Objective In this conceptual review, we propose a novel mechanistic candidate in the etiology of depression with onset in the menopause transition (a.k.a. perimenopausal depression) involving alterations in stress-responsive pathways, induced by ovarian hormone fluctuation. Methods The relevant literature in perimenopausal depression was reviewed, including its prevalence, predictors, and treatment with estrogen therapy. Subsequently, the growing evidence from animal models and clinical research in other reproductive mood disorders was synthesized to describe a heuristic model of perimenopausal depression development. Results The rate of major depressive disorder and of clinically meaningful elevations in depressive symptoms increases two- to threefold during the menopause transition. While the mechanisms by which ovarian hormone fluctuation might impact mood are poorly understood, growing evidence from basic and clinical research suggests that fluctuations in ovarian hormones and their derived neurosteroids result in altered GABAergic regulation of the hypothalamic-pituitary-adrenal (HPA) axis. Our heuristic model suggests that for some women, failure of the GABAA receptor to regulate overall GABAergic tone in the face of shifting levels of these neurosteroids may induce HPA axis dysfunction, thereby increasing sensitivity to stress, and generating a period of greater vulnerability to depression. Conclusions The proposed model provides a basis for understanding the mechanisms by which the changing hormonal environment of the menopause transition may interact with the psychosocial environment of mid-life to contribute to perimenopausal depression risk. Future research investigating this model may inform the development of novel pharmacological treatments for perimenopausal depression and related disorders such as postpartum depression and premenstrual dysphoric disorder.

Currently available drugs for unipolar major depressive disorder (MDD), which target monoaminergic systems, have a delayed onset of action and significant limitations in efficacy. Antidepressants with primary pharmacological targets outside the monoamine system may offer the potential for more rapid activity with improved therapeutic benefit. The glutamate system has been scrutinized as a target for antidepressant drug discovery. The purpose of this article is to review emerging literature on the potential rapid-onset antidepressant properties of the glutamate NMDA receptor antagonist ketamine, an established anaesthetic agent. The pharmacology of ketamine and its enantiomer S-ketamine is reviewed, followed by examples of its clinical application in chronic, refractory pain conditions, which are commonly co-morbid with depression. The first generation of studies in patients with treatment-resistant depression (TRD) reported the safety and acute efficacy of a single subanaesthetic dose (0.5 mg/kg) of intravenous ketamine. A second generation of ketamine studies is focused on testing alternate routes of drug delivery, identifying methods to prevent relapse following resolution of depressive symptoms and understanding the neural basis for the putative antidepressant actions of ketamine. In addition to traditional depression rating endpoints, ongoing research is examining the impact of ketamine on neurocognition. Although the first clinical report in MDD was published in 2000, there is a paucity of adequately controlled double-blind trials, and limited clinical experience outside of research settings. Given the potential risks of ketamine, safety considerations will ultimately determine whether this old drug is successfully repositioned as a new therapy for TRD.

The pattern of onset and general rate of cranial ossification are compared in two marsupials, Monodelphis domestica (Didelphidae) and Macropus eugenii (Macropodidae). In both species a similar suite of bones is present at birth, specifically those surrounding the oral cavity and the exoccipital, and in both postnatal events follow a similar course. The facial skeleton matures more rapidly than the neurocranium, which is characterized by an extended period of ossification. Most dermal bones begin ossification before most endochondral bones. Endochondral bones of the neurocranium are particularly extended in both the period of onset of ossification and the rate of ossification. These data confirm suggestions that morphology at birth is conservative in marsupials and we hypothesize that the pattern of cranial osteogenesis is related to two distinct demands. Bones that are accelerated in marsupials are correlated with a number of functional adaptations including head movements during migration, attachment to the teat, and suckling. However, the very slow osteogenesis of the neurocranium is probably correlated with the very extended period of neurogenesis. Marsupials appear to be derived relative to both monotreme and placental mammals in the precocious ossification of the bones surrounding the oral cavity, but share with monotremes an extended period of neurocranial osteogenesis.