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

Based on a study of 227 subjects, Jones and colleagues conclude that “there is no disadvantage …in commencing treatment with FGAs rather than atypical SGAs in people with schizophrena…” (Jones et al., 2006). Jones et al chose to compare two groups (all FGAs v.all SGAs). Although they acknowledge, in general, within-group heterogeneity, they consider the comparison between groups clinically useful. However, this perspective that in fact ignores the heterogeneity is limiting, and, in combination with the results of the study, might encourage clinicians to believe that the effectiveness of all antipsychotics is equal (with the possible exception of clozapine).

A recent report provided evidence of great variability of effectiveness across the spectrum of FGAs and SGAs (Tiihonen et al., 2006). This was an observational prospective cohort study of 2230 adults hospitalized for schizophrenia in Finland. The main outcome...  Read more

Based on a study of 227 subjects, Jones and colleagues conclude that “there is no disadvantage …in commencing treatment with FGAs rather than atypical SGAs in people with schizophrena…” (Jones et al., 2006). Jones et al chose to compare two groups (all FGAs v.all SGAs). Although they acknowledge, in general, within-group heterogeneity, they consider the comparison between groups clinically useful. However, this perspective that in fact ignores the heterogeneity is limiting, and, in combination with the results of the study, might encourage clinicians to believe that the effectiveness of all antipsychotics is equal (with the possible exception of clozapine).

A recent report provided evidence of great variability of effectiveness across the spectrum of FGAs and SGAs (Tiihonen et al., 2006). This was an observational prospective cohort study of 2230 adults hospitalized for schizophrenia in Finland. The main outcome measures were rates of discontinuation of treatment, and rehospitalization. The study found that the effectiveness within the FGA group varied as a function of route of administration Perphenazine decanoate (the only depot drug analyzed) was considerably more effective than the oral form of the same drug,; in fact, it appeared to be superior to any other drug in the study, including clozapine. Furthermore, clozapine and olanzapine showed better effectiveness than haloperidol . Other drugs in the study (FGAs and SGAs) showed inconsistent differences from haloperidol. Thus, the effectiveness af antipsychotics is not equal.

Nevertheless, in spite of methodological differences, the Jones and Tihonen studies are consistent with each other. Had Tiihonen et al. elected to create and compare two groups analogous to the Jones study (FGAs v. SGAs), the result might have been the same as shown by Jones et al: no group difference (see Tiihonen tables showing the treatments ordered by the relative risks of rehospitalization and discontinuation). This result, if presented as the sole outcome of the study, would have obscured very important differences among individual drugs.

What, then, is the useful clinical perspective based on all these data? I think that the success of perphenazine decanoate in the Tiihonen study brings up again the great importance of compliance for effectiveness. Furthermore, the choice of drug for individual patients should probably be driven by the individual properties of the drug and of the patient, rather than by the drug’s classification.

Do the SGAs exhibit greater effectiveness than the FGAs? At this stage of the game, we may seek refuge with Orwell: All antipsychotics are equal, but some antipsychotics are more equal than others.

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...  Read more

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?

The article by Kargieman and colleagues further specifies the cellular mechanisms underlying the actions of clozapine in a model of pharmacologically induced cortical dysfunction. Separately, clozapine has been demonstrated to be capable of reducing or eliminating the complex behavioral and cognitive impairments elicited by acutely administered NMDA antagonists (Geyer et al., 2001; Idris et al., 2005; Lipina et al., 2005), and these cellular mechanisms shown by Kargieman et al. may represent the level of interaction between clozapine and phencyclidine-like drugs.

What is surprising from so many of these studies is the quality of the reversal of effects produced by clozapine, despite the fact that it (like most other antipsychotic drugs) has limited efficacy both at an individual and population level. Furthermore, there remain many reports in the literature demonstrating that while some cognitive and symptomatic domains in schizophrenia...  Read more

The article by Kargieman and colleagues further specifies the cellular mechanisms underlying the actions of clozapine in a model of pharmacologically induced cortical dysfunction. Separately, clozapine has been demonstrated to be capable of reducing or eliminating the complex behavioral and cognitive impairments elicited by acutely administered NMDA antagonists (Geyer et al., 2001; Idris et al., 2005; Lipina et al., 2005), and these cellular mechanisms shown by Kargieman et al. may represent the level of interaction between clozapine and phencyclidine-like drugs.

What is surprising from so many of these studies is the quality of the reversal of effects produced by clozapine, despite the fact that it (like most other antipsychotic drugs) has limited efficacy both at an individual and population level. Furthermore, there remain many reports in the literature demonstrating that while some cognitive and symptomatic domains in schizophrenia are improved by clozapine, others clearly are not (Goldberg and Weinberger, 1996; Bilder et al., 2002). Why, then, is clozapine so effective in the PCP model? One concern, of course, is that its effects are related to a specific type of pharmacological interaction; one certainly needs to see clozapine's effects in other models that do not involve the acute administration of an NMDA antagonist.

Notably, several groups have been studying the effects of long-term administration of phencyclidine, sometimes followed by washout of the NMDA antagonist, to develop an alternative type of model that may depend upon the neuroadaptations resulting from blockade of NMDA receptors, rather than on the acute pharmacological action itself (Jentsch et al., 1997; Balla et al., 2003; Amitai et al., 2007, and many others). Whilst the specific validity of any one of these approaches is debatable, what appears to be clear is that the ability of clozapine to reverse behavioral or neurochemical deficits is much more tenuous. Is this a weakness of these models, or does it mean they are actually more realistic in their predictions?

Based upon these facts, one is left with a number of questions. First, is a model that predicts that clozapine is completely effective at blocking psychopathology or pathophysiology valid? Second, is the action of clozapine in any one model based upon one kind of manipulation really that provocative? And finally (and perhaps most importantly), is developing models that explain how clozapine works really in our best interest, or is it time to move beyond models that predict marginal gains from existing drugs, in order to look to targets flowing from the new valid genetic mechanisms that appear to hold the keys to the next generation of treatments for schizophrenia?

References:

Amitai N, Semenova S, Markou A. Cognitive-disruptive effects of the psychotomimetic phencyclidine and attenuation by atypical antipsychotic medications in rats. Psychopharmacology (Berl). 2007 Sep;193(4):521-37. Abstract

Balla A, Sershen H, Serra M, Koneru R, Javitt DC. Subchronic continuous phencyclidine administration potentiates amphetamine-induced frontal cortex dopamine release. Neuropsychopharmacology. 2003 Jan;28(1):34-44. Abstract

Bilder RM, Goldman RS, Volavka J, Czobor P, Hoptman M, Sheitman B, Lindenmayer JP, Citrome L, McEvoy J, Kunz M, Chakos M, Cooper TB, Horowitz TL, Lieberman JA. Neurocognitive effects of clozapine, olanzapine, risperidone, and haloperidol in patients with chronic schizophrenia or schizoaffective disorder. Am J Psychiatry. 2002 Jun;159(6):1018-28. Abstract

Geyer MA, Krebs-Thomson K, Braff DL, Swerdlow NR. Pharmacological studies of prepulse inhibition models of sensorimotor gating deficits in schizophrenia: a decade in review. Psychopharmacology (Berl). 2001 Jul;156(2-3):117-54. Abstract

Goldberg TE, Weinberger DR. Effects of neuroleptic medications on the cognition of patients with schizophrenia: a review of recent studies. J Clin Psychiatry. 1996;57 Suppl 9:62-5. Abstract

Idris NF, Repeto P, Neill JC, Large CH. Investigation of the effects of lamotrigine and clozapine in improving reversal-learning impairments induced by acute phencyclidine and D-amphetamine in the rat. Psychopharmacology (Berl). 2005 May;179(2):336-48. Abstract

Jentsch JD, Redmond DE Jr, Elsworth JD, Taylor JR, Youngren KD, Roth RH. Enduring cognitive deficits and cortical dopamine dysfunction in monkeys after long-term administration of phencyclidine. Science. 1997 Aug 15;277(5328):953-5. Abstract

Lipina T, Labrie V, Weiner I, Roder J. Modulators of the glycine site on NMDA receptors, D-serine and ALX 5407, display similar beneficial effects to clozapine in mouse models of schizophrenia. Psychopharmacology (Berl). 2005 Apr;179(1):54-67. Abstract

The paper by Kargieman et al. provides an interesting perspective on the effects of PCP on activity in the prefrontal cortex. Dr. Javitt brings up an excellent point in his commentary that the study highlights the importance of PCP in this preparation as a model of slow-wave sleep disturbances in schizophrenia. In anesthetized animals, field potential recordings resemble the up and down states observed in slow-wave sleep. These states are driven by NMDA receptors and, accordingly, NMDA antagonists such as PCP and ketamine should reduce them as reported. The odd thing about NMDA antagonists is that they themselves can be used as anesthetics to produce a state where slow delta oscillations predominate. For instance, robust up and down states or slow oscillations at or below delta are observed when ketamine is used as an anesthetic. Therefore, NMDA antagonists can induce a state where delta activity is prominent, yet if the subject is already in that state, the effect of the drug is to reduce such activity.

So this also may be the case with PCP. There are numerous EEG studies...  Read more

The paper by Kargieman et al. provides an interesting perspective on the effects of PCP on activity in the prefrontal cortex. Dr. Javitt brings up an excellent point in his commentary that the study highlights the importance of PCP in this preparation as a model of slow-wave sleep disturbances in schizophrenia. In anesthetized animals, field potential recordings resemble the up and down states observed in slow-wave sleep. These states are driven by NMDA receptors and, accordingly, NMDA antagonists such as PCP and ketamine should reduce them as reported. The odd thing about NMDA antagonists is that they themselves can be used as anesthetics to produce a state where slow delta oscillations predominate. For instance, robust up and down states or slow oscillations at or below delta are observed when ketamine is used as an anesthetic. Therefore, NMDA antagonists can induce a state where delta activity is prominent, yet if the subject is already in that state, the effect of the drug is to reduce such activity.

So this also may be the case with PCP. There are numerous EEG studies showing that PCP significantly increases activity in the delta band of awake humans or animals (Stockard et al., 1976; Matsuzaki and Dowling, 1985; Mattia et al.,1988; Marquis et al., 1989; Yamamoto, 1997; Sebban et al., 2002), yet reduces power in this band of anesthetized animals. Moreover, schizophrenics appear to have a significant increase in frontal delta oscillations when awake (Wuebben and Winterer, 2001), yet exhibit slow-wave sleep disturbances and lower delta count when asleep (Ganguli et al., 1987). How is that?

It may be a matter of perspective. In the awake state the cortex is highly desynchronized and firing is quite irregular with power in a variety of high-frequency bands and neurons firing at every phase angle of the field potential. With anesthetics, higher frequencies become unsustainable. Using realistic network model simulations, Durstewitz and Gabriel (2007) showed that if you come from a regime which is quite irregular and then reduce NMDA, you get clear delta wave oscillations, but as you keep reducing NMDA, these delta oscillations will become progressively reduced as well. So in the awake state, reductions in NMDA currents should relatively decrease power in many bands yet enhance delta, but if the network is already in delta, as when the subject is anesthetized or asleep, NMDA reduction would decrease power in this band. Therefore, the results of Kargieman et al., when viewed in light of the literature obtained in awake subjects and schizophrenics, confirms a non-trivial and somewhat paradoxical prediction of the NMDA theory of schizophrenia and the PCP model.

References:

Durstewitz D, Gabriel T. Dynamical basis of irregular spiking in NMDA-driven prefrontal cortex neurons. Cereb Cortex. 2007 Apr;17(4):894-908. Epub 2006 Jun 1. Abstract

Ganguli R, Reynolds CF 3rd, Kupfer DJ. Electroencephalographic sleep in young, never-medicated schizophrenics. A comparison with delusional and nondelusional depressives and with healthy controls. Arch Gen Psychiatry. 1987 Jan;44(1):36-44. Abstract

Marquis KL, Paquette NC, Gussio RP, Moreton JE. Comparative electroencephalographic and behavioral effects of phencyclidine, (+)-SKF-10,047 and MK-801 in rats. J Pharmacol Exp Ther. 1989 Dec;251(3):1104-12. Abstract

Matsuzaki M, Dowling KC. Phencyclidine (PCP): effects of acute and chronic administration on EEG activities in the rhesus monkey. Electroencephalogr Clin Neurophysiol. 1985 Apr;60(4):356-66. Abstract

Mattia A, Marquis KL, Leccese AP, el-Fakahany EE, Moreton JE. Electroencephalographic, behavioral and receptor binding correlates of phencyclinoids in the rat. J Pharmacol Exp Ther. 1988 Aug;246(2):797-802. Abstract

Sebban C, Tesolin-Decros B, Ciprian-Ollivier J, Perret L, Spedding M. Effects of phencyclidine (PCP) and MK 801 on the EEGq in the prefrontal cortex of conscious rats; antagonism by clozapine, and antagonists of AMPA-, alpha(1)- and 5-HT(2A)-receptors. Br J Pharmacol. 2002 Jan;135(1):65-78. Abstract

Stockard JJ, Werner SS, Aalbers JA, Chiappa KH. Electroencephalographic findings in phencyclidine intoxication. Arch Neurol. 1976 Mar;33(3):200-3. Abstract

Wuebben Y, Winterer G. Hypofrontality -- a risk-marker related to schizophrenia? Schizophr Res. 2001 Mar 30;48(2-3):207-17. Abstract

Yamamoto J. Cortical and hippocampal EEG power spectra in animal models of schizophrenia produced with methamphetamine, cocaine, and phencyclidine. Psychopharmacology (Berl). 1997 Jun;131(4):379-87. Abstract

The EUFEST study found that haloperidol, in comparison with several SGAs, was associated with a higher rate of overall treatment discontinuation, a higher rate of discontinuation because of lack of efficacy, a higher rate of discontinuation because of side effects, and worse outcome on the CGI and the GAF. Surprisingly, the authors’ last sentence reads: “It cannot be concluded that SGAs are more efficacious than is haloperidol….” Although restraint in scientific conclusions is generally admirable, I think that these authors are being too conservative in the interpretation of their important findings.

The reason for their hesitancy, it appears, is that the PANSS and the rehospitalization rates have not shown significant differences among drugs. Furthermore, they are concerned about the possibility of provider expectation biasing the results against haloperidol: if the psychiatrists expected haloperidol to do poorly, perhaps they were more likely to discontinue it than another treatment in which they believed. But the lack of difference on the PANSS total can have many...  Read more

The EUFEST study found that haloperidol, in comparison with several SGAs, was associated with a higher rate of overall treatment discontinuation, a higher rate of discontinuation because of lack of efficacy, a higher rate of discontinuation because of side effects, and worse outcome on the CGI and the GAF. Surprisingly, the authors’ last sentence reads: “It cannot be concluded that SGAs are more efficacious than is haloperidol….” Although restraint in scientific conclusions is generally admirable, I think that these authors are being too conservative in the interpretation of their important findings.

The reason for their hesitancy, it appears, is that the PANSS and the rehospitalization rates have not shown significant differences among drugs. Furthermore, they are concerned about the possibility of provider expectation biasing the results against haloperidol: if the psychiatrists expected haloperidol to do poorly, perhaps they were more likely to discontinue it than another treatment in which they believed. But the lack of difference on the PANSS total can have many reasons. Subanalyses of PANSS factors and data on rater training effectiveness that may be published in secondary studies could shed some light on this. Rehospitalization rates would be expected to depend on the treatment the patients received after their participation in the study was terminated; this topic is also likely to be explored later.

Provider expectations are difficult to demonstrate. The authors polled the site coordinators, asking them whether they expected haloperidol to lead to the worst outcome, or whether the outcome would be similar to that with SGAs. The authors then tested the hypothesis that the sites where haloperidol was expected to do worse would have higher discontinuation rates with haloperidol than the other sites. They found a non-significant difference in the expected direction. It should be noted that the poll occurred after the end of data collection, and that the coordinators were not blinded to the treatment assignments. Therefore, the result of the poll could have reflected experience as well as expectation.

Is it possible that the differences between haloperidol and the SGAs on CGI and GAF (but not on the PANSS) were due to their greater vulnerability to bias of these two scales than the PANSS? There are two speculations here: one, that a bias existed in this study, and two, that the scales have inherent differences in their liability to rater bias. No empirical evidence supports either of these speculations.

In summary, the EUFEST study results, based on data from close to 500 patients collected by dozens of investigators, permit more definitive conclusions than the authors have drawn in their first paper. We are looking forward to follow-up articles by this outstanding group of investigators. Practicing psychiatrists will particularly appreciate a presentation of the clinical implications of this landmark study.

This timely study, conducted by a stellar group of European investigators, adds to the continued debate about choice of medications for schizophrenia, informed by other similarly impressive pragmatic trials such as CATIE and CUTlass. Unlike the other recently published first-episode treatment study—the CAFE study (McEvoy et al., 2007)—which was double blind and compared SGAs only (risperidone versus olanzapine versus quetiapine), EUFEST better fits the model of a pragmatic trial and also included a FGA comparator. Although readers, particularly policy makers, will inevitably be drawn to the “Should I choose an FGA or SGA” content of this study, it seems to me that the most striking finding is (yet again) how frequently patients stop their medications. The 72 percent overall “All Cause” Discontinuation rate bears an uncanny resemblance to the 74 percent in CATIE and to the similar rate in the one-year CAFE first-episode study. Thus, medication non-adherence is a major treatment...  Read more

This timely study, conducted by a stellar group of European investigators, adds to the continued debate about choice of medications for schizophrenia, informed by other similarly impressive pragmatic trials such as CATIE and CUTlass. Unlike the other recently published first-episode treatment study—the CAFE study (McEvoy et al., 2007)—which was double blind and compared SGAs only (risperidone versus olanzapine versus quetiapine), EUFEST better fits the model of a pragmatic trial and also included a FGA comparator. Although readers, particularly policy makers, will inevitably be drawn to the “Should I choose an FGA or SGA” content of this study, it seems to me that the most striking finding is (yet again) how frequently patients stop their medications. The 72 percent overall “All Cause” Discontinuation rate bears an uncanny resemblance to the 74 percent in CATIE and to the similar rate in the one-year CAFE first-episode study. Thus, medication non-adherence is a major treatment issue right from the onset of treatment. Set in that light, the differences observed in the study between agents are relatively modest. The data do not endorse the preferential “lead off” with any particular agent. Indeed, much like the discussion that followed the publication of the CATIE study, these data make the case for wide availability and choice of antipsychotic medications, rather than confining to a selective FGA first or X drug before trying Y among the SGAs. I agree with Dr Volavka's comment that subsequent analyses of these valuable data may bring additional insights to the surface.

References:

McEvoy JP, Lieberman JA, Perkins DO, Hamer RM, Gu H, Lazarus A, Sweitzer D, Olexy C, Weiden P, Strakowski SD. Efficacy and tolerability of olanzapine, quetiapine, and risperidone in the treatment of early psychosis: a randomized, double-blind 52-week comparison. Am J Psychiatry. 2007 Jul ;164(7):1050-60. Abstract

Although in EUFEST, psychopathology improved to a similar extent among the different groups, durability of the medication was quite different. This is of the utmost importance when it comes to treating patients—no one would disagree that continuation on medication is crucial in the successful treatment of patients with schizophrenia. If my goal is to pick the antipsychotic that my first-episode patient will stick with the longest, olanzapine or amisulpride appears to be what the data recommend. The alternative is to prescribe something else and then switch if necessary. Curiously, amisulpride and olanzapine (and risperidone) appeared to perform better than haloperidol in the Davis meta-analysis published when EUFEST was being launched (Davis et al., 2003).

As an exercise in looking at EUFEST through the lens of evidence-based medicine, I calculated the number needed to treat (NNT) for all-cause discontinuation (Citrome, 2008). NNT yields statistically significant pair-wise...  Read more

Although in EUFEST, psychopathology improved to a similar extent among the different groups, durability of the medication was quite different. This is of the utmost importance when it comes to treating patients—no one would disagree that continuation on medication is crucial in the successful treatment of patients with schizophrenia. If my goal is to pick the antipsychotic that my first-episode patient will stick with the longest, olanzapine or amisulpride appears to be what the data recommend. The alternative is to prescribe something else and then switch if necessary. Curiously, amisulpride and olanzapine (and risperidone) appeared to perform better than haloperidol in the Davis meta-analysis published when EUFEST was being launched (Davis et al., 2003).

As an exercise in looking at EUFEST through the lens of evidence-based medicine, I calculated the number needed to treat (NNT) for all-cause discontinuation (Citrome, 2008). NNT yields statistically significant pair-wise advantages for olanzapine vs. haloperidol and quetiapine; amisulpride vs. haloperidol and quetiapine; and ziprasidone vs. haloperidol. The strongest effect sizes were olanzapine or amisulpride vs. haloperidol with an NNT of four, meaning for every four patients randomized to olanzapine or amisulpride instead of haloperidol, one additional patient on olanzapine or amisulpride completed the study on his or her initially assigned medication. Overall, the EUFEST NNT results for all-cause discontinuation are consistent with what has been observed in an NNT analysis of the CATIE data (Citrome et al., 2006).

References:

Citrome L: Interpreting and applying the EUFEST results using number needed to treat: antipsychotic effectiveness in first-episode schizophrenia. International Journal of Clinical Practice. 2008;62(5):837-840. Abstract

Citrome L, Stroup TS: Schizophrenia, Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) and number needed to treat: how can CATIE inform clinicians? International Journal of Clinical Practice. 2006;60(8):933-940. Abstract

Davis JM, Chen N, Glick ID. A meta-analysis of the efficacy of second-generation antipsychotics. Arch Gen Psychiatry. 2003; 60: 553–64. Abstract

EUFEST, CATIE, and CUtLASS: Should Atypical Antipsychotic Drugs Remain the Most Prescribed Treatment for Schizophrenia?
The EUFEST (Kahn et al., 2008) study is the third major effectiveness-style study published in the last three years whose goal has been to compare typical and atypical antipsychotic drugs in the treatment of specified subgroups of patients with schizophrenia, the others being CATIE (Lieberman et al., 2005) and CUtLASS (Jones et al., 2006). The authors of EUFEST close their report with: “…it cannot be concluded that second-generation antipsychotic drugs are more efficacious than is haloperidol in the treatment of these (first-episode schizophrenia) patients” despite the fact that the discontinuation rate was the primary endpoint, and there was a significantly lower rate of discontinuation of the atypical drugs: 40 percent for amisulpride, 33 percent for olanzapine, 53 percent for quetiapine, and 45 percent for...  Read more

EUFEST, CATIE, and CUtLASS: Should Atypical Antipsychotic Drugs Remain the Most Prescribed Treatment for Schizophrenia?
The EUFEST (Kahn et al., 2008) study is the third major effectiveness-style study published in the last three years whose goal has been to compare typical and atypical antipsychotic drugs in the treatment of specified subgroups of patients with schizophrenia, the others being CATIE (Lieberman et al., 2005) and CUtLASS (Jones et al., 2006). The authors of EUFEST close their report with: “…it cannot be concluded that second-generation antipsychotic drugs are more efficacious than is haloperidol in the treatment of these (first-episode schizophrenia) patients” despite the fact that the discontinuation rate was the primary endpoint, and there was a significantly lower rate of discontinuation of the atypical drugs: 40 percent for amisulpride, 33 percent for olanzapine, 53 percent for quetiapine, and 45 percent for ziprasidone, vs. 72 percent for haloperidol; p <0.0001). However cautious this statement, it was still not acceptable to Robert Rosenheck (2008) who, in the accompanying Lancet commentary, states: ”There clearly seems to be much less, if any [my emphasis] ground for enthusiasm about these costly drugs now than in 2002, precisely because of the finding of large, independent double-blind trials, ” by which he refers to the CATIE (Lieberman et al., 2005) and CUtLASS (Jones et al., 2006) studies. The EUFEST authors chose to downplay their primary outcome measure, which was robustly achieved, because rating scale changes were not significantly different between the atypical antipsychotic drugs and haloperidol and because CATIE and CUtLASS had reached similar conclusions with regard to more chronically ill patients.

As I will show, the disconnect between continuation with therapy and equivalence of changes in psychopathology confirmed what we had found more than a decade ago in a randomized, blinded, small N trial comparing clozapine and typical antipsychotic drugs in recent onset patients with schizophrenia who had a history of good response to typical antipsychotic drug treatment (Lee et al., 1994; 1999). The EUFEST articles ducked the more pressing question of which type of medication should be administered to first episode patients if, indeed, it cannot be concluded that one is more effective than another.

What in the “real world” is going on? Efficacy, effectiveness and hybrid studies
It is important to consider whether the EUFEST, CATIE, and CUtLASS studies should be considered hybrid rather than effectiveness studies, because these studies urge greater significance be paid to them than to efficacy studies. They are supposedly “real world,” while claiming efficacy studies are much less so, or not at all. As pointed out by Hogarty et al. (1997), studies such as EUFEST, CATIE, and CUtLASS are much closer to what is generally called a hybrid than a true effectiveness study, because of the elaborate and extensive research apparatus they employ, making it highly likely that usual clinical practice, patient behavior, and outcome were influenced by protocol design and execution, just as they are in efficacy studies. For example, the CATIE study design most certainly encouraged switching drugs within its large-scale Phase 1 component comparing perphenazine with atypical antipsychotics, and did so in a variety of ways (Meltzer and Bobo, 2006). In addition, the CATIE study design did the same in the treatment failure phase of the study by comparing unblinded clozapine with blinded comparators and using time to discontinuation as the primary endpoint. Unblinding clozapine clearly favored it since the small proportion of eligible patients who entered that phase of the study were mainly those who wanted to receive a trial of clozapine in the first place. (McEvoy et al., 2006). Kenneth Wells, a distinguished authority on the issue of effectiveness and hybrid studies concluded, and I concur: “We do not yet know whether the findings of such hybrid studies will be clinically and socially useful” (Wells, 1999). Until we do so, it would seem prudent to withstand the pressure to make the atypical antipsychotic drugs second line treatments, which has been the explicit message from some of the authors of CATIE and CUtLASS, if not EUFEST.

Clozapine and expectations for superiority of other atypical antipsychotic drugs
Consideration of the issue of whether atypical antipsychotic drugs have advantages over typical antipsychotic drugs, the driving force behind these three hybrid studies, can begin with a consideration of whether even clozapine has advantages with regard to efficacy and time to discontinuation over typical antipsychotic drugs. Though the typical and atypical antipsychotic drugs, e.g., clozapine, olanzapine, quetiapine, risperidone, ziprasidone, and aripiprazole, are referred to in all three studies as first- and second-generation antipsychotic drugs, I prefer to refer to them as typical and atypical, as they were originally called, and as they are almost universally referred to by preclinical scientists. Labeling them as “first- and second-generation” drugs is inaccurate with regard to the time frame in which clozapine, the first of the atypical antipsychotic drugs, was initially discovered and developed (which was at the same time, or even prior to, many of the so-called first-generation drugs) and contrasts it mechanistically from the typical antipsychotic drugs.

Clozapine was labeled atypical shortly after its discovery by both preclinical and clinical investigators, solely because of its lack of extrapyramidal effects (EPS) in both laboratory animals and patients. This critical advantage is due to major differences in its pharmacology, one which is shared by all of the currently marketed atypical antipsychotic drugs developed since clozapine, with the exception of sulpiride and amisulpride. The critically important shared pharmacology of the clozapine-like atypical antipsychotic drugs—olanzapine, quetiapine, risperidone, and ziprasidone—is more potent blockade of serotonin (5-HT) 2A than dopamine (DA) D2 receptors, at optimal clinical doses (Meltzer et al.,1989; 2003). Aripiprazole substitutes partial D2 receptor agonism for relatively weaker D2 antagonism but retains the 5-HT2A antagonism common to the other atypical antipsychotics other than sulpiride and amisulpride. The so-called “fast-off” hypothesis of Kapur and Seeman (2000) to explain atypicality in antipsychotic drugs is valid only for clozapine itself and quetiapine, both of which have low affinities for the D2 receptor, but not for asenapine, olanzapine, risperidone, sertindole, and ziprasidone, which have high affinities for the D2 receptor. How important fast dissociation is for even clozapine and quetiapine is unknown.

The pharmacology of sulpiride and amisulpride, which had a decisive influence in the CUtLASS study and has never been differentiated to my knowledge, involves highly selective and potent D2 and D3 receptor blockade (Caley and Weber, 1995; Scatton et al., 1997; NIMH Psychopharmacology Drug Screening Program website), yet sulpiride was the most extensively prescribed (showing clinician insight?) of the “first-generation” drugs (49 percent of patients in that arm), while amisulpride accounted for 12 percent of the atypical drugs in the “second-generation arm” in the CUtLASS study. Both drugs, while not free of EPS, meet the definition for atypicality (Rao et al., 1981; Gerlach, 1991) and have been so identified in important meta-analyses (see Rummel et al., 2003; Leucht, 2004). Regardless of whether one believes them to be typical or atypical, it would have been prudent for the CUtLASS investigators to exclude both agents rather than risk compromising the study, as I believe they did. Their inclusion is sufficient by itself to invalidate CUtLASS in my opinion, but there were at least two other major problems that affect the validity of that study. Thus, significantly greater proportions of patients who had failed prior antipsychotic drug treatments were randomized to the atypical arm—to receive either 5-HT2A/D2 antagonists or amisulpride—than to the sulpiride plus typical antipsychotic drug arm, a major flaw which was not only not corrected for, but was not mentioned anywhere in the article to my knowledge. Next, the use of long-acting medications, with their potential for better compliance, was permitted in the patients in the typical antipsychotic arm, further biasing the results for that group of agents, while there was no use of long-acting risperidone in the atypical arm. Thus, three major biases, all favoring the typical agents, were operative in the CUtLASS study. The atypicals hardly had a chance to do well, competing against themselves, with more treatment-resistant patients assigned to that group, and utilizing only oral medications.

Clozapine, for more than a decade beginning in 1975, was rejected for all but research and compassionate need purposes, because it caused a higher rate of agranulocytosis than the typical antipsychotics. We now know this occurs approximately 30 times more frequently with clozapine (~7.5/1000 vs. 0.25/1000). The US Clozapine Multicenter Trial, of which I was an author, found that clozapine was more effective than chlorpromazine for poor-outcome, treatment-resistant patients with schizophrenia (Kane et al., 1988). The conclusions of that study have been supported by many other studies, including CATIE, CUtLASS, and a recent study of treatment-resistant first-episode patients (Agid et al., 2007). Subsequent studies from my laboratory and others showed additional benefits for clozapine over other antipsychotic drugs for cognition and suicide in non-treatment-resistant as well as treatment-resistant patients (Hagger et al., 1993; Meltzer and McGurk, 1999; Woodward et al., 2005; 2007; Meltzer and Okayli, 1995; Meltzer et al., 2003), as well as quality of life (Meltzer et al., 1993). These studies included the type of patients in the CATIE and CUtLASS study. The result of the body of research from many laboratories all over the world establishing clozapine as the “gold standard” for treating schizophrenia was that the bar was set very high for the inevitable attempts to develop drugs with the efficacy of clozapine, but without its spectrum of serious, sometimes fatal side effects, which discouraged many patients and clinicians from even trying it then and now. There are, today, no more than 60,000-90,000 of the two million patients with schizophrenia who are receiving clozapine in the U.S.

Atypical antipsychotic drugs with pharmacology similar to clozapine
Publication of the serotonin-dopamine ratio hypothesis (Meltzer et al., 1989) introduced a simple means to identify drugs other than clozapine which had a low EPS potential and facilitated the development not only of aripiprazole, olanzapine, quetiapine, risperidone and ziprasidone, which are currently marketed, but also asenapine, iloperidone, laurasidone, perospirone, and sertindole (none of which are consistent with the “fast off” hypothesis), which are in advanced stages of development in the U.S., or already marketed in other countries. In addition, a host of other novel chemical structures with preclinical characteristics of atypical antipsychotic drugs consistent with the serotonin-dopamine ratio hypothesis have been reported on. The similarity of the pharmacologic profile of the marketed agents with that of clozapine may have contributed to the expectation that all drugs which had this pharmacologic profile would be superior to typical neuroleptics in all patients with schizophrenia (Lewis and Lieberman, 2008). The publication of a pivotal large, international study comparing risperidone with haloperidol and placebo, which did find some doses of risperidone to be superior to haloperidol, although only marginally so (Marder and Meibach,1994), was a likely contributor to this expectation. However, as pointed out by the authors in an accompanying editorial (Kane, 1994), it should have been noted that many of the patients in that study were possibly treatment-resistant. It is noteworthy that risperidone at a dose of 20 mg/day was one of the two risperidone doses that were reported to be more effective than haloperidol. This high dose might be expected to be more effective than haloperidol in treatment-resistant patients (see below).

The pivotal industry studies for quetiapine and ziprasidone did not claim superiority to haloperidol, except slightly greater benefits for negative symptoms, while those for olanzapine were mixed in this regard. The major pivotal study for olanzapine, as well as the overview of its pivotal trials, claimed no advantage of olanzapine over haloperidol for improvement in total psychopathology or positive symptoms (Beasley et al., 1996; Beasley et al., 1997). However, a multicenter trial conducted in countries outside the U.S. did find olanzapine superior to haloperidol (Tollefson et al., 1997). Geddes et al. (2000) provided the first meta-analysis comparing efficacy and tolerability of typical and atypical antipsychotic drugs and found no difference in efficacy between them, but fewer EPS with atypicals. Ironically, it was two academic-based meta-analytic reviews (Davis et al., 2003; Leucht et al., 2000), which concluded that the atypicals were superior to the typical agents in efficacy, that are frequently cited as the basis for the claim that the atypical agents are superior for the non-treatment-resistant patient. In a subsequent article, Davis et al. (2008) reported that the CATIE results were consistent with the Davis et al. (2003) meta-analysis in showing superiority for olanzapine, and that there was no evidence of industry bias of the studies they reviewed. Thus, CATIE and EUFEST are largely confirmatory of what industry and other studies had reported from the start: no difference in total psychopathology and positive symptom control between typical and atypical antipsychotic drugs other than clozapine. CATIE reported advantages for olanzapine, which we have suggested was due to the high dosage permitted for olanzapine and inclusion of a high proportion of treatment-resistant patients (Meltzer and Bobo, 2006), while CUtLASS reported trends for greater improvement in Quality of Life and symptom scores for their mixed typical/atypical antipsychotic-treated group, possibly for the reasons noted above. I suggest that it is possible to obtain further insight into the comparative efficacy of typical and atypical antipsychotic drugs by consideration of clozapine vs. typical antipsychotic drugs in non-treatment-resistant patients.

Is clozapine superior to typical antipsychotics in non-treatment-resistant patients?
The issue of whether clozapine itself is superior to the typical antipsychotic drugs, let alone whether the other atypical antipsychotic drugs are as well, for the non-treatment-resistant patients with schizophrenia, is one that has been explored and provides information relevant to the ongoing discussion about the merits of the two classes of drugs for treatment of the majority of patients with schizophrenia. In a trial with neuroleptic responsive patients, my colleagues and I found that clozapine had no advantages for psychopathology, compared to typical neuroleptic drugs, but that discontinuation from the treatment initially randomized to occurred significantly more frequently with the typical antipsychotic drugs ( Lee et al., 1994; 1999). (A more detailed report of the results of this study is in preparation because of its increased importance in light of some of the issues I address here). We reached this conclusion as the result of a study comparing clozapine and typical neuroleptic drugs in 85 patients with schizophrenia or schizoaffective disorder who were within a few years of the onset of psychotic symptoms, and who had been selected for being neuroleptic-responsive, These patients were randomly assigned to receive clozapine or typical neuroleptic drugs and evaluated over a two-year period. All ratings of psychopathology (baseline, 6 weeks, 3, 6, 12, and 24 months) were videotaped and rated by a single rater blind to treatment. The same, single but unblinded clinician treated all patients and made all decisions about drug continuation. Equivalent improvement in BPRS Total, Positive, or Negative symptoms, SANS and SAPS ratings CGI and Quality of Life measures was found. There were, however, significant differences in the number of dropouts. Of the 85 patients, nine (22.5 percent) assigned to clozapine and 19 (42.2 percent) to typical neuroleptics (χ2 = 3.73, p = .05) discontinued the typical antipsychotic drug treatment, for a variety of reasons. Significantly, two of the patients treated with typical neuroleptics developed tardive dyskinesia, and both were switched to clozapine, as were two patients who became resistant to typical neuroleptics during the course of treatment. There was no incentive for the patients, who were permitted to choose the typical agent they had had the best prior experience with, to discontinue the initially assigned typical neuroleptic, as the only other available treatment at the time was another typical antipsychotic drug.

The most important difference between clozapine and typical antipsychotic drugs in the Lee et al. study (Lee et al., 1994; 1999) was that treatment with clozapine improved some domains of cognition, particularly psychomotor speed and attention, as assessed by the Digit Symbol Substitution Test, and verbal fluency, as assessed by the Category Instance Generation and Controlled Word Association tests at six weeks, which was maintained throughout the one-year study. These improvements were not related to improvement in psychopathology or differences in EPS. We concluded that these results indicated that clozapine is superior to typical neuroleptics in improving specific types of cognitive function in some recent onset, neuroleptic-responsive schizophrenia, but not with regard to improvement in psychopathology. Carpenter et al. (1995) also called attention to the lack of advantage of clozapine over typical neuroleptic drugs in non-treatment-resistant patients, citing additional published literature to support their conclusion. The EUFEST results with atypical antipsychotic drugs other than clozapine, in first-episode patients, are in agreement with the results of Lee et al. and support the conclusion that expectation of advantage for symptom change should not be the reason for using an atypical antipsychotic drug in first-episode and non-treatment resistant-patients. But there are other reasons for preferring the atypicals as first-line treatment.

Is clozapine uniquely effective in treatment-resistant patients?
So if the typical and atypical drugs do not differ in their ability to reduce overall psychopathology in non-treatment-resistant and first-episode patients, are there any reasons to use atypicals, given their greater cost and metabolic side effects, in some cases, as first-line treatment? The International Psychopharmacology Algorithm Project (IPAP), a group of international experts including Jeff Lieberman and Wolfgang Fleishhacker, principal authors of CATIE and EUFEST, respectively, a project which I chaired, concluded that atypicals should be first-line for non-treatment-resistant schizophrenia (see www.IPAP.org). Contrast this with Rosenheck (2008), whose list of possible uses of atypicals is limited to patients with tardive dyskinesia, akathisia, or pseudo-parkinsonism. Rosenheck et al. (2008) recommends that clozapine is first-line in treatment-resistant patients. But is it truly superior to the other serotonin-antagonists in this regard?

Recently, my colleagues and I reported that olanzapine is equivalent to clozapine in improving psychopathology and cognition for treatment-resistant schizophrenia, when the doses of both are comparable: i.e., two to four times the doses needed for non-treatment-resistant patients (Meltzer et al., 2008). (It is generally not appreciated that the average dose of clozapine used for treatment-resistant patients, 300-700 mg/day, is two to three times the dose needed for non-treatment-resistant patients, i.e., 100-300 mg/day). Treatment for up to six months was required for the majority of treatment-resistant patients to respond to olanzapine, mean dose 35 mg/day, or clozapine, mean dose 550 mg/day (Meltzer et al., 2008). This small N study, though consistent with many uncontrolled studies, and the results of CATIE, where olanzapine was used at doses as high as 30 mg/day, needs to be replicated and extended. The benefits of high doses and prolonged monotherapy of clozapine or olanzapine for treatment-resistant patients may also hold for other serotonin-dopamine antagonists that are direct-acting dopamine antagonists, including quetiapine (1200-2000 mg/day), risperidone (12-20 mg/day), and ziprasidone (>160-640 mg/day) (Pierre et al., 2005; Deutschmann and Deutschmann, 2007). It does not hold for high doses of typical antipsychotic drugs (Kane et al., 1988). The recent report that standard doses of aripiprazole, a partial agonist with 5-HT2A antagonist and 5-HT1A agonist properties, is effective in treatment-resistant schizophrenia (Kane et al., 2007) needs to be confirmed, and, if valid, examined as to mechanism.

Are there reasons to use atypical antipsychotic drugs in non-treatment-resistant patients as first-line treatment?
Tardive dyskinesia
The consensus has been that about 30 percent of patients with schizophrenia are treatment-resistant. Clearly, clozapine itself, or possibly high doses of an atypical agent related to clozapine, is the treatment of choice for such patients. Should they, at lower doses, also be the first-line treatment for the other 70 percent, or, should they be second-line treatments, as some of the CATIE (Rosenheck et al., 2008; Lewis and Lieberman, 2008) and CUtLASS (Jones et al., 2006) authors sometimes seem to suggest. Clearly, reducing the risk for tardive dyskinesia is an important reason, as advocated by Gardos (1999), with partial concurrence by Lieberman (2007). I do not agree with those who minimize this risk—most patients with schizophrenia need to take antipsychotic drugs on a lifetime basis. Those who advocate the typical drugs as the ethically appropriate first-line treatment realize they must minimize the risk of TD to argue for using these drugs routinely (Rosenheck, 2008; Rosenheck and Lieberman, 2007). At least 20 percent of neuroleptic-treated patients are afflicted with tardive dyskinesia, and roughly 4-5 percent are expected to develop tardive dyskinesia with each year of neuroleptic treatment (Kane et al., 1988). Margolese et al. (2005), in a recent comprehensive review of tardive dyskinesia, which took into account dosage issues, age, and sex as risk factors, concluded that there is significantly less risk of developing tardive dyskinesia with atypical antipsychotic drugs. While the metabolic side effects of some of the atypicals—olanzapine and clozapine, in particular—must be given every consideration, there are serotonin-dopamine antagonists, e.g., amisulpride, aripiprazole, risperidone, and ziprasidone, which have mild adverse effects that are in the same range as those produced by typical neuroleptic drugs. Olanzapine and clozapine can then be reserved for those patients who do not respond to the drugs with better metabolic profiles, until and if it is shown that these other atypical antipsychotics are effective and safe at higher doses in treatment-resistant patients.

Cognitive improvement
The second major reason for continuing to favor the atypicals as a class is that cognitive improvement is more likely with the atypical antipsychotics than the typical antipsychotics. This is not the place to argue this hotly debated point, which is supported by mean changes in cognition favoring the atypicals (Woodward et al., 2005; 2007). The cognition data from CATIE (Keefe et al., 2007) did not support advantages for the atypical agents, but there are many unusual features of that study, which is still undergoing intensive reexamination (Harvey P, personal communication). Imaging studies show better brain function during cognitive tasks and positive changes in brain grey and white matter in patients receiving atypical versus typical antipsychotic drugs (e.g., Surguladze et al., 2007). Additional studies of this kind are needed. There is already extensive and rapidly growing preclinical evidence which shows that the atypical, but not the typical, antipsychotic drugs can reverse cognitive dysfunction produced by chronic NMDA receptor antagonists, e.g., PCP and MK-801, in rodents (Grayson et al., 2007), a model of cognitive dysfunction in schizophrenia that has many supporters in the basic neuroscience community. This may be related to their ability to enhance dopamine and acetylcholine release in the cortex (Ichikawa et al, 2002, Kuroki et al., 1999). What is evident to those familiar with this literature is that if these highly replicated preclinical findings have no clinical relevance, than there is an enormous waste of effort ongoing in the many academic and industry laboratories worldwide which use these surrogate measures as the basis for developing new drugs to improve or further improve cognition in schizophrenia. There is, I believe, too great a readiness to dismiss the evidence in support of the cognitive advantages of the atypical over the typical antipsychotic drugs for a significant proportion of patients, advantages which lead to beneficial changes in function in some.

In summary, the EUFEST study provides additional evidence that typical and atypical antipsychotic drugs do not differ in their ability to improve psychopathology in non-treatment-resistant patients, something we have known for some time, in my view. The EUFEST study also adds to the evidence that despite this, patients may remain on treatment with atypical agents for longer periods than with typical antipsychotics, including first-episode patients who are more prone to stop medication than more chronic patients. However, the take-home message is not that these drugs should become second-line (risperidone, clozapine), third-line (aripiprazole, quetiapine, ziprasidone), or fourth-line (olanzapine) therapy because of their supposed lack of cost effectiveness, as advocated by Rosenheck (2008) and Rosenheck et al. (2008). Rather, I believe it is the need for further research about the differences between these classes of drugs with regard to cognition and effects upon brain structure and function, in better described and circumscribed populations, using the most rigorous kind of experimental design, and more complete acknowledgement of the typical antipsychotics' greater risk to cause tardive dyskinesia.

References

Agid O, Remington G, Kapur S, Arenovich T, Zipursky RB (2007). Early use of clozapine for poorly responding first-episode psychosis. J Clin Psychopharmacol. 2007 27(4):369-73. Abstract

Caley CF, Weber SS. Sulpiride: an antipsychotic with selective dopaminergic antagonist properties. Ann Pharmacother. 1995; 29(2):152-60. Abstract

Carpenter, WT, Conley, RR, Buchanan, RW, Breier, A and Tamminga, CA (1995) Patient Response and Resource Management: Another View of Clozapine Treatment of Schizophrenia. Amer J Psychiatry 152: 827-832. Abstract

Deutschman DA, Deutschman DH (2007). High-dose ziprasidone in treatment-resistant schizophrenia and affective spectrum disorders: a case series. J Clin Psychopharmacol. 27:513-4. Abstract

Gardos, G (1999). Managing antipsychotic-induced tardive dyskinesia. Drug Saf.;20(2):187-93. Abstract

Geddes J, Freemantle N, Harrison P, Bebbington P (2000). Atypical antipsychotics in the treatment of schizophrenia: systematic overview and meta-regression analysis. BMJ. 321(7273):1371-6. Abstract

Gerlach J. (1991) New antipsychotics: classification, efficacy, and adverse effects Schizophr Bull. 17(2):289-309. Abstract

Grayson B, Idris NF, Neill JC (2007).. Atypical antipsychotics attenuate a sub-chronic PCP-induced cognitive deficit in the novel object recognition task in the rat. Behav Brain Res. 184(1):31-8. Abstract

Hagger C, Buckley P, Kenny JT, Friedman L, Ubogy D, Meltzer HY (1993). Improvement in cognitive functions and psychiatric symptoms in treatment- refractory schizophrenic patients receiving clozapine. Biol Psychiatry 34:702-712. Abstract

Hogarty GE, Schooler NR, Baker RW.(1997) Efficacy versus Effectiveness. Psychiatry Serv. 48: 1107. Abstract

Ichikawa J, Dai J, O’Laughlin IA, Fowler W, Meltzer HY (2002). Atypical, but not typical, antipsychotic drugs selectively increase acetylcholine release in rat medial prefrontal cortex, nucleus accumbens and striatum. Neuropsychopharmacol 26:325-39. Abstract

Jones PB, Barnes TR, Davies L, Dunn G, Lloyd H, Hayhurst KP, Murray RM, Markwick A, Lewis SW.(2006) Randomized controlled trial of the effect on Quality of Life of second- vs. first-generation antipsychotic drugs in schizophrenia: Cost Utility of the Latest Antipsychotic Drugs in Schizophrenia Study (CUtLASS 1).Arch Gen Psychiatry. 63(10):1079-87. Abstract

Kahn RS, Fleischhacker WW, Boter H, Davidson M, Vergouwe Y, Keet IP, Gheorghe MD, Rybakowski JK, Galderisi S, Libiger J, Hummer M, Dollfus S, López-Ibor JJ, Hranov LG, Gaebel W, Peuskens J, Lindefors N, Riecher-Rössler A, Grobbee DE; EUFEST study group (2008). Effectiveness of antipsychotic drugs in first-episode schizophrenia and schizophreniform disorder: an open randomised clinical trial. Lancet. 371(9618):1085-97. Abstract

Kane, JM (1994) Risperidone Am J Psychiatry 151 : 802-803, 1994. Abstract

Kane J, Honigfeld G, Singer J, Meltzer HY, the Clozaril Collaborative Study Group (1988): Clozapine for the treatment-resistant schizophrenic: a double-blind comparison with chlorpromazine/benztropine. Arch Gen Psychiatry 45:789-796.incidence and risk factors. J Clin Psychopharmacol. 8(Aug suppl): 52S-56S. Abstract

Kane JM, Meltzer HY, Carson WH, McQuade RD, Marcus RN, Sanchez R (2007) Aripiprazole for treatment-resistant schizophrenia - results of a multicenter, randomized, double-blind, comparison study versus perphenazine. J Clin Psychiatry 68:213-23. Abstract

Kapur, S., and P. Seeman (2000). Antipsychotic agents differ in how fast they come off the dopamine D2 receptors. Implications for atypical antipsychotic action. J Psychiatry Neurosci, 25, 161-6. Abstract

Keefe RSE, Bilder RM, Davis SM, Harvey PD, Palmer BW, Gold JM, Meltzer HY, Green MF, Capuano G, Stroup TS, McEvoy JP, Swartz MS, Rosenheck RA, Perkins DO, Davis CE, Hsiao JK, Lieberman JA, for the CATIE investigators and the neurocognitive working group (2007). Neurocognitive effects of antipsychotic medications in patients with chronic schizophrenia in the CATIE trial. Arch Gen Psychiatry 64:633-47. Abstract

Kuroki T, Meltzer HY, Ichikawa J.(1999) Effects of antipsychotic drugs on extracellular dopamine levels in rat medial prefrontal cortex and nucleus accumbens. J Pharmacol Exp Thera 288:774-81. Abstract

Lee MA, Jayathilake K, Meltzer HY (1999): A comparison of the effect of clozapine with typical neuroleptics on cognitive function in neuroleptic-responsive schizophrenia. Schizophr Res 37: 1-11. Abstract

Lee MA, Thompson P, Meltzer HY (1994). Effects of clozapine on cognitive function in schizophrenia. J Clin Psychiatry 55(Supplement B): 82-87. Abstract

Leucht S; (2004) Amisulpride a selective dopamine antagonist and atypical antipsychotic: results a meta-analysis of randomized controlled trials. Int. J Neuropsychopharm Suppl 1: S15-20. Abstract

Leucht S, Wahlbeck K, Hamann J, Kissling W.(2000) New generation antipsychotics versus low-potency conventional antipsychotics: a systematic review and meta-analysis. Lancet.361(9369):1581-9. Abstract

Lewis S and Lieberman, JA (2008) CATIE and CUtLASS: can we handle the truth? Br J Psychiatry. 2008 192(3):161-3. Abstract

Lieberman JA (2007) An Interview with Jeffrey A. Liebverman, Tardive Dyskinesia CNS Spectr. 12 (10) 747-750. Abstract

Lieberman JA, Stroup TS, McEvoy JP, Swartz MS, Rosenheck RA, Perkins DO, Keefe RS, Davis SM, Davis CE, Lebowitz BD, Severe J, Hsiao JK; Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) Investigators. (2005) Effectiveness of antipsychotic drugs in patients with chronic schizophrenia. N Engl J Med 22;353(12):1209-23. Abstract

Margolese HC. Chouinard G. Kolivakis TT. Beauclair L. Miller R. Annable L. Tardive dyskinesia in the era of typical and atypical antipsychotics. Part 2: Incidence and management strategies in patients with schizophrenia. Canadian Journal of Psychiatry. 50(11):703-14, 2005. Abstract

Marder SR , Meibach RC (1994) Risperidone in the treatment of schizophrenia Am J Psychiatry, 151: 825-835. Abstract

McEvoy JP, Lieberman JA, Stroup TS, Davis SM, Meltzer HY, Rosenheck RA, Swartz MS, Perkins DO, Keefe RS, Davis CE, Severe J, Hsiao JK; CATIE Investigators (2006). Effectiveness of clozapine versus olanzapine, quetiapine, and risperidone in patients with chronic schizophrenia who did not respond to prior atypical antipsychotic treatment. Am J Psychiatry. 163(4):600-10. Abstract

Meltzer H, Alphs L, Green A. Altamura A, Anand R, Bertoldi A, Bourgeois M, Chouinard G, Islam M, Kane J, Krishnan R, Lindenmayer J-P, Potkin S (2003): International Suicide Prevention Trial (InterSePT): reduced suicidality in schizophrenia with clozapine treatment Arch Genl Psychiatry 60:735, 2003.

Meltzer HY, Bobo WV (2006). Interpreting the efficacy findings in the CATIE study: what clinicians should know. CNS Spectr11: suppl 7: 14-24. Abstract

Meltzer HY, Bobo WV, Roy A, Jayathilake K, Chen Y, Ertugrul A, Anil Yağcioğlu AE, Small JG (2008) A randomized, double-blind comparison of clozapine and high-dose olanzapine in treatment-resistant patients with schizophrenia. J Clin Psychiatry. 69):274-85. Abstract

Meltzer HY, Burnett S, Bastani B, Ramirez LF (1990). Effect of six months of clozapine treatment on the quality of life of chronic schizophrenic patients. Hosp Community Psychiatry 41:892 97. Abstract

Meltzer HY, Li Z, Kaneda Y, Ichikawa J (2003) Serotonin receptors: Their key role in drugs to treat schizophrenia. Prog Neuropsychopharmacol Biol Psychiatry 27:1159-72. Abstract

Meltzer HY, Matsubara S, Lee J C. (1989) Classification of typical and atypical antipsychotic drugs on the basis of dopamine D 1, D 2 and serotonin2 pKi values. J Pharmacol Exp Thera 251:238 46, 1989. Abstract

Meltzer HY, Okayli G. The reduction of suicidality during clozapine treatment in neuroleptic-resistant schizophrenia: impact on risk-benefit assessment. American Journal of Psychiatry 152:183-90, 1995. Abstract

Pierre JM, Wirshing DA, Wirshing WC, Rivard JM, Marks R, Mendenhall J, Sheppard K, Saunders DG (2005).High-dose quetiapine in treatment refractory schizophrenia. Schizophr Res.;73(2-3):373-5. Abstract

Rao VA, Bailey J, Bishop M, Coppen A (1981).. A clinical and pharmacodynamic evaluation of sulpiride. Psychopharmacology (Berl). 1981;73(1):77-80. Abstract

Rosenheck RA (2008): Pharmacotherapy of first episode schizophrenia. Lancet. 371(9618): 1048-1049. Abstract

Rosenheck RA, Leslie DL, Busch S, Rofman ES, Sernyak M. (2008) Rethinking antipsychotic formulary policy.Schizophr Bull. 34(2):375-80. Abstract

Rosenheck RA, Lieberman JA (2007). Cost-effectiveness measures, methods, and policy implications from the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) for schizophrenia. J Clin Psychiatry. 2007 68(2):e05. Abstract

Rummel C, Hamann J, Kissling W, Leucht S. New generation antipsychotics for first episode schizophrenia. Cochrane Database Syst Rev. 2003;(4):CD004410. Abstract

Scatton B, Claustre Y, Cudennec A, Oblin A, Perrault G, Sanger DJ, Schoemaker H. Amisulpride: from animal pharmacology to therapeutic action. Int Clin Psychopharmacol. 1997 ;12 Suppl 2:S29-36. Abstract

Surguladze SA, Chu EM, Evans A, Anilkumar AP, Patel MX, Timehin C, David AS (2007).The effect of long-acting risperidone on working memory in schizophrenia: a functional magnetic resonance imaging study. J Clin Psychopharmacol. 27(6):560-70. Abstract

Tollefson GD, Beasley CM Jr, Tran PV, Street JS, Krueger JA, Tamura RN, Graffeo KA, Thieme ME (1997). Olanzapine versus haloperidol in the treatment of schizophrenia and schizoaffective and schizophreniform disorders: results of an international collaborative trial. Am J Psychiatry;154(4):457-65. Abstract

Wells, KB: Treatment Research at the Crossroads; The Scientific Interface of Clinical Trials and Effectiveness Research (1999). Amer J Psychiatry 156:5-10. Abstract

Woodward ND, Purdon SE, Meltzer HY, Zald DH (2005): A meta-analysis of neuropsychological change to clozapine, olanzapine, quetiapine, and risperidone in schizophrenia. Int J Neuropsychopharmacol 8:457-72 2005. Abstract

Woodward ND, Purdon E Scot, Meltzer HY, Zald H (2007). A meta-analysis of cognitive change with haloperidol in clinical trials of atypical antipsychotics -dose effects and comparison to practice effects. Schiz Res 89:211-24. Abstract

www. IPAP.org; The International Psychopharmacology Algorithm Project

In our recently published systematic review of randomized effectiveness trials on SGAs (Johnsen and Jorgensen, 2008), the main findings were that chronically ill patients treated with olanzapine had longer time until treatment discontinuation and/or better drug compliance compared to those treated with the other SGAs, as well as the FGAs in those studies that had an FGA arm. The SGAs and FGAs did not differ on efficacy measures, and there were surprisingly few differences among SGAs on tolerability outcomes. The most consistent tolerability difference among the SGAs was in the area of metabolic adverse effects, where olanzapine-treated patients had more weight gain and adverse influence on cholesterol and triglyceride levels. The most pronounced difference between FGAs and SGAs on tolerability outcomes was that the FGAs were associated with significantly more extrapyramidal side effects (EPS) or discontinuation owing to EPS in the majority of studies. We noticed that this finding was also replicated in the EUFEST.

In summary,...  Read more

In our recently published systematic review of randomized effectiveness trials on SGAs (Johnsen and Jorgensen, 2008), the main findings were that chronically ill patients treated with olanzapine had longer time until treatment discontinuation and/or better drug compliance compared to those treated with the other SGAs, as well as the FGAs in those studies that had an FGA arm. The SGAs and FGAs did not differ on efficacy measures, and there were surprisingly few differences among SGAs on tolerability outcomes. The most consistent tolerability difference among the SGAs was in the area of metabolic adverse effects, where olanzapine-treated patients had more weight gain and adverse influence on cholesterol and triglyceride levels. The most pronounced difference between FGAs and SGAs on tolerability outcomes was that the FGAs were associated with significantly more extrapyramidal side effects (EPS) or discontinuation owing to EPS in the majority of studies. We noticed that this finding was also replicated in the EUFEST.

In summary, we believe the evidence thus far indicates superiority for olanzapine on the effectiveness outcome of time to discontinuation in patients with chronic schizophrenia, but olanzapine-treated patients also have more weight gain and metabolic side effects, which means that this drug does not necessarily have the most beneficial ratio of numbers needed to treat (NNT) and numbers needed to harm (NNH). The FGAs have not demonstrated superiority over SGAs in effectiveness, efficacy, or tolerability measures, and are associated with more EPS in a majority of studies, indicating a less favorable NNT/NHH ratio compared to the SGAs on this outcome measure.

As a closing remark, we believe that due to very different pharmacological properties, results from studies with a single drug FGA arm cannot be inferred to the collected FGA group. In reality only haloperidol, fluphenazine, and perphenazine have been evaluated versus SGAs in the effectiveness studies thus far, and conclusions can only be drawn for these FGAs.

References:

Johnsen E, Jorgensen HA. Effectiveness of second generation antipsychotics: A systematic review of randomized trials. BMC Psychiatry. 2008 Apr 25;8(1):31. Abstract

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...  Read more

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

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).

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...  Read more

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

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...  Read more

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.

This is a striking finding, but it is difficult to know what motivated the study or how to interpret the results. The study is very small and was probably of an exploratory rather than hypothesis-testing nature, making replication doubly important. It is also unclear what sort of biological changes may underlie the apparent loss of volume in the putamen—as the authors say, it is unlikely to be cell damage or vascular. A reversible change over such a short period of time suggests possible changes in cellular fluid balance. Regardless, these results on exposure to IV drug in young healthy men may bear no relation to the effects of the drug in the routine and usually oral treatment of patients with schizophrenia and related conditions.

View all comments by Stephen Lawrie

I fully agree with the comment made by Stephen Lawrie on the paper of the Meyer-Lindenberg group (Tost et al., 2010) published in Nature Neursocience. In particular, I agree with his suggestion that cellular fluid balance may account for the haloperidol neuroplasticity finding in the striatum. This is because it is well known among psychiatrists with some pharmacology training that haloperidol has an effect on fluid balance. Canary stories (to borrow Victoria Wilcox's metaphor) with retrospective analysis of seven (!!) healthy subjects and without prior hypothesis that would have helped to account for potentially confounding variables (e.g., body fluid, electrolyte parameters, hormonal levels, etc.) in the study design should not be published. What we need in schizophrenia research are high-flying eagles—not canaries in golden cages (high-impact journals).

References:

Tost H, Braus DF, Hakimi S, Ruf M, Vollmert C, Hohn F, Meyer-Lindenberg A. Acute D2 receptor blockade induces rapid, reversible remodeling in human cortical-striatal circuits. Nat Neurosci. 2010 Aug; 13(8):920-2. Abstract

View all comments by Georg Winterer