Deep brain stimulation normalizes amygdala responsivity in treatment-resistant depression.

Deep brain stimulation (DBS) of the ventral anterior limb of the internal capsule (vALIC) is a promising intervention for treatment-resistant depression (TRD). However, the working mechanisms of vALIC DBS in TRD remain largely unexplored. As major depressive disorder has been associated with aberrant amygdala functioning, we investigated whether vALIC DBS affects amygdala responsivity and functional connectivity. To investigate the long-term effects of DBS, eleven patients with TRD performed an implicit emotional face-viewing paradigm during functional magnetic resonance imaging (fMRI) before DBS surgery and after DBS parameter optimization. Sixteen matched healthy controls performed the fMRI paradigm at two-time points to control for test-retest effects. To investigate the short-term effects of DBS de-activation after parameter optimization, thirteen patients additionally performed the fMRI paradigm after double-blind periods of active and sham stimulation. Results showed that TRD patients had decreased right amygdala responsivity compared to healthy controls at baseline. Long-term vALIC DBS normalized right amygdala responsivity, which was associated with faster reaction times. This effect was not dependent on emotional valence. Furthermore, active compared to sham DBS increased amygdala connectivity with sensorimotor and cingulate cortices, which was not significantly different between responders and non-responders. These results suggest that vALIC DBS restores amygdala responsivity and behavioral vigilance in TRD, which may contribute to the DBS-induced antidepressant effect.

Effects of peritraumatic reactions on post-traumatic stress among Kahramanmaras earthquake survivors.

PURPOSE: Peritraumatic reactions play a crucial role in the development of mental health problems, including depression and post-traumatic stress disorder. Therefore, this study sought to examine the influence of the peritraumatic reactions, including peritraumatic dissociation, peritraumatic distress, mental defeat, and tonic immobility, on post-traumatic stress disorder and major depressive disorder in earthquake survivors. MATERIALS AND METHODS: A total of 261 adult participants aged between 18 and 65 (Mage=29.20, SD = 28.06, 162 were female, and 99 were male) who were exposed to the Kahramanmaras earthquake in February 2023 were recruited in the study. Data were collected between April 10 and 18 2023, two months after the earthquake. Participants completed questionnaires, including The International Trauma Questionnaire, The International Depression Questionnaire, The Mental Defeat Questionnaire, The Tonic Immobility Scale, and The Peritraumatic Dissociative Experiences Questionnaire. RESULTS: Two-step multiple linear regression analyses indicated all peritraumatic reactions predicted both post-traumatic stress disorder and depression. Dominance analysis results showed that the contribution of peritraumatic dissociation in predicting PTSD and depression was higher among other peritraumatic reactions. CONCLUSION: The findings of the study revealed a robust association between peritraumatic reactions and both depression and PTSD, shedding light on the underlying processes in the development of trauma-related disorders. Early assessment of peritraumatic reactions may be useful in identifying individuals at risk of developing PTSD and depression.

Stressful life events increase the risk of major depressive episodes: A population-based twin study.

BACKGROUND: Previous studies have found that stressful life events (SLEs) are associated with an increased risk of adult depression. However, many studies are observational in nature and limited by methodological issues, such as potential confounding by genetic factors. Genetically informative research, such as the co-twin control design, can strengthen causal inference in observational studies. Discrete-time survival analysis has several benefits and multilevel survival analysis can incorporate frailty terms (random effects) to estimate the components of the biometric model. In the current study, we investigated associations between SLEs and depression risk in a population-based twin sample (N = 2299). METHODS: A co-twin control design was used to investigate the influence of the occurrence of SLEs on depression risk. The co-twin control design involves comparing patterns of associations in the full sample and within dizygotic (DZ) and monozygotic twins (MZ). Associations were modelled using discrete-time survival analysis with biometric frailty terms. Data from two time points were used in the analyses. Mean age at Wave 1 was 28 years and mean age at Wave 2 was 38 years. RESULTS: SLE occurrence was associated with increased depression risk. Co-twin control analyses indicated that this association was at least in part due to the causal influence of SLE exposure on depression risk for event occurrence across all SLEs and for violent SLEs. A minor proportion of the total genetic risk of depression reflected genetic effects related to SLEs. CONCLUSIONS: The results support previous research in implicating SLEs as important risk factors with probable causal influence on depression risk.

An accelerated course of TMS using intermittent theta burst for veterans with major depressive disorder: A case series.

BACKGROUND: Transcranial magnetic stimulation (TMS) is a neuro-modulation technique for treatment-resistant major depressive disorder (MDD). Standard TMS protocols for MDD involve once-daily treatment for 6 to 9 weeks. We report a case series of an accelerated TMS protocol for outpatient MDD treatment. METHODS: From July 2020 through January 2021, patients deemed appropriate candidates for TMS treatment were offered an accelerated TMS protocol consisting of intermittent theta burst stimulation (iTBS) applied to the left dorsolateral prefrontal cortex, localized by the Beam F3 method, and consisting of 5 treatments daily for 5 days. Assessment scales were obtained as part of standard clinical care. RESULTS: A total of 19 veterans received the accelerated protocol and 17 completed treatment. Statistically significant mean reductions from baseline to end of treatment were observed across all assessment scales. Remission and response rates, as defined by changes in Montgomery-Åsberg Depression Rating Scale scores, were 47.1% and 64.7%, respectively. Treatments were well tolerated without unexpected or serious adverse events. CONCLUSIONS: This case series details the safety and efficacy of an accelerated iTBS TMS protocol consisting of 25 treatments over 5 days. Improved depressive symptoms were observed, with remission and response rates similar to standard TMS protocols of daily TMS for ≥6 weeks.

Glucocorticoid Receptor (GR) antagonism as disease-modifying treatment for MDD with childhood trauma: protocol of the RESET-medication randomized controlled trial.

BACKGROUND: Major depressive disorder (MDD) is a heterogeneous psychiatric disorder. Childhood trauma (CT, emotional/physical/sexual abuse or neglect before the age of 18) is one of the largest and most consistent risk factors for development and poor course of MDD. Overactivity of the HPA-axis and the stress hormone cortisol is thought to play a role in the vulnerability for MDD following exposure to CT. Rodent experiments showed that antagonism of the glucocorticoid receptor (GR) at adult age reversed the effects of early life stress. Similarly, we aim to target MDD in individuals with CT exposure using the GR antagonist mifepristone. METHODS: The RESET-medication study is a placebo-controlled double-blind randomized controlled trial (RCT) which aims to include 158 adults with MDD and CT. Participants will be randomized (1:1) to a 7-day treatment arm of mifepristone (1200 mg/day) or a control arm (placebo). Participants are allowed to receive usual care for MDD including antidepressants. Measurements include three face-to-face meetings at baseline (T0), day 8 (T1), week 6 (T2), and two online follow-up meetings at 12 weeks (T3) and 6 months (T4). A subgroup of participants (N = 80) are included in a fMRI sub-study (T0, T2). The main study outcome will be depressive symptom severity as measured with the Inventory of Depressive Symptomatology-Self Rated (IDS-SR) at T2. Secondary outcomes include, among others, depressive symptom severity at other time points, disability, anxiety, sleep and subjective stress. To address underlying mechanisms mifepristone plasma levels, cortisol, inflammation, epigenetic regulation and fMRI measurements are obtained. DISCUSSION: The RESET-medication study will provide clinical evidence whether GR antagonism is a disease-modifying treatment for MDD in individuals exposed to CT. If effective, this hypothesis-driven approach may extend to other psychiatric disorders where CT plays an important role. TRIAL REGISTRATION: The trial protocol has been registered 01-02-2022 on ClinicalTrials.gov with ID "NCT05217758".

Chronic mild stress alters synaptic plasticity in the nucleus accumbens through GSK3ß-dependent modulation of Kv4.2 channels.

Although major depressive disorder (MDD) is highly prevalent, its pathophysiology is poorly understood. Recent evidence suggests that glycogen-synthase kinase 3ß (GSK3ß) plays a key role in memory formation, yet its role in mood regulation remains controversial. Here, we investigated whether GSK3ß activity in the nucleus accumbens (NAc) is associated with depression-like behaviors and synaptic plasticity. We performed whole-cell patch-clamp recordings of medium spiny neurons (MSNs) in the NAc and determined the role of GSK3ß in spike timing-dependent long-term potentiation (tLTP) in the chronic unpredictable mild stress (CUMS) mouse model of depression. To assess the specific role of GSK3ß in tLTP, we used in vivo genetic silencing by an adeno-associated viral vector (AAV2) short hairpin RNA against GSK3ß. In addition, we examined the role of the voltage-gated potassium Kv4.2 subunit, a molecular determinant of A-type K+ currents, as a potential downstream target of GSK3ß. We found increased levels of active GSK3ß and augmented tLTP in CUMS mice, a phenotype that was prevented by selective GSK3ß knockdown. Furthermore, knockdown of GSK3ß in the NAc ameliorated depressive-like behavior in CUMS mice. Electrophysiological, immunohistochemical, biochemical, and pharmacological experiments revealed that inhibition of the Kv4.2 channel through direct phosphorylation at Ser-616 mediated the GSK3ß-dependent tLTP changes in CUMS mice. Our results identify GSK3ß regulation of Kv4.2 channels as a molecular mechanism of MSN maladaptive plasticity underlying depression-like behaviors and suggest that the GSK3ß-Kv4.2 axis may be an attractive therapeutic target for MDD.

Pre-existing Mental Health Diagnoses Are Associated With Higher Rates of Postoperative Complications, Readmissions, and Reoperations Following Arthroscopic Rotator Cuff Repair.

PURPOSE: To investigate the association between preoperative mental health disorders and postoperative complications, readmissions, and ipsilateral revision procedures among patients undergoing arthroscopic rotator cuff repair (RCR). METHODS: A retrospective cohort study from 2010 to 2020 was performed using the PearlDiver database. Current Procedural Terminology and International Classification of Diseases codes were used to compare patients with and without mental health disorders who underwent arthroscopic RCR. Mental health disorders evaluated in this study include depressive disorder, major depressive disorder, major depressive affective disorder, bipolar disorder, dysthymic disorder, adjustment disorder, separation anxiety disorder, and posttraumatic stress disorder. Patients were matched at a 1:1 ratio based on age, sex, Charlson Comorbidity Index, body mass index, and tobacco use. Rates of complications and subsequent surgeries were compared between patients with and without a preoperative diagnosis of a mental health disorder. RESULTS: The 1-year preoperative prevalence of a mental health disorder from 2010 to 2020 was 14.6%. After 1:1 matching, patients with a mental health disorder who underwent arthroscopic RCR were nearly twice as likely to undergo a revision procedure (odds ratio 1.94, 95% confidence interval 1.76-2.14, P < .001) and more than twice as likely to experience conversion to shoulder arthroplasty (odds ratio 2.29, 95% confidence interval 1.88-2.80, P < .001) within 2 years of initial arthroscopy when compared with patients without a mental disorder. Patients with a mental disorder also experienced increased risk for 90-day readmission (1.9% vs 0%, P < .001) as well as multiple postoperative medical complications. CONCLUSIONS: Patients with pre-existing mental health diagnoses experience increased rates of 90-day postoperative complications and readmissions following arthroscopic RCR. In addition, patients with mental health diagnoses are more likely to undergo revision repair and conversion to shoulder arthroplasty within 2 years of the index procedure. LEVEL OF EVIDENCE: Level III.

Role of Tyrosine Nitrosylation in Stress-Induced Major Depressive Disorder: Mechanisms and Implications.

Major depressive disorder (MDD) has a lifetime prevalence of approximately 10% and is one of the most common diseases worldwide. Although many pathogenetic mechanisms of MDD have been proposed, molecular details and a unifying hypothesis of the pathogenesis of MDD remain to be defined. Here, we investigated whether tyrosine nitrosylation, which is caused by reaction of the C-atom 3 of the tyrosine phenol ring with peroxynitrate (ONOO-), plays a role in experimental MDD, because tyrosine nitrosylation may affect many cell functions altered in MDD. To this end, we induced stress through glucocorticoid application or chronic environmental unpredictable stress and determined tyrosine nitrosylation in the hippocampus through immuno-staining and ELISA. The role of catalases and peroxidases for tyrosine nitrosylation was measured using enzyme assays. We show that glucocorticoid- and chronic unpredictable environmental stress induced tyrosine nitrosylation in the hippocampus. Long-term treatment of stressed mice with the classical antidepressants amitriptyline or fluoxetine prevented tyrosine nitrosylation. Tyrosine nitrosylation was also prevented through i.v. application of anti-ceramide antibodies or recombinant ceramidase to neutralize or degrade, respectively, blood plasma ceramide that has been recently shown to induce experimental MDD. Finally, the application of phosphatidic acid, previously shown to be reduced in the hippocampus upon stress, also reverted stress-induced tyrosine nitrosylation. The inhibition of tyrosine nitrosylation by interfering with the formation of NO radicals at least partly restored normal behavior in stressed mice. These data suggest that tyrosine nitrosylation might contribute to the pathogenesis of MDD and targeting this process might contribute to the treatment of MDD.

Polygenic scores for schizophrenia and major depression are associated with psychosocial risk factors in children: evidence of gene-environment correlation.

BACKGROUND: Whilst genetic and environmental risk factors for schizophrenia (SCZ) and major depressive disorder (MDD) have been established, it is unclear whether exposure to environmental risk factors is genetically confounded by passive, evocative or active gene-environment correlation (rGE). STUDY OBJECTIVE: This study aims to investigate: (a) whether the genetic risk for SCZ/MDD in children is correlated with established environmental and psychosocial risk factors in two British community samples, the 1958 National Child Development Study (NCDS) and the Millennium Cohort Study (MCS), (b) whether these associations vary between both psychopathologies, and (c) whether findings differ across the two cohorts which were born 42 years apart. METHODS: Polygenic risk scores (PRS) from existing large genome-wide associations studies (GWAS) were applied to test the correlation between the child genetic risk for SCZ/MDD and known environmental risk factors. In addition, parental and child genetic data from MCS were used to distinguish between passive and evocative rGE. RESULTS: The child polygenic risk for SCZ and MDD was correlated with single parenthood in MCS. Moreover, the lack of father's involvement in child care was associated with the genetic risk for SCZ in NCDS. However, we also found associations between several indicators of low socioeconomic status and heightened genetic risk for MDD in children in both cohorts. Further, the genetic risk for MDD was associated with parental lack of interest in the child's education in NCDS as well as more maternal smoking and less maternal alcohol consumption during childhood in MCS. According to sensitivity analyses in MCS (controlling for parental genotype), more than half of our significant correlations reflected passive rGE. CONCLUSIONS: Findings suggest that several established environmental and psychosocial risk factors for SCZ and MDD are at least partially associated with children's genetic risk for these psychiatric disorders.

Risk of major depressive disorder in adolescent and young adult cancer patients in Japan.

OBJECTIVE: To estimate the risk of major depressive disorder (MDD) in adolescent and young adult (AYA) patients with cancer in Japan and identify risk factors for MDD among these patients. METHODS: This was a matched cohort study using a large claims database in Japan. Included patients were aged 15-39 years, newly diagnosed with cancer during 2012-2017 and assessable for a follow-up period of 12 months. Kaplan-Meier estimates and Cox proportional hazards models were used to calculate hazard ratios (HR) and 95% confidence intervals (CI) for MDD in the AYA patients with cancer versus age-, sex- and working status-matched cancer-free controls. A subgroups analysis of the AYA patients with cancer was performed to explore MDD risk factors. RESULTS: A total of 3559 AYA patients with cancer and 35,590 matched controls were included in the analysis. Adolescent and young adult patients with cancer had a three-fold higher risk for MDD compared with cancer-free controls (HR, 3.12; 95% CI, 2.64-3.70). Among cancer categories with >100 patients, patients with multiple cancer categories, including those with metastatic cancer (HR, 6.73, 95% CI, 3.65-12.40) and leukemia (HR, 6.30; 95% CI, 3.75-10.58), had the greatest MDD risk versus matched controls. Patients who received inpatient chemotherapy as initial treatment had a higher risk for MDD than patients without chemotherapy (HR, 0.43; 95% CI, 0.30-0.62). CONCLUSIONS: Adolescent and young adult patients in Japan with cancer are at high risk for MDD. Particularly, those with multiple cancer categories, leukemia, and those who receive aggressive anticancer treatments should be monitored closely for symptoms of MDD.

The effects of varenicline, bupropion, nicotine patch, and placebo on smoking cessation among smokers with major depression: A randomized clinical trial.

IMPORTANCE: Improving treatment outcomes for smokers with major depressive disorder (MDD) can have significant public health implications. OBJECTIVE: To evaluate the safety and efficacy of smoking cessation pharmacotherapy among smokers with MDD. DESIGN: Secondary analysis of a randomized, double-blind, active- (nicotine patch) and placebo-controlled trial of 12 weeks of either varenicline or bupropion with a 12-week follow-up. PARTICIPANTS: Community volunteers 18-75 years of age; smoke 10+ cigarettes/day; with clinically stable MDD (N = 2635) or no psychiatric disorder (N = 4028), from 140 sites in 16 countries. INTERVENTION: Twelve weeks of pharmacotherapy (placebo [PLA], nicotine replacement therapy [NRT], bupropion [BUP], varenicline [VAR]) plus brief cessation counseling. MEASURE(S): Primary safety outcome: the occurrence of ≥1 treatment-emergent, moderate to severe neuropsychiatric adverse event (NPSAE). Primary efficacy outcome: biochemically confirmed continuous abstinence (CA) during the final 4 weeks of treatment (Weeks 9-12). RESULTS: A total of 6653 participants (56% female; 39% MDD) ~47 years old. Risk of NPSAEs did not differ by medication for MDD. MDD had higher risk (p < .0001) for NPSAEs than the NPC. Efficacy (6653; intent-to-treat): CA rates for MDD versus NPC respectively were 31.2% versus 38.0% VAR; 23.0% versus 26.1% BUP; 22.6% versus 26.4% NRT; and 13.4% versus 13.7% PLA but no differential treatment effect was noted within the cohorts. All active treatments differed from PLA but VAR showed the largest effect. CONCLUSIONS: Results suggest that for MDD smokers, inclusive of those with recurrent episode, varenicline plus counseling may be the best pharmacological option for the treatment of smoking given its greater efficacy effect size and similar risk of NPSAEs. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01456936. https://clinicaltrials.gov/ct2/show/NCT01456936.

Repetitive transcranial magnetic stimulation for generalized anxiety and panic disorders: A systematic review and meta-analysis.

BACKGROUND: Repetitive transcranial magnetic stimulation (rTMS) is an FDA-approved, noninvasive modality for treating major depressive disorder and obsessive-compulsive disorder. Earlier studies evaluating therapeutic effects of rTMS on symptom scores of patients with generalized anxiety disorder (GAD) and panic disorder (PD) have yielded inconsistent findings. METHODS: We performed a systematic review and meta-analysis of interventional studies assessing the effect of rTMS on symptom scores in patients with GAD or PD with or without psychiatric comorbidities using studies published up to April 2021. We used DerSimonian-Laird random effects models to obtain pooled standardized mean difference (SMD) and 95% CI. RESULTS: A total of 13 studies consisting of 677 participants (404 treated with rTMS and 273 without rTMS) were included in this meta-analysis. In GAD patients with or without any comorbidities, rTMS therapy demonstrated significant improvements in anxiety (SMD = 1.45; P < .001) and depression (SMD = 1.65; P < .001) scores regardless of rTMS parameters. Overall anxiety (SMD = 0.24; P = .48) and panic severity (SMD = 1.19; P = .054) scores did not significantly improve after rTMS therapy in patients with PD. CONCLUSIONS: rTMS is safe and improves anxiety and depression scores only in GAD patients, regardless of underlying comorbidities or rTMS parameters.

Blood biomarkers of post-stroke depression after minor stroke at three months in males and females.

BACKGROUND: Post-stroke depression (PSD) is one of the most common neuropsychiatric complications after stroke. Studies on the underlying mechanisms and biological markers of sex differences in PSD are of great significance, but there are still few such studies. Therefore, the main objective of this study was to investigate the association of biomarkers with PSD at 3 months after minor stroke in men and women. METHODS: This was a prospective multicenter cohort study that enrolled 530 patients with minor stroke (males, 415; females, 115). Demographic information and blood samples of patients were collected within 24 h of admission, and followed up at 3 months after stroke onset. PSD was defined as a depressive disorder due to another medical condition with depressive features, major depressive-like episode, or mixed-mood features according to the Diagnostic and Statistical Manual of Mental Disorders, 5th edition (DSM-V). Univariate analysis was performed using the chi-square test, Mann-Whitney U test, or t-test. Partial least-squares discriminant analysis (PLS-DA) was used to distinguish between patients with and without PSD. Factors with variable importance for projection (VIP) > 1.0 were classified as the most important factors in the model segregation. RESULTS: The PLS-DA model mainly included component 1 and component 2 for males and females. For males, the model could explain 13% and 16.9% of the variables, respectively, and 29.9% of the variables in total; the most meaningful predictors were exercise habit and fibrinogen level. For females, the model could explain 15.7% and 10.5% of the variables, respectively, and 26.2% of the variables in total; the most meaningful predictors in the model were brain-derived neurotrophic factor (BDNF), magnesium and free T3. Fibrinogen was positively correlated with the Hamilton Depression Scale-17 items (HAMD-17) score. BDNF, magnesium, and free T3 levels were negatively correlated with the HAMD-17 score. CONCLUSIONS: This was a prospective cohort study. The most important markers found to be affecting PSD at 3 months were fibrinogen in males, and free T3, magnesium, and BDNF in females. TRIAL REGISTRATION: ChiCTR-ROC-17013993 .

Unintentional Weight Loss in Adults 65 Years or Older: A Symptom of Physical and Psychiatric Etiologies.

ABSTRACT: Unintentional weight loss is defined as a more than 5% decrease in body weight within 1 year. Various physical and psychiatric etiologies cause unintentional weight loss, including major depressive disorder (MDD). We present the case of a 69-year-old woman who lost 10 kg in 2 months. She had anhedonia, mobility limitations, and incontinence. Her Mini Nutritional Assessment score indicated malnutrition, whereas her Geriatric Depression Scale score indicated a diagnosis of MDD. Whole-body fluorodeoxyglucose (FDG)-positron emission tomography/computed tomography showed intensely increased FDG uptake in the muscles adjacent to the right and left mandibular rami and the temporal muscle, compatible with jaw clenching associated with the patient's MDD. Subsequent temporal muscle biopsy did not suggest the causes of malignant disorders, dermatomyositis, or polymyositis. Having ruled out all possible organic pathologies, the patient was thus diagnosed with MDD. Escitalopram was prescribed for her MDD, and oral nutritional supplement treatments were initiated for her malnutrition. Patients who present with unintentional weight loss should be assessed first for physical etiologies, and then psychiatric etiologies, particularly as weight loss may be a major symptom of MDD in older adults.

Screening for Depression and Suicide Risk in Children and Adolescents: US Preventive Services Task Force Recommendation Statement.

Importance: Depression is a leading cause of disability in the US. Children and adolescents with depression typically have functional impairments in their performance at school or work as well as in their interactions with their families and peers. Depression can also negatively affect the developmental trajectories of affected youth. Major depressive disorder (MDD) in children and adolescents is strongly associated with recurrent depression in adulthood; other mental disorders; and increased risk for suicidal ideation, suicide attempts, and suicide completion. Suicide is the second-leading cause of death among youth aged 10 to 19 years. Psychiatric disorders and previous suicide attempts increase suicide risk. Objective: To update its 2014 and 2016 recommendations, the US Preventive Services Task Force (USPSTF) commissioned a systematic review to evaluate the benefits and harms of screening, accuracy of screening, and benefits and harms of treatment of MDD and suicide risk in children and adolescents that would be applicable to primary care settings. Population: Children and adolescents who do not have a diagnosed mental health condition or are not showing recognized signs or symptoms of depression or suicide risk. Evidence Assessment: The USPSTF concludes with moderate certainty that screening for MDD in adolescents aged 12 to 18 years has a moderate net benefit. The USPSTF concludes that the evidence is insufficient on screening for MDD in children 11 years or younger. The USPSTF concludes that the evidence is insufficient on the benefit and harms of screening for suicide risk in children and adolescents owing to a lack of evidence. Recommendation: The USPSTF recommends screening for MDD in adolescents aged 12 to 18 years. (B recommendation) The USPSTF concludes that the current evidence is insufficient to assess the balance of benefits and harms of screening for MDD in children 11 years or younger. (I statement) The USPSTF concludes that the current evidence is insufficient to assess the balance of benefits and harms of screening for suicide risk in children and adolescents. (I statement).

How Microbes Affect Depression: Underlying Mechanisms via the Gut-Brain Axis and the Modulating Role of Probiotics.

Accumulating evidence suggests that the gut microbiome influences the brain functions and psychological state of its host via the gut-brain axis, and gut dysbiosis has been linked to several mental illnesses, including major depressive disorder (MDD). Animal experiments have shown that a depletion of the gut microbiota leads to behavioral changes, and is associated with pathological changes, including abnormal stress response and impaired adult neurogenesis. Short-chain fatty acids such as butyrate are known to contribute to the up-regulation of brain-derived neurotrophic factor (BDNF), and gut dysbiosis causes decreased levels of BDNF, which could affect neuronal development and synaptic plasticity. Increased gut permeability causes an influx of gut microbial components such as lipopolysaccharides, and the resultant systemic inflammation may lead to neuroinflammation in the central nervous system. In light of the fact that gut microbial factors contribute to the initiation and exacerbation of depressive symptoms, this review summarizes the current understanding of the molecular mechanisms involved in MDD onset, and discusses the therapeutic potential of probiotics, including butyrate-producing bacteria, which can mediate the microbiota-gut-brain axis.

Venlafaxine Stimulates an MMP-9-Dependent Increase in Excitatory/Inhibitory Balance in a Stress Model of Depression.

Emerging evidence suggests that there is a reduction in overall cortical excitatory to inhibitory balance in major depressive disorder (MDD), which afflicts ∼14%-20% of individuals. Reduced pyramidal cell arborization occurs with stress and MDD, and may diminish excitatory neurotransmission. Enhanced deposition of perineuronal net (PNN) components also occurs with stress. Since parvalbumin-expressing interneurons are the predominant cell population that is enveloped by PNNs, which enhance their ability to release GABA, excess PNN deposition likely increases pyramidal cell inhibition. In the present study, we investigate the potential for matrix metalloprotease-9 (MMP-9), an endopeptidase secreted in response to neuronal activity, to contribute to the antidepressant efficacy of the serotonin/norepinephrine reuptake inhibitor venlafaxine in male mice. Chronic venlafaxine increases MMP-9 levels in murine cortex, and increases both pyramidal cell arborization and PSD-95 expression in the cortex of WT but not MMP-9-null mice. We have previously shown that venlafaxine reduces PNN deposition and increases the power of ex vivo γ oscillations in conventionally housed mice. γ power is increased with pyramidal cell disinhibition and with remission from MDD. Herein we observe that PNN expression is increased in a corticosterone-induced stress model of disease and reduced by venlafaxine. Compared with mice that receive concurrent venlafaxine, corticosterone-treated mice also display reduced ex vivo γ power and impaired working memory. Autopsy-derived PFC samples show elevated MMP-9 levels in antidepressant-treated MDD patients compared with controls. These preclinical and postmortem findings highlight a link between extracellular matrix regulation and MDD.SIGNIFICANCE STATEMENT Reduced excitatory neurotransmission occurs with major depressive disorder, and may be normalized by antidepressant treatment. Underlying molecular mechanisms are, however, not well understood. Herein we investigate a potential role for an extracellular protease, released from neurons and known to play a role in learning and memory, in antidepressant-associated increases in excitatory transmission. Our data suggest that this protease, matrix metalloprotease-9, increases branching of excitatory neurons and concomitantly attenuates the perineuronal net to potentially reduce inhibitory input to these neurons. Matrix metalloprotease-9 may thus enhance overall excitatory/inhibitory balance and neuronal population dynamics, which are important to mood and memory.

Interpersonal psychotherapy delivered by nonspecialists for depression and posttraumatic stress disorder among Kenyan HIV-positive women affected by gender-based violence: Randomized controlled trial.

BACKGROUND: HIV-positive women suffer a high burden of mental disorders due in part to gender-based violence (GBV). Comorbid depression and posttraumatic stress disorder (PTSD) are typical psychiatric consequences of GBV. Despite attention to the HIV-GBV syndemic, few HIV clinics offer formal mental healthcare. This problem is acute in sub-Saharan Africa, where the world's majority of HIV-positive women live and prevalence of GBV is high. METHODS AND FINDINGS: We conducted a randomized controlled trial at an HIV clinic in Kisumu, Kenya. GBV-affected HIV-positive women with both major depressive disorder (MDD) and PTSD were randomized to 12 sessions of interpersonal psychotherapy (IPT) plus treatment as usual (TAU) or Wait List+TAU. Nonspecialists were trained to deliver IPT inside the clinic. After 3 months, participants were reassessed, and those assigned to Wait List+TAU were given IPT. The primary outcomes were diagnosis of MDD and PTSD (Mini International Neuropsychiatric Interview) at 3 months. Secondary outcomes included symptom measures of depression and PTSD, intimate partner violence (IPV), and disability. A total of 256 participants enrolled between May 2015 and July 2016. At baseline, the mean age of the women in this study was 37 years; 61% reported physical IPV in the past week; 91% reported 2 or more lifetime traumatic events and monthly income was 18USD. Multilevel mixed-effects logistic regression showed that participants randomized to IPT+TAU had lower odds of MDD (odds ratio [OR] 0.26, 95% CI [0.11 to 0.60], p = 0.002) and lower odds of PTSD (OR 0.35, [0.14 to 0.86], p = 0.02) than controls. IPT+TAU participants had lower odds of MDD-PTSD comorbidity than controls (OR 0.36, 95% CI [0.15 to 0.90], p = 0.03). Linear mixed models were used to assess secondary outcomes: IPT+TAU participants had reduced disability (-6.9 [-12.2, -1.5], p = 0.01), and nonsignificantly reduced work absenteeism (-3.35 [-6.83, 0.14], p = 0.06); partnered IPT+TAU participants had a reduction of IPV (-2.79 [-5.42, -0.16], p = 0.04). Gains were maintained across 6-month follow-up. Treatment group differences were observed only at month 3, the time point at which the groups differed in IPT status (before cross over). Study limitations included 35% attrition inclusive of follow-up assessments, generalizability to populations not in HIV care, and data not collected on TAU resources accessed. CONCLUSIONS: IPT for MDD and PTSD delivered by nonspecialists in the context of HIV care yielded significant improvements in HIV-positive women's mental health, functioning, and GBV (IPV) exposure, compared to controls. TRIAL REGISTRATION: Clinical Trials Identifier NCT02320799.

A new experimental design to study inflammation-related versus non-inflammation-related depression in mice.

BACKGROUND: Major depressive disorder (MDD) represents a major public health concern, particularly due to its steadily rising prevalence and the poor responsiveness to standard antidepressants notably in patients afflicted with chronic inflammatory conditions, such as obesity. This highlights the need to improve current therapeutic strategies, including by targeting inflammation based on its role in the pathophysiology and treatment responsiveness of MDD. Nevertheless, dissecting the relative contribution of inflammation in the development and treatment of MDD remains a major issue, further complicated by the lack of preclinical depression models suitable to experimentally dissociate inflammation-related vs. inflammation-unrelated depression. METHODS: While current models usually focus on one particular MDD risk factor, we compared in male C57BL/6J mice the behavioral, inflammatory and neurobiological impact of chronic exposure to high-fat diet (HFD), a procedure known to induce inflammation-related depressive-like behaviors, and unpredictable chronic mild stress (UCMS), a stress-induced depression model notably renowned for its responsivity to antidepressants. RESULTS: While both paradigms induced neurovegetative, depressive-like and anxiety-like behaviors, inflammation and downstream neurobiological pathways contributing to inflammation-driven depression were specifically activated in HFD mice, as revealed by increased circulating levels of inflammatory factors, as well as brain expression of microglial activation markers and enzymes from the kynurenine and tetrahydrobiopterin (BH4) pathways. In addition, serotoninergic and dopaminergic systems were differentially impacted, depending on the experimental condition. CONCLUSIONS: These data validate an experimental design suitable to deeply study the mechanisms underlying inflammation-driven depression comparatively to non-inflammatory depression. This design could help to better understand the pathophysiology of treatment resistant depression.

Association of clinical characteristics, disease activity and health-related quality of life in SLE patients with major depressive disorder.

OBJECTIVE: To determine the contributing factors associated with major depressive disorder (MDD) in SLE patients and examine the association between disease-specific health-related quality of life [lupus quality of life (LupusQoL)] domains and MDD. METHODS: Depression was assessed by the patient health questionnaire (PHQ)-9, and scores ≥10 indicate MDD. Demographic data, LupusQoL domains, clinical and other features of the SLE patients were described and compared between MDD (PHQ-9 ≥10) and non-MDD (PHQ-9 <10) groups using χ2 tests for categorical variables and Wilcoxon rank sum tests for non-normal continuous variables. The risk of MDD was evaluated for the patient and physician-reported features individually using log-binomial models to estimate relative risks and 95% confidence limits. RESULTS: Eighty-eight patients with SLE met eligibility criteria, with a mean (range) age of 48.6 (19-80), mostly female (80%) and with a mean disease duration of 13.2 years. Compared with the non-MDD group, patients with MDD (n = 32, 36%) were more likely to have the following SLE manifestations: mucocutaneous, vascular, ocular, pulmonary and musculoskeletal involvement. Self-rated health described as poor/fair was markedly associated with MDD (P < 0.001, relative risk = 0.48). Based on relative risks, higher pain visual analogue score, and patient and physician global assessment scores were also linked to MDD. The LupusQoL domain scores were notably lower in the MDD patients, with a statistically significant reduction in all LupusQoL domains. CONCLUSION: Predictors of MDD in SLE patients include higher scores in pain and global assessment, poor or fair self-reported health, and specific organ involvement. These findings may help clinicians to recognize and manage MDD promptly.