MC4R methylation and antipsychotic-related metabolic changes in early psychosis: findings from two prospective cohorts.

Our friend and colleague Wayne Fenton asked to write this article for the Journal because of his desire to educate other psychiatrists about the treatment of schizophrenia, including what he recognized to be a growing problem with the metabolic syndrome. This lifelong passion, which he pursued from his psychiatry residency at Yale, through his directorship of Chestnut Lodge, to his position at NIMH as Director of the Division of Adult Translational Research and Associate Director for Clinical Affairs, ended tragically with his killing during an evaluation of a psychotic young man. Wayne had worked tirelessly to secure support for new drug discovery in the NIMH programs that he directed. The Journal will be initiating in 2007 a series of articles on the discovery of new mental illness treatments. We will dedicate this series to Wayne's memory and include with it a memorial of his life and contributions to the treatment of mental illness.

Gaining: Pediatric Patients and Use of Atypical Antipsychotics

Consensus development conference on antipsychotic drugs and obesity and diabetes.

A combination of olanzapine and the opioid receptor antagonist samidorphan is under development for the treatment of schizophrenia and bipolar I disorder. The single-tablet combination treatment is intended to provide the efficacy of olanzapine while mitigating olanzapine-associated weight gain. In this phase 3 double-blind trial, the authors evaluated the weight profile of combined olanzapine/samidorphan compared with olanzapine in patients with schizophrenia. Adults (ages 18‒55 years) with schizophrenia were randomly assigned to receive either combination treatment with olanzapine and samidorphan or olanzapine treatment for 24 weeks. Primary endpoints were percent change from baseline in body weight and proportion of patients with ≥10% weight gain at week 24. The key secondary endpoint was the proportion of patients with ≥7% weight gain. Waist circumference and fasting metabolic laboratory parameters were also measured. Of 561 patients who underwent randomization (olanzapine/samidorphan combination, N=280; olanzapine, N=281), 538 had at least one postbaseline weight assessment. At week 24, the least squares mean percent weight change from baseline was 4.21% (SE=0.68) in the olanzapine/samidorphan group and 6.59% (SE=0.67) in the olanzapine group (the difference of -2.38% [SE=0.76] was significant). Significantly fewer patients in the olanzapine/samidorphan combination group compared with the olanzapine group had weight gain ≥10% (17.8% and 29.8%, respectively; number needed to treat [NNT]=7.29; odds ratio=0.50) and weight gain ≥7% (27.5% and 42.7%, respectively; NNT=6.29; odds ratio=0.50). Increases in waist circumference were smaller in the olanzapine/samidorphan combination group compared with the olanzapine group. Schizophrenia symptom improvement was similar between treatment groups. Adverse events (in ≥10% of the groups) in the olanzapine/samidorphan and olanzapine groups included weight gain (24.8% and 36.2%), somnolence (21.2% and 18.1%), dry mouth (12.8% and 8.0%), and increased appetite (10.9% and 12.3%). Metabolic changes were small and similar between treatments. Olanzapine/samidorphan combination treatment was associated with significantly less weight gain and smaller increases in waist circumference than olanzapine and was well tolerated. The antipsychotic efficacy of the combination treatment was similar to that of olanzapine monotherapy.

We performed a retrospective analysis of data involving 121 inpatients to examine the rate of weight gain during antipsychotic-free periods and during treatment with various antipsychotic drugs. Data were analyzed to determine differences in weekly weight change during antipsychotic-free (N = 65), typical antipsychotic (N = 51), or atypical antipsychotic (N = 130) treatment periods. Atypical antipsychotic treatment periods were further subdivided into olanzapine (N = 45), clozapine (N = 47), or risperidone (N = 36) treatment periods. A paired comparison was conducted on 65 patients who had an antipsychotic-free treatment period preceding or following a neuroleptic drug treatment period. In addition, patients were classified as either non-obese (with a body mass index [BMI] < or = 29.9 kg/ml) or obese (BMI > or = 30.0 kg/m2) to test whether the rate of weight gain during treatment periods was related to initial BMI. Across all treatment periods, weekly weight gain was as follows: 0.89 lb/wk (0.40 kg/wk) on atypical antipsychotic medication, 0.61 lb/wk (0.27 kg/wk) on typical antipsychotic medication, and 0.21 lb/wk (0.09 kg/wk) on no antipsychotic medications. The atypical antipsychotic versus antipsychotic-free comparison was significant (F = 3.51; df = 2,231; p = .031), while the typical antipsychotic versus antipsychotic-free comparison was not. Among the individual atypical antipsychotic medications, significantly more weight gain occurred during olanzapine treatment (1.70 lb/wk) (0.76 kg/wk) than with either clozapine (0.50 lb/wk) (0.22 kg/wk) or risperidone (0.34 lb/wk) (0.15 kg/wk) treatments (F = 7.77; df = 2,117; p = .001). In the paired analysis with patients serving as their own controls, the difference between weekly weight gain during atypical antipsychotic treatment and antipsychotic-free treatment was significant (t = -3.91; df = 44; p = .001), while the difference between weight gain during typical antipsychotic treatment and antipsychotic-free treatment was not significant. With the individual drugs. treatment with both olanzapine and clozapine caused significantly higher weekly weight gain than antipsychotic-free treatment (p = .001 and p = .036, respectively). while treatment with risperidone did not. Non-obese patients (BMI < 29.9 kg/m2) and obese patients (BMI > 30.0 kg/m2) did not differ significantly in their weight gain during typical or atypical antipsychotic treatment. Treatment with atypical antipsychotics was associated with more weight gain than treatment with typical antipsychotics. Among the atypical drugs, olanzapine was associated with more weight gain than either clozapine or risperidone. The patient's admission BMI was not associated with the amount of weight gained during subsequent antipsychotic treatment.

Back to table of contents Previous article Next article Clinical & Research NewsFull AccessAntipsychotics' Adverse Effects Found in Elderly AD PatientsJun YanJun YanSearch for more papers by this authorPublished Online:15 May 2009https://doi.org/10.1176/pn.44.10.0028Older adults with dementia experience significant weight gain and worsening cholesterol levels when they are treated with second-generation antipsychotic (SGA) medications in a pattern similar to younger patients taking antipsychotics for schizophrenia or bipolar disorder, according to new analyses of data from the Clinical Antipsychotic Trials of Intervention Effectiveness–Alzheimer's Disease (CATIE-AD).The CATIE-AD study, a large, randomized, double-blind, placebo-controlled trial funded by the National Institute of Mental Health, was conducted between April 2001 and November 2004 to investigate the effectiveness of SGAs in treating psychosis and agitation in patients with Alzheimer's disease (AD).The study investigators had previously reported that the primary outcome, time to discontinuation of the study drug for any reason in 36 weeks of treatment, did not differ significantly among patients treated with olanzapine, quetiapine, risperidone, and placebo (Psychiatric News, November 3, 2006). Despite modest effectiveness in some of the clinical indicators with active treatments, many patients discontinued antipsychotics because of intolerable adverse effects. The current study, by Ling Zheng, M.B.B.S., Ph.D., and colleagues, focused on analyzing the weight and metabolic effects of SGAs in study patients. It was published online in AJP in Advance on April 15.Among the ambulatory Alzheimer's patients who participated in the CATIE-AD trial, female patients, but not male patients, had statistically significant weight gain and an increase in body mass index (BMI) from baseline. The authors found a significant association between the duration of SGA exposure and weight gain: The longer that patients took SGAs, the more likely they would gain at least 7 percent of their body weight, a conventional standard for clinically significant weight gain. On average, female patients gained 0.14 pounds per week while taking SGAs. In subgroup analyses, the weight and BMI increases reached statistical significance in patients who were randomly assigned to olanzapine or quetiapine.In addition to weight gain, high-density lipoprotein (HDL) cholesterol level decreased and waist circumference increased significantly in patients on olanzapine compared with those on placebo. Increased waist circumference and decreased HDL cholesterol are both associated with increased risk of cardiovascular diseases. The analyses did not show a significant effect on blood pressure, triglyceride, and glucose levels associated with SGA use.Unfavorable metabolic effects associated with SGAs, including weight gain, elevated cholesterol and triglyceride levels, and altered glucose regulation/insulin insensitivity, mostly reported in child and adolescent patients taking these medications, have caused much clinical concern and media attention in recent years. The metabolic effects in older adults have been less studied. The average age of patients in the CATIE-AD study was 78 years.“The important message from the study is that elderly patients with dementia receiving antipsychotics experience some of the same changes of metabolic syndrome that younger patients have,” said Lon Schneider, M.D., a professor of psychiatry, neurology, and gerontology at the University of Southern California Keck School of Medicine, in an interview.“ Whereas it took a while for the field to recognize these metabolic changes associated with antipsychotics in younger patients, it has taken longer for us to realize they occur in elderly patients as well.”He continued, “The weight gain and metabolic effects were seen as early as 12 weeks into treatment and continued with longer use.” He noted that past clinical trials of SGAs, many sponsored by pharmaceutical companies, often lasted only six to eight weeks and did not adequately monitor metabolic effects.None of the SGAs is approved by the FDA for treating symptoms of dementia. Despite the lack of evidence for efficacy from studies such as CATIE-AD, antipsychotics are often prescribed for dementia-related behavioral disturbances for which there is no approved drug therapy. A standard black-box warning is currently required by the FDA in the labels of all antipsychotics that warns “elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death” based on data from clinical trials.The mounting evidence of potential harm, “in the context of these drugs not working very well,” should give clinicians pause for prescribing antipsychotics to dementia patients, Schneider suggested.“Metabolic Changes Associated With Second-Generation Antipsychotic Use in Alzheimer's Disease Patients: The CATIE-AD Study” is posted at<ajp.psychiatryonline.org/cgi/reprint/appi.ajp.2008.08081218v1>.▪ ISSUES NewArchived

Byline: T. Sudhakar, G. Rao, P. Prasuna, K. Vijay Sagar Introduction Since the introduction of conventional anti-psychotics in the treatment of various psychotic disorders in late 1950's the quest for better molecules continued. The reasons for the betterment resulted in the introduction of second generation antipsychotics (SGA's) which are supposed to be more patient friendly with lesser extra pyramidal symptoms lesser chances of inducing tardive dyskinesia and better impact on affective, cognitive and negative symptoms of the schizophrenia. The initial enthusiasm about SGA's within 5 yrs had settled down towards skeptical optimism to control the unwanted and potentially endangering metabolic side effects. Among the newer drugs except for Aripriprazole and to some extent Ziprasidone all other drugs produce significant weight gain and predispose the individual for hyperglycemia and hyperlipedemia. They also produce significant day time drowsiness which interferes with patients daily occupational activities. The land mark study on antipsychotic efficacy, safety and tolerability namely CATIE study had clearly shown that 74% of the patients discontinued the treatment before 18months of trial. Intolerability was one of the major reason for the discontinuation, weight gain & metabolic effects with Olanzapine was established in phase II, part of the study. However, the trend for metabolic syndrome is also noticed with Clozapine, Risperidone, Olanzapine and to some extent with Quetiapine, Ziprasidone. The other major side effect that discourages the patient to continue the treatment is daytime drowsiness. Though with dose titration this side effect can be minimized, most of the patients do not continue, because day time drowsiness interferes with their daytime work performance. So, to improve the compliance with atypical antipsychotics and to give the patients a better quality of life, it becomes imperative that we should find various strategies including pharmacotherapy and diet control. Modafinil is a novel, non amphetamine psycho stimulant though it is not a typical sympathomimetic amine and has only weak affinity for dopamine uptake carrier site. It also acts on anterior hypothalamic nucleus and adjacent area. It is currently being promoted for excessive daytime sleepiness that occurs in Narcolepsy and also sleep apnoea. In 5% of cases it is known to produce anorexia and increase the alertness. In this, study we are making an attempt to explore whether, a non amphetamine drug like modafinil for reducing daytime drowsiness, would be of any utility in preventing daytime drowsiness associated with atypical antipsychotics. As this drug also has got anorexia and weight loss as adverse events, it would be worth while to see, whether add on therapy of modafinil with atypical especially Olanzapine, Risperidone, Clozapine (widely prescribed atypicals in India) would in anyway influence the daytime sleepiness, weight gain, hyperglycemia & hyperlipidemia. Review of Literature Atypical Anti Psychotics Versus Conventional Antipsychotics. Conventional antipsychotic agents which have been the mainstay of treatment in Schizophrenia and other psychotic disorders for over forty years have a number of limitations. This had prompted a search for new agents with greater efficacy and fewer side effects. So the serotonin dopamine antagonists (SDA) (Janssen et al ,1988) came into the practice which is at present the mainstay of treatment in patients with schizophrenia and other psychoses. But atypical antipsychotics are also not without side effects. Atypicality mainly refers to infrequent occurence of extrapyramidal syndromes in clinical setting. During recent years, it was found that akathisia is still common and tardive dyskinesia is also not uncommon with atypical drugs as earlier thought. Hence Second Generation Anti psychotics would be a better name that was suggested for this group of drugs. …

Weight gain during treatment with antipsychotics is a prominent side-effect, especially with some second-generation antipsychotics, such as olanzapine and clozapine, and pharmacological treatments which ameliorate this side-effect are important to investigate. Decreases in histaminergic transmission in the brain induced by antipsychotics may be one of the mechanisms contributing to weight gain. Since betahistine is a histaminergic agonist, it may potentially counteract the weight gain effects of antipsychotics. We conducted a double-blind placebo-controlled study to evaluate the effects of 12weeks of treatment with betahistine (N = 29) or placebo (N = 22) in adolescents and adults on anthropomorphically measured weight-related parameters, appetite, and fasting glucose-lipid and leptin levels in 51 patients treated with first and/or second-generation antipsychotics who had gained weight during treatment or had high body-mass-index (BMI). Psychopathology and side-effects were also assessed with relevant scales. In a sub-group of patients being treated with olanzapine or clozapine (n = 26), betahistine was significantly (P < .05) better than placebo in preventing increases in weight (3.1kg less weight gain than placebo), BMI, and waist circumference. Betahistine did not decrease weight or BMI in patients treated with other antipsychotics. There was also no effect of betahistine on preventing weight or BMI gain in the total combined sample of all subjects. Betahistine did not significantly improve appetite or glucose-lipid measures in either subgroup. There were no significant differences in side-effects or psychopathology changes in the betahistine- vs. placebo-treated patients. These results suggest that betahistine may potentially be a useful adjunctive drug for decreasing weight gain in patients treated with antipsychotics that are potent histamine antagonists, such as olanzapine or clozapine, but may not be useful for this purpose in patients on other antipsychotic medications. The results justify larger placebo-controlled studies to further confirm these effects before specific recommendations can be made for routine use.

Increasing numbers of reports concerning diabetes, ketoacidosis, hyperglycaemia and lipid dysregulation in patients treated with second-generation (or atypical) antipsychotics have raised concerns about a possible association between these metabolic effects and treatment with these medications. This comprehensive literature review considers the evidence for and against an association between glucose or lipid dysregulation and eight separate second-generation antipsychotics currently available in the US and/or Europe, specifically clozapine, olanzapine, risperidone, quetiapine, zotepine, amisulpride, ziprasidone and aripiprazole. This review also includes an assessment of the potential contributory role of treatment-induced weight gain in conferring risk for hyperglycaemia and dyslipidaemia during treatment with different antipsychotic medications. Substantial evidence from a variety of human populations, including some recent confirmatory evidence in treated psychiatric patients, indicates that increased adiposity is associated with a variety of adverse physiological effects, including decreases in insulin sensitivity and changes in plasma glucose and lipid levels. Comparison of mean weight changes and relative percentages of patients experiencing specific levels of weight increase from controlled, randomised clinical trials indicates that weight gain liability varies significantly across the different second generation antipsychotic agents. Clozapine and olanzapine treatment are associated with the greatest risk of clinically significant weight gain, with other agents producing relatively lower levels of risk. Risperidone, quetiapine, amisulpride and zotepine generally show low to moderate levels of mean weight gain and a modest risk of clinically significant increases in weight. Ziprasidone and aripiprazole treatment are generally associated with minimal mean weight gain and the lowest risk of more significant increases. Published studies including uncontrolled observations, large retrospective database analyses and controlled experimental studies, including randomised clinical trials, indicate that the different second-generation antipsychotics are associated with differing effects on glucose and lipid metabolism. These studies offer generally consistent evidence that clozapine and olanzapine treatment are associated with an increased risk of diabetes mellitus and dyslipidaemia. Inconsistent results, and a generally smaller effect in studies where an effect is reported, suggest limited if any increased risk for treatment-induced diabetes mellitus and dyslipidaemia during risperidone treatment, despite a comparable volume of published data. A similarly smaller and inconsistent signal suggests limited if any increased risk of diabetes or dyslipidaemia during quetiapine treatment, but this is based on less published data than is available for risperidone. The absence of retrospective database studies, and little or no relevant published data from clinical trials, makes it difficult to draw conclusions concerning risk for zotepine or amisulpride, although amisulpride appears to have less risk of treatment-emergent dyslipidaemia in comparison to olanzapine. With increasing data from clinical trials but little or no currently published data from large retrospective database analyses, there is no evidence at this time to suggest that ziprasidone and aripiprazole treatment are associated with an increase in risk for diabetes, dyslipidaemia or other adverse effects on glucose or lipid metabolism. In general, the rank order of risk observed for the second-generation antipsychotic medications suggests that the differing weight gain liability of atypical agents contributes to the differing relative risk of insulin resistance, dyslipidaemia and hyperglycaemia. This would be consistent with effects observed in nonpsychiatric samples, where risk for adverse metabolic changes tends to increase with increasing adiposity. From this perspective, a possible increase in risk would be predicted to occur in association with any treatment that produces increases in weight and adiposity. However, case reports tentatively suggest that substantial weight gain or obesity may not be a factor in up to one-quarter of cases of new-onset diabetes that occur during treatment. Pending further testing from preclinical and clinical studies, limited controlled studies support the hypothesis that clozapine and olanzapine may have a direct effect on glucose regulation independent of adiposity. The results of studies in this area are relevant to primary and secondary prevention efforts that aim to address the multiple factors that contribute to increased prevalence of type 2 diabetes mellitus and cardiovascular disease in populations that are often treated with second-generation antipsychotic medications.

Background: Children and adolescents with serious mental illness may experience improved psychiatric stability with second generation antipsychotic (SGA) medication treatment, but unfortunately may also experience unhealthy weight gain adverse events. Aims: To describe behavioral weight loss intervention for weight gain children and adolescents being treated with antipsychotic medications. Method: Six obese children and adolescents with long-term antipsychotic medication exposure were included in the study. The efficacy of the intervention was evaluated with a battery of anthropomorphic and metabolic assessments, including weight, body mass index percentile, whole body adiposity, liver fat content, fasting plasma glucose and lipid levels. Participants and their parents also filled out a treatment satisfaction questionnaire after study completion. Results and Discussion: All participants attended all sixteen sessions of the intervention and experienced beneficial changes in adiposity, fasting lipid levels, and liver fat content associated with weight stabilization. Participants and their parents reported a high level of satisfaction with the treatment. Conclusion: Antipsychotic-related weight gain is an important public health issue for children and adolescents requiring ongoing antipsychotic treatment to maintain psychiatric stability. Family-based behavioral weight loss treatment can be feasibly delivered and is acceptable to children and adolescents taking antipsychotic medications and their families.

Weight gain: gained by waiting?

Schizophrenia, Antipsychotics, and the Metabolic Syndrome: Is There a Silver Lining?

Schizophrenia, Antipsychotics, and the Metabolic Syndrome: Is There a Silver Lining?

Atypical antipsychotics are first-line drugs to treat schizophrenia with a reduced rate of extrapyramidal effects [1]. However, studies have also noted their capacity to cause obesity in addition to metabolic abnormalities [2]. This is also true of risperidone, which has been observed to increase weight by a mean of 2.10 kg [3] and to maintain the same weight at 1 year. This weight gain has been noted to be extreme, persistent and, in some cases, may be irreversible with atypical antipsychotics [4, 5] including risperidone [6]. However, the risk is lower when compared with olanzapine and clozapine [6]. Risperidone also has controversial effects on metabolic parameters, with the majority of studies showing an increase in weight and triglyceride concentrations [3, 7], whereas others have demonstrated a decrease in overall body mass index (BMI) [8] as well as a reversal of other antipsychotic-induced hypertriglyceridaemia [9]. We present the case of a drug-naive schizophrenic patient who, while being treated with risperidone over 6 weeks, experienced changes in lipid profile with an overall increase in BMI and excessive gain in weight which returned to baseline on discontinuation. A White 32-year-old married woman with a diagnosis of paranoid schizophrenia (International Classification of Diseases 10), who had been drug-naive for the previous 8 months, was admitted and started on risperidone 3 mg day−1. The severity of psychotic symptoms was assessed using the Brief Psychiatric Rating Scale (BPRS). Family history was negative for psychiatric illness, obesity and diabetes mellitus. On day 1 (BPRS = 34), her BMI was 17.7 (height 150 cm, weight 40 kg, waist circumference 69 cm). Baseline fasting serum lipid profile and glucose were: cholesterol 104 mg dl−1 (range 150–200 mg dl−1), triglycerides 86 mg dl−1 (range 60–150 mg dl−1), low density lipoprotein (LDL) 87 mg dl−1 (range 0–100 mg dl−1), very low density lipoproteins (VLDL) 18 mg dl−1 (range 12–33 mg dl−1) and fasting blood glucose (FBS) 100 mg%. At the end of first 2 weeks, a modest improvement in psychotic symptoms was observed (BPRS score = 20), with modest weight gain (3 kg, BMI 19) and an increase in waist circumference to 74 cm. During the next 2 weeks, she gained another 3 kg (BMI 20.4; waist circumference 80 cm), complained of increased appetite and carbohydrate cravings and was noted to be eating voraciously. As there was minimal improvement in her psychotic symptoms (BPRS score = 18), risperidone was gradually increased to 6 mg day−1 without signs of adverse effects. However, she continued to gain weight (weight 48 kg, BMI 21.4; waist circumference 86 cm) over the next 2 weeks (weeks 4–6). All attempts to reduce her weight by restricting her diet and increasing her activity failed. A repeat biochemistry revealed elevated concentrations of cholesterol (194 mg dl−1), triglyceride (99 mg dl−1), LDL (133 mg dl−1) and VLDL (40 mg dl−1), with normal FBS (86 mg%). A decision to discontinue risperidone was taken in view of persisting psychotic symptoms and adverse metabolic parameters (Naranjo algorithm evaluation obtained a score of 6, which indicates that it is ‘probable’ that the adverse reaction was due to the drug) and she was started on haloperidol along with depot fluphenazine. At 1 month's follow-up, she had reduced her weight (42 kg) and waist circumference (70 cm) with reduction to almost baseline concentrations in all metabolic parameters (cholesterol 110 mg dl−1, triglyceride 94 mg dl−1, LDL 97 mg dl−1, VLDL 27 mg dl−1 and FBS 90 mg%), which was maintained at 3 months' follow-up. The patient had no abnormalities of thyroid function or her menstrual cycle during the 6 weeks of treatment with risperidone. It is worth noting that she complied well with pharmacotherapy, as assessed by pill count. Risperidone-induced weight gain is more pronounced in the young, men, those with lower BMI and of non-White race [10]. Weight change of 7% above baseline is taken as clinically significant. Moreover, short-term weight gain has been associated with a good clinical response [2]. However, our patient was female and had significant weight gain of 20% above baseline, which was, however, associated with poor clinical response. Metabolic changes, as seen by dose-dependent elevations of cholesterol, triglyceride, LDL and VLDL concentrations within 6 weeks of risperidone therapy, are other atypical features seen in our patient. The combination of increasing weight along with abdominal adiposity and dyslipidaemic changes may herald the onset of metabolic syndrome. Furthermore, the increase in BMI from 17 to 21 within 6 weeks may also signal the beginning of obesity, as BMI > 22 has been defined as being overweight for Asians and Indians [11-13]. However, all these changes were rapidly reversible on discontinuation of the drug, making it imperative that clinicians identify early and monitor susceptible patients on antipsychotics, so that progression to metabolic syndrome may be prevented.

It has been over 10 years since the initiation of the National Institute of Mental Health (NIMH) Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) study and 5 years since the first publication of its primary results (1). In this period, the initial report has been cited in the literature over 1,600 times (2) while more than 80 articles from the study’s extensive database (Table 1), as well as a book serving as an archive of the study’s results and implications (3), have been published. In the meantime, several more randomized trials comparing the effectiveness of antipsychotics have been completed (4–6), meta-analyses that bear on the findings of the CATIE study have been performed (7, 8), and commentaries on CATIE’s findings and critiques of its methodology have been published (9–11). All of these help us to view the CATIE study in a broader context and enable us to determine what we really learned from it. When the CATIE study was designed in 1999– 2000, the prevailing opinion of researchers and clinicians alike was that the newer (second-generation) antipsychotic drugs were vastly superior to the older (first-generation) antipsychotic drugs in efficacy and safety. This largely reflected the results of studies sponsored by the manufacturers of the new drugs (12, 13), marketing messages of pharmaceutical companies and the hopes of many who wanted better treatments. Indeed, the hypothesis and expectation of the CATIE study investigators was that the firstgeneration antipsychotic perphenazine would be inferior to the newer agents. Consequently, the finding that perphenazine was similar in effectiveness to most other medications had a profound effect that extended beyond the scientific and psychiatric communities to the lay public and various stakeholder groups. Somewhat sensational news reports decried the preferential use and greater cost of the newer medications and the marketing practices that led to them. For example, the September 21, 2005, editorial page of The New York Times opined, “A government-financed study has provided the strongest evidence yet that the system for approving and promoting drugs is badly out of whack. The study compared five drugs used to treat schizophrenia and found that most of the newest, most heavily prescribed drugs were no better than an older drug that is far cheaper. The nation is wasting billions of dollars on heavily marketed drugs that have never proved themselves in head-to-head competition against cheaper competitors” (14). But what did we really learn from the CATIE study? In this commentary, we summarize its major implications and their relevance to clinical practice. We will also address some of the study’s most relevant critiques.