Continuation phase treatment outcomes for switching, combining, or augmenting strategies for treatment-resistant major depressive disorder: A VAST-D report.

BACKGROUND: This secondary analysis of the VA Augmentation and Switching Treatments for Depression study compared the continuation phase treatment outcomes of three commonly used second-step treatment strategies following at least one prior failed medication treatment attempt. METHODS: In total, 1522 outpatients with MDD were randomized to switching to bupropion-SR (S-BUP), combining with bupropion-SR (C-BUP), or augmenting with aripiprazole (A-ARI). Following 12 weeks of acute phase treatment, 725 entered the 24-week continuation treatment phase. Depressive symptom severity, relapse, "emergent" remission, anxiety, suicidal ideation, quality of life, health status, and side effects were compared. RESULTS: We did not find clinically significant differential treatment effects with the exception that A-ARI was associated with less anxiety than S-BUP or C-BUP. Participants who entered continuation treatment as remitters had milder depressive symptom severity and lower relapse rates than those not in remission; they also experienced more improvement on most other outcomes. A-ARI was associated with less anxiety, insomnia, and dry mouth but more somnolence, extrapyramidal effects, akathisia, abnormal laboratory values, and appetite and weight gain. CONCLUSIONS: Continuation treatment is a dynamic period. Regardless of the treatment, participants who entered continuation treatment at Week 12 in full remission continued to have better outcomes over the subsequent 24 weeks than those who were not in remission at the start of the continuation phase.

Continuity of genetic and environmental influences on clinically assessed major depression from ages 18 to 45.

BACKGROUND: Studies on the stability of genetic risk for depression have relied on self-reported symptoms rather than diagnoses and/or short follow-up time. Our aim is to determine to what degree genetic and environmental influences on clinically assessed major depressive disorder (MDD) are stable between age 18 and 45. METHODS: A population-based sample of 11 727 twins (6875 women) born between 1967 and 1991 was followed from 2006 to 2015 in health registry data from primary care that included diagnoses provided by treating physicians. Individuals with schizophrenia or bipolar disorder (n = 163) were excluded. We modelled genetic and environmental risk factors for MDD in an accelerated longitudinal design. RESULTS: The best-fitting model indicated that genetic influences on MDD were completely stable from ages 18 to 45 and explained 38% of the variance. At each age, the environmental risk of MDD was determined by the risk at the preceding observation, plus new environmental risk, with an environmental correlation of +0.60 over 2 years. The model indicated no effects of shared environment and no environmental effects stable throughout the observational period. All long-term stability was therefore explained by genetic factors. CONCLUSIONS: Different processes unfolded in the genetic and environmental risk for MDD. The genetic component is stable from later adolescence to middle adulthood and accounted for nearly all long-term stability. Therefore, molecular genetic studies can use age-heterogenous samples when investigating genetic risk variants of MDD. Environmental risk factors were stable over a short span of years with associations rapidly decreasing and no evidence of permanent environmental scarring.

Effects of lithium on suicide and suicidal behaviour: a systematic review and meta-analysis of randomised trials.

AIMS: Lithium has long been believed to reduce the risk of suicide and suicidal behaviour in people with mood disorders. Previous meta-analyses appeared to support this belief, but excluded relevant data due to the difficulty of conducting meta-analysis of rare events. The current study is an updated systematic review and meta-analysis that includes all eligible data, and evaluates suicide, non-fatal suicidal behaviour (including suicidal ideation) and suicide attempts. METHODS: We searched PubMed, PsycINFO and Embase and some trial registers. We included all randomised trials comparing lithium and placebo or treatment as usual in mood disorders published after 2000, to ensure suicide was reliably reported. Trial quality was assessed using the Cochrane Risk of Bias tool. Pooled data were analysed using Fisher's Exact test. In addition, meta-analysis was conducted using various methods, prioritizing the Exact method. All trials were included in the analysis of suicide initially, regardless of whether they reported on suicide or not. We conducted a sensitivity analysis with trials that specifically reported on suicides and one that included trials published before 2000. Pre-specified subgroup analyses were performed involving suicide prevention trials, trials excluding people already taking lithium, trials involving people with bipolar disorder exclusively and those involving people with mixed affective diagnoses. Non-fatal suicidal behaviour and suicide attempts were analysed using the same methods, but only trials that reported these outcomes were included. PROSPERO registration: CRD42021265809. RESULTS: Twelve eligible studies involving 2578 participants were included. The pooled suicide rate was 0.2% for people randomised to lithium and 0.4% with placebo or treatment as usual, which was not a statistically significant difference; odds ratio (OR) = 0.41 (95% confidence interval 0.03-2.49), p = 0.45. Meta-analysis using the Exact method produced an OR of 0.42 (95% confidence interval 0.01-4.5). The result was not substantially different when restricted to 11 trials that explicitly reported suicides and remained statistically non-significant when including 15 trials published before 2000 (mostly in the 1970s). There were no significant differences in any subgroup analysis. There was no difference in rates of all non-fatal suicidal behaviour in seven trials that reported this outcome, or in five trials that reported suicide attempts specifically. Meta-analyses using other methods also revealed no statistically significant differences. CONCLUSIONS: Evidence from randomised trials is inconclusive and does not support the idea that lithium prevents suicide or suicidal behaviour.

Single, Repeated, and Maintenance Ketamine Infusions for Treatment-Resistant Depression: A Randomized Controlled Trial.

(Reprinted with permission from The American Journal of Psychiatry 2019; 176:401-409).

Risk of eating disorders in international adoptees: a cohort study using Swedish national population registers.

AIMS: Compared to the general population, adoptees are more often referred to specialist psychiatric treatment, exhibit increased risk of suicide and display more symptoms of attention-deficit/hyperactivity-disorder. However, little is known about the impact of being an adoptee on the risk of developing an eating disorder. The aim of the present study was to assess whether international adoptees have a higher risk for eating disorders than native Swedes. METHODS: In the present retrospective cohort study, data from the Swedish total population registers on individuals born between 1979 and 2005 were used to assess whether international adoptees residing in Sweden (n = 25 287) have a higher risk for anorexia nervosa (AN) and other eating disorders (OED) than non-adoptees with Swedish-born parents from the general population (n = 2 046 835). The patterns of these results were compared to those for major depressive disorder (MDD), obsessive-compulsive disorder (OCD), and anxiety disorders to determine whether any observed effects were unique to eating disorders or reflected a more general impact on mental health outcomes. RESULTS: A survival analysis adjusting for relevant demographic covariates revealed an elevated risk of all examined psychiatric disorders in international adoptees: hazard ratios (95% confidence intervals) are 1.21 (1.04-1.41) for AN, 1.60 (1.44-1.79) for OED, 1.90 (1.81-2.00) for MDD, 1.25 (1.09-1.44) for OCD, and 1.69 (1.60-1.78) for anxiety disorders. CONCLUSIONS: Elevated risk of eating disorders as well as of MDD, OCD, and anxiety disorders was found in international adoptees. A parallel pattern between AN and OCD was observed, which both display less elevated rates than the other diagnoses. A considerable number of biological, environmental, and societal factors have been suggested to explain the observed differences in mental health between adoptees and non-adoptees, but they remain primarily theoretical.

Role of Neuronal VEGF Signaling in the Prefrontal Cortex in the Rapid Antidepressant Effects of Ketamine.

OBJECTIVE: The N-methyl-d-aspartate receptor antagonist ketamine produces rapid and sustained antidepressant actions even in patients with treatment-resistant depression. Vascular endothelial growth factor (VEGF) has been implicated in the effects of conventional monoamine-based antidepressants, but the role of VEGF in the rapid antidepressant actions of ketamine remains unclear. The authors examined whether neuronal VEGF signaling in the medial prefrontal cortex (mPFC) mediates the rapid antidepressant actions of ketamine. METHODS: The authors used a combination of approaches, including conditional, neuron-specific knockout of VEGF or its receptor, Flk-1; antibody neutralization; viral-mediated knockdown of Flk-1; and pharmacological inhibitors. Further in vitro and in vivo experiments were performed to examine whether neuronal VEGF signaling was required for the neurotrophic and synaptogenic actions of ketamine that underlie its behavioral actions. RESULTS: The behavioral actions of systemic ketamine are blocked by forebrain excitatory neuron-specific deletion of either VEGF or Flk-1 or by intra-mPFC infusion of a VEGF neutralizing antibody. Moreover, intra-mPFC infusions of VEGF are sufficient to produce rapid ketamine-like behavioral actions, and these effects are blocked by neuron-specific Flk-1 deletion. The results also show that local knockdown of Flk-1 in mPFC excitatory neurons in adulthood blocks the behavioral effects of systemic ketamine. Moreover, inhibition of neuronal VEGF signaling blocks the neurotrophic and synaptogenic effects of ketamine. CONCLUSIONS: Together, these findings indicate that neuronal VEGF-Flk-1 signaling in the mPFC plays an essential role in the antidepressant actions of ketamine.

No Support for Historical Candidate Gene or Candidate Gene-by-Interaction Hypotheses for Major Depression Across Multiple Large Samples.

OBJECTIVE: Interest in candidate gene and candidate gene-by-environment interaction hypotheses regarding major depressive disorder remains strong despite controversy surrounding the validity of previous findings. In response to this controversy, the present investigation empirically identified 18 candidate genes for depression that have been studied 10 or more times and examined evidence for their relevance to depression phenotypes. METHODS: Utilizing data from large population-based and case-control samples (Ns ranging from 62,138 to 443,264 across subsamples), the authors conducted a series of preregistered analyses examining candidate gene polymorphism main effects, polymorphism-by-environment interactions, and gene-level effects across a number of operational definitions of depression (e.g., lifetime diagnosis, current severity, episode recurrence) and environmental moderators (e.g., sexual or physical abuse during childhood, socioeconomic adversity). RESULTS: No clear evidence was found for any candidate gene polymorphism associations with depression phenotypes or any polymorphism-by-environment moderator effects. As a set, depression candidate genes were no more associated with depression phenotypes than noncandidate genes. The authors demonstrate that phenotypic measurement error is unlikely to account for these null findings. CONCLUSIONS: The study results do not support previous depression candidate gene findings, in which large genetic effects are frequently reported in samples orders of magnitude smaller than those examined here. Instead, the results suggest that early hypotheses about depression candidate genes were incorrect and that the large number of associations reported in the depression candidate gene literature are likely to be false positives.

Electroencephalographic Biomarkers for Treatment Response Prediction in Major Depressive Illness: A Meta-Analysis.

OBJECTIVE: Reducing unsuccessful treatment trials could improve depression treatment. Quantitative EEG (QEEG) may predict treatment response and is being commercially marketed for this purpose. The authors sought to quantify the reliability of QEEG for response prediction in depressive illness and to identify methodological limitations of the available evidence. METHOD: The authors conducted a meta-analysis of diagnostic accuracy for QEEG in depressive illness, based on articles published between January 2000 and November 2017. The review included all articles that used QEEG to predict response during a major depressive episode, regardless of patient population, treatment, or QEEG marker. The primary meta-analytic outcome was the accuracy for predicting response to depression treatment, expressed as sensitivity, specificity, and the logarithm of the diagnostic odds ratio. Raters also judged each article on indicators of good research practice. RESULTS: In 76 articles reporting 81 biomarkers, the meta-analytic estimates showed a sensitivity of 0.72 (95% CI=0.67-0.76) and a specificity of 0.68 (95% CI=0.63-0.73). The logarithm of the diagnostic odds ratio was 1.89 (95% CI=1.56-2.21), and the area under the receiver operator curve was 0.76 (95% CI=0.71-0.80). No specific QEEG biomarker or specific treatment showed greater predictive power than the all-studies estimate in a meta-regression. Funnel plot analysis suggested substantial publication bias. Most studies did not use ideal practices. CONCLUSIONS: QEEG does not appear to be clinically reliable for predicting depression treatment response, as the literature is limited by underreporting of negative results, a lack of out-of-sample validation, and insufficient direct replication of previous findings. Until these limitations are remedied, QEEG is not recommended for guiding selection of psychiatric treatment.

Single, Repeated, and Maintenance Ketamine Infusions for Treatment-Resistant Depression: A Randomized Controlled Trial.

OBJECTIVE: Subanesthetic ketamine doses have been shown to have rapid yet transient antidepressant effects in patients with treatment-resistant depression, which may be prolonged by repeated administration. The purpose of this study was to evaluate the antidepressant effects of a single ketamine infusion, a series of repeated ketamine infusions, and prolongation of response with maintenance infusions. METHODS: Forty-one participants with treatment-resistant depression completed a single-site randomized double-blind crossover comparison of single infusions of ketamine and midazolam (an active placebo control). After relapse of depressive symptoms, participants received a course of six open-label ketamine infusions administered thrice weekly over 2 weeks. Responders, classified as those participants who had a ≥50% decrease in their scores on the Montgomery-Åsberg Depression Rating Scale (MADRS), received four additional infusions administered once weekly (maintenance phase). RESULTS: Compared with midazolam, a single ketamine infusion elicited a significantly greater reduction in depressive symptoms at the primary efficacy endpoint (24 hours postinfusion). Linear mixed models revealed cumulative antidepressant effects with repeated infusions and doubling of the antidepressant response rate. Fifty-nine percent of participants met response criteria after repeated infusions, with a median of three infusions required before achieving response. Participants had no further change in MADRS scores during weekly maintenance infusions. CONCLUSIONS: Repeated ketamine infusions have cumulative and sustained antidepressant effects. Reductions in depressive symptoms were maintained among responders through once-weekly infusions. These findings provide novel data on efficacious administration strategies for ketamine in patients with treatment-resistant depression. Future studies should further expand on optimizing administration to better translate the use of ketamine into clinical settings.

General Predictors and Moderators of Depression Remission: A VAST-D Report.

OBJECTIVE: Almost two-thirds of patients with major depressive disorder do not achieve remission with initial treatments. Thus, identifying and providing effective, feasible, and safe "next-step" treatments are clinical imperatives. This study explores patient baseline features that might help clinicians select between commonly used next-step treatments. METHODS: The authors used data from the U.S. Department of Veterans Affairs (VA) Augmentation and Switching Treatments for Improving Depression Outcomes (VAST-D) study, a multisite, randomized, single-blind trial of 1,522 Veterans Health Administration patients who did not have an adequate response to at least one course of antidepressant treatment meeting minimal standards for dosage and duration. For 12 weeks, participants received one of three possible next-step treatments: switch to another antidepressant-sustained-release bupropion; combination with another antidepressant-sustained-release bupropion; or augmentation with an antipsychotic-aripiprazole. Life table regression models were used to identify baseline characteristics associated with remission overall (general predictors) and their interaction with remission among the three treatment groups (moderators). RESULTS: Remission was more likely for individuals who were employed, less severely and chronically depressed, less anxious, not experiencing complicated grief symptoms, did not experience childhood adversity, and had better quality of life and positive mental health. Two features suggested specific next-step treatment selections: age ≥65 years (for whom augmentation with aripiprazole was more effective than switch to bupropion) and severe mixed hypomanic symptoms (for which augmentation with aripiprazole and combination with bupropion were more effective than switch to bupropion). CONCLUSIONS: If replicated, these preliminary findings could help clinicians determine which patients with depression requiring next-step treatment will benefit most from a specific augmentation, combination, or switching strategy.

The excess costs of depression: a systematic review and meta-analysis.

AIMS: Major depressive disorders are highly prevalent in the world population, contribute substantially to the global disease burden and cause high health care expenditures. Information on the economic impact of depression, as provided by cost-of-illness (COI) studies, can support policymakers in the decision-making regarding resource allocation. Although the literature on COI studies of depression has already been reviewed, there is no quantitative estimation of depression excess costs across studies yet. Our aims were to systematically review COI studies of depression with comparison group worldwide and to assess the excess costs of depression in adolescents, adults, elderly, and depression as a comorbidity of a primary somatic disease quantitatively in a meta-analysis. METHODS: We followed the PRISMA reporting guidelines. PubMed, PsycINFO, NHS EED, and EconLit were searched without limitations until 27/04/2018. English or German full-text peer-reviewed articles that compared mean costs of depressed and non-depressed study participants from a bottom-up approach were included. We only included studies reporting costs for major depressive disorders. Data were pooled using a random-effects model and heterogeneity was assessed with I2 statistic. The primary outcome was ratio of means (RoM) of costs of depressed v. non-depressed study participants, interpretable as the percentage change in mean costs between the groups. RESULTS: We screened 12 760 articles by title/abstract, assessed 393 articles in full-text and included 48 articles. The included studies encompassed in total 55 898 depressed and 674 414 non-depressed study participants. Meta-analysis showed that depression was associated with higher direct costs in adolescents (RoM = 2.79 [1.69-4.59], p < 0.0001, I2 = 87%), in adults (RoM = 2.58 [2.01-3.31], p < 0.0001, I2 = 99%), in elderly (RoM = 1.73 [1.47-2.03], p < 0.0001, I2 = 73%) and in participants with comorbid depression (RoM = 1.39 [1.24-1.55], p < 0.0001, I2 = 42%). In addition, we conducted meta-analyses for inpatient, outpatient, medication and emergency costs and a cost category including all other direct cost categories. Meta-analysis of indirect costs showed that depression was associated with higher costs in adults (RoM = 2.28 [1.75-2.98], p < 0.0001, I2 = 74%). CONCLUSIONS: This work is the first to provide a meta-analysis in a global systematic review of COI studies for depression. Depression was associated with higher costs in all age groups and as comorbidity. Pooled RoM was highest in adolescence and decreased with age. In the subgroup with depression as a comorbidity of a primary somatic disease, pooled RoM was lower as compared to the age subgroups. More evidence in COI studies for depression in adolescence and for indirect costs would be desirable.

Scientific Issues Relevant to Improving the Diagnosis, Risk Assessment, and Treatment of Major Depression.

Over the past two decades, research in the biology and treatment of major depression has led to advances in our understanding of the biology of the disorder and to the development of novel treatments. While progress has been made, a number of key issues have emerged regarding diagnosis of the disorder and how we develop and test new therapies. Among these are the potential need to include new dimensions in the diagnostic criteria, the limited utility of clinical predictors of response, the moving away from traditional blinded trials in major depression, and whether preclinical models tell us much about novel drug development. These issues need to be addressed to avoid the field's embarking on trails of research and treatment development that could actually mislead or misdirect our efforts to develop better diagnostic tools and more effective treatments. Possible solutions to these problems are proposed.

Polygenic Risk: Predicting Depression Outcomes in Clinical and Epidemiological Cohorts of Youths.

OBJECTIVE: Identifying risk factors for major depression and depressive symptoms in youths could have important implications for prevention efforts. This study examined the association of polygenic risk scores (PRSs) for a broad depression phenotype derived from a large-scale genome-wide association study (GWAS) in adults, and its interaction with childhood abuse, with clinically relevant depression outcomes in clinical and epidemiological youth cohorts. METHODS: The clinical cohort comprised 279 youths with major depression (mean age=14.76 years [SD=2.00], 68% female) and 187 healthy control subjects (mean age=14.67 years [SD=2.45], 63% female). The first epidemiological cohort included 1,450 youths (mean age=13.99 years [SD=0.92], 63% female). Of those, 694 who were not clinically depressed at baseline underwent follow-ups at 6, 12, and 24 months. The replication epidemiological cohort comprised children assessed at ages 8 (N=184; 49.2% female) and 11 (N=317; 46.7% female) years. All cohorts were genome-wide genotyped and completed measures for major depression, depressive symptoms, and/or childhood abuse. Summary statistics from the largest GWAS to date on depression were used to calculate the depression PRS. RESULTS: In the clinical cohort, the depression PRS predicted case-control status (odds ratio=1.560, 95% CI=1.230-1.980), depression severity (ß=0.177, SE=0.069), and age at onset (ß=-0.375, SE=0.160). In the first epidemiological cohort, the depression PRS predicted baseline depressive symptoms (ß=0.557, SE=0.200) and prospectively predicted onset of moderate to severe depressive symptoms (hazard ratio=1.202, 95% CI=1.045-1.383). The associations with depressive symptoms were replicated in the second epidemiological cohort. Evidence was found for an additive, but not an interactive, effect of the depression PRS and childhood abuse on depression outcomes. CONCLUSIONS: Depression PRSs derived from adults generalize to depression outcomes in youths and may serve as an early indicator of clinically significant levels of depression.

Empirical evidence for definitions of episode, remission, recovery, relapse and recurrence in depression: a systematic review.

AIMS.: For the past quarter of a century, Frank et al.'s (1991) consensus-based definitions of major depressive disorder (MDD) episode, remission, recovery, relapse and recurrence have been the paramount driving forces for consistency in MDD research as well as in clinical practice. This study aims to review the evidence for the empirical validation of Frank et al.'s proposed concept definitions and to discuss evidence-based modifications. METHODS.: A literature search of Web of Science and PubMed from 1/1/1991 to 08/30/2017 identified all publications which referenced Frank et al.'s request for definition validation. Publications with data relevant for validation were included and checked for referencing other studies providing such data. RESULTS.: A total of 56 studies involving 39 315 subjects were included, mainly presenting data to validate the severity and duration thresholds for defining remission and recovery. Most studies indicated that the severity threshold for defining remission should decrease. Additionally, specific duration thresholds to separate remission from recovery did not add any predictive value to the notion that increased remission duration alleviates the risk of reoccurrence of depressive symptoms. Only limited data were available to validate the severity and duration criteria for defining a depressive episode. CONCLUSIONS.: Remission can best be defined as a less symptomatic state than previously assumed (Hamilton Rating Scale for Depression, 17-item version (HAMD-17) ⩽4 instead of ⩽7), without applying a duration criterion. Duration thresholds to separate remission from recovery are not meaningful. The minimal duration of depressive symptoms to define a depressive episode should be longer than 2 weeks, although further studies are required to recommend an exact duration threshold. These results are relevant for researchers and clinicians aiming to use evidence-based depression outcomes.

Long-Term Outcomes of Subcallosal Cingulate Deep Brain Stimulation for Treatment-Resistant Depression.

OBJECTIVE: Deep brain stimulation of the subcallosal cingulate (SCC DBS) has been studied as a potential treatment for severe and refractory major depressive disorder since 2005. The authors used an open-label, long-term follow-up design to examine participants enrolled in a clinical trial of SCC DBS for treatment-resistant depression. METHODS: Long-term outcome data were collected for 28 patients (20 with major depressive disorder and seven with bipolar II disorder; one patient in the major depression subgroup was later reclassified as having bipolar II disorder) receiving SCC DBS for 4-8 years. RESULTS: Response and remission rates were maintained at ≥50% and ≥30%, respectively, through years 2-8 of the follow-up period. Three-quarters of all participants met the treatment-response criterion for more than half of their duration of participation in the study, with 21% of all patients demonstrating continuous response to treatment from the first year onward. Of 28 participants, 14 completed ≥8 years of follow-up, 11 completed ≥4 years, and three dropped out before 8 years. The procedure itself was generally safe and well tolerated, and there were no side effects of acute or chronic stimulation. The rate of medical or surgical complications was consistent with the rate observed in studies of DBS for other indications. There were no suicides. CONCLUSIONS: In >8 years of observation, most participants experienced a robust and sustained antidepressant response to SCC DBS.

Trajectories of Response to Dorsolateral Prefrontal rTMS in Major Depression: A THREE-D Study.

OBJECTIVE: Repetitive transcranial magnetic stimulation (rTMS) is an effective treatment for refractory major depressive disorder, yet no studies have characterized trajectories of rTMS response. The aim of this study was to characterize response trajectories for patients with major depression undergoing left dorsolateral prefrontal cortex rTMS and to determine associated baseline clinical characteristics. METHODS: This was a secondary analysis of a randomized noninferiority trial (N=388) comparing conventional 10-Hz rTMS and intermittent theta burst stimulation (iTBS) rTMS. Participants were adult outpatients who had a primary diagnosis of major depressive disorder, had a score ≥18 on the 17-item Hamilton Depression Rating Scale (HAM-D), and did not respond to one to three adequate antidepressant trials. Treatment was either conventional 10-Hz rTMS or iTBS rTMS applied to the dorsolateral prefrontal cortex, 5 days/week over 4-6 weeks (20-30 sessions). Group-based trajectory modeling was applied to identify HAM-D response trajectories, and regression techniques were used to identify associated characteristics. RESULTS: Four trajectories were identified: nonresponse (N=43, 11%); rapid response (N=73, 19%); higher baseline symptoms, linear response (N=118, 30%); and lower baseline symptoms, linear response (N=154, 40%). Significant differences in response and remission rates between trajectories were detectable by week 1. There was no association between treatment protocol and response trajectory. Higher baseline scores on the HAM-D and the Quick Inventory of Depression Symptomatology-Self-Report (QIDS-SR) were associated with the nonresponse trajectory, and older age, lower QIDS-SR score, and lack of benzodiazepine use were associated with the rapid response trajectory. CONCLUSIONS: Major depression shows distinct response trajectories to rTMS, which are associated with baseline clinical characteristics but not treatment protocol. These response trajectories with differential response to rTMS raise the possibility of developing individualized treatment protocols.

The Genetic Epidemiology of Treated Major Depression in Sweden.

OBJECTIVE: The authors examined the heritability of treated major depression in a twin and full/half-sibling design, to describe key genetic epidemiological features of major depression and to determine which clinical indices of genetic liability optimally predict risk of depression in relatives. METHOD: The authors examined all treated cases of major depression in Sweden recorded in inpatient, specialist, and primary care registries and, using OpenMx, estimated the etiologic role of genetic and environmental factors from monozygotic and dizygotic twin pairs and full and half siblings reared together and apart (total N=1,718,863 pairs). Eight indices of genetic risk were examined in 875,010 proband-relative pairs. RESULTS: The heritability of major depression in men and women was estimated at 0.41 (95% CI=0.21, 0.49) and 0.49 (95% CI=0.31, 0.56), respectively, in the twin design and 0.36 (95% CI=0.31, 0.38) and 0.51 (95% CI=0.51, 0.53), respectively, in the independent full/half-sibling design. The best estimate of the correlation in genetic effects across sexes was 0.89 (95% CI=0.87, 0.91). The results also showed evidence of modest shared environmental effects (0.02-0.05). Seven of the eight indices predicted risk for major depression in relatives, with stronger effects in those more closely related. The strongest indices were early age at onset, recurrence, comorbid anxiety disorder, and measures of clinical severity. CONCLUSIONS: In a large national sample, the heritability of major depression was similar when estimated from twin and full/half-sibling designs. The heritability of major depression was greater in women than in men, with the two sexes sharing most but not all genetic risk factors. In affected individuals, genetic risk for major depression could be meaningfully assessed from commonly available clinical indices.

Ketamine: A Review for Clinicians.

A growing series of clinical trials and case series now suggest that ketamine-originally used as an anesthetic agent-potentially offers an exciting new treatment option for severe depression. Increasing numbers of studies show that ketamine can provide prompt relief for many depressed patients, including those with severe treatment-refractory depression. Although the effects of a single treatment are commonly short-lived, multiple infusion protocols may offer sustained relief. The uniquely rapid onset of antidepressant action raises the potential for ketamine use in a variety of clinical situations, including the prevention or shortening of hospital stays, the treatment of acute suicidal ideation, and the facilitation of medication crossovers. Ketamine, in combination with other multimodal treatment approaches, including psychotherapy, may further augment response effect and duration. Promises of efficacy have led to increasingly unbridled use to treat a variety of psychiatric disorders, with diverse approaches and treatment environments, despite inadequate data demonstrating the true clinical efficacy and safety of the various protocols or a thorough understanding of mechanisms of action. This article briefly reviews the history of ketamine's development as a potential antidepressant, current hypotheses related to its mechanisms of action, and existing evidence for its safety and efficacy with a focus on clinicians' interests.

Epigenetic Aging in Major Depressive Disorder.

OBJECTIVE: Major depressive disorder is associated with an increased risk of mortality and aging-related diseases. The authors examined whether major depression is associated with higher epigenetic aging in blood as measured by DNA methylation (DNAm) patterns, whether clinical characteristics of major depression have a further impact on these patterns, and whether the findings replicate in brain tissue. METHOD: DNAm age was estimated using all methylation sites in blood of 811 depressed patients and 319 control subjects with no lifetime psychiatric disorders and low depressive symptoms from the Netherlands Study of Depression and Anxiety. The residuals of the DNAm age estimates regressed on chronological age were calculated to indicate epigenetic aging. Major depression diagnosis and clinical characteristics were assessed with questionnaires and psychiatric interviews. Analyses were adjusted for sociodemographic characteristics, lifestyle, and health status. Postmortem brain samples of 74 depressed patients and 64 control subjects were used for replication. Pathway enrichment analysis was conducted using ConsensusPathDB to gain insight into the biological processes underlying epigenetic aging in blood and brain. RESULTS: Significantly higher epigenetic aging was observed in patients with major depression compared with control subjects (Cohen's d=0.18), with a significant dose effect with increasing symptom severity in the overall sample. In the depression group, epigenetic aging was positively and significantly associated with childhood trauma score. The case-control difference was replicated in an independent data set of postmortem brain samples. The top significantly enriched Gene Ontology terms included neuronal processes. CONCLUSIONS: As compared with control subjects, patients with major depression exhibited higher epigenetic aging in blood and brain tissue, suggesting that they are biologically older than their corresponding chronological age. This effect was even more profound in the presence of childhood trauma.

Molecular Genetic Analysis Subdivided by Adversity Exposure Suggests Etiologic Heterogeneity in Major Depression.

OBJECTIVE: The extent to which major depression is the outcome of a single biological mechanism or represents a final common pathway of multiple disease processes remains uncertain. Genetic approaches can potentially identify etiologic heterogeneity in major depression by classifying patients on the basis of their experience of major adverse events. METHOD: Data are from the China, Oxford, and VCU Experimental Research on Genetic Epidemiology (CONVERGE) project, a study of Han Chinese women with recurrent major depression aimed at identifying genetic risk factors for major depression in a rigorously ascertained cohort carefully assessed for key environmental risk factors (N=9,599). To detect etiologic heterogeneity, genome-wide association studies, heritability analyses, and gene-by-environment interaction analyses were performed. RESULTS: Genome-wide association studies stratified by exposure to adversity revealed three novel loci associated with major depression only in study participants with no history of adversity. Significant gene-by-environment interactions were seen between adversity and genotype at all three loci, and 13.2% of major depression liability can be attributed to genome-wide interaction with adversity exposure. The genetic risk in major depression for participants who reported major adverse life events (27%) was partially shared with that in participants who did not (73%; genetic correlation=+0.64). Together with results from simulation studies, these findings suggest etiologic heterogeneity within major depression as a function of environmental exposures. CONCLUSIONS: The genetic contributions to major depression may differ between women with and those without major adverse life events. These results have implications for the molecular dissection of major depression and other complex psychiatric and biomedical diseases.