Women are more susceptible than men to certain stress-related psychiatric disorders, such as depression. Preclinical studies aim to understand these sex differences by studying male and female rats in stress models. In this chapter, we review sex differences in behavioural aspects, as well as neurochemical and neurobiological findings derived from acute, repeated and chronic stress models. In particular, we focus on sex differences in depressive-like symptomatology expressed in the forced swim test, the chronic mild stress (CMS) and the learned helplessness models, the Flinders Sensitive Line rats (FSL), which is a genetic model of depression and in the lipopolysaccharide (LPS)-induced sickness behaviour, a putative inflammatory model of depression. Also, sex differences in stress effects on learning and memory parameters are discussed, because cognitive alterations are often seen in sex-differentiated psychiatric disorders. The observed behavioural alterations are often linked with abnormalities in the endophenotype, such as in hormonal, neurochemical, immune and neuroplasticity indices. From these data, it is clear that all stress models have strengths and limitations that need to be recognized in order to use them effectively in the investigation of sex differences in affective disorders.

INTRODUCTION: Sex differences have been identified in antidepressant treatment; however, it remains unclear to what extent pharmacokinetics contributes to these differences. As current antidepressant pharmacotherapy is less than optimal, understanding the role of sex in pharmacokinetics may substantially contribute to a gender-based optimized treatment. AREAS COVERED: An unrestricted PubMed literature search on antidepressant pharmacokinetics and sex was performed. Sex differences in absorption, distribution, metabolism and elimination of antidepressants, as well as the interaction of sex with age, genetic polymorphisms and gonadal hormones are discussed. We also provide an overview of how each antidepressant presents a particular sex-differentiated pharmacokinetic profile. Most antidepressants present to some extent pharmacokinetic sex differences, which often are further accentuated by gonadal hormones. In most cases, women, particularly elderly women, are expected to have higher exposure to antidepressants when dosed in a similar way as men. EXPERT OPINION: Although the available pharmacokinetic evidence indicates that women should receive lower doses of antidepressants and men should receive higher doses, current guidelines do not recommend dose adjustment, because these sex differences are considered to be clinically insignificant. Unless we understand the link between pharmacokinetics and pharmacodynamics of antidepressants, it will be difficult to determine whether sex differences are of clinical importance or not. Thus, further systematic and particularly focused research is needed on sex differences in pharmacokinetics.

OBJECTIVE: Insomnia is frequently underrecognized in medical wards; therefore, we assessed the prevalence and explored medical and psychological variables associated with insomnia. METHOD: The Athens Insomnia Scale and the Hospital Anxiety and Depression Scale (HADS) were completed in 235 inpatients along with demographic data, admission diagnosis, lifetime psychiatric diagnosis and prescribed psychotropics. RESULTS: The overall insomnia prevalence was 37%. Logistic regression showed that HADS anxiety and depression cases and patients with infections were more likely to have insomnia (OR 24.2, 6.1 and 5.4, respectively). CONCLUSIONS: Patients with depressive and mainly anxiety symptoms are more likely to experience insomnia in medical wards. Patients with infections are also likely to have insomnia, independently of depressive and anxiety symptoms, and appropriate interventions should be applied.

Electroconvulsive therapy (ECT) is an effective treatment and, with the proper risk-minimizing strategies, is relatively safe even in depressed patients with cardiovascular diseases. Specifically, patients with cardiac rhythm management devices (CRMDs) require particular attention because no controlled trials exist to support current empirical recommendations. We present a depressed patient with a pacemaker successfully treated with ECT, and we critically review the relevant literature. Pooled results from 63 patients and 821 ECT sessions showed that 90% of ECT sessions have been performed on depressed patients with their pacemakers in sensing mode and rate adaptation, where available, activated as well. Only 4% of sessions were performed with those functions disabled, whereas no data was available for 6% of ECT sessions. Pooled results from case series and reports highlight a discrepancy between current clinical practice and many guidelines. Electroconvulsive therapy is probably safe in depressed patients with asynchronous fixed-rate pacemakers, although there is a risk of ventricular tachycardia and fibrillation. A larger body of case series and reports suggests that there might be no need to convert synchronous demand pacemakers to asynchronous fixed-rate pacing. Regarding patients with implantable cardioverter defibrillators, antitachycardia treatment was deactivated during most ECT sessions. In depressed patients with CRMDs anticholinergics might be best avoided. In all cases, proper ECT procedures, namely, patient and pacemaker electrical isolation, strict grounding and adequate muscle relaxation along with interrogation and monitoring of CRMDs before and after each session should ensure uncomplicated electroconvulsive treatments.

Disorders such as depression and anxiety exhibit strong sex differences in their prevalence and incidence, with women also differing from men in their response to antidepressants. Furthermore, receptors for corticotrophin releasing hormone (CRHR1) and arginine vasopressin receptor subtype 1b (AVPR1b) are known to contribute to the regulation of mood and anxiety. In the present study, we compared the anxiety profile and CRHR1 and AVPR1b expression levels in control Sprague-Dawley (SD) rats and rats of the SD-derived Flinders Sensitive Line (FSL), a genetic model of depression. Additionally, given the apparent sex differences in the therapeutic efficacy of antidepressants and because antidepressants are commonly used to treat comorbid anxiety and depressive symptoms, we assessed whether the anxiolytic effects of an antidepressant occur in a sex-dependent manner. Male and female FSL rats were treated with citalopram 10 mg/kg once daily for 14 days and were then tested in the open field and the elevated plus maze paradigms. Upon completion of the behavioural analysis, AVPR1b and CRHR1 expression levels were monitored in the hypothalamus and the prefrontal cortex (PFC) using Western blotting. According to our results, male FSL rats were more anxious than control SD rats, a difference abolished by citalopram treatment. Baseline anxiety levels were similar in female FSL and SD rats, and citalopram further reduced anxiety in female FSL rats. Importantly, whereas citalopram altered AVPR1b expression in the hypothalamus of male FSL rats, its actions on this parameter were restricted to the PFC in female FSL rats. In both sexes of FSL rats, citalopram did not alter CRHR1 expression in either the hypothalamus or PFC. Our results demonstrate that antidepressant treatment reduces anxiety levels in FSL rats of both sexes: the magnitude of treatment effect was related to the starting baseline level of anxiety and the antidepressant elicited sexually differentiated neurobiological responses in specific brain regions.