Schizophrenia Research Forum - A Catalyst for Creative Thinking

New Schizophrenia Drug Studies Offer Threads of Hope

3 September 2008. The need for treatments that act on the full spectrum of schizophrenia symptoms—including positive, negative, and cognitive—remains critical. While the likelihood of a single compound filling this bill remains slim, several recent papers may lead to incremental gains. For example, several new publications describe the selectivity, efficacy, and safety of compounds that target cholinergic systems in schizophrenic brain, whereas another new study examines the use of estrogen for schizophrenia. Writing about the cholinergic papers in the August issue of the American Journal of Psychiatry, Jeffrey Lieberman of Columbia University and colleagues opine that these data "suggest that the tide may be turning and that rational drug development may have arrived in psychiatry."

With the hypothesis of dopamine dysregulation at the forefront, schizophrenia medications have historically targeted this system, as well as other monoaminergic neurotransmitters—primarily via dopamine D2 and serotonin 5HT2A receptors—through the use of receptor antagonists. Available antipsychotics have been successful at treating positive symptoms, including hallucinations, delusions, and thought disorders. Unfortunately, efficacy in treating negative (ahedonia, alogia, and asociality) and cognitive symptoms (deficits in attention, executive function, and memory) via conventional antipsychotics has yielded disappointment. Although reduction of positive symptoms may enable individuals with schizophrenia to function outside of institutions, addressing negative and cognitive symptoms may greatly improve their ability to work and maintain relationships, thus enhancing their quality of life.

Enhancing cognition
Reflecting growing interest in cognitive symptoms in schizophrenia, the U.S. National Institute of Mental Health (NIMH) established the MATRICS (Measurement and Treatment Research to Improve Cognition in Schizophrenia) initiative, which has included the development of the MATRICS Consensus Cognitive Battery. Studies examining novel pharmacological approaches against cognitive deficits in schizophrenia, such as targeting the cholinergic system, have been established as a goal of this initiative.

Much like the monoaminergic neurons, the majority of cholinergic cells are located in small discrete subcortical nuclei, from which their axonal projections fan out throughout the brain to modulate neuronal activity. (The major exceptions are the cholinergic interneurons of the striatum.) Drugs that act on the cholinergic system target one or both of the two receptor subtypes, the nicotinic and/or muscarinic acetylcholine receptors. Nicotinic receptors (nAChRs) are found at highest concentrations in the medial temporal lobe, and there is evidence of the involvement of this region in schizophrenia pathology. Expression of one specific receptor, α-7, is reduced in postmortem tissue from schizophrenic brain.

Muscarinic receptors are also intriguing targets for cognitive enhancement, and muscarinic agonists have shown some efficacy against cognitive symptoms in Alzheimer’s disease. Interestingly, these compounds also appeared to reduce some of the psychotic symptoms of Alzheimer's disease. Additional support for targeting muscarinic receptors comes from evidence that muscarinic antagonists have the opposite effects—causing psychotic symptoms. Animal models have also shown both cognitive enhancement with muscarinic agonists and cognitive decline with muscarinic antagonists. In preclinical models of schizophrenia, modulation of M4 and M5 appear to show the most promise. Low muscarinic receptor binding has also been documented in postmortem tissue from people with schizophrenia, in prefrontal cortex, hippocampal formation, and striatum. (Recent reviews of cholinergic systems in schizophrenia include Conn et al., 2008; Lieberman et al., 2008; and Raedler et al., 2007).

Targeting the nicotinic acetylcholine receptor…
In the August issue of the American Journal of Psychiatry, Robert Freedman of the University of Colorado and colleagues from several other institutions report data from a Phase 2 trial of the efficacy and safety of 3-(2,4-dimethoxybenzylidene) anabaseine (DMXB-A), a nicotinic agonist, in 31 schizophrenic individuals. DMXB-A is a partial agonist of the α-7-receptor subtype. Evidence suggests that modulation of the α-7 nicotinic receptor subtype, in particular, can improve attention, learning, and working memory (for a recent review, see Cincotta et al., 2008). The MATRICS initiative has in fact identified this receptor subtype as a possible therapeutic target for schizophrenia treatment.

Twenty-two men and nine women fulfilling DSM-IV criteria for schizophrenia, between the ages of 22 and 60, were included in the study. DMXB-A was added to the participants’ existing antipsychotic medications, in most cases second-generation drugs other than clozapine. The subjects received four weeks of twice-daily placebo, 75 mg b.i.d. DMXB-A, or 150 mg b.i.d. DMXB-A. The study was a double-blind, crossover design, so all subjects received each treatment for periods of four weeks. The MATRICS cognitive battery was used to assess cognitive symptoms and the Brief Psychiatric Rating Scale (BPRS) and Scale for the Assessment of Negative Symptoms (SANS) were used to assess overall and negative symptoms, respectively.

Disappointingly, DMXB treatment did not result in differentiation from placebo in the primary efficacy variable for this trial, which was performance on the six domains of the MATRICS Consensus Cognitive Battery. These domains include processing speed, attention/vigilance, working memory, verbal learning, visual learning, and reasoning/problem solving. There were no differences between either DMXB-A dosage and placebo. The authors suggest that practice effects on the cognitive battery may have obscured actual treatment effects (see SRF related news story). Significant improvements in the SANS total score for negative symptoms and nearly significant improvement on the BPRS overall symptoms score were observed for the higher DMXB-A dose. DMXB-A may therefore be at least somewhat effective for negative symptoms of schizophrenia, but thus far does not seem to have effects on cognitive problems in schizophrenia.

…and its muscarinic cousin
In the same issue of the American Journal of Psychiatry, Anantha Shekhar and colleagues at Indiana University School of Medicine, Eli Lilly and Company, and Merck Research Laboratories published a pilot study of the compound xanomeline. This somewhat selective M1 and M4 receptor agonist is currently in development for the treatment of schizophrenia in a collaboration between Eli Lilly and Merck. The rationale for this approach is based on muscarinic regulation of dopamine levels in areas of the brain believed to be critically involved in psychosis. The same compound is also being studied for possible use in Alzheimer’s disease.

Twenty subjects were included in this double-blind, placebo-controlled, four-week study. The subjects were between 18 and 60 years old and were diagnosed with DSM-IV criteria for schizophrenia or schizoaffective disorder as their only axis I disorder. The primary efficacy measures were total symptom scores and improvement in scores on the Positive and Negative Syndrome Scale (PANSS), BPRS, and Clinical Global Impression (CGI). The subjects were also given a neuropsychological battery to measure cognitive function. Significantly greater improvement in total BPRS scores versus placebo was observed by week 1 of treatment and continued throughout the study. The xanomeline group also showed significantly superior improvements versus placebo in total PANSS scores, and in PANSS positive and negative symptom subscales. In terms of cognitive effects, the xanomeline group had greater improvements than those taking placebo in verbal learning and short-term memory. Specific measures that achieved statistical significance included list learning, story recall, delayed memory, and digit span tests. The results show that xanomeline has some potential for treating both negative and cognitive symptoms of schizophrenia (as well as positive), although further study is clearly warranted.

One limitation of xanomeline is that it also activates M2, M3, and M5 cholinergic receptors, leading to unwanted side effects; thus, many drug developers are active in designing M1- or M4-specific drugs (see, e.g., Langmead et al., 2008; Niswender et al., 2008; Nawaratne et al., 2008). A new study by W. Y. Chan and colleagues at Eli Lilly and Company as well as collaborators at several institutions, published in the Proceedings of the National Academy of Sciences, describes LY2033298, a compound that targets an allosteric site—i.e., not the site where acetylcholine docks—on human M4 receptors. The drug is selective for an allosteric site on this cholinergic receptor subtype, which may be particularly important for cholinergic regulation of dopaminergic cells involved in psychosis.

In this preclinical study, Chan and colleagues determined the selectivity of LY2033298 for the M4 muscarinic receptor subtype using several in vitro assays. The researchers also examined allosteric modulation of M4 via LY2033298 using radioligand binding assays and found that agonist but not antagonist binding is potentiated by this compound. Finally, LY2033298’s activity in animal models of antipsychotic drug efficacy was tested. LY2033298 attenuated behavior in two models of antipsychotic efficacy—conditioned avoidance responding and prepulse inhibition—when administered with the muscarinic agonist oxotremorine. Microdialysis studies indicated that LY2033298 modulated dopaminergic systems in prefrontal cortex. Since this is only a preclinical study, further studies are clearly needed to elucidate the value of LY2033298 for treating schizophrenia.

Can estrogen help?
Finally, Jayashri Kulkarni and colleagues at Alfred Hospital and Monash University in Melbourne, Australia, recently examined the use of transdermal estradiol in women with schizophrenia. As they note in the August issue of the Archives of General Psychiatry, interest in estrogen has been spurred by the observation that women are vulnerable to a first psychotic episode or to relapse during both the postpartum period and during menopause, when estrogen levels are lowered. Interestingly, improvement in psychosis and relapse is often observed during pregnancy in women with schizophrenia. (For more information, see Riecher-Rossler and Seeman, 2002 and Hafner, 2003).

One hundred and two women meeting DSM-IV criteria for schizophrenia, schizoaffective disorder, or schizophreniform disorder participated in this double-blind trial. All were of child-bearing age. The subjects continued their antipsychotic medication, which included the full range of available atypical and typical antipsychotics. Fifty-six women received adjunctive estradiol and 46 received placebo. Schizophrenic symptoms were assessed at baseline and days seven, 14, 21, and 28 using the PANSS.

Significant improvement in positive and general psychopathological symptoms was observed over time for the estradiol group versus the placebo group, although no differences in negative symptoms were observed between groups. Although this therapy may serve as a useful adjunct to existing antipsychotic medication in women, unfortunately, estradiol seems to have no novel effects of reducing negative symptoms of schizophrenia. It should be noted that cognitive symptoms were not assessed in this study.

For now, an incremental approach
As in other complicated disorders, the therapeutic approach for schizophrenia is likely to involve multiple approaches, including non-pharmacological. However, there were disappointing results recently from the psychosocial treatment front. Mette Bertelsen and colleagues in Denmark reported on an intensive early-intervention program of the Danish government (called OPUS) for first-episode psychotic patients, who were provided assertive community treatment, psychoeducational family treatment, and psychosocial training. Compared to treatment as usual, this program improved clinical outcomes after two years, but the effects diminished by five years after the initiation of the program (Bertelsen et al., 2008). The outcome of this study underscores the unfortunate reality that while pharmacology is not always a panacea, it seems to be the best hope for real gains in schizophrenia.

Available antipsychotic drugs have had variable success at reducing (primarily positive) symptoms, and since many patients discontinue medication due to side effects, new drugs are greatly needed. Although the trials described in this article are of some interest (and drugs targeting glutamatergic neurotransmission have had recent success; see SRF related news story), the new approaches seem to offer uncertain hope. If they achieve regulatory approval, their clinical use will provide the true test.—Alisa Woods.

References:

Chan WY, McKinzie DL, Bose S, Mitchell SN, Witkin JM, Thompson RC, Christopoulos A, Lazareno S, Birdsall NJ, Bymaster FP, Felder CC. Allosteric modulation of the muscarinic M4 receptor as an approach to treating schizophrenia. Proc Natl Acad Sci U S A. 2008 Aug 5;105(31):10978-83. 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. Initial phase 2 trial of a nicotinic agonist in schizophrenia. Am J Psychiatry. 2008 Aug 1;165(8):1040-7. Abstract

Kulkarni J, de Castella A, Fitzgerald PB, Gurvich CT, Bailey M, Bartholomeusz C, Burger H. Estrogen in severe mental illness: a potential new treatment approach. Arch Gen Psychiatry. 2008 Aug 1;65(8):955-60. Abstract

Shekhar A, Potter WZ, Lightfoot J, Lienemann J, Dubé S, Mallinckrodt C, Bymaster FP, McKinzie DL, Felder CC. Selective muscarinic receptor agonist xanomeline as a novel treatment approach for schizophrenia. Am J Psychiatry. 2008 Aug 1;165(8):1033-9. Abstract

Lieberman JA, Javitch JA, Moore H. Cholinergic agonists as novel treatments for schizophrenia: the promise of rational drug development for psychiatry. Am J Psychiatry. 2008 Aug 1;165(8):931-6. Abstract

Comments on News and Primary Papers
Comment by:  John Michael Brummer
Submitted 6 September 2008
Posted 6 September 2008
  I recommend the Primary Papers
Comments on Related News


Related News: Studies Explore Glutamate Receptors as Target for Schizophrenia Monotherapy

Comment by:  Dan Javitt, SRF Advisor
Submitted 3 September 2007
Posted 3 September 2007

A toast to success, or new wine in an old skin?
Patil et al. present a landmark study. It is the kind of study that represents the best of how science should work. It pulls together the numerous strands of schizophrenia research from the last 50 years, from the development of PCP psychosis as a model for schizophrenia in the late 1950s, through the links to glutamate, the discovery of metabotropic receptors, and the seminal discovery in 1998 by Moghaddam and Adams that metabotropic glutamate 2/3 receptor (mGluR2/3) agonists reverse the neurochemical and behavioral effects of PCP in rodents (Moghaddam and Adams, 1998. The story would not be possible without the elegant medicinal chemistry of Eli Lilly, which provided the compounds needed to test the theories; the research support of NIMH and NIDA, who have been consistent supporters of the “PCP theory”; or the hard work of academic investigators, who provided the theories and the platforms for testing. The study is large and the effects robust. Assuming they replicate (and there is no reason to suspect that they will not), this compound, and others like it, will represent the first rationally developed drugs for schizophrenia. Patients will benefit, drug companies will benefit, and academic investigators and NIH can feel that they have played their role in new treatment development.

Nevertheless, it is always the prerogative of the academic investigator to ask for more. In this case, we do not yet know if this will be a revolution in the treatment of schizophrenia, or merely a platform shift. What is striking about the study, aside from the effectiveness of LY2140023, is the extremely close parallel in both cross-sectional and temporal pattern of response between it and olanzapine. Both drugs change positive and negative symptoms in roughly equal proportions, despite their different pharmacological targets. Both drugs show approximately equal slopes over a 4-week period. There is no intrinsic reason why symptoms should require 4 or more weeks to resolve, or why negative and positive symptoms should change in roughly the same proportion with two medications from two such different categories, except that evidently they do.

There are many things about mGluR2/3 agonists that we do not yet know. The medication used here was administered at a single, fixed dose. It is possible that a higher dose might have been better, and that optimal results have not yet been achieved. The medications were used in parallel. It is possible that combined medication might be more effective than treatment with either class alone. The study was stopped at 4 weeks, with the trend lines still going down. It is possible that longer treatment duration in future studies might lead to even more marked improvement and that the LY and olanzapine lines might separate. No cognitive data are reported. It is possible that marked cognitive improvement will be observed with these compounds when cognition is finally tested, in which case a breakthrough in pharmacotherapy will clearly have been achieved.

If one were to look at the glass as half empty, then the question is why the metabotropic agonist did not beat olanzapine, and why the profiles of response were so similar. If these compounds work, as suggested in the article by modulating mesolimbic dopamine, then it is possible that metabotropic agonists will share the same therapeutic limitations as current antipsychotics—good drugs certainly and without the metabolic side effects of olanzapine, but not “cures.” The recent study with the glycine transport inhibitor sarcosine by Lane and colleagues showed roughly similar overall change in PANSS total (-17.1 pts) to that reported in this study, but larger change in negative symptoms (-5.5 pts), and less change in positive symptoms (-2.3 pts) in a similar type of patient population. Onset of effect in the sarcosine study also appeared somewhat faster. The sarcosine study was smaller (n = 20) and did not include a true placebo group. As with the Lilly study, it was only 4 weeks in duration, and did not include cognitive measures. It also included only two, possibly non-optimized doses. As medications become increasingly available to test a variety of mechanisms, side-by-side comparisons will become increasingly important.

There are also causes for concern and effects to be watched. For example, a side effect signal was observed for affect lability in the LY group, at about the same prevalence rate as weight increase in the olanzapine group. What this means for the mechanism and how this will effect treatment remains to be determined. Since these medications are agonists, there is concern that metabotropic receptors may downregulate over time. Thus, whether treatment effects increase, decrease, or remain constant over the course of long-term treatment will need to be determined. Nevertheless, 50 years since the near-contemporaneous discovery of both PCP and chlorpromazine, it appears that glutamatergic drugs for schizophrenia may finally be on the horizon.

References:

Moghaddam B, Adams BW. Reversal of phencyclidine effects by a group II metabotropic glutamate receptor agonist in rats. Science. 1998 Aug 28;281(5381):1349-52. Abstract

View all comments by Dan Javitt

Related News: Studies Explore Glutamate Receptors as Target for Schizophrenia Monotherapy

Comment by:  Gulraj Grewal
Submitted 4 September 2007
Posted 4 September 2007
  I recommend the Primary Papers

Related News: Antipsychotics and Cognition: Practice Makes Perfect Confounder

Comment by:  Richard Keefe
Submitted 12 October 2007
Posted 12 October 2007

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).

View all comments by Richard Keefe

Related News: Antipsychotics and Cognition: Practice Makes Perfect Confounder

Comment by:  Narsimha Pinninti (Disclosure)
Submitted 15 October 2007
Posted 15 October 2007
  I recommend the Primary Papers

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

Related News: Antipsychotics and Cognition: Practice Makes Perfect Confounder

Comment by:  Saurabh Gupta
Submitted 15 October 2007
Posted 15 October 2007
  I recommend the Primary Papers

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

Related News: Antipsychotics and Cognition: Practice Makes Perfect Confounder

Comment by:  Sebastian Therman
Submitted 17 October 2007
Posted 17 October 2007

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

Related News: Antipsychotics and Cognition: Practice Makes Perfect Confounder

Comment by:  Andrei Szoke
Submitted 1 November 2007
Posted 5 November 2007
  I recommend the Primary Papers

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).

View all comments by Andrei Szoke

Related News: Antipsychotics and Cognition: Practice Makes Perfect Confounder

Comment by:  Patricia Estani
Submitted 7 November 2007
Posted 8 November 2007
  I recommend the Primary Papers

Related News: Studies Explore Glutamate Receptors as Target for Schizophrenia Monotherapy

Comment by:  Shoreh Ershadi
Submitted 8 June 2008
Posted 9 June 2008
  I recommend the Primary Papers

Related News: ICOSR 2011—Some Hope for Alleviating Negative Symptoms

Comment by:  Kimberly E. Vanover
Submitted 20 June 2011
Posted 20 June 2011

Thank you for your summary of the presentations from the New Drug Session at ICOSR 2011 on the Schizophrenia Research Forum. The Forum is a helpful and important resource.

I just wanted to clarify your description of ITI-007’s properties at the D2 site. As a dopamine phosphorylation modulator, ITI-007 acts as a pre-synaptic partial agonist and a post-synaptic antagonist with mesolimbic/mesocortical selectivity (Wennogle et al., 2008). In addition to its antagonism of 5-HT2A receptors and unique interaction with D2 receptors, it has affinity for D1 receptors, consistent with partial agonism linked to downstream increases in NMDA NR2B receptor phosphorylation (Zhu et al., 2008), and it is a serotonin reuptake inhibitor (Wennogle et al., 2008). Unfortunately, the short, 10-minute talk during the ICOSR session wasn’t sufficient time to go into the details of the mechanism and supporting preclinical data.

I did notice that a brief description for the mode of action for ITI-007 is listed as “5-HT2A antagonist + dopamine phosphoprotein modulator” with a role in schizophrenia listed as “DA stabilizer + 5hT-T inhibitor” in the Forum’s Drugs in Clinical Trials section. This is a nice, brief way to describe a rather complex mechanism.

References:

Wennogle LP, Snyder GL, Hendrick JP, Vanover KE, Tomesch JT, Li P, O’Callaghan JP, Miller DB, Fienberg AA, Davis RE, Mates S (2008) Unique antipsychotic profile of a novel 5-HT2A receptor antagonist and dopamine receptor protein phosphorylation modulator. Schizophrenia Research 98:Suppl1:15.

Zhu H, Snyder GL, Vanover KE, Rana M, Tsui T, Hendrick JP, Li P, Tomesch J, O’Brien JJ, Guo H, Davis RE, Fienberg AA, Wennogle LP, Mates S (2008) ITI-007: A novel 5-HT2A antagonist and dopamine protein phosphorylation modulator (DPPM) induces a distinct NR2B expression pattern in mouse brain. Program No. 155.14 2008 Neuroscience Meeting Planner. Washington, DC Society for Neuroscience, 2008. Online.

View all comments by Kimberly E. Vanover

Related News: Cholinergic Drug Improves Cognition in Nonsmokers With Schizophrenia

Comment by:  Britta Hahn
Submitted 7 October 2012
Posted 7 October 2012

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

Tan BL (2009) Profile of cognitive problems in schizophrenia and implications for vocational functioning. Aust Occup Ther J 56: 220-228. Abstract

View all comments by Britta Hahn

Related News: Cholinergic Drug Improves Cognition in Nonsmokers With Schizophrenia

Comment by:  Georg Winterer (Disclosure)
Submitted 30 October 2012
Posted 30 October 2012

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

View all comments by Georg Winterer