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Background: The literature has shown depression to be associated with an increased risk of dementia. In addition, hormone therapy can be a responsive treatment option for a certain type of depression. In this study, we examined the association between hormone therapy, including lifetime oral contraceptive (OC) use, and hormone replacement therapy (HRT) after menopause with the occurrence of dementia among female patients with depression. Methods: The South Korean national claims data from January 1, 2005, to December 31, 2018, was used. Female subjects aged 40 years or older with depression were included in the analyses. Information on hormone therapy was identified from health examination data and followed up for the occurrence of dementia during the average follow-up period of 7.72 years. Results: Among 209,588 subjects, 23,555 were diagnosed with Alzheimer's disease (AD) and 3023 with vascular dementia (VD). Lifetime OC usage was associated with a decreased risk of AD (OC use for < 1 year: HR, 0.92 [95% CI, 0.88–0.97]; OC use for ≥ 1 year: HR, 0.89 [95% CI, 0.84–0.94]), and HRT after menopause was associated with a decreased risk of AD (HRT for < 2 years: HR, 0.84 [95% CI, 0.79–0.89]; HRT for 2–5 years: HR, 0.80 [95% CI, 0.74–0.88]; and HRT for ≥ 5 years : HR, 0.78 [95% CI, 0.71–0.85]) and VD (HRT < 2 years: HR, 0.82 [95% CI, 0.71–0.96]; HRT for 2–5 years: HR, 0.81 [95% CI, 0.64–1.02]; and HRT for ≥ 5 years: HR, 0.61 [95% CI, 0.47–0.79]). Conclusions: In this nationwide cohort study, lifetime OC use was associated with a decreased risk of AD, and HRT after menopause was associated with a decreased risk of AD and VD among female patients with depression. However, further studies are needed to establish causality. [ABSTRACT FROM AUTHOR]

In clinical trials, placebo response is considered a beneficial effect arising from multiple factors, including the patient's expectations for the treatment. Its presence makes the classical parallel study design suboptimal and can bias the inference. The sequential parallel comparison design (SPCD), a two‐stage design where the first stage is a classical parallel study design, followed by another parallel design among placebo subjects from the first stage, was proposed to address the shortcomings of the classical design. In SPCD, in lieu of treatment effect, a weighted average of the mean treatment difference in Stage I among all randomized subjects and the mean treatment difference in Stage II among placebo non‐responders was proposed as the efficacy measure. However, by linking two possibly different populations, this weighted average lacks interpretability, and the choice of weight remains controversial. In this work, under the principal stratification framework, we propose a causal estimand for the treatment effect under each of three clinically important principal strata: Always Responders, Never Responders, and Drug‐only Responders. To make the stratum treatment effect identifiable, we introduce a set of assumptions and two sensitivity parameters. By further considering the strata as latent characteristics, the sensitivity parameters can be estimated. An extensive simulation study is conducted to evaluate the operating characteristics of the proposed method. Finally, we apply our method on the ADAPT‐A study data to assess the benefit of low‐dose aripiprazole adjunctive to antidepressant therapy treatment. [ABSTRACT FROM AUTHOR]

The brain circuitry of depression and anxiety/fear is well-established, involving regions such as the limbic system and prefrontal cortex. We expand prior literature by examining the extent to which four discrete factors of anxiety (immediate state anxiety, physiological/panic, neuroticism/worry, and agitation/restlessness) among depressed outpatients are associated with differential responses during reactivity to and regulation of emotional conflict. A total of 172 subjects diagnosed with major depressive disorder underwent functional magnetic resonance imaging while performing an Emotional Stroop Task. Two main contrasts were examined using whole brain voxel wise analyses: emotional reactivity and emotion regulation. We also evaluated the association of these contrasts with the four aforementioned anxiety factors. During emotional reactivity, participants with higher immediate state anxiety showed potentiated activation in the rolandic operculum and insula, while individuals with higher levels of physiological/panic demonstrated decreased activation in the posterior cingulate. No significant results emerged for any of the four factors on emotion regulation. When re-analyzing these statistically-significant brain regions through analyses of a subsample with (n = 92) and without (n = 80) a current anxiety disorder, no significant associations occurred among those without an anxiety disorder. Among those with an anxiety disorder, results were similar to the full sample, except the posterior cingulate was associated with the neuroticism/worry factor. Divergent patterns of task-related brain activation across four discrete anxiety factors could be used to inform treatment decisions and target specific aspects of anxiety that involve intrinsic processing to attenuate overactive responses to emotional stimuli. [ABSTRACT FROM AUTHOR]

Option generation is a critical process in decision making, but previous studies have largely focused on choices between options given by a researcher. Consequently, how we self-generate options for behaviour remain poorly understood. Here, we investigated option generation in major depressive disorder and how dopamine might modulate this process, as well as the effects of modafinil (a putative cognitive enhancer) on option generation in healthy individuals. We first compared differences in self-generated options between healthy non-depressed adults [n = 44, age = 26.3 years (SD 5.9)] and patients with major depressive disorder [n = 54, age = 24.8 years (SD 7.4)]. In the second study, a subset of depressed individuals [n = 22, age = 25.6 years (SD 7.8)] underwent PET scans with 11C-raclopride to examine the relationships between dopamine D2/D3 receptor availability and individual differences in option generation. Finally, a randomized, double-blind, placebo-controlled, three-way crossover study of modafinil (100 mg and 200 mg), was conducted in an independent sample of healthy people [n = 19, age = 23.2 years (SD 4.8)] to compare option generation under different doses of this drug. The first study revealed that patients with major depressive disorder produced significantly fewer options [t(96) = 2.68, P = 0.009, Cohen's d = 0.54], albeit with greater uniqueness [t(96) = -2.54, P = 0.01, Cohen's d = 0.52], on the option generation task compared to healthy controls. In the second study, we found that 11C-raclopride binding potential in the putamen was negatively correlated with fluency (r = -0.69, P = 0.001) but positively associated with uniqueness (r = 0.59, P = 0.007). Hence, depressed individuals with higher densities of unoccupied putamen D2/D3 receptors in the putamen generated fewer but more unique options, whereas patients with lower D2/D3 receptor availability were likely to produce a larger number of similar options. Finally, healthy participants were less unique [F(2,36) = 3.32, P = 0.048, partial η2 = 0.16] and diverse [F(2,36) = 4.31, P = 0.021, partial η2 = 0.19] after taking 200 mg versus 100 mg and 0 mg of modafinil, while fluency increased linearly with dosage at a trend level [F(1,18) = 4.11, P = 0.058, partial η2 = 0.19]. Our results show, for the first time, that option generation is affected in clinical depression and that dopaminergic activity in the putamen of patients with major depressive disorder may play a key role in the self-generation of options. Modafinil was also found to influence option generation in healthy people by reducing the creativity of options produced. [ABSTRACT FROM AUTHOR]

Although previous studies have suggested that childhood trauma and parental death are strongly associated with suicidality in adulthood, it is still unclear how these factors interact within the same population. A total of 1396 adults were recruited through nationwide multistage probability sampling in South Korea. Subjects were evaluated through face-to-face interviews using the Suicidality Module of the Mini-International Neuropsychiatric Interview and the Early Trauma Inventory Self Report-Short Form. Among the 1396 adults, the group that experienced both childhood trauma and parental death had the highest current suicidality risks (F = 12.16, p < 0.0001) and lifetime suicide attempt ([chi] = 35.81, p < 0.0001) compared with the other groups, which were only childhood trauma, only parental death, and neither. Multivariate logistic regression analyses revealed that middle-to-high current suicidality risk and lifetime suicide attempt were significantly associated with concurrent childhood trauma and parental death (odds ratio, 3.64; 95% confidence interval, 1.99-6.65) as well as with only childhood trauma (odds ratio, 1.95; 95% confidence interval, 1.33-2.87), after adjusting for age, sex, education, marital status, household monthly income, and living area. Emotional abuse was the only type of childhood trauma significantly associated with higher current suicidality scores in those who experienced childhood parental death than in those who did not (F = 3.26, p = 0.041). Current suicidality risk and lifetime suicide attempt are associated with experiencing both parental death and trauma, especially emotional abuse, in childhood, whereas experiencing only childhood parental death is associated with neither. [ABSTRACT FROM AUTHOR]

Background Thyroid dysfunction and elevated thyroid stimulating hormone (TSH) are common in patients with depression. TSH might exert its function in the brain through blood levels of brain-derived neurotrophic factor (BDNF). BDNF decreases during depressed states and normalize after treatment. The gap is that the association between TSH and BDNF in patients with major depressive disorder (MDD) is unknown. Methods We studied 105 subjects ≥18 years of age with MDD and measured serum, plasma, and platelet BDNF at baseline, 1 month and 3 months during antidepressant treatment. Other baseline measurements included hypothalamic–pituitary–thyroid axis hormones such as TSH, triiodothyronine (T3) and thyroxine (T4); hypothalamic-pituitary-adrenal (HPA) axis hormones and hypothalamic-pituitary-gonadal (HPG) axis hormones and prolactin. Results Linear mixed model effect analyses revealed that baseline TSH level was negatively associated with changes of serum BDNF from baseline to 3 months ( F =7.58, p =0.007) after adjusting for age, sex, and body mass index, but was not associated with plasma and platelet BDNF. In contrast, T3 and T4, HPA axis hormones, HPG axis hormones, and prolactin were not associated with serum, plasma, or platelet BDNF levels. Patients in the highest quartile of TSH showed significantly lower serum BDNF than in the other quartiles ( F =4.54, p =0.038), but no significant differences were found based on T3 and T4 levels. Limitations TSH was only measured at baseline. Conclusions Higher TSH is associated with lower baseline and reduced the increase of serum BDNF levels during antidepressant treatment in patients with MDD. [ABSTRACT FROM AUTHOR]

Background Major depressive disorder (MDD) and traumatic experience are independent risk factors for lifetime suicide attempt (LSA). However, the relationships between trauma history and depressive symptomatology as they relate to LSA are not fully understood. Methods A total of 12,532 adults, randomly selected through one-person-per-household method, completed a face-to-face interview using the Korean version of Composite International Diagnostic Interview (K-CIDI) and a questionnaire for LSA (response rate 80.2%). Results Among 825 subjects with MDD, 141 subjects reported an LSA (17.1%). LSAs were significantly greater in those who had experienced any trauma than in those who had not (χ²=34.66, p<0.0001). Multivariate logistic regression showed that only feelings of worthlessness were significantly associated with LSA among 20 depression symptoms in individuals with MDD (AOR=3.08, 95% CI 1.70-5.60). Feelings of worthlessness was associated with LSA in those who had experienced serious trauma (AOR=5.02, 95% CI 3.35-7.52), but not in those who had not. Serious traumas associated with LSA included military combat, witnessing a violent crime, rape or sexual assault, a bad beating, being threatened by others, and learning about traumas to others. Serious trauma showed no significant association with LSA in those who did not have feelings of worthlessness. PTSD was a comorbidity that showed the highest odds ratio with LSA in individuals with MDD. Conclusions Feelings of worthlessness are more strongly associated with LSA than other depression symptoms in individuals with MDD, and it is significantly associated with LSA in those who experienced serious trauma but not in those who did not. [ABSTRACT FROM AUTHOR]

The lack of biomarkers to inform antidepressant selection is a key challenge in personalized depression treatment. This work identifies candidate biomarkers by building deep learning predictors of individual treatment outcomes using reward processing measures from functional magnetic resonance imaging, clinical assessments, and demographics. Participants in the EMBARC (Establishing Moderators and Biosignatures of Antidepressant Response in Clinical Care) study (n = 222) underwent reward processing task-based functional magnetic resonance imaging at baseline and were randomized to 8 weeks of sertraline (n = 106) or placebo (n = 116). Subsequently, sertraline nonresponders (n = 37) switched to 8 weeks of bupropion. The change in Hamilton Depression Rating Scale was measured after treatment. Reward processing, clinical measurements, and demographics were used to train treatment-specific deep learning models. The predictive model for sertraline achieved R 2 of 48% (95% CI, 33%–61%; p < 10−3) in predicting the change in Hamilton Depression Rating Scale and number-needed-to-treat (NNT) of 4.86 participants in predicting response. The placebo model achieved R 2 of 28% (95% CI, 15%–42%; p < 10−3) and NNT of 2.95 in predicting response. The bupropion model achieved R 2 of 34% (95% CI, 10%–59%, p < 10−3) and NNT of 1.68 in predicting response. Brain regions where reward processing activity was predictive included the prefrontal cortex and cerebellar crus 1 for sertraline and the cingulate cortex, caudate, orbitofrontal cortex, and crus 1 for bupropion. These findings demonstrate the utility of reward processing measurements and deep learning to predict antidepressant outcomes and to form multimodal treatment biomarkers. [ABSTRACT FROM AUTHOR]

Objectives: Transdiagnostic treatments increasingly include emotion regulation training focused on use of emotional suppression and acceptance. Despite the frequent use of these treatments in depression, little is known about the effects of these strategies in this population. Design: An experimental study. Methods: Eighty Veterans with unipolar depression participated in a study examining effects of these strategies on emotional responding (subjective, behavioural, and physiological). Physiological measures included: heart rate (HR), respiration (Resp), skin conductance (SC), and corrugator electromyography. On Day 1, participants were randomised to one of three conditions (acceptance, suppression, or control) and underwent an autobiographical sad mood induction. On Day 2, participants underwent a similar mood induction one week later. Results: The suppression group demonstrated reduced physiological reactivity (Resp and SC) on Day 1. However, the suppression group reported decreased positive affect on Day 2. Conclusions: Results support short‐term effectiveness and longer term costs from suppression use among depressed individuals. Findings may inform application of transdiagnostic emotion regulation treatments and suggest suppression functions differently in depressed versus other clinical populations. [ABSTRACT FROM AUTHOR]

Importance: Acute agitation is common in patients with bipolar disorder and requires urgent management to relieve distress and to prevent escalation to aggressive behavior.Objective: To evaluate the effect of orally absorbed, sublingual dexmedetomidine, a selective α2A-adrenergic receptor agonist on symptoms of acute agitation in patients with bipolar disorder.Design, Setting, and Participants: Phase 3, randomized, double-blind, placebo-controlled trial conducted in 15 sites in the US with enrollment between February 24, 2020, and April 27, 2020, and final follow-up on May 21, 2020. A total of 380 adults with bipolar I or II disorder were randomized and 362 completed the study.Interventions: Participants were randomized to 3 groups: sublingual dexmedetomidine 180 μg (n = 127), sublingual dexmedetomidine 120 μg (n = 127), or placebo (n = 126).Main Outcomes and Measures: The primary efficacy end point was the mean change from baseline at 2 hours for the Positive and Negative Syndrome Scale-Excited Component (PEC) total score. The range of possible total scores is 5 (absence of agitation) to 35 (extremely severe). The secondary end point was the earliest time of a statistically significant change in PEC total score from baseline for the drug vs placebo. On the primary efficacy end point, to account for multiplicity associated with comparing 2 sublingual dexmedetomidine doses with placebo, the 2-sided significance level for each dose vs placebo was set at .025.Results: Of 380 patients randomized (mean age, 45.6 years; 54.8% women; and 56.1% Black individuals), 378 (99.5%) self-administered the study medication and completed the study. Baseline agitation was mild to moderate, with an overall mean PEC total score of 18.0. Two hours after taking the medication, the mean changes from baseline in PEC total score were -10.4 for sublingual dexmedetomidine 180 μg, -9.0 for sublingual dexmedetomidine 120 μg, and -4.9 for placebo. Least-square mean differences from placebo in the sublingual dexmedetomidine groups at 2 hours were -5.4 (97.5% CI, -6.6 to -4.2) for 180 μg and -4.1 (97.5% CI, -5.3 to -2.9) for 120 μg (both doses P < .001 vs placebo). Treatment effects began 20 minutes after taking the medication among patients in the sublingual dexmedetomidine groups (least-square mean difference for 180 μg, -1.1 [97.5% CI, -2.0 to -0.2]; P = .007; for 120 μg, -1.0 [97.5% CI, -1.9 to -0.1]; P = .009). Adverse events occurred in 35.7% of patients taking 180 μg of dexmedetomidine, 34.9% taking 120 μg, and 17.5% taking placebo. The most common adverse events (≥5%) in the respective 180 μg, 120 μg, and placebo groups were somnolence (21.4% and 20.6% vs 4.8%); dry mouth (4.8% and 7.1% vs 0.8%); hypotension (6.3% and 4.8% vs 0%); and dizziness (5.6% and 5.6% vs 0.8%).Conclusions and Relevance: Among patients with mild to moderate agitation associated with bipolar disorder, treatment with a sublingual film formulation of dexmedetomidine 120 μg or 180 μg, compared with placebo, resulted in significantly greater reduction in the agitation score at 2 hours. Further research is needed to understand the spectrum of patients for whom this treatment would be effective and feasible and to better understand the clinical importance of the observed effect size.Trial Registration: ClinicalTrials.gov Identifier: NCT04276883. [ABSTRACT FROM AUTHOR]

Abstract: Objective: Major depressive disorder (MDD) is associated with suicide. Although several studies have reported its association with low serum lipid, few studies have investigated relationships between current suicidality and lipid profiles, comparing with other blood measures in MDD patients. Methods: The study population consisted of 555 subjects with MDD who were ≥18years old, evaluated by the Mini International Neuropsychiatric Interview (MINI) with the suicidality module. At the evaluation visit, we measured serum lipid profiles including total cholesterol, triglycerides (TG), low-density lipoprotein (LDL), high-density lipoprotein (HDL), and very low-density lipoprotein (VLDL), and blood measures such as fasting glucose, total protein, albumin, blood urea nitrogen, creatinine, thyroid hormones, red and white blood cells, platelet count, hemoglobin, and hematocrit. Results: Recent attempters who had attempted suicide within the past month showed significantly lower TG and higher HDL levels than lifetime and never attempters, using Tukey's post-hoc analysis. Recent attempters exhibited lower TG and higher HDL than those with recent suicide ideation and wish to self-harm and those without previous attempt. Linear regression analysis revealed that TG was negatively associated with current suicidality scores (β=−0.187, p=0.039), whereas VLDL was positively associated with the recent suicide status (β=0.198, p=0.032) after controlling for age and sex. There were no significant differences between the groups in terms of other serum lipid profiles and blood measures. Conclusions: Low serum TG, high HDL and VLDL levels are associated with recent suicide attempt or recent suicide status in patients with MDD. [Copyright &y& Elsevier]

Abstract: Current suicidal ideation and attempts are more commonly found in female patients with major depressive disorder (MDD) than in males. However, little is known about the relationship between activity of female reproductive hormones and suicide. The study population consisted of 490 female MDD patients of age ≥18. They were assessed by the Mini-International Neuropsychiatric Interview. At the same visit, we measured blood Follicle-Stimulating Hormone (FSH), Luteinizing Hormone (LH), estradiol, progesterone, Adrenocorticotropic Hormone (ACTH), cortisol, thyroid hormones, and prolactin. Blood FSH showed a significant difference among female MDD patients with suicide attempt, those with ideation, and those without within the previous month. Post-hoc analysis also showed that FSH was significantly lower in MDD patients with suicide attempt and ideation than those without, whereas other hormones showed no differences between those with and without attempt. FSH was negatively associated with current suicidality scores after adjustment for age and education years in all age groups. FSH was significantly lower in those with current suicide ideation or attempt than those without in age 45 years or under, but not in other age groups. In conclusion, blood FSH is significantly lower in female MDD patients with current suicide attempt or ideation than those without, especially in age 45 years or under. [Copyright &y& Elsevier]

Although previous studies have shown that childhood parental death influences suicide attempts of their offspring, few studies have examined influence of gender and age at exposure. Koreans show the third highest suicide rate in the world, and many children and adolescents lost their parents during and after the Korean War. A total of 12,532 adults, randomly selected through a one-person-per-household method, completed the Korean version of the Composite International Diagnostic Interview and questionnaire for suicidal ideation, plan, and attempt (response rate 80.2%). A total of 2,332 subjects experienced biological parental death in childhood (18.6%). Male suicide attempts were associated with age of exposure to maternal death from 0 to 4 years (adjusted OR = 4.48, 95% CI 1.32-15.18) and from 5 to 9 years (adjusted OR = 5.52, 95% CI 1.97-16.46), but not with paternal death, after adjusting for age, education years, marital status, monthly income, and psychiatric comorbidities. Female suicide attempts were associated with paternal death from 5 to 9 years (adjusted OR = 2.20, 95% CI 1.13-4.27), but not with maternal death. Childhood parental death is significantly associated with lifetime suicide attempt in the opposite-gender offspring, especially when exposure occurs before age 10. [ABSTRACT FROM AUTHOR]

Background: Non-racemic amisulpride (SEP-4199) is an 85:15 ratio of aramisulpride:esamisulpride with a 5-HT7 and D2 receptor binding profile optimized for the treatment of bipolar depression. The aim of this study was to evaluate the efficacy and safety of SEP-4199 for the treatment of bipolar depression.Methods: Patients meeting DSM-5 criteria for bipolar I depression were randomized to 6 weeks of double-blind, placebo-controlled treatment with SEP-4199 200 mg/d or 400 mg/d. The primary endpoint was change in the Montgomery-Asberg Depression Rating Scale (MADRS) at Week 6. The primary efficacy analysis population consisted of patients in Europe and US (n = 289); the secondary efficacy analysis population (ITT; n = 337) included patients in Japan.Results: Endpoint improvement in MADRS total score was observed on both the primary analysis for SEP-4199 200 mg/d (P = 0.054; effect size [ES], 0.31) and 400 mg/d (P = 0.054; ES, 0.29), and on the secondary (full ITT) analysis for SEP-4199 200 mg/d (P = 0.016; ES, 0.34) and 400 mg/d (P = 0.024; ES, 0.31). Study completion rates were 81% on SEP-4199 200 mg/d, 88% on 400 mg/d, and 86% on placebo. SEP-4199 had low rates of individual adverse events (<8%) and minimal effects on weight and lipids; median increases in prolactin were +83.6 μg/L on 200 mg/d, +95.2 μg/L on 400 mg/d compared with 0.0 μg/L on placebo.Limitations: The study excluded patients with bipolar II depression and serious psychiatric or medical comorbidity.Conclusion: Study results provide preliminary proof of concept, needing confirmation in subsequent randomized trials, for the efficacy of non-racemic amisulpride in bipolar depression. [ABSTRACT FROM AUTHOR]

Objective: It has been suggested that there is a mechanism by which nonsteroidal anti-inflammatory drugs (NSAIDs) may interfere with antidepressant response, and poorer outcomes among NSAIDtreated patients were reported in the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study. To attempt to confirm this association in an independent population-based treatment cohort and explore potential confounding variables, the authors examined use of NSAIDs and related medications among 1,528 outpatients in a New England health care system. Method: Treatment outcomes were classified using a validated machine learning tool applied to electronic medical records. Logistic regression was used to examine the association between medication exposure and treatment outcomes, adjusted for potential confounding variables. To further elucidate confounding and treatment specificity of the observed effects, data from the STAR*D study were reanalyzed. Results: NSAID exposure was associated with a greater likelihood of depression classified as treatment resistant compared with depression classified as responsive to selective serotonin reuptake inhibitors (odds ratio=1.55, 95% Cl=1.21-2.00). This association was apparent in the NSAIDs only group but not in those using other agents with NSAID-like mechanisms (cyclooxygenase-2 inhibitors and saucylates). Inclusion of age, sex, ethnicity, and measures of comorbidity and health care utilization in regression models indicated confounding; association with outcome was no longer significant in fully adjusted models. Reanalysis of STAR*D results likewise identified an association in NSAIDs but not NSAID-like drugs, with more modest effects persisting after adjustment for potential confounding variables. Conclusions: These results support an association between NSAID use and poorer antidepressant outcomes in major depressive disorder but indicate that some of the observed effect may be a result of confounding. [ABSTRACT FROM AUTHOR]

Abstract: The use of Complementary and Alternative Medicine (CAM) for physical and mental problems has increased significantly in the US over the past two decades, and depression is one of the leading indications for the use of CAM. This article reviews some of the lesser-known natural products with potential psychiatric applications that are starting to emerge with some scientific and clinical evidence and may constitute a next wave of natural antidepressants: Rhodiola rosea, chromium, 5-Hydroxytryptophan (5-HTP) and inositol. Background information, efficacy data, proposed mechanisms of action, recommended doses, side effects, and precautions are reviewed. We found some encouraging data for the use of these natural products in specific populations of depressed patients. R. rosea is an adaptogen plant that can be especially helpful in treating asthenic or lethargic depression, and may be combined with conventional antidepressants to alleviate some of their common side effects. Chromium has a beneficial effect on eating-related atypical symptoms of depression, and may be a valuable agent in treating atypical depression and seasonal affective disorder. Inositol may be useful in the treatment of bipolar depression when combined with mood stabilizers. Evidence for the clinical efficacy of 5-HTP is also promising but still preliminary. Although more well-designed and larger controlled studies are needed before any substantive conclusions can be drawn, the available evidence is compelling and these natural products deserve further investigation as a possibly significant addition to the antidepressant armamentarium. [Copyright &y& Elsevier]

The purpose of this meta-analysis is to examine the relationship between selective serotonin reuptake inhibitor (SSRI) starting dose and treatment outcome in major depressive disorder (MDD). Medline/Pubmed, EMBASE, the Cochrane database, as well as a number of online clinical trial registries were searched for double-blind, placebo-controlled, fixed-dose trials comparing different starting doses of SSRIs for MDD. Data from nine trials ( n=2340) were combined using a random-effects model. Patients randomized to receive the usual starting dose (10 mg escitalopram; 20 mg fluoxetine, paroxetine, citalopram; 50 mg sertraline and fluvoxamine) were less likely to respond than patients who received higher starting doses (RR=0.9; P=0.04; response rate 50.8 vs. 54.8%). The rate of discontinuation due to adverse events was lower among the usual starting dose group (9.8%) compared to the higher starting dose group (16.5%).Initiating treatment with SSRIs at doses higher than those typically used in clinical trials/settings is associated with higher response rates but also higher rates of discontinuation due to intolerance. Developing treatment strategies allowing clinicians to deliver higher initial SSRI doses while enhancing the tolerability of treatment may represent an alternative approach to improving the efficacy of treatment of MDD. [ABSTRACT FROM AUTHOR]

Background: Diurnal mood variation (DMV) with early morning worsening is considered a classic symptom of melancholic features of major depressive disorder (MDD) according to the Diagnostic and Statistical Manual. This report used data from the sequenced treatment alternatives to relieve depression study to determine whether DMV was associated with treatment outcome to citalopram. Methods: Two thousand eight hundred and seventy-five outpatients with nonpsychotic MDD were evaluated during a 14-week trial of the selective serotonin reuptake inhibitor citalopram. Participants were divided into three groups: those with “classic” DMV (early morning worsening), those with any form of DMV (morning, afternoon, or evening worsening), and those with no DMV. Participants with classic DMV and those with any form of DMV were compared to those with no DMV in terms of baseline sociodemographic and clinical characteristics, treatment outcomes, and treatment features. Results: Minor baseline clinical characteristics and treatment feature differences were found between participants with and without DMV. Participants with classic morning DMV had slightly higher response rates than those without DMV. However, no differences were found in response or remission between either group of participants with DMV and those with no DMV. Conclusion: DMV does not appear to be associated with a unique prominent pattern of response to selective serotonin reuptake inhibitor treatment in patients with depression, and does not appear to be a serotonergically modulated process. Further evaluation is necessary to determine if this relationship holds true for dopaminergic and noradrenergic antidepressant agents, such as dual-acting agents or antidepressant medication combinations. Depression and Anxiety, 2009. © 2009 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]

• Depression and anxiety significantly predict smartphone overuse. • Found significant relationship of smartphone overuse with internet and game overuse. • More smartphone overuse reported in people diagnosed with alcohol dependence. • More smartphone overuse reported in people diagnosed with nicotine dependence. • More females and singles were identified as smartphone over-users. Smartphone is one of the essential items. However, it may negatively affect a user's mental health when it is overused. The study aimed to investigate associations of smartphone overuse with depression, anxiety, and the relationship with other addictive behaviors and disorders. A total of 2,509 subjects were randomly selected through a one-person-per-household method. Smartphone Overuse Screening Questionnaire (SOS-Q) and the Korean version of the Composite International Diagnostic Interview (K-CIDI) were used. Linear regression and Pearson correlation analyses were performed to evaluate associations of smartphone overuse with depression, anxiety, and relationship with other addictive psychiatric disorders respectively. Among 2509 participants, 138 (14.76%) demonstrated smartphone overuse. Participants who used their smartphones for more than three hours a week were more likely to be single and females compared to those who used their smartphones for less than three hours a week. Smartphone overuse showed significant associations with depression, anxiety disorder, and a significant relationship with internet and game overuse, alcohol dependence, and nicotine dependence disorder. Internet-related behavior showed the strongest relationship with smartphone overuse. Although the sample size was adequate, a large number of subjects did not complete the questionnaire. People with psychiatric disorders should be advised to use smartphones in moderation. [ABSTRACT FROM AUTHOR]

Anxiety disorders often are accompanied by painful physical symptoms. This report assessed the effectiveness of duloxetine in improving anxiety symptoms, pain severity, and patient functioning in adults diagnosed with generalized anxiety disorder (GAD), who presented with clinically significant pain symptoms. Data were pooled from two multicenter, randomized, double-blind, placebo-controlled clinical studies evaluating the efficacy of duloxetine 60–120 mg once daily compared with placebo in the treatment of GAD. The primary patient population for these analyses was patients with baseline Visual Analog Scale (VAS) overall pain severity score ≥30. Of the 798 randomized patients that had baseline VAS scores, approximately 44.4% of GAD patients were identified as having baseline VAS overall pain severity score ≥30 (duloxetine N=208, placebo N=146). Duloxetine-treated patients had significantly greater improvement compared with placebo-treated patients on anxiety symptoms (measured by Hamilton Anxiety Scale total score), on patient functioning (measured by the Sheehan Disability Scale Global Functional Impairment Score and across all Sheehan Disability Scale domains), and on all VAS pain items. Patients achieving remission at endpoint, and patients with lower scores on the Clinical Global Impression of Improvement and Patient Global Impression of Improvement scales had greater improvement in VAS pain severity scores. These results suggest that in patients with GAD who present with clinically significant pain symptoms, duloxetine is effective in reducing anxiety symptoms, pain severity, and in improving patient functioning. Depression and Anxiety 0:1–11, 2007. © 2007 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]

To examine the long-term safety, tolerability, and effectiveness of duloxetine in the treatment of major depressive disorder in a naturalistic study design meant to mimic clinical practice. Data were from the long-term, open-label, extension phase that followed a 12-week acute-treatment, multicenter study of adult outpatients with major depressive disorder. After the first week of the acute phase, all patients were treated with at least 60 mg daily duloxetine, which could be titrated to a maximum dose of 120 mg daily. Outcome measures were collected at monthly visits and included spontaneously reported adverse events, weight, vital signs, and the 17-item Hamilton Depression Rating scale. Seventy-two of the 177 (40.7%) patients who entered the extension phase of this study completed the study. The mean duration of participation in the extension was 305 days, with total exposure ranging from 68 to 707 days. Of the 177 patients who entered the extension, only 12 or 13 (7.0%) showed clinically significant worsening of depression that led to study discontinuation. The mean 17-item Hamilton Depression Rating scale score remained below 7 throughout the extension. A total of 21/177 patients (11.9%) discontinued due to adverse events during extension treatment. The adverse events causing discontinuation during the extension, with the exception of weight gain, were generally not unique to the extension phase, with 11/21 patients (52.0%) discontinuing due to adverse events that were first reported during acute treatment. Weight gain was reported as a reason for discontinuation during extension treatment in 4/177 (2.3%) patients. In this open-label study, efficacy was maintained for most patients. The adverse events causing discontinuation during the extension phase were generally not unique to the extension phase. Few patients experienced significant weight gain. Depression and Anxiety 0:1–8, 2007. © 2007 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]

The evaluation of new drug entities with specific modes of action may be hampered by rigid diagnostic classification systems and patient selection processes that do not focus on the anticipated symptomatic, behavioral, and functional outcomes to be achieved. Patients enrolled in central nervous system (CNS) clinical trials may present with a heterogeneous group of symptoms representing several syndromes or subtypes, subsumed under the same diagnosis in the DSM-IV classification system. As a result, enrolled patients may not have the valid illness characteristics of interest to the particular study. We propose that clinical drug development needs to focus on the primary nosological entity likely to be affected by a new drug entity's mode of action. Ideally, a valid patient will have the acute primary symptoms that the novel drug is supposed to influence. In this article, we propose operational criteria to delineate a more symptom-specific and ecologically valid approach to the identification of the valid patient for clinical trials. [ABSTRACT FROM AUTHOR]

Background: Recent studies suggest that the treatment of major depressive disorder (MDD) with newer antidepressant drugs that simultaneously enhance norepinephrine and serotonin neurotransmission might result in higher response and remission rates than the selective serotonin reuptake inhibitors (SSRIs). The goal of our work was to compare response rates among patients with MDD treated with either of these two broad categories of antidepressant drugs. Methods: Medline/Pubmed, EMBase, clinical trial registries, program syllabi from major psychiatric meetings held since 1995, and documents from relevant pharmaceutical companies were searched for double-blind, randomized trials comparing a newer serotonergic-noradrenergic antidepressant drug (venlafaxine, duloxetine, milnacipran, mirtazapine, mianserin, or moclobemide) with an SSRI for MDD. Results: Ninety-three trials (n = 17,036) were combined using a random-effects model. Treatment with serotonergic + noradrenergic antidepressant drugs was more likely to result in clinical response than the SSRIs (risk ratio [RR] = 1.059; response rates 63.6% versus 59.3%; p = .003). There was no evidence for heterogeneity among studies combined (p = 1.0). Excluding each individual agent did not significantly alter the pooled RR. With the exception of duloxetine (.985), RRs for response for each individual serotonergic + noradrenergic antidepressant drug were within the 95% confidence interval of the pooled RR (1.019–1.101). Conclusions: Serotonergic-noradrenergic antidepressant drugs seem to have a modest efficacy advantage compared with SSRIs in MDD. With the Number Needed to Treat (NNT) statistic as one indicator of clinical significance, nearly 24 patients would need to be treated with dual-action antidepressant drugs instead of SSRIs in order to obtain one additional responder. This difference falls well below the mark of NNT = 10 suggested by the United Kingdom’s National Institute of Clinical Excellence but nonetheless might be of public health relevance given the large number of depressed patients treated with SSRI /serotonin-norepinephrine reuptake inhibitor (SNRI) antidepressant drugs. Further research is needed to examine whether larger differences between classes of antidepressant drugs might exist in specific MDD sub-populations or for specific MDD symptoms. [Copyright &y& Elsevier]

Abstract: Distinct factors have been identified as potential predictors of antidepressant treatment response. Although autonomic function changes have been described in depressive subjects, their value as predictors of antidepressant response has not been systematically evaluated. Eight un-medicated patients with major depressive order (MDD) have their skin conductance (SC) and heart rate variability (HRV) measured at basal condition and during four induced emotional states: happy, angry, sad and neutral. The high frequency (HF) and low frequency (LF) power parameters of HRV were assessed. Subsequently, patients were treated with fluoxetine 20 mg/day for 8 weeks. The antidepressant response was measured with the Beck Depression Inventory (BDI). The BDI percentage reduction correlated significantly with HRV responses during sad condition in LF power, and during happy condition with LF/HF ratio. The BDI percentage reduction also correlated significantly with HR responses in happy and in neutral conditions, and also with SC responses in neutral condition. These preliminary findings indicate that automatic responses to induced emotions may predict antidepressant response in MDD patients. Confirmatory studies are warranted. [Copyright &y& Elsevier]

Abstract: Introduction: Clinicians routinely ask patients with major depressive disorder (MDD) about their family history. It is unknown, however, if patients who report a positive family history differ from those who do not. This study compared the demographic and clinical features of a large cohort of treatment-seeking outpatients with non-psychotic MDD who reported that they did or did not have at least one first-degree relative who had either MDD or bipolar disorder. Methods: Subjects were recruited for the STAR∗D multicenter trial. Differences in demographic and clinical features for patients with and without a family history of mood disorders were assessed after correcting for age, sex, race, and ethnicity. Results: Patients with a family history of mood disorder (n =2265; 56.5%) were more frequently women and had an earlier age of onset of depression, as compared to those without such a history (n =1740; 43.5%). No meaningful differences were found in depressive symptoms, severity, recurrence, depressive subtype, or daily function. Conclusions: Women were twice as likely as men to report a positive family history of mood disorder, and a positive family history was associated with younger age of onset of MDD in the proband. Consistent with prior research, early age of onset appears to define a familial and, by extension, genetic subtype of major depressive disorder. [Copyright &y& Elsevier]

Objective: The purpose of this study was to compare the effectiveness and tolerability of tranylcypromine and combination treatment with extended-release venlafaxine and mirtazapine in patients with treatment-resistant major depression whose current depressive episode had not responded adequately to treatment in three prior prospective medication trials. Method: Adult outpatients with nonpsychotic major depressive disorder who had not achieved remission or had withdrawn from treatment because of intolerance in three previous prospective medication trials were randomly assigned to receive open-label treatment with either tranylcypromine (N=58) or extended-release venlafaxine plus mirtazapine (N=51). The primary outcome measure was whether patients achieved remission, which was defined as a score ≤7 at exit on the 17-item Hamilton Depression Rating Scale (HAM-D). The HAM-D was administered by telephone by raters to whom treatment was masked. Results: Remission rates were not significantly different between the two treatment groups (6.9% for the tranylcypromine group and 13.7% for the venlafaxine plus mirtazapine group). The mean daily dose at exit for tranylcypromine was 36.9 mg (SD=18.5); for venlafaxine, 210.3 mg (SD=95.2); and for mirtazapine, 35.7 mg (SD=17.6). Tranylcypromine was associated with significantly less symptom reduction and greater attrition due to intolerance. Conclusions: Remission rates were modest for both the tranylcypromine group and the extended-release venlafaxine plus mirtazapine group, and the rates were not statistically different between groups. The lower side effect burden, lack of dietary restrictions, and ease of use of venlafaxine and mirtazapine suggest that this combination may be preferred over tranylcypromine for patients with highly treatment-resistant depression who have not benefited adequately from several prior treatments. [ABSTRACT FROM AUTHOR]

Objective Pattern analysis has identified two types of response patterns to antidepressants: “true drug” response (TDR) and “placebo pattern” response (PPR). This study examines the relationship between cognitive factors and TDR and PPR to fluoxetine. Methods We assessed 310 outpatients meeting DSM-III-R criteria for major depressive disorder (MDD) who were enrolled in an 8-week open trial of fluoxetine 20 mg/day. Response patterns were determined using the clinical global impressions-improvement (CGI-I). We administered the following self-rated scales to all patients at the baseline visit and at endpoint: perceived stress scale (PSS), cognitions questionnaire (CQ), Beck hopelessness scale (BHS) and dysfunctional attitudes scale (DAS). Results One hundred and thirty-four patients had TDR, 66 patients had PPR, and 110 patients were non-responders (NR). Demographic variables and severity of depression at baseline (HAMD-17) were not significantly different between the two response pattern groups. We compared cognitive factors before and after treatment across patients with TDR and PPR, and there were no significant differences at baseline in CQ, PSS, BHS, and DAS scores. At endpoint, outpatients with PPR had significantly lower scores on the PSS (p < 0.001) compared to the patients with TDR, even after adjusting for multiple comparisons and severity of depression at endpoint. Conclusions Significant differences in cognitive/psychological factors, specifically lower post-treatment perceived stress, accompany “placebo” pattern of response to antidepressant treatment and differentiate it from “true drug” response pattern, as defined by pattern analysis. Copyright © 2006 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Objective: The study aimed to assess the antidepressant efficacy and tolerability of adjunctive ropinirole in outpatients with treatment-resistant depression (TRD).Method: The study sample consisted of patients with a major depressive episode (diagnosed according to DSM-IV criteria) and TRD. Ropinirole 0.25 to 1.5 mg daily was added to tricyclic antidepressants or selective serotonin reuptake inhibitors. We conducted assessments at baseline and at weeks 2, 4, 8, 12, and 16. We defined response as a 50% or greater reduction of the Montgomery-Asberg Depression Rating Scale (MADRS) total score plus a score of 1 ("very much improved") or 2 ("much improved") on the Clinical Global Impression of Improvement scale at endpoint. Tolerability was monitored with the Dosage Record Treatment Emergent Symptom Scale.Results: Seven patients had major depressive disorder, and 3 had bipolar II disorder. The mean maximum dose of ropinirole was 1.33 mg daily. Mean (SD) scores on the MADRS decreased from 29.6 (7.6) at baseline to 16.9 (12.1) at endpoint (P < 0.02). At endpoint, 4 of 10 (40%) patients were responders. Two patients discontinued ropinirole because of dizziness.Conclusions: These pilot data suggest that, in selected cases of TRD, ropinirole augmentation of antidepressants is effective and relatively well tolerated. [ABSTRACT FROM AUTHOR]

Major depressive disorder (MDD) is a highly prevalent disease, frequently characterized by recurrent or chronic course, and by comorbidity with other medical illnesses. The lifetime prevalence of MDD ranges up to 17% in the general population, and it almost doubles in patients with diabetes (9–27%), stroke (22–50%), or cancer (18–39%). Moreover, MDD worsens the prognosis, quality of life, and treatment compliance of patients with comorbid medical illnesses. Similar to what is observed with other comorbid illnesses, MDD worsens the outcome of kidney disease patients by increasing both morbidity and mortality. Treatment of depressive symptoms in renal failure patients increases medication acceptability and therefore potentially improves the overall patient outcome. The issue of the safety of antidepressant treatment in subjects with renal failure is frequently counterbalanced by the risks associated with depression comorbidity, provided that antidepressants with a low volume of distribution and low protein binding are prescribed, and most important, at low initial doses. Screening for CYP isoenzyme interactions with current medications is also recommended before starting antidepressant treatment. [ABSTRACT FROM AUTHOR]

Background. Research studies have focused attention on the importance of the comorbidity of personality disorders and depression. Methods. The present review examines seven potential explanations for the overlap to clarify the nature of the relationship, if any, between depression and personality disorder diagnoses. Results. There may be many explanations for the potential overlap of personality disorders (PD) and major depressive disorder (MDD). For example, the distinction between states and traits may not be as clear and definitive as suggested in the DSM-IV. In some cases, depression may influence personality pathology, and may even lead to personality disorders. In other cases, personality disorders may lead to MDD. Conclusion. Further research may clarify the nature of the relationship, if any, between depression and personality disorder diagnoses, as well as the relationship between comorbidity and treatment response. [ABSTRACT FROM AUTHOR]

Background: Anger attacks, characterized by sudden episodes of intense anger with autonomic arousal, have been described in patients with major depressive disorder (MDD). This study compared the prevalence and clinical significance of anger attacks in unipolar versus bipolar depression. Methods: Using the questionnaire of Fava et al. [Psychopharmacol. Bull. 27(3) (1991) 275–279], we assessed rates of anger attacks among outpatients with MDD (n=50) or bipolar disorder (BPD) (n=29) who were currently in a pure depressive episode. Results: Anger attacks were significantly more common among bipolar (62%) than unipolar (26%) depressed individuals. In a multiple logistic regression, the presence of anger attacks emerged as a significant predictor of bipolarity. Limitations: This preliminary finding should be confirmed in a larger sample. Conclusions: These results suggest that anger attacks may be a common feature of bipolar depression. [Copyright &y& Elsevier]

Background: To mitigate the psychological burdens of COVID-19 for frontline clinicians (FCs), we adapted an existing evidence-based resiliency program, Stress Management and Resilience Training Relaxation Response Program (SMART-3RP), for FCs. This analysis explores moderators of stress coping to determine which subgroups of FCs benefited most from SMART-3RP.Methods: 102 FCs from Mass General Brigham hospitals engaged in the adapted SMART-3RP. Assessments were completed at group entry (Week 0) and completion (Week 4). The primary outcome was stress coping, and we examined 15 possible baseline moderators. We fit linear mixed effects regression models and assessed potential baseline moderators using a likelihood ratio test. We report model-based estimates and confidence intervals for each moderator-by-time interaction (i.e., differential effect), where positive/negative values indicate more/less improvement in average perceived stress coping.Results: Stress coping improved from Week 0 to Week 4 (mean improvement [95% CI] = 0.9 [0.6 to 1.2]). FCs with higher anxiety (differential effect [95% CI] = 0.3 [0.1 to 0.4]), depression (0.4 [0.2 to 0.6]), and loneliness (0.4 [0.1 to 0.6]), but lower levels of mindfulness (CAMS-Rfocus: 1.0 [0.4 to 1.6]; CAMS-Raccept: 1.3 [0.7 to 2.0]) and self-compassion (0.4, [0.1 to 0.8]) at baseline experienced greater benefits in perceived stress coping from the SMART-3RP. Baseline health uncertainty along with sociodemographic and work characteristics did not moderate stress coping.Discussion: Results highlight particular sub-populations of FCs that may benefit more from a stress management intervention, especially during emergency responses (e.g., COVID-19 pandemic). [ABSTRACT FROM AUTHOR]

Major depressive disorder is a common, recurrent, disabling and costly disorder that is often severe and/or chronic, and for which non-remission on guideline concordant first-line antidepressant treatment is the norm. A sizeable percentage of patients diagnosed with MDD do not achieve full remission after receiving antidepressant treatment. How to understand or approach these 'refractory', 'TRD' or 'difficult to treat' patients need to be revisited. Treatment resistant depression (TRD) has been described elsewhere as failure to respond to adequate treatment by two different antidepressants. This definition is problematic as it suggests that TRD is a subtype of major depressive disorder (MDD), inferring a boundary between TRD and depression that is not treatment resistant. However, there is scant evidence to suggest that a discrete TRD entity exists as a distinct subtype of MDD, which itself is not a discrete or homogeneous entity. Similarly, the boundary between TRD and other forms of depression is predicated at least in part on regulatory and research requirements rather than biological evidence or clinical utility. This paper aims to investigate the notion of treatment failure in order to understand (i) what is TRD in the context of a broader formulation based on the understanding of depression, (ii) what factors make an individual patient difficult to treat, and (iii) what is the appropriate and individualised treatment strategy, predicated on an individual with refractory forms of depression? Expert contributors to this paper were sought internationally by contacting representatives of key professional societies in the treatment of MDD – World Federation of Societies for Biological Psychiatry, Australasian Society for Bipolar and Depressive Disorders, International Society for Affective Disorders, Collegium Internationale Neuro-Psychopharmacologium and the Canadian Network for Mood and Anxiety Treatments. The manuscript was prepared through iterative editing. The concept of TRD as a discrete subtype of MDD, defined by failure to respond to pharmacotherapy, is not supported by evidence. Between 15 and 30% of depressive episodes fail to respond to adequate trials of 2 antidepressants, and 68% of individuals do not achieve remission from depression after a first-line course of antidepressant treatment. Failure to respond to antidepressant treatment, somatic therapies or psychotherapies may often reflect other factors including; biological resistance, diagnostic error, limitations of current therapies, psychosocial variables, a past history of exposure to childhood maltreatment or abuse, job satisfaction, personality disorders, co-morbid mental and physical disorders, substance use or non-adherence to treatment. Only a subset of patients not responding to antidepressant treatment can be explained through pharmacokinetic or pharmacodynamics mechanisms. We propose that non remitting MDD should be personalised, and propose a strategy of 'deconstructing depression'. By this approach, the clinician considers which factors contribute to making this individual both depressed and 'resistant' to previous therapeutic approaches. Clinical formulation is required to understand the nature of the depression. Many predictors of response are not biological, and reflect a confluence of biological, psychological, and sociocultural factors, which may influence the illness in a particular individual. After deconstructing depression at a personalised level, a personalised treatment plan can be constructed. The treatment plan needs to address the factors that have contributed to the individual's hard to treat depression. In addition, an individual with a history of illness may have a lot of accumulated life issues due to consequences of their illness, and these should be addressed in a recovery plan. A 'deconstructing depression' qualitative rubric does not easily provide clear inclusion and exclusion criteria for researchers wanting to investigate TRD. MDD is a polymorphic disorder and many individuals who fail to respond to standard pharmacotherapy and are considered hard to treat. These patients are best served by personalised approaches that deconstruct the factors that have contributed to the patient's depression and implementing a treatment plan that adequately addresses these factors. The existence of TRD as a discrete and distinct subtype of MDD, defined by two treatment failures, is not supported by evidence. [ABSTRACT FROM AUTHOR]

• Patients with resistant depression and suicidal ideation got a single dose of ketamine or placebo. • Those who received ketamine had lower suicide scores 30 days after the infusion. • However, recurrence of suicidal ideation was extensive in both groups. • Ketamine may have a role as an adjunct to standard treatments in this patient group. This study aimed to assess the effect of a single infusion of intravenous (IV) ketamine on suicidal ideation in patients with treatment-resistant depression (TRD). Patients with TRD were randomized in a double-blind fashion to a single infusion of IV ketamine or IV midazolam placebo. Suicidal ideation was measured using the Montgomery-Asberg Depression Rating Scale (MADRS) suicide item at 3, 5, 7, 14 and 30 days post infusion. Clinically significant suicidal ideation was defined as a MADRS suicide item score ≥2. Forty patients who received IV ketamine and 16 who received IV midazolam had suicide item scores of ≥2 at baseline (IV ketamine group mean 2.90±0.74; IV midazolam group 2.69±0.70). The mean suicide scores of these groups differed significantly from each other on day 30; the IV ketamine group had a lower mean score than controls (2.03±1.59 vs. 3.00±1.41, t -test p = 0.049; Hedges' g 0.71). Among patients with a suicide score of ≥2 at baseline and <2 at day 3, the two groups did not differ significantly on mean scores changes at days 3, 5, 7, 14 or 30. Recurrence of suicidal ideation was extensive in both treatment groups. A single infusion of IV ketamine may reduce suicidal ideation in TRD out to 30 days post infusion, but early anti-suicidal effects appear to diminish rapidly. This post-hoc analysis was not powered to compare different doses of ketamine. A single infusion of IV ketamine might have a role as an adjunct to standard treatments in patients with TRD and suicidal ideation. Trial registration: NCT01920555. [ABSTRACT FROM AUTHOR]

The frequent comorbidity of anxiety disorders and mood disorders has been documented in previous studies. However, it remains unclear whether specific anxiety traits or disorders are more closely associated with unipolar major depression (MDD) or bipolar disorder (BPD). We sought to examine whether MDD and BPD can be distinguished by their association with specific types of anxiety comorbidity. Individuals with a primary lifetime diagnosis of either bipolar disorder (N=122) or major depressive disorder (N=114) received diagnostic assessments of anxiety disorder comorbidity, and completed questionnaires assessing anxiety sensitivity and neuroticism. The differential association of these anxiety phenotypes with MDD versus BPD was examined with multivariate modeling. Panic disorder and generalized anxiety disorder (GAD) specifically emerged amongst all the anxiety disorders as significantly more common in patients with BPD than MDD. After controlling for current mood state, anxiety sensitivity and neuroticism did not differ by mood disorder type. This study supports prior research suggesting a specific panic disorder–bipolar disorder connection, and suggests GAD may also be differentially associated with BPD. Further research is needed to clarify the etiologic basis of anxiety disorder/BPD comorbidity and to optimize treatment strategies for patients with these co-occurring disorders. [Copyright &y& Elsevier]

Background: Emerging data suggest cannabis use is a component cause of psychotic disorders; however, the sequence of processes accounting for this association is poorly understood. Some clues have come from studies in laboratory settings showing that acute cannabis intoxication is associated with subclinical hallucinations and delusional thinking, i.e., "psychotic experiences". Although psychotic experiences are relatively common, those that are severe and distressing are linked to an increased risk of developing a psychotic disorder. This study aimed to investigate the association between the frequency of cannabis use and psychotic experiences in young adults.Methods: 1034 U.S. college students completed questionnaires to assess: cannabis use in the past week, delusional ideation (Peters Delusions Inventory), hallucinations (Launay-Slade Hallucinations Scale-Extended), and depression (Beck Depression Inventory).Results: Participants reporting higher rates of weekly cannabis use were more likely to report hallucinatory experiences and delusional ideation. The relationship between cannabis use and hallucinatory experiences, but not the relationship between cannabis use and delusional ideation, remained significant after controlling for levels of depression. Moreover, those who reported greater amounts of cannabis use had more distressing delusional ideas, that were held with more conviction.Conclusions: Cannabis use is linked to the presence of subclinical hallucinations and delusional ideation in U.S. college students. [ABSTRACT FROM AUTHOR]

For people with current and remitted substance use disorder (SUD), the COVID-19 pandemic increases risk for symptom exacerbation and relapse through added stressors and reduced service access. In response, mutual-help groups and recovery community organizations have increased access to online recovery support meetings. However, rigorous studies examining online recovery support meeting participation to inform best practices have not yet been conducted. In the absence of such studies, a review of relevant literature, considered in context of potential barriers and drawbacks, suggests the risk-to-benefit ratio is favorable. Particularly given limited in-person SUD service access resulting from COVID-19 precautions, online recovery support meetings may help mitigate a key public health problem during an ongoing, public health pandemic. [ABSTRACT FROM AUTHOR]

Objectives: Clinical trials in psychiatry frequently report results from lengthy, comprehensive assessments to characterize a subject emotionally, cognitively, and behaviorally before and after treatment. However, the potential treatment implications of these results and how they translate into clinical practice remain unclear. Conversely, the Clinical Global Impressions (CGI) scales are quick, intuitive assessments used to assess the functional impact of a treatment in clinically relevant terms. The objectives of the present analyses are to translate scores from comprehensive assessments of symptom severity and functional impairment into clinically meaningful CGI levels. Methods: These post-hoc analyses use data integrated from four pivotal Phase 3 trials in attention-deficit/hyperactivity disorder (ADHD) in children and adolescents treated with the novel nonstimulant SPN-812 (Viloxazine Extended-Release). In this study, we evaluated the ADHD Rating Scale-5 (ADHD-RS-5) and Weiss Functional Impairment Rating Scale-Parent (WFIRS-P), assessments of symptom severity and functional impairment, respectively, by linking these scales with the CGI scales at baseline and end of study. Results: For participants that improved, a one-level change on the CGI-Improvement (CGI-I) was associated with a 10-15-point change on the ADHD-RS-5, and a 0.2-0.5-point change on the WFIRS-P. On the CGI-I, ratings of much improved and very much improved were associated with a percent score decrease (i.e., improvement) of ∼55% and 80% on the ADHD-RS-5 and ∼40% and 70% on the WFIRS-P, respectively. Differences between children and adolescents were minor and are unlikely to be clinically meaningful. Conclusion: These post-hoc analyses provide clinically meaningful benchmarks for the interpretation of scores on the ADHD-RS-5 and WFIRS-P in terms of CGI evaluations in subjects with ADHD. These results may be useful for physicians seeking to understand a treatment's potential impact on their ADHD patients or for researchers looking to define their study results within a clinically relevant context. Data are from clinical trials NCT03247530, NCT03247543, NCT03247517, and NCT03247556. [ABSTRACT FROM AUTHOR]

Objective: To identify data-driven subgroups in Major Depressive Disorder (MDD) in order to elucidate underlying neural correlates and determine if these subgroups have utility in predicting response to antidepressant versus placebo.Methods: Using 27 clinical measures at baseline of Establishing Moderators and Biosignatures of Antidepressant Response for Clinical Care for Depression (EMBARC) study, participants with MDD (n=244) were sub grouped using principal component (PC) analysis. Baseline-to-week-8 changes in depression severity with sertraline versus placebo were compared in these subgroups. Resting-state functional connectivity of these subgroups were compared to those of healthy controls (n=38).Results: Eight subgroups were identified from four PCs: (PC1) severity of depression-associated symptoms, (PC2) sub-threshold mania and anhedonia, (PC3) childhood trauma, medical comorbidities, and sexual dysfunction, and (PC4) personality traits of openness and agreeableness. Participants with high childhood trauma experienced greater improvement with sertraline (Cohen's d=0.87), whereas those with either higher levels of subthreshold hypomanic symptoms (Cohen's d=0.67) or with lower levels of agreeableness and openness experienced greater improvement with placebo (Cohen's d=0.71). Participants with high childhood trauma had greater connectivity between salience and dorsal attention networks, whereas those with higher levels of subthreshold hypomanic symptoms and lower levels of agreeableness and openness had greater connectivity within limbic network and that of visual network with hippocampus and dorsal attention network.Conclusion: Assessing history of childhood trauma, presence of subthreshold hypomanic symptoms and personality traits may help to identify subgroups of patients with MDD who respond differentially to sertraline or placebo and have distinct neural signatures. [ABSTRACT FROM AUTHOR]

Previous studies have investigated the role of inflammatory markers in suicidality of patients with major depressive disorder (MDD) or panic disorder (PD). However, few studies have investigated associations between serum inflammatory cytokine levels and suicidality. We hypothesized that MDD and PD status might be significantly associated with serum inflammatory cytokines and that we could predict levels of improvement in suicide ideation intensity using serum inflammatory biomarkers in patients with MDD and PD. For this study, 41 patients with MDD, 52 patients with PD, and 59 healthy control (HC) subjects were enrolled. Psychological measurements and serum inflammatory markers such as interleukin (IL) −6, −10, interferon (IFN)-γ, tumor necrosis factor (TNF)-α, and C reactive protein (CRP) were examined. A total of five visits were completed during 12 weeks. After controlling for confounding factors, log-transformed IL-6 (ln_IL-6) at baseline (MDD: 0.297 ± 0.626; PD: 0.342 ± 0.723; HC: −0.121 ± 0.858; p = 0.007, >0.0017, 0.05/30) and mean ln_IL-6 (MDD: 0.395 ± 0.550, PD: 0.249 ± 0.544, HC: −0.139 ± 0.622, p = 0.002, >0.0017, 0.05/30) levels were trends towards significantly higher in patients with MDD and PD than in HC. In MDD patients, a higher level of basal ln_TNF-α was a significant predictor of ΔSSI (changes in SSI scores between baseline and week 12) even after controlling for changes of depression symptoms and baseline SSI scores (standardized β = 0.541, p = 0.002 < 0.0028, 0.05/18). In conclusion, we could predict ΔSSI using baseline inflammatory biomarkers for patients with MDD. [ABSTRACT FROM AUTHOR]

Tikslai. Šios rekomendacijos sukurtos siekiant užtikrinti pacientų, sergančių depresiniu sutrikimu (DS) (angl. major depressive disorder, MDD) saugumą ir padėti stebėti ir valdyti gydymo antidepresantais nepageidaujamus poveikius. Rekomendacijomis siekiama informuoti gydytojus apie su gydymu susijusias rizikas ir apie metodus, kaip šias rizikas sumažinti. Metodai. Ekspertai bendraautoriai buvo pakviesti kontaktuojant su pagrindinių suinteresuotųjų šalių tarptautinių profesinių draugijų atstovais, dirbančiais DS gydymo srityje (ASBDD, CANMAT, WFSBP ir ISAD). Rankraštis buvo parengtas ir redaguotas, kol pasiektas galutinis susitarimas. Rezultatai. Tinkamas rizikos įvertinimas prieš farmakoterapiją ir saugumo stebėjimas farmakoterapijos metu yra esminiai veiksniai, kad sušvelninti nepageidaujamus reiškinius, optimizuoti vaistinio preparato teikiamą naudą, įvertinti ir valdyti nepageidaujamus reiškinius, kai jie atsiranda. Farmakoterapijos rizikos veiksniai skiriasi atsižvelgiant į individualias paciento savybes ir skiriamą gydymo režimą. Rizikos veiksniai turi būti atidžiai įvertinti prieš pradedant farmakoterapiją ir pasirenkamos tinkamos individualios gydymo taktikos. Kai kurie antidepresantai siejami su specifinėmis saugumo problemomis, kurios turi būti išspręstos. Išvados. Antidepresantų sukeliamų nepageidaujamų reiškinių gydymui būtinas tinkamas vertinimas ir stebėjimas, siekiant pagerinti rizikos ir naudos santykį ir pagerinti klinikinius rezultatus. [ABSTRACT FROM AUTHOR]

Background: Little is known about the long-term outcomes of repeated ketamine infusions for depression. We conducted a retrospective chart review to investigate outcomes of maintenance intravenous ketamine treatment at Massachusetts General Hospital.Methods: Eighty-five patients with treatment-resistant depression (TRD) who started intravenous ketamine from October 2018 to November 2019 were examined. Symptom severity was evaluated with the 16-item Quick Inventory of Depressive Symptomatology-Self Report scale (QIDS-SR16) at every visit prior to administration. The initial ketamine dose was usually 0.5 mg/kg infused over 40 min. Intravenous ketamine was administered twice-weekly for three weeks in an induction phase, followed by maintenance with a variable administration schedule and dose. Response was defined as a ≥50% reduction in total QIDS-SR16 score from baseline.Results: Forty (47.1%) of the 85 patients who started treatment discontinued during or right after the induction phase; 3 (3.5%) were still on induction at the time of this report, and 42 (49.4%) transitioned to maintenance after completing induction. Among these patients, 14 (16.5%) discontinued during maintenance and 28 (32.9%) continued on maintenance. The mean ketamine dosage during maintenance was 0.91±0.28 mg/kg. Fifteen out of 82 patients (18.3%) responded to induction treatment and 6 (7.3%) remained in responder status at the time of data analysis during maintenance. Three patients discontinued ketamine due to side-effects.Conclusions: Despite the apparently low response rate in QIDS-SR16 scores and considerable out-of-pocket costs, almost half of real-world outpatients with TRD decided to continue with maintenance ketamine treatment due to perceived significant improvement. [ABSTRACT FROM AUTHOR]

Standard guidelines recommend selective serotonin reuptake inhibitors as first-line antidepressants for adults with major depressive disorder, but success is limited and patients who fail to benefit are often switched to non–selective serotonin reuptake inhibitor agents. This study investigated whether brain- and behavior-based markers of reward processing might be associated with response to bupropion after sertraline nonresponse. In a two-stage, double-blinded clinical trial, 296 participants were randomized to receive 8 weeks of sertraline or placebo in stage 1. Individuals who responded continued on another 8-week course of the same intervention in stage 2, while sertraline and placebo nonresponders crossed over to bupropion and sertraline, respectively. Data from 241 participants were analyzed. The stage 2 sample comprised 87 patients with major depressive disorder who switched medication and 38 healthy control subjects. A total of 116 participants with major depressive disorder treated with sertraline in stage 1 served as an independent replication sample. The probabilistic reward task and resting-state functional magnetic resonance imaging were administered at baseline. Greater pretreatment reward sensitivity and higher resting-state functional connectivity between bilateral nucleus accumbens and rostral anterior cingulate cortex were associated with positive response to bupropion but not sertraline. Null findings for sertraline were replicated in the stage 1 sample. Pretreatment reward sensitivity and frontostriatal connectivity may identify patients likely to benefit from bupropion following selective serotonin reuptake inhibitor failures. Results call for a prospective replication based on these biomarkers to advance clinical care. [ABSTRACT FROM AUTHOR]

Vasopressin 1B (V 1B) receptor has a pivotal role in the regulation of the hypothalamus-adrenal-pituitary axis, and V 1B receptor antagonists have shown efficacy in a number of preclinical models of depression. The efficacy and safety of, TS-121 (active ingredient: THY1773), a novel V 1B receptor antagonist, was investigated in patients with major depressive disorder (MDD) who had an inadequate response to current antidepressant therapy. In a randomized, double-blind, placebo-controlled phase 2 study, 51 MDD patients (43 of whom completed the study) were randomly assigned to either TS-121 10 mg, 50 mg or placebo for 6 weeks treatment period. The primary endpoint was change from baseline on the Montgomery-Åsberg Depression Rating Scale (MADRS) score at week 6. The study was conducted from Jul 2017 to Dec 2018. The changes from baseline in MADRS score at week 6 (Least Square Mean [95% Confidence interval] were: TS-121 10 mg (-9.0 [-13.9, -4.1]), TS-121 50 mg (-9.0 [-13.4, -4.5]), and placebo (-6.4 [-10.7, -2.2]). TS-121 groups showed greater numerical reductions in MADRS score change from baseline compared to placebo, though these reductions did not achieve statistical significance. Similar trends of numerically greater improvements in TS-121 groups were observed across secondary endpoints. Higher baseline urinary and hair cortisol levels were associated with a greater separation between TS-121 groups and the placebo group in the primary endpoint. These findings, combined with favorable safety and tolerability, warrant further investigation of TS-121 in an adequately powered study in patients with MDD. • TS-121 is a novel V 1B receptor antagonist whose target indication is MDD. • Non-significant improvements in efficacy assessments were noted in TS-121 groups. • TS-121 may be most efficacious in MDD patients with HPA axis hyperactivity. • No apparent dose related safety trends were noted in any of safety assessments. [ABSTRACT FROM AUTHOR]

Background: Predicting patients who convert to bipolar disorder is important for deciding appropriate treatment for young adults with major depressive disorder (MDD). We focused on the predictive factors of bipolar conversion in a large population of young adults.Methods: A nationwide, population-based electronic medical records database from the Health Insurance Review & Assessment service of South was used to investigate adjusted hazard ratio (HR) of each potential predictor of the bipolar converter group compared to the non-converter group using Cox regression analysis including age of onset, medication use, clinical features, comorbid disorders, admission, self-harm, and negative life events in childhood.Results: Among 291,721 subjects who were initially diagnosed with MDD in young adults, 12,376 subjects experienced diagnostic conversion to bipolar disorder. The cumulative incidence was 6.46% during the average 3.26 years of follow-up. Among the predictive factors during diagnosis of MDD, antipsychotic use (HR 3.12, 95%CI, 2.99-3.26, p < 0.0001) and mood stabilizers (HR 2.45, 95%CI, 2.35-2.55, p < 0.0001) showed the strongest association with diagnostic conversion to bipolar disorder. In addition, female sex, younger age of onset, mood stabilizer use, recurrent depression, psychotic symptoms, and admission to a psychiatric ward during diagnosis of MDD were also associated with diagnostic conversion to bipolar disorder.Conclusion: In young adults with MDD, antipsychotic and mood stabilizer use during diagnosis of MDD were the strongest predictive factors with diagnostic conversion to bipolar disorder during follow-up. If young adults with MDD need antipsychotics or mood stabilizer, patients should be carefully evaluated for possibility of bipolar disorder. [ABSTRACT FROM AUTHOR]

Objective: Major depressive disorder is associated with aberrant resting-state functional connectivity across multiple brain networks supporting emotion processing, executive function, and reward processing. The purpose of this study was to determine whether patterns of resting-state connectivity between brain regions predict differential outcome to antidepressant medication (sertraline) compared with placebo.Methods: Participants in the Establishing Moderators and Biosignatures of Antidepressant Response in Clinical Care (EMBARC) study underwent structural and resting-state functional MRI at baseline. Participants were then randomly assigned to receive either sertraline or placebo treatment for 8 weeks (N=279). A region of interest-based approach was utilized to compute functional connectivity between brain regions. Linear mixed-model intent-to-treat analyses were used to identify brain regions that moderated (i.e., differentially predicted) outcomes between the sertraline and placebo arms.Results: Prediction of response to sertraline involved several within- and between-network connectivity patterns. In general, higher connectivity within the default mode network predicted better outcomes specifically for sertraline, as did greater between-network connectivity of the default mode and executive control networks. In contrast, both placebo and sertraline outcomes were predicted (in opposite directions) by between-network hippocampal connectivity.Conclusions: This study identified specific functional network-based moderators of treatment outcome involving brain networks known to be affected by major depression. Specifically, functional connectivity patterns of brain regions between and within networks appear to play an important role in identifying a favorable response for a drug treatment for major depressive disorder. [ABSTRACT FROM AUTHOR]

Background: The optimal dose of S-adenosyl methionine (SAMe) for major depressive disorder (MDD) remains unclear. The objective of this analysis was to address whether a dose increase provided further improvement in cases of insufficient response using data from an existing randomized clinical trial.Methods: Sixty-five patients with MDD who failed to respond to SAMe 1,600 mg/day, escitalopram 10 mg/day, or placebo for 6 weeks were treated with doubled doses of the allocated treatments for the following 6 weeks. Changes in 17-item Hamilton Depression Rating Scale, Inventory of Depressive Symptomatology-Self Rated, and Systematic Assessment for Treatment Emergent Events-Specific Inquiry were compared between the lower and higher dose treatments in each treatment group and among the higher dose treatments of SAMe, escitalopram, and placebo.Results: Various depression severity scores decreased significantly for all three treatment arms during the higher dose treatment. No within-group and between-group differences were found in any of the efficacy measures when comparing the doses and treatments. There was a significant difference in reported abdominal discomfort among patients receiving the higher dose of SAMe (31.3%), compared to escitalopram (8.7%) and placebo (3.8%) (χ2=7.32, p = 0.026).Limitations: The sample size was relatively small. The study duration for dose increase was relatively short.Conclusions: Patients with MDD failing to respond to 1,600 mg/day of SAMe may improve after increasing the dose to 3,200 mg/day, but we cannot rule out the contribution of a placebo effect and time-related improvement. The risk of abdominal discomfort may be increased with higher doses of SAMe. [ABSTRACT FROM AUTHOR]

Background: Subclinical delusional ideas, including persecutory beliefs, in otherwise healthy individuals are heritable symptoms associated with increased risk for psychotic illness, possibly representing an expression of one end of a continuum of psychosis severity. The identification of variation in brain function associated with these symptoms may provide insights about the neurobiology of delusions in clinical psychosis. Methods: A resting-state functional magnetic resonance imaging scan was collected from 131 young adults with a wide range of severity of subclinical delusional beliefs, including persecutory ideas. Because of evidence for a key role of the amygdala in fear and paranoia, resting-state functional connectivity of the amygdala was measured. Results: Connectivity between the amygdala and early visual cortical areas, including striate cortex (V1), was found to be significantly greater in participants with high (n = 43) v. low (n = 44) numbers of delusional beliefs, particularly in those who showed persistence of those beliefs. Similarly, across the full sample, the number of and distress associated with delusional beliefs were positively correlated with the strength of amygdala-visual cortex connectivity. Moreover, further analyses revealed that these effects were driven by those who endorsed persecutory beliefs. Conclusions: These findings are consistent with the hypothesis that aberrant assignments of threat to sensory stimuli may lead to the downstream development of delusional ideas. Taken together with prior findings of disrupted sensory-limbic coupling in psychosis, these results suggest that altered amygdala-visual cortex connectivity could represent a marker of psychosis-related pathophysiology across a continuum of symptom severity. [ABSTRACT FROM AUTHOR]

Background: A link between brain-derived neurotrophic factor (BDNF) expression and the mood regulatory effect of leptin has been suggested in the pathophysiology of major depressive disorder (MDD). We investigated treatment response and pre-treatment leptin and BDNF in patients with MDD and with panic disorder (PD).Methods: We recruited 41 patients with MDD, 52 patients with PD, and 59 matched healthy controls. All subjects completed five visits (at baseline, 2, 4, 8, and 12 weeks), and both MDD and PD patients were treated with standard pharmacotherapy for 12 weeks. Plasma BDNF (pBDNF) and blood leptin levels were obtained along with a 17-item Hamilton Depression Scale rating (HDRS-17) score at every visit.Results: The ratio of pre-treatment pBDNF to leptin was significantly lower in patients with MDD and PD compared to healthy controls (p = 0.024), but was not associated with severity of depressive or anxiety symptoms. Pre-treatment pBDNF:leptin ratio was significantly higher in treatment responders than in non-responders (p = 0.012) in MDD but not in PD. This difference was larger in MDD patients with appetite loss (p = 0.034). In multivariate analysis, pre-treatment pBDNF:leptin ratio was significantly associated with treatment responsiveness (Adjusted Odds Ration [AOR] = 2.50, 95% CI 1.02-6.14) in MDD.Limitation: small sample size; limited information on detailed pharmacological effects.Conclusions: A relatively higher ratio of pre-treatment pBDNF to leptin was associated with greater treatment response in MDD but not in PD. Further research should focus on exploration of a link between BDNF and leptin underlying neuronal plasticity in depression. [ABSTRACT FROM AUTHOR]

Background: While riluzole has been investigated for the treatment of depression, little is known about its longer-term efficacy and optimal treatment duration in treatment-resistant depression (TRD). The objective of this study is to characterize the longer-term outcome of adjunctive riluzole therapy for TRD in an open-label extension of an 8-week acute treatment trial.Methods: The data from 66 patients with TRD who received adjunctive riluzole in a 12-week open-label extension phase were analyzed. Response rates (⩾50% reduction in the Mongomery-Asberg Depression Rating Scale [MADRS] score), relapse rates (a MADRS score of ⩾22 in patients who had previously achieved response), and adverse events were examined in patients who had achieved response at the end of the acute phase and those who had not.Results: Among acute phase responders, the maintained response rate was 66.7% (8/12) and the relapse rate was 8.3% (1/12). In acute phase non-responders, the response rate was 24.1% (13/54). The most commonly reported adverse event was fatigue (9.1%). Three cases were considered serious adverse events; vomiting (n = 1), shortness of breath (n = 1), and aborted suicide attempt (n = 1).Limitations: This longer-term study was open-label and uncontrolled. The sample size was relatively small.Conclusions: Longer-term adjunctive riluzole appears relatively well tolerated and beneficial for maintaining previous response. Additionally, approximately one fourth of patients who did not respond to 8-week antidepressant treatment might respond if treated with riluzole for 12 weeks. Those findings warrant further investigation because adjunctive riluzole could represent an option for treatment of depression when standard antidepressants have failed. [ABSTRACT FROM AUTHOR]