Schizophrenia may be bad for your metabolic health, and the associated behaviors such as diet, exercise, and smoking create very substantial risk. Proper medical care and prevention is generally not provided. Added to this burden is the fact that antipsychotic drugs may substantially increase risk for the metabolic syndrome. Not all antipsychotic drugs are similar in this regard, and prescribing patterns need to be extensively influenced by knowledge of differential adverse effects between drugs. It is not sufficent to monitor an obesity index since this is often neglected; hyperlipidemia may occur without weight gain, and reversing adverse effects is challenging.

View all comments by William Carpenter

The relation between fatty acid and dopamine needs basic consideration. Two-week-old pups of mother rats fed n-3 polyunsaturated fatty acid-deficient diets (3 weeks before and 2 weeks after birth) showed an increase of D2 (and D1) receptors in the mesolimbic-mesocortical pathways of mothers and many brain areas of the pups (Kuperstein et al., 2005). The depressing effects of increased cholesterol level may be seen in reverse.

The effects of different antipsychotics on the immune system and fungal pathogens need consideration also. Antipsychotics reduce calcineurin protein levels and elevate phosphatase activity of calcineurin in striatum and prefrontal cortex (Rushlow et al., 2005). Calcineurin increases fungal pathogens and its inhibition is related to immune suppression (Cruz et al., 2001). Antipsychotics need further study in relation to...  Read more

The relation between fatty acid and dopamine needs basic consideration. Two-week-old pups of mother rats fed n-3 polyunsaturated fatty acid-deficient diets (3 weeks before and 2 weeks after birth) showed an increase of D2 (and D1) receptors in the mesolimbic-mesocortical pathways of mothers and many brain areas of the pups (Kuperstein et al., 2005). The depressing effects of increased cholesterol level may be seen in reverse.

The effects of different antipsychotics on the immune system and fungal pathogens need consideration also. Antipsychotics reduce calcineurin protein levels and elevate phosphatase activity of calcineurin in striatum and prefrontal cortex (Rushlow et al., 2005). Calcineurin increases fungal pathogens and its inhibition is related to immune suppression (Cruz et al., 2001). Antipsychotics need further study in relation to calcineurin, immune suppression, and fatty acids.

References:
Kuperstein F, Yakubov E, Dinerman P, Gil S, Eylam R, Salem N Jr, Yavin E. Overexpression of dopamine receptor genes and their products in the postnatal rat brain following maternal n-3 fatty acid dietary deficiency. J Neurochem. 2005 Dec;95(6):1550-62. Epub 2005 Nov 23. Abstract Rushlow WJ, Seah YH, Belliveau DJ, Rajakumar N. Changes in calcineurin expression induced in the rat brain by the administration of antipsychotics. J Neurochem. 2005 Aug;94(3):587-96. Abstract Cruz MC, Fox DS, Heitman J. Calcineurin is required for hyphal elongation during mating and haploid fruiting in Cryptococcus neoformans. EMBO J. 2001 Mar 1;20(5):1020-32. Abstract

In what may be a landmark study of lifestyle intervention in schizophrenia, Australian dietitian Sherryn Evans was highly successful in limiting weight gain in newly diagnosed schizophrenia patients treated with olanzapine (Evans et al., 2005). Nutritionally educated patients were only 2 kg heavier after 3 months and 6 months, and were happier; controls were 6 kg and 9.9 kg heavier at the same time points.

The key to nutritional success is close supervision, best provided in community centers accessible to schizophrenia patients. A gym would help. F. M. Baker once ran a program in a poor area of Baltimore, in which the patients were collected daily and brought in, to cook their own (healthy) meals and take part in psychosocial therapy; medication compliance improved, and readmission rates fell dramatically.

The adverse metabolic effects of most newer antipsychotic drugs have stimulated a renaissance of interest in nutritional factors and physical health in schizophrenia that will hopefully...  Read more

In what may be a landmark study of lifestyle intervention in schizophrenia, Australian dietitian Sherryn Evans was highly successful in limiting weight gain in newly diagnosed schizophrenia patients treated with olanzapine (Evans et al., 2005). Nutritionally educated patients were only 2 kg heavier after 3 months and 6 months, and were happier; controls were 6 kg and 9.9 kg heavier at the same time points.

The key to nutritional success is close supervision, best provided in community centers accessible to schizophrenia patients. A gym would help. F. M. Baker once ran a program in a poor area of Baltimore, in which the patients were collected daily and brought in, to cook their own (healthy) meals and take part in psychosocial therapy; medication compliance improved, and readmission rates fell dramatically.

The adverse metabolic effects of most newer antipsychotic drugs have stimulated a renaissance of interest in nutritional factors and physical health in schizophrenia that will hopefully encourage the entry of dietitians and exercise physiologists into the treatment arena. They have much to offer.

A well-planned low-fat, grain- and legume-rich diet, as in the Australian study, will improve cell membrane structure in brain and body by allowing omega-3 and -6 essential fatty acid levels to rise (the key to controlling diabetes and heart risk). The same diet also provides the key nutrient inositol, a seed-derived glucose isomer that imitates the anxiolytic action of clozapine-type drugs, and so would treat the comorbid anxiety seen in a third of patients with schizophrenia (which promotes hypertension, diabetes, cardiac mortality, smoking, negative symptoms, and suicide).

The inositol hexaphosphate in edible seeds is itself a potent iron-binding antioxidant (Graf et al., 1987), prominent in the diet of healthy centenarians, and in the whole grains is known to reduce coronary disease progression in the Iowa Women's Health Study (Erkkila et al., 2005): So here is a simple life-extender and artery protector for schizophrenia patients, too, anxious or not, who eat corn, grains, and beans.

Omega-3 fatty acids already look promising in schizophrenia (Puri and Richardson, 1998), so if oily fish intake is low, two or three fishoil capsules a day—costing little—might help both brain and cardiac risk.

More studies must be designed to research variables that affect heart disease in schizophrenia. I think that integrating medical services, for example, adding nutritional treatment or dietary services to psychiatric support is essential to prevent the metabolic syndrome commonly observed in schizophrenic patients.

View all comments by Patricia Estani

Is there any evidence of an increased incidence of arrhythmias, especially tachycardia, in schizophrenia?

View all comments by SuSanne Henriksen

This paper provides good insight into the limitations of trials secondary to confounding design variables.

View all comments by James Manning IV

The Lieberman et al. CATIE study is a landmark large-scale clinical trial of antipsychotic drug therapy and will generate considerable discussion in the coming months. It offers important insights about real-world treatment of individuals with the diagnosis of schizophrenia, in the sense of typical practices in clinics around the country and the clinical experience of many practitioners. It probably comes as no surprise that the response to available antipsychotic agents is suboptimal and that differences between drugs are not dramatic in many cases.

One of the questions that comes to my mind about the results is whether and to what degree they are generalizable. Do the results of this study accurately characterize the effects of these drugs across the spectrum of patients with chronic schizophrenia who are treated with them? In other words, are the patients in the CATIE trial representative of the patients with chronic schizophrenia who are in need of these medications? I believe there are several indicators to suggest that they may not be. First, of the subjects in this...  Read more

The Lieberman et al. CATIE study is a landmark large-scale clinical trial of antipsychotic drug therapy and will generate considerable discussion in the coming months. It offers important insights about real-world treatment of individuals with the diagnosis of schizophrenia, in the sense of typical practices in clinics around the country and the clinical experience of many practitioners. It probably comes as no surprise that the response to available antipsychotic agents is suboptimal and that differences between drugs are not dramatic in many cases.

One of the questions that comes to my mind about the results is whether and to what degree they are generalizable. Do the results of this study accurately characterize the effects of these drugs across the spectrum of patients with chronic schizophrenia who are treated with them? In other words, are the patients in the CATIE trial representative of the patients with chronic schizophrenia who are in need of these medications? I believe there are several indicators to suggest that they may not be. First, of the subjects in this trial, most of whom (75 percent) were male, 40 percent had been or were married. Second, the mean age at first antipsychotic treatment was 26 years. Third, 30 percent of the subjects were on no medication when they entered the trial. These are all somewhat atypical characteristics in my experience, especially for a predominantly male sample.

In the NIMH schizophrenia genetic study that I direct, we have extensively evaluated over 600 subjects with schizophrenia from around the country. In our sample, the mean age at first antipsychotic treatment is 21 and the ever-married rate is 15 percent, and our sample is one-third female. Moreover, less than 10 percent of our sample is unmedicated at the time that they are evaluated. The finding that a mean dose of 20 mg of perphenazine was as effective as other medications also is somewhat surprising in my experience, as having used this drug for many years, I have rarely seen chronic, actively symptomatic patients respond well without dosing around 32 milligrams and above. Is it possible that the CATIE trial inadvertently enrolled patients more in the schizophrenia spectrum end of the distribution of patients receiving these drugs who may tend not to show as clear benefit? Or maybe the size and breadth of the CATIE trial obscured the signal from the more classic patient with schizophrenia for whom antipsychotic treatment is essential.

It will be interesting to see whether other academic schizophrenia centers concur with the demographics of my experience as noted above or those of CATIE. Multicenter studies—and CATIE involved 57 centers each contributing relatively small samples over a 2-year period—are susceptible to dilution effects and to the possibility that the sample is clinically "noisy." It will be interesting to see, when data analyses from the next stages appear, whether differences are found in the results from different centers who participated in the trial. Will CATIE have told the story of how these drugs work in patients who receive them, or will it have failed to identify the signal from the noise?

I also have not seen the response at that dose of perphenazine and even the atypical antipsychotics in chronic schizophrenics. In fact, the only medication that seemed to have an adequate "real-life" dose was olanzapine.

View all comments by Max Schubert

It seems that the doses used are not equivalent, and the researchers have used somewhat lower doses of perphenazine and risperidone (in favor of olanzapine). Thus, it is obvious that perphenazine and risperidone have showed smaller efficacy.

View all comments by Iulian Iancu

There is evidence that the Chinese traditional medicines may be an alternative approach in the treatment of schizophrenia. Our recent studies indicate that the extraction of gingko biloba may increase the effectiveness of antipsychotic drugs, but reduce their side effects. This finding may provide a new clue to develop a novel therapeutic drug for treatment of schizophrenia.

References:
1. Zhang XY, Zhou DF, Zhang PY, Wu GY, Su JM, Cao LY. A double-blind, placebo-controlled trial of extract of Ginkgo biloba added to haloperidol in treatment-resistant patients with schizophrenia. Journal of Clinical Psychiatry. 2001; 62(11):878-83. Abstract

2. Zhang XY, Zhou DF, Su JM, Zhang PY. The effect of extract of ginkgo biloba added to haloperidol on superoxide dismutase in inpatients with chronic schizophrenia. Journal of Clinical Psychopharmacology 2001;21(1):85-88. Abstract

View all comments by Xiang Zhang

Reply to Dr. Weinberger's questions about the generalizability of the CATIE sample, by Marvin Swartz, for the CATIE investigators
As CATIE investigators, we have been mindful of concerns about the generalizability of the CATIE sample. In response to a similar concern, our colleague Jeffrey Swanson at Duke compared CATIE participants to a quasi-random sample of 1,413 patients enrolled in the Schizophrenia Care and Assessment Program (SCAP), an observational, non-interventional study of schizophrenia treatment in usual care settings in the United States. The two samples were similar in demographic characteristics, e.g., gender (70 percent male in SCAP, 74 percent male in CATIE), age (mean age = 43 years in SCAP, mean age = 41 years in CATIE), and education (36 percent of SCAP participants had a high school education and 28 percent attended college; in CATIE these percentages were 35 percent and 39 percent, respectively). The CATIE study had a lower proportion of participants from racial minority backgrounds (40 percent vs. 54 percent). The samples also resembled...  Read more

Reply to Dr. Weinberger's questions about the generalizability of the CATIE sample, by Marvin Swartz, for the CATIE investigators
As CATIE investigators, we have been mindful of concerns about the generalizability of the CATIE sample. In response to a similar concern, our colleague Jeffrey Swanson at Duke compared CATIE participants to a quasi-random sample of 1,413 patients enrolled in the Schizophrenia Care and Assessment Program (SCAP), an observational, non-interventional study of schizophrenia treatment in usual care settings in the United States. The two samples were similar in demographic characteristics, e.g., gender (70 percent male in SCAP, 74 percent male in CATIE), age (mean age = 43 years in SCAP, mean age = 41 years in CATIE), and education (36 percent of SCAP participants had a high school education and 28 percent attended college; in CATIE these percentages were 35 percent and 39 percent, respectively). The CATIE study had a lower proportion of participants from racial minority backgrounds (40 percent vs. 54 percent). The samples also resembled each other in clinical characteristics. Nearly one-third of the patients in both studies had recently been hospitalized. The CATIE sample had slightly higher average scores on psychotic symptom severity than the SCAP patients (mean PANSS total score = 75 vs. 71), and also slightly higher scores on functioning and quality of life (mean Heinrichs-Carpenter QLS score = 63 vs. 57) (Haya Ascher-Svanum, Ph.D., Senior Research Scientist, Eli Lilly and Company; personal communication). These similarities provide some confidence that CATIE’s RCT design did not result in a biased selection of patients.

Thanks for your comments on the CATIE study.

The antipsychotic drugs mainly treat psychosis (in contrast to cognition impairments and primary negative symptoms). In the CATIE study, the drugs tested share the same mechanism of action (D2 antagonism). Clozapine aside, the second-generation drugs (SGA) have not established superior efficacy over first-generation drugs (FGA). The FDA has granted no such claim, and the Cochrane reviews do not support superior antipsychotic efficacy. The appearance of superiority, including the terrific organization of data in the Davis meta-analyses, may be extensively based on last observation carried forward, excessive dose of the FGA, failure to pretreat with anti-parkinsonian drugs, sponsor bias, and a number of other methodological problems including the fact that most study subjects are doing poorly on FGA when recruited into comparative studies. "Atypical antipsychotic" means only low extrapyramidal symptoms at therapeutic dosing. In this regard, the CATIE findings are not surprising, but simply point to the considerable shortfall in effectiveness associated with current treatments....  Read more

The antipsychotic drugs mainly treat psychosis (in contrast to cognition impairments and primary negative symptoms). In the CATIE study, the drugs tested share the same mechanism of action (D2 antagonism). Clozapine aside, the second-generation drugs (SGA) have not established superior efficacy over first-generation drugs (FGA). The FDA has granted no such claim, and the Cochrane reviews do not support superior antipsychotic efficacy. The appearance of superiority, including the terrific organization of data in the Davis meta-analyses, may be extensively based on last observation carried forward, excessive dose of the FGA, failure to pretreat with anti-parkinsonian drugs, sponsor bias, and a number of other methodological problems including the fact that most study subjects are doing poorly on FGA when recruited into comparative studies. "Atypical antipsychotic" means only low extrapyramidal symptoms at therapeutic dosing. In this regard, the CATIE findings are not surprising, but simply point to the considerable shortfall in effectiveness associated with current treatments. The drugs will vary considerably along side effect liabilities, and matching patient to side effect profile is the key to individualizing drug choice at the moment.

As to time on drug, there was not a long-acting depot arm to the study, and this method should probably be considered in substantially more patients than is the practice in the U.S. Olanzapine did a little better on the time on drug measure, and risperidone was second. This may relate to the fact that these were the two most common drugs used at study onset, so more patients with known tolerability to these drugs began the trial. In any case, concern with weight and the metabolic syndrome will drastically cut the time on drug for olanzapine in current practice.

It is almost impossible to have a level playing field in comparative drug studies, since optimal dosing and individualized dosing parameters are simply little known with most antipsychotic drugs. In this regard, we don't know if quetiapine and ziprasidone would have done better at higher dose; or if risperidone being yoked to olanzapine led to suboptimal dosing in many cases. In Rosenheck's JAMA report, he observed that pretreatment with an anti-parkinsonian drug led to similar effectiveness comparing olanzapine with haloperidol. Would perphenazine have been even better with anti-cholinergic pretreatment?

In my view, this is a critically important study in that it reasonably represents an effectiveness study in typical settings [probably more representative than the Weinberger data set (see Weinberger commentary)] without sponsor bias. As such, it has succeeded in calling public attention to the relative lack of progress associated with "me-too" dopamine blocking antipsychotic drugs. This conclusion is reinforced by the U.K. study reported by Peter Jones at the ICOSR where SGA did not beat FGA on the primary endpoint (quality of life) or on many secondary measures. Another head-on comparison study with public support.

My hope is that industry will devote discovery resources to the challenging problems of novel treatments with new molecular targets addressing problems with impaired cognition and primary negative psychopathology. Refining antipsychotic drugs has not advanced therapeutics much since the introduction of chlorpromazine. Reducing the neuroleptic adverse effects of FGA is a real advance, especially considering the excessive dosing. But significant new liabilities are associated with some of the SGA. We now need to meet the efficacy challenge for the components of schizophrenia that mainly cause poor functional outcomes.

Dr. Swarz's comment providing data from the SCAP study is helpful in confirming that CATIE patients are similar in many phenomenological respects to other patients in schizophrenia treatment programs. Indeed, in terms of PANSS ratings, sex ratios, age at enrollment in the study, and history of recent hospitalizations, CATIE patients are not substantially different from patients we see at the NIH in Bethesda, Maryland and we saw when our program was located at St. Elizabeths Hospital in Washington, D.C. In my comment, I asked specifically about three CATIE characteristics that seemed atypical to me: age at first antipsychotic treatment (26), precentage of patients who were or had been married (40%), and percentage of patients who were unmedicated at the time they volunteered for the study (30%). It would enlighten this discussion if Dr. Swarz would report these data from the SCAP study.

View all comments by Daniel Weinberger

It would be interesting to learn from Dr. Swartz and the CATIE investigators (a) the age at first antipsychotic treatment, (b) the percentage of patients who were or had been married, and (c) the percentage of patients who were unmedicated at the time they volunteered for the study in the SCAP sample. I suspect these three variables, if available, will more closely resemble those of the CATIE trial sample than the CBDB sibling study sample.

Dr. Weinberger has suggested that the CATIE trial inadvertently enrolled patients more in the schizophrenia spectrum end of the distribution, or maybe the size and breadth of the CATIE trial obscured the signal from the more classic patient with schizophrenia, so the results may not be generalizable. I suspect that differences in criteria for recruitment and retention between the CBDB sibling study and the CATIE study explain the differences among the demographic variables of the samples.

The clinical characteristics of the CBDB sibling study sample are what one would expect in a study whose purpose is to find associations between...  Read more

It would be interesting to learn from Dr. Swartz and the CATIE investigators (a) the age at first antipsychotic treatment, (b) the percentage of patients who were or had been married, and (c) the percentage of patients who were unmedicated at the time they volunteered for the study in the SCAP sample. I suspect these three variables, if available, will more closely resemble those of the CATIE trial sample than the CBDB sibling study sample.

Dr. Weinberger has suggested that the CATIE trial inadvertently enrolled patients more in the schizophrenia spectrum end of the distribution, or maybe the size and breadth of the CATIE trial obscured the signal from the more classic patient with schizophrenia, so the results may not be generalizable. I suspect that differences in criteria for recruitment and retention between the CBDB sibling study and the CATIE study explain the differences among the demographic variables of the samples.

The clinical characteristics of the CBDB sibling study sample are what one would expect in a study whose purpose is to find associations between genetic variation and neuroimaging/neuropsychological phenotypes, among affected and unaffected family members. The usual patient included in the CBDB sample probably: had onset of active symptoms in late adolescence or early adulthood (i.e., high school or college age, before many people marry); was started on medications earlier in life; and had more intact nuclear families (parents, siblings, etc.) than the usual CATIE subject. Patients with later onset of illness or milder symptoms (who are more likely to be or have been married) and who did not start on medications once psychotic symptoms occurred, were less compliant with their medications, and/or had fewer intact family relationships were unlikely to successfully travel to Bethesda and complete two full days of research testing. The CATIE recruitment strategy did not exclude the unusual patient with treatment of symptoms later in adulthood, require intact nuclear family, or require compliance with medications at time of study entry.

The CBDB sample better represents a "textbook case" of schizophrenia. Many patients who do meet DSM-IV criteria for schizophrenia may not be good candidates for a genetics study, but may still have schizophrenia and are appropriate candidates for a large clinical study. This would suggest that the findings can be generalized to other groups of patients with the illness, though perhaps not the "classic" cases of schizophrenia gathered in the CBDB study.

Is there any published evidence that gingko biloba could be useful in containing the side effects of clozapine and other atypicals, or are there studies in progress?

View all comments by Captain Johann Samuhanand

Reply to comment by Johann Samuhanand
To our best knowledge, there is no published evidence that gingko biloba could be useful in reducing the side effects of clozapine and other atypicals. However, using the same group of patients with schizophrenia as we reported previously (Zhang et al., 2001), our recent study has shown that chronic patients with schizophrenia demonstrated significantly lower CD3+, CD4+, and IL-2 secreting cells, together with CD4/CD8 ratio, than did healthy controls at baseline. After a 12-week treatment, EGb added to haloperidol treatment increased the initially low peripheral CD3+, CD4+, and IL-2 secreting cells, together with CD4/CD8 ratio. There was only a significant increase in CD4+ cells in the placebo plus haloperidol group. These findings suggest that ginkgo biloba may improve the decreased peripheral immune functions in schizophrenia (Zhang et al., 2006).

As we have known, although clozapine is superior over the other drugs in terms of efficacy,...  Read more

Reply to comment by Johann Samuhanand
To our best knowledge, there is no published evidence that gingko biloba could be useful in reducing the side effects of clozapine and other atypicals. However, using the same group of patients with schizophrenia as we reported previously (Zhang et al., 2001), our recent study has shown that chronic patients with schizophrenia demonstrated significantly lower CD3+, CD4+, and IL-2 secreting cells, together with CD4/CD8 ratio, than did healthy controls at baseline. After a 12-week treatment, EGb added to haloperidol treatment increased the initially low peripheral CD3+, CD4+, and IL-2 secreting cells, together with CD4/CD8 ratio. There was only a significant increase in CD4+ cells in the placebo plus haloperidol group. These findings suggest that ginkgo biloba may improve the decreased peripheral immune functions in schizophrenia (Zhang et al., 2006).

As we have known, although clozapine is superior over the other drugs in terms of efficacy, it can severely deplete white blood cells, leading to limitations on its use. If gingko biloba may indeed produce beneficial effects on the immune system in schizophrenia, there is a possibility that ginkgo biloba may be useful in reducing the side effects of clozapine, at least in regard to immune function.

On the other hand, a limitation of the design of our previous study (Zhang et al., 2001) is the use of haloperidol as the antipsychotic treatment at a time when atypical antipsychotic drugs are the standard of care. Therefore, a further study is warranted to investigate whether ginkgo biloba shows similar benefits in augmenting the atypical antipsychotics, which already have the capacity to improve the positive and negative symptoms and have better profiles in terms of extrapyramidal side effects.

References:
Zhang XY, Zhou DF, Zhang PY, Wu GY, Su JM, Cao LY. A double-blind, placebo-controlled trial of extract of Ginkgo biloba added to haloperidol in treatment-resistant patients with schizophrenia. Journal of Clinical Psychiatry. 2001; 62(11):878-83. Abstract

Zhang XY, Zhou DF, Cao LY, Wu GY. The effects of Ginkgo biloba extract added to haloperidol on peripheral T-cell subsets in drug-free schizophrenia: a double-blind, placebo-controlled trial. Psychopharmacology 2006 (in press)

I recommend this clear and well-written paper for students to understand the basis of the CATIE studies.

I agree with Dr. Weinberger about the variables that could obscure the results in the target population or the schizophrenic population. His remarks about the control conditions or the dissection of the variables in the study are important. The difference between typical and atypical drugs is clear in these data.

New drugs, diferent from the typical and atypical drugs, based on new genetics research and new genetic routes must be developed in order to achieve new successes in the treatment of schizophrenia.

I think that atypical antipsychotics do not mean only low extrapyramidal symptoms at therapeutic doses. Several studies have demonstrated that atypical drugs(especially olanzapine) are better than typical drugs in important characteristics such as cognitive functioning.

View all comments by Patricia Estani

The most important current development of new antipsychotic drugs is focused on two mechanisms, the α7-nicotinic receptor agonists that are good new candidates for the management of the disease (Martin et al., 2004) and, most recently (and I think probably the closest to development), is the one that focuses on glutamatergic neurotransmission (Coyle and Tsai, 2004).

On the other hand, I think that behavioral and cognitive therapy, as well as family support and family management given by a professional in this area of health, are important to ensure an excellent result in schizophrenic patients.

References:
Martin LF, Kem WR, Freedman R. Alpha-7 nicotinic receptor agonists: potential new candidates for the treatment of schizophrenia. Psychopharmacology (Berl). 2004 Jun ;174(1):54-64. Abstract

Coyle JT, Tsai G. The NMDA receptor glycine modulatory site: a therapeutic target for improving cognition and reducing negative symptoms in schizophrenia. Psychopharmacology (Berl). 2004 Jun ;174(1):32-8. Abstract

View all comments by Patricia Estani

[Disclosure: R. Fisher was Study Coordinator, Recruiter, and Diagnostician for the Byerly Group at UT Southwestern CATIE site, the second-largest enrollment site in the study.]

The CATIE study is likely the best designed and implemented research project ever conducted regarding schizophrenia and relevant psychopharmacology. The extensively collected data will have an enormous heuristic value in the study and evaluation of this disorder in all aspects of schizophreinia. I found Drs. Lieberman and McEvoy to be true professionals in this study design.

View all comments by Robert Fisher

These are solid studies. I wonder, though, how many of these patients are on statins to prevent atherosclerosis? Is there evidence that people with schizophrenia at risk of atherosclerosis (perhaps most of them?) are routinely given proper cardiovascular medicine?

View all comments by Steven Erickson

I would like to underscore a point that emerges from the important paper by Saha and colleagues (an excellent summary is provided above by Victoria Wilcox). Currently the focus on inequalities/disparities in public health has paid attention mainly to socioeconomic and ethnic/racial disparities. This paper and some other recent papers draw attention to the disparities in health between people with and without severe mental illness. I view this disparity as being in large part rooted in discrimination experienced by people with mental illness, rather than being inherent in their illness. People with a severe mental illness should have the right to high quality health care and prevention, even if care and prevention has to be tailored to their special needs so that it can be utilized.

View all comments by Ezra Susser

It has been known for years that some—not necessarily all—second-generation drugs have severe metabolic side effects. These effects are common, not rare. Metabolic changes induced will increase risk of an early death substantially unless persons receiving these treatments are immune to effects observed in the general population. In fact, cardiovascular disease, stroke, diabetes, and pulmonary disease are already associated with early death of persons with schizophrenia where mortality rates are already two to six times standard mortality rates (see SRF related news story). The fact that these populations have increased risk from other lifestyle problems (e.g., diet, sedentary lifestyle, smoking, and stress) increases the need for clinicians to minimize risk from iatrogenic sources. The importance of the report by Correll et al. is not based on surprising new data. Rather, it is the ability to bring extensive attention to this problem to the broad medical field and the public.

The increased...  Read more

It has been known for years that some—not necessarily all—second-generation drugs have severe metabolic side effects. These effects are common, not rare. Metabolic changes induced will increase risk of an early death substantially unless persons receiving these treatments are immune to effects observed in the general population. In fact, cardiovascular disease, stroke, diabetes, and pulmonary disease are already associated with early death of persons with schizophrenia where mortality rates are already two to six times standard mortality rates (see SRF related news story). The fact that these populations have increased risk from other lifestyle problems (e.g., diet, sedentary lifestyle, smoking, and stress) increases the need for clinicians to minimize risk from iatrogenic sources. The importance of the report by Correll et al. is not based on surprising new data. Rather, it is the ability to bring extensive attention to this problem to the broad medical field and the public.

The increased safety and efficacy of second-generation antipsychotic drugs was debunked before the turn of the century, and the value of the CATIE and CUtLASS studies was more in their ability to spark the public discussion than in surprising new data (Lieberman et al., 2005; Jones et al., 2006). In young people, the antipsychotic drugs with serious metabolic adverse profiles should rarely be considered. Clozapine for some childhood-onset schizophrenia patients may be one of the exceptions. Antipsychotic drugs are usually prescribed with long-term use in mind. If a clinician considers this essential therapy—as it often is in schizophrenia, less so in bipolar disorder, where effective and safer drugs are available—selection of compounds based on safety and tolerability is essential. In this regard, prescribing drugs such as olanzapine is very difficult to defend. The importance of this report being published in JAMA is underscored by the reports of Lilly directing representatives to market olanzapine to primary care providers who are less aware of the metabolic effects (see, e.g., Attorney General’s Settlement).