Current Neuropharmacology - Volume 3, Issue 1, 2005

Pharmacologic approaches that diminish dopamine-mediated neural transmission in brain have antipsychotic actions in humans. Blockade of D2 family dopamine receptors is the most common strategy. A paradoxical strategy of using dopamine agonists in particular circumstances to similarly diminish dopaminergic transmission is based on the known function of dopamine autoreceptors and on consideration of the intrinsic activity of dopamine agonists. It was apomorphine that first suggested the effectiveness of dopamine agonist treatment for schizophrenia. Now a partial dopamine agonist aripiprazole has come to market for psychosis and others are in development. This chapter reviews the clinical pharmacology of partial dopamine agonists and their development for the treatment of schizophrenia.

Schizophrenia is the most disabling psychiatric disorder and one of the world's top ten causes of long-term disability, affecting 1% of the population worldwide. The major symptoms of schizophrenia, psychosis (positive symptoms), apathy, social withdrawal (negative symptoms) and cognitive impairment, become manifest in late adolescence/early adulthood and persist thereafter, resulting in chronic disability. The pharmacotherapy of schizophrenia has evolved from typical antipsychotics (dopamine D2 receptor antagonists) to atypical antipsychotics (mixed D2 and serotonin 5-HT2A antagonists with activity at various other receptors) with improved efficacy and side effect profile. More recently, the glutamate/ N-methyl-Daspartate glutamate receptor (NMDAR) hypothesis of schizophrenia has been formulated. This hypothesis is supported by the observation that administration of NMDAR blockers to human volunteers is psychotomimetic and administration to schizophrenic patients exacerbates pre-existing symptoms. This has generated an interest to develop novel antipsychotics focused on the identification of novel molecular targets and susceptibility genes that result in deregulation of glutamatergic, GABAergic and dopaminergic neurotransmission. In particular, metabotropic glutamate (mGlu) receptors mGlu2/3 and mGlu5 are prominently expressed in relevant forebrain regions and their activation modulates glutamatergic transmission and NMDAR function in the mammalian brain. The activity of mGlu2/3 and mGlu5 receptor agonists and more recently, the activity shown by selective mGlu2 and mGlu5 receptor allosteric potentiators in preclinical models of psychosis are promising. Further evaluation of the efficacy and side effect profile of potent, selective and brain-penetrant mGlu receptor activators may provide novel therapeutic avenues for the treatment of schizophrenia.

Current antipsychotic medications are efficacious for the positive symptoms of schizophrenia. However, there remains a significant unmet need for alternate strategies that could result in improved tolerability and/or efficacy for negative and cognitive symptoms. A growing body of research suggests that NMDA mediated neuronal activity is involved in the etiology of schizophrenia. Glycine binds to a modulatory glycineB strychnine-insensitive binding site on the NR1 subunit of the NMDA receptor complex and acts necessary co-agonist for activation of the NMDA receptor. Thus, several approaches have emerged aimed towards modulating this glycine binding site. To date, the glycineB site agonists glycine and D-serine, the partial agonist, D-cycloserine and the glycine reuptake inhibitor, sarcosine, have been shown to provide relief to schizophrenic patients. These clinical findings, combined with a growing body of preclinical literature, support the notion that enhancing synaptic glycineB activity leads to an increase in the effectiveness of normal glutamatergic signaling at the NMDA receptor complex and provides efficacy for schizophrenic patients. Accordingly, the present review examines the role of glycineB site modulation as a therapeutic approach for the treatment of schizophrenia.

Cognitive deficits, including impairments in working memory that have been linked to the prefrontal cortex, are among the most debilitating and difficult to treat features of schizophrenia. Consequently, the identification of potential targets informed by the pathophysiology of the illness is needed to develop novel pharmacological approaches for ameliorating these deficits. Postmortem studies of the prefrontal cortex in schizophrenia subjects have revealed disturbances restricted to a subpopulation of inhibitory neurons that includes chandelier neurons, whose axon terminals synapse on the axon initial segment of pyramidal neurons. Chandelier neurons play an important role in synchronizing pyramidal neuron activity and appear to be a critical component of the prefrontal cortical circuitry that subserves working memory function. Therefore, in this paper we review evidence suggesting that drugs which selectively enhance chandelier neuron-mediated inhibition of prefrontal pyramidal neurons may improve working memory dysfunction in schizophrenia. Potential novel targets for such agents include GABAA receptors that contain the α2 subunit. In addition, we discuss potential complementary mechanisms for enhancing inhibitory input to pyramidal cell bodies, including drugs with activity at the CB1 receptor of the endocannabinoid system. The development of pathophysiologically-based treatments that selectively remediate disturbances in specific neural circuits underlying working memory may provide an effective approach to improving cognitive deficits in schizophrenia.

Schizophrenia is a well recognized and debilitating psychiatric disorder composed of several symptoms. Despite the clinical efficacy of present typical and atypical antipsychotics to alleviate positive symptoms, negative symptoms and cognitive disorders are not optimally controlled. Thus, there is an unmet medical need to develop novel medications with improved tolerability and efficacy for the treatment of these symptoms. Clinical observations over the past four decades have accumulated to support a role of central muscarinic cholinergic neurotransmission in psychosis. Indeed, recent studies have shown that acetylcholine esterase inhibitors as well as weakly selective muscarinic agonists such as xanomeline improved neuropsychiatric symptoms and cognitive function in Alzheimer's disease patients. Preclinically, a large body of studies has highlighted the involvement of muscarinic cholinergic signaling in cognition and psychosis. However the lack of truly selective drugs for the five muscarinic receptors has prevented an unambiguous determination of the role of each receptor subtypes in these behaviors. Recent progress in behavioral studies of mice deficient for the muscarinic receptors and in the discovery of selective muscarinic agonists have started to unravel the contribution of muscarinic receptor subtypes to complex behaviors. Accordingly, this review examines the potential of selectively targeting muscarinic receptor subtypes as a therapeutic approach for the treatment of psychotic disorders.

Significant gender differences have been described for psychiatric disease prevalence and receipt of psychotropic medication. Second generation antipsychotic (SGAs) drugs are not a homogenous group as they differ in their receptor profiles, clinical efficacy and side effects. Gender differences in pharmacokinetics and side effects of second generation antipsychotic drugs have been investigated in several studies indicating that there is a distinct differences between men and women both for the SGAs as a whole group and for specific drugs in particular. Nevertheless the influence of gender on efficacy and side effects of antipsychotic agents is still not well established. Even though higher rates of side effects are reported in women, recommended pharmacological dosage regimes do not differ between male and female patients. For SGAs, the reasons for a higher risk in females may be multi-causal including gender-related differences in pharmacokinetics, pharmacodynamics, pharmacogenetics, immunological and hormonal factors as well as differences in the use of medications by women compared with men. In this review we give a brief overview of gender-specific pharmacokinetic factors leading probably to distinguished clinical outcome in both sexes. Furthermore the implication of gender on common side effects of SGAs such as weight gain, glucose and lipid abnormalities, hyperprolactinemia, cardiac and sexual side effects is discussed with specific reference to studies done on schizophrenic patients.