For many years, following the introduction of chlorpromazine in the 1950s, little progress was made in the discovery of new drugs for schizophrenia (Reynolds, 1992). Dopamine D2 receptor blockade was recognised as the only therapeutic target for antipsychotics (Creese et al, 1976) and the inevitable consequences of striatal blockade remained problematic. However, the strategies and stimuli for discovery of new drugs changed with the introduction of new, atypical antipsychotics in the 1990s. These include clozapine, remoxipride (now withdrawn), olanzapine, risperidone and sertindole (Kerwin & Taylor, 1996). The goal of antipsychotic drug development has always been to widen the therapeutic ratio between efficacy and adverse effects. These new drugs have in the main achieved this. However, which therapeutic targets these drugs employ remains a mystery, and this information is clearly important for future research into more selectively targeted agents.

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.

Antipsychotic agents have been the mainstay in the management of schizophrenia for a number of years. Their therapeutic efficacy is primarily attributed to dopamine receptor antagonism (Creese et al, 1976), leading to a reduction in the positive symptoms of schizophrenia such as paranoia and hallucinations. Unfortunately, they have little effect on the negative symptoms (such as flattened affect, poverty of speech, anhedonia and social withdrawal) or cognitive deficits. The blockade of central dopamine receptors by classical antipsychotic agents also leads to the development of both acute and chronic motor disturbances (extrapyramidal side-effects) (EPS) (Meltzer, 1992).

Significant associations have been reported between cognitive decline, dementia and measures of cardiovascular and cerebrovascular disease. Such findings raise important possibilities for prevention of dementia through reducing the burden of vascular pathology. However, given the long prodromal periods for both clinical vascular disease and dementia, the most fruitful way forward may lie in investigating the effects of risk factors for vascular disease, rather than clinical vascular disease itself. Hypertension has received considerable attention in this respect although it is only recently, thanks to findings from prospective population-based research, that the complex interrelationship between blood pressure levels and cognitive decline has begun to be clarified.

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.