Modern antipsychotic drugs: a critical overview

Abstract

SynthèseA ntipsychotic drugs are useful for treating a range of severe psychiatric disorders. Applications include the short-term treatment of acute psychotic, manic and psychotic-depressive disorders as well as agitated states in delirium and dementia and the long-term treatment of chronic psychotic disorders including schizophrenia, schizoaffective disorder and delusional disorders. Newer, "second-generation" antipsychotic drugs have largely replaced older phenothiazine, thioxanthene and butyrophenone neuroleptics in clinical practice (Table 1).1,2 The development of modern antipsychotic drugs was stimulated by a landmark 1988 study that showed clozapine to be superior in efficacy to chlorpromazine in schizophrenia patients resistant to high doses of haloperidol and to have none of the adverse neurologic effects typical of older antipsychotic agents.3 Clozapine was considered "atypical" in having a very low risk of adverse extrapyramidal symptoms. This term has since been applied broadly and uncritically to antipsychotic drugs marketed in the past decade, despite their striking chemical, pharmacologic and clinical heterogeneity. 4 In this overview we consider the neuropharmacology, efficacy and adverse effects of conventional antipsychotics and specific modern antipsychotic drugs. NeuropharmacologyThe venerable hypothesis that schizophrenia is caused by increased cerebral activity of the neurotransmitter dopamine was based primarily on the finding that dopamine agonists produced or worsened psychosis and that antagonists were clinically effective against psychotic and manic symptoms. 5 Blocking dopamine D 2 receptors may be a critical or even sufficient neuropharmacologic action of most clinically effective antipsychotic drugs, especially against hallucinations and delusions, but it is not necessarily the only mechanism for antipsychotic activity. Moreover, this activity, and subsequent pharmacocentric and circular speculations about altered dopaminergic function, have not led to a better understanding of the pathophysiology or causes of the several still idiopathic psychotic disorders, nor have they provided a non-empirical, theoretical basis for the design or discovery of improved treatments for psychotic disorders.The neuropharmacodynamics of specific modern antipsychotic drugs vary greatly, with little evidence for a unifying theory of antipsychotic activity or of drug design (Table 2). Clozapine in particular is complex: it binds loosely and transiently to D 2 receptors and interacts at dopamine (D 1 , D 3 and D 4 ), histamine (H 1 ), acetylcholine muscarinic (M 1 ) and serotonin (5-HT 2A , 5-HT 2C , 5-HT 6 and 5-HT 7 ) receptors and α 1 adrenoceptors. [6][7][8] This complexity leaves the very low risk of extrapyramidal symptoms and unexcelled antipsychotic effectiveness of clozapine unexplained.9 Postural dizziness, sedation and increased appetite may reflect actions of clozapine and some other antipsychotic agents at α 1 , H 1 and 5-HT 2C receptors respectively. Olanzapine demonstrates significant anti-...

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