Atomoxetine in abstinent cocaine users: Sex differences

Data presented are from a sex-differences secondary analysis of a human laboratory investigation of single doses of atomoxetine (40 mg and 80 mg) versus placebo in abstinent individuals with cocaine use disorders (CUD). Subjective drug effects, cognitive performance and cardiovascular measures were assessed. The primary atomoxetine dose analyses (which do not consider sex as a factor) are reported in full elsewhere (DeVito et al., 2017) [1].


Subject area
Pharmacology More specific subject area

Pharmacotherapy for Cocaine Use Disorder (CUD)
Type of data Text file, table How data was acquired Human laboratory setting. Self-report questionnaires, computerized cognitive testing, heart rate and blood pressure measurements.

Data format
Analyzed Experimental factors Within-subject fixed factor of 'dose' (placebo, 40 mg, 80 mg atomoxetine); between-subject factor of 'sex' (male, female) Contents lists available at ScienceDirect journal homepage: www.elsevier.com/locate/dib

Experimental features
Double-blind, placebo-controlled, within-subject cross-over design with one pill condition (placebo, 40 mg or 80 mg atomoxetine) on each test day, with washout time between test days. Participants met criteria for cocaine use disorder but were abstinent from cocaine for 1-12 months.

Data source location
West Haven, CT Data accessibility Data is not available in a public repository.

Value of the data
There are no pharmacotherapies currently approved for the treatment of CUD. Pharmacotherapies with low abuse potential but cognitive enhancing properties could be effective adjunct therapies for CUD, since poorer cognitive function has been linked with worse clinical outcomes including risk of relapse [2][3][4][5][6][7].
Sex is a potentially important factor which could contribute to individual variability in response to medication [18]. Sex differences have been demonstrated in the etiology, disease course, health consequences and treatment response of CUDs (e.g. [19][20][21][22][23]), including poorer clinical outcomes for women in trials of medications for CUDs (e.g. disulfiram [24], modafinil [25], naltrexone [26]). There is mixed evidence of sex differences in response to atomoxetine for attention deficit hyperactivity disorder (ADHD) ( [27], but see also [28]). Preclinical research indicates greater efficacy for atomoxetine in males than females [29,30]. Although data specifically testing sex differences in atomoxetine response is limited, convergent evidence underlines the likelihood of sex-sensitive effects of noradrenergic medication for substance use disorders (e.g. [31]).
The sample size in the current data was underpowered to investigate sex differences properly.
These preliminary data may be hypothesis-generating for future studies of atomoxetine in men and women with CUD.

Data
Data presented are from a secondary analyses of sex differences. Data are subjective drug effects, cardiovascular response, and computerized cognitive task outcomes in abstinent individuals with cocaine use disorder (CUD) who received placebo, 40 mg atomoxetine and 80 mg atomoxetine. The detailed methods and primary dose effects analyses from this dataset are reported elsewhere [1].
Baseline and demographics data are reported in full in Table 1. Data for the effects of atomoxetine by sex on cardiovascular responses, subjective drug responses, mood and cognitive function are reported in Table 2. Briefly, treatment-by-sex interactions on drug-like effects showed more positive (euphoria) and less negative (dysphoria, sedation) subjective effects in women relative to men in response to the medication versus placebo. For mood, treatment-by-sex interactions reflected atomoxetine dose-related decreases in 'fatigue' and 'depression' in men, but increases in women. Furthermore, treatment-by-sex interaction indicated reduced 'tension' at the low-dose (relative to placebo or high-dose) condition, in men but not women. In terms of cognitive function, a treatmentby-sex interaction on Immediate Memory Task (IMT) revealed dose-related improvements (e.g., faster correct responses) in men, but a trend of dose-related decrements in performance in women.

Experimental design, materials and methods
Methods are described in detail elsewhere [1]. Participants were otherwise healthy individuals (N ¼ 39) who met diagnostic criteria for cocaine dependence in early remission (i.e., abstinent 430 days, o1 year).
In this randomized, double-blind, placebo-controlled, within-subject crossover design participants received 40 mg, 80 mg atomoxetine, and placebo treatment, one pill per day, over three test days. Test days were scheduled approximately 6 days apart. Order of treatment condition (across test days) was randomly assigned and counter-balanced across individuals.
Outcome measures included cardiovascular (heart rate, blood pressure), subjective drug effects (Drug Effects Questionnaire (DEQ) [32]; Addiction Research Center Inventory (ARCI) [33]), mood   Profile of Mood States (POMS) [34], and cognitive tasks measuring memory, attention and response inhibition performance (Immediate Memory Task (IMT) [35][36][37]; CANTAB Rapid Visual Information Processing (RVP) [38]; CANTAB Stop Signal Task (SST) [39]). For demographic and baseline data, men and women were compared using analysis of variance (ANOVA) for continuous, or logistic regression for categorical variables. A mixed-effect repeatedmeasures analysis assessed in JMP (version 11.0) for treatment effect; including a fixed main effect for treatment (placebo, 40 or 80 mg atomoxetine), a random effect for participant, and a between subject factor of sex (men, women) and sex by treatment effect interaction term. When data was collected across multiple time points, all post-pill administration time-points were included in the analyses. To account for possible carryover effects of the medication or learning/test-retest effects across testing days, analyses were re-run including test day (1,2,3) and test day interactions. Findings (i.e., significance level) remained stable with and without test day, therefore data are presented from the simpler analysis excluding day. Bonferroni corrections were applied for the number of outcomes tested within each domain (cardiovascular, subjective drug effect, mood, cognition). Reported data survive Bonferroni corrections unless otherwise stated.