This placebo-controlled, double-blind study (n=69) investigated the dissociated effects of ketamine in young healthy individuals (aged 18-30) and found that men had greater depersonalization and amnestic symptoms than women. The study also found that age was a factor in the overall effect of ketamine on dissociative symptoms with men with rising age being less affected than women. This conclusion links gender and age to the effects of drugs and recommends including them as factors so that psychiatric treatments could be more effective.
Ketamine is a drug that reduces depressive and elicits schizophrenia-like symptoms in humans. However, it is largely unexplored whether women and men differ with respect to ketamine-action and whether age contributes to drug-effects. In this study we assessed dissociative symptoms via the Clinician Administered Dissociative States Scale (CADSS) in a total of 69 healthy subjects aged between 18 and 30 years (early adulthood) after ketamine or placebo infusion. Dissociative symptoms were generally increased only in the ketamine group post-infusion. Specifically, within the ketamine group, men reported significantly more depersonalization and amnestic symptoms than women. Furthermore, with rising age only men were less affected overall with respect to dissociative symptoms. This suggests a sex-specific protective effect of higher age which may be due to delayed brain maturation in men compared to women. We conclude that it is crucial to include sex and age in studies of drug effects in general and of ketamine-action in specific to tailor more efficient psychiatric treatments.
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.
Papers cited by this study that are also in Blossom
Coyle, C. M., Laws, K. R. · Human Psychopharmacology (2015)
William Deakin, J. F., Lees, J., McKie, S. et al. · JAMA Psychiatry (2008)
Luckenbaugh, D. A., Niciu, M. J., Ionescu, D. F. et al. · Journal of Affective Disorders (2014)
Murrough, J. W., Iosifescu, D. V., Chang, L. C. et al. · American Journal of Psychiatry (2013)
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.
Statistical analyses were conducted via SPSS 23 (IBM). First independent samples t-or U-tests compared the placebo and ketamine group with respect to demographical variables. Further women and men in the ketamine group were also compared for the same variables. To assess whether placebo and ketamine group differed for baseline or post-infusion dissociative symptoms, a 2 × 2 independent samples analysis of variance (ANOVA) was conducted including the within-subject-factor Time (baseline, post-infusion) and the between-subject-factor Treatment (placebo, ketamine). To investigate dissociative symptoms in the ketamine group, a multivariate analysis of covariance (MANCOVA) with sex (women, men) as fixed factor and the three CADSS-subscales (scores after ketamine infusion) as dependent variables was conducted to assess sex differences across all subscales. Test statistics are reported according to Pillai's Trace. Furthermore, a univariate ANCOVA was computed to assess sex differences for the total score. To adjust for potential differences on the total dose depending on body weight, this variable was added as a covariate to both tests. In each case, the statistical threshold was set to α = 0.05. P-values between 0.05 and 0.09 were labeled trend-significant.
The present study investigated whether dissociative symptoms as induced by the anti-depressive drug ketamine differ as a function of sex and age. In general, a subanesthetic dose of ketamine led to profound dissociate symptoms affecting women and men, though men showed significantly stronger symptom manifestation regarding depersonalization and amnesia than women. Furthermore, taking into account our participants age, in men dissociative symptoms in total and derealization in specific decreased with rising age while this association was not observed in women. Surprisingly, the effects of sex and age on ketamine's actions have not been broadly examined in humans, although prevalence rates and symptomatology of mental disorders associated with the glutamate system and ketamine-action, e.g., depression, significantly differ between women and men. Although animal studies point to a variation in sensitivity to antidepressant and addictive effects of ketamine depending on age and sex, human studies rarely report sex or age effects. In humans, the reported differences between women and men focused on metabolites and hepatic clearance of ketamine, biomarkersor side effects.reported that S-Ketamine is metabolized faster in female subjects and the effect of ketamine is greater on cardiac output and heat pain. Another study which used racemic ketamine, as also used in the current study indicated a sex-specific metabolism of ketamine in depressed and bipolar patients. Additionally, a previous meta-analysis reported a significant association between effect sizes of ketamine response at later time points, i.e., 7 days post-infusion, and percentage males, but the number of included studies that contributed data was quite low. Reviewing the relevant literature,stressed that most of the clinical studies lack the information about sensitivity to the effects of ketamine because generally one particular dose of ketamine is administered instead of an application of a dose-response regime like in animal studies. Indeed,showed that men are more sensitive to verbal and subjective memory disturbances induced by intravenous ketamine infusions, of which doses ranged between 0.5 and 1.3 mg/kg. Likewise, in the current study male participants reported higher subjective memory disturbances measured by CADSS supporting earlier findings by Morgan et al. The single dose regime that was applied in the current study might have hindered the clear sex effect insensitivity to the amnesic effect of ketamine. More studies using a wider range of doses would be beneficial to understand both the role of sex and age in effects of ketamine. Concerning age effects, dissociative effects of ketamine were negatively associated with age only in male participants. Early adulthood is a critical development stage that engenders vulnerability for a variety of mental disorders for women and men. Plenty of previously reported findings indicate that the effects of ketamine show variation across participants according to the basal status of associated circuits. Regarding clinical populations, reports on geriatric patients are scarce but seem to be similar to generally observed effects (although see, but the samples were very small or case-control studies. Regarding depressed adolescents and young adults, studies investigating antidepressant effects of ketamine are virtually non-existent. This study is limited in that we specifically focused on young adults, thus included only data from participants younger than 30 years. However, to fully test our assumption of an age-specific decline of dissociative symptoms in men, future studies should include a broader age range, informing about age-and sexspecific effects across different developmental stages (e.g., from puberty to menopause and further) as changes across the lifespan have been reported for cerebral glutamate levels in menand serum levels in women. Moreover, a modulatory role of estradiol has been shown in animal studies addressing glutamate transmission. Regarding ketamine, sex differences in ketamine pharmacokinetics in rats have been reported, however, the impact of circulating hormone levels was negligible. Another limitation to be addressed is the lack of measurements of ketamine and its active metabolites in the blood. Evidence indicates that the metabolism of both racemic and S-ketamine differ between men and women. A common limitation of placebo-controlled ketamine studies is the reliability of blinding. Ketamine induces symptoms that are evident mostly to the participants and also to the involved scientists. For this reason, studies are conducted with active placebos like midazolam, which result in their own caveats. In summary, male participants in our study reported stronger depersonalization and amnestic symptoms following ketamine infusion. Interestingly, this effect was potentiated by age, i.e., the younger the age the stronger the symptoms. Thus, our findings suggest a sex-specific protective effect of age, which may be due to progressed brain maturation in women compared to men. We conclude that it is crucial to include sex and age in studies of drug effects in general and of ketamine-action in specific to tailor more efficient psychiatric treatment strategies.
Create a free account to open full-text PDFs.
Niciu, M. J., Shovestul, B. J., Jaso, B. A. et al. · Journal of Affective Disorders (2018)
Wright, K. N., Kabbaj, M. · Current Opinion in Behavioral Sciences (2018)
Zanos, P., Moaddel, P. J., Morris, P. J. et al. · Nature (2016)
Papers in Blossom that reference this study
Zhornitsky, S., Pelletier, R., Assaf, R. et al. · Progress in Neuro-Psychopharmacology and Biological Psychiatry (2022)
Ramaekers, J. G., Hutten, N. P. W., Mason, N. L. et al. · Journal of Psychopharmacology (2020)