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.
Abstract
“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.”
Authors: Birgit Derntl, Jonas Hornung, Zumrut D. Sen, Lejla Colic, Meng Li & Martin Walter
Summary
INTRODUCTION
Ketamine is an N-methyl-D-aspartate (NMDA) receptor antagonist that has been shown to decrease depressive symptoms in humans and induces schizophrenia-like symptoms including positive and negative symptoms. Additionally, ketamine induced dissociative symptoms can predict the antidepressant response in major depression patients.
In animal studies, ketamine has different effects in male and female, and in humans, men show a larger decline of verbal memory after drug infusion. However, most studies did not investigate an effect of sex or the interaction of sex and age on any of the ketamine induced symptoms and physiological alterations.
Ketamine is primarily an NMDA receptor antagonist, and its consequent enhancing effect in the function of another glutamatergic ionotropic receptor, AMPA receptor, is well known. Women show higher levels of glutamate compared to men, and serum levels increase with older age in women.
Sex and age effects have been extensively explored in animal studies, with women experiencing a 1 – 2 year earlier peak of gray maturation and reduced cortical gray matter loss during adolescence/early adulthood.
In view of sexual dimorphisms and differing maturation processes in the orbital and medial PFC, we expected sex differences in dissociative symptoms after single ketamine infusion in healthy young women and men during early adulthood.
Participants
A randomized, double-blind, placebo-controlled trial was conducted on 29 healthy female and 40 male participants. They received either a racemic ketamine or a placebo infusion and provided written informed consent prior to participation and received financial compensation for their participation.
Procedure
Participants completed a baseline assessment of the CADSS and then received an infusion of ketamine +/ racemate for 40 min. They were monitored for cardiovascular response every 5 min and again 20 – 40 min after infusion.
Statistical Analysis
Statistical analyses were conducted via SPSS 23 (IBM). A 2 x 2 independent samples ANOVA was conducted to assess whether placebo and ketamine group differed for baseline or post-infusion dissociative symptoms.
To investigate dissociative symptoms in the ketamine group, a multivariate analysis of covariance (MANCOVA) and a univariate ANCOVA were conducted. P-values between 0.05 and 0.09 were labeled trend-significant.
Correlation Analyses
To assess whether age was associated with symptom manifestation, partial correlations controlling for weight were conducted separately for women and men.
General Effects of Ketamine Infusion
A 2 -2 ANOVA detected a significant interaction of Treatment and Time, indicating enhanced dissociative symptoms only in the ketamine group immediately post-infusion.
Group Depending on CADSS Subscale
The MANCOVA and ANCOVA showed that ketamine had a significant effect on sex, with men experiencing higher scores on the depersonalization and amnesia subscales.
Sex- and Subscale Specific Effects in Connection With Participant Age
We assessed whether participant age was associated with symptom manifestation in the CADSS total and sub-scores, separately for men and women. We found that in men, symptom manifestation decreased more strongly with age than in women.
DISCUSSION
The present study investigated whether dissociative symptoms differ as a function of sex and age. It was found that men showed significantly stronger symptom manifestation regarding depersonalization and amnesia than women.
Although animal studies have shown that ketamine affects men and women differently, human studies rarely report sex or age effects. However, a meta-analysis of included studies indicated that there is a significant association between effect sizes of ketamine response at later time points and percentage males.
Wright and Kabbaj (2018) stressed that most clinical studies lack information about sensitivity to the effects of ketamine. Furthermore, Morgan et al. (2006) showed that men are more sensitive to verbal and subjective memory disturbances induced by intravenous ketamine infusions.
Ketamine’s dissociative effects were negatively associated with age only in male participants. The effects of ketamine in geriatric patients were similar to generally observed effects, but the samples were very small or case-control studies.
This study is limited in that it focused on young adults and included only data from participants younger than 30 years. However, future studies should include a broader age range and should also address sex-specific effects across different developmental stages.
Ketamine infusion potentiates depersonalization and amnestic symptoms, and this effect is stronger in younger patients. This may be due to progressed brain maturation in women compared to men.