Since the John Davis meta-analysis in the 1970s (the second meta-analysis in medicine; see Davis, 1975), there is little doubt that drug beats placebo in relapse prevention. What is terrific here are the details on aspects of course that are addressed and more information on the risk side to complement benefit. I will comment on two findings. First, depot beats oral. Especially in the United States, we need to move depot into an attractive option and first-line approach (assuming oral administration of the same compound supports safety in the individual). Second, I have thought that there is little evidence for second-generation antipsychotics being superior to first-generation antipsychotics (clozapine excepted) in efficacy and effectiveness, and that the strongest case for second-generation antipsychotics was better relapse prevention. This meta-analysis failed to support this supposed advantage, and I have to adjust my view in this regard.
The van Os and Howes commentary merits a serious and thoughtful read. It gives emphasis to how early and modest the field is in discovery for the psychopharmacology of schizophrenia. In the 60 years since chlorpromazine, progress has been narrow, not very innovative, and not very robust.
Davis JM. Overview: maintenance therapy in psychiatry: I. Schizophrenia. Am J Psychiatry . 1975 Dec ; 132(12):1237-45. AbstractView all comments by William Carpenter
Antipsychotics are (generally) effective in relapse prevention—however, evidence-based indicators for more individualized treatment are needed.
Leucht and colleagues (Leucht et al., 2012) conducted a new, highly comprehensive, but also very differentiated meta-analysis on the relapse preventive efficacy of antipsychotic drugs as compared to placebo, which is now published in The Lancet. In addition, detailed comments are provided by van Os and Howes (van Os and Howes, 2012) in the same issue. As in former reviews addressing this topic, the results clearly underline that antipsychotics are (generally) effective in preventing relapse in schizophrenia compared to placebo with average one-year relapse rates of 27 percent versus 64 percent, an estimated risk ratio of 0.4, and a number of 3 needed to treat (to benefit) patients. On the other hand, and despite this high-grade evidence, many patients with schizophrenia still show cognitive, affective, motivational, or "functional" deficits and impairments in the longer illness course. This indicates that antipsychotics are not so effective in all symptom domains and contributes to the notion by some researchers that schizophrenia is still a "poor outcome" disorder, in particular as compared to other mental disorders (Jobe and Harrow, 2005). Thus, further efforts are needed to develop drug and other treatment strategies to affect the illness course more comprehensively. In this regard, a more uniform and broadly accepted definition of "relapse" would be very helpful. For example, the consensus-based definition of "remission" (Andreasen et al., 2005) has stimulated a large amount of research and enables a better comparison of results across studies.
Some other aspects are noteworthy to address. First, it is still unclear how long antipsychotic treatment has to be maintained, especially after a first episode. A comparison of evidence-based treatment guidelines from different countries developed on highest-quality criteria yielded no or inconsistent recommendations regarding the duration of maintenance treatment (Gaebel et al., 2011). In the last years, different trials compared maintenance treatment (MT) with (stepwise) drug discontinuation (mostly supplemented by early drug intervention based on early signs for relapse, i.e., targeted intermittent treatment/IT) in the long-term treatment of first-episode patients. Whether drug treatment was discontinued after six months (Wunderink et al., 2007), after one year (Gaebel et al., 2011), or, as just published, after two years (Emsley et al., 2012; observational design after drug discontinuation), risk for relapse did noticeably increase after drug discontinuation (up to fivefold after one year compared to further MT). On the other hand, a considerable proportion of patients remains stable under intermittent treatment (in the Gaebel et al., 2011, trial, about 50 percent after MT in the first year). In addition, a relevant proportion of patients (about 20 percent) remain relapse free and develop only one illness episode also if drug treatment was suspended (e.g., Harrow et al., 2012).
There are other significant findings indicating that different patients respond differently to similar treatment strategies. Although efficacy of antipsychotics in general is proven, a distinct proportion of patients suffers from partial remission, symptom recurrence, or relapse despite antipsychotic treatment. This applies also to depot treatment, which minimizes adherence problems, although some patients do relapse, as once again shown in a recent placebo-controlled trial not yet included in the Leucht review (Kane et al., 2012). Similarly, the inconclusive results regarding abrupt versus stepwise drug discontinuation and the development of a "supersensitivity" psychosis represent (to a great extent) different effects in different patients. This corresponds to a finding of our own discontinuation trial, in which assured pre-treatment with antipsychotics and an excellent treatment response have been predictors for deterioration in the case of drug discontinuation (Gaebel et al., 2011). It seems that some patients do very well with antipsychotics (often mistaken by themselves as not being in need of drugs), and that they are the ones who should be recommended to rather maintain than to discontinue treatment.
Based on the Vulnerability-Stress-Coping-model for schizophrenia, many influencing factors contribute to illness development and course. Accordingly, schizophrenia represents a heterogeneous illness due to various pathogenetic factors. Thus, different effects in different patients to similar treatment strategies are to be expected. On the other hand, different antipsychotics do also show some differences in efficacy on different symptom domains (Leucht et al., 2009), as well as in side effect and receptor profiles (Correll, 2010). Thus, besides developing new drugs and other treatment strategies, research should also focus on matching the right patient to the right treatment strategy. This requires the availability of valid (i.e., evidence-based) indicators to enable effective individual treatment decisions. This could be clinical indicators (like symptom characteristics, response, adherence, etc.) or biological markers such as genetic variants, neurophysiological, chemical, or functional parameters (among others). For example, Mössner et al. (Mössner et al., 2009) analyzed data from the first-episode study incorporating the above-mentioned discontinuation trial (Gaebel et al., 2011) regarding genetic characteristics and drug response. They found that response in the negative symptom domain is different according to a common polymorphism (-1019C/G) located in the promoter region of the serotonin (5-HT) 1A receptor gene only for the SGA risperidone (as compared to haloperidol). Other observational trials show similar effects, but well-controlled RCTs are needed to provide sound evidence. Accordingly, we are now preparing a trial in which patients with primary negative symptoms are randomly allocated to different SGAs to investigate response differences in the negative symptom domain in relation to their (-1019C/G) polymorphisms.
Leucht S, Tardy M, Komossa K, Heres S, Kissling W, Salanti G, Davis JM (2012). Antipsychotic drugs versus placebo for relapse prevention in schizophrenia: a systematic review and meta-analysis. Lancet. 379:2063-71. Abstract
van Os J, Howes OD (2012). Antipsychotic drugs for prevention of relapse. Lancet. 2012; 379):2030-1. Abstract
Jobe TH, Harrow M. Long-term outcome of patients with schizophrenia: a review. Canadian Journal of Psychiatry. 2005; 50, 892-900. Abstract
Andreasen NC, Carpenter WT, Kane JM, Lasser RA, Marder SR, Weinberger DR. Remission in schizophrenia: proposed criteria and rationale for consensus. Am J Psychiatry 2005;62:441-449. Abstract
Gaebel W, Riesbeck M, Wobrock T (2011): Schizophrenia guidelines across the world: a selective review and comparison. Int Rev Psychiatry. 23: 379-87. Abstract
Wunderink L, Nienhuis FJ, Sytema S, Slooff CJ, Knegtering R, Wiersma D. Guided discontinuation versus maintenance treatment in remitted first-episode psychosis: relapse rates and functional outcome. J Clin Psychiatry, 2007, 68:654-61. Abstract
Gaebel W, Riesbeck M, Wölwer W, Klimke A, Eickhoff M, von Wilmsdorff M, Lemke M, Heuser I, Maier W, Huff W, Schmitt A, Sauer H, Riedel M, Klingberg S, Köpcke W, Ohmann C, Möller HJ; German Study Group on First-Episode Schizophrenia (2011): Relapse prevention in first-episode schizophrenia: Maintenance vs. intermittent drug treatment with prodrome-based early intervention. Results of a randomized controlled trial within the German Research Network on Schizophrenia. J Clin Psychiatry. 72: 205-18. Abstract
Emsley R, Oosthuizen PP, Koen L, Niehaus DJ, Martinez G (2012). Symptom recurrence following intermittent treatment in first-episode schizophrenia successfully treated for 2 years: a 3-year open-label clinical study. J Clin Psychiatry. 73: e541-e547. Abstract
Harrow M, Jobe TH, Faull RN. Do all schizophrenia patients need antipsychotic treatment continuously throughout their lifetime? A 20-year longitudinal study. Psychol Med. 2012 Feb 17:1-11. Abstract
Kane JM, Sanchez R, Perry PP, Jin N, Johnson BR, Forbes RA, McQuade RD, Carson WH, Fleischhacker WW. Aripiprazole Intramuscular Depot as Maintenance Treatment in Patients With Schizophrenia: A 52-Week, Multicenter, Randomized, Double-Blind, Placebo-Controlled Study. J Clin Psychiatry 2012;73(5):617-624. Abstract
Leucht S, Corves C, Arbter D, Engel RR, Li C, Davis JM (2009). Second-generation versus first-generation antipsychotic drugs for schizophrenia: a meta-analysis. Lancet; 373: 31-41. Abstract
Correll CU (2010). From receptor pharmacology to improved outcomes: individualising the selection, dosing, and switching of antipsychotics. Eur Psychiatry. 25 Suppl 2:S12-21. Abstract
Mössner R, Schuhmacher A, Kühn KU, Cvetanovska G, Rujescu D, Zill P, Quednow BB, Rietschel M, Wölwer W, Gaebel W, Wagner M, Maier W (2009). Functional serotonin 1A receptor variant influences treatment response to atypical antipsychotics in schizophrenia. Pharmacogenet Genomics;19:91-4. Abstract
View all comments by Wolfgang Gaebel