Antidepressant medications have been available for more than fifty years, yet the proportion of patients helped by the various classes of these agents has hardly changed at all. This despite greater insight into the disorder at a biological level based on knowledge derived from contemporary advances in neuroscience. Two fundamental issues may lie at the heart of this apparent paradox. First, depression is a highly heterogeneous disorder and almost certainly is not a single ‘disease’ entity. The diagnosis is based on the clustering of a discrete set of symptoms, within a defined time frame and as such is best described as a syndrome or disorder. The cause(s) of depression remain unknown and are, in all probability, multi-factorial. The identification of bio-marker defined depression sub-groups may aid both more precise diagnoses and better treatment outcomes. Secondly, the development of pharmacological treatments has been limited by the prevailing aetiological hypothesis of the disorder, the monoamine hypothesis. While it is now well recognised that such a postulate is limited in its explanatory power, both for aetiology and treatment, it has, nevertheless, driven drug development for well over five decades. Clearly, while monoamines surely are important in mediating responses to antidepressant medication, they are almost certainly not the only important driver. Thus the shortcomings in such agents have been well recognised almost since their inception. Principal among these drawbacks has been speed of onset of action with full recovery and remission taking several weeks if not months. Additionally, the relative lack of efficacy of medications in all likelihood reflects the heterogeneity of the disorder and the inability to define predictive factors such as symptom patterns, personality variables or biomarkers, which are responsive to particular pharmacological properties of individual medications. Serious adverse events, side effects, cardiovascular safety and multiple potential drug interactions have also been cited as drawbacks of the existing plethora of antidepressant medications. While few medications have yet emerged into clinical practice based on the insights gleaned from recent basic studies, the notion of targeting multiple, relevant sites in the central nervous system to improve treatment outcomes in major depression has produced some new agents. These so called multi-modal antidepressants simultaneously interact with several different receptors and transporter molecules thought to contribute to antidepressant responses. Expanding the effects on central monoamine activity through the development of so-called triple reuptake inhibitors has been one multi-modal approach to the treatment of depression. Amitifiadine is the first triple reuptake exemplar to reach early clinical trials. To date clinical outcomes could be described as mixed. Vilazodone and vortioxetine are multi-modal agents which target reuptake mechanisms as well as other neurotransmitter receptors. This review examines the pharmacological properties of these new agents and critically evaluates their efficacy in clinical trials with a particular emphasis on whether the multi-modal approach obviates some of the perceived shortcomings of existing medications. Achievement of high remission rates in depression is increasingly recognised as the bench mark of an efficacious drug. The extent to which these new agents achieve better remission rates can be regarded as a measure of the extent to which the multi-modal hypothesis is realized and may guide treatment approaches into the future.
Keywords: Depression, monoamines, multimodal medications, remission, response, triple reuptake inhibitors, vilazodone, vortioxetine.
