One of the major clinical challenges in the treatment of schizophrenia is the treatment of negative symptoms, which are particularly associated with poor long-term outcome. Clozapine is often effective in the treatment of a great proportion of previously neuroleptic refractory patients. Its utility is, however, limited by the high risk of agranulocytosis. Depressive and negative symptoms such as anhedonia, lack of interest, motor retardation and social withdrawal show some overlap. Because of the similarities between negative and depressive symptoms in schizophrenic patients and the success of antidepressants in the treatment of depressive symptoms in schizophrenic disorders, the augmentation of antipsychotics by SSRI antidepressants has repeatedly been suggested as a promising strategy in schizophrenic patients with negative symptoms. Besides several open studies, five controlled trials of the effect of SSRI addition to current treatment with classic neuroleptic agents, have been published. They reveal some evidence for increased efficacy of conventional antipsychotics after addition of SSRIs. Neither placebo-controlled studies nor open trials have revealed additional efficacy of antipsychotic/SSRI combination on the positive symptoms or depressive symptoms in comparison with antipsychotic treatment alone, but the patients in the reviewed studies had been generally selected for their prominent negative symptoms, their neuroleptic resistance or their chronicity. There seems to be, however, clear evidence supporting the efficacy of SSRI augmentation of conventional antipsychotics in the treatment of negative schizophrenic symptoms. The data on clozapine reveal no additional therapeutic potential if pharmacokinetic interactions are controlled for. Path analysis allows an estimate whether, and to which degree, the effect of a treatment on a symptom is mediated by effects on other symptoms. Path analysis has, though, not been reported for antipsychotic/SSRI combinations until now. Nevertheless, SSRI augmentation in the treatment of schizophrenia seems to act directly, has only limited efficacy in treating depressive symptoms, and does not seem to have an effect on positive symptoms or EPS. Furthermore, there is no evidence for an increased efficacy due to increased plasma levels of typical neuroleptics. A paradox exists, as both the serotonin-agonists and antagonists produce similar effects in combination with dopamine-blocking drugs. As reasons for this paradox have been proposed: the complexity of multiple 5HT receptor types, their differing distribution, their different serotonin-affinity and their partly divergent postsynaptic effects. In conclusion, some inferences can be made despite the limitations of the data. There is some evidence for increased efficacy of conventional antipsychotics in negative symptoms after addition of SSRIs, and, whereas path analyses are still lacking, this seems to be a direct effect. SSRIs may be an alternative to clozapine, especially in patients for whom there are contraindications for a clozapine treatment. As yet, there is no convincing rationalization for the paradox that both serotonergic and antiserotonergic substances, e.g. atypical antipsychotics, may improve negative symptoms