Introduction

Appreciation of the importance of dopamine for psychiatry arose from two observations. Firstly, antipsychotic drugs accelerate brain dopamine turnover, whereas drugs without antipsychotic activity do not. There is also a close correlation between the milligram potency of antipsychotics and their affinity for the dopamine D2 receptor subfamily.

Secondly, amphetamine abuse can cause a psychotic state indistinguishable from schizophrenia. In animal models, the stimulatory motor effects of amphetamine on behaviour are primarily due to dopamine release. This suggests that schizophrenia may be due to dopaminergic over activity. Much diverse evidence has accumulated to support the presence of dopaminergic dysfunction in some aspects of the schizophrenic syndrome.

Over activity of the mesolimbic dopamine pathway has been suggested as the mechanism underlying the `positive' symptoms of psychosis such as delusions, hallucinations, disordered thinking and bizarre behaviour. Conversely, `negative' symptoms such as loss of drive, poverty of thought, social withdrawal and personality deterioration have been attributed to dopaminergic under activity, particularly in the prefrontal cortex.

The powerful psychotogen phencyclidine also produces a schizophrenia-like state. Its psychotic effect is due to antagonism of a receptor for the excitatory amino acid glutamate. Dopamine and glutamate interact in the neostriatum and it is possible that dysfunction in both neurotransmitters occurs in the psychoses.

Dopamine receptor antagonists - antipsychotics

Psychosis is a mental state where there is a grossly impaired appreciation of reality as evidenced by the presence of delusions, hallucinations and bizarre behaviour. Many disorders cause psychosis, including organic states, schizophrenia, mania, psychotic depression and paranoid syndromes.

Evidence now demonstrates persuasively that antipsychotics reverse the symptoms of psychosis (and prevent their recurrence) in all psychotic states, although efficacy can vary considerably (e.g. chronic paranoid states are often refractory).

Antipsychotics include phenothiazines (chlorpromazine, thioridazine, trifluoperazine, fluphenazine decanoate), butyrophenones (haloperidol, droperidol), thioxanthenes (thiothixene) and phenylbutylpiperidines (pimozide). These drugs differ in adverse effect profiles, but have equivalent effects in diminishing the positive symptoms of psychosis. They are less beneficial for negative symptoms. About one third of patients fail to respond adequately to these drugs, and many patients experience serious adverse effects.

Among the extra pyramidal adverse effects characteristic of antipsychotics, patients find akathisia (an irresistible restlessness) troubling and may fail to comply as a result. Dystonic reactions (oculogyric crisis, torticollis, opisthotonus, laryngeal dystonia) and secondary Parkinsonism also occur frequently. In the long term, there is a risk of tardive dyskinesia (usually manifesting as choreiform movements in the oro-bucco-facial region) which can become irreversible. Other important adverse effects include sedation, anticholinergic effects (dry mouth, blurred vision, urinary retention, constipation, tachycardia), weight gain, photosensitivity, pigmentation, hyperprolactinaemia and neuroleptic malignant syndrome.

Antipsychotics were thought to act solely by blocking the dopamine D2 receptor subfamily in mesocorticolimbic pathways, while causing extra pyramidal adverse effects through nigrostriatal dopamine blockade. Recently, D3 and D4 receptor subtypes have been identified. As both receptor types have significant homology with the D2 receptor subtype, the issue of which receptors are involved in the antipsychotic effect is being re-evaluated.

New antipsychotics

The partial efficacy and adverse effects of standard antipsychotics has prompted the search for new drugs. Since the older antipsychotics block cholinergic, noradrenergic and histaminergic, as well as dopaminergic receptors, many adverse effects occur. One research strategy has been to develop highly selective D2 subfamily blocking drugs e.g. remoxipride. Remoxipride is an effective antipsychotic with relatively few anticholinergic or autonomic adverse effects, and with less propensity than haloperidol to cause extra pyramidal adverse effects. However, there have been a number of recent reports of aplastic anaemia in patients taking remoxipride and the drug has subsequently been withdrawn from the market.

Another approach has been to develop drugs with combined dopaminergic-serotonergic blocking activity, based on a possible mechanism of action of clozapine. Risperidone is one of a number of new drugs which are currently under evaluation.

Clozapine

The atypical antipsychotic clozapine, a dibenzodiazepine (see `New drugs' Aust Prescr 1993;16:68), is more effective than standard antipsychotics in some patients with treatment-resistant psychoses, diminishing both positive and negative symptoms. However, 1-2% of patients develop agranulocytosis which occurs usually in the first 18 weeks of treatment. In the U.S.A., clozapine has been administered to more than 23 000 patients with weekly monitoring of white cell counts: there have been 465 cases of agranulocytosis and 7 deaths. In most of the fatalities, the patients were taking multiple drugs.

Clozapine has a number of other troublesome adverse effects including excessive sedation, hypersalivation, fitting, anticholinergic symptoms and weight gain. However, its apparent superior efficacy and the paucity of extra pyramidal adverse effects (including tardive dyskinesia) explain its extensive usage overseas.

The neurochemical mechanisms involved in clozapine's atypical action are not understood. Effects on serotonergic systems and the D1, D3 and D4 receptor subtypes may be important. Additionally, the strong anticholinergic properties of clozapine may serve as an intrinsic antidote to its extra pyramidal adverse effects.

Dopamine agonists

Levodopa and bromocriptine, used to treat Parkinson's disease, do not infrequently cause organic psychoses. Bromocriptine has a role in the management of neuroleptic malignant syndrome, a rare but potentially fatal complication of antipsychotic treatment.

Conclusion

The probable importance of dopaminergic mechanisms in some psychiatric disorders and in the action of antipsychotics has been evident for some time. However, it is now apparent that the relationships are not straightforward. Dopamine systems are complicated, and interactions with other neurochemical systems even more so. The biological developments parallel appreciation of the complexity of psychotic symptoms and their variable responsiveness to treatment. Research endeavours now increasingly focus on specific psychobiological hypotheses.

Further reading

Keks NA, Kulkarni J, Copolov DL. Treatment of schizophrenia. Med J Aust 1989;151:462-7.

Copolov DL, Keks NA. Neuroleptic malignant syndrome. Aust Prescr 1991;14:7-9.

Baldessarini RJ, Frankenburg FR. Clozapine: a novel antipsychotic agent [see comments]. N Engl J Med 1991;324:746-54. Comment in: N Engl J Med 1991;325:518-9.

Alvir JM, Lieberman JA, Safferman AZ, Schwimmer JL, Schaaf JA. Clozapine-induced agranulocytosis: incidence and risk factors in the United States. N Engl J Med 1993;329:162-7.

Self-test questions

The following statements are either true or false.

1. Approximately a third of patients taking antipsychotic drugs will fail to respond adequately.

2. Patients with Parkinson's disease treated with levodopa may develop paranoid ideation.

Answers to self-test questions

1. True

2. True