2004 overview: Developments in pharmacological treatment of schizophrenia

In this overview Dr Stefan Leucht, Germany, discusses some of the issues in schizophrenia that attracted special interest in 2004.

The important new developments in the pharmacological treatment of schizophrenia in the last year actually started in December 2003. The group around Shitij Kapur and Rob Zipursky from Toronto published a meta-analysis in the prestigious Archives of General Psychiatry that challenged the delay of onset of antipsychotic drug action hypothesis that had been described in textbooks over decades (ref. 1).

It had been a widely held belief that it takes on average several weeks until antipsychotic drugs show their first effect. Agid and colleagues, however, in a meta-analysis of more than 8000 patients from randomised controlled trials with acute exacerbations of schizophrenia found a significantly greater reduction of symptoms in week 1 than the additional change between week 1 and week 2.

In addition, the mean reduction of symptoms at week 2 was greater than the additional reduction at week 4. These effects were found not only for general symptoms, but also for psychotic symptoms and after the subtraction of a placebo effect. Thus, the early reduction of symptoms could not only be explained by non-specific sedation.

The newly formulated "early onset of antipsychotic action" hypothesis has major implications concerning the mechanism of action of antipsychotic drugs: to date the theory was that the antipsychotic effect is not mediated directly by the blockade of dopamine receptors, but – because the effect seemed to be delayed - rather the expression of postsynaptic changes. If there really were no delay of onset of action, it would be more likely that the antipsychotic effect is a direct one on the dopamine system.

Aripiprazole

A second important development in 2004 was the introduction of aripiprazole in many European and other countries, while it had already been available in the United States in 2003.

Aripiprazole is a new compound that is quite unique for two reasons: Although it does not seem that aripiprazole is more effective than other old and new drugs for the treatment of the symptoms of schizophrenia, it seems to be relatively free of side-effects that have been a major concern of old and new drugs.

It induces only few EPS, it does not have major effects on prolactin and the QTc-interval in the ECG and it is not associated with significant weight gain.

Furthermore, aripiprazole seems to have a special mechanism of action: while all other available antipsychotics are antagonists of dopamine receptors, aripiprazole is a partial agonist at the dopamine receptor. This means that – at least in theory – in situations where there is too much dopamine (positive symptoms) the drug blocks dopamine-D₂-receptors, while in situations where there is hypodopaminergic tone (negative symptoms) dopaminergic effects are enhanced.

Although this is aripiprazole’s most typical effect, it is also like other atypicals an antagonist at serotonin-5-HT_2A-receptors, and a partial agonist at serotonine 5-HT_1A-receptors. Aripiprazole had been tested in more than 5000 randomised patients before it was released on the market. I think that such a high number of patients randomised before market release is also unique in the history of antipsychotics and is important for drug safety.

Depot form of risperidone

Another relatively recently released antipsychotic drug has also had a major impact on developments in 2004 – the depot form of risperidone, risperidone consta. While we are still waiting for methodologically sound long-term studies that compare risperidone depot with oral risperidone to really prove that the depot reduces rates of relapse and rehospitalisation, risperidone’s manufacturer has initiated a number of studies on the issue of compliance.

The most elegant study in this field may be the report by Weiden and colleagues 2004 (ref. 2). They retrospectively analysed the pharmacy refill data of a cohort of more than 4000 Medicaid patients in California. Gaps in treatment that were due to the fact that the patients did not go to the pharmacy to have their medication refilled were correlated with rates of rehospitalisation.

The study did not only show a general association between gaps in treatment and rehospitalisation, but also that even gaps as small as 11 days led to a doubled risk for rehospitalisation.

Thus, this study showed for the first time that even partial non-compliance substantially increases the relapse risk. It should also be noted that in another recent large study with a similar methodology (ref. 3) the use of atypical antipsychotics was not associated with higher compliance rates than the use of typical antipsychotics.

Effects on cognition

It is a widely held belief that is supported by increasing evidence that atypical antipsychotics have beneficial effects on the cognitive symptoms of schizophrenia. However, the effects of typical antipsychotics on cognition had never been systematically analysed until this year a meta-analysis on this issue was published in Biological Psychiatry (ref. 4).

It was probably surprising to many experts in the field that – overall – conventional antipsychotics such as haloperidol had positive effects on cognition in schizophrenia. However, the effect was modest. A general problem in this field is that a high number of cognitive tests is available that are similar but not the same.

This limits the comparability of different studies. I think that it was an important step forward that a group of experts (the MATRICS conference) started to work on a consensus in this area (ref. 5).

Developments in evidence-based medicine

Finally, I want to mention some of the recent developments in evidence-based medicine. The American Psychiatric Association has published an update of its schizophrenia guidelines this year (ref. 6).

The Cochrane Schizophrenia Group (ref. 7), a key-player in the area of evidence-based medicine, has celebrated its tenth anniversary. This group has now produced 89 systematic reviews on all aspects of treatment of schizophrenia.

Ten of the reviews have been published last year and all of them can be found in the Cochrane Library, an electronic database that is available either as a CD-Rom or via the internet. These reviews have been used as a basis for guidelines such as those of the National Institute for Clinical Evidence in the UK (ref. 8) so that I would like to invite the reader to use this valuable source of information.

References

1. Agid O, Kapur S, Arenovich T, Zipursky RB. Delayed-onset hypothesis of antipsychotic action - A hypothesis tested and rejected. Archives of General Psychiatry 2003; 60: 1228-1235

2. Weiden PJ, Kozma C, Grogg A, Locklear J. Partial compliance and risk of rehospitalization among California Medicaid patients with schizophrenia. Psychiatric Services 2004; 55(8): 886-91.

3. Gilmer TP, Dolder CR, Lacro JP, Folsom DP, Lindamer L, Garcia P, Jeste DV. Adherence to treatment with antipsychotic medication and health care costs among medicaid beneficiaries with schizophrenia. American Journal of Psychiatry 2004; 161: 692-699

4. Mishara AL, Goldberg TE. A meta-analysis and critical review of the effects of conventional neuroleptic treatment on cognition in schizophrenia: Opening a closed book. Biological Psychiatry 2004; 55: 1013-1022

5. Green MF, Nuechterlein KH, Gold JM, Barch DM, et al. Approaching a consensus cognitive battery for clinical trials in schizophrenia: the NIMH-MATRICS conference to select cognitive domains and test criteria. Biological Psychiatry 2004; 56: 301-307

6. Lehman AF, Lieberman JA, Dixon LB, McGlashan TH, Miller AL, Perkins DO, et al. Practice guideline for the treatment of patients with schizophrenia, second edition. American Journal of Psychiatry 2004; 161: 1-56

7. Adams CE, Coutinho E, Duggan L, Gilbody S, Leucht S, Wahlbeck K: Cochrane Schizophrenia Group in The Cochrane Library Chichester, UK, John Wiley & Sons Ltd, 2004

8. National Institute for Clinical Excellence. Guidance on the use of newer (atypical) antipsychotic drugs for schizophrenia. www.nice.org.uk 2002