Cell-mediated side effects of psychopharmacological treatment

Both antidepressants and neuroleptics are widely used in psychopharmacologi cal treatment. In view of the often equal efficacy of substances belonging to the same class of drugs, potential side effects have become the most Imp ortant criteria for the selection of a specific drug. The therapeutic effec t of antidepressants is mediated by their inhibition of the reuptake of the neurotransmitters noradrenaline and of serotonin. Significant adverse effe cts may occur through the interaction of the antidepressants with other rec eptors believed not to be related to the therapeutic action, most important ly the muscarinic acetylcholine receptor (M), the histamine-1 (H-1) recepto r and the alpha-1 (alpha (1)) adrenergic receptor. In contrast to the class ical tricyclic antidepressants, the newly available selective serotonin reu ptake inhibitors neither block the M-1-, H-1- nor the a, receptors. Althoug h the rate of side effects is considerably lower compared to tricyclic anti depressants, adverse effects may, however, occur through the stimulation of different serotonin receptor subtypes (5-HT2A, 5-HT2B, and 5-HT3), leading to anxiety, sleep disturbances and nausea. Neuroleptics are often administered for years or even decades in the treatm ent of schizophrenia or schizoaffective disorder. The main adverse effects are extrapyramidal symptoms, including parkinsonism, akathisia, dystonic re actions, and tardive dyskinesias. With the introduction of the atypical neu roleptics (e.g. clozapine, risperidone, olanzapine) it became apparent that the antipsychotic effect and the extrapyramidal unwanted effect are not al ways and inextricably linked. The evidence for the hypotheses of the pathog enetic mechanisms leading to extrapyramidal side effects is reviewed. Both the dopamine receptor hypersensitivity hypothesis and the hypothesis of mit ochondrial respiratory chain inhibition are as yet based on indirect eviden ce. However, if, as suggested by the analyses of mitochondrial energy metab olism, the antipsychotic effect and the adverse effects are unrelated prope rties of neuroleptics, new principles should be applied in the development of novel neuroleptics. Neuroleptics might then be developed that are effect ively antipsychotic but are less likely to produce limiting extrapyramidal side effects.