Clozapine as an early‐stage treatment

It has now been thirty years since a pivotal clinical trial on the effectiveness of clozapine was published (1). Following that study, clozapine received regulatory approval in many countries for treatment-resistant schizophrenia and has remained the only drug approved for that indication. While treatment resistance in schizophrenia is a serious issue, with at least 30% of patients not benefiting sufficiently from other antipsychotics, the question of an earlier application of clozapine in the course of illness has received less attention. This is unfortunate, considering the evidence that clozapine is typically prescribed relatively late in the course of illness, which may exacerbate the persistence of psychotic symptoms and further impair daily functioning. Early prescription of clozapine may thus have the potential to improve outcomes for patients with schizophrenia. Thirty years later, a new meta-analysis by Okhuijsen-Pfeifer and colleagues (2) in the current issue of Acta Psychiatrica Scandinavica presents evidence that clozapine may indeed be effective earlier in the course of illness, before treatment resistance has developed. As the authors rightly point out in the introduction, it is an ongoing debate as to when to start clozapine treatment, which may contribute to the underutilization of clozapine (3). Another reason may be that clinicians are concerned about side-effects. Indeed, clozapine is often discontinued prematurely because of adverse effects that could potentially be managed (4). Hence, the authors reviewed the evidence for clozapine’s efficacy as a first and second-line treatment, with the goal to help clinicians balance clozapine’s side-effects with its benefits in early disease stages. Interestingly, Okhuijsen-Pfeifer and colleagues found that clozapine did indeed outperform other antipsychotics in schizophrenia spectrum disorders and was more effective than first-line risperidone (2). There was an important limitation, however, in that there were only five studies available that had tested clozapine as a first or second-line treatment, and when only the three randomized controlled trials (RCTs) were included, the clozapine benefit was not statistically significant (although the effect remained positive; Hedges’ g = 0.17, P = 0.3). After adding the two naturalistic studies, the benefit was significant, if relatively small (Hedges’ g = 0.22, P = 0.03). While the authors rightfully refrained from recommending clozapine as a first-line treatment (since they had not investigated its overall tolerability), future studies may wish to take adverse events into account in order to test whether the benefit indicated by the authors outweighs the risk of unwanted side-effects. The question of whether the inclusion of the naturalistic studies may have lead to a conservative rather than an optimistic bias is an interesting one. Indeed, one could expect that clozapine would be used in the more severely ill patients, who may also be more difficult to treat (2). Because of the mandatory blood tests, however, clozapine treatment does require an amount of treatment adherence that may have resulted in a bias for the more adherent patients, which may in turn have inflated effect sizes of clozapine compared to other antipsychotics. Thus, while there is a place for observational studies, RCTs remain the gold standard to address such confounding, and the enthusiasm for large observational studies (5) needs to be balanced with a healthy dose of skepticism (6). One argument against RCTs that is often heard is that they do not represent the ‘real world’ patient population. In other words, patients in clinical practice are said to be different from those enrolled in an RCT, and the treatment effect is said to vary substantially according to the type of patient. Consequently, the argument goes, one cannot rely on results from RCTs since they include artificially and highly selected patients. However, it is important to remember that RCTs are designed to answer questions about relative efficacy: is the treatment on average more effective than the comparator? They give unbiased and generalizable estimates of relative efficacy. Observational studies cannot reliably provide unbiased estimates of average treatment effects, and they almost certainly cannot provide estimates of heterogeneity of treatment effects (HTE), for which much more complex designs are needed (7). Thus, it is often underappreciated that the evidence for HTE is actually scarce (8). In other words, it is often claimed, but rarely tested, that patients respond very differently to antipsychotic treatment, simply because we do not run the sort of clinical