Individual and sex differences in antidepressant drug response: an experimental approach

Abstract

Major depression is associated with both dysregulation of the hypothalamic pituitary adrenal (HPA) axis and serotonergic deficiency. Women experience major depression at roughly twice the rate of men. Inconclusive clinical evidence assists the notion that responsiveness to antidepressant pharmacotherapy is sexually dimorphic with the two sexes presenting differential responses when treated with antidepressant agents. Notably, responsiveness to antidepressant agents presents marked inter-individual variability, the biological basis of which remains elusive. Few available data showed the interaction of the antidepressant agent’s effects with female hormonal fluctuations, estrogen has been implicated in antidepressant like activity in both male and female rats.The aims of this thesis were to investigate putative sex differences to chronic antidepressant treatment with the TCA clomipramine in rats selected on the basis of their reactions to novelty. The thesis also sought to investigate the effect of sub-acute SSRI sertraline treatment in male rats and in female rats at different phases of estrous cycle.Our data revealed that high novelty-seeker (HR) male rats were more responsive to clomipramine treatment as far as the alleviation of behavioural despair is concerned, compared to low novelty-seeker (LR) males and female. Chronic clomipramine treatment attenuated depressive like symptomatology in the forced swim test (FST) of behavioural despair in both sexes albeit in the opposite novelty-seeking phenotypes (i.e. in male HR and female LR). In male HR rats, clomipramine treatment diminished serotonergic neurochemical responses post-FST exposure in all limbic brain regions examined, while these were boosted in their LR counterparts. Dopaminergic and glutamatergic neurochemistry also presented phenotype-related alterations. On the contrary, in females the neurochemical substrate was only modestly affected. Corticosteroid responses were augmented in female but attenuated in male drug-treated rats.Our data also revealed that sertraline enhanced swimming and decreased immobility duration at both doses. Serotonergic activity was not altered by the two-day swim stress in either brain region, while subchronic sertraline treatment enhanced 5-HT levels and decreased 5-HIAA/5-HT in the hippocampus and the prefrontal cortex. The serotonin turnover rate (5-HIAA/5-HT ratio) decrease is probably indicative of reduced 5-HT metabolism, as a result of 5-HT reuptake inhibition. This effect was significant in the prefrontal cortex of unstressed rats only after a higher dose of sertraline. In the prefrontal cortex, but not in the hippocampus, immobility duration was negatively correlated with 5-HT tissue levels, whereas swimming duration was positively correlated with 5-HT. These results indicate that after antidepressant treatment, behaviour during the FST can be predictive of respective serotonergic changes, especially in the prefrontal cortex.However, our data indicated that high sertraline dose treatment enhanced swimming duration at diestrus I, high sertraline dose treatment enhanced climbing duration and low dose enhanced swimming duration in diestrus II, low sertraline dose treatment enhanced swimming in estrus. Both low and high sertraline doses treatment decreased immobility in all phases of the estrous cycle. Interestingly, our results revealed an effect of the estrous cycle following high sertraline dose treatment between diestrus I, diestrus II and proestrus. In low sertraline dose treatment effect of the estrous cycle was revealed between proestrus and estrus. There was also a positive correlation between uterus weight and swimming duration during the FST test sessions.Overall, the current dataset lends further support that the male sex may benefit to a greater extent when treated with TCAs and reveals that individual differences are associated with qualitative and quantitative sex-related behavioural and neurochemical manifestations in response to chronic antidepressant treatment. The data indicated that after antidepressant treatment, behaviour during the FST can be predictive of respective serotonergic changes, especially in the prefrontal cortex. The data further support that the estrous cycle has an impact on antidepressant drug response.