The thrust of development of new antipsychotic drugs has been to identify new compounds that have enhanced antipsychotic efficacy and have lesser side-effects than standard neuroleptic compounds. Drug development strategies no longer concentrate on D2 receptor antagonism but aim to produce novel compounds. The following have been pursued: (a) selective dopamine receptor antagonists; (b) serotonin receptor agonists and antagonists (5-HT1a,e, 5-HT2, 5-HT3) or mixed 5-HT2 - D2 receptor antagonist; (c) selective dopamine agonists or partial agonists; and (d) sigma-site and excitatory amino-acid antagonists. Such compounds are at various stages of development. The only drug which has truly distinguished itself as ‘atypical’ is clozapine. Its mechanism of action is unknown and the search for it, in large part, has been the impetus for development of the compounds listed above.

Whereas some metabolites of antipsychotic drugs are psychoactive and contribute to clinical improvement, recent studies have provided evidence that certain metabolites contribute to side-effects which can be disabling enough to negate clinical improvement as regards the psychosis. The route of administration of the drug can determine the amount of metabolite produced in the body and affect how the patient feels in response to the treatment.

Positron emission tomography studies of regional brain metabolic activity, cerebral blood flow and D2 dopamine receptor binding in schizophrenics and controls are reviewed. Methodological influences on the validity of the data generated by these technologies include problems with measurement as well as clinical and anatomical heterogeneity. Work in these fields to date, however, has produced strong support for the role of D2 dopamine receptor blockade in antipsychotic efficacy. Neuroleptic-induced changes in regional brain metabolism over time have also been observed; however, the relationship between such actions and symptomatic change needs to be further clarified. Future studies on time-course of neuroleptic-associated changes in regional brain metabolism, blood flow and dopamine receptor binding in schizophrenics have the potential to provide greater insight into the relationship of these actions to symptomatic changes and drug-induced side-effects.

Dopamine receptors have been divided into two major types – D1 and D2 – based primarily on pharmacological and biochemical criteria. Recent advances in the molecular biology of the dopamine receptor system have allowed the identification and characterisation of at least five distinct neuronal dopamine receptor genes (D1 to D5). These genes encode dopamine receptors belonging to the D1 receptor family, termed D1 and D5, and three D2-like receptors, termed D2, D3 and D4. These receptors are distinguished on the basis of their primary structure, chromosomal location, mRNA size and tissue distribution, and biochemical and pharmacological differences. Although individually these receptor subtypes may not be directly and exclusively involved in the maintenance or expression of schizophrenia, alterations of any of the receptors may contribute to the perturbation or instability of dopaminergic homeostasis in the brain. What was once thought to be a simple two-receptor system seems to have emerged as an intricate and interactive entity. This review summarises what is currently understood about dopamine receptors, their role in antipsychotic drug action, and their association with psychosis.

Since existing depression scales were designed for assessment of depression in non-psychotic populations, such scales have items which do not distinguish depressed from non-depressed psychotic subjects. The authors describe a new scale, the Calgary Depression Scale, which was designed for the assessment of depression in schizophrenia. The scale was derived from two existing scales by factor analysis and reliability analysis. It has been further tested in two new samples. In the first it has been shown to be reliable, congruent with a self-report scale and valid. In the second sample it has been shown that there is no overlap with negative or extrapyramidal symptoms.

The outcome of clinical drug trials is influenced both by biological and by non-biological factors. Non-biological factors can be subdivided into methodological factors and non-drug factors. The former are related to the definition and measurement of treatment course, response, and outcome itself; the latter cover characteristics of the patient, the treatment milieu, the patient's milieu apart from treatment, and (planned) psychosocial interventions. Although their mechanism of interaction with treatment outcome is not yet fully understood, these non-drug factors should be routinely monitored in clinical trials for three practical reasons: (a) to control for the heterogeneity of outcome; (b) to develop individualised outcome predictors; and (c) to promote the development of individualised guidelines for treatment indication.

The recent development of new neuroleptics that differ from the conventional neuroleptics in both mechanism of action and side-effects profile has introduced problems in their clinical assessment, and highlighted ongoing issues in the design and methodology of clinical trials. These issues are broadly grouped and discussed as follows: sampling problems and selection of patients; design issues; problems in measurement; ensuring compliance; recognition of extrapharmacological issues; and statistical models. For patients to benefit from the development of new neuroleptics, clinical settings have to be prepared for testing their efficacy and safety without too much delay in well designed clinical trials.

This paper reviews the assumptions and efficacy of two strategies for dose reduction during maintenance treatment in schizophrenia: low dose and targeted medication. Studies of low-dose treatment suggest that it can be used for relatively short periods of time or if the dosage reduction is moderate. Studies of targeted treatment suggest that relapse risk increases significantly compared with standard-dose treatment and that there are few offsetting advantages. The paper also reports initial findings from the NIMH Treatment Strategies in Schizophrenia Study, which compares low dose, targeted treatment and a standard dose in the context of two forms of family treatment. Early stabilisation of patients is lower than expected, but patient characteristics are useful in predicting likelihood of stabilisation.

Beyond the continuing use of neuroleptic medication, psychopharmacological treatment approaches during the maintenance phase of schizophrenia often involve adjunctive medication. Appropriate use of such ‘polypharmacy’ can be crucial to patients in achieving their optimal levels of symptom management and functional capacity, although the risks of side-effects and medication interactions must be weighed. This paper reviews the use of adjunctive anti-Parkinsonian medication, benzodiazepines, propranolol, antidepressants, lithium, and carbamazepine in this context. It also explores a strategy of identifying secondary syndromes in the longitudinal course of schizophrenia which can be approached psychopharmacologically.