Vol 4 n° 4 - Drug Development
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odern psychopharmacology began in the 1950s with the discovery of chlorpromazine and later haloperi- dol, drugs that were mainly discovered by serendipity.A vast number of similar phenothiazine- and butyrophe- none-structured “me too” drugs with similar receptor binding profiles and therapeutic benefit were developed in the subsequent years (the so-called typical antipsy- chotics).The first real alternative to these drugs, in terms of mode of action and therapeutic outcome, became available with the introduction of clozapine (an atypical antipsychotic).The discovery of clozapine, and drugs like it, led to the dopamine hypothesis of schizophrenia,1 which had a high impact on the search for neurotrans- mitter functions. However, the pathophysiology of schiz- ophrenic symptoms and the related mechanism of action of antipsychotics could not be fully explained. It became increasingly evident that schizophrenia is both a com- plex disease, in which numerous factors contribute to the symptomatology, and  a  heterogeneous  disease, most probably  resulting  from  many  different  pathological causes. To  underline  this, no  convincing  evidence  of abnormal biological findings valid for all or most of the patients with schizophrenia could be found. However, most clinical studies could demonstrate that antipsy- chotics were an effective treatment in schizophrenia and that they considerably ameliorated the outcome of the disease.The disadvantage of these drugs are their major side effects, such as parkinsonian symptoms, dyskinesia, and akathisia, due to the extrapyramidal motor system, and sometimes depressive effects. Keywords: schizophrenia; new treatment; immunology Author  affiliations:  Psychiatric  University  Hospital,  Munich,  Department  of Neurochemistry, Munich, Germany Address for correspondence: Psychiatric University Hospital, Department of Neurochemistry, Nußbaumstraße 7, 80336 Munich, Germany (e-mail: Manfred.Ackenheil@psy.med.uni-muenchen.de) P h a r m a c o l o g i c a l   a s p e c t s 4 2 6 Developments in antipsychotic therapy with regard to hypotheses for schizophrenia Manfred Ackenheil, MD; Klaus Weber, MPharm M The typical antipsychotic drugs like chlorpromazine and haloperidol were discovered by serendipity in the 1950s. A number of so-called “me too” drugs with similar chem- ical structures and modes of action were marketed in the subsequent years. The first atypical antipsychotic, clozap- ine, was an exception because it lacked some of the phar- macological  properties  of  the  typical  antipsychotics related to the extrapyrimidal motor system. This unique feature of clozapine significantly broadened understand- ing of the mode of action of antipsychotics, and created new hypotheses for schizophrenia. Hypothesis-orientated development of new drugs was only recently initiated. Abnormalities of the immune system in schizophrenia are being increasingly discussed: shifts in the levels of T helper cells subsets 1 and 2 (Th1 and Th2) have been observed, and studies with risperidone and the cyclooxengenase (COX2) inhibitor celecoxib as an add-on therapy have pro- vided very promising results. The glutamate N-methyl-D- aspartate (NMDA) receptors have also been investigated in relation to neuropathological abnormalities in pre- frontal areas of the brain of patients with schizophrenia. This may lead to new technologies like artificial networks related to the glutamate NMDA receptor system. New molecular  biological  techniques  used  in  pharmaco- genomics and proteomics offer new and exciting direc- tions for future drug developments. Dialogues Clin Neurosci. 2002;4:426-431.