2005 overview: Developments in the pharmacological treatment of schizophrenia

A very important development in the pharmacological treatment of schizophrenia was that a first conceptualised definition of what remission is (ref. 1 ). To define remission in schizophrenia is more complexe than in mood-disorders, where simple cut-offs of scales such as a total score of the Hamilton Rating Scale of Depression below eight are widely accepted criteria.

Schizophrenia is composed by so many symptoms the occurrence of which differs in dependence on the phase of the illness (e.g. positive symptoms in the acute phase and negative symptoms in the maintenance phase) that a new approach had to be used.

Remission was defined as the absence of significant symptoms that contribute to the diagnosis according to DSM-IV. These symptoms can be measured using the PANSS items. If all of the following PANSS items are only mild or better remission can be assumed:

• Delusions – items P1 (delusions) and G9 (unusual thought content)
• Hallucinations – item P3 (hallucinatory behaviour)
• Disorganised speech – item P2 (conceptual disorganisation)
• Grossly disorganised or catatonic behaviour – item G5 (mannerism and posturing)
• Negative symptoms – items N1 (blunted affect), N4 (social withdrawal) and N6 (lack of spontaneity)

As an additional time criteria a persistence of the remission criteria for at least 6 months is necessary. The first studies showing that these criteria can be applied to antipsychotic drug trials and provide meaningful results have been published (ref. 2; ref. 3 )).

A clinical perspective on BPRS and the PANSS

Related work by Leucht and colleagues for the first time tried to explain what the BPRS and the PANSS mean from a clinical perspective (ref. 4; ref. 5 ). Using the statistical procedure "equipercentile linking" they correlated BPRS/PANSS total scores with CGI-severity scores and percentage BPRS/PANSS change from baseline scores with CGI-improvement scores.

They found that e.g. a 25% reduction of the BPRS/PANSS roughly corresponds to "minimal improvement" according to a clinical impression. They conclude that a 50% BPRS/PANSS reduction is a more appropriate cut-off to define response at least in acutely ill, non-refractory patients.

Time course of the drug effect

The time course of the antipsychotic drug effect remains a hot topic. Kapur and colleagues (ref. 6) analysed two studies in acutely ill patients with schizophrenia and agitation and found that olanzapine and haloperidol were more effective than placebo in reducing the positive symptoms of schizophrenia as early as 24 hours after initiation of treatment.

Importantly, this effect remained when unspecific sedation was controlled for. This study is thus a further piece of a puzzle showing that the time course of the antipsychotic drug effect is not delayed but rather antipsychotics start to work very early, but obviously substantially more time is needed before their full effect is obtained.

Long DUP associated with worse outcome

In the last decade there was an enormous interest in the question as to whether prolonged duration of untreated psychosis (DUP) is associated with poor outcome. Max Marshall and colleagues (ref. 7) nicely summarised all these studies in a meta-analysis and clearly confirmed that long DUP is associated with worse outcome. However, whether the relationship is causal can not be proven by this meta-analysis.

Gaebel and colleagues (ref. 8) published the first review of the quality of national schizophrenia practice guidelines. 27 guidelines from 21 countries were analysed. On average the quality of the guidelines was at best moderate, however, some guidelines of outstanding quality do exist.

The authors concluded that there is a need for a core set of recommendations that are developed by an international organisation that can then be adapted especially by poorer countries that have not the resources to develop their own guidelines.  

Typical versus atypical

In the "typical versus atypical" antipsychotic debate I find three publications especially noteworthy. The first one is a large, more than two-year, multi-center study comparing risperidone with haloperidol at low doses (mean modal doses 3.3 mg/day and 2.9 mg/day, respectively).

Despite the low haloperidol doses used, there were more EPS and more tardive dyskinesia in the haloperidol than in the risperidone group, and the relapse rates in the haloperidol group were significantly higher (ref. 9). The second one was derived from a first-episode study comparing olanzapine with haloperidol (ref. 10).

MRI imaging showed that haloperidol was associated with statistically significant grey matter loss while olanzapine was not. Interpretations of this finding are that either haloperidol has toxic effects or that olanzapine has neuroprotective effects.

CATIE

Last but not least, any summary of the new developments in 2005 must speak of CATIE, a large industry-independent, randomised, double-blind study comparing four atypical antipsychotics olanzapine, quetiapine, risperidone and ziprasidone with the conventional compound perphenazine in 1493 patients with schizophrenia (ref. 11).

The duration was 18 months. Some argued that the most important result was that after 18 months overall 74% of the patients discontinued study medication. I personally do not find this result surprising, because previous work had already shown that even in short-term antipsychotic drug trials drop-out rates can be higher than 50% (ref. 12).

Furthermore, in CATIE discontinuing medication did not mean dropping out of the study completely. Patients rather had the possibility to just move on to the next phase of the study which has not been published yet. In terms of general effectiveness, olanzapine was associated with the lowest drop-out due to any reason rate and with the strongest PANSS reduction.

Not more efficacious

Furthermore, the other atypical antipsychotics were not more efficacious than the conventional compound perphenazine. The most important results in terms of side-effects were that olanzapine was associated with most weight gain and that perphenazine was not associated with more EPS or tardive dyskinesia than the atypicals (an exception was a slightly, but significantly higher drop-out due to EPS rate of the perphenazine group).

A number of methodological issues are currently under debate: for example, patients with tardive dyskinesia could not be randomised to the perphenazine group, the dose range of olanzapine (7.5 to 30 mg/day) was relatively broad compared to the other atypicals (quetiapine 200-800 mg/day, risperidone 1.5 to 6 mg/day, ziprasidone 40 to 160 mg/day), and the validity of the outcome "discontinuation due to any reason" can be questioned.

A conclusive evaluation of CATIE may be premature. To date not even all results of the studies first phase have been published. We are still waiting for the results on cognition and on specific aspects of psychopathology such as negative and positive symptoms. Then results of phase two will follow in which drop-outs of phase 1 will be randomized to either clozapine or one of the other atypicals, or to ziprasidone or one of the other atypicals. Probably these results will be described in the future summary of "what was new in 2006". 

References

1. Andreasen NC, Carpenter WT Jr, Kane JM, Lasser RA, Marder SR and Weinberger DR. Remission in schizophrenia: proposed criteria and rationale for consensus . American Journal of Psychiatry 2005; 162 (3); 441-449

2. Lasser RA, Bossie CA, Gharabawi GM and Kane JM. Remission in schizophrenia: Results from a 1-year study of long-acting risperidone injection. Schizophrenia Research 2005; 77 (2-3); 215-227

3. Kissling W, Heres S, Lloyd K, Sacchetti E, Bouhours P, Medori R and Llorca PM. Direct transition to long-acting risperidone - analysis of long-term efficacy. Journal of Psychopharmacology 2005; 19 (5 Supp); 15-21

4. Leucht S, Kane JM, Kissling W, Hamann J, Etschel E and Engel R. Clinical implications of Brief Psychiatric Rating Scale scores. British Journal of Psychiatry 2005; 187; 366-371

5. Leucht S, Kane JM, Kissling W, Hamann J, Etschel E and Engel RR. What does the PANSS mean? Schizophrenia Research 2005; 79 (2-3); 21-238

6. Kapur S, Arenovich T, Agid O, Zipursky R, Lindborg S and Jones B. Evidence for onset of antipsychotic effects within the first 24 hours of treatment. American Journal of Psychiatry 2005; 162 (5); 939-946

7. Marshall M, Lewis S, Lockwood A, Drake R, Jones P and Croudace T. Association between duration of untreated psychosis and outcome in cohorts of first-episode patients: a systematic review. Archives of General Psychiatry 2005; 62 (9); 975-983

8. Gaebel W, Weinmann S, Sartorius N, Rutz W and McIntyre JS. Schizophrenia practice guidelines: international survey and comparison. British Journal of Psychiatry 2005; 187; 248-255

9. Schooler N, Rabinowitz J, Davidson M, Emsley R, et al.; Early Psychosis Global Working Group. Risperidone and haloperidol in first-episode psychosis: a long-term randomized trial. American Journal of Psychiatry 2005; 162 (5); 947-953

10. Lieberman JA, Tollefson GD, Charles C, Zipursky R, et al.; HGDH Study Group. Antipsychotic drug effects on brain morphology in first-episode psychosis. Archives of General Psychiatry 2005; 62 (4); 361-370

11. Lieberman JA, Stroup TS, McEvoy JP, et al.; Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) Investigators. Effectiveness of antipsychotic drugs in patients with chronic schizophrenia. New England Journal of Medicine 2005; 353 (12); 1209-1223

12. Wahlbeck K, Tuunainen A, Ahokas A and Leucht S. Dropout rates in randomised antipsychotic drug trials. Psychopharmacology (Berl) 2001; 155 (3); 230-233