Optimizing the glutamatergic challenge model for psychosis, using S+ -ketamine to induce psychomimetic symptoms in healthy volunteers

J Psychopharmacol. 2015 Apr;29(4):401-13. doi: 10.1177/0269881115570082. Epub 2015 Feb 17.


The psychomimetic effects that occur after acute administration of ketamine can constitute a model of psychosis and antipsychotic drug action. However, the optimal dose/concentration has not been established and there is a large variety in outcome measures. In this study, 36 healthy volunteers (21 males and 15 females) received infusions of S(+)-ketamine or placebo to achieve pseudo-steady state concentrations of 180 and 360 ng/mL during two hours. The target of 360 ng/mL induced increasingly more intensive effects than expected, and the targets were subsequently reduced to 120 and 240 ng/mL, which were considered tolerable. There was a clear, concentration-dependent psychomimetic effect as shown on all subscales of the positive and negative syndrome scale (e.g. positive subscale +43.7%, 95%CI 34.4-53.7%, p < 0.0001 for 120 ng/mL and +70.5%, 95%CI 59.0-82.8%, p < 0.0001 for 240 ng/mL) and different visual analogue scales. The startle reflex was inhibited (prepulse inhibition) by both main target concentrations to a similar extent, suggesting a maximum effect. Ketamine was found to constitute a robust model for induction of psychomimetic symptoms and the optimal concentration range for a drug interaction study would be between 100 and 200 ng/mL.

Trial registration: ClinicalTrials.gov NCT01101659.

Keywords: Clinical pharmacology; biomarkers; psychosis model; psychotic disorders; schizophrenia.

Publication types

  • Randomized Controlled Trial

MeSH terms

  • Adolescent
  • Adult
  • Cross-Over Studies
  • Dose-Response Relationship, Drug
  • Double-Blind Method
  • Excitatory Amino Acid Antagonists / administration & dosage
  • Excitatory Amino Acid Antagonists / pharmacology*
  • Female
  • Humans
  • Ketamine / administration & dosage
  • Ketamine / pharmacology*
  • Male
  • Psychiatric Status Rating Scales
  • Psychoses, Substance-Induced / etiology*
  • Psychoses, Substance-Induced / psychology
  • Reflex, Startle / drug effects*
  • Young Adult


  • Excitatory Amino Acid Antagonists
  • Ketamine

Associated data

  • ClinicalTrials.gov/NCT01101659