Sex differences in response to ketamine as a rapidly acting intervention for treatment resistant depression

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Abstract

Background

While ketamine has been increasingly studied for treatment resistant depression (TRD), the impact of sex differences on treatment outcomes has not been well studied. The objective was to ascertain whether there were differences in response to a single administration of ketamine for TRD between men and women, and between pre- and post-menopausal women.

Methods

A randomized, double-blind, placebo-controlled trial (N = 99; N = 50 male; N = 49 female) was conducted to investigate the efficacy of intravenous ketamine versus active placebo as augmentation of antidepressant therapy for TRD. Patients were assigned to one of five arms; one-time administration of ketamine of varying doses (i.e., 0.1, 0.2, 0.5, and 1.0 mg/kg), and one group receiving active placebo (intravenous midazolam). A priori-planned analyses were conducted to compare responses between women and men, as well pre-vs. postmenopausal women.

Results

Analyses demonstrated no significant differences between women and men in terms of treatment response (F(1,80) = 0.06, p = 0.80). There were no significant differences in the frequency of adverse effects (AEs) reported by those assigned to ketamine treatment groups (p > 0.21 for all AEs reported more than once), although women reported more headaches (12% vs. 6%, p = 0.30) and nausea (10% vs. 6%, p = 0.47). In comparing pre-vs. postmenopausal women, no differences in efficacy were observed (F(1,76) = 0.36, p = 0.55).

Conclusions

Results do not support differential efficacy or tolerability of ketamine for the treatment of TRD between women and men, nor based on menopause status among women. However, larger trials with these a priori aims are needed to confirm these results.

Introduction

Ketamine has progressively received increased attention as an expeditiously acting treatment for major depressive disorder (MDD), treatment resistant depression (TRD), and suicidality (Duman et al., 2016, Sanacora et al., 2017, Tundo et al., 2015, Wilkinson et al., 2018). Ketamine is a dissociative anesthetic and an antagonist of N-methyl-d-aspartate receptors (NMDAr) (Duman et al., 2016, Sanacora et al., 2017, Tundo et al., 2015, Wilkinson et al., 2018). A consensus statement around the use of ketamine for the treatment of depression was recently published, detailing the robust and rapid antidepressant effects of ketamine in randomized controlled trials, while underscoring the limitations of the current evidence base (Sanacora et al., 2017). As ketamine use becomes more prevalent and accessible, a better understanding of predictors of patient response and tolerability is needed. Previous studies have suggested that there may be sex differences among men and women in terms of response to monoaminergic antidepressants (Kornstein et al., 2000, Kornstein et al., 2006, Sloan and Kornstein, 2003, Young et al., 2009), and it would be important to know if differences occurred with ketamine use. Also, it is possible that treatment responses may differ among women according to menopause status, with premenopausal women responding differently to postmenopausal women, and that perimenopausal women may also have different treatment responses. Previously in the assessment of treatment responses to SSRI and SNRI therapy in two large studies, Kornstein et al. did not find differences among women based on menopause status nor exogenous sex hormone treatment (Kornstein et al., 2014, Kornstein et al., 2013). However, in a study in which patients received either the tricyclic antidepressant imipramine or the SSRI sertraline, women responded better to sertraline than to imipramine overall, with premenopausal women showing a significantly more robust response to sertraline than imipramine, a difference not found among postmenopausal women (8). In the same study, men were found to have better responses to imipramine than sertraline, representing a significant sex difference in treatment response.

It is plausible that men and women may respond differently to ketamine treatment, and that women may respond variably based on reproductive lifecycle status, specifically regarding whether they are pre- or postmenopausal. Animal models suggest that the neuropsychiatric sequelae of ketamine may be affected by sex and gonadal steroids. In one study, ketamine was found to induce a schizophrenia-like state in male and diestrous female rats (in a low estradiol phase), while these behaviors were not observed in female rats during the high estrous phase (Celia Moreira Borella et al., 2016), suggesting that a high-estrogen state may dampen a ketamine-related response. Other findings in animal studies have also suggested that sex may influence rates of ketamine metabolism (Guo et al., 2016, Livingston and Waterman, 1977).

In animal models of depression, sex differences in response to ketamine have been inconsistent and challenging to apply to humans. Female rats appear to respond more robustly to ketamine administration in the forced swim test, although effects may last longer in males (Franceschelli et al., 2015). There may be an interaction between estrogen and ketamine, with female rats demonstrating more of an antidepressant-like response to low dose ketamine, not observed among male or ovariectomized female rats. Antidepressant-like effects that are not observed in ovarectomized animals have been observed when physiological replacement of both estrogen and progesterone were provided (Carrier and Kabbaj, 2013, van den Buuse et al., 2015). In another study of repeated ketamine administration, male rats experienced an antidepressant-like effect, while female rats demonstrated behaviors consistent with anxiety and depression (Thelen et al., 2016). Ketamine administration in animals has also led to observations about neurochemical effects differentiated by sex (Sarkar and Kabbaj, 2016, Thelen et al., 2016). Taken together, these studies support the assessment of possible sex differences in response to ketamine in humans and potential roles of estrogen and progesterone in those differences.

In humans, few studies have yet to inform whether ketamine administration might have clinically important sex differences in the treatment of depression or other neuropsychiatric indications. In a pooled analysis of four studies assessing ketamine infusions as a treatment for MDD or bipolar depression, investigators did not find that sex was predictive of depression outcomes (Niciu et al., 2014). However, a meta-analysis that included N = 437 patients demonstrated that men appeared to maintain antidepressant responses to ketamine longer than women after a single dose administration (Coyle and Laws, 2015). Regarding tolerability, in a study of ketamine abusers undergoing substance abuse treatment, withdrawal symptoms and subjectively reported cognitive symptoms were more common among females compared to males (Chen et al., 2014). In contrast, in a retrospective study of fifty patients who received ketamine for sedation or pain relief on medical and surgical units, no differences in psychiatric adverse effects were found (Rasmussen, 2014).

This trial of ketamine was conducted as part of a collaboration between the MGH Clinical Trials Network and Institute (CTNI), multiple academic sites, and the National Institute of Mental Health (NIMH), with the goal of assessing rapid onset antidepressant effects of treatment with a range of ketamine doses (Fava et al., in press).

We aimed to assess the impact of sex and female lifecycle status on the short-term antidepressant effects of ketamine infusions. The objective of these a priori analyses were to: 1) assess sex differences in rapid antidepressant response to ketamine treatment between men and women, with the primary outcome in depression response at 24 h, 2) to assess differences in antidepressant response between pre- and postmenopausal women, and 3) to assess the potential impact of gonadal sex hormones at baseline on the antidepressant response of ketamine in females, to ascertain whether sex hormones may serve as a potential biomarker of response.

Section snippets

Overview

These analyses were planned a priori as part of a multi-site treatment study designed to assess the rapid-onset antidepressant effects of ketamine therapy for TRD and to assess the efficacy of differential dosing (Fava et al., in press). In brief, this was a randomized, double-blind, placebo-controlled study of the acute efficacy of intravenous ketamine or placebo added to ongoing, stable, and adequate antidepressant therapy (ADT) in the treatment of adults with TRD. Subjects were consented,

Methods and study medication

Participants were screened between 7 and 28 days, during which eligibility was determined, and prohibited medications were discontinued. Eligible subjects proceeded to the baseline visit. Participants were stratified by body mass index (BMI) (≤30 and > 30), and were block randomized into each of the five arms of the study. N = 99 total subjects were randomly assigned to each of these five arms in a 1:1:1:1:1 fashion; four of these treatment groups received ketamine at different single-dose

Baseline comparisons

Please see Table 1 for comparisons at baseline between men and women, and between pre- and postmenopausal women. Because the number of perimenopausal women was so small (N = 3), these women were excluded from statistical comparisions. On most variables at baseline, men and women were similar, as were pre- and postmenopausal women, with the exception of the expected finding that postmenopausal women being older than premenopausal women.

Effect of gender on response to ketamine at Day 1

When testing the 2-group difference (all ketamine groups

Discussion

These findings support that one-time use of ketamine is a similarly effective and tolerable treatment for TRD for both women and men. Specifically, these analyses did not demonstrate significant differences in response to ketamine between the two groups, and also did not discern differences in treatment response between pre- and postmenopausal women. The results of these analyses are consistent with two past studies, which reported that sex did not have a significant effect on depression

Funding source

National Institute of Mental Health; NIH-NIMH HHSN271201100006I.

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