On The Future Of Antidepressant Treatments: Targeting Neurotrophic Factors And Plasticity

For 60-plus years the explanatory model for Major Depressive Disorder (MDD) has been the monoamine theory, which states that low levels of monoamine neurotransmitters or alterations in their post-synaptic receptors are responsible for depressive symptoms. Drugs designed to elevate synaptic monoamine levels have remained the first line of pharmacotherapy prescribed by clinicians for MDD patients. However, these drugs have shortcomings. Despite evidence that current antidepressants elevate synaptic monoamine levels within hours of administration, these drugs require four to six weeks of daily administration before symptom relief appears. Furthermore, approximately half of patients taking typical antidepressants never achieve full symptom relief. The therapeutic lag time and low response rates associated with typical antidepressants suggests that elevation of monoaminergic activity may not be their true mechanism of antidepressant action and brings into question the validity of the monoamine theory. As a result, novel biological targets have been investigated for development of more reliable and faster-acting antidepressants. Recent work has shown that low doses of ketamine, a glutamatergic N-methyl-D-aspartate (NMDA) receptor antagonist, can provide depressive symptom relief within hours of administration. What is interesting about these findings is that ketamine works on a completely different biological system than typical antidepressants. Moreover, a number of non-drug treatments, such as electro-convulsive therapy, psychotherapies, and exercise have proven efficacious in treating depressive symptoms. Understanding the biological mechanisms that underlie all of these various treatment modalities may provide evidence for a more valid explanatory model of MDD. In a review of relevant literature examining biologic alterations produced by monoaminergic antidepressants, ketamine and other glutamatergic agents, psychotherapies, electroconvulsive shock therapy, or exercise a commonality was identified: all of the treatments promote the growth of new synapses (synaptogenesis) and the growth of new neurons (neurogenesis). This finding prompts support for the developing Stress-Neurogenic Theory of depression. This theory suggests depressive symptoms are due to chronic, unpredictable stressors which stimulate the production of stress hormones leading to cell death in major brain areas and treatment for depression is dependent upon stimulating the brain’s natural processes responsible for the growth of new connections and new cells in affected brain regions.

Name thesis:degree_name

Ph.D. in Psychology

Level thesis:degree_level

Dissertation

Discipline thesis:degree_discipline

Psychology

Year dc:date.available

2018

Author dc:creator

• White, Stephen W

Contributors dc:contributor

• Kenneth J. Sufka
• Robert Brown
• John M. Rimoldi

• Ketamine-Sensitive
• Monoamine Theory
• Stress-Neurogenic Theory
• Treatment-Resistant
• Neurosciences

Repository record dc:identifier

https://egrove.olemiss.edu/etd/840

OAI identifier oai:identifier

oai:egrove.olemiss.edu:etd-1839