The STAR*D trial: revealing the need for better treatments.
ABSTRACT STAR*D (Sequenced Treatment Alternatives to Relieve Depression) continues to stimulate debate. The landmark trial demonstrated the feasibility of large-scale, community-based studies conducted without pharmaceutical company support. The results provided insight into nonresponse to initial treatment with selective serotonin reuptake inhibitors and alternatives for second- and third-line treatment options and suggested opportunities for personalized approaches to depression care. However, initial and one-year remission rates (28% and 70%, respectively) suggest that important goals for treatment of this disabling disease remain out of reach and that the bar for antidepressants has been set far too low.
- Australian and New Zealand Journal of Psychiatry 01/2014; · 3.77 Impact Factor
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ABSTRACT: The intravenous administration of scopolamine produces rapid antidepressant effects. Generally, failing multiple previous antidepressant trials is associated with a poor prognosis for response to future medications. This study evaluated whether treatment history predicts antidepressant response to scopolamine. Treatment resistant patients (2 failed medication trials) (n=31) and treatment naïve patients (no exposure to psychotropic medication) (n=31) with recurrent major depressive or bipolar disorder participated in a double-blind, placebo-controlled, crossover clinical trial. Following a placebo lead-in, participants randomly received P/S or S/P (P=3 placebo; S=3 scopolamine (4ug/kg) sessions 3 to 5 days apart). The Montgomery-Asberg Depression Rating Scale (MADRS) was the primary outcome measure. A linear mixed model was used to examine the interaction between clinical response and treatment history, adjusting for baseline MADRS. Treatment resistant and treatment naïve subjects combined responded significantly to scopolamine compared to placebo (F=15.06, p<0.001). Reduction in depressive symptoms was significant by the first post-scopolamine session (F=42.75, p<0.001). A treatment history by scopolamine session interaction (F=3.37, p=0.04) indicated treatment naïve subjects had lower MADRS scores than treatment resistant patients; this was significant after the second scopolamine infusion (t=2.15, p=0.03). Post-hoc analysis: Also, we used a single regimen to administer scopolamine, and smokers were excluded from the sample, limiting generalizability. Treatment naïve and treatment resistant patients showed improved clinical symptoms following scopolamine, while those who were treatment naïve showed greater improvement. Scopolamine rapidly reduces symptoms in both treatment history groups, and demonstrates sustained improvement even in treatment resistant patients.Journal of Affective Disorders 06/2014; 162:39-42. · 3.76 Impact Factor
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ABSTRACT: The N-methyl-d-aspartate (NMDA) receptor antagonist ketamine has rapid and potent antidepressant effects in treatment-resistant major depressive disorder and bipolar depression. These effects are in direct contrast to the more modest effects seen after weeks of treatment with classic monoaminergic antidepressants. Numerous open-label and case studies similarly validate ketamine's antidepressant properties. These clinical findings have been reverse-translated into preclinical models in an effort to elucidate ketamine's antidepressant mechanism of action, and three important targets have been identified: mammalian target of rapamycin (mTOR), eukaryotic elongation factor 2 (eEF2), and glycogen synthase kinase-3 (GSK-3). Current clinical and preclinical research is focused on (a) prolonging/maintaining ketamine's antidepressant effects, (b) developing more selective NMDA receptor antagonists free of ketamine's adverse effects, and (c) identifying predictor, mediator/moderator, and treatment response biomarkers of ketamine's antidepressant effects.Annual Review of Pharmacology 01/2014; 54:119-39. · 21.54 Impact Factor