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Antipsychotics (Part 1)† David Cunningham Owens Advances in psychiatric treatment (2012), vol. 18, 323–336 doi: 10.1192/apt.bp.109.006908 Meet the relatives: a reintroduction ARTICLE to the clinical pharmacology of ‘typical’ antipsychotics (Part 1)† David Cunningham Owens ‘atypical’ or ‘second-generation’, should be banned David Cunningham Owens is SUMMARY from teaching and practice (Fischer-Barnicol 2008; Professor of Clinical Psychiatry at the University of Edinburgh and an A number of pragmatic trials have cast doubt Owens 2008; Leucht 2009), allowing the entire on the concept of ‘atypicality’ in relation to anti­ honorary consultant psychiatrist at field of antipsychotics, old and new, to become the Royal Edinburgh Hospital. He psychotic drugs, and some commentators have available for equal consideration in individualised trained originally in general medicine argued that the dichotomy between ‘typical’ (‘first­ treatment planning. and neurology before turning to generation’) and ‘atypical’ (‘second­generation’) psychiatry, where his interests compounds is artificial and should be abandoned, This overlooks an obvious fact – that a have revolved around the biological leaving the entire class of antipsychotics available generation of trainees has now reached seniority basis and treatment of psychotic for consideration in more individualised treatment in psychiatry without gaining much, if any, disorders, especially schizophrenia. planning. However, younger psychiatrists now experience in the use of antipsychotics available He is a member of the teaching faculty of the British Association gain little or no experience in the use of older before the mid-1990s. This is important, for one for Psychopharmacology and of the antipsychotics. This is the first of two articles lesson from CATIE might be that we were not UK drug regulatory authority, the addressing practical issues for consideration in very good at using the older drugs in the first Commission on Human Medicines. Professor Owens is one of the prescribing the older antipsychotics available place. This article offers a brief clinical overview in the UK. It covers background, including the few remaining clinical academics of the so-called ‘first-generation’ (‘conventional’ fundamental clinical action of antipsychotics, in the UK to partake in routine or ‘typical’) antipsychotics currently available in general adult psychiatric practice. the nature of drug licensing and identification the UK (Box 1). While a ‘clinical pharmacology’ Correspondence Professor of pharmacological parameters that may be of David Cunningham Owens, Royal value in prescribing decisions, and discusses approach would be ideal, formal study of these Edinburgh Hospital, Kennedy Tower, the phenothiazines: chlorpromazine, promazine, compounds was generally sparse, so a large part Morningside Terrace, Edinburgh levomepromazine, pericyazine, perphenazine, of what follows encompasses my own experience as EH10 5HF, UK. Email: david.owens@ trifluoperazine and prochlorperazine. a clinician now sufficiently ‘senior’ to have accrued ed.ac.uk some years of their utilisation. DECLARATION OF INTEREST The article focuses on oral preparations, as †See pp. 337–350 and 351–352, None. these still comprise the ‘essential’ first step in this issue the treatment of most psychotic illnesses and are The Clinical Antipsychotic Trials of Intervention the group to have suffered most neglect with the Effectiveness (CATIE) study (Lieberman 2005) is introduction of new products. arguably the highest-profile psychopharmacology trial ever, for this was a study with a sting in its History message – that, in effect, for over a decade, psy- The surgeon Henri Laborit was given belated chiatry had got it wrong (Owens 2008). There are access to the newly developed ‘chloropromazine’ still those who reject such radical interpretation (sic ) in 1951, after psychiatrists had noticed only (Naber 2009) but much of CATIE’s prodigious sedation (Owens 1999). He detected something output has been aimed at addressing potential different – ‘detachment’, ‘indifference’, an affective design flaws and, overall, it has stood up well to a change that was unique and distinct from sedation. level of scrutiny most studies avoid. Furthermore, And he noted this (subsequently termed ataraxy) it is now only one of a series of pragmatic studies of after single and, by our standards, small doses differing designs and outcomes, and not sponsored (50–75 mg usually administered by intramuscular by industry (Jones 2006; Kahn 2008; Fischer- injection). ‘Ataraxics’ lost out to ‘neuroleptics’ in Barnicol 2008; Sikich 2008), pointing to the christening the new class of drugs, which was unavoidable conclusion that the distinction between unfortunate, for ataraxy refers to a particular ‘typical’ and ‘atypical’ antipsychotics is artificial. mental state effect (possibly the target action) that This has led some to argue that any term implying is key to understanding the clinical pharmacology a dichotomous split in antipsychotic drugs, such as of the entire class, whereas neuroleptic points to 323 Owens Licensing is not about what doctors can and BOX 1 Older (‘first­generation’) cannot prescribe. These are clinical decisions antipsychotics currently available in reserved to individual practitioners. Licensing the UK (oral formulationsa) was introduced in the wake of the thalidomide Phenothiazines disaster of the 1960s and is about the claims • Chlorpromazine manufacturers are permitted to make in pursuit b of sales. For pharmaceutical companies, licensing • Promazine is a commercial imperative, the mechanism that • Levomepromazine (methotrimeprazine) allows them to, in effect, advertise their wares. • Pericyazine (periciazine) Just because a product has achieved a licence • Perphenazine for an indication does not mean it is the only b • Prochlorperazine compound endowed with the necessary benefits. It • Trifluoperazine simply means that the manufacturer has invested in the studies to justify promoting that drug for Thioxanthenes that indication. It is inevitable, therefore, that • Flupentixol (flupenthixol) doctors hear a lot about ‘new’ licensed indications, c • Zuclopenthixol (zuclopentixol) for telling us was the point of all that expenditure Butyrophenones and diphenylbutylpiperidines in creating the script. This clamour does not allow • Haloperidol us to infer that the story is either specific to their b • Benperidol product or previously untold. The clinical diversity of antipsychotics was • Pimozide evident from the start, with a number being Substituted benzamides advocated for anxiety and depression rather than • Sulpiride – or in addition to – schizophrenia, as well as non- a. The following are also available as depots: flupentixol, psychiatric indications. Furthermore, by the 1980s zuclopenthixol (esterified with decanoic acid), fluphenazine, it was difficult to undertake studies on bipolar pipotiazine, haloperidol. disorder treated with lithium alone, for clinical b. Uncommonly used as antipsychotics or with limited/no practice relied heavily on combined regimes of data for efficacy. c. Also esterified with acetic acid. lithium and antipsychotics. Antipsychotics licensed for use in mood disorders may reflect new drug actions. More probably, this a group of side-effects. The loss of the concept is simply formalises evidentially what was clinical the more regrettable for there has been hardly wisdom before – that (some) antipsychotics any investigation of the neural basis of ataraxy, beneficially affect mood. an astonishing oversight of basic pharmacological mechanisms in such a widely utilised class of Principles drugs. By the late 1950s, the subjective features There are no specific ‘rules’ for prescribing comprising ataraxy had become subsumed under older antipsychotics that should not apply to the mild/early Parkinsonism, an assumption as newer drugs also, though the formulations and significant if it is wrong as if it is correct. marketing materials for newer drugs make it easier The importance of this lies in the realisation to suspend the decision-making ‘algorithms’ that that antipsychotics (as the neuroleptics came to should be exercised in making conscious choices. be called) may create, as class effects, subjective Prescribing has become all too mechanical. states that, first, are difficult if not impossible For exam purposes, trainees tend to organise to distinguish from illness-related disorders and antipsychotics in terms of chemical groupings, second, can have detrimental consequences for although this was not the traditional emphasis. quality of life and adherence. Antipsychotics can Initially, clinical considerations predominated be difficult drugs for patients to take but can also (Ellenbroek 1993). Europeans dissented from US be difficult for doctors to prescribe sensitively. psychiatrists in believing that antipsychotics were fundamentally different and could be classified A note on ‘indications’ along various efficacy/tolerability axes, though In recent years, the pharmaceutical industry none of the often intricate systems proposed (e.g. has moved to extend indications for new anti- the star scheme of Bobon et al (1972) and the multi- psychotics, especially to certain mood states. focal scheme of Fisher-Cornelsson et al (1974)), This has highlighted doctors’ confusion about the achieved general acceptance. Most clinicians nature of drug licensing. would now accept the American view that in 324 Advances in psychiatric treatment (2012), vol. 18, 323–336 doi: 10.1192/apt.bp.109.006908 Meet
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