Understanding the biological basis of psychiatric disease: What's next?

Psychiatric disease is one of the greatest health challenges of our time. The pipeline for conceptually novel therapeutics remains low, in part because uncovering the biological mechanisms of psychiatric disease has been difficult. We asked experts researching different aspects of psychiatric disease: what do you see as the major urgent questions that need to be addressed? Where are the next frontiers, and what are the current hurdles to understanding the biological basis of psychiatric disease?

Elevated emotion network connectivity is associated with fluctuations in depression.

Elevated emotion network connectivity is thought to leave people vulnerable to become and stay depressed. The mechanism through which this arises is however unclear. Here, we test the idea that the connectivity of emotion networks is associated with more extreme fluctuations in depression over time, rather than necessarily more severe depression. We gathered data from two independent samples of N = 155 paid students and N = 194 citizen scientists who rated their positive and negative emotions on a smartphone app twice a day and completed a weekly depression questionnaire for 8 wk. We constructed thousands of personalized emotion networks for each participant and tested whether connectivity was associated with severity of depression or its variance over 8 wk. Network connectivity was positively associated with baseline depression severity in citizen scientists, but not paid students. In contrast, 8-wk variance of depression was correlated with network connectivity in both samples. When controlling for depression variance, the association between connectivity and baseline depression severity in citizen scientists was no longer significant. We replicated these findings in an independent community sample (N = 519). We conclude that elevated network connectivity is associated with greater variability in depression symptoms. This variability only translates into increased severity in samples where depression is on average low and positively skewed, causing mean and variance to be more strongly correlated. These findings, although correlational, suggest that while emotional network connectivity could predispose individuals to severe depression, it could also be leveraged to bring about therapeutic improvements.

The role of stress in perinatal depression and anxiety - A systematic review.

Perinatal depression (PND) and anxiety affect around 20% of women, but available pharmacotherapy is not sufficiently effective in 20-60% of them, indicating a need for better understanding of these diseases. Since stress is a significant risk factor for PND, the aim was to examine the role of biological, environmental and psychological stress in PND and anxiety through a systematic literature search. Overall 210 studies were included, among which numerous rodent studies showed that perinatal stress induced depressive-like and anxious behavior, which was associated with HPA-axis alterations and morphological brain changes. Human studies indicated that the relationship between cortisol and perinatal depression/anxiety was not as clear and with many contradictions, although social and psychological stress were clearly positively associated with PND. Finally, oxytocin, synthetic neuroactive steroid and n-3 PUFA diet have been identified as potentially beneficial in the therapy of PND and anxiety, worth to be investigated in the future.

Genetics, epigenetics, and neurobiology of childhood-onset depression: an umbrella review.

Depression is a serious and persistent psychiatric disorder that commonly first manifests during childhood. Depression that starts in childhood is increasing in frequency, likely due both to evolutionary trends and to increased recognition of the disorder. In this umbrella review, we systematically searched the extant literature for genetic, epigenetic, and neurobiological factors that contribute to a childhood onset of depression. We searched PubMed, EMBASE, OVID/PsychInfo, and Google Scholar with the following inclusion criteria: (1) systematic review or meta-analysis from a peer-reviewed journal; (2) inclusion of a measure assessing early age of onset of depression; and (3) assessment of neurobiological, genetic, environmental, and epigenetic predictors of early onset depression. Findings from 89 systematic reviews of moderate to high quality suggest that childhood-onset depressive disorders have neurobiological, genetic, environmental, and epigenetic roots consistent with a diathesis-stress theory of depression. This review identified key putative markers that may be targeted for personalized clinical decision-making and provide important insights concerning candidate mechanisms that might underpin the early onset of depression.

Risk for diagnosis or treatment of mood or anxiety disorders in adults after SARS-CoV-2 infection, 2020-2022.

COVID-19 is associated with increased risks for mood or anxiety disorders, but it remains uncertain how the association evolves over time or which patient groups are most affected. We conducted a retrospective cohort study using a nationwide database of electronic health records to determine the risk of depressive or anxiety disorder diagnoses after SARS-CoV-2 infection by 3-month blocks from January 2020 to April 2022. The study population comprised 822,756 patients (51.8% female; mean age 42.8 years) with COVID-19 and 2,034,353 patients with other respiratory tract infections (RTIs) (53.5% female, mean age 30.6 years). First time diagnoses of depressive or anxiety disorders 14 days to 3 months after infection, as well as new or new plus recurrent prescriptions of antidepressants or anxiolytics, were compared between propensity score matched cohorts using Kaplan-Meier survival analysis, including hazard ratio (HR) and 95% confidence interval (CI). Risk of a new diagnosis or prescription was also stratified by age, sex, and race to better characterize which groups were most affected. In the first three months of the pandemic, patients infected with SARS-CoV-2 had significantly increased risk of depression or anxiety disorder diagnosis (HR 1.65 [95% CI, 1.30-2.08]). October 2021 to January 2022 (HR, 1.12 [95% CI, 1.06-1.18]) and January to April 2022 (HR, 1.08 [95% CI, 1.01-1.14]). Similar temporal patterns were observed for antidepressant and anxiolytic prescriptions, when the control group was patients with bone fracture, when anxiety and depressive disorders were considered separately, when recurrent depressive disorder was tested, and when the test period was extended to 6 months. COVID-19 patients ≥65 years old demonstrated greatest absolute risk at the start of the pandemic (6.8%), which remained consistently higher throughout the study period (HR, 1.20 [95% CI, 1.13-1.27]), and overall, women with COVID-19 had greater risk than men (HR 1.35 [95% CI 1.30-1.40]).

Evaluating the depression state during perinatal period by non-invasive scalp EEG.

Perinatal depression, with a prevalence of 10 to 20% in United States, is usually missed as multiple symptoms of perinatal depression are common in pregnant women. Worse, the diagnosis of perinatal depression still largely relies on questionnaires, leaving the objective biomarker being unveiled yet. This study suggested a safe and non-invasive technique to diagnose perinatal depression and further explore its underlying mechanism. Considering the non-invasiveness and clinical convenience of electroencephalogram for mothers-to-be and fetuses, we collected the resting-state electroencephalogram of pregnant women at the 38th week of gestation. Subsequently, the difference in network topology between perinatal depression patients and healthy mothers-to-be was explored, with related spatial patterns being adopted to achieve the classification of pregnant women with perinatal depression from those healthy ones. We found that the perinatal depression patients had decreased brain network connectivity, which indexed impaired efficiency of information processing. By adopting the spatial patterns, the perinatal depression could be accurately recognized with an accuracy of 87.88%; meanwhile, the depression severity at the individual level was effectively predicted, as well. These findings consistently illustrated that the resting-state electroencephalogram network could be a reliable tool for investigating the depression state across pregnant women, and will further facilitate the clinical diagnosis of perinatal depression.

Neuromelanin-sensitive MRI of the substantia nigra distinguishes bipolar from unipolar depression.

Depression in bipolar disorder (BD-II) is frequently misdiagnosed as unipolar depression (UD) leading to inappropriate treatment and downstream complications for many bipolar sufferers. In this study, we evaluated whether neuromelanin-MR signal and volume changes in the substantia nigra (SN) can be used as potential biomarkers to differentiate BD-II from UD. The signal intensities and volumes of the SN regions were measured, and contrast-to-noise ratio (CNR) to the decussation of the superior cerebellar peduncles were calculated and compared between healthy controls (HC), BD-II and UD subjects. Results showed that compare to HC, both BD-II and UD subjects had significantly decreased CNR and increased volume on the right and left sides. Moreover, the volume in BD-II group was significantly increased compared to UD group. The area under the receiver operating characteristic curve (AUC) for discriminating BD from HC was the largest for the Volume-L (AUC, 0.85; 95% confidence interval [CI]: 0.77, 0.93). The AUC for discriminating UD from HC was the largest for the Volume-L (AUC, 0.76; 95% CI: 0.65, 0.86). Furthermore, the AUC for discriminating BD from UD was the largest for the Volume-R (AUC, 0.73; 95% CI: 0.62, 0.84). Our findings suggest that neuromelanin-sensitive magnetic resonance imaging techniques can be used to differentiate BD-II from UD.

Daytime eating prevents mood vulnerability in night work.

Shift workers have a 25 to 40% higher risk of depression and anxiety partly due to a misalignment between the central circadian clock and daily environmental/behavioral cycles that may negatively affect mood and emotional well-being. Hence, evidence-based circadian interventions are required to prevent mood vulnerability in shift work settings. We used a stringently controlled 14-d circadian paradigm to assess mood vulnerability during simulated night work with either daytime and nighttime or daytime-only eating as compared with simulated day work (baseline). Simulated night work with daytime and nighttime eating increased depression-like mood levels by 26.2% (p-value adjusted using False Discovery Rates, pFDR = 0.001; effect-size r = 0.78) and anxiety-like mood levels by 16.1% (pFDR = 0.001; effect-size r = 0.47) compared to baseline, whereas this did not occur with simulated night work in the daytime-only eating group. Importantly, a larger degree of internal circadian misalignment was robustly associated with more depression-like (r = 0.77; P = 0.001) and anxiety-like (r = 0.67; P = 0.002) mood levels during simulated night work. These findings offer a proof-of-concept demonstration of an evidence-based meal timing intervention that may prevent mood vulnerability in shift work settings. Future studies are required to establish if changes in meal timing can prevent mood vulnerability in night workers.

Noradrenaline activation of hippocampal dopamine D1 receptors promotes antidepressant effects.

Dopamine D1 receptors (D1Rs) in the hippocampal dentate gyrus (DG) are essential for antidepressant effects. However, the midbrain dopaminergic neurons, the major source of dopamine in the brain, only sparsely project to DG, suggesting possible activation of DG D1Rs by endogenous substances other than dopamine. We have examined this possibility using electrophysiological and biochemical techniques and found robust activation of D1Rs in mouse DG neurons by noradrenaline. Noradrenaline at the micromolar range potentiated synaptic transmission at the DG output and increased the phosphorylation of protein kinase A substrates in DG via activation of D1Rs and ß adrenergic receptors. Neuronal excitation preferentially enhanced noradrenaline-induced synaptic potentiation mediated by D1Rs with minor effects on ß-receptor-dependent potentiation. Increased voluntary exercise by wheel running also enhanced noradrenaline-induced, D1R-mediated synaptic potentiation, suggesting a distinct functional role of the noradrenaline-D1R signaling. We then examined the role of this signaling in antidepressant effects using mice exposed to chronic restraint stress. In the stressed mice, an antidepressant acting on the noradrenergic system induced a mature-to-immature change in the DG neuron phenotype, a previously proposed cellular substrate for antidepressant action. This effect was evident only in mice subjected to wheel running and blocked by a D1R antagonist. These results suggest a critical role of noradrenaline-induced activation of D1Rs in antidepressant effects in DG. Experience-dependent regulation of noradrenaline-D1R signaling may determine responsiveness to antidepressant drugs in depressive disorders.

Multiple integrated social stress induces depressive-like behavioral and neural adaptations in female C57BL/6J mice.

Despite women representing most of those affected by major depression, preclinical studies have focused almost exclusively on male subjects, partially due to a lack of ideal animal paradigms. As the persistent need regarding the sex balance of neuroscience research and female-specific pathology of mental disorders surges, the establishment of natural etiology-based and systematically validated animal paradigms for depression with female subjects becomes an urgent scientific problem. This study aims to establish, characterize, and validate a "Multiple Integrated Social Stress (MISS)" model of depression in female C57BL/6J mice by manipulating and integrating daily social stressors that females are experiencing. Female C57BL/6J mice randomly experienced social competition failure in tube test, modified vicarious social defeat stress, unescapable overcrowding stress followed by social isolation on each day, for ten consecutive days. Compared with their controls, female MISS mice exhibited a relatively decreased preference for social interaction and sucrose, along with increased immobility in the tail suspension test, which could last for at least one month. These MISS mice also exhibited increased levels of blood serum corticosterone, interleukin-6 L and 1ß. In the pharmacological experiment, MISS-induced dysfunctions in social interaction, sucrose preference, and tail suspension tests were amended by systematically administrating a single dose of sub-anesthetic ketamine, a rapid-onset antidepressant. Compared with controls, MISS females exhibited decreased c-Fos activation in their anterior cingulate cortex, prefrontal cortex, nucleus accumbens and some other depression-related brain regions. Furthermore, 24 h after the last exposure to the paradigm, MISS mice demonstrated a decreased center zone time in the open field test and decreased open arm time in the elevated plus-maze test, indicating anxiety-like behavioral phenotypes. Interestingly, MISS mice developed an excessive nesting ability, suggesting a likely behavioral phenotype of obsessive-compulsive disorder. These data showed that the MISS paradigm was sufficient to generate pathological profiles in female mice to mimic core symptoms, serum biochemistry and neural adaptations of depression in clinical patients. The present study offers a multiple integrated natural etiology-based animal model tool for studying female stress susceptibility.

Chronotype and subjective sleep quality predict white matter integrity in young people with emerging mental disorders.

Protecting brain health is a goal of early intervention. We explored whether sleep quality or chronotype could predict white matter (WM) integrity in emerging mental disorders. Young people (N = 364) accessing early-intervention clinics underwent assessments for chronotype, subjective sleep quality, and diffusion tensor imaging. Using machine learning, we examined whether chronotype or sleep quality (alongside diagnostic and demographic factors) could predict four measures of WM integrity: fractional anisotropy (FA), and radial, axial, and mean diffusivities (RD, AD and MD). We prioritised tracts that showed a univariate association with sleep quality or chronotype and considered predictors identified by ≥80% of machine learning (ML) models as 'important'. The most important predictors of WM integrity were demographics (age, sex and education) and diagnosis (depressive and bipolar disorders). Subjective sleep quality only predicted FA in the perihippocampal cingulum tract, whereas chronotype had limited predictive importance for WM integrity. To further examine links with mood disorders, we conducted a subgroup analysis. In youth with depressive and bipolar disorders, chronotype emerged as an important (often top-ranking) feature, predicting FA in the cingulum (cingulate gyrus), AD in the anterior corona radiata and genu of the corpus callosum, and RD in the corona radiata, anterior corona radiata, and genu of corpus callosum. Subjective quality was not important in this subgroup analysis. In summary, chronotype predicted altered WM integrity in the corona radiata and corpus callosum, whereas subjective sleep quality had a less significant role, suggesting that circadian factors may play a more prominent role in WM integrity in emerging mood disorders.

Trajectories of depressive symptoms 10 years after stroke and associated risk factors: a prospective cohort study.

BACKGROUND: Previous studies have investigated the risk factors for post-stroke depression at only one timepoint, neglecting its dynamic nature. We aimed to identify trajectories of post-stroke depression from multiple assessments and explore their risk factors. METHODS: We did a population-based cohort study with the South London Stroke Register (1995-2019). All stroke patients with three or more measurements of the Hospital Anxiety and Depression Scale were included. We identified trajectories of post-stroke depression over a 10-year follow-up using group-based trajectory modelling. We determined the optimal number and shape of trajectories based on the lowest Bayesian information criterion, average posterior probability of assignment of each group over 0·70, and inclusion of at least 5% of participants within each group. We used multinomial logistic regression adjusted for age, sex, ethnicity, comorbidity, physical disability, stroke severity, history of depression and cognitive impairment to explore associations with different trajectories. FINDINGS: The analysis comprised 1968 participants (mean age 64·9 years [SD 13·8], 56·6% male and 43·4% female, 65·1% white ethnicity, 30·7% severe disability and 32·7% severe stroke). We identified four patterns of symptoms: no depressive symptoms (14·1%, n=277), low symptoms (41·7%, n=820), moderate symptoms and symptoms worsening early and then improving (34·6%, n=681), and high and increasing symptoms (9·7%, n=190). Compared with no depressive symptom trajectory, patients with severe disability, severe stroke, pre-stroke depression, and cognitive impairment were more likely to be in the moderate and high symptom groups (adjusted odds ratios [ORs] 2·26 [95% CI 1·56-3·28], 1·75 [1·19-2·57], 2·20 [1·02-4·74], and 2·04 [1·25-3·32], respectively). Female sex was associated with high depression (OR 1·65 [1·13-2·41]), while older age (≥65 years) was associated with moderate depression (OR 1·82 [1·36-2·45]). In men, the ORs for patients with severe disability, severe stroke, pre-stroke depression, and cognitive impairment being in the high depression group were 1·91 (1·01-3·60), 2·41 (1·26-4·60), 2·57 (0·84-7·88), and 2·68 (1·28-5·60), respectively. In women, the ORs were 1·08 (0·52-2·23), 1·30 (0·60-2·79), 19·2 (2·35-156·05), and 3·80 (1·44-10·01), respectively. INTERPRETATION: Female sex and older age were associated with distinct courses of depressive symptoms. In men, high depressive symptom trajectory was associated with severe stroke and severe disability, which was not the case in women. These findings were limited to patients with three or more assessments, who tended to have less severe disabilities than excluded patients and might not generalise to all stroke survivors. FUNDING: National Institute for Health and Care Research (NIHR).

Maintenance or Discontinuation of Antidepressants in Primary Care.

BACKGROUND: Patients with depression who are treated in primary care practices may receive antidepressants for prolonged periods. Data are limited on the effects of maintaining or discontinuing antidepressant therapy in this setting. METHODS: We conducted a randomized, double-blind trial involving adults who were being treated in 150 general practices in the United Kingdom. All the patients had a history of at least two depressive episodes or had been taking antidepressants for 2 years or longer and felt well enough to consider stopping antidepressants. Patients who had received citalopram, fluoxetine, sertraline, or mirtazapine were randomly assigned in a 1:1 ratio to maintain their current antidepressant therapy (maintenance group) or to taper and discontinue such therapy with the use of matching placebo (discontinuation group). The primary outcome was the first relapse of depression during the 52-week trial period, as evaluated in a time-to-event analysis. Secondary outcomes were depressive and anxiety symptoms, physical and withdrawal symptoms, quality of life, time to stopping an antidepressant or placebo, and global mood ratings. RESULTS: A total of 1466 patients underwent screening. Of these patients, 478 were enrolled in the trial (238 in the maintenance group and 240 in the discontinuation group). The average age of the patients was 54 years; 73% were women. Adherence to the trial assignment was 70% in the maintenance group and 52% in the discontinuation group. By 52 weeks, relapse occurred in 92 of 238 patients (39%) in the maintenance group and in 135 of 240 (56%) in the discontinuation group (hazard ratio, 2.06; 95% confidence interval, 1.56 to 2.70; P<0.001). Secondary outcomes were generally in the same direction as the primary outcome. Patients in the discontinuation group had more symptoms of depression, anxiety, and withdrawal than those in the maintenance group. CONCLUSIONS: Among patients in primary care practices who felt well enough to discontinue antidepressant therapy, those who were assigned to stop their medication had a higher risk of relapse of depression by 52 weeks than those who were assigned to maintain their current therapy. (Funded by the National Institute for Health Research; ANTLER ISRCTN number, ISRCTN15969819.).

Loneliness and Depressive Symptoms Are High Among Older Adults With Digestive Disease and Associated With Lower Perceived Health.

BACKGROUND & AIMS: Current approaches to managing digestive disease in older adults fail to consider the psychosocial factors contributing to a person's health. We aimed to compare the frequency of loneliness, depression, and social isolation in older adults with and without a digestive disease and to quantify their association with poor health. METHODS: We conducted an analysis of Health and Retirement Study data from 2008 to 2016, a nationally representative panel study of participants 50 years and older and their spouses. Bivariate analyses examined differences in loneliness, depression, and social isolation among patients with and without a digestive disease. We also examined the relationship between these factors and health. RESULTS: We identified 3979 (56.0%) respondents with and 3131 (44.0%) without a digestive disease. Overall, 60.4% and 55.6% of respondents with and without a digestive disease reported loneliness (P < .001), 12.7% and 7.5% reported severe depression (P < .001), and 8.9% and 8.7% reported social isolation (P = NS), respectively. After adjusting for covariates, those with a digestive disease were more likely to report poor or fair health than those without a digestive disease (odds ratio [OR], 1.25; 95% CI, 1.11-1.41). Among patients with a digestive disease, loneliness (OR, 1.43; 95% CI, 1.22-1.69) and moderate and severe depression (OR, 2.93; 95% CI, 2.48-3.47; and OR, 8.96; 95% CI, 6.91-11.63, respectively) were associated with greater odds of poor or fair health. CONCLUSIONS: Older adults with a digestive disease were more likely than those without a digestive disease to endorse loneliness and moderate to severe depression and these conditions are associated with poor or fair health. Gastroenterologists should feel empowered to screen patients for depression and loneliness symptoms and establish care pathways for mental health treatment.

The role of amygdala-ventral pallidum pathway in depression-like behaviors in male mice.

The basolateral amygdala (BLA) appears to serve an important function in the pathophysiology of depression. Depressive symptoms, such as anhedonia are largely caused by dysfunction in the brain's reward system, in which the ventral pallidum (VP) participates in by controlling dopamine release. However, the role of the BLA-VP pathway in the development of depression remains poorly understood. To investigate this pathway, we employed the Chronic Unpredictable Mild Stress (CUMS) mouse model, in which we injected retroAAV expressing GFP-Cre into the VP and AAV expressing hM4Di-mCherry into the BLA. We then used CNO to activate the Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) for all behavioral tests. The CUMS procedure resulted in significant depression symptoms such as decreased sucrose preference, limited weight gain, decreased immobile latency, and increased immobile time in the forced swim and tail suspension tests. Inhibition of the BLA-VP glutamatergic projections reversed these depression-like behaviors. We found that suppressing the BLA-VP circuitry had beneficial effects on CUMS-induced depression-like behaviors such as anorexia, anhedonia, and despair. Specifically, upon suppression of glutamatergic projections in the BLA-VP circuitry, these depression-like behaviors were significantly alleviated, which highlights the vital role of this circuitry in the development of depression. Furthermore, the beneficial effects of suppressing this circuitry seem to be associated with the brain's reward system, warranting further investigation.

Association of Diabetes Mellitus in Pregnancy and Perinatal Depression.

OBJECTIVE: Diabetes is frequently linked with depression, and both conditions are common complications during pregnancy. However, research findings exploring the relationship between diabetes mellitus in pregnancy (DMP) and perinatal depression (PND) have been inconsistent. Thus, this study seeks to examine the association between DMP and PND in a prospective population-based cohort. METHODS: Women aged 18 to 48 years ( n = 4459) were identified from the Biology, Affect, Stress, Imaging and Cognition study. The diagnosis of DMP was based on International Classification of Diseases code O24 from medical records and was classified as pregestational, gestational, or unspecified diabetes. PND was assessed using psychometric instruments, clinical interviews, and/or register data and categorized into antepartum or postpartum depression. Multivariable logistic regressions were used to study the associations of DMP with antepartum and postpartum depression. The association between DMP and continuous depression scores, antepartum and postpartum, was investigated with multivariable linear regressions. RESULTS: Of 4459 pregnancies, 949 women had antepartum depression (21.2%) and 1123 had postpartum depression (25%). DMP had a prevalence of 1.2%. Women with DMP had twofold higher odds for postpartum depression compared with women without DMP. Although no association was observed between DMP and antepartum depression, DMP was associated with higher antepartum depression scores. CONCLUSIONS: Our study shows an association between DMP and PND, which might be considered a risk factor when screening for high-risk groups.

Bidirectional Associations Between Pain and Perceived Stress Among Veterans: Depressive Disorder as a Predisposing Factor.

OBJECTIVE: Military veterans who were injured in combat very often report pain along with co-occurring perceived stress and preexisting depressive disorder. The systems model of pain is a theoretical model suggesting that pain and perceived stress are bidirectionally associated at the within-person level, and associations are heightened among those with depressive disorder. However, the systems model of pain has not been adequately tested. Testing the systems model of pain could illuminate salient treatment targets for combat-injured veterans with pain and co-occurring psychological problems. METHODS: The present study empirically tests the systems model of pain among a sample of combat-injured veterans ( N = 902) surveyed five times during an 18-month period. We used a multigroup, autoregressive latent trajectory with structured residual statistical model to test the within-person associations between pain and perceived stress and determine whether associations differ between veterans with and without a positive screen for depressive disorder. RESULTS: In line with the systems model of pain, pain and perceived stress were bidirectionally associated only among combat-injured veterans with depressive disorder. Among such veterans, perceived stress was positively associated with subsequent pain ( b = 0.12; 95% confidence interval = 0.06-0.17), and pain was positively associated with subsequent perceived stress ( b = 0.44; 95% CI = 0.11-0.77). CONCLUSIONS: Our work highlights the interplay between pain and its psychological correlates among a particularly at-risk population. Clinicians addressing pain and perceived stress among combat-injured veterans should be prepared to identify and address depressive disorder.

Developmental pathway for first onset of depressive disorders in females: from adolescence to emerging adulthood.

BACKGROUND: Although risk markers for depressive disorders (DD) are dynamic, especially during adolescence, few studies have examined how change in risk levels during adolescence predict DD onset during transition to adulthood. We compared two competing hypotheses of the dynamic effects of risk. The risk escalation hypothesis posits that worsening of risk predicts DD onset beyond risk level. The chronic risk hypothesis posits that persistently elevated risk level, rather than risk change, predicts DD onset. METHODS: Our sample included 393 girls (baseline age 13.5-15.5 years) from the adolescent development of emotions and personality traits project. Participants underwent five diagnostic interviews and assessments of risk markers for DD at 9-month intervals and were re-interviewed at a 6-year follow-up. We focused on 17 well-established risk markers. For each risk marker, we examined the prospective effects of risk level and change on first DD onset at wave six, estimated by growth curve modeling using data from the first five waves. RESULTS: For 13 of the 17 depression risk markers, elevated levels of risk during adolescence, but not change in risk, predicted first DD onset during transition to adulthood, supporting the chronic risk hypothesis. Minimal evidence was found for the risk escalation hypothesis. CONCLUSIONS: Participants who had a first DD onset during transition to adulthood have exhibited elevated levels of risk throughout adolescence. Researchers and practitioners should administer multiple assessments and focus on persistently elevated levels of risk to identify individuals who are most likely to develop DD and to provide targeted DD prevention.

Efficacy and Safety of Valbenazine in Japanese Patients With Tardive Dyskinesia and Schizophrenia/Schizoaffective Disorder or Bipolar Disorder/Depressive Disorder: Primary Results and Post Hoc Analyses of the J-KINECT Study.

PURPOSE: This post hoc analysis investigated whether a patient's underlying psychiatric disease (schizophrenia/schizoaffective disorder [SCHZ] or bipolar disorder/depressive disorder [MOOD]) influenced the efficacy or safety of valbenazine for tardive dyskinesia (TD) in an Asian population. METHODS: We analyzed data from J-KINECT, a multicenter, phase II/III, randomized, double-blind study, which consisted of a 6-week placebo-controlled period followed by a 42-week extension where Japanese patients with TD received once-daily 40- or 80-mg valbenazine. We compared the change from baseline in Abnormal Involuntary Movement Scale total score and Clinical Global Impression of TD score between patients with SCHZ and those with MOOD, and incidence of treatment-emergent adverse events. RESULTS: Of 256 patients included in the placebo-controlled period, 211 continued to the long-term extension. The mean change from baseline in Abnormal Involuntary Movement Scale total score at week 6 (95% confidence interval) was -1.8 (-3.2 to -0.5) and -3.3 (-4.7 to -1.9) in the valbenazine 40- and 80-mg groups, respectively (SCHZ group), and -2.4 (-3.9 to -0.9) and -3.5 (-5.1 to -1.9) in the valbenazine 40- and 80-mg groups, respectively (MOOD group), demonstrating improvement at either dose level over placebo, regardless of the underlying disease. These results were maintained to week 48, and improvements of Clinical Global Impression of TD scores were similar. There were no notable differences in the incidence of serious or fatal treatment-emergent adverse events by underlying disease; differences in the incidence of worsening schizophrenia and depression were attributed to underlying disease progression. CONCLUSIONS: Safety and efficacy of long-term valbenazine therapy for TD did not vary according to underlying psychiatric disease.

Discovering the Potential Value of Coenzyme Q10 as an Adjuvant Treatment in Patients With Depression.

PURPOSE/BACKGROUND: Depressive disorder or mental cold is the most common mental disorder, and depression exists all over the world and in all countries and cultures. The results of several studies have shown that using compounds with antioxidant properties has been fruitful in patients with depression. Coenzyme Q10 (CoQ10) is a fat-soluble antioxidant and exerts its antioxidant effect by directly neutralizing free radicals or reducing tocopherol and preventing the inhibition of mitochondrial activity because of oxidative stress. This study aimed to investigate the effects of oral CoQ10 in patients with depression as an adjunctive treatment. METHODS/PROCEDURES: Sixty-nine patients with moderate and severe depression were randomly divided into 2 CoQ10 groups (36) and placebo (33). The first group of patients received CoQ10 supplements at a dose of 200 mg daily for 8 weeks along with standard interventions and treatments for depression, and the second group received standard treatments for depression along with a placebo. The change in the score of Montgomery-Åsberg Depression Rating Scale depression scale was evaluated 4 and 8 weeks after the intervention. Also, at baseline and 8 weeks later at the end of the study, serum levels of total antioxidant capacity, total thiol groups, nitric oxide, malondialdehyde, and interleukin 6 were assessed. FINDINGS/RESULTS: The changes in the depression score at the end of the study showed that, in the group receiving the CoQ10 supplement after 8 weeks, there was a reduction in depression symptoms, which was statistically significant compared with before the start of the study Meanwhile, no significant changes were observed in the patients of the placebo group in terms of symptom reduction. Compared with baseline and the placebo condition, serum levels of nitric oxide and total thiol groups significantly decreased and increased, respectively. Also, no statistically significant changes were observed for interleukin 6, malondialdehyde, and total antioxidant capacity. IMPLICATIONS/CONCLUSIONS: A dose of 200 mg of CoQ10 supplement daily for 8 weeks can reduce depression and fatigue, as well as improve the quality of life of patients with depression. In addition, CoQ10 can significantly improve inflammation and oxidative stress status in patients with depression.