Depressive signs and symptoms in schizophrenia: a prospective blinded trial of olanzapine and haloperidol

Arch Gen Psychiatry. 1998 Mar;55(3):250-8. doi: 10.1001/archpsyc.55.3.250.


Background: Depressive signs and symptoms during the course of schizophrenia are common and have been associated with impaired recovery and a higher risk of self-harm. Novel antipsychotic agents introduce new pharmacological avenues that may differentially affect schizophrenic signs and symptoms, including depression.

Methods: This was a 17-country investigation of 1996 patients with schizophrenia or a related diagnosis randomly assigned to a blinded, comparative trial of the novel antipsychotic agent olanzapine (5-20 mg/d) or the conventional D2 antagonist haloperidol (5-20 mg/d). Patients were evaluated with the Positive and Negative Syndrome Scale, the Montgomery-Asberg Depression Rating Scale, and the Simpson-Angus Rating Scale. The trial consisted of a 6-week and a 46-week masked responder maintenance period.

Results: At least moderate depressive signs and symptoms (Montgomery-Asberg Depression Rating Scale score, > or =16) were seen in slightly more than half of this sample. Although both treatments were associated with short-term baseline-to-end point improvement on the Montgomery-Asberg Depression Rating Scale, olanzapine-associated improvements were significantly superior to those observed with haloperidol (P=.001). Furthermore, the response rate for the group receiving olanzapine (> or =50% improvement on the Montgomery-Asberg Depression Rating Scale after at least 3 weeks of treatment) was also significantly higher (P=.008). Analysis demonstrated that improvement in positive, negative, and/or extrapyramidal symptoms was associated with mood improvement (indirect effect); however, most of the olanzapine treatment effect on mood was a primary direct effect (57%) that alone was significantly greater than that seen with haloperidol treatment (P<.001).

Conclusions: Depressive signs and symptoms in schizophrenia are responsive to treatment. The pleotrophic pharmacological features of olanzapine, through 1 or more non-D2-mediated pathways, likely contribute to its superior treatment effect. Better control of the mood disorders accompanying schizophrenia holds the possibility for improved patient outcomes.

Publication types

  • Clinical Trial
  • Comparative Study
  • Multicenter Study
  • Randomized Controlled Trial

MeSH terms

  • Adult
  • Antipsychotic Agents / therapeutic use*
  • Benzodiazepines
  • Comorbidity
  • Depressive Disorder / diagnosis
  • Depressive Disorder / drug therapy*
  • Depressive Disorder / epidemiology
  • Double-Blind Method
  • Female
  • Haloperidol / therapeutic use*
  • Humans
  • Male
  • Olanzapine
  • Pirenzepine / analogs & derivatives*
  • Pirenzepine / therapeutic use
  • Prospective Studies
  • Psychiatric Status Rating Scales / statistics & numerical data
  • Schizophrenia / diagnosis
  • Schizophrenia / drug therapy*
  • Schizophrenia / epidemiology
  • Schizophrenic Psychology
  • Severity of Illness Index
  • Treatment Outcome


  • Antipsychotic Agents
  • Benzodiazepines
  • Pirenzepine
  • Haloperidol
  • Olanzapine