Zubin Bhagwagar, PhD John M. Kane, MD

Introduction

Although the weather in Toronto was chilly and capricious, delegates to the 2006 Annual Meeting of the American Psychiatric Association were treated to heartwarming news about recent advances in the understanding of the biological basis of schizophrenia. Scattered throughout the meeting were a number of presentations that gave the weary clinician hope for improved treatment of this severe, chronic, and disabling condition. The main focus of these advances centered on the interaction between glutamate and dopamine, and also recent findings from genetic studies of patients with schizophrenia.
Molecular Mechanisms

In a symposium entitled, "Not Just Dopamine Any More: Emerging Glutamatergic Therapies for Schizophrenia," Professor Joseph Coyle from Harvard Medical School, Cambridge, Massachusetts, and Editor of the Archives of General Psychiatry, described molecular mechanisms that had recently been identified as being of interest in schizophrenia.[1] These mechanisms are predominantly glutamatergic, and he described in some detail the 2 classes of ionotropic glutamate receptors, namely the AMPA/kainate receptors (AMPAR) and the n-methyl d-aspartate receptors (NMDAR).

The AMPAR (GluR 1-4) are the primary mediators of excitatory postsynaptic currents (EPSCs). The NMDAR (NR1; NR2A-D) contribute to the EPSC and play a more fundamental role in coincidence detection. EPSCs and coincidence detection are believed to be important mediators of neuroplasticity in mechanisms such as learning and memory, and these may be disrupted in schizophrenia. At the resting membrane potential, the NMDAR channel is blocked by Mg2+, which is removed upon depolarization. The NMDAR channels are sufficiently large to readily transduce Ca2+, which activates the intracellular kinases that ultimately regulate gene expression. The recruitment of NMDAR during high presynaptic glutamatergic activity results in the permanent increase in synaptic efficacy known as long-term potentiation (LTP).[2] Influx of Ca2+ through the NMDAR during LTP causes the recruitment of AMPAR from intracellular stores to the synapse. Persistent hyperactivity through a glutamatergic pathway can cause sprouting of postsynaptic spines via NMDAR activation, further strengthening synaptic connections. NMDAR activation has trophic effects, especially during development, with inactivity of NMDAR resulting in neuronal apoptosis.

Another unique characteristic of the NMDAR is that, in addition to the binding site for the agonist, glutamate, there is a glycine modulatory site (GMS) to which glycine and/or d-serine bind. The GMS needs to be occupied for glutamate to open the channel. The availability of d-serine depends upon the activities of serine racemase (SR) and the degrading enzyme d-amino acid oxidase (DAAO),[3] whereas the availability of glycine is determined by the activity of the glycine transporter, GlyT-1.[4] Notably, both SR and GlyT1, as well as the glutamate transporters that protect against excitotoxicity (EAAT 1 and 2), are expressed exclusively in astrocytes, indicating a vital role of astroglia in modulating glutamatergic neurotransmission.

Dr. Coyle concluded that regulation of the availability of glycine/d-serine at the GMS plays a critical role in optimal NMDAR function.

Insights From Neuroimaging

Anissa Abi-Dargham, Professor of Clinical Psychiatry and Radiology at Columbia University College of Physicians & Surgeons in New York, NY, continued this line of thought, presenting a thorough overview of the neurochemistry of schizophrenia during the symposium, "Advances in Schizophrenia."[5] She described the conventional model of schizophrenia in which hyperfunction of the dopaminergic system in subcortical regions is postulated to cause the positive symptoms of the illness while a relative hypofunction of the dopaminergic system in the prefrontal cortical region is believed to be responsible for negative symptoms. The key difference between the dopaminergic systems in these 2 regions is that the frontal regions lack the dopamine transporter, the protein that clears released dopamine from the synapse, and thus relies on catechol-O-methyl transferase (COMT; the enzyme that catabolizes dopamine) to clear dopamine from the synapse.[6]

Professor Abi-Dargham gave a clear account of a large number of neuroimaging studies that use molecular imaging with positron emission tomography (PET) or single photon emission computerized tomography (SPECT), and further informed us regarding the pathophysiology of the illness. She described how these studies had nearly unanimously shown an increased formation of presynaptic dopamine,[7] increased release of dopamine from the presynaptic terminal,[8-11] and a slight increase in dopamine D2 receptors[12] and in prefrontal dopamine D1 receptors.[13] The latter finding has been shown to relate to the concept of working memory (the ability to store relevant pieces of information, such as a telephone number, for a short time),[13] which has also been shown to be impaired in patients with schizophrenia.

Professor Abi-Dargham also described recent studies that implicate the glutamatergic system in the pathophysiology of the illness. The key receptor system in this case is the n-methyl d-aspartate (NMDA) receptor, which has been shown to be underfunctioning in schizophrenia.[14] This property was demonstrated in human studies in which the anesthetic agent, ketamine, an NMDA receptor antagonist, produced positive and negative symptoms, and cognitive distortions in healthy subjects very similar to those seen in schizophrenia.[15] Chronic ketamine users exhibit a regionally selective upregulation of D1 receptor availability in the dorsolateral prefrontal cortex, a phenomenon observed following chronic dopamine depletion in animal studies.[16] She also described how these abnormalities may be caused by glutamatergic projections from the prefrontal cortex to the striatum and cited recent unpublished data that support this proposition. Of interest, patients with a diagnosis of substance abuse and schizophrenia may have 2 levels of pathology, with NMDA receptor dysfunction and dopaminergic receptor abnormalities, which may feed into each other and worsen the situation.
Dopamine and Motivational Salience

Although Professor Abi-Dargham shed light on the intricate connections between glutamate and dopamine, Shitij Kapur, MD, PhD, Professor of Psychiatry and Chief of Research at the University of Toronto, provided a tantalizing twist to the dopaminergic hypothesis of schizophrenia.[17] Dr. Kapur expanded on his view of dopamine in psychosis.[18] Drawing from previous work, he spoke of dopamine not only mediating the phenomenon of hedonia[19] but of dopamine release preceding the hedonic event[20] and also mediating adverse events.[21] He contended that dopamine may be responsible for the phenomenon of "motivational salience,"[18] a process whereby neutral events and representations grow to be attention-grabbing, capturing thoughts and behavior. He described psychosis as resulting from an aberrant sense of novelty and an abnormal salience to relatively innocuous stimuli, which are mediated through a dysfunctional dopaminergic system.

He discussed how psychotic phenomena arise when the patient develops a cognitive scheme to explain aberrant salience. When this aberrant salience captures behavior or causes distress, it attracts attention, subsequent hospitalization, and treatment with appropriate antidopaminergic agents. In support of this, he challenged the widely held belief that there is a lag in the onset of antipsychotic effect following treatment, citing a recent meta-analysis conducted by his group.[22] In a subsequent study,[23] factor analysis showed that an independent change in psychosis (which included conceptual disorganization, hallucinatory behavior, and unusual thought content) was evident within the first 24 hours after receiving antipsychotic medications. This improvement in core psychosis was not mediated unidirectionally by changes in nonspecific behavioral effects or other psychopathology.[23]
Neurocognition in Schizophrenia

In an industry-supported symposium, "New Developments in Schizophrenia: From Neurobiology to Public Health," Robert Bilder PhD, Professor of Psychology at UCLA, Los Angeles, California,[24] reminded us of the ongoing cognitive deficits in patients with schizophrenia and quantified the effect size of this dysfunction as being around 1 (effect sizes of greater than 0.8 are considered large[25]). He also described a study (in press) that showed that the Clinical Antipsychotic Trials in Intervention Effectiveness (CATIE) composite score of neurocognitive function was 1.59 standard deviation units lower in the patient population.[26] He related these deficits to problems with connectivity of neural networks, especially the fronto-striato-pallido-thalamic and fronto-striato-cerebellar. He reminded participants that enduring and long-lasting changes in cognitive function are likely in patients with schizophrenia. In a recent study,[27] he showed that, in the subset of patients for whom Scholastic Aptitude Test (SAT) scores were available, WAIS-R Full Scale IQ was 11.5 points lower than predicted from earlier SAT scores, suggesting a substantial decline in cognitive ability accompanying the initial episode of illness.[27] These findings suggest that schizophrenia is marked by substantial cognitive deficits in the first grade, that additional, subtle declines may precede the overt onset of psychotic symptoms, and that the initial episode of illness is marked by additional decline. He also related these deficits to polymorphisms of the COMT gene, where the allele with methionine has low activity and results in higher prefrontal dopamine levels and, perhaps, better cognitive performance.[6,28]
Genetics of Schizophrenia

Patrick F. Sullivan, MD, Professor of Psychiatry at University of North Carolina, Chapel Hill, gave an enlightening and highly informative lecture regarding the genetic basis of schizophrenia.[29] Clearly the disorder cannot be explained by a single gene or Mendelian genetics, and most likely results from multiple genes of small effect. He reminded us that the human genome comprises 3,300,000,000 base pairs that form approximately 30,000 genes, of which 6% are conserved throughout various species. Among the many pieces of evidence, work from the Institute of Psychiatry in London suggests that, of all risk factors, a family history of schizophrenia has the highest odds ratio (close to 10) and provides the most compelling data for the genetic basis of schizophrenia.

Dr. Sullivan elucidated previous family, adoption, and twin studies, which provide support for theoretical notions of the genetic basis of the illness. He then explained the 3 strategies employed in current research. The first is to study copy number changes in genes (insertions, deletions, etc). This strategy suggests involvement of the area 22q11, which is implicated in the DiGeorge or velocardiofacial syndrome. The other major finding from analysis of copy number changes is the gene called "Disrupted in Schizophrenia 1" (DISC1), which was identified at the breakpoint on chromosome 1 of the balanced translocation (1;11)(q42.1;q14.3) that co-segregated in a large Scottish family with a wide spectrum of major mental illnesses.

Dr. Sullivan suggested that the second strategy, linkage analysis (studying the segregation of genetic markers with illness in large pedigrees), has not contributed to our understanding of the illness because no gene was implicated in more than 4 studies and many in not more than a single study.[30]

Dr. Sullivan contended that the third strategy, association studies (case control studies), are productive with the accumulated data providing particular support for DISC1, DTNBP1 (the gene encoding dystrobrevin binding protein 1, or dysbindin), neuregulin 1 (NRG1), and regulator of G-protein signaling 4 (RGS4). He suggested that each of these genes has received support from multiple lines of evidence with imperfect consistency. For example, the case for each of these as a candidate gene for schizophrenia is supported by linkage studies. The preponderance of association study findings provides further support for a role of these genes in schizophrenia. mRNA from each gene is expressed in the prefrontal cortex and in other areas of the brain, lending face and construct validity, and additional neurobiological data link the functions of these genes to biological processes thought to be related to schizophrenia: DISC1 modulates neurite outgrowth[31]; other evidence supports the involvement of NRG1 in the development of the CNS[32]; and RGS4 may modulate intracellular signaling for many G-protein-coupled receptors.[33] Moreover, DTNBP1 and RGS4 have been reported to be differentially expressed in postmortem brain samples of individuals with schizophrenia. In conclusion, he suggested small sample size, diagnostic heterogeneity, and other parsimonious explanations as the main reasons for the nonreplication of various studies, but proposed that the field will advance dramatically in the next 2-5 years.
Novel Treatments for Schizophrenia

Although considerable work has advanced our understanding of the illness, no conclusions can be drawn until these findings are translated from the laboratory to the clinic. Although early attempts may not have met with unqualified success, progress is being made.

Most of the work in this area builds on the glutamatergic interactions described by Dr. Coyle and Dr. Abi-Dargham. Indeed, glutamatergic-modulating agents have been assessed in randomized controlled trials. Donald Goff, MD,[34] presented the results of a clinical trial of an AMPA receptor-positive modulator (AMPAkine) CX516 that had been compared with placebo in a recently concluded randomized clinical trial in combination with clozapine.[35] In the initial study, CX516 was tolerated well and was associated with moderate to large, between-group effect sizes, compared with placebo, involving improvements in measures of attention and memory. However, Dr. Goff presented data from a recently concluded larger trial, which found that the drug did not differ from placebo in terms of efficacy measures or improved cognition. Nevertheless, this is a good example of how preclinical science identifies new molecules that may have therapeutic benefit. Dr. Goff also discussed why the trial may not have found efficacy and suggested specific actions of the molecule that were likely responsible for the lack of effect. He asserted that the line of inquiry was scientifically valid and expressed optimism about the potential for future trials.

Similarly, Daniel Javitt, MD, from the Nathan Kline Institute for Psychiatric Research in New York, NY, presented results of a clinical trial comparing glycine, d-serine, and placebo in schizophrenia.[36] Again, although this study found no clear benefit from either of the 2 active treatments, a subgroup of inpatients responded to glycine, which was moderately encouraging, as was its effect when used in conjunction with typical antipsychotic agents. He noted that previous trials have suggested a role for glycine in the treatment of schizophrenia[37] and that this line of inquiry was encouraging. Dr. Javitt also described the potential role of glycine transport inhibitors as future treatments as similar to the way selective serotonin reuptake inhibitors act in the treatment of depression.

In contrast to the outcomes reported by Dr. Javitt, Scott Woods, MD, from Yale University School of Medicine, New Haven, Connecticut, reported encouraging preliminary results from an open-label study of glycine treatment in prodromal patients, and the initiation of a placebo-controlled trial based on these initial findings.[38]

In an industry-supported symposium, John M. Kane, MD, from the Albert Einstein College of Medicine, Bronx, New York, discussed the current understanding of the role of atypical antipsychotics in the treatment of schizophrenia.[39,40] Citing recent meta-analyses, he clarified the role these drugs take in the acute and chronic management of schizophrenia, and also showed that only 9 patients need to be treated with atypicals to produce 1 additional responder, compared with low-potency antipsychotics.[41] To put this "number needed to treat" (NNT) in perspective, the recently published Collaborative Atorvastatin Diabetes Study (CARDS)[42] showed that atorvastatin markedly reduced vascular events in patients with type 2 diabetes mellitus. The NNT with atorvastatin was 27 for 4 years to prevent 1 event.[43]
Results From the CATIE Trial

It was difficult to find a talk on schizophrenia at the conference that did not mention the results from the recently concluded CATIE trial.[44] In the same symposium, Dr. Kane[39] briefly outlined the design of the CATIE study. Phase 1 was a 57-site, double-blind, randomized treatment assignment of approximately 1500 patients with schizophrenia (not first episode or treatment resistant) to olanzapine, quetiapine, risperidone, ziprasidone, or the typical agent perphenazine. In phase 2, patients who discontinued phase 1 were allowed to choose either clozapine or ziprasidone as an alternative to randomization to quetiapine, olanzapine, or risperidone. In phase 3, patients who discontinued phase 2 were allowed to choose open-label treatments.

As reported elsewhere, results of phase 1 showed that the majority of patients in each group discontinued their assigned treatment because of inefficacy or intolerable side effects, or for other reasons. Rates of discontinuation were lowest for olanzapine, and the efficacy of the conventional antipsychotic agent perphenazine appeared similar to that of quetiapine, risperidone, and ziprasidone. Olanzapine was associated with more weight gain and increases in measures of glucose and lipid metabolism.

Other presentations also brought out results from the other stages of the CATIE study. For example, 99 patients who discontinued treatment with olanzapine, quetiapine, risperidone, or ziprasidone in phase 1 or 1-B of the trials, primarily because of inadequate efficacy, were randomly assigned to open-label treatment with clozapine (n = 49) or blinded treatment with another, newer atypical antipsychotic the patients had not previously received in the trial (olanzapine [n = 19], quetiapine [n = 15], or risperidone [n = 16]). The results showed that for these patients, clozapine was more effective than switching to another, newer atypical antipsychotic.[45]
Conclusion

We can be optimistic about the future development of novel treatments for schizophrenia. Studies like CATIE have begun to inform rational pharmacotherapy and will also influence study design for future therapeutic molecules.
References

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