This is a report of a joint World Psychiatric Association/International College of Neuropsychopharmacology (WPA/CINP) workgroup concerning the risk/benefit ratio of antipsychotics in the treatment of schizophrenia. It utilized a selective but, within topic, comprehensive review of the literature, taking into consideration all the recently discussed arguments on the matter and avoiding taking sides when the results in the literature were equivocal. The workgroup’s conclusions suggested that antipsychotics are efficacious both during the acute and the maintenance phase, and that the current data do not support the existence of a supersensitivity rebound psychosis. Long-term treated patients have better overall outcome and lower mortality than those not taking antipsychotics. Longer duration of untreated psychosis and relapses are modestly related to worse outcome. Loss of brain volume is evident already at first episode and concerns loss of neuropil volume rather than cell loss. Progression of volume loss probably happens in a subgroup of patients with worse prognosis. In humans, antipsychotic treatment neither causes nor worsens volume loss, while there are some data in favor for a protective effect. Schizophrenia manifests 2 to 3 times higher mortality vs the general population, and treatment with antipsychotics includes a number of dangers, including tardive dyskinesia and metabolic syndrome; however, antipsychotic treatment is related to lower mortality, including cardiovascular mortality. In conclusion, the literature strongly supports the use of antipsychotics both during the acute and the maintenance phase without suggesting that it is wise to discontinue antipsychotics after a certain period of time. Antipsychotic treatment improves long-term outcomes and lowers overall and specific-cause mortality.

The advent of the newer “atypical” antipsychotics has revolutionized pharmacologic treatment of schizophrenia (SZ) and other psychotic disorders. In contrast to the first-generation conventional neuroleptics, these second-generation antipsychotic agents possess a broader spectrum of efficacy and cause fewer motor side effects such as extrapyramidal symptoms and tardive dyskinesia. Despite their substantial advantages, however, these second-generation agents also have significant limitations in terms of both efficacy and adverse effects. Several strategies to address these shortcomings are currently under study and some of these are likely to become part of our therapeutic armamentarium in the future. Current shortcomings in the pharmacologic treatment of SZ and strategies under investigation to address each of these deficiencies are reviewed. New formulations of existing medications and new antipsychotics under development are discussed. Developing adjunctive treatment strategies to address each of the major psychopathologic domains in SZ are summarized. The potential application of genetic information to treatment-matching in SZ is reviewed and likely refinements in the practice of evidence-based medicine in the pharmacotherapy of SZ are considered.

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.

A 27-year-old neuroleptic-stabilised schizophrenic patient presented with a three-day history of psychomotor retardation, disturbed sleep, and social and emotional withdrawal following reduction of his anticholinergic dosage; his symptoms had intensified after an increase in neuroleptic dosage, based on a diagnosis of psychotic decompensation. Recognition of a cholinergic syndrome and institution of appropriate anticholinergic treatment resulted in rapid improvement. The clinical distinction between a cholinergic overdrive state and schizophrenic exacerbation, while sometimes difficult, can be critical in selecting appropriate management.