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.
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.
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