypothesis
David L Streiner
(PDF)

Brief Communication
Association of Substance Abuse and Depression Among Adolescent Psychiatric Inpatients
Carla Kmett Danielson, James C Overholser, Zeeshan A Butt
(PDF)

Book Reviews
(PDF)

Drugs and Addictive Behaviour.
Reviewed by
Nady el-Guebaly, MD, FRCPC

Evidence and Experience in Psychiatry. Volume 5. Bipolar Disorder.
Reviewed by
Verinder Sharma, MB, BS, FRCPC

Letters to the Editor
(PDF)

Re: Unfree Associations: Inside Psychoanalytic Institutes

Reply: Unfree Associations: Inside Psychoanalytic Institutes

Improving the Mood Disorder Questionnaire to Detect Bipolar II Disorder

Mnemonic for the Diagnosis of Hypomania Associated with Bipolar II Disorder

Aripiprazole-Induced Improvement in Tardive Dyskinesia

Dependent Personality Disorder as a Marker of “Battered Husband Syndrome”: A Case Exemplar

Visually Enhanced Psychosexual Therapy (VEST) in a Multicultural Community

Review Paper

From Chlorpromazine to Clozapine—Antipsychotic Adverse Effects and the Clinician’s Dilemma

Sabina Abidi, MD¹, Sreenivasa M Bhaskara, MB, FRCPC, MRCPsych, DPM²

Schizophrenia is a chronic, debilitating disease with significant morbidity and mortality that often requires antipsychotic pharmacotherapy for life. In the manner of both commentary and literature review, this paper examines the historical perspective and current dilemma faced by clinicians treating patients with schizophrenia. In an attempt to improve patients’ quality of life, clinicians must take into account the morbidity and mortality associated with the adverse effects of pharmacotherapy. We are still reminded of the long-term sequelae of treatment decisions made for over 40 years in our chronic patients (that is, irreversible tardive dyskinesia [TD]), reminders that now lead us to avoid many of the conventional antipsychotics. This reminder becomes especially pertinent today as we stand only 1 decade after the introduction of the atypicals and begin to realize that these medications carry their own adverse effects, the long-term consequences of which are only just emerging. The key question to be considered is whether atypicals are in fact safer and better or whether they are merely different in their side effect profiles, compared with the older, typical neuroleptics. Recommendations, including the need for early identification of high-risk populations and effective monitoring programs, are presented along with the importance of informed consent and the therapeutic alliance when making treatment decisions.

Background and Historical Perspective

From the introduction of conventional antipsychotics that sparked massive deinstitutionalization in the 1960s to the reintroduction of clozapine in 1988 and the discovery of atypical antipsychotics, the struggle to effectively treat schizophrenia and related disorders continues. The introduction of chlorpromazine (CPZ) in 1954 was an indisputable advance in psychiatry. CPZ’s efficacy in treating the positive symptoms of schizophrenia is well established. Over the next 20 years, about 40 similar medications were introduced worldwide into the market, comprising a class of antipsychotic medications now termed “typicals.” All typicals studied have similar mechanisms of action and comparable efficacy (1). The choice of medication among the typicals thus is largely based on their relative side effect profile. The 2 most troublesome side effects are extrapyramidal side effects (EPSEs) and TD. The debilitating symptoms of EPSEs are now known to occur in 75% to 90% of patients taking typicals (2). The annual cumulative incidence of TD in young, healthy adults taking typicals is 4% to 5% (3), and the risk increases with age and duration of exposure to the medication (4). Further, cases of TD were recognized as being disfiguring, irreversible, and potentially fatal as early as the late 1960s (5,6). Moreover, studies began to emerge suggesting that much of the functional disability associated with schizophrenia is associated with negative symptoms and cognitive deficits (7), for which the typicals showed little potential treatment efficacy. After a hiatus of almost 15 years, clozapine was reintroduced in North America following the landmark trial by Kane and others in 1988 comparing clozapine with CPZ in treatment-refractory schizophrenia. It was the first antipsychotic shown to be more effective then haloperidol and CPZ for positive symptoms and, incidentally, negative symptoms and also offered a better side effect profile free of EPSEs and TD (8). With its unique pharmacology and relatively low D2 antagonism and more potent 5-HT2 antagonism, clozapine became the prototype atypical antipsychotic (9). The confirmation of clozapine’s superior efficacy in treating patients with schizophrenia, compared with the typical antipsychotics, triggered further pharmaceutical industry research for more similarly effective, newer medications.

Atypicals: Efficacy for Positive and Negative Symptoms and Cognitive Deficits

As discussed, the efficacy of clozapine for positive symptoms has been clearly established. With respect to treatment- refractory patients, clozapine has been demonstrated to be more effective than the typical antipsychotics (8,10). To date, no persuasive evidence has been presented suggesting that any other atypical shares clozapine’s efficacy for positive symptoms in treatment-refractory patients. However, clozapine’s superior efficacy over typicals for negative symptoms and cognitive function has not been unequivocally established. In fact, Kane and others recently attempted to address this issue in patients with moderately refractory schizophrenia and found that, while clozapine offered superior clinical benefit for positive symptoms at comparable dosages to haloperidol, treatment effects did not extend to negative symptoms (11). Bilder and others compared clozapine, risperidone, and olanzapine to haloperidol on 16 measures of neurocognitive functioning and found only a modest neurocognitive benefit from clozapine treatment that was not superior to the other drugs (12). Atypicals introduced in Canada in the 1990s include risperidone, olanzapine, quetiapine, and recently ziprasidone, with more in the pipeline. Their efficacy in the treatment of positive symptoms of schizophrenia has also been well established. A recent metaregression analysis evaluated outcomes with the use of atypicals (namely, amisulpride, olanzapine, quetiapine, risperidone, sertindole, and clozapine) vs typicals (namely, haloperidol). The study showed that there was substantial overall heterogeneity among trials with no evidence to suggest that any individual atypical had a specific effect on positive or negative symptoms. Benefits seemed to be evenly spread among them (13). Conventional neuroleptics seem to have only minor effects on most aspects of cognition in schizophrenia, and in some cases these drugs are known to exacerbate cognitive deficits (1,12). There are several recent studies suggesting that atypical antipsychotics may have a beneficial and differential effect on cognition, depending on the drug. To date, these are modest effects; their clinical significance requires further elucidation and development.

Emerging Adverse Effects of the Atypicals

Numerous trials have demonstrated that the atypicals as a group are clearly better than the typicals with respect to the decreased incidence of EPSEs and TD (1,3,5,9,14). These medications are now increasingly being recommended as first-line treatments (with the exception of clozapine, which is reserved for refractory cases).

In reviewing research with the atypicals over the last 10 years, long-term side effects of these medications are emerging. Reports about endocrine and metabolic side effects such as hyperprolactinemia, weight gain, obesity, dyslipidemias, diabetes, and cardiac adverse effects are becoming a serious cause for concern.

Cardiac Adverse Effects
Concerns about the ability of atypicals to cause sudden death owing to increased QTc prolongation, torsades de pointes, and other cardiovascular events have produced wariness about the extensive use of these drugs. Cardiovascular risks associated with clozapine such as tachycardia, myocarditis, pericarditis, hypotension, and cardiomyopathy have been known for nearly a decade (15–17). Recently, the US FDA has revised the package insert for clozapine to indicate an increased risk for myocarditis. Elevation of the QTc interval of 10 ms or more is considered a significant concern with antipsychotic use. In a study of 164 patients, 4/6 antipsychotics compared had a mean change greater than 10 ms. Thioridazine had the greatest increase at 35.6 ms. Of the atypicals, ziprasidone had a change of 20.3 ms; quetiapine, of 14.5 ms; risperidone, of 11.6 ms; and olanzapine, of 6.8 ms (17,18). People with schizophrenia have an increased risk for development of cardiovascular illness that seems to be inherent in the psychiatric illness itself. These risks, combined with the risks of the pharmacotherapy and lifestyle choices such as smoking, make the cardiovascular death rate among schizophrenia patients higher than that among the general population (17).

Dyslipidemia
Concerns about hypertriglyceridemia and antipsychotic use were raised first in 1995. Clozapine has been linked to an increased risk of hypertriglyceridemia and dyslipidemias (19,20). Among 82 patients in a 5-year naturalistic study, those treated with clozapine for 1 year gained more than 40% of their body weight and had significantly increased serum triglycerides during the 60-month trial period (20). Other reports have documented a mean increase in fasting serum triglycerides of 60 to 70 mg/dL associated with both short- and long- term olanzapine treatment (21). While modest triglyceride increases were described with early typicals, the large increases seen with clozapine-, olanzapine-, and quetiapine- treated patients are likely related to the distinct pharmacology of the atypicals (22). Cases of severe hyperlipidemia have been reported among most atypicals, except for risperidone. In a study of 4 clozapine-treated patients with hypertriglyceridemia, it was reported that the triglycerides normalized after switching to risperidone (23). Patients with elevated triglycerides are at risk for acute pancreatitis and long-term cardiovascular morbidity (22).

Hyperprolactinemia
Hyperprolactinemia is a common side effect of the typical antipsychotics by virtue of the reciprocal action of dopamine on prolactin secretion, specifically in the tuberoinfundibular tract. It is often underdiagnosed owing to patient hesitation to mention the problems caused by elevated prolactin, such as sexual dysfunction, gynecomastia, and galactorrhea (24). Atypical antipsychotics, such as olanzapine, quetiapine, and clozapine, are fairly mesolimbic-specific in their dopamine blockade and thus have a lower risk of prolactin elevation. The normal range of prolactin levels (in nonlactating subjects) is 1 to 25 µg/L (24). An analysis of 3 double-blind multicentre trials in patients taking risperidone (dosages of 4 to 12 mg daily), haloperidol (dosages of 5 to 20 mg daily), and olanzapine (dosages of 5 to 20 mg daily) concluded that risperidone caused the greatest increase in prolactin (by 45 to 80 µg/L). Haloperidol intermediately increased prolactin (by 17 µg/L), and olanzapine moderately increased prolactin (by 1 to 4 µg/L). There did not appear to be a dosage-dependent relation between drugs and prolactin increase (25). The prolactin increase caused by olanzapine is often transient in the first few weeks of use and often returns to baseline levels or even lower thereafter (24). To date, studies have shown that the effect of ziprasidone on prolactin is insignificant. Short-term consequences of elevated prolactin are amenorrhea, early menopause, galactorrhea, gynecomastia, sexual dysfunction, prolonged erection, priapism, and loss of fertility (in women), while long-term effects include decreased bone density and osteoporosis (24,25). Patients with schizophrenia are already candidates for osteoporosis, owing to their sedentary lifestyle, smoking, and poor nutrition. All these changes can lead to poor compliance with antipsychotic therapy.

Hyperglycemia or Diabetes Mellitus
Reports of new-onset diabetes and diabetic ketoacidosis in patients treated with clozapine (20,26–28), olanzapine (28–30), and quetiapine (28,31,32) continue to accumulate. Among 82 patients treated with clozapine in a 5-year naturalistic study, 37% were diagnosed with adult-onset diabetes, and 72% of them went on to require oral hypoglycemic agents or insulin therapy for their glucose dysregulation (20). Since 1994, most studies of the emergence of hyperglycemia and diabetes during treatment with atypical antipsychotics involved clozapine (n = 20), followed by olanzapine (n = 13), quetiapine (n = 3) and risperidone (n = 4). Most frequently, hyperglycemia was not dosage-dependent and was reversible with cessation of treatment with olanzapine and clozapine but reappeared after reintroduction of the drug (33). Schizophrenia is a known risk factor for adult-onset diabetes mellitus. Therefore, the risk is enhanced with neuroleptics, particularly olanzapine and clozapine, but also with some low-potency conventional neuroleptics. Diabetes-associated morbidity includes such problems as cardiovascular disease, cerebrovascular disease, and renal disease and leads to a significant increased risk of mortality (34).

Weight Gain
Weight gain has become an issue recently with results of reports that 2 of the atypicals (clozapine and olanzapine) are associated with a higher risk of excessive weight gain than any other drugs (20,35). Almost all antipsychotics produce some weight gain, but there are differences among them. An analysis of weight-gain trends after 10 weeks of treatment with antipsychotics demonstrated a hierarchical effect on weight gain as follows: clozapine > olanzapine >> sertindole >> risperidone >> haloperidol >> ziprasidone (36, 37). We now know that weight gain as an adverse effect of antipsychotics continues beyond this short time period. In a 5-year naturalistic study involving 82 patients (20), those treated with clozapine for at least 1 year gained weight to varying degrees, which continued to 46 months after initiation. A few of these patients gained more than 40% of their body weight (14). Weight gain (particularly increased abdominal girth) has been significantly correlated with treatment response to olanzapine, (35,36). There are documented increases in body mass index (BMI; BMI = weight in kilograms/[height in metres]2) by almost 10% after 1.4 years of treatment with olanzapine, as well as development of abnormal fasting glucose during treatment (29). To date, several analyses have shown varying degrees of association between all atypicals and weight gain (35–37). Presently, there are no clinical markers to help predict patients with a higher risk of weight gain and the extent of the weight gain expected.

Consequences of Weight Gain
Overweight and obesity have reached epidemic levels in almost all developed countries. In the US alone, 1/2 adults is overweight (BMI 25 to 29.9) or obese (BMI > 30) (38). Adults in the general population with a BMI greater than 25 are at higher risk for developing common, weight-associated diseases and metabolic abnormalities, and it is known that excess abdominal fat is associated with dyslipidemia, hypertension, and glucose intolerance (39). As patients gain weight and become mildly-to-severely obese, their risk for medical complications increases (Table 1) (40). More than 80% of estimated obesity-attributable deaths (deaths due to the increased risk of comorbid conditions with obesity) occur in individuals with a BMI > 30 (41). Studies have also shown that, even among people with a low-risk profile (for example, nonsmokers and no history of cardiac disease), an increment of 1.0 in BMI is still associated with a higher mortality from all causes including cardiovascular disease (42). Being overweight is also a powerful determinant in the occurrence of type II diabetes mellitus (43). The Framingham Offspring Study cohort revealed a 46% and 61% increased risk of diabetes in men and women, respectively, associated with small increments in weight (44).

The psychological consequences of weight gain are numerous (Table 1). Patients who gain weight report a lower overall sense of well-being, and it is well known as a leading cause of medication noncompliance (39,45).

Epidemiological Morbidity and Mortality Trends: General Population vs Schizophrenia Patients

It is well documented that smoking tobacco, sedentary lifestyles, elevated systolic blood pressure, increased blood glucose levels, and centripetal fat accumulation are all recognized factors that further increase weight-related morbidity and mortality risks (39,46). Table 2 shows further risk factors for both diabetes and cardiovascular diseasse in the general population. Epidemiologists, endocrinologists, and cardiologists have expressed increasing concern about the rise in these risks based on current population trends (for example, smoking, inactive lifestyles, obesity, and poor diet). These concerns are (expected to be) substantially higher for people with schizophrenia, especially since the advent of antipsychotics.

It is known that the risk in the general population for developing weight-related disease doubles in smokers (47). According to a Statistics Canada survey in 1998–1999, 23% of Canadians smoked tobacco, 51% led inactive lifestyles, and close to 40% were considered overweight. The prevalences of diabetes and high blood pressure in the same time frame were 4% and 10.54%, respectively (48). Further, the prevalence of obesity almost tripled from 5.6% to 14.8% between 1985 and 1998 (49). For persons with schizophrenia, it is reasonable to assume that the above figures are likely to be significantly higher by virtue of their illness and unhealthier lifestyles. For example, studies have shown that 80% to 90% of patients with mental illness smoke (50), thereby quadrupling smoking- related morbidity and mortality in this population. Patients are often limited by financial constraints, social stigma, and poor insight, leading them to make unhealthy food choices and adopt predominantly sedentary lifestyles. Even prior to the initiation of antipsychotics, persons with schizophrenia have an increased risk for developing hyperglycemia, cardiovascular abnormalities, and diabetes that appears to be a preexisting diathesis inherent to the illness itself (51). This puts patients at an increased risk, compared with the general population, for developing abnormal metabolic syndromes and morbidities as a function of their illness and lifestyle. For example, syndrome X is a condition characterized by glucose intolerance, dyslipidemia, insulin resistance, hypertension, central obesity, and atherosclerosis. The syndrome can be acquired in the face of persistent obesity, inactive lifestyle, and physical and psychological stressors (39). It stands to reason that the risk of acquiring such syndromes and the morbidity associated with it can be further compounded with the use of the atypicals.

Intervention and Monitoring

Recent studies on the metabolic side effects of the atypicals have generally recommended patient monitoring of blood glucose, weight, and lipid profile (46). Almost all suggest regular exercise programs and healthier lifestyle and food choices for patients (39). In real-life community settings, the expectations such programs place on a patient with chronic schizophrenia would require a great deal of motivation, self-discipline, and consistency, which are difficult even for the average healthy person and thus intuitively difficult for persons with schizophrenia. People with schizophrenia are already handicapped by the inherent negative symptoms and cognitive deficits of the illness. This can be made worse by their psychosocial and financial limitations and may interfere with their ability to make healthy nutritional and lifestyle choices (Table 2) (46). A recent study examining weight gain in the first year of treatment in an early-psychosis program demonstrated that, even though patients were informed about weight gain and advised to increase their exercise and limit food intake, there was an average 12% increase in weight in the first year of treatment with atypical antipsychotics. The authors concluded that information and advice on this issue do not prevent weight gain in patients (52). As discussed, many patients carry morbidity and mortality risks inherent to the illness and their lifestyles that can be further compounded by the effect of the atypical medications. These factors can be extremely difficult to monitor, let alone control, especially in an outpatient setting. The intent here is not to disregard or underestimate weight-reduction strategies. Rather, it is to exemplify the realities faced by patients and their clinicians when trying to make appropriate treatment decisions.

The Clinician’s Dilemma

From a historical perspective, our capacity to recognize the dangers of medication side effects has been rather slow. For instance, the first report of TD developing after neuroleptic treatment was in 1957 (53), and further reports accumulated during the 1960s. However, it was not until the early 1970s that pharmaceutical package inserts consistently cited TD as an adverse effect. It took another decade for widespread recognition of TD as a serious and potentially irreversible side effect of neuroleptics. Another example is thioridazine, a typical antipsychotic drug that had been commonly used for decades for schizophrenia. In the early 1990s, thioridazine was recognized to cause prolongation of the QTc interval, cardiac arrhythmia (17), and sudden death and yet only received a boxed warning package insert in July 2000. Also, owing to the concern about new-onset or worsened diabetes with atypical antipsychotics, Japan has recently launched package inserts advising of this risk with both olanzapine and quetiapine, years after the initial documentation of this risk with these drugs. The implication of these actions, however delayed, leads to the clinician’s difficulty in being confident at any time in making current treatment decisions.

Clozapine provides an illustrative challenge in balancing the risks and benefits of treatment. The risk of death from agranulocytosis caused by clozapine therapy is 1:10 000. The suicide risk for patients with treatment-resistant schizophrenia is 1:10 (17). Despite the substantial difference in risk, clinicians seem to be hesitant to prescribe clozapine to this population.

From a different perspective, Sussman makes an equally interesting comment based on data from the Framingham Heart Study’s public-use data set (54). He notes that the use of clozapine would prevent 492 suicide deaths per 100 000 patients with schizophrenia over a 10-year period. At the same time, clozapine would be associated with a 10-kg weight increase. He further points out that there would be an estimated additional 416 deaths owing to the clozapine-induced weight gain in the same time frame. He suggests that the magnitude of weight gain induced by such antipsychotic agents may clearly have important deleterious effects on mortality and health (54) that must be weighed against the assumed therapeutic benefits of the drug.

The crux of the matter remains that clinicians practice in a naturalistic setting where there is a dynamic interplay of many complex factors that are difficult to factor in, let alone control. Within this contextual reality, we continue to struggle to find the best antipsychotic drugs for our patients from among the numerous medications available. Since the atypicals are all equally effective, the choice of drug for any given patient is still determined by their relative adverse-effect profile. With all the emerging evidence of adverse effects of the atypicals and concerns about the long-term endocrine and cardiovascular adverse effects of these drugs in the first decade of their use, this clinical decision becomes an increasingly difficult one. How does one chose between the potential risk for TD vs obesity, diabetes, or cardiovascular morbidity and mortality? There are no clear answers.

Implications and Recommendations

Given the complexities involved in choosing an antipsychotic for any given patient where the long-term consequences are still under investigation, the responsibility remains with the clinician to make these difficult decisions on an individual basis. One needs to remain cautious and give earnest consideration to the risk–benefit ratio of prescribing a particular antipsychotic, be it typical or atypical, in all spheres of the patient’s life. The importance of the informed decision- making process and a good doctor–patient relationship becomes particularly critical to foster a strong, long-term therapeutic alliance. Discussing the potential effects of the medications available as well as identifying the patients’ motivation and capacity for change with regard to lifestyle is necessary. Early identification of patients with high-risk factors for obesity, diabetes, and cardiac disease is essential and requires increased monitoring and management.

The practice of conducting baseline investigations and regular monitoring of glucose, prolactin, lipids, weight, EKG, and cardiovascular status when starting a patient on antipsychotic treatment is essential. Although there are general guidelines, there is an urgent need for a collaboration of experts in the fields of psychiatry, endocrinology, cardiology, and neurology to jointly delineate clear and practical guidelines for monitoring adverse effects of antipsychotics. The need for the development of practical interventions in high-risk patient groups who need to remain on these medications indefinitely cannot be understated when attempting to achieve quality patient care in the treatment of schizophrenia.

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Authors

Manuscript received September 2002, revised, and accepted March 2003.

1. Fourth-year Psychiatry Resident, Dalhousie University, Halifax, Nova Scotia.

2. Assistant Professor, Dalhousie University, Halifax, Nova Scotia; Staff Psychiatrist, Bedford/Sackville Mental Health, Lower Sackville, Nova Scotia.

Address for correspondence: Dr SM Bhaskara, Bedford/Sackville Mental Health, 11 Glendale Avenue, Lower Sackville, NS B4C 3P2

e-mail: Sreenivasa.Bhaskara@cdha.nshealth.ca

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