Neurobiology and Target validation of novel therapeutic agents in mood disorders

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This Report involves work collected under protocols 08-M-0196 (NCT00759395); 08-M-0150 (NCT00697268); 14-M-0085 (NCT02122562); 14-M-0041 (NCT02049385); and 07-M-0152 (NCT00472576). Results this past year: 1) Increased fear-potentiated startle in major depressive disorder patients with lifetime history of suicide attempt. We found that the magnitude of fear-potentiated startle was increased in depressed patients with lifetime suicide attempts compared to those without a lifetime history of suicide attempt. Increased fear-potentiated startle in suicide attempters suggests the role of amygdala in depressed patients with a suicide attempt history. Findings highlight the importance of anxiety symptoms in the treatment of patients at increased suicide risk. 2) P11 levels in natural killer cells and monocytes and antidepressant response to chronic citalopram. We found that p11 levels in natural killer cells and monocytes correlated with antidepressant response to citalopram. 3) Lithium and nitric oxide levels in subjects with bipolar disorder during depressive episodes. We found that lithium treatment significantly increased plasma nitric oxide levels after 6 weeks of treatment in comparison to baseline levels in bipolar depression. Baseline oxide levels during depressive episodes showed no difference when matching up to healthy controls. The present findings suggest that lithium upregulates nitric oxide signaling in unmedicated BD with short illness duration. 4) BDNF plasma levels after antidepressant treatment with sertraline and transcranial direct current stimulation. We measured BDNF plasma levels at baseline and endpoint, observing no significant changes of BDNF levels after treatment. In addition, no significant changes were observed in responders and non-responders as well as no relationships between BDNF levels and clinical and psychopathological variables related to depression. Thus, in one of the few placebo-controlled trials evaluating BDNF changes over an antidepressant treatment course, we did not observe BDNF increase regardless of clinical improvement in depressed patients. 5) We described the methodology and validation of a clinical protocol using 11C-rolipram in patients with major depression and healthy controls. We found that image-derived input function is a good alternative to full arterial input function for 11C-rolipram PET clinical scans. 6) Catecholamine depletion in first-degree relatives of individuals with mood disorders: An (18)Ffluorodeoxyglucose positron emission tomography study. Our results suggest that sensitivity to catecholamine depletion may be a phenotypic marker of vulnerability to mood disorders that is characterized at the neurophysiological level by disinhibition of the striatum and its efferent projections comprising the limbic-cortical-striatal-pallidal-thalamic circuitry. 7) Independence of familial transmission of mania and depression. We found that there was specificity of familial aggregation of bipolar I (BP I; odds ratio (OR)=8.40; 3.27-20.97; h2=0.83) and major depressive disorder (OR=2.26; 1.58-3.22; h2=0.20), but not BP II. The familial aggregation of BP I was primarily attributable to the familial specificity of manic episodes after