Current Drug Targets-CNS & Neurological Disorders - Volume 1, Issue 2, 2002

With the use of chlorpromazine and other traditional antipsychotics for psychosis, it was soon discovered that the antipsychotic efficacy of this class of medications was closely associated with their ability to block dopamine D2 receptors in the brain. This prompted the hypothesis that the etiology of schizophrenia and other psychotic illnesses might be caused by a dysregulation of dopamine. This hypothesis, that the dopamine system explains schizophrenia symptoms, however, is far from complete and the treatment with conventional antipsychotic medications is far from ideal. There has been a great deal of speculation regarding the role of serotonin receptor antagonism in regards to antipsychotic effects. The second generation antipsychotics (SGAs), clozapine, risperidone, olanzapine, quetiapine and ziprasidone all have relatively high serotonin to dopamine binding ratios. Serotonin receptor binding may be important to these drugs' actions, possibly by stimulating dopamine activity in mesocortical pathways. Yet, while the mechanism of action of SGAs as a group remain unsolved, it is important to note that the SGAs offer many clinical benefits to treatment as compared to traditional antipsychotics and are quickly emerging as first-line therapy for schizophrenia. In addition to lower rates of EPS and tardive dyskinesia, other benefits to treatment with this class of antipsychotics include better treatment of negative symptoms, better compliance, possible benefits for cognitive impairments, lower rates of relapse and rehospitalization, and more cost-effective therapy. Within the class of SGAs, however, differences exist both in efficacy and side effects and these will be described. Optimization of treatment and understanding the exact mechanism of action of current antipsychotic medications will help pave the way for new drug targets in the future.

Comorbid alcohol and substance use disorders occur commonly among patients with schizophrenia and contribute to the morbidity of schizophrenia. These comorbid disorders add greatly to the financial costs and emotional toll that schizophrenia places on patients, families and the entire mental health system. While the basis for the increased abuse of alcohol and other substances in patients with schizophrenia have been linked by some investigators to ”self-medication“ of negative symptoms of schizophrenia or extrapyramidal system effects of typical antipsychotics, we have presented a neurobiologic formulation suggesting that alcohol or other substances may transiently correct a dysfunction of the dopamine-mediated mesocorticolimbic pathways in patients with schizophrenia - pathways linked to brain reward circuits. This formulation further suggests that alcohol or other substances serve to transiently enhance the functioning of this circuit by improving the ”signal detection“ capability of the dopamine-rich mesocorticolimbic pathways. Treatment of comorbid substance use disorder in patients with schizophrenia involves careful use of psychosocial approaches aimed at fostering program participation and at enhancing the likelihood of abstinence. While the typical antipsychotics do not limit the comorbid substance use, and may actually worsen it, preliminary data suggest the novel antipsychotic clozapine may have the unusual ability to dramatically decrease alcohol and other substance use in patients with schizophrenia. It is not clear whether other novel antipsychotics share this ability of clozapine to limit alcohol and substance abuse. We have proposed that the effect of clozapine in this population may relate to its broad pharmacological effects, including its relatively weak blockade of the dopamine D2 receptor and its potent blockade of the serotonergic 5-HT2 receptor and the noradrenergic alpha 1 and alpha 2 receptors. Studies of other agents, employed in the pharmacotherapy of alcohol and substance use disorders without schizophrenia, are currently underway in patients with schizophrenia and comorbid disorders.

The early demonstration of chlorpromazine efficacy in schizophrenia and its subsequent identification as a dopamine receptor antagonist, established the only known mechanism for antipsychotic development to date. By extension, it is easy to hypothesize that any mechanism shown to reduce dopamine-mediated transmission in brain will have antipsychotic properties. The evaluation of partial dopamine agonists for antipsychotic efficacy and their application in the treatment of psychosis has derived from this background. Partial dopamine agonists at the D2 dopamine receptor, have high affinity for that receptor, but reduced intrinsic activity. These agonists have higher affinity for the presynaptic autoreceptor than for the postsynaptic receptor. Hence, these compounds reduce dopamine synthesis and release through an agonist action at the dopamine autoreceptor. Moreover, the agonists have lower intrinsic activity at the postsynaptic receptor than its natural ligand dopamine. Therefore, they diminish the dopaminergic signal at postsynaptic sites as well through delivering a reduced message; this component of drug action becomes more prominent the lower the intrinsic activity of the drug. Several partial dopamine agonists have been evaluated in schizophrenia. One of them, aripiprazole, is nearing approval for marketing. With partial dopamine agonist treatment, advantages should accrue to schizophrenia treatment in the areas of affect control and cognitive performance.

Schizophrenia patients have insufficient inhibitory processing of identical paired auditory stimuli. This deficient ”auditory gating“ is thought to have physiological relevance, and its severity correlates with certain measures of both positive and negative symptoms. Schizophrenia patients also represent the heaviest smoking population subgroup. Because smoking temporarily normalizes their auditory gating deficit, this may represent a form of self-medication. Although this deficit is unresponsive to treatment with typical antipsychotic drugs, it does respond to the atypical antipsychotic clozapine. The normalization of this deficit by smoking may account for some of the intense drive to smoke that is experienced by schizophrenia patients. However, the normalizing effect of nicotine is transient and is not observed with repeated administration. Auditory gating is modulated by the α7 nicotinic receptor subtype, a rapidly desensitizing low-affinity nicotinic receptor. Agents that selectively activate the α7 receptor represent a novel class of therapeutic agents for use in the treatment of schizophrenia. Whether selective α7 agonists will have beneficial effects on symptoms other than the auditory gating deficit has not yet been established. The first developed α7-selective agonist, 3-2,4-dimethoxybenzylidene anabaseine (DMXB-A), normalizes auditory gating in three distinct animal models of the deficit. DMXB-A is a prototype for this potential new drug class, but proof-of-concept for this type of pharmacotherapy will not be available until the completion of planned clinical trials assessing DMXB-A's effects in schizophrenia patients. Additional avenues to the potential normalization of auditory gating deficits are also discussed, focusing on the novel efficacy of clozapine and the potential utility of allosteric modulators of nicotinic receptors.

The family of 5 muscarinic acetylcholine receptors belongs to the superfamily of G protein coupled neurotransmitter receptors that serve in part as regulators of synaptic function. Muscarinic receptors are anatomically positioned in cortical and subcortical areas and modulate dopaminergic and glutamatergic neurotransmission thought to be dysfunctional in schizophrenia. Neurochemical studies have shown that dopamine and muscarinic receptors reciprocally modulate one another. For example, the muscarinic agonist xanomeline increases extracellular levels of dopamine and Fos expression in cortical areas greater than subcortical areas, similar to effects of atypical antipsychotics. In electrophysiological studies, xanomeline with acute and chronic administration decreased firing of the mesocorticolimbic dopamine A10 tract, but not the motoric dopamine A9 tract. Behavioral investigations have shown that muscarinic agonists, like dopamine antagonists, inhibit conditioned-avoidance responding and dopamine-agonist-induced behaviors including hyperactivity, climbing behavior and disruption of prepulse inhibition, models for positive symptoms of schizophrenia. Transgenic knockout mice lacking M4 receptors are hyperactive and hyper-responsive to dopamine D1 agonists, suggesting a dynamic balance between the dopamine and M4 receptors. Muscarinic agonists had activity in animal models of negative symptoms, cognitive dysfunction and affective disorders, symptoms that are prominent in schizophrenic patients. Consistent with effects in animal models, preliminary clinical investigation indicates that muscarinic agonists like xanomeline may be effective in the pharmacotherapy of schizophrenia. Thus, we hypothesize that a combined M1 agonist to promote cognition and a M4 agonist for antipsychotic-like effects would treat the symptom domains of schizophrenia without parasympathomimetic side effects.

Evidence implicating dysfunction of glutamatergic neurotransmission rests largely on the finding that antagonists of the NMDA subtype of glutamate receptor, especially the dissociative anesthetics like ketamine, can reproduce the full range of symptoms as well as the physiologic manifestation of schizophrenia such as hypofrontality, impaired prepulse inhibition and enhanced subcortical dopamine release. To test the hypothesis that schizophrenia may result from NMDA receptor hypofunction a number of clinical trials have examined the effects of agents that act on the glycine modulatory site on the NMDA receptor. Glycine, D-serine, and the partial agonist, D-cycloserine, have been shown to improve cognition and decrease negative symp- toms in schizophrenic subjects receiving typical antipsychotics. Results with D-cycloserine suggest that clozapine may enhance glycine modulatory site occupancy. Preliminary results with an allosteric modulator of the AMPA subtype of glutamate receptor suggest enhanced cognitive functions in subjects treated with clozapine.

Glutamatergic pathways, metabotropic receptors, and ionotropic α-amino-3-hydroxy-5-methylisoxazole-4-proprionic acid (AMPA), kainate and N-methyl-D-aspartate (NMDA) receptors are all implicated in the etiology and management of schizophrenia. As concerns NMDA receptors, open channel blockers (OCBs) such as phencyclidine (PCP) elicit psychotic symptoms in human subjects. This observation underpins biochemical studies indicating that a deficit in activity at NMDA receptors may be associated with psychotic states. Inasmuch as agonists at the NMDA recognition site are excitotoxic, drugs acting via the co-agonist, glycineB (GLYB) site are more promising clinical candidates as antipsychotic agents. Glycine (GLY) itself, a further endogenous agonist, D-Serine, and inhibitors of GLY reuptake are active in certain experimental models predictive of antipsychotic properties. Further, in controlled clinical trials, GLY and D-Serine enhance the ability of conventional neuroleptics such as haloperidol to improve cognitive and negative symptoms. Their actions are mimicked by the partial agonist, D-cycloserine (DCS). However, these agents exert little effect alone and may interfere with therapeutic actions of the atypical antipsychotic, clozapine. An important issue in the interpretation of drug actions at GLYB sites is their degree of occupation by endogenous GLY and D-Serine - although they are unlikely to be saturated. Further, distinct ”subtypes“ of GLYB site-bearing NMDA receptor may fulfill differential roles in psychotic states Finally, blockade of certain populations of NMDA receptor may be of use in the management of schizophrenia. This article reviews the complex role of GLYB sites / NMDA receptors and their endogenous ligands in the pathogenesis and treatment of psychotic states.

Agonists for mGlu2 / 3 receptors decrease the evoked release of glutamate at certain (ie. forebrain / limbic) glutamatergic synapses, indicating that the functional role of mGlu2 and / or mGlu3 receptors is to suppress glutamate excitations. This offers a mechanism for dampening glutamate excitation under pathological states resulting from excessive glutamate release. Based, in part, on the psychotomimetic actions of phencyclidine (PCP)- like drugs, excessive or pathological glutamate release has been implicated in a number of clinical conditions including psychosis. With this in mind, the pharmacology of multiple mGlu2 / 3 receptor agonists have been investigated in PCP treated rats. Agonists for mGlu2 / 3 receptors such as LY354740 and LY379268 have been shown to block certain behavioral responses to PCP in rats. The effects of mGlu2 / 3 agonists on PCP-induced behaviors are blocked by a low doses of a selective mGlu2 / 3 receptor antagonist, indicating that these actions are mediated via mGlu2 / 3 receptors. In addition, mGlu2 / 3 agonists potently suppress glutamate release in rat prefrontal cortex, as relfected by excitatory post-synaptic potentials (EPSPs) induced by serotonin (5-HT) acting on 5HT2A receptors. These actions of LY354740 and LY379268 are also blocked by a selective mGlu2 / 3 antagonist. Atypical antipsychotic drugs such as clozapine also suppress 5-HT-induced EPSPs in this brain region, thus suggesting a common pathway for the actions of atypical antipsychotic drugs and mGlu2 / 3 receptor agonists. As glutamatergic dysfunction has been implicated in psychotic states and possibly in the etiology of schizophrenia, clinical studies with mGlu2 / 3 agonists may be warranted to further explore the validity of the glutamatergic hypothesis of schizophrenia.

Schizophrenia is a major health problem that affects 2 million individuals in the United States. Antipsychotics offer considerable symptomatic relief and, although commonly discovered by screening with single biological targets, most interact with multiple receptors and signaling pathways. Considerable evidence from family and twin studies demonstrates genetic components and multiple chromosomal regions associated with schizophrenia. The polygenic nature of schizophrenia and multiple mechanisms for most effective agents indicate the need for broader approaches to target identification. Gene expression profiling of post-mortem human brain tissue simultaneously reveals the expression of many thousands of genes. A comparison of tissue from normals and patients provides a ‘disease signature’ of aberrantly expressed genes. ‘Drug signatures’ are the gene expression changes of cultured human or animal neurons treated with psychiatric drugs, and from animals chronically treated with these drugs. A selection of genes from disease and drug signatures can create a set of targets whose changes may better predict disease and its treatment by effective agents. This multi-parameter high throughput screening (MPHTSSM) approach evaluates the mRNA expression pattern of cultured cells exposed to candidate compounds. Compounds that normalize genes altered in schizophrenia may better address its underlying causes. Drugs that mimic gene expression changes that are consistently altered by effective antipsychotic agents provide a drug improvement strategy if efficacy is enhanced or side effects are attenuated.