Journal of Clinical Pharmacy and Therapeutics (2006) 31, 523–534 REVIEW ARTICLE Treatment of psychosis: 30 years of progress I. R. De Oliveira* MD PhD andM.F.Juruena MD *Department of Neuropsychiatry, School of Medicine, Federal University of Bahia, Salvador, BA, Brazil and Department of Psychological Medicine, Institute of Psychiatry, King’s College, University of London, London, UK phrenia. Thirty years ago, psychiatrists had few SUMMARY neuroleptics available to them. These were all Background: Thirty years ago, psychiatrists had compounds, today known as conventional anti- only a few choices of old neuroleptics available to psychotics, and all were liable to cause severe extra them, currently defined as conventional or typical pyramidal side-effects (EPS). Nowadays, new antipsychotics, as a result schizophrenics had to treatments are more ambitious, aiming not only to suffer the severe extra pyramidal side effects. improve psychotic symptoms, but also quality of Nowadays, new treatments are more ambitious, life and social reinsertion. We briefly but critically aiming not only to improve psychotic symptoms, outline the advances in diagnosis and treatment but also quality of life and social reinsertion. Our of schizophrenia, from the mid 1970s up to the objective is to briefly but critically review the present. advances in the treatment of schizophrenia with antipsychotics in the past 30 years. We conclude DIAGNOSIS OF SCHIZOPHRENIA that conventional antipsychotics still have a place when just the cost of treatment, a key factor in Up until the early 1970s, schizophrenia diagnoses poor regions, is considered. The atypical anti- remained debatable. The lack of uniform diagnostic psychotic drugs are a class of agents that have criteria led to relative rates of schizophrenia being become the most widely used to treat a variety of very different, for example, in New York and psychoses because of their superiority with London, as demonstrated in an important study regard to extra pyramidal symptoms. We can which became known as the United States–United envisage different therapeutic strategies in the Kingdom Study (1). A recent study using stan- future, each uniquely targeting a different dardized criteria (2) showed similar prevalence of dimension of schizophrenia, be it positive, neg- schizophrenia and mood disorders across the ative, cognitive or affective symptoms. Atlantic (3). The DSM-III (Diagnostic and Statistical Manual Keywords: atypical antipsychotic, pharmacology, of Mental Disorders, 3rd Edition) (4) incorporated psychosis, schizophrenia, treatment criteria developed by Feighner et al. (5) – the Washington University Criteria, which required the presence of symptoms for at least 6 months. INTRODUCTION Such criteria established schizophrenia as a chronic In 2005, the Journal of Clinical Pharmacy and and severe disorder, with few patients achieving Therapeutics marked its 30th year. Of all the out- full recovery (3). Currently, the DSM is in its 4th standing advances in medical practice over this version (6) and its diagnostic criteria are used period, one of the most impressive has taken place worldwide, standardizing the diagnosis of schizo- in the field of diagnosis and treatment of schizo- phrenia and allowing results of clinical trials to be compared. Received 10 September 2006, Accepted 3 October 2006 Advances in two other fields have led to great Correspondence: Prof. Irismar Reis de Oliveira, Avenida Arau´ jo improvement in our understanding and diagnosis Pinho, 124/2002, Canela 10110-150, Salvador, BA, Brazil. Tel.: +55 (71) 3351 5296; fax: +55 (71) 3241 7154; e-mail: of schizophrenia: neuroimaging studies and gen- [email protected] etics. At the time the Journal was launched, Ó 2006 The Authors. Journal compilation Ó 2006 Blackwell Publishing Ltd 523 524 I. R. De Oliveira and M. F. Juruena studying the living brain was becoming safe with widely used and shown to be effective in the the introduction of imaging techniques, enabling treatment of positive symptoms of schizophrenia symptoms and brain structures to be correlated. In and related psychoses, as well as in preventing 1980, Crow (7) made a distinction between schi- psychotic relapses (11). However, crucial limita- zophrenia type I, with more positive symptoms tions such as persistent symptoms in 25–60% of the correlated with increased dopamine (DA) type 2 patients (labelled either treatment refractory, or receptors and type II schizophrenia, with more partial responders), only modest improvement of negative symptoms correlated with an enlarged negative and cognitive symptoms and a variety of ventricle and a diminished cerebral cortex. Positive side effects both acute (e.g. EPS) and chronic [e.g. symptoms include unusual experiences such as tardive dyskinesia (TD)] represent a major draw- perceptual abnormalities (hallucinations) and back of these drugs (12). Nevertheless, research fixed, false, irrational beliefs (delusions). Negative interest lagged behind these clinical observations symptoms comprise a lack of ordinary mental and it took almost 20 years to ‘jump-start’ focused activities such as thoughts and motivation. Studies research to delineate these conditions and identify using magnetic resonance imaging (MRI) have their determinants. All studies during this period demonstrated structural and functional brain were mainly clinical and descriptive in nature. By abnormalities, predominantly involving frontal the mid-1980s, all that could be accomplished in and temporal lobes, and in most cases already research had already been achieved, within the present at the onset of illness, which usually constraints of research methodologies available at manifests during adolescence or young adulthood. the time. Early diagnosis began to play an important role For many years, it was widely accepted that any in the strategy of treatment, and there was a effective drugs for schizophrenia should also growing interest in the length of time between induce EPS, where the term ‘neuroleptic’ was symptoms’ first appearance in individuals and the originally used to describe such neurological side- time they first received treatment, and whether this effects. However, adverse effects, such as move- period of untreated psychosis was associated with ment disorders and sedation, are problematic and illness outcome. Perkins et al. (8) found that the can result in non-compliance with medication. longer the patient remained untreated, the worse Positive symptoms, such as delusions, hallucina- was the response to antipsychotic treatment and tions and thought disorders are more often in acute severity of negative symptoms on first treatment. phases of the illness than are negative symptoms, Another promising area is the use of MRI to such as poverty of speech, lack of motivation, monitor and define partial and full resistance to apathy and inability to express emotions (13). medication, as several abnormal brain changes Negative symptoms, however, are probably more have been recently correlated with the antipsy- disabling and may not respond as well to typical chotic treatment (9). antipsychotic drugs. Finally, recent molecular genetic studies have Atypical antipsychotic drugs, by definition, dif- identified several strong candidates for suscepti- fer from typical antipsychotic agents in producing bility genes, such as the gene for dysbindin significantly fewer EPS and carrying a lower risk of (DTNBP1), the gene for neuregulin-1 (NRG1) and TD in vulnerable clinical populations at doses that the locus G72/G30 (10). The clinical implication of result in comparable control of psychosis. The these findings are not yet evident, and most of the atypical drugs differ from the typicals in their genetic findings to date lack diagnostic specificity, mechanism of action, but not all share the same although these genes are set to open up new vistas mechanism. Many, but not all, atypicals have been for neurobiological research. found to improve cognitive function, which could be their most important advantage with regard to efficacy. Clozapine, the prototype of these agents, TYPICAL VS. ATYPICAL ANTIPSYCHOTICS has been found to improve delusions and halluci- A number of typical, conventional, antipsychotics nations in patients who fail to respond to other have been developed since chlorpromazine was antipsychotic drugs, and to reduce the risk of sui- discovered in the early 1950s. They have been cide. These agents have been found to increase Ó 2006 The Authors. Journal compilation Ó 2006 Blackwell Publishing Ltd, Journal of Clinical Pharmacy and Therapeutics, 31, 523–534 Treatment of psychosis: 30 years of progress 525 cortical DA and acetylcholine release, as well as to and amisulpride, and it is now understood that this have a variety of effects on the glutamatergic sys- exception may largely be attributed to these drugs tem not shared by the typical agents. Effects on having a higher peripheral/central distribution neuronal survival and plasticity, together with ratio, thereby leading to excessive DA blockade decreased neurotoxicity, might also contribute to in the pituitary that lies outside the blood–brain their clinical advantage over typical neuroleptic barrier (21). drugs (14). ‘Atypical’ is a term widely used to describe some The term ‘atypical’ was first introduced to des- antipsychotics with specific characteristics such as cribe clozapine, since its properties were found to minimal risk of acute and chronic movement dis- be different from the older, conventional, or typical orders