Postulated Mechanisms

Pharmacological. Preclinical studies of antidepressant drugs (serotonin and nore-pinephrine reuptake inhibitors, monamine oxidase inhibitors, tricyclics) demonstrate a chain of events including acute aminergic reuptake or degradation enzyme inhibition and more chronic presynaptic autoregulatory desensitization, up and down-regulation of multiple postsynaptic receptor sites, adaptation of intracellular signal transduction pathways, and neurotrophic effects (Bauer and Frazer, 1994; Vaidya and Duman, 2001). Requisite brain regions mediating actual response effects are unknown, although putative primary sites of action in the dorsal raphe, locus ceruleus, hippocampus, and hypothalamus, with secondary changes in frontal cortex are demonstrated (Blier and de Montigny, 1999; Freo et al., 2000).

Somatic. Changes in many of these same systems are seen with electrocon-vulsive therapy, with an emerging focus on common changes in intracellular signal transduction pathways. Axonal sprouting indicative of neurotrophic effects has also been identified in the dendate gyrus in animal electroconvulsive shock models (Nibuya et al., 1997). Other somatic treatments such as vagal nerve stimulation and repetitive transcranial magnetic stimulation are in early stages of investigation with an emphasis on studies of requisite neural pathways rather than specific biochemical or molecular effects. Preliminary imaging studies suggest modulation of selective limbic-cortical pathways, although results are quite variable (Lomarev et al., 2002; Teneback et al., 1999). Similar mechanisms are postulated for surgical ablation where three distinct lesions, anterior capsulotomy, cingulotomy, and subcau-date tractotomy—all show comparable clinical antidepressant efficacy but disrupt different white matter targets (Cosgrove and Rauch, 1995). Both top-down (cortico-thalamic, cortico-limbic) and bottom-up (thalamo-cortical, limbic-cortical) mechanisms have been proposed, although the precise limbic, subcortical, and cortical targets or pathways necessary for amelioration of depressive symptoms are not yet characterized. Chronic chemical changes associated with these ablative lesions have not been studied.

Cognitive. Nonpharmacological antidepressant treatments such as cognitive behavioral therapy and interpersonal psychotherapy aim to facilitate changes in depression-relevant cognitions, affective bias, and maladaptive information processing, modifying specific but alternative neural processes to those likely targeted by medication and somatic treatments (Beck et al., 1979; Derubeis et al., 1990). The time course of symptom changes with cognitive behavioral therapy, for example, suggests primary cortical sites of action with top-down neural effects, as improvement in hopelessness and views of self and mood precede changes in vegetative and motivational symptoms—a timeline not seen in patients treated with pharmacotherapy (Rush et al., 1982). Brain correlates of these phenomena are in early stages of investigation (see neuroimaging section below).

Anxiety and Depression 101

Anxiety and Depression 101

Everything you ever wanted to know about. We have been discussing depression and anxiety and how different information that is out on the market only seems to target one particular cure for these two common conditions that seem to walk hand in hand.

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