Neuroreceptor imaging has been used to examine dopamine function in schizophrenia. The evidence from PET and SPECT studies suggests that there is excess dopamine release subcortically, in the striatum, and that dopaminergic transmission may be abnormal in the cortex also, because of an upregulation in D1 receptors. We have found that patients with schizophrenia have higher subcortical levels of intrasynaptic dopamine (and have a greater proportion of D2 receptors occupied by dopamine) at baseline than controls. Those patients who had the highest levels of dopamine were the ones whose positive symptoms responded best to six weeks of treatment with an antipsychotic. Recent studies have also produced new evidence of dopaminergic disturbance in the cortex. When controls were compared with patients with schizophrenia, we found a significant increase in D1 receptors in patients, but only in the dorsolateral prefrontal cortex. Patients were also studied while they undertook a test of working memory. While there was no relationship between test performance and D1 binding potential for controls, those patients with the highest densities (most pathological levels) of D1 receptors performed the worst on the test. Both the D1 upregulation and the poor working memory may be secondary to a chronic, possibly neurodevelopmental deficit in dopamine innervation of the dorsolateral prefrontal cortex in schizophrenia. The D1 binding potential may prove to be a good biomarker with which to identify those patients suffering from schizophrenia who are most likely to benefit from treatment with a D1 agonist. A D1 receptor radiotracer that is sensitive to endogenous dopamine competition would be very valuable in the further exploration of this area.

Dopamine is implicated in the pathogenesis of both the positive and the negative symptoms of schizophrenia. Clinical efficacy of antipsychotic drugs, without the production of side-effects, may be achieved by a dose–response separation of pharmacological function, regional (i.e., anatomical) selectivity of action, or by the selective targeting of neuroreceptors. The atypical antipsychotics have many different ways of acting on receptors in the brain, but they have in common a decreased likelihood of producing extrapyramidal side-effects. Patients respond well to them by showing improvements of both positive and negative symptoms. The preclinical profile of amisulpride shows specificity for D2/D3 dopamine receptors and selective activity in the limbic system. There is evidence that amisulpride is effective in treating both the negative and positive symptoms of schizophrenia, and that it has a low propensity to induce motor side-effects. Therefore, both positive and negative symptoms can be treated, without inducing these side-effects, by selectively targeting dopamine receptors.

Information-processing in the prefrontal cortex is abnormal in patients with schizophrenia. From functional neuroimaging and other studies, it appears that neurons of the dorsolateral prefrontal cortex are effectors of core clinical and biological phenomena associated with the illness. Cognitive deficits qualitatively similar to those in patients with schizophrenia are also found in their healthy siblings and other relatives. The evidence for abnormal prefrontal function in healthy siblings suggests that the deficit in information-processing is part of the biology of genetic susceptibility. Therefore, genetic variations in human DNA that affect this kind of information-processing may contribute part of the genetic risk for the illness. COMT is an enzyme that is distributed widely throughout the brain, but seems to be uniquely relevant to how dopamine affects information-processing in the prefrontal cortex. There is a common variation in the genetic sequence of the COMT gene, which causes a dramatic change in its enzyme activity. In people with schizophrenia, in their healthy siblings, and also in normal controls, the COMT genotype predicts 4% of the variation in human executive cognition and working memory. We have thus identified a genetic mechanism in the human species that affects the efficiency and efficacy of information-processing in the prefrontal cortex. It is, also, a weak genetic risk factor for schizophrenia: in family studies, it increases the risk of schizophrenia by 50-80%. Prefrontal neuronal tuning may be a target for new drug development in the future.

From birth to two years, preschizophrenic children show much higher rates of neuromotor abnormalities and negative affective displays than their healthy siblings. Retrospectively, parents report that preschizophrenic children show more social and interpersonal problems and more abnormalities of thought. Similar results have been found with adolescents who have schizotypal personality disorder. Adolescence appears to be a critical period for the emergence of psychopathology in general, but especially for psychotic disorders. This may in large part be through the actions of gonadal and adrenal hormones, including cortisol, and in particular their influence on the expression of genes. In the case of schizophrenia, these are presumably the vulnerability genes. Patients with schizophrenia have heightened baseline levels of cortisol, and a heightened cortisol response to some biological challenges. Cortisol levels are positively correlated with symptom severity. In addition, the hippocampus, which modulates the activity of the HPA axis, is abnormal in schizophrenia. The HPA axis and hippocampal complex are modulatory neural systems; in the case of schizophrenia, what they might be modulating is the expression of abnormalities in dopamine neurotransmission. Whilst we assume that schizophrenia has prenatal neurodevelopmental origins, neural maturational processes that occur later in life, especially in adolescence, have significant implications for the expression of the illness. It is likely that preventive interventions for schizophrenia, be they pharmacological or behavioural, will have the best chance of success if they are directed at adolescents who are showing preschizophrenic indicators.

For young people experiencing a first-episode of schizophrenia, the first and most important matter to be attended to, once the diagnosis of schizophrenia has been made and patients have entered the care system, is to establish a treatment alliance. The next step is to conceive an individually tailored treatment programme (non-pharmacological as well as pharmacological). The use of antipsychotic drugs needs to be carefully discussed with both patients and families, as medication tends to have a poor public perception. Maintaining treatment is vitally important in terms of relapse prevention, but people who suffer a first-episode tend to terminate treatment early. Patients often discontinue their medication because of side-effects, although a number of other factors can also exert a negative influence on the continuous intake of medication. Among others, these include insufficient information provided to patients and significant others as well as lack of insight and problems in the doctor-patient-relationship. The published data indicate that the outcome of treatment is better for younger patients in a first-episode of schizophrenia than it is for patients who are more chronically ill. However, young patients are much more sensitive to compliance problems than older patients. The main challenge in this phase of the illness is therefore to convince patients that maintenance treatment is necessary in order to assure the best possible outcome.

In terms of the phenomenology of schizophrenia, there are four targets for drug treatments: positive symptoms, negative symptoms, affective dysfunction, and cognitive dysfunction. Because of the side-effects of both conventional antipsychotics and the new atypicals, there still is a need to search for better-tolerated antipsychotics. Conventional antipsychotics have two principal limitations: 30–40% of patients have an insufficient response to them, and they have a large variety of adverse effects. Side-effects will reduce patients’ compliance with treatment, as well as their immediate quality of life, and may therefore unfavorably affect rehabilitation. Four principal features differentiate atypical from conventional antipsychotics, yet have not been established for all atypicals: fewer extrapyramidal side-effects, greater efficacy in the treatment of negative symptoms, specific pharmacological receptor binding profiles, and greater selective effect on the mesolimbic dopamine neurons than on nigrostriatal neurons. The pharmacological profile of amisulpride is completely different to that of other atypical antipsychotics. It has a high selectivity for D2 and D3 dopamine receptors, and thus would be expected to be devoid of unwanted side-effects associated with action on other neurotransmitter systems. It acts preferentially on the mesocortical and mesolimbic systems. It has an earlier onset of action than haloperidol. Amisulpride is a compound with a dual mode of action. At low doses it blocks presynaptic dopamine autoreceptors, inducing an increased dopaminergic neurotransmission, and at high doses it blocks postsynaptic dopaminergic activity. It is at least as effective as haloperidol, flupenthixol, and risperidone in controlling positive symptoms, as well as having efficacy for negative symptoms. It has less propensity to induce weight gain than do other atypical antipsychotics. For the 60–80% of patients with schizophrenia who require long-term treatment, drug tolerability is crucially important, as it will improve compliance, and therefore reduce relapse rate.