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.

This compound looks promising because it has good bioavailability and passes through the blood-brain barrier. It differs from DMXB-A in that it is a full agonist, which some people believe targets the α7 nicotinic receptor more fully, but also may have more problems with desensitization, which is not tested in this paper. They administer the drug to animals that are pretreated with amphetamine to cause a sensorimotor gating deficit, and thereby an animal model of schizophrenia. (I favor the use of DBA mice, which are abnormal in their gating because genetically they have fewer nicotinic receptors, as is the case with people with schizophrenia.) The authors are able to correct the gating deficit with their drug. However, they do not then let the deficit become abnormal (or artificially induce the abnormality again) and then give a second dose of their drug to see if they can again get a response, which would show that the receptor does not desensitize and the drug will work with repeated dosing. This is the problem with nicotine. We were able to get a second response with...  Read more

This compound looks promising because it has good bioavailability and passes through the blood-brain barrier. It differs from DMXB-A in that it is a full agonist, which some people believe targets the α7 nicotinic receptor more fully, but also may have more problems with desensitization, which is not tested in this paper. They administer the drug to animals that are pretreated with amphetamine to cause a sensorimotor gating deficit, and thereby an animal model of schizophrenia. (I favor the use of DBA mice, which are abnormal in their gating because genetically they have fewer nicotinic receptors, as is the case with people with schizophrenia.) The authors are able to correct the gating deficit with their drug. However, they do not then let the deficit become abnormal (or artificially induce the abnormality again) and then give a second dose of their drug to see if they can again get a response, which would show that the receptor does not desensitize and the drug will work with repeated dosing. This is the problem with nicotine. We were able to get a second response with DMXB-A, and Karen Stevens has this kind of data in a paper on DMXB-A in mice (Stevens et al., 1998). This has not been true with other nicotinic compounds (Stevens and Wear, 1997). Finally, it is important to note that this is in animal models; who knows what it will do in humans?

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 study by Zhang et al. (2012) provides further evidence for the therapeutic potential of partial α7 nicotinic acetylcholine receptor (nAChR) agonists in the treatment of the cognitive deficits associated with schizophrenia. Given the impact of this symptom group on psychosocial functioning (Green et al., 2004; Tan, 2009) and the current absence of effective treatments, the importance of such findings is easily seen. Tropisetron administered over 10 days improved immediate and delayed memory subscales of the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) and improved P50 auditory gating deficits in 40 non-smoking inpatients with schizophrenia.

The evidence for enhanced auditory gating was strong, with the reduction in the S2/S1 ratio being entirely due to a decrease in S2 amplitude with no change in S1. By limiting the study sample to patients who displayed P50 gating deficits at baseline (~40 percent of all screened patients), the authors may...  Read more

The study by Zhang et al. (2012) provides further evidence for the therapeutic potential of partial α7 nicotinic acetylcholine receptor (nAChR) agonists in the treatment of the cognitive deficits associated with schizophrenia. Given the impact of this symptom group on psychosocial functioning (Green et al., 2004; Tan, 2009) and the current absence of effective treatments, the importance of such findings is easily seen. Tropisetron administered over 10 days improved immediate and delayed memory subscales of the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) and improved P50 auditory gating deficits in 40 non-smoking inpatients with schizophrenia.

The evidence for enhanced auditory gating was strong, with the reduction in the S2/S1 ratio being entirely due to a decrease in S2 amplitude with no change in S1. By limiting the study sample to patients who displayed P50 gating deficits at baseline (~40 percent of all screened patients), the authors may have selected a subpopulation of patients particularly prone to showing benefits from α7 nAChR agonist treatment, possibly due to a larger incidence of genetic mutations reducing α7 nAChR subunit expression (Leonard et al., 2002) in this subsample. This type of pre-screening may indeed be a clinical approach to be considered prior to α7 agonist treatment. However, the measurement reliability of the P50 S2/S1 ratio tends to be low, and the degree to which P50 gating deficits predict treatment success with α7 agonists remains to be determined. Despite the large role that this ERP has played as an endophenotype of schizophrenia guiding drug development, evidence that P50 gating deficits are related to higher cognitive functions is still sparse (Potter et al., 2006). Zhang et al. found that changes in P50 gating from baseline to day 10 were correlated with changes in RBANS scores, collapsing data across all four treatment groups (including placebo). However, such correlations may be based on day-to-day fluctuations in cognitive state that could affect both measures in the same manner. More evidence is needed to clarify the clinical significance of improvements in P50 gating.

The finding that effects of tropisetron were seen mostly on memory indices differs from studies with the partial α7 agonist DMXB-A (Olincy et al., 2006; Freedman et al., 2008) and a previous study with tropisetron (Shiina et al., 2010), which reported effects predominantly on attention/vigilance indices. Larger trials may be able to determine more conclusively the cognitive domains beneficially affected by α7 agonists. Relatively flat dose-response curves were observed with tropisetron, consistent with a partial agonist mode of action. The finding that the largest dose (20 mg) produced no added benefits but tended to be associated with more side effects argues for the choice of lower doses.

Caution is warranted to not let positive findings with α7 agonists convey the impression that non-α7 nAChR subtypes are irrelevant for the treatment of cognitive deficits in schizophrenia. Indeed, non-α7 subtypes such as α4β2 mediate beneficial effects of nAChR agonists on cognitive performance (e.g., Dunbar et al., 2007; Grottick et al., 2003; Hahn et al., 2003; Levin, 2002), including improvements in sensory gating (Radek et al., 2006). The advantage of targeting α7 over other nAChR subtypes remains to be established by direct comparison. There is also a need for direct comparisons of α7-selective agonists with broader acting nAChR agonists to determine whether this subtype captures all cognitive benefit to be harvested from nAChR modulation in the treatment of schizophrenia.

References:

Dunbar G, Boeijinga PH, Demazières A, Cisterni C, Kuchibhatla R, Wesnes K, Luthringer R (2007) Effects of TC-1734 (AZD3480), a selective neuronal nicotinic receptor agonist, on cognitive performance and the EEG of young healthy male volunteers. Psychopharmacology 191: 919-29. Abstract

Freedman R, Olincy A, Buchanan RW, Harris JG, Gold JM, Johnson L, Allensworth D, Guzman-Bonilla A, Clement B, Ball MP, Kutnick J, Pender V, Martin LF, Stevens KE, Wagner BD, Zerbe GO, Soti F, Kem WR. (2008) Initial phase 2 trial of a nicotinic agonist in schizophrenia. Am J Psychiatry 165: 1040-7. Abstract

Green MF, Kern RS, Heaton RK (2004) Longitudinal studies of cognition and functional outcome in schizophrenia: implications for MATRICS. Schizophr Res 72: 41-51. Abstract

Grottick AJ, Haman M, Wyler R, Higgins GA (2003) Reversal of a vigilance decrement in the aged rat by subtype-selective nicotinic ligands. Neuropsychopharmacology 28: 880-7. Abstract

Hahn B, Sharples CG, Wonnacott S, Shoaib M, Stolerman IP (2003) Attentional effects of nicotinic agonists in rats. Neuropharmacology 44: 1054-67. Abstract

Leonard S, Gault J, Hopkins J, Logel J, Vianzon R, Short M, Drebing C, Berger R, Venn D, Sirota P, Zerbe G, Olincy A, Ross RG, Adler LE, Freedman R (2002) Association of promoter variants in the alpha7 nicotinic acetylcholine receptor subunit gene with an inhibitory deficit found in schizophrenia. Arch Gen Psychiatry 59: 1085-96. Abstract

Levin ED (2002) Nicotinic receptor subtypes and cognitive function. J Neurobiol 53: 633-640. Abstract

Olincy A, Harris JG, Johnson LL, Pender V, Kongs S, Allensworth D, Ellis J, Zerbe GO, Leonard S, Stevens KE, Stevens JO, Martin L, Adler LE, Soti F, Kem WR, Freedman R. (2006) Proof-of-concept trial of an alpha7 nicotinic agonist in schizophrenia. Arch Gen Psychiatry 63: 630-8. Abstract

Potter D, Summerfelt A, Gold J, Buchanan RW (2006) Review of clinical correlates of P50 sensory gating abnormalities in patients with schizophrenia. Schiz Bull 32: 692-700. Abstract

Radek RJ, Miner HM, Bratcher NA, Decker MW, Gopalakrishnan M, Bitner RS (2006) Alpha4beta2 nicotinic receptor stimulation contributes to the effects of nicotine in the DBA/2 mouse model of sensory gating. Psychopharmacology 187: 47-55. Abstract

Shiina A, Shirayama Y, Niitsu T, Hashimoto T, Yoshida T, Hasegawa T, Haraguchi T, Kanahara N, Shiraishi T, Fujisaki M, Fukami G, Nakazato M, Iyo M, Hashimoto K (2010) A randomised, double-blind, placebo-controlled trial of tropisetron in patients with schizophrenia. Ann Gen Psychiatry 9: 27. Abstract

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The paper of Zhang et al. once more presents promising findings suggesting that nicotinic α7 (partial) agonists may eventually be used as cognition enhancers in schizophrenia. Since several completed studies about the effect of nicotinic agonists on P50 gating and cognitive parameters are now around, we should try to figure out what distinguishes the negative and positive studies.

In the particular case of tropisetron, it certainly needs to be acknowledged that this drug also is a serotonin 5-HT3 antagonist. Previous studies (e.g., Adler et al., 2005) have already suggested that drugs that act as antagonists at this receptor improve P50 gating. Since antagonism of 5-HT3 increases release of acetylcholine, this may add to the direct partial agonist effect of tropisetron at the (low affinity) α7 nicotinic receptor as well as other nicotinic receptors, including high-affinity α4β2 receptors. In this regard, we should also acknowledge that agonists that act at other nicotinic receptors (α4β2) are now...  Read more

The paper of Zhang et al. once more presents promising findings suggesting that nicotinic α7 (partial) agonists may eventually be used as cognition enhancers in schizophrenia. Since several completed studies about the effect of nicotinic agonists on P50 gating and cognitive parameters are now around, we should try to figure out what distinguishes the negative and positive studies.

In the particular case of tropisetron, it certainly needs to be acknowledged that this drug also is a serotonin 5-HT3 antagonist. Previous studies (e.g., Adler et al., 2005) have already suggested that drugs that act as antagonists at this receptor improve P50 gating. Since antagonism of 5-HT3 increases release of acetylcholine, this may add to the direct partial agonist effect of tropisetron at the (low affinity) α7 nicotinic receptor as well as other nicotinic receptors, including high-affinity α4β2 receptors. In this regard, we should also acknowledge that agonists that act at other nicotinic receptors (α4β2) are now under investigation and show promising results when it comes to cognition enhancement in schizophrenia (e.g., varenicline).

Varenicline is primarily a partial agonist of the α4β2 subtype (although agonism at α7 has also been reported). Notably, other than tropisetron, varenicline is an agonist of 5-HT3 receptors. This is puzzling, adding to the confusion about the true cognition-enhancing effect in cholinergic drugs. It might be (exclusively) α7, but it is too early to jump to this conclusion. For instance, we recently published a negative proof-of-mechanism study on allosteric α7 nicotinic receptor modulation and P50 sensory gating in schizophrenia (Winterer et al., 2013).

In my opinion, what we need now is to go back to healthy probands (Phase 1) and select a range of drugs with different receptor profiles, but which have in common that they all act directly or indirectly at nicotinic receptors. These drugs then should be systematically tested for their effects on electrophysiological surrogate measures, including P50 gating, as well as cognitive measures, followed by corresponding investigations (using a preselected subset of compounds) in schizophrenia patients. Of course, this would require collaboration between R&D of different pharmaceutical companies—in other words: an industrial network approach is the unmet need!

References:

Adler LE, Cawthra EM, Donovan KA, Harris JG, Nagamoto HT, Olincy A, Waldo MC. Improved p50 auditory gating with ondansetron in medicated schizophrenia patients. Am J Psychiatry . 2005 Feb ; 162(2):386-8. Abstract

Winterer G, Gallinat J, Brinkmeyer J, Musso F, Kornhuber J, Thuerauf N, Rujescu D, Favis R, Sun Y, Franc MA, Ouwerkerk-Mahadevan S, Janssens L, Timmers M, Streffer JR. Allosteric alpha-7 nicotinic receptor modulation and P50 sensory gating in schizophrenia: A proof-of-mechanism study. Neuropharmacology . 2013 Jan ; 64(1):197-204. Abstract