Adverse effects of risperidone on spatial working memory in first-episode schizophrenia

Arch Gen Psychiatry. 2006 Nov;63(11):1189-97. doi: 10.1001/archpsyc.63.11.1189.


Context: Working memory impairments are a central neurocognitive feature of schizophrenia. The nature of these impairments early in the course of illness and the impact of antipsychotic drug treatment on these deficits are not well understood. The oculomotor delayed response task is a translational spatial working memory paradigm used to characterize the neurophysiologic and neurochemical aspects of working memory in the primate brain.

Objective: To examine oculomotor delayed response task performance in patients with first-episode schizophrenia before and after antipsychotic drug treatment.

Design, setting, and participants: Twenty-five antipsychotic drug-naive, acutely ill patients with first-episode schizophrenia performed an oculomotor delayed response task at baseline before any drug treatment and again after 6 weeks of risperidone treatment. Twenty-five matched healthy controls were studied in parallel.

Main outcome measure: Accuracy for remembered spatial locations on an oculomotor delayed response task.

Results: Before treatment, patients demonstrated baseline impairment in the ability to maintain spatial location information in working memory at longer delay-period durations (8 seconds), when maintenance demands on working memory were greatest. After 6 weeks of risperidone treatment and significant clinical improvement, this pretreatment impairment worsened such that patients were uniformly impaired across all delay period durations (1-8 seconds). This occurred in the absence of any generalized adverse effect on oculomotor systems or significant extrapyramidal adverse effects.

Conclusions: Deficits in the maintenance of spatial information in working memory are present early in the course of illness. Risperidone treatment exacerbated these deficits, perhaps by impairing the encoding of information into working memory. Studies with nonhuman primates performing oculomotor delayed response tasks suggest that the apparent adverse effect of risperidone might result from treatment-related changes in modulatory functions of prefrontal D1 receptor systems.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acute Disease
  • Adolescent
  • Adult
  • Antipsychotic Agents / adverse effects*
  • Antipsychotic Agents / therapeutic use
  • Female
  • Follow-Up Studies
  • Humans
  • Male
  • Memory / drug effects
  • Memory / physiology
  • Memory Disorders / chemically induced*
  • Memory Disorders / diagnosis
  • Memory Disorders / psychology
  • Middle Aged
  • Oculomotor Nerve / drug effects
  • Oculomotor Nerve / physiology
  • Psychomotor Performance / drug effects
  • Psychomotor Performance / physiology
  • Reaction Time / drug effects
  • Reaction Time / physiology
  • Risperidone / adverse effects*
  • Risperidone / therapeutic use
  • Saccades / drug effects
  • Saccades / physiology
  • Schizophrenia / diagnosis
  • Schizophrenia / drug therapy*
  • Schizophrenic Psychology*
  • Space Perception / drug effects*
  • Space Perception / physiology
  • Task Performance and Analysis


  • Antipsychotic Agents
  • Risperidone