Interaction of Sex and Age on the Dissociative Effects of Ketamine Action in Young Healthy Participants

Ketamine is an N-methyl-D-aspartate (NMDA) receptor antagonist that produces rapid antidepressant effects at subanaesthetic doses and, acutely, schizophrenia-like and dissociative symptoms. Previous work has shown that the degree of ketamine-induced depersonalisation can predict antidepressant response in depressed patients, but relatively little research has examined whether sex or age moderate ketamine's acute psychotomimetic or dissociative effects in humans. Animal studies and a small number of human reports suggest sex- and age-dependent differences in behavioural, neurochemical and pharmacokinetic responses to ketamine and related glutamatergic processes, and developmental changes in prefrontal cortex maturation occur across late adolescence and early adulthood. Walter and colleagues designed the present study to test whether dissociative symptoms after a single subanaesthetic ketamine infusion differ by sex and whether age within early adulthood (18–30 years) modulates these effects. The investigators assessed dissociative phenomena using the Clinician-Administered Dissociative States Scale (CADSS), which measures derealisation, depersonalisation and amnestic symptoms, in healthy young men and women following ketamine or placebo infusion. Participants were age-matched and the age range was restricted to capture ongoing brain maturation during early adulthood.

This randomised, double-blind, placebo-controlled trial recruited healthy volunteers by public advertisement. After screening for medical and psychiatric health (including the Mini-International Neuropsychiatric Interview, BPRS, HAM-D and HAM-A) and for MR compatibility, 69 participants aged 18–30 years were enrolled: 29 women and 40 men. Subjects were randomised to receive either racemic ketamine (0.5 mg/kg over 40 minutes) or saline placebo infused continuously in 50 ml volumes. Blinding covered participants, clinicians and study staff. Fourteen women (mean age 23.43, SD 2.47) and 21 men (mean age 24.57, SD 2.51) received ketamine; 15 women (mean age 24.33, SD 2.66) and 19 men (mean age 24.00, SD 1.97) received placebo. The ethics committee approved the protocol and participants provided informed consent. Dissociative symptoms were measured with the CADSS at baseline, immediately after the end of infusion, and again 20–40 minutes post-infusion. The CADSS yields subscales for depersonalisation, derealisation and amnestic effects as well as a total score. During infusion, cardiovascular parameters were monitored every 5 minutes and at 20 and 60 minutes after infusion; participants were also asked about their general condition for safety. Statistical analysis used SPSS 23. Baseline differences were tested with independent-samples t‑ or U‑tests. To test general ketamine effects, a 2 × 2 ANOVA was run with within-subject factor Time (baseline, post-infusion) and between-subject factor Treatment (placebo, ketamine). Sex differences within the ketamine group were examined with a multivariate analysis of covariance (MANCOVA) using the three CADSS subscales as dependent variables and sex as a fixed factor; Pillai’s Trace was reported. A univariate ANCOVA evaluated sex differences on the total CADSS score. Body-weight-dependent total dose was included as a covariate where appropriate. For age associations, partial correlations controlling for weight were computed separately in men and women, and Fisher’s z tests compared correlation coefficients between sexes; multiple-comparison correction set an effective threshold of p < 0.0125. The statistical alpha was 0.05 and p-values between 0.05 and 0.09 were labelled as trend-significant.

Demographic and baseline psychiatric measures did not differ significantly between the ketamine and placebo groups, nor between men and women within groups, except for body weight. The 2 × 2 ANOVA indicated a robust effect of ketamine on dissociative symptoms: main effects of Treatment and Time and a Treatment × Time interaction were all significant, F(1,67) = 39.65, p < 0.001, η2 = 0.37, reflecting increased CADSS scores only in the ketamine group immediately after infusion. Within the ketamine-treated participants, MANCOVA and subsequent univariate analyses showed sex-specific differences on CADSS measures. Men reported significantly greater depersonalisation and greater amnestic symptoms than women following ketamine infusion; the text reports these sex differences for depersonalisation and amnesia but does not provide full univariate test statistics in the extracted text. To examine age effects, partial correlations (controlling for weight) were calculated separately by sex. In men there were significant negative correlations between age and CADSS total score and between age and derealisation (older men showed lower symptom levels), with depersonalisation showing a trend-level relationship. Fisher’s z tests comparing sexes showed significant sex differences in the age–symptom relationship for derealisation (z = -3.08, p = 0.002) and for the CADSS total score (z = -2.99, p = 0.003), indicating that symptom scores decreased with age more strongly in men than in women. Correlation differences between sexes were not significant for depersonalisation (z = -1.59, p = 0.11) or amnesia (z = -0.98, p = 0.33).

Walter and colleagues interpret their findings as evidence that males experience stronger acute ketamine-induced depersonalisation and amnestic symptoms than females in early adulthood, and that increasing age within the 18–30 year range is associated with attenuated dissociative responses in men but not women. They situate these results within preclinical and limited clinical literature showing sex- and age-dependent variability in ketamine sensitivity, metabolism and glutamatergic function. The authors suggest that differential maturation of prefrontal and glutamatergic circuits between sexes—women tending to reach cortical maturation earlier than men—could underlie the observed sex-by-age interaction. The investigators acknowledge several limitations. The sample was restricted to young adults under 30 years, so the age-related finding cannot be generalised across the lifespan; the extracted text notes that inclusion of a broader age range (from puberty to menopause and beyond) would be needed to map developmental trajectories. Blood measurements of ketamine and active metabolites were not obtained, limiting interpretation regarding pharmacokinetic contributors to sex differences. The single-dose design precludes exploration of dose–response effects and may obscure sex differences detectable across varied dosing. Blinding is an additional concern in ketamine studies because ketamine’s subjective effects are often obvious to participants and investigators; the authors note that active placebo controls (for example midazolam) have their own caveats. Finally, they emphasise that the literature on human sex- and age-effects for ketamine is sparse and inconsistent, and they call for further research including dose-response protocols, broader age ranges, and measurement of pharmacokinetics and hormonal status to better understand sex- and age-specific effects and to inform tailoring of psychiatric treatments.