title: Optimizing the glutamatergic challenge model for psychosis, using S+ -ketamine to induce psychomimetic symptoms in healthy volunteers.
abstract: 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.
authors.affiliation: Centre for Human Drug Research, Leiden, The Netherlands danielkleinloog@gmail.com.
authors.forename: Daniël
authors.initials: D
authors.lastname: Kleinloog
authors.affiliation: Centre for Human Drug Research, Leiden, The Netherlands.
authors.forename: Anna
authors.initials: A
authors.lastname: Uit den Boogaard
authors.affiliation: Leiden University Medical Centre, Leiden, The Netherlands.
authors.forename: Albert
authors.initials: A
authors.lastname: Dahan
authors.affiliation: Leiden University Medical Centre, Leiden, The Netherlands.
authors.forename: René
authors.initials: R
authors.lastname: Mooren
authors.affiliation: Centre for Human Drug Research, Leiden, The Netherlands.
authors.forename: Erica
authors.initials: E
authors.lastname: Klaassen
authors.affiliation: Centre for Human Drug Research, Leiden, The Netherlands.
authors.forename: Jasper
authors.initials: J
authors.lastname: Stevens
authors.affiliation: Centre for Human Drug Research, Leiden, The Netherlands.
authors.forename: Jan
authors.initials: J
authors.lastname: Freijer
authors.affiliation: Centre for Human Drug Research, Leiden, The Netherlands Leiden University Medical Centre, Leiden, The Netherlands.
authors.forename: Joop
authors.initials: J
authors.lastname: van Gerven
mesh_terms: D000293:Adolescent; D000328:Adult; D018592:Cross-Over Studies; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D018691:Excitatory Amino Acid Antagonists / Q000008:administration & dosage / Q000494:pharmacology*; D005260:Female; D006801:Humans; D007649:Ketamine / Q000008:administration & dosage / Q000494:pharmacology*; D008297:Male; D011569:Psychiatric Status Rating Scales; D011605:Psychoses, Substance-Induced / Q000209:etiology* / Q000523:psychology; D013216:Reflex, Startle / Q000187:drug effects*; D055815:Young Adult
chemical_list: D018691:Excitatory Amino Acid Antagonists; D007649:Ketamine
keywords: Clinical pharmacology; biomarkers; psychosis model; psychotic disorders; schizophrenia