Heart Disease and Depression in Females Estrous Cycle Influence over Senstivity to Ketamine’s Antidepressant Effects

Depression affects approximately 7% of adults in the US annually and is one of the most common mental disorders. One striking aspect of this disorder, is that it affects women at about twice the rate as compared to men. Furthermore, women with cardiovascular diseases are more likely to experience depression as compared to male counterparts. Thus, women with cardiovascular complications represent an extremely vulnerable population for mood disorder. Given the disparity in depression prevalence, it is not surprising that women are also more likely to take antidepressant treatments as compared to men. While the dose of the antidepressant prescribed is similar across the board, there is mounting evidence that the efficacy of and sensitivity to these treatments differ between the sexes. However, the majority of preclinical investigations into the effectiveness and biochemical mechanisms of antidepressants have been conducted in male subjects. This is a serious gap in our knowledge, and investigations into the mechanisms underlying differences in depression prevalence and antidepressant response is imperative. As such, this dissertation aimed to identify potential peripheral and neural changes associated with onset of depression in females with cardiovascular disease, and to examine the neural mechanisms underlying the sex differences in sensitivity to antidepressants. There is substantial evidence that depression is experienced at a much higher rate in individuals with chronic conditions, such as cardiovascular disease. Within this population, women with cardiovascular diseases represent an extremely vulnerable population for mood disorder, comorbid for these conditions at about twice the rate as compared to men. Despite the well-established comorbidity, the mechanisms linking these disorders remain elusive. The first chapter of this dissertation aimed to identify the expression of core behavioral features of mood disorder in female mice bearing a knock-in sarcomeric mutation, which is exhibited in human hypertrophic cardiomyopathy (HCM). We then investigated peripheral physiological indicators of stress in these mice, and discovered significant adrenal gland hypertrophy and a dominant sympathetic nervous system tone. Through the use of magnetic resonance imaging, we found reduced volume in mood-related brain regions in females with HCM. We also observed significant reductions in hippocampal neurotrophic signaling markers in females with HCM as compared to controls. These results suggest that prolonged systemic HCM stress is central to mood disorder expression; possibly through induction of structural and functional brain changes. In direct contrast to the negative impact of stress/depression on the structure and function of the brain, many antidepressants reverse these changes and promote neurogenesis. In recent years, ketamine has shown great promise as an antidepressant. A single infusion can exert effects within hours of treatment, and this rapid action is a unique feature of ketamine. Most antidepressants need to be taken for weeks to months to exert therapeutic effects, and often the first medication prescribed is not effective. Ketamine represents a great advancement in the field, especially for individuals suffering from depression and cardiovascular dysfunction. In this population, the use of ketamine could circumvent the potential for negative interactions between cardiac medications and chronic antidepressants. Since females are more likely to take antidepressants as compared to males, we wanted to examine how the males and females differed in behavioral and neurochemical responses to ketamine. Our group and others have previously reported that female rodents are more sensitive to the antidepressant-like effect of ketamine. There is some evidence that ovarian hormones may promote sensitivity to antidepressants, yet the precise molecular mechanism of females’ heightened sensitivity to ketamine remains unclear. In order to fill these critical gaps in our knowledge, the second chapter of this dissertation aimed to determine the role of endogenous ovarian hormones and their respective receptor subtypes to promote ketamine sensitivity. Behavioral responses to ketamine were examined in males, females in diestrus 1 (D1, low hormone), and females in proestrus (Pro, high hormone) using the forced swim test. Males and D1 females exhibited similar sensitivity, while Pro females responded to doses of ketamine that were subthreshold for effects in male and D1 counterparts. Through the use of selective estrogen receptor modulators (SERMS), we examined the role of estrogen receptor subtypes (ERα and ERβ) and progesterone receptors (PR) to promote ketamine sensitivity. We found that D1 females treated with ERα and ERβ SERMS responded to ketamine treatment, which suggests that estrogen action at these receptors may enhance ketamine sensitivity. Another aim of chapter two was to determine if the molecular mechanisms previously shown to mediate ketamine’s antidepressant effects in male rodents also apply to females. Since many of the rapid intracellular signaling cascades initiated by ketamine are also influenced by ovarian hormones (e.g., brain-derived neurotrophic factor), we used Western blot to investigate the expression and activation of their shared targets. We confirmed previous reports in males that ketamine activated a variety of neurotrophic signaling cascades in the prefrontal cortex and hippocampus, and extended them to include D1 and Pro females. As a first step towards identifying the neural mechanism of Pro females’ sensitivity, we found that these females exhibited activation of Akt and CaMKIIα in response to a dose of ketamine that only they were sensitive to. While these results need to be confirmed in vivo, together they suggest that ovarian hormones increase behavioral sensitivity to ketamine by enhancing ketamine’s effects on PI3K and CaMKIIα signaling within mood-related brain regions. These studies examined the expression and molecular mechanisms of mood disorder-like behaviors in a mouse model of cardiovascular dysfunction. We focused on females with HCM, since they represent an especially vulnerable population for mood disorder. We also investigated the hormonal and biochemical contributors to sex differences in sensitivity to ketamine. This work lays a foundation for future investigation of the effectiveness of ketamine to reverse depression-associated features in females with HCM. By targeting the natural flux in ovarian hormones, it may be possible to safely and effectively treat these females with a low dose of ketamine.