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Major depressive disorder (MDD) is one of the most disabling diseases worldwide and is becoming a significant public health threat. Current treatments forMDDprimarily consist of monoamine-targeting agents and have limited efficacy. However, the glutamate neurotransmitter system has recently come into focus as a promising alternative for novel antidepressant treatments. We review the current data on the glutamate NMDA receptor antagonist ketamine, which has been shown in clinical trials to act as a rapid antidepressant inMDD.We also examine ketamine efficacy on dimensions of psychopathology, including anhedonia, cognition, and suicidality, consistent with theNIMH Research Domain Criteria initiative. Other aspects of ketamine reviewed in this paper include safety and efficacy, different administration methods, and the risks of misuse of ketamine outside of medical settings. Finally, we conclude with a discussion of glutamatergic agents other than ketamine currently being tested as novel antidepressants. [ABSTRACT FROM AUTHOR]

Levomilnacipran is a novel serotonin and norepinephrine reuptake inhibitor (SNRI) for the treatment of major depressive disorder. This paper reviews up-to-date data on the pharmacology, short- and long-term efficacy, safety and tolerability of levomilnacipran. The drug differs from previously available SNRIs in having twice the potency for norepinephrine versus serotonin reuptake inhibition. In four of the six short-term clinical trials, levomilnacipran was statistically significantly more efficacious than placebo. The only available relapse prevention study did not show reduction in time to relapse, perhaps because relapse rates were low. The commonest adverse events occurring twice as often as on placebo were nausea, hyperhidrosis, constipation, tachycardia, vomiting, erectile dysfunction, palpitations, and ejaculation disorder. In a few patients, hypertension or orthostatic hypotension may occur. Levomilnacipran has been shown to be effective in the short-term treatment of major depressive disorder and may represent an incremental advance. However, further research about its efficacy in subgroups of patients and comparing it to other antidepressants is needed. [ABSTRACT FROM AUTHOR]

Objective: Efficacy and safety of long-term use of antidepressants (AD) in bipolar disorder (BD) patients remains highly controversial. Here we performed a meta-analysis of randomized controlled trials (RCTs) exploring the efficacy and safety of long-term AD use in BD patients.Methods: English-written literature published in peer-reviewed journal was systematically searched from Pubmed, EMBASE, CENTRAL, PsycINFO and Clinicaltrials.gov. Each database was searched from its first available time to August 31, 2016. Additional papers were searched from recent guidelines, expert consensus and systematic reviews by hand. RCTs exploring the efficacy and safety of long-term (≥4m) antidepressant treatment for patients with bipolar disorder were eligible. Two authors (HF, JL) independently extracted the data. Risk ratio (RR), number needed to treat (NNT) and/or number needed to harm (NNH) for new depressive episodes and new manic/hypomanic episodes were calculated. Subgroup analyses were performed based on treatment regimen (AD monotherapy or combined with MS), types of antidepressants, funding source, bipolar subtypes and treatment duration.Results: Eleven trials with 692 bipolar disorder patients were included in the meta-analysis. The risk of bias assessment demonstrated moderate bias risk. Antidepressants were superior to placebo in reducing new depressive episodes in bipolar disorders without increasing risk of new manic/hypomanic episodes either used as monotherapy or in combination with MS. Subgroup analyses revealed that greater benefit and lower risk may be achieved in BD II than in BD I. However, compared with MS monotherapy, AD monotherapy significantly increased the risk of affective switch with no improvement in prophylaxis of new depressive episodes.Conclusions: Reduced new depressive episodes may be achieved by long-term AD treatment with no significantly increased risk of new manic/hypomanic episodes in BD, particularly in BD II. The elevated risk of affective switch of AD monotherapy compared with MS monotherapy may be contributed to the protective effect of MS in diminishing manic/hypomanic episodes. Further studies are needed to verify our findings. [ABSTRACT FROM AUTHOR]

Impairments in verbal working memory are evident in major depression. Verbal working memory is comprised of the components of encoding, maintenance and retrieval. Whether the neural impairments are expressed in specific components, and how pharmacological therapy could modify the neural correlates are not well understood. We investigated the neural correlates of verbal working memory components in depression using the Sternberg task in a longitudinal magnetic resonance imaging study. Serial scans were acquired in 23 patients (mean age 39.8 years) during an acute depressive episode and following 12 weeks of pharmacological therapy with duloxetine and in 22 matched healthy controls (mean age 39.1 years) at the same time points. A significant group by time interaction was evident during the long maintenance phase, extending from the left middle frontal to the middle temporal and caudate regions, in which there was reduced activation in healthy participants at the follow -up scan but there were no changes in patients. Persistent neural engagement during the maintenance phase following treatment was revealed in major depression. The findings emphasize that impairments in verbal working memory may be initiated in the maintenance phase in major depression in order to sustain performance. Further research with larger sample size and using randomized, placebo-controlled double-blind studies are required to confirm our results. [ABSTRACT FROM AUTHOR]

Background Saffron, a spice derived from the flower of Crocus sativus, has now undergone several trials examining its antidepressant effects and, in a recent meta-analysis, was confirmed to be effective for the treatment of major depression. Objective To provide an expanded systematic analysis of the completed clinical studies on saffron and depression, detailing dosages, extract sources, standardisations, safety profile and treatment duration; and, through a narrative review, to examine its potential antidepressant mechanisms of action. Design In the systematic review of clinical trials, electronic databases were searched for high-quality, randomised, double-blind studies, with placebo or antidepressant controls. A narrative review of in vivo and in vitro studies was conducted to examine its potential antidepressant mechanisms of action. Results In the systematic review, six studies were identified. In the placebo-comparison trials, saffron had large treatment effects and, when compared with antidepressant medications, had similar antidepressant efficacy. Saffron's antidepressant effects potentially are due to its serotonergic, antioxidant, anti-inflammatory, neuro-endocrine and neuroprotective effects. Conclusions Research conducted so far provides initial support for the use of saffron for the treatment of mild-to-moderate depression. Further research is required to expand our understanding of the role and actions of saffron in major depression. Copyright © 2014 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

This article proposes a number of recommendations for the treatment of generalized social phobia, based on a systematic literature review and meta-analysis. An optimal treatment regimen would include a combination of medication and psychotherapy, along with an assertive clinical management program. For medications, selective serotonin reuptake inhibitors and dual serotonin-norepinephrine reuptake inhibitors are first-line choices based on their efficacy and tolerability profiles. The nonselective monoamine oxidase inhibitor, phenelzine, may be more potent than these two drug classes, but because of its food and drug interaction liabilities, its use should be restricted to patients not responding to selective serotonin reuptake inhibitors or serotonin-norepinephrine reuptake inhibitors. There are other medication classes with demonstrated efficacy in social phobia (benzodiazepines, antipsychotics, alpha-2-delta ligands), but due to limited published clinical trial data and the potential for dependence and withdrawal issues with benzodiazepines, it is unclear how best to incorporate these drugs into treatment regimens. There are very few clinical trials on the use of combined medications. Cognitive behavior therapy appears to be more effective than other evidence-based psychological techniques, and its effects appear to be more enduring than those of pharmacotherapy. There is some evidence, albeit limited to certain drug classes, that the combination of medication and cognitive behavior therapy may be more effective than either strategy used alone. Generalized social phobia is a chronic disorder, and many patients will require long-term support and treatment. [ABSTRACT FROM AUTHOR]

Objective: To test the hypothesis that in patients with major depressive disorder (MDD), the response for specific Hamilton Depression Rating Scale items will differ for duloxetine compared with selective serotonin reuptake inhibitors (SSRIs) and that patterns of response will differ based on symptom severity at baseline. Method: Data were pooled from all Lilly-sponsored clinical trials where duloxetine was compared with placebo and an SSRI in patients with MDD: 7 randomized, double-blind, fixed-dose, 8-week studies of duloxetine (n = 1,133) versus SSRI (n = 689) versus placebo (n = 641). Duloxetine doses were 40, 60, 80 and 120 mg/day. SSRI doses were 10 mg/day (escitalopram) and 20 mg/day (fluoxetine and paroxetine). Results: Compared to SSRI-treated patients, duloxetine-treated patients had a significantly greater (p ≤ 0.05) reduction in the 17-item Hamilton Depression Rating Scale (HAMD17) total score and HAMD17 items of work and activities, psychomotor retardation, genital symptoms and hypochondriasis. Differences favoring the SSRIs approached significance for middle insomnia (p = 0.057) and late insomnia (p = 0.06), with effect sizes at least twice the magnitude of the corresponding effect sizes for duloxetine. Similarly, the advantage for duloxetine versus the SSRIs approached significance for general somatic symptoms (p = 0.056), with an effect size twice that observed for the SSRIs. The HAMD17 total score difference was driven mostly by patients with lower baseline MDD severity (HAMD17 total score ≤19), where the HAMD17 effect size advantage for duloxetine over combined SSRIs was statistically significant (p = 0.031). Conclusion: Potentially important differences in symptom response patterns were found between duloxetine and the combined SSRIs depending on symptom severity, and different HAMD17 items responded differently to duloxetine compared with SSRIs. Understanding these differences may be useful in tailoring antidepressant therapy for individual patients. Copyright © 2007 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

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