Prevalence and nature of side effects during clozapine maintenance treatment and the relationship with clozapine dose and plasma concentration

Int Clin Psychopharmacol. 2007 Jul;22(4):238-43. doi: 10.1097/YIC.0b013e32819f8f17.


Clozapine is associated with non-neurological side effects that can be subjectively unpleasant and/or clinically serious. We sought to: (i) assess the nature and prevalence of side effects experienced by patients receiving maintenance treatment with clozapine and (ii) explore the relationship between clozapine plasma concentration and side effect burden. Patients were receiving clozapine maintenance treatment. Open questioning followed by systematic enquiry using the Antipsychotic Non-neurological Side Effects Rating Scale were used to assess side effects. Trough plasma clozapine and norclozapine concentrations were measured. One hundred and three patients participated. On open questioning, 61 patients reported a total of 117 side effects, whereas systematic enquiry identified an additional 649 side effects, with each patient reporting at least one. Clozapine plasma concentrations were significantly but weakly correlated with total Antipsychotic Non-neurological Side Effects Rating Scale score (Pearson correlation=0.29, P<0.004). Patients with a plasma clozapine concentration >0.25 mg/l were significantly more likely to have moderate/severe side effects than patients with lower plasma concentrations (63/76 vs. 12/23, chi=9.07, d.f.=1, P<0.01). The side-effect burden associated with maintenance clozapine treatment is high and the true extent can only be ascertained by systematic inquiry. The use of target plasma concentrations below those used for acute treatment should be explored as a strategy for minimizing side effects.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Antipsychotic Agents / administration & dosage*
  • Antipsychotic Agents / adverse effects*
  • Antipsychotic Agents / blood
  • Clozapine / administration & dosage*
  • Clozapine / adverse effects*
  • Clozapine / analogs & derivatives
  • Clozapine / blood
  • Clozapine / metabolism
  • Disorders of Excessive Somnolence / chemically induced
  • Disorders of Excessive Somnolence / epidemiology
  • Female
  • Humans
  • Male
  • Middle Aged
  • Prevalence
  • Psychotic Disorders / drug therapy
  • Schizophrenia / drug therapy
  • Sexual Dysfunction, Physiological / chemically induced
  • Sexual Dysfunction, Physiological / epidemiology
  • Sialorrhea / chemically induced
  • Sialorrhea / epidemiology


  • Antipsychotic Agents
  • norclozapine
  • Clozapine