A brief history of the development of antidepressant drugs: From monoamines to glutamate.

Abstract

Major depressive disorder (MDD) is a chronic, recurring, and debilitating mental illness that is the most common mood disorder in the United States. It has been almost 50 years since the monoamine hypothesis of depression was articulated, and just over 50 years since the first pharmacological treatment for MDD was discovered. Several monoamine-based pharmacological drug classes have been developed and approved for the treatment of MDD; however, remission rates are low (often less than 60%) and there is a delayed onset before remission of depressive symptoms is achieved. As a result of a “proof-of-concept” study in 2000 with the noncompetitive NMDA antagonist ketamine, a number of studies have examined the glutamatergic systems as viable targets for the treatment of MDD. This review will provide a brief history on the development of clinically available antidepressant drugs, and then review the possible role of glutamatergic systems in the pathophysiology of MDD. Specifically, the glutamatergic review will focus on the N-methyl-D-aspartate (NMDA) receptor and the efficacy of drugs that target the NMDA receptor for the treatment of MDD. The noncompetitive NMDA receptor antagonist ketamine, which has consistently produced rapid and sustained antidepressant effects in MDD patients in a number of clinical studies, has shown the most promise as a novel glutamatergic-based treatment for MDD. However, compounds that target other glutamatergic mechanisms, such as GLYX-13 (a glycine-site partial agonist at NMDA receptors) appear promising in early clinical trials. Thus, the clinical findings to date are encouraging and support the continued search for and the development of novel compounds that target glutamatergic mechanisms.

Mechanism Underlying Acupuncture-Ameliorated Depressive Behaviors by Enhancing Glial Glutamate Transporter in Chronic Unpredictable Mild Stress (CUMS) Rats

“…The glutamatergic dysfunction implicated in neural plasticity and cellular resilience may then contribute to the pathophysiology of depressive disorder, and riluzole was evaluated as a treatment for depression in both human and rodents [28]. A recent preclinical, observational, open-label study showed great improvement in the riluzole group compared to the placebo group [29,30].…”

Cannabis Withdrawal: a Review of Neurobiological Mechanisms and Sex Differences

“…Copersino et al retrospectively assessed cannabis withdrawal in a convenience sample of cannabis users and found that females endorsed significantly fewer instances of craving, increased sex drive, and greater instances of upset stomach compared to males [71]. More recently, Herrmann et al reported findings from a randomized clinical trial for the treatment of cannabis use disorder, and while males and females did not differ with regard to quantity of current cannabis use, females had significantly greater total withdrawal scores, endorsed a significantly higher incidence of withdrawal symptoms, and were more likely to experience irritability, violent outbursts, and nausea [19]. There was no difference between females and males on the average severity of individual withdrawal symptoms, however, among those who reported experiencing nervousness/anxiety, restlessness, or increased aggression during their last quit attempt, severity ratings of those symptoms were greater for females compared with males.…”

“…Recent work has called attention to the significance of sex differences in cannabis dependence and cannabis withdrawal [14]. Although cannabis use is more prevalent among males [1], females progress more rapidly from initial use to cannabis dependence [15, 16], exhibit worse treatment outcomes [17, 18], and experience greater withdrawal symptom severity [19]. Furthermore, evidence suggests that the endocannabinoid system, the primary neurobiological system implicated in cannabis withdrawal and cannabis reinforcement, is sexually dimorphic in nature [20] and may explain between-subjects variability in cannabis withdrawal [21].…”

Effect of probiotic interventions on depressive symptoms: A narrative review evaluating systematic reviews

“…It is often associated with major medical illnesses, such as cardiovascular disease, diabetes, and cancer, adding to their morbidity . Medications were first used as treatments for depression in 1958, and the first antidepressant medication to be marketed as such, imipramine, was introduced in 1959 . Since the 1980s, pharmacological treatment with antidepressant medications has been a major modality of therapeutic intervention in the management of depressive disorders .…”