Acute Antidepressant Treatment Research Articles

Antidepressant emergent mood switch in major depressive disorder: onset, clinical correlates and impact on suicidality.

Antidepressant (AD)- emergent mood switch (AEMS) is a common complication of bipolar depression. This study aimed to investigate the prevalence and clinical correlates of subthreshold AEMS (i.e. not fulfilling DSM criteria for hypomanic episodes) in major depressive disorder (MDD) and, prognostically, its impact on AD treatment outcome and suicidality. The study involved 425 outpatients with MDD followed during the acute phase (12 weeks) and continuation (weeks 13-28) AD treatment. AEMS was assessed through the Altman Self-Rating Mania scale (ASRM ≥ 6). Several clinical features differentiated individuals with or without subthreshold AEMS (n = 204 vs. 221): negative self-perception [odds ratio (OR) 1.017-1.565]; panic disorder (OR 1.000-1.091); subthreshold hypomanic episodes (OR 1.466-13.352); childhood emotional abuse (OR 1.053-2.447); lifetime suicidal behaviour (OR 1.027-1.236); AD-related remission (χ 2 = 22.903 P < 0.0001) and suicide ideation (χ 2 = 16.701 P < 0.0001). In AEMS earlier onset showed a strong correlation with bipolar spectrum disorder (overall score: P = 0.0053; mixed depression: P = 0.0154; subthreshold hypomania: P = 0.0150) whereas late-onset was associated with more severe suicidal behaviour ( P < 0.001). In conclusion, our results demonstrate that subthreshold mood switches occur frequently in unipolar depression during acute AD treatment as well as in continuation phase. Time of switch onset seems to have the greatest diagnostic and prognostic value.

Investigating the Role of Maintenance TMS Protocols for Major Depression: Systematic Review and Future Perspectives for Personalized Interventions.

Repetitive Transcranial Magnetic Stimulation (rTMS) has been approved by the FDA as an effective intervention for Treatment-Resistant Depression (TRD). However, there is little evidence about maintenance protocol necessity. The aim of this systematic review is to identify, characterize, and evaluate the current maintenance TMS protocols for MDD and TRD patients who have received acute treatment. A literature search was conducted following the PRISMA guidelines of 2015 on PubMed, Scopus, and Web of Science databases for publications up to March 2022. Fourteen articles were included. High protocol heterogeneity was observed. Most studies highlighted significant efficacy of maintenance protocols in decreasing relapse risk, suggesting that administering two or fewer stimulations per month is ineffective in sustaining an antidepressant effect or in reducing the risk of relapse in responder patients. The risk of relapse was most pronounced after five months from the acute treatment. Maintenance TMS appears to be a resourceful strategy to maintain acute antidepressant treatment effects, significantly reducing relapse risk. The ease of administering and the ability to monitor treatment adherence should be considered when evaluating the future use of maintenance TMS protocols. Further studies are needed to clarify the clinical relevance of overlapping acute TMS effects with maintenance protocols and to evaluate their long-term effectiveness.

Blood cell ratios in mood and cognitive outcomes following electroconvulsive therapy

Systemic inflammation is commonly reported in depression, with dysregulation of both the innate and adaptive arms of the immune system documented. Obtaining ratios of neutrophils, platelets, and monocytes to counts of lymphocytes (NLR, PLR, MLR, respectively) represents a low-cost and easily reproducible measure of an individual's inflammatory burden that can be calculated effortlessly from routine clinical full white blood cell counts. Electroconvulsive therapy (ECT) remains the most effective acute antidepressant treatment for depression but is often limited by its cognitive side-effects. Here, we examined differences in blood cell ratios in subgroups of depressed patients (unipolar/bipolar, psychotic/non-psychotic, early-onset/late-onset) and ECT-related subgroups (responder/non-responder, remitter/non-remitter). We also explored the relationships between blood cell ratios and depression severity and immediate cognitive outcomes post-ECT. Our results show baseline NLR was raised in patients with psychotic depression. In the entire group of patients, significant negative correlations were noted between the PLR and SII and baseline HAM-D24 score, signifying that lower systemic inflammation is associated with more severe depressive symptoms. Significant positive correlations were noted between various blood cell ratios and mean time to recovery of orientation in the entire group of patients and in depression subgroups, indicating that increased peripheral inflammation is linked to worse cognitive outcomes post-ECT. Overall, our results suggest that assessment of blood cell ratios could be useful for predicting mood changes in patients at risk of developing depressive episodes or relapse following successful treatment or for identifying those at risk for cognitive side-effects following ECT.

Montelukast and risk for antidepressant treatment failure

ObjectiveWhile implicated in causing depression, no studies have examined the impact of montelukast on antidepressant effectiveness. We examined whether existing montelukast therapy was associated with acute antidepressant treatment failure (objective 1), and whether montelukast initiation was associated with depression relapse during maintenance antidepressant therapy (objective 2), relative to inhaled corticosteroid (ICS). MethodsPatients with asthma and depression were identified using national Veterans Health Administration data from 2007 to 2019. Objective 1: 12,109 patients initiated an antidepressant after receiving montelukast or ICS for 6 months. The primary outcome was acute antidepressant treatment failure, defined as subsequent initiation of a new antidepressant or augmenting agent within 6 months. Objective 2: 14,673 patients initiated montelukast or ICS after receiving stable antidepressant monotherapy for 6 months. The primary outcome of depression relapse was defined by a subsequent change in the pre-existing maintenance antidepressant regimen within 6 months. Both objectives employed a retrospective cohort design with log-binomial regression. ResultsObjective 1: Acute antidepressant failure was observed in 21.3% (628/2943) and 22.3% (2044/9166) of patients receiving montelukast versus ICS, respectively. Relative risk in adjusted analyses was 0.98 (95% CI: 0.90, 1.07). Objective 2: Depression relapse was observed in 24.4% (288/1182) and 22.4% (3027/13,491) of patients initiating montelukast versus ICS, respectively. Relative risk in adjusted analyses was 1.08 (95% CI: 0.96, 1.20) within 6 months and 1.50 (95% CI: 1.16, 1.93) within 45 days. ConclusionDiscontinuation of existing montelukast therapy is unnecessary when initiating antidepressants. However, potential evidence for depression relapse following montelukast initiation warrants additional investigation.

Acute Efficacy and Safety of Escitalopram Versus Desvenlafaxine and Vortioxetine in the Treatment of Depression With Cognitive Complaint: A Rater-Blinded Randomized Comparative Study.

Objective This study aimed to compare the efficacy and safety of escitalopram, vortioxetine, and desvenlafaxine for acute treatment of major depressive disorder (MDD) with cognitive complaint (CC). Methods A total of 129 patients with MDD who also complained of CC were randomized evenly to either escitalopram, vortioxetine, or desvenlafaxine group and underwent a multi-center, six-week, rater-blinded, and head-to-head comparative trial. Differences in depressive symptoms following treatment were measured using the Hamilton Depression Rating Scale (HAMD) and the Montgomery-Åsberg Depression Rating Scale (MADRS). Subjective cognitive function and the presence of adverse events were assessed. Results The three antidepressant treatment groups did not show significant differences in the improvement of depressive symptoms as measured by HAMD and MADRS. Desvenlafaxine treatment was associated with a superior treatment response rate in depressive symptoms compared to vortioxetine or escitalopram treatment. However, no significant differences were found in the remission rate of depressive symptoms. The three antidepressant treatment groups did not show significant differences in the improvement of CC. Adverse profiles of each treatment group were tolerable, with no significant differences. Conclusion In acute antidepressant treatment for MDD with CC, escitalopram, vortioxetine, and desvenlafaxine presented similar efficacy in relief of depressive symptoms; however, desvenlafaxine was associated with a superior treatment. Further studies are needed to confirm these results by investigating the therapeutic efficacy and safety profile of long-term antidepressant treatment of MDD with CC (Clinical Trial Registry, http://cris.nih.go.kr/cris/en/: KCT0002173).

MiR-9-5p is involved in the rescue of stress-dependent dendritic shortening of hippocampal pyramidal neurons induced by acute antidepressant treatment with ketamine

Converging clinical and preclinical evidence demonstrates that depressive phenotypes are associated with synaptic dysfunction and dendritic simplification in cortico-limbic glutamatergic areas. On the other hand, the rapid antidepressant effect of acute ketamine is consistently reported to occur together with the rescue of dendritic atrophy and reduction of spine number induced by chronic stress in the hippocampus and prefrontal cortex of animal models of depression. Nevertheless, the molecular mechanisms underlying these morphological alterations remain largely unknown.Here, we found that miR-9-5p levels were selectively reduced in the hippocampus of rats vulnerable to Chronic Mild Stress (CMS), while acute subanesthetic ketamine restored its levels to basal condition in just 24h; miR-9-5p expression inversely correlated with the anhedonic phenotype. A decrease of miR-9-5p was reproduced in an in vitro model of stress, based on primary hippocampal neurons incubated with the stress hormone corticosterone. In both CMS animals and primary neurons, decreased miR-9-5p levels were associated with dendritic simplification, while treatment with ketamine completely rescued the changes.In vitro modulation of miR-9-5p expression showed a direct role of miR-9-5p in regulating dendritic length and spine density in mature primary hippocampal neurons. Among the putative target genes tested, Rest and Sirt1 were validated as biological targets in primary neuronal cultures. Moreover, in line with miR-9-5p changes, REST protein expression levels were remarkably increased in both CMS vulnerable animals and corticosterone-treated neurons, while ketamine completely abolished this alteration. Finally, the shortening of dendritic length in corticosterone-treated neurons was shown to be partly rescued by miR-9-5p overexpression and dependent on REST protein expression.Overall, our data unveiled the functional role of miR-9-5p in the remodeling of dendritic arbor induced by stress/corticosterone in vulnerable animals and its rescue by acute antidepressant treatment with ketamine.

Conditional power of antidepressant network meta-analysis

BackgroundConditional power of network meta-analysis (NMA) can support the planning of randomized controlled trials (RCTs) assessing medical interventions. Conditional power is the probability that updating existing inconclusive evidence in NMA with additional trial(s) will result in conclusive evidence, given assumptions regarding trial design, anticipated effect sizes, or event probabilities.MethodsThe present work aimed to estimate conditional power for potential future trials on antidepressant treatments. Existing evidence was based on a published network of 502 RCTs conducted between 1979-2018 assessing acute antidepressant treatment in major depressive disorder (MDD). Primary outcomes were efficacy in terms of the symptom change on the Hamilton Depression Scale (HAMD) and tolerability in terms of the dropout rate due to adverse events. The network compares 21 antidepressants consisting of 231 relative treatment comparisons, 164 (efficacy) and 127 (tolerability) of which are currently assumed to have inconclusive evidence.ResultsRequired sample sizes to achieve new conclusive evidence with at least 80% conditional power were estimated to range between N = 894 - 4190 (efficacy) and N = 521 - 1246 (tolerability). Otherwise, sample sizes ranging between N = 49 - 485 (efficacy) and N = 40 - 320 (tolerability) may require stopping for futility based on a boundary at 20% conditional power. Optimizing trial designs by considering multiple trials that contribute both direct and indirect evidence, anticipating alternative effect sizes or alternative event probabilities, may increase conditional power but required sample sizes remain high. Antidepressants having the greatest conditional power associated with smallest required sample sizes were identified as those on which current evidence is low, i.e., clomipramine, levomilnacipran, milnacipran, nefazodone, and vilazodone, with respect to both outcomes.ConclusionsThe present results suggest that conditional power to achieve new conclusive evidence in ongoing or future trials on antidepressant treatments is low. Limiting the use of the presented conditional power analysis are primarily due to the estimated large sample sizes which would be required in future trials as well as due to the well-known small effect sizes in antidepressant treatments. These findings may inform researchers and decision-makers regarding the clinical relevance and justification of research in ongoing or future antidepressant RCTs in MDD.

Phenotypes of reinforcement sensitivity as predictors of the response to acute antidepressant treatment in rats

One of the biggest threats to modern societies is the increasing prevalence of mood disorders. Cognitive deficits associated with depressive and bipolar disorders are a major driver of functional impairment and the ensuing disability of the suffering individuals. Growing evidence has indicated strong inter-individual differences in the vulnerability to development and effectivity of treatment of these psychiatric conditions, linking various levels of reinforcement sensitivity with specific mood conditions. In this study, we took a unique opportunity to investigate how trait sensitivity to reinforcement determines the reactivity of rats to acute antidepressant treatment.For this, using a preclinical version of the probabilistic reversal-learning (PRL) paradigm, we identified 4 phenotypes of sensitivity to negative and positive feedback in rats, which could represent various types of potential vulnerability to affective disorders. Subsequently, using the light/dark box (LDB) and progressive ratio schedule of reinforcement (PRSR) tests, we evaluated inter-phenotypic differences in the effects of acute treatment with 3 different antidepressant drugs (escitalopram, mirtazapine and clomipramine, each in 3 doses) on anxiety and appetitive motivation of experimental animals.We report statistically significant differences between the investigated phenotypes of reinforcement sensitivity in the effects of acute escitalopram treatment on anxiety in the LDB test. We also report phenotype-independent effects of mirtazapine on motivation and anxiety and a lack of effect of clomipramine.These results demonstrate for the first time that trait sensitivity to reinforcement could have important implications for the effectiveness of treatment in affective disorders.

Is short-term antidepressant treatment effective and safe in bipolar depression? Results from an observational multicenter study.

To investigate the short-term effectiveness and the short-term and long-term safety of acute antidepressant (AD) treatment of bipolar depression in a naturalistic setting. Patients with bipolar (n=86) or unipolar (n=111) depression were consecutively recruited and treated with AD (combined with mood stabilizer [MS] and/or second-generation antipsychotics in bipolar depression). Exclusion criteria were mixed depression, high mood instability, previous predominantly mixed depression (both bipolar and unipolar depression), rapid cycling course and previous switch AD-emerging (bipolar depression). After 12 weeks of treatment, no difference was found in remission, response and improvement rates between bipolar and unipolar depression. Concerning short-term safety, switching and suicidality did not differ significantly between the two groups, and no suicide attempt was observed. Concerning long-term safety, patients with bipolar depression had a significant reduction of depressive and total recurrences during the year of follow-up, compared to the year before entering the study, without significant changes in (hypo)mania and mixed depression recurrences, and suicide rates. Acute AD treatment of bipolar depression is effective in the short-term and safe in the short- and long-term, when administered in combination with MSs and/or second-generation antipsychotics, with a low risk of switch, mixed depression and cycle acceleration.

Trait Sensitivity to Negative and Positive Feedback Does Not Interact With the Effects of Acute Antidepressant Treatment on Hedonic Status in Rats.

Aberrant cognition plays a pivotal role in the development and maintenance of depression. One of the most important cognitive distortions associated with depression is aberrant sensitivity to performance feedback. Under clinical conditions, this sensitivity can be measured using the probabilistic reversal learning (PRL) test, which has also been recently implemented in animal studies. Although the evidence for the coexistence of depression and altered feedback sensitivity is relatively coherent, it is unclear whether this sensitivity can influence the effectiveness of antidepressant treatment. In the present research, we investigated how trait sensitivity to negative and positive feedback interacts with the effects of acute antidepressant treatment on hedonic status in rats. We tested a cohort of rats with a series of 10 PRL tests, and based on this screening, we classified each animal as sensitive or insensitive to negative and positive feedback. Subsequently, in the Latin square design, we evaluated the effects of a single administration of two antidepressant drugs (each at three different doses: agomelatine: 5, 10, and 40 mg/kg; mirtazapine 0.5, 1, and 3 mg/kg) on the hedonic status of rats in the sucrose preference tests. There was no statistically significant interaction between trait sensitivity to feedback and the effects of acute antidepressant treatment on hedonic status in rats.

Antidepressant-like effects of ketamine in a mouse model of serotonergic dysfunction

Traditional monoaminergic treatments of depression frequently exhibit suboptimal tolerability and effectiveness. The ‘short’ (s) allele variant of 5-HTTLPR is known to compromise transcriptional efficacy of the serotonin transporter (5-HTT) and can reduce treatment response to traditional antidepressants (e.g. selective serotonin reuptake inhibitors or SSRIs). This study sought to establish the 5-HTT knock-out (KO) line as a mouse model of SSRI-resistant depression and assess its response to a novel glutamatergic antidepressant, ketamine, a non-competitive N-methyl-d-aspartate receptor (NMDAR) antagonist. Following acute antidepressant treatment, 5-HTT KO mice and wild-type (WT) controls were subjected to the forced-swim test (FST), one of the most widely used techniques to detect acute antidepressant response. As hypothesised, when assessed 30 min after administration in the FST, the SSRI sertraline (20 mg/kg, i.p.) produced antidepressant-like effects in WT control but not in 5-HTT KO mice. In contrast, ketamine (20 mg/kg, i.p.) induced antidepressant-like effects in both genotypes. 5-HTT KO mice also exhibited a reduced locomotor response to both MK-801 (another NMDAR antagonist) and ketamine, and reduced GluN2A protein levels in the hippocampus, suggesting glutamatergic dysfunction in this model. These results highlight the utility of 5-HTT KO mice as a relevant model of SSRI-resistant depression and demonstrate that ketamine can produce acute antidepressant-like effects in conditions of 5-HTT deficiency. These findings extend existing literature that indicates ketamine is effective in ameliorating symptoms of treatment-resistant depression and may have implications for understanding the cellular and molecular mechanisms underlying the antidepressant effects of ketamine.This article is part of the special issue entitled ‘Serotonin Research: Crossing Scales and Boundaries’.

Acute and Long-Term Antidepressant Treatment Success in Adolescents With Anxiety (AtLAS-A)

Acute and Long-Term Antidepressant Treatment Success in Adolescents With Anxiety (AtLAS-A)

Bilateral Repetitive Transcranial Magnetic Stimulation in Older Adults with Depression

Depression is the most common, treatable, mental disorder in late life, making it a major public health concern: 2 to 4 % of persons over the age of 65 suffer from major depression. Current pharmacological treatments for LLD, however, provide modest efficacy. Rates of treatment resistance in randomized controlled trials (RCT) in LLD range from 55-81% using first line antidepressants. The failure of first line treatment to induce remission in patients leads to impaired psychosocial function and diminished quality of life. Depression in older adults, and non-response to antidepressants, is associated with low connectivity in the cognitive control network. Cognition, in particular executive function and processing speed, are often impaired in LLD. It is an important predictor of acute antidepressant treatment outcome. In a 2010 report from the National Institutes of Health (NIH), depression was identified as one of six potentially modifiable risks for cognitive decline, AD, or both. Successful interventions targeting depression could reduce the prevalence of AD by up to 15% in North America, making depression the second most promising target for prevention studies after physical inactivity. Data from three randomized sham controlled trials that have included older adults show converging evidence for the efficacy of bilateral repetitive transcranial magnetic stimulation in this population. Emerging data suggests that intermittent theta burst stimulation (TBS) is similar in effectiveness to high frequency rTMS. An ongoing study is exploring the effectiveness of bilateral (low frequency right then high frequency left) dorsolateral prefontal rTMS compared to continuous TBS right and intermittent TBS left in older adults with depression while also examining the effects on cognition. The design and interim results of this trial will be presented.

Effects of cognitive judgement bias and acute antidepressant treatment on sensitivity to feedback and cognitive flexibility in the rat version of the probabilistic reversal-learning test

Depressive disorders are often associated with cognitive biases. In this study, we investigated, in an animal model, whether cognitive judgement bias, measured as a stable and enduring behavioural trait, could modulate the effects of antidepressant drugs on other cognitive processes associated with depression. For this purpose, we identified rats displaying ‘pessimistic’ and ‘optimistic’ traits in a series of ambiguous-cue interpretation (ACI) tests. Subsequently, in the preclinical version of the probabilistic reversal-learning (PRL) test, allowing multiple reversals within a test session, we compared the effects of acute administration of 5 different antidepressant (AD) drugs (agomelatine, escitalopram, clomipramine, mirtazapine and venlafaxine) on cognitive flexibility and sensitivity to positive/negative feedback in optimistic and pessimistic animals.We report that, following acute treatment with agomelatine, the proportion of lose-shift behaviours in the PRL test was significantly reduced in pessimistic animals compared to optimists. We also demonstrate that acute treatment with another antidepressant drug, mirtazapine, significantly increased the sensitivity of rats to positive feedback, as indexed by the increased proportion of win-stay behaviour following probabilistic reward. This effect was independent of cognitive bias and was associated with a reduced number of reversals made by the animals. Three other tested drugs had no significant effects on behavioural measures assessed in our study.

Effectivity of acute antidepressant treatment is determined by the valence of cognitive judgment bias in rats

Effectivity of acute antidepressant treatment is determined by the valence of cognitive judgment bias in rats

Long-Term Acute-Phase Treatment With Antidepressants, 8 Weeks and Beyond: A Systematic Review and Meta-Analysis of Randomized, Placebo-Controlled Trials.

In clinical practice, acute antidepressant treatment is often applied for several months until remission is achieved. However, data on treatment outcomes beyond 8 weeks are sparse and no systematic review exists to date. This study aims at assessing efficacy and tolerability of antidepressants compared to placebo in acute treatment at and beyond 8 weeks. MEDLINE, Embase, PsycINFO, and CENTRAL databases were systematically searched through March 2014 using generic terms for depressive and affective disorders combined with generic terms for individual drugs and placebo. Double-blind, randomized, placebo-controlled studies of 8 weeks or more comparing antidepressant monotherapy to placebo in adult patients with acute depressive disorder. Data extraction and synthesis followed guidelines of the Cochrane Collaboration. All data were extracted independently by 2 reviewers. Primary outcome was standardized mean difference (SMD) between antidepressant and placebo; secondary outcomes were response, remission, and dropouts. Of 6,043 articles screened, we selected 104 studies that met criteria and included 35,052 patients. Active treatment was statistically significantly superior to placebo, with consistent effect sizes (SMD [95% CL]) after 8, 12, 16, 20, and 24 weeks: 0.27 (0.24, 0.30), 0.34 (0.25, 0.43), 0.24 (0.09, 0.40), 0.31 (0.12, 0.51), and 0.34 (0.18, 0.50), respectively. Results remained stable across secondary outcomes and subgroup and sensitivity analyses. Effect sizes of antidepressant monotherapy compared to placebo seem to be stable over 6 months. These results challenge the assumption that long-term antidepressant effects are due to the natural course of the disorder rather than to a pharmacologic effect.

PS56. A smaller percentage of unipolar depression patients with manic or hypomanic switch during acute antidepressant treatment convert to bipolar disorder

PS56. A smaller percentage of unipolar depression patients with manic or hypomanic switch during acute antidepressant treatment convert to bipolar disorder

Citalopram's mechanism for decreasing immobility time in the Tail Suspension Test

Different antidepressants often target common serotonergic and dopaminergic systems. However, antidepressants are not 100% effective suggesting that there are still multiple cellular mechanisms contributing to depression. Antidepressant responses by novel compounds are typically identified in preclinical models using the Tail Suspension Test (TST), a behavioral stress model that measures immobility time after exposure to an inescapable environment. The TST can predict chronic antidepressant efficacy after acute administration, where effective antidepressants decrease immobility time. Although the predictive validity of the TST is well established, the cellular mechanisms underlying the antidepressant‐driven immobility responses remain unknown. The purpose of this study is to identify the central nervous system cellular pathways that respond to the TST. Two antidepressants will be used in this study: olanzapine, and citalopram, which target the GABA and serotonin systems, respectively. Common pathways mediating the immobility effects of these antidepressants will be identified by immunohistological analysis using phosphorylated extracellular signal‐related kinases as markers of neuronal activity. What was found was that the phosphorylation of extracellular regulated kinases was a mediating step to citalopram's mechanism in decreasing immobility time. The implications of this study include the identification of cellular pathways activated by acute antidepressant treatment, the minimum cellular pathways that are necessary for efficacious therapeutic effects, and facilitating the synthesis of compounds that properly combat depression.

Effect of antidepressant treatment on cognitive impairments associated with depression: a randomised longitudinal study

Antidepressant treatment failure is a common problem worldwide. In this study, we assess whether or not an important aspect of depression, cognitive impairment, is untreated by antidepressants by studying the effect of acute antidepressant treatment on a range of cognitive domains. In this randomised longitudinal study, which is part of the International Study to Predict Optimized Treatment in Depression (iSPOT-D) trial, we assessed the effects of acute antidepressant treatment in a large patient population, across clinical remission outcomes, on a range of cognitive domains: attention, response inhibition, executive function during visuospatial navigation, cognitive flexibility, verbal memory, working memory, decision speed, information processing speed, and psychomotor response speed. We enrolled patients from primary or specialty care clinics in a multicentre, international, open-label, randomised, prospective trial. Eligible patients (aged 18-65 years) were previously untreated or were willing to undergo a 1-week medication washout before the study start, and could not have had inadequate response to study medications in the past. We enrolled a large population of medication-free (ie, untreated) outpatients in a depressive episode and assessed them for cognitive function at enrolment (pre-treatment), and again after 8 weeks of treatment with one of three antidepressant drugs (escitalopram, sertraline, or venlafaxine extended-release). Patients were randomly assigned (1:1:1) to one of the three antidepressants using a blocked randomisation procedure (block size of 12). As a comparison group, we also simultaneously enrolled matched healthy participants. Healthy participants received no medication or intervention, but were assessed for change in cognitive and clinical measures during the same interval and testing protocol. Therefore, this group acts as a test-retest control for the primary outcome measure examined in this study, change in cognitive measures over 8 weeks of treatment in depressed patients. This study is registered with ClinicalTrials.gov, number NCT00693849. Between Dec 8, 2008, and Sept 30, 2011, we enrolled 1008 eligible people into the study. Impairment in five domains-attention, response inhibition, verbal memory, decision speed, and information processing-showed no relative improvement with acute treatment (controlling for time or repeated testing), irrespective of antidepressant treatment group, even in patients whose depression remitted acutely according to clinical measures. Broader cognitive impairment was associated with greater illness chronicity (earlier illness onset) but not with symptom severity or previous antidepressant failures. Depression is associated with impairments in higher-order cognitive functions and information processing, which persist independently of clinical symptom change with treatment. We recorded no difference between the three antidepressants tested, with none showing efficacy for these impairments. Although the 8-week treatment period limits interpretation to acute treatment effects, it does highlight cognitive impairment as an untargeted contributor to incomplete treatment success. Brain Resource Company Operations Pty Ltd and NIH.

Clinical risk factors for weight gain during psychopharmacologic treatment of depression: results from 2 large German observational studies.

Weight gain during psychopharmacologic treatment has considerable impact on the clinical management of depression, treatment continuation, and risk for metabolic disorders. As no profound clinical risk factors have been identified so far, the aim of our analyses was to determine clinical risk factors associated with short-term weight development in 2 large observational psychopharmacologic treatment studies for major depression. Clinical variables at baseline (age, gender, depression psychopathology, anthropometry, disease history, and disease entity) were analyzed for association with percent change in body mass index (BMI; normal range, 18.5 to 25 kg/m(2)) during 5 weeks of naturalistic psychopharmacologic treatment in patients who had a depressive episode as single depressive episode, in the course of recurrent unipolar depression or bipolar disorder according to DSM-IV criteria. 703 patients participated in the Munich Antidepressant Response Signature (MARS) project, an ongoing study since 2002, and 214 patients participated in a study conducted at the University of Muenster from 2004 to 2006 in Germany. Lower BMI, weight-increasing side effects of medication, severity of depression, and psychotic symptoms could be identified as clinical risk factors associated with elevated weight gain during the initial treatment phase of 5 weeks in both studies. Based on these results, a composite risk score for weight gain consisting of BMI ≤ 25 kg/m(2), Hamilton Depression Rating Scale (17-item) score > 20, presence of psychotic symptoms, and administration of psychopharmacologic medication with potential weight-gaining side effects was highly discriminative for mean weight gain (F4,909 = 26.77, P = 5.14E-21) during short-term psychopharmacologic treatment. On the basis of our results, depressed patients with low to normal BMI, severe depression, or psychotic symptoms should be considered at higher risk for weight gain during acute antidepressant treatment. We introduce a new risk score that might be considered in psychopharmacologic decisions for the prevention of weight gain and resulting metabolic disorders.