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Concept: Bupropion

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Individuals with a history of recurrent depression have a high risk of repeated depressive relapse or recurrence. Maintenance antidepressants for at least 2 years is the current recommended treatment, but many individuals are interested in alternatives to medication. Mindfulness-based cognitive therapy (MBCT) has been shown to reduce risk of relapse or recurrence compared with usual care, but has not yet been compared with maintenance antidepressant treatment in a definitive trial. We aimed to see whether MBCT with support to taper or discontinue antidepressant treatment (MBCT-TS) was superior to maintenance antidepressants for prevention of depressive relapse or recurrence over 24 months.

Concepts: Selective serotonin reuptake inhibitor, Bipolar disorder, Major depressive disorder, Bupropion, Sertraline, Mindfulness-based cognitive therapy

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Amygdala circuitry and early life stress (ELS) are both strongly and independently implicated in the neurobiology of depression. Importantly, animal models have revealed that the contribution of ELS to the development and maintenance of depression is likely a consequence of structural and physiological changes in amygdala circuitry in response to stress hormones. Despite these mechanistic foundations, amygdala engagement and ELS have not been investigated as biobehavioral targets for predicting functional remission in translational human studies of depression. Addressing this question, we integrated human neuroimaging and measurement of ELS within a controlled trial of antidepressant outcomes. Here we demonstrate that the interaction between amygdala activation engaged by emotional stimuli and ELS predicts functional remission on antidepressants with a greater than 80% cross-validated accuracy. Our model suggests that in depressed people with high ELS, the likelihood of remission is highest with greater amygdala reactivity to socially rewarding stimuli, whereas for those with low-ELS exposure, remission is associated with lower amygdala reactivity to both rewarding and threat-related stimuli. This full model predicted functional remission over and above the contribution of demographics, symptom severity, ELS, and amygdala reactivity alone. These findings identify a human target for elucidating the mechanisms of antidepressant functional remission and offer a target for developing novel therapeutics. The results also offer a proof-of-concept for using neuroimaging as a target for guiding neuroscience-informed intervention decisions at the level of the individual person.

Concepts: Selective serotonin reuptake inhibitor, Bipolar disorder, Norepinephrine, Bupropion, Sertraline

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The association between the use of antidepressants during gestation and the risk of autism spectrum disorder (ASD) in children is still controversial. The etiology of ASD remains unclear, although studies have implicated genetic predispositions, environmental risk factors, and maternal depression.

Concepts: Autism, Pervasive developmental disorder, Asperger syndrome, Autism spectrum, PDD-NOS, Selective serotonin reuptake inhibitor, Bupropion, Sertraline

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BACKGROUND: An ancillary finding in previous research has suggested that the use of antidepressant medications increases the risk of developing Clostridium difficile infection (CDI). Our objective was to evaluate whether depression or the use of anti-depressants altered the risk of developing CDI, using two distinct datasets and study designs. METHODS: In Study 1, we conducted a longitudinal investigation of a nationally representative sample of older Americans (n = 16,781), linking data from biennial interviews to physician and emergency department visits, stays in hospital and skilled nursing facilities, home health visits, and other outpatient visits. In Study 2, we completed a clinical investigation of hospitalized adults who were tested for C. difficile (n = 4047), with cases testing positive and controls testing negative. Antidepressant medication use prior to testing was ascertained. RESULTS: The population-based rate of CDI in older Americans was 282.9/100,000 person-years (95% confidence interval (CI)) 226.3 to 339.5) for individuals with depression and 197.1/100,000 person-years for those without depression (95% CI 168.0 to 226.1). The odds of CDI were 36% greater in persons with major depression (95% CI 1.06 to 1.74), 35% greater in individuals with depressive disorders (95% CI 1.05 to 1.73), 54% greater in those who were widowed (95% CI 1.21 to 1.95), and 25% lower in adults who did not live alone (95% CI 0.62 to 0.92). Self-reports of feeling sad or having emotional, nervous or psychiatric problems at baseline were also associated with the later development of CDI. Use of certain antidepressant medications during hospitalization was associated with altered risk of CDI. CONCLUSIONS: Adults with depression and who take specific anti-depressants seem to be more likely to develop CDI. Older adults who are widowed or who live alone are also at greater risk of CDI.

Concepts: Selective serotonin reuptake inhibitor, Bupropion, Sertraline, Clostridium difficile

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Depression is prevalent in diabetes and is associated with increased risks of hyperglycaemia, morbidity and mortality. The effect of antidepressant medication (ADM) on glycaemic control is uncertain owing to a paucity of relevant data. We sought to determine whether the use of ADM is associated with glycaemic control in depressed patients with type 2 diabetes.

Concepts: Diabetes mellitus type 2, Diabetes mellitus, Illness, Selective serotonin reuptake inhibitor, Bipolar disorder, Bupropion, Sertraline, Loneliness

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To identify the impact of industry involvement in the publication and interpretation of meta-analyses of antidepressant trials in depression.

Concepts: Selective serotonin reuptake inhibitor, Bipolar disorder, Bupropion, Sertraline

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SUN(^_^)D, the Strategic Use of New generation antidepressants for Depression, is an assessor-blinded, parallel-group, multicenter pragmatic mega-trial to examine the optimum treatment strategy for the first- and second-line treatments for unipolar major depressive episodes. The trial has three steps and two randomizations. Step I randomization compares the minimum and the maximum dosing strategy for the first-line antidepressant. Step II randomization compares the continuation, augmentation or switching strategy for the second-line antidepressant treatment. Step III is a naturalistic continuation phase. The original protocol was published in 2011, and we hereby report its updated protocol including the statistical analysis plan.

Concepts: Selective serotonin reuptake inhibitor, Bipolar disorder, Major depressive disorder, Major depressive episode, Bupropion, Sertraline

28

We examined the effects of an intensive lifestyle intervention (ILI), compared with a diabetes support and education (DSE) control intervention, on long-term changes in depression symptoms, antidepressant medication (ADM) use, and health-related quality of life (HRQoL) in overweight/obese individuals with type 2 diabetes.

Concepts: Diabetes mellitus type 2, Antidepressant, Selective serotonin reuptake inhibitor, Bipolar disorder, Bupropion, Sertraline

28

BACKGROUND: The burden of rising health care expenditures has created a demand for information regarding the clinical and economic outcomes associated with Complementary and Alternative Medicines. Clinical controlled trials have found St. John’s wort to be as effective as antidepressants in the treatment of mild to moderate depression. The objective of this study was to develop a model to assess the cost-effectiveness of St. John’s wort based on this evidence. METHODS: A Markov model was constructed to estimate health and economic impacts of St. John’s wort versus antidepressants. Outcomes were treatment costs, quality-adjusted life years (QALYs) and Net Monetary Benefits (NMB). Probabilistic analyses were conducted on key model parameters. RESULTS: The average NMB across 5000 simulations identified St. John’s wort as the strategy with the highest net benefit. The total cost savings for SJW were $359.66 and $202.56 per individual for venlafaxine and sertraline respectively, with a gain of 0.08 to 0.12 QALYs over the 72 weeks of the model. LIMITATIONS: A lack of direct comparative clinical trial data comparing SJW to venlafaxine and limited data with sertraline as a comparator was a major limitation. CONCLUSIONS: In this model, St. John’s wort was shown to be a cost-effective alternative to generic antidepressants. Patients are more likely to receive treatment for a duration consistent with professional guidelines for treatment of major depression due to reduced incidence of adverse effects, improving outcomes. This represents an important option in the treatment of Major Depressive Disorder.

Concepts: Clinical trial, Selective serotonin reuptake inhibitor, Major depressive disorder, Bupropion, Sertraline, Fluoxetine, Venlafaxine, St John's wort

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Regulator of G protein signaling 4 (Rgs4) is a signal transduction protein that controls the function of monoamine, opiate, muscarinic, and other G protein-coupled receptors via interactions with Gα subunits. Rgs4 is expressed in several brain regions involved in mood, movement, cognition, and addiction and is regulated by psychotropic drugs, stress, and corticosteroids. In this study, we use genetic mouse models and viral-mediated gene transfer to examine the role of Rgs4 in the actions of antidepressant medications. We first analyzed human postmortem brain tissue and found robust up-regulation of RGS4 expression in the nucleus accumbens (NAc) of subjects receiving standard antidepressant medications that target monoamine systems. Behavioral studies of mice lacking Rgs4, including specific knockdowns in NAc, demonstrate that Rgs4 in this brain region acts as a positive modulator of the antidepressant-like and antiallodynic-like actions of several monoamine-directed antidepressant drugs, including tricyclic antidepressants, selective serotonin reuptake inhibitors, and norepinephrine reuptake inhibitors. Studies using viral-mediated increases in Rgs4 activity in NAc further support this hypothesis. Interestingly, in prefrontal cortex, Rgs4 acts as a negative modulator of the actions of nonmonoamine-directed drugs that are purported to act as antidepressants: the N-methyl-D-aspartate glutamate receptor antagonist ketamine and the delta opioid agonist (+)-4-[(αR)-α-((2S,5R)-4-Allyl-2,5-dimethyl-1-piperazinyl)-3-methoxybenzyl]-N,N-diethylbenzamide. Together, these data reveal a unique modulatory role of Rgs4 in the brain region-specific actions of a wide range of antidepressant drugs and indicate that pharmacological interventions at the level of RGS4 activity may enhance the actions of such drugs used for the treatment of depression and neuropathic pain.

Concepts: Signal transduction, Opioid, Serotonin, Antidepressant, Selective serotonin reuptake inhibitor, Bupropion, Tricyclic antidepressant, Norepinephrine reuptake inhibitor