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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

View all comments by Patricia Estani

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

View all comments by SuSanne Henriksen

I believe that the results of the CATIE study indirectly support the core principle of treatment, that is, it should be comprehensive, using a biopsychosocial approach. The large number of dropouts is but one example of the limitations of relying on antipsychotic medication alone in the treatment of schizophrenia. We know that psychosocial treatments enhance compliance and overall outcome. See, for example, the study that my colleagues and I conducted on relapse prevention in schizophrenia, which had a small number of dropouts over 18 months (Herz et al., 2000).

References:
Herz MI, Lamberti JS, Mintz J, Scott R, O'Dell SP, McCartan L, Nix G. A program for relapse prevention in schizophrenia: a controlled study. Arch Gen Psychiatry. 2000 Mar;57(3):277-83. Abstract

View all comments by Marvin Herz

Evaluating the effect of adding risperidone to clozapine is an example of clinical practice getting out ahead of evidence and theory. It has become common practice, so we need to know the answer. The combination surely will add adverse effects, but what hypothesis supports the notion of increased efficacy? Clozapine has superior efficacy for psychosis in treatment-resistant patients and low occupancy (fast on/off) at the dopamine 2 receptor. Is this important for diminished motor adverse effects or for superior efficacy? If so, adding risperidone will terminate this advantage. I think this may be the case for adverse effects, but we tested the partial occupancy hypothesis and the D2/5HT ratio hypothesis for clozapine (Carpenter et al., 1998) and found that full D2 occupancy did not interfere with clozapine superiority. But in this analysis, we found no evidence that being on a drug with high affinity for the D2 receptor combined with clozapine gave any efficacy advantage and recommended against the...  Read more

Evaluating the effect of adding risperidone to clozapine is an example of clinical practice getting out ahead of evidence and theory. It has become common practice, so we need to know the answer. The combination surely will add adverse effects, but what hypothesis supports the notion of increased efficacy? Clozapine has superior efficacy for psychosis in treatment-resistant patients and low occupancy (fast on/off) at the dopamine 2 receptor. Is this important for diminished motor adverse effects or for superior efficacy? If so, adding risperidone will terminate this advantage. I think this may be the case for adverse effects, but we tested the partial occupancy hypothesis and the D2/5HT ratio hypothesis for clozapine (Carpenter et al., 1998) and found that full D2 occupancy did not interfere with clozapine superiority. But in this analysis, we found no evidence that being on a drug with high affinity for the D2 receptor combined with clozapine gave any efficacy advantage and recommended against the practice.

To reason in the other direction, it is clear that risperidone has its best benefit/adverse effect profile at low doses. Combining risperidone with another antipsychotic could move that profile in an unfavorable direction.

But clinicians are stuck. In most patients, no matter what the pharmacotherapy, response is incomplete. It is understandable that doctors try “harder,” and increasing dose and polypharmacy seem the only way. When only first-generation drugs were available, this routinely lead to excessive doses with more adverse effects, poorer adherence, and no evidence for better efficacy. Are we now repeating this mistake with polypharmacy? This clozapine/risperidone report is well done, and the failure to observe an advantage for the combination should be a decisive influence on this common practice.

References:

Carpenter WT, Zito JM, Vitrai J, Volavka J. Hypothesis testing: is clozapine’s superior efficacy dependent on moderate D2 receptor occupancy? Biol Psychiatry. 1998 Jan 15;43(2):79-83. Abstract

The paper by Honer et al., which reported a lack of benefit from augmentation of clozapine by risperidone in patients with schizophrenia who were partial responders to clozapine, is consistent with our previous report which had the same design but was of somewhat shorter duration (Anil Yagcioglu et al., 2005), with the exception that we found that improvement in psychopathology after the addition of placebo was superior to risperidone. A second paper from our double-blind, randomized trial has been submitted which showed that improvement in cognition with placebo was often, but not always, greater than that with risperidone as well. Honer et al. explicitly stated that their results were consistent with ours. We proposed, based upon my hypothesis that more potent blockade of 5-HT2A than D2 receptors contributed to the beneficial effects of...  Read more

The paper by Honer et al., which reported a lack of benefit from augmentation of clozapine by risperidone in patients with schizophrenia who were partial responders to clozapine, is consistent with our previous report which had the same design but was of somewhat shorter duration (Anil Yagcioglu et al., 2005), with the exception that we found that improvement in psychopathology after the addition of placebo was superior to risperidone. A second paper from our double-blind, randomized trial has been submitted which showed that improvement in cognition with placebo was often, but not always, greater than that with risperidone as well. Honer et al. explicitly stated that their results were consistent with ours. We proposed, based upon my hypothesis that more potent blockade of 5-HT2A than D2 receptors contributed to the beneficial effects of clozapine (Meltzer et al., 1989), that the reason for the superior response to placebo in our trial was that risperidone, by adding D2 receptor blockade to clozapine, interfered with the beneficial effects of being part of a clinical study with its increased clinical contact and supportive nature. The results of our study and that of Honer contrast with a third study (Josaissen et al., 2005), which found risperidone addition improved psychopathology more than placebo.

The New England Journal of Medicine editorial from John M. Davis is a very disappointing commentary on this important confirmation of our research in a key area because it has a number of serious errors in fact and gratuitous criticism of industry-funded studies which, at least in this case, are easily refutable. Davis stated that our study and that of Josiassen et al. were industry-funded, as contrasted with the Honer et al. study, which was funded by the Stanley Medical Research Foundation, of which Davis has been a long-time adviser. The implication is clear that the industry-funded studies are biased. Davis then continues his effort to raise doubt about industry-funded studies by contrasting the results of his several meta-analyses of industry-funded clinical trials, which found advantages of atypical over typical antipsychotic drugs, with that of the NIMH-funded CATIE study, which did not (Lieberman et al., 2005).

In fact, our study was clearly marked as having been funded by the Stanley Medical Research Foundation, the William K. Warren Medical Research Foundation, and the Janssen Pharmaceutical Company, manufacturer of risperidone. The Josaissen study was industry-supported. Instead of evaluating the three studies for their merits, or even reading the paper carefully (in the case of our study), Davis would have us doubt their validity because they were industry-supported. This is unacceptable in my view. His call for more industry and non-industry studies is a smoke screen for his real message, that industry-funded studies are biased. I and my coauthors can vouch for the fact that none of the three funders of our pioneering research exerted the least influence on the design, performance, or write-up of our work. Janssen was informed of the results of the study as called for in our contract and made no effort, nor should it have, to restrain or modify the message. This, in fact, has been consistent with my entire experience with major pharma and biotech companies. If Professor Davis has had more negative experiences with industry in this regard, he should make them public. As it is, he offers incorrect information to raise doubts about industry-funded research at a time when it is already under attack in the area of clinical trials and when continued investment on its part in clinical research in psychiatry is urgently needed, in my view. What we need is more thoughtful consideration of the merits and shortcomings of all clinical trials regardless of funding source. The clinical investigators and funder of the CATIE trial are now finding that merely because their study was government-funded, it is not being taken by many as the last word in informing us about antipsychotic drug treatment in schizophrenia.

References:

Honer WG, Thornton AE, Chen EY, Chan RC, Wong JO, Bergmann A, Falkai P, Pomarol-Clotet E, McKenna PJ, Stip E, Williams R, MacEwan GW, Wasan K, Procyshyn R; Clozapine and Risperidone Enhancement (CARE) Study Group. Clozapine alone versus clozapine and risperidone with refractory schizophrenia. N Engl J Med 2006;354:518-20. Abstract

Anil Yagcioglu AE, Kivircik Akdede BB, Turgut TI, Tumuklu M, Yazici MK, Alptekin K, Ertugrul A, Jayathilake K, Gogus A, Tunca Z, Meltzer HY 2005. A double-blind controlled study of adjunctive treatment with risperidone in schizophrenic patients partially responsive to clozapine: efficacy and safety. J Clin Psychiatry 2005; 66:63-72. Abstract

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

Davis JM. The choice of drugs for schizophrenia. N Engl J Med 2006;354: 518-20. Abstract

Josiassen RC, Joseph A, Kohegyi E, Stokes S, Dadvand M, Paing WW, Shaughnessy RA. Clozapine augmented with risperidone in the treatment of schizophrenia: a randomized, double-blind, placebo-controlled trial. Am J Psychiatry. 2005 Jan;162(1):130-6. 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. Effectiveness of antipsychotic drugs in patients with chronic schizophrenia. N Engl J Med. 2005 Sep 22;353(12):1209-23. Epub 2005 Sep 19. Abstract

Our paper (Honer et al., 2006) and the associated editorial by Dr. John M. Davis (Davis, 2006) concerning augmentation of risperidone with clozapine drew some commentary in this Forum, and recently, three letters to the Editor of the New England Journal of Medicine. The April 27 issue of the NEJM also includes our response, and a response from Dr. Davis. The first of the letters, from Grass and colleagues (Grass et al., 2006) concerns the broader issues of the confidence with which we can conclude that risperidone augmentation of clozapine offers no benefit, and the degree to which the results of this approach to antipsychotic polypharmacy can be generalized to other combinations of antipsychotic drugs. Basically, our conclusion in the paper is that the difference between risperidone and placebo augmentation of clozapine is unlikely to be...  Read more

Our paper (Honer et al., 2006) and the associated editorial by Dr. John M. Davis (Davis, 2006) concerning augmentation of risperidone with clozapine drew some commentary in this Forum, and recently, three letters to the Editor of the New England Journal of Medicine. The April 27 issue of the NEJM also includes our response, and a response from Dr. Davis. The first of the letters, from Grass and colleagues (Grass et al., 2006) concerns the broader issues of the confidence with which we can conclude that risperidone augmentation of clozapine offers no benefit, and the degree to which the results of this approach to antipsychotic polypharmacy can be generalized to other combinations of antipsychotic drugs. Basically, our conclusion in the paper is that the difference between risperidone and placebo augmentation of clozapine is unlikely to be associated with a moderate-to-large effect size, such as would be observed with switching a group of patients from typical antipsychotics to clozapine. Smaller differences cannot be excluded. However, as clarified by Dr. Davis in the recent issue, one of the two previous, smaller placebo-controlled studies showed relative benefit for placebo versus risperidone augmentation, at least for positive symptoms (Anil Yagcioglu et al., 2005). The NEJM letters from Meltzer and colleagues (Meltzer et al., 2006) and from Gerson (Gerson, 2006) concern the Davis editorial which accompanied our paper. Dr. Meltzer’s concerns about the editorial are also presented in his commentary in the Forum, and Dr. Davis has graciously apologized for his errors in the current response in the Journal, and clarified that monitoring of white cell counts provides a safe approach for patients taking this medication.

We still face the broader issue of antipsychotic polypharmacy, which appears reasonably prevalent despite a very small evidence base. Our trial was initially designed with the hope that risperidone, being a high-affinity dopamine D2 antagonist, would be an optimum drug to augment the low D2 affinity of clozapine. This was not the case, and strictly speaking our results cannot be generalized beyond this combination of medications. Much larger studies would be needed if a non-inferiority design were to be used. For example, subjects currently treated with antipsychotic polypharmacy could be randomized to continuation or to substitution with placebo for all but one antipsychotic drug. A preliminary, uncontrolled study indicated this strategy was successful in most, but not all cases (Suzuki et al., 2004). Perhaps new findings concerning the consequences of antipsychotic polypharmacy for cognitive function (Kawai et al., 2006) and the economic costs (Stahl and Grady, 2006) will also contribute to improving evidence-based practice.

References:

Anil Yagcioglu AE, Kivircik Akdede BB, Turgut TI, Tumuklu M, Yazici MK, Alptekin K, et al. A double-blind controlled study of adjunctive treatment with risperidone in schizophrenic patients partially responsive to clozapine: efficacy and safety. J Clin Psychiatry 2005; 66: 63-72. Abstract

Davis JM. The choice of drugs for schizophrenia. N Engl J Med. 2006 Feb 2;354(5):518-20. Abstract

Gerson SL. Clozapine alone versus clozapine and risperidone for refractory schizophrenia. N Engl J Med. 2006 Apr 27;354(17):1846-8; author reply 1846-8. Abstract

Grass G, Hellmich M, Leweke FM. Clozapine alone versus clozapine and risperidone for refractory schizophrenia. N Engl J Med. 2006 Apr 27;354(17):1846-8; author reply 1846-8. Abstract

Honer WG, Thornton AE, Chen EY, Chan RC, Wong JO, Bergmann A, Falkai P, Pomarol-Clotet E, McKenna PJ, Stip E, Williams R, Macewan GW, Wasan K, Procyshyn R, . Clozapine alone versus clozapine and risperidone with refractory schizophrenia. N Engl J Med. 2006 Feb 2;354(5):472-82. Abstract

Kawai N, Yamakawa Y, Baba A, Nemoto K, Tachikawa H, Hori T, et al. High-dose of multiple antipsychotics and cognitive function in schizophrenia: the effect of dose-reduction. Prog Neuropsychopharmacol Biol Psychiatry 2006; (in press).

Meltzer HY, Yagcioglu AE, Akdede BB. Clozapine alone versus clozapine and risperidone for refractory schizophrenia. N Engl J Med. 2006 Apr 27;354(17):1846-8; author reply 1846-8. Abstract

Stahl SM, Grady MM. High-cost use of second-generation antipsychotics under California's Medicaid program. Psychiatric Serv 2006; 57: 127-129. Abstract

Suzuki T, Uchida H, Tanaka KF, Nomura K, Takano H, Tanabe A, et al. Revising polypharmacy to a single antipsychotic regimen for patients with chronic schizophrenia. Int J Neuropsychopharmacol 2004; 7: 133-142. Abstract

In light of the limitations of first- and second-generation antipsychotics and other pharmacological agents for the treatment of cognitive impairments in schizophrenia, the demonstration of an acute benefit of DMXB-A for cognitive performance and sensory gating is of considerable potential interest. Patients with schizophrenia are characterized by a broad range of cognitive impairments (Nuechterlein et al., 2004). These impairments have been shown to be a major determinant of poor functional outcome (Green et al., 2004). The NIMH has made a substantial commitment to facilitate the development of new pharmacological treatments for cognitive impairments through their funding of the Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) and Treatment Units for Research on Neurocognition and Schizophrenia   Read more

In light of the limitations of first- and second-generation antipsychotics and other pharmacological agents for the treatment of cognitive impairments in schizophrenia, the demonstration of an acute benefit of DMXB-A for cognitive performance and sensory gating is of considerable potential interest. Patients with schizophrenia are characterized by a broad range of cognitive impairments (Nuechterlein et al., 2004). These impairments have been shown to be a major determinant of poor functional outcome (Green et al., 2004). The NIMH has made a substantial commitment to facilitate the development of new pharmacological treatments for cognitive impairments through their funding of the Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) and Treatment Units for Research on Neurocognition and Schizophrenia (TURNS) initiatives. The MATRICS process selected the α7 nicotinic receptor as one of the top targets for the treatment of cognitive impairments in patients with schizophrenia (Geyer and Tamminga, 2004).

In the current study, 12 subjects with schizophrenia were administered DMXB-A, an α7 nicotinic receptor partial agonist. The study was designed to assess the proof of concept that increased stimulation of the α7 nicotinic receptor would enhance performance on a cognitive battery and improve sensory gating, as measured by the P50 dual click paradigm. There is extensive preclinical and clinical rationale for this approach, but few drugs are available to directly assess the efficacy of the approach. The results clearly support the benefit of this approach, but a number of questions will need to be addressed in future studies before the ultimate utility of this approach is known. The most important issue is whether the acute efficacy observed with essentially a single dose will translate to a persistence of an effect with chronic drug administration. Tachyphylaxis develops rapidly with repeated stimulation of the α7 nicotinic receptor. Preclinical data suggest that this may not be an issue with DMXB-A, but long-term exposure data are required to directly address this issue. Second, two DMXB-A doses were evaluated. The results were different between the two doses, but how different is unclear, because of the small sample size. Preclinical data suggest that α7 nicotinic receptor partial agonists may show an inverse u-shaped response curve. The loss of efficacy at higher doses underscores the importance and potential difficulty in delineating the most effective dose range. Third, subjects who used nicotine products in the last month were excluded from the study. Patients with schizophrenia who do not smoke cigarettes are in the minority, and perhaps represent less than a third of the total population. The question of whether the beneficial effect of the drug would generalize to patients who smoke cigarettes will eventually need to be evaluated. Finally, the most pronounced effect was observed for the RBANS attention index. This effect is consistent with previous studies of acute nicotine administration in patients with schizophrenia. Future studies will need to evaluate whether the effect of DMXB-A is largely limited to attention or whether it will have significant benefit for other cognitive domains.

In summary, the demonstration that the acute administration of DMXB-A produces improved performance on a neuropsychological battery is an important first step in developing a novel therapeutic approach for one of the most critical areas of schizophrenia therapeutics.

References:

Nuechterlein KH, Barch DM, Gold JM, Goldberg TE, Green MF, Heaton RK. Identification of separable cognitive factors in schizophrenia. Schizophr Res. 2004; 72: 29-39. Abstract

Green MF, Kern RS, Heaton RK. Longitudinal studies of cognition and functional outcome in schizophrenia: implications for MATRICS. Schizophr Res. 2004;7 2: 41-51. Abstract

Geyer MA, Tamminga CA. Measurement and treatment research to improve cognition in schizophrenia: neuropharmacological aspects. Psychopharm. 2004; 174: 1-2.

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?

Discontinuation studies like Wunderink's are problematic because it is difficult to tell whether relapse is due to genuine recurrence reflecting original natural history, or drug withdrawal. There is little evidence to show what length of tapering protocol might be most appropriate.

To illustrate the difficulty, consider what happens in Tourette syndrome:

"Rapid discontinuation from drugs such as haloperidol, pimozide, and fluphenazine may lead to severe withdrawal effects. In general, discontinuation of medication may lead to 2 to 3 months of increased symptoms. Thus, if those medications are withdrawn, it cannot be expected that the patient's "real" status will be visible for quite a while. Some patients may improve for a few weeks after neuroleptic discontinuation and then worsen after an additional week or so, remain worse for a while, and then gradually improve. Side effects such as cognitive blunting, troubles with memory, feelings of dullness, poor motivation, school and sociable phobias, excessive appetite, and sedation may lift rather...  Read more

Discontinuation studies like Wunderink's are problematic because it is difficult to tell whether relapse is due to genuine recurrence reflecting original natural history, or drug withdrawal. There is little evidence to show what length of tapering protocol might be most appropriate.

To illustrate the difficulty, consider what happens in Tourette syndrome:

"Rapid discontinuation from drugs such as haloperidol, pimozide, and fluphenazine may lead to severe withdrawal effects. In general, discontinuation of medication may lead to 2 to 3 months of increased symptoms. Thus, if those medications are withdrawn, it cannot be expected that the patient's "real" status will be visible for quite a while. Some patients may improve for a few weeks after neuroleptic discontinuation and then worsen after an additional week or so, remain worse for a while, and then gradually improve. Side effects such as cognitive blunting, troubles with memory, feelings of dullness, poor motivation, school and sociable phobias, excessive appetite, and sedation may lift rather quickly over days to several weeks, while emergent tic symptoms remain or become worse. Thus, the decision to discontinue neuroleptics, particularly haloperidol, may be harder than their initiation. Withdrawal must be planned so that the patient's life is disrupted as little as possible. Often, patients and their families will have great difficulty in tolerating the discontinuation and will need a good deal of support from the physician."

(From Guide to the Diagnosis and Treatment of Tourette Syndrome. Ruth Dowling Bruun, M.D., Donald J. Cohen, M.D., James F. Leckman, M.D. Tourette Syndrome Association. 1984. Published online at Internet Mental Health, a website by Canadian psychiatrist Philip Long.)

If this was schizophrenia and the individual was in a trial, he or she would be back on meds like a shot, rather than helped through what might be a temporary exacerbation.

I have to say I find it impossible to believe there would be no difference in side effect profile between individuals on and off atypical antipsychotics. There is a flaw in the protocol.

It is clear that some patients with schizophrenia can do well off antipsychotic medication most of the time. The challenge is how to identify them and develop strategies to minimize the possibility of full relapse. The Harrow study is very helpful in that regard. A small percentage of first break patients will not have another relapse after recovering from the episode even if they are off medication. The benefits and risks should be discussed with the patient if he/she wants to be off medication.

In my studies, I have identified patient characteristics that help identify which patient might succeed off medication, including first break. They should have insight into their illness and not lose it if they begin to relapse; be capable of recognizing their early warning signs of impending relapse and be willing to take APDs when this occurs (having a cooperative family helps); no history of violence or suicidality during prior psychotic episodes; no history of rapid decompensation in prior episodes; and not a drug abuser. Patients should be taught to recognize early signs of...  Read more

It is clear that some patients with schizophrenia can do well off antipsychotic medication most of the time. The challenge is how to identify them and develop strategies to minimize the possibility of full relapse. The Harrow study is very helpful in that regard. A small percentage of first break patients will not have another relapse after recovering from the episode even if they are off medication. The benefits and risks should be discussed with the patient if he/she wants to be off medication.

In my studies, I have identified patient characteristics that help identify which patient might succeed off medication, including first break. They should have insight into their illness and not lose it if they begin to relapse; be capable of recognizing their early warning signs of impending relapse and be willing to take APDs when this occurs (having a cooperative family helps); no history of violence or suicidality during prior psychotic episodes; no history of rapid decompensation in prior episodes; and not a drug abuser. Patients should be taught to recognize early signs of relapse and coping skills to deal with them. See Herz et al. (2000) describing a strategy for relapse prevention. In this study, patients were on maintenance APDs.

Marvin Herz writes, "A small percentage of first break patients will not have another relapse after recovering from the episode even if they are off medication. The benefits and risks should be discussed with the patient if he/she wants to be off medication."

But surely the bigger issue is that patients can have relapses whether on antipsychotics or not. The real question is who will, taking into account serious physical side effects, significant increased mortality, and cognitive effects, benefit overall and long term from antipsychotics.

Well, maybe not the 20 percent or so who show little or no functional response; they are getting a heap of side effects for minimal benefit. And for those in the middle, i.e., excluding those 20 percent who would have gotten better anyway—leaving 60 percent of the total—well, we do not know, because discontinuation effects fatally flaw the maintenance studies. It is impossible to accurately judge the impact of discontinuation on relapse rates (see previous post). Discontinuation studies also miss out those who are...  Read more

Marvin Herz writes, "A small percentage of first break patients will not have another relapse after recovering from the episode even if they are off medication. The benefits and risks should be discussed with the patient if he/she wants to be off medication."

But surely the bigger issue is that patients can have relapses whether on antipsychotics or not. The real question is who will, taking into account serious physical side effects, significant increased mortality, and cognitive effects, benefit overall and long term from antipsychotics.

Well, maybe not the 20 percent or so who show little or no functional response; they are getting a heap of side effects for minimal benefit. And for those in the middle, i.e., excluding those 20 percent who would have gotten better anyway—leaving 60 percent of the total—well, we do not know, because discontinuation effects fatally flaw the maintenance studies. It is impossible to accurately judge the impact of discontinuation on relapse rates (see previous post). Discontinuation studies also miss out those who are not stable, read not doing well on antipsychotics; the trials only include those who are stable on antipsychotics. So the take-home efficacy data is nothing like as sound as presented. And we know, do we not?, that there is hard evidence of biased trial design, selective reporting, fraudulent use and analysis of data and ghost writing. Sad but undeniably true.

The Harrow study shows 40 percent off meds, and they are, as a cohort, doing better than those on antipsychotics. Some have psychosis, but as is very, very clear, so do many on antipsychotics. It is a fair bet that those reported as doing very badly on antipsychotics would do better off antipsychotics.

Look at 5-year outcomes from a service-based model built around antipyschotic restriction, e.g., Seikkula in Finland. It's flawed, but it is real-world stuff, and outcomes are very good with 29 percent on antipsychotics. I see no evidence the specific Open Dialogue approach is itself contributing to the good outcomes, but if you're looking for what happens to those off antipsychotics, this is as good a place as any.

So where does all this leave us? In my view, it is time for an independent and unbiased review of all the available literature, including claims that early intervention with antipsychotics prevents cognitive decline. Maybe the majority of reviewers should be eminent researchers with expertise in relevant disciplines, rather than psychiatrists.

Folks, you need to build a credible evidence base for current practice, because you do not have one. Many of you are acting like you're giving out insulin for diabetes; indeed, some of you make that analogy. But the data do not support you.

References:

Seikkula J, Aaltonen J, Alakare B, Haarakangas K, Keranen J, Lehtinen K. Five-year experience of first-episode nonaffective psychosis in open-dialogue approach: Treatment principles, follow-up outcomes, and two case studies. Psychotherapy Research, March 2006; 16(2): 214.

Dixon LB, Lehman AF, Levine J. Conventional antipsychotic medications for schizophrenia. Schizophr Bull. 1995;21(4):567-77. Review. Abstract

Hellewell JS. Treatment-resistant schizophrenia: reviewing the options and identifying the way forward. J Clin Psychiatry. 1999;60 Suppl 23:14-9. Review. Abstract

Sarah Yates dismisses the importance of maintenance medication in preventing relapse, because patients relapse on or off medication. It is known that the majority of patients alternate between acute episodes (relapse) and periods of full or partial remission. There have been randomized controlled studies comparing an intermittent (targeted) medication strategy with maintenance medication which have all found that intermittent medication results in much higher relapse rates over 2 years. In our study, it was 30 percent for intermittent and 16 percent for those on maintenance (Herz et al., 1991). Other studies have found even larger differences favoring maintenance.

Relapses are highly undesirable for patients and their families. After each relapse, re-hospitalizations are lengthier and patients may not recover to their previous level of symptoms and functioning. However, a German study found no benefit in maintenance medication for first break patients (Gaebel et al., 2002). My...  Read more

Sarah Yates dismisses the importance of maintenance medication in preventing relapse, because patients relapse on or off medication. It is known that the majority of patients alternate between acute episodes (relapse) and periods of full or partial remission. There have been randomized controlled studies comparing an intermittent (targeted) medication strategy with maintenance medication which have all found that intermittent medication results in much higher relapse rates over 2 years. In our study, it was 30 percent for intermittent and 16 percent for those on maintenance (Herz et al., 1991). Other studies have found even larger differences favoring maintenance.

Relapses are highly undesirable for patients and their families. After each relapse, re-hospitalizations are lengthier and patients may not recover to their previous level of symptoms and functioning. However, a German study found no benefit in maintenance medication for first break patients (Gaebel et al., 2002). My basic point is that identifying characteristics of patients who might benefit from being off medication most of the time is important, but we must develop strategies to protect them from the likelihood of having relapses.

I think that the question of this research news—must the administration of antipsychotic drugs be forever?—is one of the most important questions that really began an excellent debate among the scientific community.

The article by Dr. J. Bola (Bola, 2006; also see SRF related news story) is a really excellent article in this regard, not only for a clinical discussion but also for a research discussion. I think that the scientific community must take these ideas as one of the most important issues for future discussion in the field of schizophrenia research.

View all comments by Patricia Estani

In my opinion, these papers confirm and disclose, with stringent scientific methodology, a wide range of phenomena, until now not adequately investigated and understood, observed in countries with a very strong commitment to community-based mental health care, like Italy. The following phenomena listed are typical of a community-based mental health system, which is specifically organized by rules and recommendations of the National Plan of Italian Government:

1. A large proportion of schizophrenia-schizoaffective patients isn’t ever admitted in a psychiatric inpatient unit.

2. The antipsychotic mean doses are lower in Italy than in the U.S., and many patients show a “satisfactory” response at dosage much lower than expected.

3. Many patients and their caregivers (usually parents or partner) manage their antipsychotic daily dosage by themselves, adjusting the dosage according to their needs. Surprisingly, very often this management works!

4. Psychosocial interventions reduce the need for antipsychotics and are currently delivered in a special unit of Mental...  Read more

In my opinion, these papers confirm and disclose, with stringent scientific methodology, a wide range of phenomena, until now not adequately investigated and understood, observed in countries with a very strong commitment to community-based mental health care, like Italy. The following phenomena listed are typical of a community-based mental health system, which is specifically organized by rules and recommendations of the National Plan of Italian Government:

1. A large proportion of schizophrenia-schizoaffective patients isn’t ever admitted in a psychiatric inpatient unit.

2. The antipsychotic mean doses are lower in Italy than in the U.S., and many patients show a “satisfactory” response at dosage much lower than expected.

3. Many patients and their caregivers (usually parents or partner) manage their antipsychotic daily dosage by themselves, adjusting the dosage according to their needs. Surprisingly, very often this management works!

4. Psychosocial interventions reduce the need for antipsychotics and are currently delivered in a special unit of Mental Health Department termed the “Daytime Center.”

5. The prevalence of schizophrenia “at the service” is systematically lower than expected, suggesting thus that many patients are adequately treated in the community by private practice or GP.

6. Experimental studies conducted by my colleagues and me suggest that the main variable predicting admission in a long-term residential rehabilitation facility is the occurrence of turbulent and violent behavior at least once in the course of illness. Such patients take antipsychotics at higher dosage than controls (Di Michele et al., 2007), show an inadequate control of their positive and negative symptoms, and are admitted at least once to a hospital psychiatric unit.

7. Patients in care by mental health centers have invariably poor prognoses: they do not work, have attempted suicide at least once, are unmarried or divorced (Di Michele and Bolino, 2004). The younger the age of first contact, the poorer is the prognosis.

In conclusion, even though we have much more information than in the past about the outcome and prognosis of patients admitted in a psychiatric unit, information about patients who attend community care is scarce and dispersed, but potentially valuable and of great interest for research. This approach will reduce the heterogeneity of the disease in terms of outcome and social disability. In my opinion, the perspective of investigation of drug treatment in schizophrenia should be expanded because many potential confounders influence the therapeutic response and prognosis, especially in a naturalistic setting.

I am not dismissing the importance of maintenance medication; I am saying that the randomized controlled studies quoted by Marvin Herz, which show advantages of maintenance over intermittent medication, are so fundamentally flawed by inadequate tapers and potential discontinuation effects that it is difficult to interpret the results (see my previous posts).

In addition, design of the studies gives an apparently distorted effect, because significant numbers of patients, up to 40 percent, who continue to experience psychotic symptoms whilst taking antipsychotics are not included in the trial, so one is examining a subset of “good” drug responders, giving a false picture of antipsychotic efficacy. The evidence shows that a significant proportion of “good” responders would have recovered without drug treatment in the first place. No drug treatment is not equivalent to treatment and withdrawal.

For these reasons the clearest way to truly assess the benefit of long-term maintenance medication is to use placebo-controlled RCTs (Bola,...  Read more

I am not dismissing the importance of maintenance medication; I am saying that the randomized controlled studies quoted by Marvin Herz, which show advantages of maintenance over intermittent medication, are so fundamentally flawed by inadequate tapers and potential discontinuation effects that it is difficult to interpret the results (see my previous posts).

In addition, design of the studies gives an apparently distorted effect, because significant numbers of patients, up to 40 percent, who continue to experience psychotic symptoms whilst taking antipsychotics are not included in the trial, so one is examining a subset of “good” drug responders, giving a false picture of antipsychotic efficacy. The evidence shows that a significant proportion of “good” responders would have recovered without drug treatment in the first place. No drug treatment is not equivalent to treatment and withdrawal.

For these reasons the clearest way to truly assess the benefit of long-term maintenance medication is to use placebo-controlled RCTs (Bola, 2006; see SRF related news story. Available trials do not show benefits from automatic long-term antipsychotic use. In the current climate it is difficult to plan such trials. We must therefore look to naturalistic studies such as Seikkula's to indicate likely outcome of restricted use of antipsychotics.

What I am saying is that the results of such trials seem at face value to be at odds with results from discontinuation trials; in other words, outcome is much better than one would predict, and this is because discontinuation trials tend to bias outcome. Quotes based on data such as presented by Marvin Herz suggest a straightforward scenario whereby relapse rate for those maintained on antipsychotics is half that for those off antipsychotics. This is very misleading, indeed, plain wrong, which is why there is surprise that the 40 percent of patients with schizophrenia off antipsychotics in the Harrow study are doing much better as a cohort than those on antipsychotics. Would results have been even better if discontinuation effects had been minimized by seeking to avoid drug use, wherever possible, in the first place? Given the implications for forcible medication, a scientific analysis of all the available data is long overdue. In my opinion, severely restricted use of antipsychotics, as in Seikkula's study, is the right answer. At the very least, the evidence base for current “orthodox” practice requires more research to plug glaring holes.

I have been interested in this issue for a long time, first as a treatment issue and later as an ethics problem. Key aspects of the discussions are often misconceptualized. My view is as follows:

1. The issue is never drugs or no drugs, but rather how to integrate therapies.

2. Continuous medication is not the only active pharmacotherapy strategy. Targeted antipsychotic treatment is effective (less so than continuous for relapse prevention, but perhaps better for negative symptoms and similar to overall outcome measures). A targeted approach may be optimal for patients who refuse continuous medication, for patient subjects in off-medication protocols for research, and for a subgroup with good prognostic indicators who want to consider managing their recovery process off medication. The targeted approach addresses relapse prevention by intervening early in exacerbation and by assuring continuity of clinical care (see Buchanan and Carpenter, 1996, for overview).

3. Off-medication research is feasible and ethically defensible. The Helsinki Declaration was a flawed...  Read more

I have been interested in this issue for a long time, first as a treatment issue and later as an ethics problem. Key aspects of the discussions are often misconceptualized. My view is as follows:

1. The issue is never drugs or no drugs, but rather how to integrate therapies.

2. Continuous medication is not the only active pharmacotherapy strategy. Targeted antipsychotic treatment is effective (less so than continuous for relapse prevention, but perhaps better for negative symptoms and similar to overall outcome measures). A targeted approach may be optimal for patients who refuse continuous medication, for patient subjects in off-medication protocols for research, and for a subgroup with good prognostic indicators who want to consider managing their recovery process off medication. The targeted approach addresses relapse prevention by intervening early in exacerbation and by assuring continuity of clinical care (see Buchanan and Carpenter, 1996, for overview).

3. Off-medication research is feasible and ethically defensible. The Helsinki Declaration was a flawed guideline and had not been accepted as binding in most countries. The recent "Clarification" brings it into line with ethical justification for off-medication research. We have addressed this change and how to proceed with off-medication studies in schizophrenia (Carpenter et al., 2003). Key points are strong scientific merit, inclusion/exclusion criteria to select patients to maximize safety, and early detection of exacerbation or failure to improve with a targeted antipsychotic drug intervention.

References:

Buchanan RW, Carpenter WT. Targeted maintenance treatment in schizophrenia: Issues and recommendations. CNS Drugs. 1996; 4:240-245.

Carpenter WT, Schooler NR, Kane JM. The rationale and ethics of medication-free research in schizophrenia. Arch Gen Psychiatry. 1997;54:401-407. Abstract

Carpenter WT, Appelbaum PS, Levine RJ. The declaration of Helsinki and clinical trials: A focus on placebo-controlled trials in schizophrenia. American Journal of Psychiatry. 2003;160:356-362. Abstract

Have followed the comments above with great interest. I come to this from the perspective of someone who studies the mechanisms of antipsychotics—usually focusing on the acute and the shorter-term, but find myself increasingly getting interested in the longer-term issues.

I think there can be little denying that antipsychotics administered to those acutely psychotic lead to less distress for those treated and better ability for the rest of us to work with them. The short-term mechanism (D2 blockade) and short-term gains are rather undeniable.

The question is, what are the longer-term trade-offs? This remains a complex question. From a biological perspective the introduction of any drug, including antipsychotics, is an external challenge for the body. The body responds by trying to establish homeostasis and compensate for this challenge. We have shown both in animals (Samaha et al., 2007) and in humans (Silvestri et al., 2000) that, in certain situations and certain...  Read more

Have followed the comments above with great interest. I come to this from the perspective of someone who studies the mechanisms of antipsychotics—usually focusing on the acute and the shorter-term, but find myself increasingly getting interested in the longer-term issues.

I think there can be little denying that antipsychotics administered to those acutely psychotic lead to less distress for those treated and better ability for the rest of us to work with them. The short-term mechanism (D2 blockade) and short-term gains are rather undeniable.

The question is, what are the longer-term trade-offs? This remains a complex question. From a biological perspective the introduction of any drug, including antipsychotics, is an external challenge for the body. The body responds by trying to establish homeostasis and compensate for this challenge. We have shown both in animals (Samaha et al., 2007) and in humans (Silvestri et al., 2000) that, in certain situations and certain individuals, the system responds to resist drug action by producing new receptors. Exactly how this comes about is not known. However, it seems reasonable to suggest that in this longer-term counter-response of the brain to the drug (and not just in the initial effect of the drug on the brain) may lie the clue to the longer-term outcomes: why some do well and others don't; why some relapse on the meds and others don't; and why some can tolerate withdrawal and others can't.

A few years ago I read an article by Whitaker, an author who does not generally write in this field (Whitaker, 2004). I cite and bring that article to the attention of this dialogue. The abstract says: "Although the standard of care in developed countries is to maintain schizophrenia patients on neuroleptics, this practice is not supported by the 50-year research record for the drugs. A critical review reveals that this paradigm of care worsens long-term outcomes, at least in the aggregate, and that 40 percent or more of all schizophrenia patients would fare better if they were not so medicated. Evidence-based care would require the selective use of antipsychotics, based on two principles: (a). no immediate neuroleptisation of first-episode patients; (b). every patient stabilized on neuroleptics should be given an opportunity to gradually withdraw from them. This model would dramatically increase recovery rates and decrease the percentage of patients who become chronically ill."

I do not agree with this rather radical position—but it does provide a very different perspective from mainstream thinking at the moment. I do often share it with my residents and fellows, not to endorse this position but to remind them that the jury is still out on the really long-term (years) effects of antipsychotics.

The whole idea of "to drug or not to drug" is rather new to me. As a schizoaffective patient for many years who has been mostly compliant with my psychiatrist's direction, I can only say that this might only add confusion to the issue. I attend a lot of discussion and support groups for people with bipolar disorder and schizophrenia. The message I hear the most is to keep taking one's meds. The reason that this message is so often repeated is simply that it is so frequently rejected or ignored by so many patients. The biggest reason for relapse and continued problems is noncompliance. Once patients learn that other patients are experimenting with discontinuing medication, you will simply have more cases of noncompliance. Most patients don't live in a vacuum and most don't necessarily do what they are told. While many lack insight, they do not lack free will.

View all comments by James C. Matthews

Thanks to all for an interesting debate.

William Carpenter writes, "The issue is never drugs or no drugs, but rather how to integrate therapies."

The therapeutic issue remains drug or no drug if one assumes appropriate social and emotional support will be available to all from diagnosis. At any given point in management the decision that really matters, and is directly influenced by the psychiatrist, is drug or no drug. All other specific therapies are of unproven utility (with the possible exception of cognitive behavior therapy), and can be administered concurrently with drugs. So what therapy is it one is integrating drug use with? I think the issue is whether the long-term goal is to maximize drug use, or minimize drug use, both in terms of numbers of individuals treated, and dose (including number of antipsychotics prescribed concurrently), and duration once treated.

My fundamental position is that careful assessment of long-term data suggests that the goal should be to minimize use of antipsychotics for psychosis including schizophrenia, and in most cases...  Read more

Thanks to all for an interesting debate.

William Carpenter writes, "The issue is never drugs or no drugs, but rather how to integrate therapies."

The therapeutic issue remains drug or no drug if one assumes appropriate social and emotional support will be available to all from diagnosis. At any given point in management the decision that really matters, and is directly influenced by the psychiatrist, is drug or no drug. All other specific therapies are of unproven utility (with the possible exception of cognitive behavior therapy), and can be administered concurrently with drugs. So what therapy is it one is integrating drug use with? I think the issue is whether the long-term goal is to maximize drug use, or minimize drug use, both in terms of numbers of individuals treated, and dose (including number of antipsychotics prescribed concurrently), and duration once treated.

My fundamental position is that careful assessment of long-term data suggests that the goal should be to minimize use of antipsychotics for psychosis including schizophrenia, and in most cases this is exactly the opposite of current professional practice.

I would argue that Harrow's study lends weight to the good clinical service outcomes found in circumstances where the issue is precisely antipsychotic or no antipsychotic at initiation of medical involvement. In Seikkula's study 71 percent of non-affective psychotic patients had no antipsychotic administered for the duration of the 5-year study (Seikkula et al., 2006). The other 29 percent had antipsychotics administered at some stage, but not necessarily continuously. In such a service there is no absolute clinical rule that dictates drug or no drug; rather, individual circumstances are weighed in each case. At any given decision point, however, the issue is drug or no drug, and the emphasis is self-evidently on minimizing use of antipsychotics. In the short term, benzodiazepines may be utilized to this end. If William Carpenter is saying the issue is never (or shouldn't be) universal use of drugs or universal condemnation of drugs, then I heartily agree. If he is saying that everyone with psychosis or schizophrenia must necessarily be medicated with an antipsychotic at some point, I think I disagree. (Where is the evidence this is in the best long-term interest of all patients? What evidence there is suggests otherwise; Bola, 2006; Whitaker, 2004). If he is saying that those started on antipsychotics at any point should have an opportunity to come off again, and there is a pressing need to determine how best to manage this, I agree.

Withdrawal studies involving cessation of antipsychotic over days or weeks are likely a mistake. Factors likely to compromise success in studies such as Wunderink et al. are the fact that the studies are open, and criteria for relapse are vague.

As it is hard to withdraw, maybe impossible for some, this ought to be taken into account when initiating patients to treatment; if initiation can be avoided, it should be avoided.

Considering Harrow and Jobe

Does long-term use of antipsychotics protect against poor outcome? Consider the following quotes from Harrow and Jobe:

• "Eighty percent of the schizophrenia patients on antipsychotics at the 15-year follow-ups had been on an antipsychotic at the 2-year follow-up."
• "Nineteen of the 23 of schizophrenia patients (83 percent) with uniformly poor outcome at the 15-year follow-ups were on antipsychotic medications."
• "… at the 10-year follow-ups, 79 percent of the patients with schizophrenia on antipsychotics had psychotic activity."
• "Sixty-four percent of the schizophrenia patients treated with antipsychotic medications at the 15-year follow-ups had psychotic activity."

It is reasonable to argue that had these individuals not been on antipsychotics, the long-term outcome would have been even worse. But, has anyone ever proven this properly? What if the opposite is true? It is my understanding that overall outcomes are no better, maybe worse, than they were in pre-neuroleptic times (Hegarty et al., 1994). The Harrow study does not assess tardive dyskinesia, tardive dysmentia, heart disease, stroke, respiratory illness, obesity, metabolic disturbance, diabetes, suicide rate, death rate. If long-term side effects are added to the balance, what is overall cost-benefit? Okay, the worse-outcome patients may be easier to manage, though by no means all would be disruptive or violent without treatment, but is it ethical to treat with dangerous and debilitating drugs to this end? Was physical lobotomy justified for management purposes?

Do those who choose to take themselves off drugs do worse in the long run than they would otherwise have done? Or do they do considerably better? How do so many manage to get off drugs and stay off drugs? Is it because they are not in a clinical setting, choose their own pace for withdrawal, and are not put back on drugs at the first sign of relapse/psychosis? It is not clear from the Harrow study whether the 40 percent off drugs were monitored; the suggestion is many were no longer seen in a clinic and so made their own judgment regarding need or cost/benefit of medication.

Harrow and Jobe also write, "Of the schizophrenia patients not on any medications at the 15-year follow-up, 29 percent were on antipsychotics at the 2-year follow-up." In other words, 70 percent of the 40 percent off antipsychotics had come off at a relatively early stage.

Further quotes from Harrow and Jobe:

• "Those who were unmedicated at the 15-year follow-ups had previously experienced (5, 7.5, and 10.5 years earlier) significantly more periods of recovery (p <.001) than those on antipsychotic medications at the 15-year follow-ups."
• "… at the 10-year follow-ups, 23 percent of those not on any medications had psychotic activity at 15-year follow-up; 28 percent of those not on any medications had signs of psychotic activity."
• "… at the 15-year follow-up, 12 of the 64 schizophrenia patients (19 percent) were in a period of recovery. This includes eight of the 20 schizophrenia patients (40 percent) not on any psychiatric medications. It includes significantly fewer (two of the 39) patients with schizophrenia (5 percent) on antipsychotic medications. Two of the other five schizophrenia patients on other medications but not on antipsychotics also were in recovery at the 15-year period."

It is not clear what the full pattern of antipsychotic use was over the 15-year period, although there is a clear correlation between drug status at 2 years and at 15, suggesting those off drugs tended to stay off drugs. There is evidence of increasing benefit off drugs over time. This is itself important; short-term results do not necessarily translate into long-term outcome.

The trouble with the Harrow study is that it is chicken and egg—do individuals do well long-term off antipsychotics because they had a milder variant of schizophrenia to start with, or because personality traits which increase likelihood of proactive drug cessation translate into better outcome due to less exposure to toxic and habituating effects of drug, or because personality traits can improve ability to cope with psychosis and negative effects? Or a combination of the three? Would overall outcome be better if everyone in the study were forced to take antipsychotics long-term, or if no one took antipsychotics at any stage (assuming the choice was one extreme or the other)? A very big question if you think about it enough, and I would be interested to hear the answer. Would outcomes be better overall if professionals rather than patients always decided who should go on, come off, and when? Or would they be better if patients were allowed to determine cost/benefit for themselves, including those with uniformly poor outcome who may feel side effects are awful, but are not permitted to come off drugs? How dependent is patient perception on professional advice? Is there evidence that automatic medication with antipsychotics on evidence of psychotic activity is beneficial in the long term; how big would the cohort off antipsychotics at 15 years be if such automatic medication was enforced; and what would the impact be?

Discussions of the Harrow paper have tended to assume that all of the 60 percent left on antipsychotics were benefiting overall, and so the challenge is to identify the small proportion who can remain free of psychosis with no drug. This totally ignores the fact that 83 percent of the very worst outcome cases were on antipsychotics, and around 70 percent on antipsychotics had psychotic activity. In other words, the drugs do not work well long-term, if at all, in a significant number of cases. In fact, this study could be interpreted as suggesting they might be detrimental long-term. The neat premise that if someone has psychotic activity the solution is necessarily to put them on antipsychotics, and, hey, presto! they will no longer experience psychosis, is not supported by the evidence in the paper.

In crude terms the Harrow study could be read as suggesting a third of patients with schizophrenia (worst-outcome cases) were not benefiting from antipsychotics (indeed maybe harm exceeds benefit), at least a third were managing reasonably well and avoiding side effects off antipsychotics, and the cost/benefits of antipsychotic use for the remaining third are debatable.

Even the Wunderink study suggests discontinuation should be tried. Twenty percent discontinued successfully, and only 25 percent of those in the discontinuation group experienced relapse, loosely defined but not severe since in fact the maintenance treatment group spent slightly longer in hospital than the discontinuation group. To suggest there are no benefits to being off medication is shortsighted (see below).

What Are the Costs of Antipsychotic Treatment?
Why does all this matter so much? If antipsychotics benefit some, then isn't it best to play on the safe side and treat everyone who might benefit?

The side effects of the antipsychotics are continuously downplayed. These are terrible drugs, arguably second only to chemotherapy, possibly worse in some respects. I won’t produce an exhaustive list of side effects, pyramidal effects, but will concentrate on key issues. All the available evidence suggests the drugs not only cause significant morbidity, but also mortality, although for a variety of reasons (which could be discussed elsewhere), the available data likely underestimate the problem. (See Joukamaa et al., 2006; Osborn et al., 2007 for death-rate studies). Joukamaa found a 2.5 increase in death rate for each neuroleptic administered, a sixfold increase for those on three or more concurrent antipsychotics. Osborn found very significant increases in death rates from coronary heart disease and stroke. Both studies were weighted for confounding factors, and the Osborn study has a systematic bias, which means seriously mentally ill people registered as being off antipsychotics may have been on antipsychotics or other harmful psychotrophics for long periods, or may have been in hospital on high doses.

Life expectancy for those with schizophrenia is reduced by over 25 years, with main causes of death cited as coronary heart disease and diabetes. Some deaths are unexplained (Colton et al., 2006). The fact that there have been few systematic long-term studies of either total morbidity burden or mortality is scientifically and ethically unacceptable, and undermines the concept of evidence-based medicine, particularly when medication can be enforced. The big problem with increased mortality associated with common disorders is it is easy to ignore. If a significant number of patients die of drug-related coronary heart disease, it's no one's problem. If far fewer patients (a handful) die of a rare problem (e.g., white blood cell abnormalities, as with clozapine), suddenly there is a huge ethical problem. Is it ethics? Or is it that because death is directly attributable to drug, it looks bad, and someone has to carry the can. No one forces anyone to stay on clozapine if there are white cell changes, even if that individual is benefiting from the drug, and it is the only drug that appears to work. There is weekly monitoring at huge cost, to pick up a few rare cases. Why? Because, horror, someone might die. Yet when I raise the question of morbidity and mortality I am told, by some psychiatrists, "All drugs have side effects." What is that supposed to mean? If the rare problems caused by clozapine were attributable to anything but drug, no one would bat an eyelid because in any individual case it would be difficult to prove it was drug-related (even though in some it would be), and no psychiatrist would ever need to feel culpable; more important, he or she would not get into trouble. Something is very wrong.

At root there are significant numbers of people who do not care whether those with schizophrenia are dying due to drug or not, let alone suffering unacceptable side effects. At the very least, they are not looking. Some claim the Osborn study shows a protective effect of antipsychotics at low doses, but he himself writes (personal communication) that the data collection methodology justifies no such conclusion. Within the limitations of the data, the conclusion is antipsychotics are associated with mortality in a dose-dependent manner. Osborn also writes (personal communication) the study was incapable of showing effects of atypicals because there were so few on atypicals, and in addition no one was on atypicals long enough to study the two parameters the researchers looked at, i.e., death from coronary heart disease and stroke, both of which tend to be long-term effects. The atypicals, with all their increasingly well-understood metabolic effects, though many individuals are not monitored, are likely worse than the typicals, though the long-term data are not available.

The drugs also cause tardive dyskinesia in over 40 percent of patients long-term, with evidence atypicals will have similar outcome (de Leon, 2007) and tardive dysmentia is associated with this, i.e., there is clear evidence of irreversible brain damage affecting motor skills and mental faculties. Imaging studies indicate dose-related drug-induced loss of brain volume; properly controlled experiments with monkeys suggest significant reductions in brain volume (e.g., 10 percent in parietal lobe) and reduction in glial cells after only 1 year on atypicals or typicals (Konopaske et al., 2006). As discussed previously in this thread there is evidence the drugs cause upregulation of dopamine receptors, with potential for worsening of the condition they are designed to treat.

In addition, and by no means least, the effect of antipsychotics is frequently a kind of death of the personality—they cause numbing, avolition, and compromise higher thinking skills, as normal volunteers attest. Doctors were unable to work after administration (Belmaker and Wald, 1977), and there are numerous accounts of detrimental cognitive and emotional effects on volunteers. I can attest to the effects of atypicals firsthand, as I have an organic illness which is thought to have triggered a psychosis and (possibly) necessitated use of a low-dose antipsychotic for a relatively brief period. Chemical lobotomy is an excellent description, interestingly no longer in use. Presumably it is no longer considered ethical, and no one wants to consider the full implications of treatment. It took several weeks for the worst effects to appear. Normal life was only possible once I was off the drug. Does this make me an antipsychiatrist? Certainly not. Would it make me likely to worry about those subjected to enforced use of such drugs, particularly since the literature accompanying the drugs gives little indication of cognitive effects? Well, of course.

If I have the professional expertise to read primary data objectively (I have a Ph.D. in inherited neuromuscular diseases, was Research Director of a large medical charity for over 15 years, instigated the European Neuromuscular Centre, and chaired a Primary Care Trust on strategic development and provision of clinical service) and question the evidence base for current use of antipsychotics and for overall cost/benefit, is it reasonable to do so? Absolutely. Does it serve my purpose to approach the literature with any intrinsic bias? Well, the interesting thing is my original bias was by and large in favor of antipsychotic use, but after ploughing my way through hundreds of key papers, including all those underpinning the U.K. National Institute of Clinical Excellence (NICE) guidelines, and seeking the advice of scientific and clinical colleagues as questions arose, I became more and more concerned. So far no one has been able to produce the evidence needed to alleviate those fears.

If anything, NICE guidelines are probably biased by over-reliance on short-term studies and poorly designed withdrawal studies. It hardly helps that despite NICE guidelines suggesting discontinuation of antipsychotics 1 to 2 years after a psychotic episode, based on expert assessment of all available evidence, the majority of U.K. psychiatrists and GPs fail to instigate this. Despite the NICE recommendation that multiple antipsychotics should not be prescribed, and atypicals and typicals should not be used concurrently except for crossovers, this is common practice. A recent Health Commission survey which sent specialist pharmacists into U.K. psychiatric hospitals found a third of patients were being given more than the recommended dose, and more than 70 percent of prescriptions were considered inappropriate, often because of inadvisable concurrent prescribing, including more than one antipsychotic (see BBC news story).

Consequences of Forced Intervention
Here is a big issue. What about scope for (in effect) indefinite forcible treatment in the community following one admission to hospital for mental illness, as the current U.K. mental health bill proposes? A Community Treatment Order (CTO) could be issued without court involvement, and will permit anyone deemed to be noncompliant with treatment to be returned to hospital for treatment, probably a depot injection in many cases. There is no appeal, and the Order can be renewed at 6-month intervals. Most psychiatrists believe all but a very small minority of individuals with schizophrenia will do better long-term if maintained on antipsychotics, and it is more ethical to err on the side of caution, i.e., over-treat rather than under-treat. Where is the real evidence? The CATIE study fits with the Harrow study in that it suggests in the real world patients do come off medication, either because side effects are intolerable, or because they see no clinical benefit (Lieberman et al., 2005). Are we risking abusive situations because psychiatrists’ perceptions will be able to override reality? In other words, those who would have done much better long-term off drugs, or at least by choosing for themselves when and how to take drugs, will now be forced onto drugs.

Some patients may do better in a regimen of long-term forcible medication, but who will these be? The current U.K. bill makes no attempt to even define this population; as it stands, the legislation can apply to anyone hospitalized for mental illness.

Good-quality, long-term randomized placebo controlled trials are needed to address the questions in this post, or at least matched service cohorts, and despite William Carpenter's argument, the current climate precludes this. Even if the ethical argument is won (and it is debatable it only applies to good prognosis patients), who is going to fund the large well-designed unbiased trials needed to provide a definitive answer? One, or a series, which will overturn current orthodoxy. The pharmaceutical companies? Do the pharmaceutical industries have a vested interest in minimizing use of antipsychotics, or drawing attention to the fact there may be an issue? Okay, say we've found the money, and we've found the impartial scientists and clinicians committed to answering the right questions, with the intelligence, breadth of knowledge, insight, and freedom to design the studies so that they will in fact answer those questions ethically. How long will the studies take? Ten years? Fifteen years? In the meantime, I believe it morally wrong to act as if the drugs are "safe and effective," and choosing not to take them is almost by definition a sign of insanity. Implementation of poorly defined CTOs is just one example of behaving as if there is a guaranteed benefit, at acceptable cost. Increasing use in (often nonpsychotic) children, who have no choice, and in presymptomatic adolescents, who may be making poorly informed choices, are other examples....

This goes back to the original argument: what treatment regimen does the balance of available long-term data suggest? Seikkula's 5-year study indicates the advisability of restricting initiation of antipsychotics wherever possible. Harrow's study could be read as a manifesto for patient choice. The CATIE study suggests given the choice, patients tend to come off drugs. Bola, at the very least, highlights the need for more placebo-controlled data. But, I hear readers exclaim, what about those with no insight, i.e., who fail to recognize they are ill. If a patient never regains insight, then are the drugs working, and is it ethical to continue them? If the patient does regain insight, then what is wrong with an advance directive? Is “insight” always taken to mean recognition of illness, or is it often taken to mean recognition that drug treatment is beneficial to the individual, i.e., benefit outweighs cost? If the patient thinks treatment isn't beneficial, is the patient by definition lacking in insight? Is benefit to the patient always the goal, or is social management and protective medicine also a consideration? In the current climate almost anything can happen to a patient on antipsychotics, no questions asked, but should something go wrong while the patient is not medicated, the psychiatrist is considered culpable.

Who has some decent evidence showing that there is a causal relationship between duration of non-drug-treated psychosis and outcome? In other words, demonstrated by a long-term randomized placebo-controlled trial comparing immediate treatment of acute-onset psychosis with delayed or no treatment? The prognosis for slow-onset schizophrenia has long been understood to be poorer than for acute-onset schizophrenia. and slow-onset cases are more likely to have delayed treatment. In addition if you delay treatment of schizophrenia, let alone acute psychosis, at least 20 percent, and often many more, will recover spontaneously (Dixon et al., 1995). If you compare those who do not recover well with a cohort with very recent onset of psychosis, there is obviously going to be a difference in favor of the recent-onset cases.

This whole topic is crucial. The advent of CTOs means that psychiatrists' perceptions can and will override the reality of the current situation. The reality is once in the community, patients make their own judgments regardless of orthodoxy, and many come off drugs. Most are not supported in this (according to patient surveys conducted by MIND, the U.K.’s foremost mental health charity).

The Harrow study suggests that long-term, and on balance, the patients are more likely to get it right than anyone else. If they didn't, the outcomes would have been reversed. Listening to most psychiatrists, one would predict, indeed be certain, that the outcomes would have been reversed. There are plenty of psychiatrists, and even more GPs who would argue 100 percent of the patients in the Harrow study should have been on antipsychotics continuously; either that or they would enforce or recommend long periods on antipsychotics, creating a situation where discontinuation was effectively impossible. The Harrow study is counterintuitive to many, as is the finding that outcome (based on identical diagnostic criteria across countries) is better in countries with very low use of antipsychotics (15 percent; Jablensky, 1992). Common criticisms of the second WHO study are unfounded (Jablensky, 1994).

The tragedy is that there is no overall evidence CTOs are even beneficial for those targeted few they are designed to serve. And the potential for negative long-term impact on health has not been thoroughly assessed. Yet they have the potential to destroy the lives of many, particularly if broadly applied as will be feasible in the U.K. The Institute of Psychiatry, King's College London, has published a new report, “International Experiences of Using Community Treatment Orders” by Dr Rachel Churchill, Professor Matthew Hotopf, and associated coauthors. The report explains that there is no robust evidence as yet to prove whether community treatment orders (CTOs) are beneficial or harmful to patients (see BBC news story). This report represents the most comprehensive and thorough review of research into international experiences of using compulsory treatment orders, summarizing evidence from 72 databased empirical studies undertaken in six countries over the last 30 years.

It is only possible for such legislation to come into force when lay politicians are fed the false idea that antipsychotics are "safe and effective." Unfortunately, the pharmaceutical companies are involved in this both directly via lobbying to government and indirectly by just about any means possible. Does this worry anyone?

Evidence-based medicine? First, the evidence base is flawed, and from what we know of proven practice by pharmaceutical companies, deliberately distorted on a number of levels; second, many psychiatrists feel free to do whatever they wish, regardless of any evidence. Fancy forcible long-term maintenance, without appeal, on a doubled risperidone depot, haloperidol chaser, and four other concurrent psychotrophics anyone? Think it couldn't happen? Think it advisable?

So, should we be minimizing or maximizing use of antipsychotics?

References:

Belmaker RH, Wald D. Haloperidol in normals. Br J Psychiatry. 1977 Aug 1;131():222-3. Abstract

Bola JR. Medication-free research in early episode schizophrenia: evidence of long-term harm? Schizophr Bull . 2006 Apr 1 ; 32(2):288-96. Abstract

Colton CW, Manderscheid RW. Congruencies in increased mortality rates, years of potential life lost, and causes of death among public mental health clients in eight states. Prev Chronic Dis. 2006 Apr 1;3(2):A42. Abstract

Dixon LB, Lehman AF, Levine J (1995) Conventional antipsychotic medications for schizophrenia. Schizophr Bull 21:567–577. Abstract

Hegarty JD, Baldessarini RJ, Tohen M, Waternaux C, Oepen G. One hundred years of schizophrenia: a meta-analysis of the outcome literature. Am J Psychiatry. 1994 Oct 1;151(10):1409-16. Abstract

Assen Jablensky, Psychological Medicine, suppl. 20 (1992), 1-95.

Joukamaa M, Heliövaara M, Knekt P, Aromaa A, Raitasalo R, Lehtinen V. Schizophrenia, neuroleptic medication and mortality. Br J Psychiatry. 2006 Feb 1;188():122-7. Abstract

Konopaske GT, Dorph-Petersen KA, Pierri JN, Wu Q, Sampson AR, Lewis DA. Effect of chronic exposure to antipsychotic medication on cell numbers in the parietal cortex of macaque monkeys. Neuropsychopharmacology. 2007 Jun;32(6):1216-23. Epub 2006 Oct 25. 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, . Effectiveness of antipsychotic drugs in patients with chronic schizophrenia. N Engl J Med . 2005 Sep 22 ; 353(12):1209-23. Abstract

Osborn DP, Levy G, Nazareth I, Petersen I, Islam A, King MB. Relative risk of cardiovascular and cancer mortality in people with severe mental illness from the United Kingdom's General Practice Rsearch Database. Arch Gen Psychiatry. 2007 Feb 1;64(2):242-9. Abstract

de Leon J. The effect of atypical versus typical antipsychotics on tardive dyskinesia: a naturalistic study. Eur Arch Psychiatry Clin Neurosci. 2007 Apr 1;257(3):169-72. Abstract

Seikkula J, Aaltonen J, Alakare B, Haarakangas K, Keranen J, Lehtinen K. Five-year experience of first-episode nonaffective psychosis in open-dialogue approach: Treatment principles, follow-up outcomes, and two case studies. Psychotherapy Research, March 2006; 16(2): 214.

Whitaker R. The case against antipsychotic drugs: a 50-year record of doing more harm than good. Med Hypotheses. 2004 Jan 1; 62(1):5-13. Abstract

Efficacy of Treatment Has to Be Related to Safety
The three articles and their summary provided by the Schizophrenia Research Forum address very important questions in long-term treatment of schizophrenia. Due to the efficacy of (first- and second-generation) antipsychotics (FGAs, SGAs) florid psychotic symptoms mostly remit under initiated and maintained treatment in the acute and stabilization phase. However, this mental illness is in most cases (about 80 percent) characterized by symptom recurrence or relapse, and long-term (low-dose) maintenance treatment is indicated to prevent relapse and maintain or improve patients' level of functioning. Like nearly all drugs, antipsychotics can also cause side effects, like extrapyramidal reactions, tachycardia, hypotension, lethargy, impotence, or hyperprolactinaemia (mainly by FGAs), agranulocytosis (Clozapine), weight gain, or metabolic effects (mainly discussed for the newer SGAs). However, contrary to the SRF summary, serious side effects are rather infrequent and uncommon. Nevertheless, to avoid (potential) harm for...  Read more

Efficacy of Treatment Has to Be Related to Safety
The three articles and their summary provided by the Schizophrenia Research Forum address very important questions in long-term treatment of schizophrenia. Due to the efficacy of (first- and second-generation) antipsychotics (FGAs, SGAs) florid psychotic symptoms mostly remit under initiated and maintained treatment in the acute and stabilization phase. However, this mental illness is in most cases (about 80 percent) characterized by symptom recurrence or relapse, and long-term (low-dose) maintenance treatment is indicated to prevent relapse and maintain or improve patients' level of functioning. Like nearly all drugs, antipsychotics can also cause side effects, like extrapyramidal reactions, tachycardia, hypotension, lethargy, impotence, or hyperprolactinaemia (mainly by FGAs), agranulocytosis (Clozapine), weight gain, or metabolic effects (mainly discussed for the newer SGAs). However, contrary to the SRF summary, serious side effects are rather infrequent and uncommon. Nevertheless, to avoid (potential) harm for patients, antipsychotic treatment should be kept as short (and in the lowest dose) as possible. Hence, the respective questions arise: How long should long-term treatment after remission of schizophrenic symptoms and stabilization be maintained? Are there alternative long-term treatment strategies to continuous treatment? Are longer periods without medication indicated? Which kind of patient is eligible?

Guidelines recommend evidence-based treatment
These questions are not new and have all (admittedly not sufficiently) been addressed by former studies. Evidence has been summarized by different national and international psychiatric associations and integrated to guideline recommendations (for a review see Gaebel et al., 2005). Contrary to Sarah Yates, they can be seen as ("credible") evidence-based recommendations to assist practitioners in treatment decisions. Based on our review, the three guidelines with highest (quality) scores are the ones from NICE (2002), APA (2004), and RANZCP (2002; revised in 2005). In addition, the German guideline has been recently revised based on the highest methodological standard (Gaebel et al., 2005).

According to these guidelines, (long-term) treatment should be maintained after a first episode in schizophrenia for at least 1 year; after a relapse for 2-5 years and for multiple-episode patients indefinite maintenance treatment is recommended.

To minimize side effects, especially tardive dyskinesia (TD) to some extent caused by FGAs, and to deal with frequent partial or complete noncompliance, targeted intermittent treatment has been provided in the late 1970s. In stable patients, drug treatment is gradually and stepwise discontinued and restarted in case of early warning signs (EWS) or prodromal symptoms of an impending relapse (requiring teaching patients and relatives to recognize EWS; see Marvin Herz's contribution). However, the risk for relapse was shown to be noticeably higher for targeted intermittent compared to maintenance treatment for schizophrenia patients in general (Kane, 1999), and intermittent treatment appears to increase rather than decrease the risk for TD (APA, 2004). In addition, the accuracy of relapse prediction based on prodromal symptoms or early warning signs is limited (Gaebel and Riesbeck, 2007). Reflecting these results, guidelines recommend (reservedly) targeted intermittent treatment as an alternative long-term treatment strategy after gradual and stepwise drug discontinuation and under close monitoring of early warning signs for an impending relapse. Against this background, the discontinuation strategy described by Nishikawa et al. (2007; increasing drug breaks and afterwards dose reduction) seems less appropriate.

Differential indication for targeted intermittent treatment?
On the other hand, research suggests that intermittent treatment seems more feasible in special groups of patients, particularly in first-episode patients. In a post-hoc analysis, maintenance treatment was found to be superior to targeted intermittent treatment regarding relapse prevention only in multiple-episode patients; however, both long-term treatment strategies were shown to be equally effective in first-episode patients (Gaebel et al. 2002). In recent years several new research programs on first-episode schizophrenia have been implemented, some of them focusing on the indicated duration of long-term (maintenance) treatment and the efficacy of targeted intermittent treatment. The (prospective) study of Wunderink et al. (2007), however, resulted in a twofold enhanced risk for relapse under intermittent compared to continued drug treatment, also in first-episode patients. Since continued maintenance treatment is recommended for the first post-acute year, their design—treatment was withdrawn already after a 6-month remission period—is debatable. A comprehensive program on optimization of long-term treatment for first-episode schizophrenia was conducted within the German Research Program on Schizophrenia (GRNS; Wölwer et al., 2003), which was funded by the German Ministry of Education and Research. In the first post-acute year, antipsychotic treatment was maintained (randomized controlled trial comparing low-dose haloperidol with risperidone; Gaebel et al., 2004; 2007), combined with different psychological strategies (2 months’ psychoeducation vs. 12 months’ cognitive behavioral therapy). In the second post-acute year, antipsychotics in patients sufficiently stable were randomly either continued or (stepwise) discontinued. Under both conditions, an early intervention was initiated in case of prodromal symptoms or other early warning signs as guided by a comprehensive decision algorithm (Gaebel and Riesbeck, 2007). Similarly to Wunderink and colleagues’ (2007), first (and preliminary) results indicate a significantly higher risk for relapse under targeted intermittent treatment. On the other hand, about 50 percent of patients having been discontinued remain stable in the second treatment year. However, final analyses have to be awaited.

All these data indicate that targeted intermittent treatment bears a higher risk for relapse also in first-episode patients. On the other hand, there are patients who remain stable although discontinued from antipsychotics. How can these patients be identified? The results from Harrow and Jobe (2007) demonstrate that patients with a favorable prognosis, as indicated by a higher premorbid level of functioning and favorable personality factors (e.g., internal locus of control), are more likely to remain stable over longer periods off medication. The respective prognostic analyses from the Wunderink et al. study, as well as our own data, will be provided in the near future. Nevertheless, expectations have to be scaled down, since replication of prognostic factors rarely succeeds. Even if factors can be replicated, applicability to an individual patient is still difficult. Appropriate cut-off scores have to be defined based on prognostic/diagnostic parameters (mainly sensitivity and specificity). In addition, according to the comprehensive aetiopathogenetic Vulnerability-Stress-Coping-model for schizophrenia, symptom (re-)exacerbation depends on (high biological) vulnerability, the occurrence of stressful life events, and (maladaptive) coping strategies. Accordingly, a better prognosis could be expected, if (markers of) all these factors are considered in addition to other relevant course indicators. As data from the first-episode long-term study within the GRNS indicates, the highest risk for relapse or deterioration is given if all three factors are present simultaneously.

Shared decision-making based on empirical evidence and practice
Bringing all issues together on a decision for the appropriate long-term treatment strategy after recovering from an acute episode in schizophrenia has to consider different factors regarding premorbid prognostic factors, indicators of vulnerability and illness course, coping abilities, and (future) stress exposure. Last but not least, one essential factor is added by the individual needs and preferences of the patient and his/her social environment. Accordingly, based on best knowledge, mainly provided by the treating psychiatrist and the individual needs expressed by the patient, pros and cons of the different treatment strategies have to be discussed leading to a shared decision. Nevertheless, more research regarding different long-term treatment strategies and their differential indication is needed to provide the evidence base for individual decisions.

References:

Lehman AF, Lieberman JA, Dixon LB, McGlashan TH, Miller AL, Perkins DO, Kreyenbuhl J; American Psychiatric Association; Steering Committee on Practice Guidelines. American-Psychiatric-Association (APA): Practice guideline for the treatment of patients with schizophrenia, second edition. Am J Psychiatry, 2004; 161(Suppl): 1-56. Abstract

Gaebel W, Falkai P, Weinmann S, Wobrock T. Behandlungsleitlinie Schizophrenie. In: S3 Praxisleitlinien in Psychiatrie und Psychotherapie. edited by Deutsche Gesellschaft für Psychiatrie, Psychotherapie und Nervenheilkunde (DGPPN). Darmstadt: Steinkopf Verlag, 2005.

Gaebel W, Jänner M, Frommann N, Pietzcker A, Köpcke W, Linden M, Müller P, Müller-Spahn F, Tegeler J: First vs. multiple episode schizophrenia: Two-year outcome of intermittent and maintenance medication strategies. Schizophrenia Research, 2002; 53, 145-159. Abstract

Gaebel W, Möller HJ, Buchkremer G, Ohmann C, Riesbeck M, Wölwer W, von Wilmsdorff M, Bottlender R, Klingberg S: Pharmacological long-term treatment strategies in first episode schizophrenia. Study design and preliminary results of an ongoing RCT within the German Research Network on Schizophrenia. Europ Arch Psychiatry Clin Neurosci, 2004; 254:129-140. Abstract

Gaebel W, Riesbeck M, Wölwer W, Klimke A, Eickhoff M, von Wilmsdorff M, Jockers-Scherübl MC, Kühn K, Lemke M, Bechdolf A, Bender S, Degner D, Schlösser R, Schmidt LG, Schmitt A, Jäger M, Buchkremer G, Falkai P, Klingberg S, Köpcke W, Maier W, Häfner H, Ohmann C, Salize HJ, Schneider F, Möller HJ Maintenance treatment with risperidone or low-dose haloperidol in first-episode schizophrenia. One-year results of a randomized controlled trial within the German Research Network on Schizophrenia. J Clin Psychiatry, 2007 (in press).

Gaebel W, Riesbeck M. Revisiting the relapse predictive validity of prodromal symptoms in schizophrenia. Schizophrenia Research, 2007 (in press).

Gaebel W, Weinmann S, Sartorius N, Rutz W, McIntyre JS. Schizophrenia practice guidelines: international survey and comparison. Br J Psychiatry. 2005;187:248-55. Abstract

Harrow M, Jobe TH. Factors involved in outcome and recovery in schizophrenia patients not on antipsychotic medications: a 15-year multifollow-up study. J Nerv Ment Dis. 2007, 195(5):406-14. Abstract

Kane JM. Management strategies for the treatment of schizophrenia. J Clin Psychiatry; 1999, 60 (Suppl 12): 13-17. Abstract

Leucht S, Barnes TR, Kissling W, Engel RR, Correll C, Kane JM. Relapse prevention in schizophrenia with new-generation antipsychotics: a systematic review and exploratory meta-analysis of randomized, controlled trials. Am J Psychiatry; 2003, 160:1209-1222. Abstract

National Institute for Clinical Excellence (NICE). Guidance on the use of newer (atypical) antipsychotic drugs for the treatment of schizophrenia. Technology Appraisal Guidance 2002; 43 (http://www.nice.org.uk)

Nishikawa T, Hayashi T, Koga I, Uchida Y. Neuroleptic withdrawal with remitted schizophrenics: a naturalistic follow-up study. Psychiatry. 2007;70(1):68-79. Abstract

Royal Australian and New Zealand College of Psychiatrists (RANZCP). Royal Australian and New Zealand College of Psychiatrists clinical practice guidelines for the treatment of schizophrenia and related disorders. Aust NZ J Psychiatry, 2005; 39:1-30.

Wölwer W, Buchkremer G, Häfner H, Klosterkötter J, Maier W, Möller HJ, Gaebel W. German research network on schizophrenia - bridging the gap between research and care. Europ Arch Psychiatry Clin Neurosci; 2003, 253:321-329. Abstract

Wunderink L, Nienhuis FJ, Sytema S, Slooff CJ, Knegtering R, Wiersma D. Guided discontinuation versus maintenance treatment in remitted first-episode psychosis: relapse rates and functional outcome. J Clin Psychiatry, 2007, 68:654-61. Abstract

Sarah Yates provides an interesting and informative comment touching on many relevant issues—please read. My thoughts on a couple of these issues are as follows:

1. Minimizing or maximizing antipsychotic drug administration may be a public health issue, but it is not the concept for treating an individual. The issue is optimizing drug therapy (as well as other therapies). In this regard, the evidence base is very weak and practice is probably very bad. Drugs do not come to market with good evidence for optimal dosing even in the acute situation. The doctor's responsibility will be to develop recommendations at each phase of illness based on relatively little information. And the available data will be on groups of patient subjects in illness phase and other circumstances different from the individual being treated.

2. Optimizing will depend on many things, but decisions on how to approach this are developed in the doctor/patient relationship in the broad context of the recovery process. Here an appreciation of risks and benefits is ascertained with attention to...  Read more

Sarah Yates provides an interesting and informative comment touching on many relevant issues—please read. My thoughts on a couple of these issues are as follows:

1. Minimizing or maximizing antipsychotic drug administration may be a public health issue, but it is not the concept for treating an individual. The issue is optimizing drug therapy (as well as other therapies). In this regard, the evidence base is very weak and practice is probably very bad. Drugs do not come to market with good evidence for optimal dosing even in the acute situation. The doctor's responsibility will be to develop recommendations at each phase of illness based on relatively little information. And the available data will be on groups of patient subjects in illness phase and other circumstances different from the individual being treated.

2. Optimizing will depend on many things, but decisions on how to approach this are developed in the doctor/patient relationship in the broad context of the recovery process. Here an appreciation of risks and benefits is ascertained with attention to the patient's value system.

3. As a clinical concept, the "no drug" proposition is applicable only if based on an anti-drug ideology. The usual situation should be when and how to use drugs and when and how to be off medication. I would also view the "continuous medication always" as based on ideology.

4. The symptom reduction and relapse prevention effects of dopamine antagonists are valid, and may apply to virtually all patients with schizophrenia and psychosis. The concept of non-responders is flawed, for the patients who have a very inadequate response may be more symptomatic if off drug. And there are not alternative, robust antipsychotic therapies that exclude dopamine antagonists. There is no evidence that those persons doing poorly on drugs would do better without (even adverse effects included in the consideration).

5. Classifying drugs as first- and second-generation or typical and atypical is not useful for therapeutic or adverse effect considerations. Generally, efficacy and effectiveness is similar across these drugs (clozapine excepted), but adverse effects vary widely and need to be defined at the individual drug (rather than drug class) level. Minimizing risk by careful selection of drug and dose is the most important effect the doctor's decision can have on the risk/benefit equation.

6. Clinicians need to develop effective collaboration with patients who do not (or will not) consume medication in the recommended manner. Poor adherence is common, and for many reasons. In general, I think clinicians have not effectively engaged in developing alternative strategies, let alone identifying persons who may be good candidates for reducing risks by being off medication (and on a targeted drug strategy). Herz provides some guidelines in his comments in this forum.

Yates brings up many other issues, but I'll leave this discussion with the assertion that key issues in clinical care cannot be anchored in compelling evidence at this time. But the primary question concerning antipsychotic drug treatment for schizophrenia is not yes or no, but how.

I welcome much of what William Carpenter has to say, though, as he points out, all of it is up for debate, as there are no certainties. However, I think it a little harsh to state, "As a clinical concept, the ‘no drug’ proposition is applicable only if based on an anti-drug ideology." No drug ever, for anyone under any circumstances, yes: this is an ideology. To raise the legitimate concern that once an individual is started on drugs it may be very hard to ever stop them, at least for some individuals, is not an ideology. It is a pragmatic concern, from which follows the premise that if it is possible to avoid drugs, it might well be a good idea to do so, and the long-term outcome might be better. As discussed previously, there is evidence to suggest this is not such a silly idea as many suppose. Seikkula is not an ideologist in the sense that patients sometimes do go on antipsychotics, on a needs basis.

In my own case, I tapered from 1.5 mgs risperidone to 0.25 mgs every third day, over nearly a year, although clearly I was on a very low dose for most of that time. (You...  Read more

I welcome much of what William Carpenter has to say, though, as he points out, all of it is up for debate, as there are no certainties. However, I think it a little harsh to state, "As a clinical concept, the ‘no drug’ proposition is applicable only if based on an anti-drug ideology." No drug ever, for anyone under any circumstances, yes: this is an ideology. To raise the legitimate concern that once an individual is started on drugs it may be very hard to ever stop them, at least for some individuals, is not an ideology. It is a pragmatic concern, from which follows the premise that if it is possible to avoid drugs, it might well be a good idea to do so, and the long-term outcome might be better. As discussed previously, there is evidence to suggest this is not such a silly idea as many suppose. Seikkula is not an ideologist in the sense that patients sometimes do go on antipsychotics, on a needs basis.

In my own case, I tapered from 1.5 mgs risperidone to 0.25 mgs every third day, over nearly a year, although clearly I was on a very low dose for most of that time. (You could say most of my treatment was one long taper.) I still experienced marked somatic symptoms on total withdrawal, and this lasted for around 2 weeks. Given the effects of low dose, I am likely a poor metabolizer. Genotyping tests can classify individuals as poor, moderate, or extensive metabolizers, and this can lead to huge differences in therapeutic effect and toxicity of psychotrophics ( Gillman, 2007; Bondy and Spellmann, 2007). Yet another complicating factor to add to the mix.

To my knowledge there is no satisfactory study to show whether poor responders would do better long term off drugs or not. Therefore, it remains a legitimate question.

May I add that I thought Wolfgang Gaebel's post very well referenced and a useful contribution to the discussion. I do not necessarily agree with him on all issues. but it is good to get the data (even if it is flawed to a greater or lesser extent). How he can make his assertions regarding tolerability and safety I do not know. The data do not support him. Omission is not evidence. I referenced some of the recognized problems.

Antipsychotics have terrible side effects. I agree that NICE guidelines are probably the best of the bunch; I do not want to throw the baby out with the bathwater. However, if you look at the discontinuation studies that underpin them, there is almost certainly a biasing of results due to withdrawal effects. Determining the extent of this bias, and how much appropriate tapering might affect it, is largely guesswork. The recommended 2- to 5-year maintenance on drug after a second or subsequent psychotic episode is pretty much a guess. Which is it to be, 2 or 5? At least the guidelines raise the question, presumably answered by an individualized review.

References:

Bondy B, Spellmann I. Pharmacogenetics of antipsychotics: useful for the clinician? Curr Opin Psychiatry. 2007 Mar;20(2):126-30. Review. Abstract

Gillman, K (2007). Cytochrome P450 Enzymes: http://www.psychotropical.com/1_cyp_introduction.shtml, accessed 17 July 2007.

I believe the jury is out to decide if long-term antipsychotic treatment is hazardous or not in terms of brain biology. The new generation of antipsychotics clearly increases the risk for other medical problems, thus the re-emerging interest in targeted antipsychotic treatments.

Nobody likes to use a medication all the time. I found most of my patients to be reluctantly compliant on their medications after many self-trials of no medication periods with fairly dramatic psychosocial consequences.

In my experience, the main determinant of success of targeted antipsychotic treatment is not the severity of symptoms such as delusions, but if and how fast insight is lost. There are clear subgroups where the first sign of a relapse is quick loss of insight, while others may keep partial insight throughout relapse of other symptoms. If the desire, and origins of the desire to go off medications, are well addressed in therapy, the second group does enjoy medication-free periods, if not complete medication-free life, albeit almost always with residual symptoms.

Please note...  Read more

I believe the jury is out to decide if long-term antipsychotic treatment is hazardous or not in terms of brain biology. The new generation of antipsychotics clearly increases the risk for other medical problems, thus the re-emerging interest in targeted antipsychotic treatments.

Nobody likes to use a medication all the time. I found most of my patients to be reluctantly compliant on their medications after many self-trials of no medication periods with fairly dramatic psychosocial consequences.

In my experience, the main determinant of success of targeted antipsychotic treatment is not the severity of symptoms such as delusions, but if and how fast insight is lost. There are clear subgroups where the first sign of a relapse is quick loss of insight, while others may keep partial insight throughout relapse of other symptoms. If the desire, and origins of the desire to go off medications, are well addressed in therapy, the second group does enjoy medication-free periods, if not complete medication-free life, albeit almost always with residual symptoms.

Please note that for younger patients the desire to go off medications often reflects a desire to wish a nasty, lifelong illness away rather than a side effect problem.

Also, perhaps Drs. Carpenter and Kapur can comment on older papers that examined long-term outcomes of depot medications to oral variants, which is integral to this discussion.

As stated in the CATIE and CAFÉ neurocognition manuscripts, it is possible that the small improvements in neurocognitive performance following randomization to one of the antipsychotic treatments in these studies are due solely to practice effects or expectation biases. This statement is affirmed by the excellent recent study by Goldberg et al. in which improvements in cognitive performance were almost identical in magnitude to the practice effects found in healthy controls. While these data may be perhaps disappointing to the hope that second-generation medications improve cognition, they may also suggest that cognitive performance is less recalcitrant to change than previously expected.

In the context of a double-blind study design, the degree of cognitive enhancement observed for each treatment group is a function of three major variables: treatment effect, placebo effect, and practice effect. In studies of antipsychotic medications without a placebo control group, practice and placebo effects in schizophrenia cannot be...  Read more

As stated in the CATIE and CAFÉ neurocognition manuscripts, it is possible that the small improvements in neurocognitive performance following randomization to one of the antipsychotic treatments in these studies are due solely to practice effects or expectation biases. This statement is affirmed by the excellent recent study by Goldberg et al. in which improvements in cognitive performance were almost identical in magnitude to the practice effects found in healthy controls. While these data may be perhaps disappointing to the hope that second-generation medications improve cognition, they may also suggest that cognitive performance is less recalcitrant to change than previously expected.

In the context of a double-blind study design, the degree of cognitive enhancement observed for each treatment group is a function of three major variables: treatment effect, placebo effect, and practice effect. In studies of antipsychotic medications without a placebo control group, practice and placebo effects in schizophrenia cannot be disentangled from treatment effects. They also cannot be disentangled from each other. Recent data from a double-blind study comparing the effects of donepezil hydrochloride and placebo in a highly refined sample of 226 patients with schizophrenia stabilized while taking second-generation antipsychotics suggested that patients taking placebo had neurocognitive effect size improvements (0.22 SD after being tested twice over 6 weeks; 0.45 SD after the third assessment at 12 weeks) on the same test battery used in the CATIE and CAFÉ studies, suggesting a practice or placebo effect (Keefe et al., Neuropsychopharmacology, in press) consistent with the improvements reported in the CATIE and CAFÉ treatment studies. These cognitive improvements are in contrast to test-retest data collected in patients with schizophrenia tested with the MATRICS Consensus Cognitive Battery (MCCB; Nuechterlein et al., in press) and the Brief Assessment of Cognition in Schizophrenia (BACS; Keefe et al., 2004), which showed very little practice effects. The contrast of the data from these test-retest studies that did not involve the initiation of new treatments with cognitive improvements following the initiation of antipsychotic treatment or placebo suggests that attribution biases beyond simple practice effects may be at work.

Test-retest data from patients tested twice within a briefer period than the test interval in the four treatment studies discussed above suggest that schizophrenia patients demonstrate relatively small improvements in executive functions (Keefe et al., 2004; Nuechterlein et al., in press) and the WAIS digit-symbol test (Nuechterlein et al., in press), and medium improvements on tests of verbal memory only when identical versions are repeated (Hawkins and Wexler, 1999; Keefe et al., 2004) but not on tests of verbal fluency (Keefe et al., 2004; Nuechterlein et al., in press). In the donepezil/placebo study, patients who received placebo improved substantially across several cognitive domains. Although not tested directly, this series of results suggests that the magnitude of placebo effects in cognitive enhancement trials may exceed the reported size of practice-related improvements in studies of schizophrenia patients tested twice without the prospect of the initiation of a cognitive intervention.

The greater improvements in cognition found in the context of a placebo-controlled trial could be due to a variety of psychological factors. When a patient enters into a trial or is treated with a medication that is believed to contribute beneficially to cognitive performance, rater bias and expectation bias can have strong effects on performance. Patients who are told that their cognitive abilities might improve may be able to perform better on the test batteries used in the study simply because their expectations become more optimistic. Second, testers who believe that a patient will have cognitive improvement, or hope for such improvement, could administer the tests in a more hopeful, positive manner, which can help the patient raise his or her expectations for performance and thus engage motivational systems that were previously disengaged (Keefe, 2006). Such expectation bias can also lead to inaccuracies in scoring; since many cognitive tests require the use of judgment to determine final scores, hopeful testers are more likely to give the “benefit of the doubt” to patients after they have entered into a study in which the treatment is potentially cognitively enhancing. Third, this same type of expectation could have an impact on the support that a patient receives in his or her community/living situation. If the people who interact regularly with the patient begin looking for better performance on cognitively related tasks, these expectations could become self-fulfilling in that they may raise the confidence and motivation of the patient to perform well on such tasks, including cognitive testing.

The factors associated with improvement during a placebo-controlled trial are indeed complex, and it is difficult to distinguish practice effects from placebo effects. However, the relatively small clinical improvement in test-retest designs without treatment or placebo intervention suggests that any potential practice effects may at least be potentiated by placebo effects.

The implications for this series of results include a methodological caution and a reason for optimism. Regarding the caution, future trials of cognitive-enhancing compounds might need to be designed in such a way that practice and placebo are reduced. Very few treatment studies of patients with schizophrenia have employed a priori methodological strategies to reduce the magnitude of potential practice effects, such as the use of a placebo run-in period with one or more administrations of the cognitive battery prior to randomization. Regarding the optimism, these studies suggest that schizophrenia cognition (perhaps especially when freed from the dampening effects of large doses of high potency medications such as haloperidol) could be more plastic that had been previously assumed; it is possibly as sensitive to experience-dependent learning in schizophrenia patients as healthy controls, and it may benefit from improved psychological expectations. While this is a methodological nuisance for clinical trial designs, it may also reveal an unexpectedly large potential gain for psychological interventions such as cognitive remediation, cognitive-behavioral therapy, and even encouragement.

References:

Goldberg TE, Goldman RS, Burdick KE, Malhotra AK, Lencz T, Patel RC, Woerner MG, Schooler NR, Kane JM, Robinson DG. Cognitive improvement after treatment with second-generation antipsychotic medications in first-episode schizophrenia: Is it a practice effect? Arch Gen Psychiatry. 2007 Oct;64:1115-1122. Abstract

Hawkins KA, Wexler BE (1999). California Verbal Learning Test practice effects in a schizophrenia sample. Schizophr Res 39: 73-78. Abstract

Keefe RSE. Missing the sweet spot: Disengagement in schizophrenia. Psychiatry, 2006; 3: 36-41.

Keefe RSE, Malhotra AK, Meltzer H, Kane JM, Buchanan RW, Murthy A, Sovel M, Li, C, Goldman R. Efficacy and safety of donepezil in patients with schizophrenia or schizoaffective disorder: Significant placebo/practice effects in a 12-week, randomized, double-blind, placebo-controlled trial. Neuropsychopharmacology, 2007 [Epub ahead of print]. Abstract

Keefe RSE¸ Goldberg TE, Harvey PD, Gold JM, Poe M, Coughenour L. The Brief Assessment of Cognition in Schizophrenia: Reliability, sensitivity, and comparison with a standard neurocognitive battery. Schizophrenia Research, 2004; 68: 283-297. Abstract

Nuechterlein KH, Green MF, Kern RS, Baade LE, Barch D, Cohen J, Essock S, Fenton WS, Frese FJ, Gold JM, Goldberg T, Heaton R, Keefe RSE, Kraemer H, Mesholam-Gately R, Seidman LJ, Stover E, Weinberger D, Young AS, Zalcman S, Marder SR. The MATRICS consensus cognitive battery: Part 1. Test selection, reliability, and validity. The American Journal of Psychiatry (in press).

This article questions the prevailing notion that antipsychotic medication (particularly second-generation antipsychotics) improve cognitive functioning in individuals with schizophrenia. As the authors rightly note, practice effects should be taken into account before attributing improvements to drug effects.

View all comments by Narsimha Pinninti

I propose that future studies should use computational cognitive assessment tools like CANTAB or CogTest, which have at least two advantages. These tools have multiple similar test modules, so on each testing during one study, participants get a similar but not the same test to assess the same cognitive function. Besides, computational assessment also reduces chances of subjective bias on the part of investigator.

References:

Levaux MN, Potvin S, Sepehry AA, Sablier J, Mendrek A, Stip E. Computerized assessment of cognition in schizophrenia: promises and pitfalls of CANTAB. Eur Psychiatry. 2007 Mar;22(2):104-15. Review. Abstract

View all comments by Saurabh Gupta

One remedy would be repeated practice over time before the actual baseline, sufficient to reach asymptotic ability. Computerized testing of reaction time measures, short-term memory span, etc. would all be quite cheap and easy to implement, for example, as a weekly session.

View all comments by Sebastian Therman

We recently completed a meta-analysis on "Longitudinal studies of cognition in schizophrenia" (to be published in the British Journal of Psychiatry) based on 53 studies providing data for 31 cognitive variables. When enough data were available (19 variables from eight cognitive tests), we compared the results of schizophrenic participants to those of normal controls.

Given the differences in methods and the fact that most of the studies included in our meta-analysis reported results of patients being past their first episode (FE), it is surprising how close our results and conclusions are compared to those of Goldberg et al. In our analysis we found that, with two exceptions (semantic verbal fluency and Boston naming test, which were stable), participants with schizophrenia improved their performances. The improvement was statistically significant for 19 variables (out of 29). However, controls also showed improvement in most of the variables due to the practice effect. A significant improvement (definite practice effect) was present for 10 variables, an improvement that...  Read more

We recently completed a meta-analysis on "Longitudinal studies of cognition in schizophrenia" (to be published in the British Journal of Psychiatry) based on 53 studies providing data for 31 cognitive variables. When enough data were available (19 variables from eight cognitive tests), we compared the results of schizophrenic participants to those of normal controls.

Given the differences in methods and the fact that most of the studies included in our meta-analysis reported results of patients being past their first episode (FE), it is surprising how close our results and conclusions are compared to those of Goldberg et al. In our analysis we found that, with two exceptions (semantic verbal fluency and Boston naming test, which were stable), participants with schizophrenia improved their performances. The improvement was statistically significant for 19 variables (out of 29). However, controls also showed improvement in most of the variables due to the practice effect. A significant improvement (definite practice effect) was present for 10 variables, an improvement that did not reach significance (possible practice effect) was present in six more variables, and three variables showed no improvement. When compared with schizophrenic patients, controls showed similar improvement for 11 variables, significantly more improvement for seven variables (six of them from the “definite practice effect” group, one from the “possible practice effect”) and for one variable less improvement (the Stroop interference score). Thus, these results suggest that for most of the cognitive variables, improvement seen in schizophrenic subjects does not exceed improvement due to the practice effect.

It is interesting to mention that in our analysis only two variables improved significantly more when patients had a change in their medication from first-generation antipsychotics (FGAs) to second-generation antipsychotics (SGAs). These variables were time to complete TMT B and the delayed recall of the Visual Reproduction (from the WMS). In the Goldberg et al. study the only two tests that showed more improvement in schizophrenic subjects than in controls were also the TMT and visual reproduction. Although in our study schizophrenic subjects did not improve more than controls, the two results (Goldberg’s and ours) taken together could be an indirect argument for a differential, specific effect of SGAs on those two (visuo-spatial) tasks. The placebo effect—see the comment by Richard Keefe—could explain why improvement in the study by Goldberg et al. was greater than in our meta-analysis. Studies of effects of changing medication in the opposite direction, from SGAs to FGAs, could contribute to validate or invalidate these hypotheses.

Goldberg et al. suggested that there could be a set of task characteristics that could be used to develop tasks resistant to the practice effect. Our own results are less optimistic as they show that phonemic verbal fluency, despite a very similar format, does not share the “practice resistance” with the semantic verbal fluency. However, we think that there is already a wealth of data that could be used to select the best cognitive tests. An alternative solution is the use of scales and questionnaires for evaluating cognition (that are sensible to the placebo effect but not to the practice effect).

References:

Szoke A, Trandafir A, Dupont M-E, Meary A, Schurhoff F, Leboyer M. Longitudinal studies of cognition in schizophrenia. British Journal of Psychiatry (in press).

Implicit in the findings of Schmid et al. is the idea that the relationship among ligand, receptor signaling, and cellular context is an extremely complex one that will take a great deal more work to tease out. Thus, Dr. Bryan Roth has proposed on a number of occasions (see, for example, Gray and Roth, 2007; Abbas and Roth, 2005) that novel approaches for drug discovery may prove more effective in producing schizophrenia drugs that have greater therapeutic efficacy with lower side effect liability. Since it will likely be many years before the field has a detailed understanding of the "nitty-gritty" of the receptor signaling and trafficking relevant to schizophrenia and its treatment, we have suggested a number of approaches that are less reliant on such information.

For example, approaches based on screening for drugs that either mimic the gene expression profiles of gold standard drugs such as clozapine or normalize schizophrenia-associated changes in gene expression are being...  Read more

Implicit in the findings of Schmid et al. is the idea that the relationship among ligand, receptor signaling, and cellular context is an extremely complex one that will take a great deal more work to tease out. Thus, Dr. Bryan Roth has proposed on a number of occasions (see, for example, Gray and Roth, 2007; Abbas and Roth, 2005) that novel approaches for drug discovery may prove more effective in producing schizophrenia drugs that have greater therapeutic efficacy with lower side effect liability. Since it will likely be many years before the field has a detailed understanding of the "nitty-gritty" of the receptor signaling and trafficking relevant to schizophrenia and its treatment, we have suggested a number of approaches that are less reliant on such information.

For example, approaches based on screening for drugs that either mimic the gene expression profiles of gold standard drugs such as clozapine or normalize schizophrenia-associated changes in gene expression are being explored. Another approach is behavior-based screening, in which targeted screens are performed with drugs to find those that have efficacy in animal disease models. A further related approach, exemplified by Psychogenics' Smartcube(TM) (the associated database is called Smartbase[TM]) involves injecting drugs and monitoring the resulting behavior using computer-based machine learning to generate a multidimensional behavioral signature for gold standard drugs. Drugs can then be screened to look for those that mimic gold standard drugs in terms of their signatures. Though Psychogenics does not appear to have done much (at least publicly) with this approach, it represents the sort of innovative thinking that may prove fruitful in future behavior-based drug discovery efforts since it is not dependent on knowing anything about the mechanism. In the end, at least in the near future, we believe such approaches may prove extremely useful in drug discovery efforts since they do not rely on extensive mechanistic knowledge of the processes underlying schizophrenia.

References:

Gray JA, Roth BL. The pipeline and future of drug development in schizophrenia. Mol Psychiatry. 2007 Oct ;12(10):904-22. Abstract

Abbas A, Roth B. Progress towards better understanding and treatment of major psychiatric illnesses. Drug Discov Today. 2005 Jul 15;10(14):960-2. 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

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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

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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

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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

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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

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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

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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

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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

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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.