A GLUTAMATERGIC HYPOTHESIS OF MOOD/ANXIETY DISORDERS

Half a century after the monoamine hypothesis of mood/anxiety disorders, it is widely accepted that maladaptive changes in brain excitatory/inhibitory circuitry have a primary role in pathophysiology of mood/anxiety disorders. However, although most of what we allude to as \u201cneuroplasticity changes\u201d has been detected in glutamatergic neurons and circuitry, by far predominant in the brain, we still refer by default to a \u201cmonoamine hypothesis\u201d, without having a clearly defined \u201cglutamate hypothesis\u201d of depression. The neuroplasticity hypothesis posits that volumetric changes consistently found in limbic and cortical areas of depressed subjects are in good part due to remodeling of neuronal dendritic arbors and loss of synaptic spines. Concurrently, a wealth of data from animal models of stress have shown that different types of behavioral stress enhance glutamate release and transmission in limbic/cortical areas and have powerful effects on structure/morphology, inducing dendritic remodeling, reduction of synaptic spines and global volumetric reductions resembling those observed in depressed patients. Therefore, although monoaminergic transmission has a primary role in the modulation of emotion and cognition, we believe it is time to recognize and posit that mainly excitatory transmission mediates the complex emotional/cognitive changes associated with depression, and also likely represents the actual final common pathway of therapeutic treatments (both psychotherapy and antidepressants) for depression and other mood/anxiety disorders. Importantly, while all antidepressant drugs available have a monoamine-based mechanism or at least a monoamine-based component in their mechanism, only 50-60% of depressed patients respond to first treatment. This means there is a large space for improvement in antidepressant treatments if non-monoamine targets are taken into account and new compounds are developed that target directly glutamate transmission and related pathways