While clozapine has been demonstrated to be efficacious in refractory schiz
ophrenia and possibly schizoaffective as well as bipolar disorders, a subst
antial number of patients still remain unresponsive. One strategy in treati
ng these refractory patients is to augment clozapine with other somatic tre
atments. This article reviews the efficacy and safety of the combination of
clozapine with other somatic treatments. A total of 70 articles mere obtai
ned from a manual, as well as computerized (Medline), search of the English
language literature from 1978 to March 1998, Few controlled studies exist;
most mere case reports/series. From these data, the greatest risk of adver
se effects seems to be associated with clozapine combined with benzodiazepi
nes, valproate, or lithium, but no currently evaluated combination is absol
utely unsafe. In terms of efficacy, the data suggest a number of potential
augmentation strategies, although controlled data are few. Combination ther
apies with clozapine are common in clinical practice, despite a lack of emp
irical data, and the benefits and risks of these combinations need to be sy
stematically reviewed.