Although the presence of hyperdopaminergia has been demonstrated in the brains of people with schizophrenia, at least in some circumstances, other neurotransmitters are important in this disorder, and a glutamatergic deficiency model of schizophrenia is proposed. It is suggested that the amount of sensory input allowed to reach the cerebral cortex is restricted by an inhibitory effect of the striatal complexes on the thalamus, thereby protecting it from being overwhelmed. Several strands of evidence are presented to support the concept that a weakened glutamatergic tone increases the risk of sensory overload and of exaggerated responses in the monoaminergic systems that could result in psychosis.

While increased dopamine activity is central to our current understanding of the pathophysiology of schizophrenia, dysregulation of a single neurotransmitter is unlikely to explain the disorder adequately. It is argued here that the muscarinic aspects of schizophrenia should be reassessed for a number of reasons. These include current evidence that cholinergic modulation affects both positive and negative symptoms, and neuroendocrine and polysomnographic data that suggest an increased muscarinic cholinergic activity in schizophrenia. In addition, the interactions between the dopaminergic and cholinergic systems are becoming better understood and appear to occur especially in regions that are thought to be relevant in schizophrenia. The fact that the highest affinity of clozapine, with its unique therapeutic profile, is to the muscarinic receptor encourages further evaluation. Finally, the use of anticholinergic agents to treat extrapyramidal side-effects and the fact that many antipsychotic agents have intrinsic anticholinergic activity suggest that the role of the cholinergic system in schizophrenia needs to be more clearly delineated.

Almost all the neurons in the brain are influenced by the excitatory amino acid glutamate. Glutamatergic neurotransmission has been associated functionally with a number of physiological processes and with certain pathophysiological processes, including schizophrenia. Imaging studies provide indirect evidence that glutamate may be involved in schizophrenia. Positron emission tomography scanning has shown a correlation between positive symptoms of schizophrenia and abnormalities of glucose metabolism in components of the limbic system with the highest concentration of glutamate receptors. Studies with ketamine, an anaesthetic that antagonises the N-methyl-D-aspartate (NMDA) glutamate receptor, show an exacerbation or worsening of positive symptoms when this drug is administered to patients with schizophrenia. Regional cerebral blood flow studies with ketamine show that the drug produces increased blood flow in the anterior cingulate cortex, the area where high concentrations of NMDA receptors exist and where alterations in glucose metabolism seem to occur in people with schizophrenia. Diminished glutamatergic neurotransmission in the hippocampal gluatamate-mediated efferent pathways and cerebral dysfunction in the hippocampus and its target areas, particularly the anterior cingulate cortex, may underlie some of the clinical manifestations of schizophrenia.

Cognitive impairment is a central feature of schizophrenia and has been correlated with negative symptoms and impaired social functioning. There is a growing body of data suggesting that the so-called atypical antipsychotic drugs (e.g. clozapine, risperidone, and olanzapine) are better at enhancing cognitive function than traditional neuroleptics. Preclinical studies of information processing using a pre-pulse inhibition model show that the mechanism of action of both olanzapine and clozapine for cognitive enhancement may involve glutamatergic/N-methyl-D-aspartate (NMDA) antagonism. Using positron emission tomography, we have described the metabolic and neurochemical correlates of cognitive impairment induced by glutamatergic/ NMDA antagonism. A better understanding of the underlying causes of cognitive impairment may contribute to elucidating the pathophysiology of schizophrenia and the development of more efficacious treatments for this disorder.

Currently, patients with schizophrenia are usually considered refractory to treatment if they continue to be floridly symptomatic despite receiving treatment with conventional antipsychotic agents. Attempts to improve their response by increasing the dosage, adding supplementary drugs, or switching to agents of another class have not been very successful, and may increase side-effects. Clozapine can be effective, but it is a difficult drug to administer and has therefore been reserved for patients who are doing poorly. With the recent introduction of newer, safer antipsychotic agents, however, even patients who have milder refractory symptoms that persist after treatment with conventional antipsychotics can now be treated.

The discovery of new drugs for psychiatric and neurological disorders has been greatly facilitated by advances in molecular biology, genetics and chemistry. Several examples are given of how these revolutionary advances have been applied to the discovery of new drugs that selectively modify serotonergic neurotransmission, including compounds which may prove to be more effective antidepressants.

The primary aim of the long-term treatment of patients with schizophrenia is to prevent relapse, which is costly both in psychological and economic terms. Although with conventional antipsychotic drugs relapse may occur despite compliance with maintenance regimens, the rate of relapse is reduced in compliant patients. However, this benefit is achieved at the cost of side-effects and the risk of developing tardive dyskinesia, even among patients who have taken these drugs for only a year or two. To provide the therapeutic benefits of maintenance medication without its drawbacks, intermittent dosing and long-term therapy with reduced doses of conventional medications have been explored. The atypical antipsychotic agent, olanzapine, has been shown to be effective maintenance medication and has an improved safety profile.

Olanzapine is a novel antipsychotic agent displaying a unique and pleotrophic pharmacology, which distinguishes it from other existing treatments. Clinical investigations employing olanzapine have demonstrated a number of potential therapeutic advantages in reference not only to placebo but also to contemporary drug standards in the management of psychosis. This paper reviews data on the pharmacokinetics, efficacy and safety of olanzapine, its benefits for quality of life, and economic aspects to assist clinicians in determining where they can usefully employ it.

Olanzapine, an atypical antipsychotic, has a broad receptor binding profile, which may account for its pharmacological effects in schizophrenia. In vitro receptor binding studies showed a high affinity for dopamine D2, D3, and D4 receptors; all 5-HT2 receptor subtypes and the 5-HT6 receptor; muscarinic receptors, especially the M1 subtype; and α1-adrenergic receptors. In vivo studies showed that olanzapine had potent activity at D2 and 5 -HT2A receptors, but much less activity at D1 and muscarinic receptors, and that it inhibited dopaminergic neurons in the A10 but not the A9 tract, suggesting that this agent will not cause extrapyramidal side-effects (EPS). Microdialysis studies showed that olanzapine increased the extracellular levels of norepinephrine and dopamine, but not 5-HT, in the prefrontal cortex, and increased extracellular dopamine levels in the neostriatum and nucleus accumbens, areas ofthe brain associated with schizophrenia. Studies of gene expression showed that olanzapine 10 mg/kg also increased Fos expression in the prefrontal cortex, the dorsolateral striatum, and the nucleus accumbens. These findings are consistent with the effectiveness of olanzapine on both negative and positive symptoms and suggest that, with careful dosing, olanzapine should not cause EPS.

Olanzapine possesses a broad pharmacological profile, interacting with a range of different neurotransmitter receptors. Although its affinity for muscarinic receptors is relatively greater than for dopamine receptors, on schedule-controlled behaviour olanzapine displays a profile resembling a dopamine antagonist. Likewise, in a test of cognitive function, olanzapine does not produce anticholinergic-like deficits. In drug discrimination assays, olanzapine substitutes for clozapine in clozapine-trained animals and clozapine generalises to olanzapine in olanzapine-trained animals. Olanzapine also reverses the behavioural deficits produced by inhibiting N-methyl-D-aspartate receptor glutamatergic transmission. This profile suggests that olanzapine will be effective against both positive and negative symptoms of schizophrenia while producing minimal extrapyramidal side-effects.