Schizophrenia Research Forum - A Catalyst for Creative Thinking

Food for Thought—Weight Gain and Mortality in the Mentally Ill

14 February 2007. Is medication spoiling your Valentine’s Day? Many people on prescription medication find that they are heavier on the bathroom scales, a major dilemma when tempted by designer truffles. But more importantly, weight gain can be a significant health risk and, as exemplified by two new studies, may be particularly dangerous for people who suffer from major mental illness.

Writing in the February Archives of General Psychiatry, David Osborn and colleagues at the Royal Free and University College Medical School, London, report that people with severe mental illness have increased risk of dying from coronary heart disease and stroke. In some cases that risk is threefold higher than normal. In this week’s PNAS online, Solomon Snyder and colleagues at The Johns Hopkins University School of Medicine, Baltimore, Maryland, reveal how certain antipsychotic medications can lead to weight gain, a major risk factor for cardiovascular disease. The researchers report that some second-generation “atypical” antipsychotic medications upset metabolic balance by acting like an antihistamine in the hypothalamus, the region of the brain that controls food intake. The finding suggests ways to develop newer “low calorie” antipsychotics.

Perhaps these results will also help spur more research like that reported by Suzanne Archie of McMaster University in Hamilton, Ontario, Canada, and colleagues in the February issue of Psychiatric Services. Archie and colleagues report on successful efforts to help some patients with schizophrenia lose weight, specifically those identified by the "transtheoretical model" as being ready to make lifestyle changes (Archie et al., 2007).

Weight gain and antipsychotics
When atypical antipsychotic drugs (AAPDs) were introduced, they were considered a vast improvement on the older “typical” antipsychotics, which had some severe side effects, including Parkinson-like symptoms. Even though the recent CATIE study has cast some doubt on the efficacy of AAPDs (see SRF related news story), they are still widely prescribed to people with schizophrenia or other psychoses, despite the propensity for piling on the pounds. Correcting this side effect would not only make these drugs more tolerable, but it might also make them safer.

To address the reason for this side effect, Solomon and colleagues turned their attention to the hypothalamus and to AMP kinase (AMPK) in particular. This enzyme plays a major role in lipid metabolism in the periphery, but in the hypothalamus it appears to play a key role in regulating food intake. Agents that induce anorexia, such as the hormone leptin, activate hypothalamic AMPK, while orexigenic agents, which induce weight gain, have the opposite effect, inhibiting the enzyme.

First author Sangwon Kim and colleagues found that the orexigenic AAPDs, including clozapine, olanzapine, and to a lesser extent quetiapine, lower levels of active AMPK in mouse hypothalamus tissue, while the non-orexigenic AAPDs did not. In the case of clozapine and olanzapine, the effect was quite potent, with EC50s (the amount that gives a 50 percent response) of about 10 nM. The researchers also found that the AAPDs could offset the anorexic effects of leptin—in live mice, clozapine could prevent leptin-induced activation of AMPK.

These findings might make one wonder if AAPDs interfere with leptin signaling. Kim and colleagues tested this idea and found that the antipsychotics have no affinity for leptin receptors or for those that bind neuropeptide Y or α-MSH, two other hormones that regulate metabolism. Instead, the authors discovered that the major metabolic effect of AAPDs relates to their affinities for histamine H1 receptors. When Kim and colleagues tested the orexigenic AAPDs in mice with no H1 receptors, there was no change in AMPK activity. The finding helps explain why the orexigenic activity of AAPDs correlates with their affinity for these receptors (see Wirshing et al., 1999) and why using antihistamines, such as those found in cold and allergy medicines, can lead to weight gain.

In an accompanying commentary, Herbert Meltzer, Vanderbilt University School of Medicine, notes that we have now “come full circle,” because the original antipsychotic drugs were developed in the search of a better antihistamine. “Thus, identification of the H1R as an important target for minimizing weight gain raises the possibility of using this information to guide therapeutic attempts to alleviate the metabolic side effects and to develop novel AAPDs, lacking H1R antagonism, which should cause fewer metabolic side effects,” Meltzer writes.

The cardiovascular consequences
The second study shows why such new and improved drugs may be valuable. While AAPDs are not the sole reason for increased mortality among people with severe mental illness (SMI), Osborn and colleagues report that they do slightly increase the risk for coronary heart disease and stroke in that population. However, it is important to note that patients not taking these medications also have greater risk for cardiovascular disease than the general population. The authors also looked at cancer cases but found no correlation between cancer deaths and severe mental illness.

Osborn and colleagues used the United Kingdom’s general practice research database to obtain mortality rates among more than 46,000 people with severe mental illness. They compared this data with figures from over 300,000 controls. They found that mortality due to coronary heart disease in 18-49-year-old SMI patients was 3.2-fold higher than in controls. This risk decreased with age—for those aged 50-75 and those over 75, the relative risk compared to controls was 1.86 and 1.05, respectively. Stroke data showed a similar age-dependent pattern, though the increased risks were not as high.

When antipsychotic medications were taken into account, the results became quite complex. At the lowest doses it seems that these medications may be slightly protective, though patients with severe mental illness were still at higher risk than controls. At the highest doses, however, antipsychotics do seem to slightly elevate the risk of dying from both coronary heart disease (CHD) and stroke. But when the authors looked at atypical antipsychotics alone, they did not find any association with mortality. The authors note that this is counterintuitive, given the metabolic effects of these drugs.

There were limitations in the study, as acknowledged by the authors. They did not compare antipsychotics that do and do not lead to weight gain, for example, and in fact, they did not address the issue of weight at all except to emphasize that those who are overweight may not be prescribed atypical antipsychotics. They did comment that “CHD lifestyle factors, such as poor diet and exercise, which are more prevalent in people with SMI, provide another important focus for intervention.”

While this study highlights the importance of monitoring cardiovascular disease in the severely mentally ill, more work needs to be done to understand the relationship. One major factor that is worth keeping an eye on is the relatively recent trend toward prescribing atypical antipsychotics: “…it is possible that any effect on CHD mortality may not have occurred within the period of our study,” write the authors.

As for tumors, data from this large dataset suggests that mentally ill patients are neither more nor less likely to die from cancer. Some previous studies have suggested that patients with schizophrenia may have reduced incidence of cancer (see Grinshpoon et al., 2005); however, there are also conflicting reports (see Dalton et al., 2005; Dalton et al., 2004). The relationship between cancer and mental illness may also be worthy of further study.—Tom Fagan.

Reference:
Kim SF, Huang AS, Snowman AM, Teuscher C, Snyder SH. Antipsychotic drug-induced weight gain mediated by histamine H1 receptor-linked activation of hypothalamic AMP-kinase. PNAS early edition.

Osborn DPJ, Levy G, Nazareth I, Petersen I, Islam A, King MB. Relative risk of Cardiovascular and cancer mortality in people with severe mental illness from the United Kingdom’s general practice research database.

Comments on News and Primary Papers
Comment by:  Mary Reid
Submitted 12 March 2007
Posted 14 March 2007

Atmaca and colleagues report that atypical antipsychotic-, especially clozapine- and olanzapine-induced weight gain is related to increased levels of leptin. How does this tie in with the study by Sangwon Kim and colleagues, who found that clozapine and olanzapine lower levels of active AMPK in mouse hypothalamus tissue while leptin activates hypothalamic AMPK?

Wannamethee et al. conclude, "Plasma leptin is associated with insulin resistance, inflammation, and disturbances in homeostasis independent of waist circumference, suggesting possible pathways by which leptin may influence risk of cardiovascular disease." They also report that leptin is lowered in cigarette smokers.

It is of interest that De Rosa and colleagues report reduced activation of FOXP3 by leptin. Is this a positive or a negative in schizophrenia? Is there a predisposition to develop autoimmune disease with long-term use of these drugs?

View all comments by Mary Reid

Comments on Related News


Related News: CATIE Comes to Surprising Conclusions

Comment by:  Daniel Weinberger, SRF Advisor
Submitted 18 October 2005
Posted 18 October 2005

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?

View all comments by Daniel Weinberger

Related News: CATIE Comes to Surprising Conclusions

Comment by:  Scott Hemby
Submitted 19 October 2005
Posted 19 October 2005
  I recommend the Primary Papers

Related News: CATIE Comes to Surprising Conclusions

Comment by:  David Lewis, SRF Advisor
Submitted 19 October 2005
Posted 19 October 2005
  I recommend the Primary Papers

Related News: CATIE Comes to Surprising Conclusions

Comment by:  Max Schubert
Submitted 19 October 2005
Posted 19 October 2005
  I recommend the Primary Papers

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

Related News: CATIE Comes to Surprising Conclusions

Comment by:  Iulian Iancu
Submitted 20 October 2005
Posted 20 October 2005
  I recommend the Primary Papers

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

Related News: CATIE Comes to Surprising Conclusions

Comment by:  Xiang Zhang
Submitted 20 October 2005
Posted 21 October 2005
  I recommend the Primary Papers

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

Related News: CATIE Comes to Surprising Conclusions

Comment by:  Alonso Montoya
Submitted 21 October 2005
Posted 21 October 2005
  I recommend the Primary Papers

Related News: CATIE Comes to Surprising Conclusions

Comment by:  Alexander Miller
Submitted 21 October 2005
Posted 21 October 2005
  I recommend the Primary Papers

Related News: CATIE Comes to Surprising Conclusions

Comment by:  Marvin Swartz
Submitted 26 October 2005
Posted 26 October 2005

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.

View all comments by Marvin Swartz

Related News: CATIE Comes to Surprising Conclusions

Comment by:  William Carpenter, SRF Advisor (Disclosure)
Submitted 26 October 2005
Posted 26 October 2005

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.

View all comments by William Carpenter

Related News: CATIE Comes to Surprising Conclusions

Comment by:  Daniel Weinberger, SRF Advisor
Submitted 29 October 2005
Posted 30 October 2005

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

Related News: CATIE Comes to Surprising Conclusions

Comment by:  Robert McClure (Disclosure)
Submitted 31 October 2005
Posted 1 November 2005
  I recommend the Primary Papers

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.

View all comments by Robert McClure

Related News: CATIE Comes to Surprising Conclusions

Comment by:  Captain Johann Samuhanand
Submitted 7 November 2005
Posted 7 November 2005

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

Related News: CATIE Comes to Surprising Conclusions

Comment by:  Xiang Zhang
Submitted 8 November 2005
Posted 9 November 2005
  I recommend the Primary Papers

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)

View all comments by Xiang Zhang

Related News: CATIE Comes to Surprising Conclusions

Comment by:  Patricia Estani
Submitted 25 November 2005
Posted 25 November 2005
  I recommend the Primary Papers

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

Related News: CATIE Comes to Surprising Conclusions

Comment by:  Mike Irwin
Submitted 29 November 2005
Posted 29 November 2005
  I recommend the Primary Papers

Related News: CATIE Comes to Surprising Conclusions

Comment by:  Patricia Estani
Submitted 13 December 2005
Posted 13 December 2005
  I recommend the Primary Papers

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

Related News: CATIE Comes to Surprising Conclusions

Comment by:  Robert Fisher
Submitted 24 December 2005
Posted 28 December 2005
  I recommend the Primary Papers

[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

Related News: Mortality Gap Growing for People With Schizophrenia

Comment by:  Ezra Susser, SRF Advisor
Submitted 11 December 2007
Posted 11 December 2007
  I recommend the Primary Papers

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

Related News: Clozapine: The Safest Antipsychotic?

Comment by:  John McGrath, SRF Advisor
Submitted 23 July 2009
Posted 23 July 2009
  I recommend the Primary Papers

The results of this study are surprising. In those with schizophrenia, those on clozapine had by far the lowest relative risk of death (compared to patients on other antipsychotics). Compared to older medications, atypical antipsychotics, to date, do not seem to be impacting on the relative risk of death.

I congratulate the authors on this impressive study. The study is another reminder of the utility of population-based record linkage studies. Thank heavens for the Nordic countries' health registers.

A few years ago we wondered if the differential mortality rate for schizophrenia was worsening over time (Saha et al., 2007). In addition to differential access to health care, we worried that the adverse effects of atypical antipsychotics might be a “ticking time bomb” for worsening mortality in the decades to come. The new Finnish study shows a more nuanced picture emerging.

While the results are thought provoking, let’s not forget about the main game. We all agree that there is still much more work to be done in optimizing the general physical health of people with schizophrenia.

References:

Saha S, Chant D, McGrath J. A systematic review of mortality in schizophrenia: is the differential mortality gap worsening over time? Arch Gen Psychiatry . 2007 Oct 1 ; 64(10):1123-31. Abstract

View all comments by John McGrath

Related News: Children and Teens Gain Weight Quickly on Second-generation Antipsychotics

Comment by:  William Carpenter, SRF Advisor (Disclosure)
Submitted 29 October 2009
Posted 29 October 2009

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).

View all comments by William Carpenter

Related News: Clozapine: The Safest Antipsychotic?

Comment by:  Francine Benes, SRF Advisor
Submitted 4 November 2009
Posted 4 November 2009

Clozapine: A First-Line Antipsychotic?
Tiihonen et al., of the University of Kuopio in Finland, compared mortality rates in over 66,000 patients with schizophrenia with the entire population of Finland and concluded that clozapine should be used as a first-line drug in the treatment of this disorder. Clozapine is a very effective antipsychotic, and for patients who have received it for several years, the improvement in clinical status can be quite remarkable (Lindstrom, 1988; Agid et al., 2008). Additionally, the improved mortality rate of patients on clozapine may be attributable, at least in part, to the close monitoring of their white blood cell count (WBC).

The stipulation that weekly or biweekly blood samples must be drawn is not an issue that can be viewed lightly, because approximately 1-2 percent of patients on clozapine may show significant decreases in their WBC. This may be a harbinger of agranulocytosis, a potentially lethal form of morbidity in which the bone marrow loses its ability to generate leukocytes; death remains a significant risk for patients taking this drug (Taylor et al., 2009). To some, this may seem like a small price to pay for an improved quality of life. For others, however, it represents an unacceptable degree of risk. Additionally, many patients consider the requirement for frequent blood drawing as intrusive and/or painful and refuse to have it done (personal observation).

Perhaps the greatest source of resistance to using clozapine as a “first-line” drug is the psychiatrist who is faced with this decision. In general, most believe that they would be exposing their patient to unnecessary risk and prefer to look toward other, more “benign” antipsychotic drugs (APDs) for treatment options. In practice, however, the second-generation atypical APDs are not necessarily better candidates for “first-line” use, because they may be even more likely to cause excessive weight gain, diabetes mellitus, and cardiovascular disease (Wehring et al., 2003; Henderson et al., 2005) and result in increased mortality (Meatherall and Younes, 2002). In addition to the risk of agranulocytosis, clozapine may also cause unacceptable amounts of sedation, drooling, and weight gain. Typical APDs, on the other hand, are associated with other side effects that can be quite debilitating. These include extrapyramidal movement disorders, such as 1) akathisia, a condition that may cause a worsening of symptoms as a result of agitation; 2) drug-induced Parkinsonism, in which hypokinesia usually complicates the negative symptoms of schizophrenia; and 3) tardive dyskinesia, a syndrome in which there are involuntary movements of the tongue and lips that can result in significant disability and even disfigurement (Peacock et al., 1996).

In considering the choice of an APD for a “first-episode” patient with schizophrenia, all of these factors must be considered. It is impossible to know how a particular patient with no prior history of having taken an APD will respond to any given drug. What may be an excellent “first-line” drug for one patient may not be so for another. So, the choice of a “first-line” drug requires that the doctor and patient work together to identify the APD that is most appropriate at a particular time in the course of the illness, particularly if the patient has a treatment-sensitive or treatment-resistant form of schizophrenia (Wang et al., 2004).

References:

Agid O, Kapur S, Remington G. Emerging drugs for schizophrenia. Expert Opin Emerg Drugs. 2008;13:479-95. Abstract

Henderson DC, Nguyen DD, Copeland PM, Hayden DL, Borba CP, Louie PM, Freudenreich O, Evins AE, Cather C, Goff DC. Clozapine, diabetes mellitus, hyperlipidemia, and cardiovascular risks and mortality: results of a 10-year naturalistic study. J Clin Psychiatry. 2005;66:1116-21. Abstract

Lindstrom LH. The effect of long-term treatment with clozapine in schizophrenia: a retrospective study in 96 patients treated with clozapine for up to 13 years. Acta Psychiatr Scand. 1988;77:524-9. Abstract

Meatherall R, Younes J. Fatality from olanzapine induced hyperglycemia. J Forensic Sci. 2002;47:893-6. Abstract

Peacock L, Solgaard T, Lublin H, Gerlach J . Clozapine versus typical antipsychotics. A retro- and prospective study of extrapyramidal side effects. Psychopharmacology (Berl). 1996; 124:188-96. Abstract

Taylor DM, Douglas-Hall P, Olofinjana B, Whiskey E, Thomas A. Reasons for discontinuing clozapine: matched, case-control comparison with risperidone long-acting injection. Br J Psychiatry. 2009;194:165-7. Abstract

Wang PS, Ganz DA, Benner JS, Glynn RJ, Avorn J. Should clozapine continue to be restricted to third-line status for schizophrenia?: a decision-analytic model. J Ment Health Policy Econ. 2004;7:77-85. Abstract

Wehring HJ, Kelly DL, Love RC, Conley RR. Deaths from diabetic ketoacidosis after long-term clozapine treatment. Am J Psychiatry. 2003;160:2241-2. Abstract

View all comments by Francine Benes

Related News: Clozapine: The Safest Antipsychotic?

Comment by:  Edward Orton (Disclosure)
Submitted 18 November 2009
Posted 18 November 2009
  I recommend the Primary Papers

Dr. Benes notes that clozapine is "...a very effective antipsychotic, and...improvement in clinical status can be quite remarkable." The mortality figures reported by Tihonen et al. have proved quite striking to schizophrenia researchers. The perception within the psychiatry community that clozapine is too risky for first-line therapy needs further assessment and discussion. Only about 5 percent of schizophrenics in the U.S. receive clozapine (Lieberman, 2009), leaving the vast majority of patients undermedicated because of this perception. The major issue with starting a patient on clozapine is WBC monitoring. I would like to call upon the NIMH to establish a major study in which schizophrenics are introduced to clozapine on an inpatient basis for 30-60 days to establish safety. It is well known that most WBC events associated with clozapine occur in the first few weeks of treatment. Also, I note that current prescribing practice with clozapine actually allows for monthly blood monitoring after 12 months of continuous clozapine use. Thus, the burden of monitoring diminishes sharply after one year.

References:

Lieberman J. A Beacon of Hope: Prospects for Preventing and Recovering from Mental Illness. NARSAD Research Quarterly 2 (1), Winter 2009.

View all comments by Edward Orton