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How CATIE brought us back to Kansas: a critical re-evaluation of the concept of atypical antipsychotics and their place in the treatment of schizophrenia

  • David Cunningham Owens


The subdivision of the class of antipsychotic drugs into two discrete groups – ‘conventional’ (or first generation) and ‘atypical’ (or second generation) – has been adopted as standard, with the latter generally accepted as ‘better’ and widely recommended as automatic first-line choices. However, this perception has been thrown into confusion with the results of large pragmatic trials that failed to identify advantages with the new, more expensive drugs, while identifying worrying tolerability issues. This article explores the origins of ‘atypicality’, its construction on the back of a confusing and weak clinical validator (diminished liability to promote parkinsonism) and how even in relation to the archetypical atypical, clozapine, the uncertain boundaries of drug-induced extrapyramidal dysfunction may be contributing to confusion about ‘efficacy’ and ‘tolerability’. It argues that abandoning atypicality would open up clinical practice to all drugs of a single class of ‘antipsychotics’ and allow for individualised risk/benefit appraisal as a basis for truly tailored treatment recommendations.

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Supplementary Table S1-S2

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How CATIE brought us back to Kansas: a critical re-evaluation of the concept of atypical antipsychotics and their place in the treatment of schizophrenia

  • David Cunningham Owens
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Selective publication of Clinical trials?

AK Al-Sheikhli, Consultant Psychiatrist
19 February 2008

I believe that there is an advantage of 2nd generation antipsychotics over 1st generation in that they are less likely to cause tardive dyskinesia and akathasia and therefore the stigma attached to these. Nevertheless the paper highlights other considerations which may have over-emphasised their relative benefits. Something not mentioned is the bias shown by the preferential publication of clinical trials withpositive results (Turner et al, 2008).


Turner et al, N Eng J Med(2008), Selective Publication of antidepressants trials and its influence on apparent efficacy,358,252-260.
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Conflict of interest: None Declared

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Triangulating Views on Antipsychotics

John Cookson, Consultant
29 January 2008

The article by David Cunningham Owens (APT Jan 2008) is one of the most thoughtful, stimulating, witty and clinically relevant that APT has published. It urges us to reconsider our views on what we call “atypical”antipsychotics.

As an authority on extrapyramidal symptoms, he describes how the absence of Parkinsonian side effects may endow an antipsychotic with other advantages, including lower risks of depression and cognitive impairment, and of worsening negative and perhaps also positive symptoms of schizophrenia. There is no doubt that haloperidol (widely used in clinical trials as a comparator) can be made to appear a very inferior drug, by prescribing it without prophylactic anticholinergic medication. Thus the “efficacy trials”, where this was done, carry a bias against the classical antipsychotic. Owens is not surprised that the “effectiveness studies” such as CATIE fail to show consistent advantages for newer (“atypical”) antipsychotics in schizophrenia during maintenance treatment.

It would be a mistake to interpret his paper as undermining the conclusion that the “atypicals” represent a therapeutic advance, or to support a conspiratorial view of the pharmaceutical industry. Advances inthe treatment of psychosis and severely disturbed behaviour have come veryslowly over 150 years, from the use of bromide salts (1857), and sedatives(chloral in 1869; barbiturates from 1905; antihistamines in the 1940s and benzodiazepines from 1961). It was the fortuitous discoveries of the properties of lithium from 1948, and chlorpromazine (a product of the antihistamine industry) from 1952, that represent the beginnings of modernpsychotherapeutics. Naturally, drug innovators, such as Paul Janssen (1926-2003) who discovered haloperidol (1958), wanted to produce an antipsychotic that would produce fewer extrapyramidal side effects and greater efficacy than haloperidol and the other older drugs. They saw theopportunity to do this, firstly by selective blockade of subtypes of dopamine receptors (the benzamide drugs), and later by modifying the structure of clozapine (e.g. olanzapine and quetiapine) and by attempting to mimic its pharmacological actions, especially blockade of serotonin (5-HT) receptors (e.g. risperidone). All of these drugs were tested in animal models designed to identify a lower risk of extrapyramidal side effects. As such the “atypicals” represent the application of neuroscientific knowledge and logic to drug development. What this has produced for clinicians (treating some of the most devastating human disorders) is a range of therapeutic options with a variety of different side effects and possibly some differences in efficacy.

The “effectiveness” studies discussed by Owens involved randomisationof the patients to receive one of several possible drugs. This is a somewhat unnatural procedure which avoids the crucial step in which a clinician discusses with the patient and then decides which of the available drugs might best suit that individual’s needs.

The findings of CATIE (funded independently of industry) do suggest that some “atypicals” are more likely than other drugs to be continued, for reasons of both efficacy and individual side effects, although the differences are relatively small.

A third angle from which to view treatments is that of the “observational study”, in which a large cohort of patients is allocated a treatment, chosen by the clinician. These studies tend to confirm that the individual properties of different drugs (sedation, weight gain and metabolic effects, endocrine and sexual side effects, and extrapyramidal side effects) do occur in the “real world” setting as predicted by the efficacy trials. Such studies tend to be sponsored by the industry and therefore to attract more scepticism. However the findings should be included in a “triangulated” view of the role of “atypical antipsychotics”. This combined information is the basis on which the clinician can make the “individualised risk/benefit appraisal” recommendedby Owens and illustrated in his Figure 2.

The industry has been richly rewarded for its investment in research in neuroscience and psychosis, and it will need this success to make the further investments that are required to explore the wealth of informationthat is arising from the basic neurosciences. For example, the exploration of glutamate (and the phencyclidine –PCP - model of psychosis)and endocannabinoids and their interaction with dopamine, are also tantalising subjects for therapeutic research and development. Moreover the understanding of the function and pharmacology of dopamine pathways has probably much more to tell us about psychosis, mood disorders and addictions.

Dr John Cookson is a consultant in general adult psychiatry at the Royal London Hospital and East London Foundation Trust. He trained in physiology and pharmacology before clinical medicine. He has provided advice and lectures at meetings sponsored by the manufacturers of several atypical antipsychotics including those mentioned in this article. He metPaul Janssen and reviewed his biography.
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