Major Depressive Disorder Duration Research Articles

A real-world study examining the impact of esketamine nasal spray in people living with major depressive disorder in Australia and New Zealand

IntroductionEsketamine has been approved in Australia and New Zealand as a third-line antidepressant treatment for treatment resistant depression. This study describes changes in quality of life, depressive symptoms and productivity in participants treated with esketamine in real-world settings. MethodsParticipants were recruited from an esketamine early access program and had not responded to two or more different antidepressants and not received neurostimulation for their current depressive episode. Participants received esketamine for 16 weeks or longer. Data collected included Assessment of Quality-of-Life scale (AQoL-8D), Hamilton Depression Rating Scale (HAM-D) and Work Productivity Activity Index (WPAI). ResultsParticipants (n = 105) had a mean age of 38.7 years (standard deviation (SD) = 14.6) and were predominantly female (59.0%). The mean duration of major depressive disorder was 7.2 years (SD = 4.2) and almost half of participants had been treated with 3–5 prior therapies. After 16-weeks on esketamine, participants showed improvement of greater than 10% across all dimensions of AQoL-8D, HAM-D scores decreased 8.0 points, and activity impairment decreased 20.4% as measured by WPAI. LimitationsThis was a non-randomized and unblinded study and may have selection and reporting bias. The population was not necessarily representative of the broader Australian and New Zealand population. It is not possible to determine if the results will be sustained or changed if participants received treatment for longer. ConclusionsEsketamine early access program participants, who were a real-world cohort with extensive prior treatment, showed clinically significant improvements in quality of life, depression severity and productivity after 16-weeks on treatment.

Educational inequalities in major depressive disorder prevalence, timing and duration among adults over the life course: a microsimulation analysis based on the Lifelines Cohort Study.

Educational inequalities in major depressive disorder (MDD) pose a major challenge. Tackling this issue requires evidence on the long-term impact of intervening on modifiable factors, for example lifestyle and psychosocial factors. For this reason, we aimed to simulate the development of educational inequalities in MDD across the life course, and to estimate the potential impact of intervening on modifiable factors. We used data from the prospective Dutch Lifelines Cohort Study to estimate the required input for a continuous-time microsimulation. The microsimulation allowed us to project the development of educational inequalities in MDD between ages 18 and 65, and to assess the potential benefit of intervening on quality of social contacts, health literacy and smoking. On average, an additional 19.1% of individuals with low education will ever experience MDD between ages 18 and 65 compared with those with high education. Additionally, individuals with low education generally will develop MDD 0.9 years earlier and spend 1.2 years more with MDD, than individuals with high education. Improving the quality of social contacts in individuals with low education produced the largest effect; it would reduce the inequalities in the prevalence, onset and duration of MDD by an average of 18.4%, 18.3% and 28.6%, respectively. Intervening on modifiable factors, particularly quality of social contacts, in individuals with low education could help reduce the estimated educational inequalities in MDD over the life course.

Long-term outcomes of an internet-delivered cognitive enhancement intervention targeting residual cognitive deficits after major depressive disorder: a 2-year follow-up of an open trial.

Cognitive deficits are common and disabling residual symptoms following major depressive disorder (MDD) and are related to increased risk of relapse. Residual cognitive deficits should thus be considered an important target for treatment. However, few have reported long-term outcomes of interventions targeting residual cognitive deficits. This study aimed to (1) investigate change between pre-treatment and 2-year follow-up assessments in cognitive deficits, rumination, and symptoms of MDD after an internet-delivered intervention targeting residual cognitive deficits; (2) to investigate stability in outcomes between 6-month and 2-year follow-up assessments; (3) to report the number of participants' experiencing a new episode of MDD in the follow-up period; and (4) to investigate differences in outcomes between those who experienced a new episode of MDD and those who did not. A total of 43 partly remitted adults were included to test a guided internet-delivered intervention, which consisted of 10 modules involving psychoeducation, cognitive strategies, and attention training. Participants were assessed at pre-treatment, post-treatment, after 6-months, and after 2-years, with measures assessing self-reported residual cognitive deficits, rumination, symptoms of MDD and relapse. Overall, 32 participants completed the 2-year follow-up assessment. Between the pre-treatment and 2-year follow-up assessments, there was a reduction in cognitive deficits and rumination, while there was an increase in symptoms of MDD. Cognitive deficits were stable between the 6-month and the 2-year follow-up, while there was an increase in rumination and symptoms of MDD. Thirteen of 32 participants reported a new episode of MDD during the follow-up period. The relapse group reported longer duration of MDD at pre-treatment and showed a difference in all outcomes after 2 years compared to the no-relapse group. The no-relapse group showed improvement in MDD symptoms at post-treatment, while the relapse group did not. Delivering cognitive enhancement interventions over the internet is potentially related to stable improvements in residual cognitive deficits. The effects on rumination and symptoms of MDD are less certain. Lack of improvement in MDD symptoms after the intervention period should be investigated as an indicator of relapse. Results should be interpreted with caution due to the lack of control group and sample size.

Volumes of hippocampal subfields suggest a continuum between schizophrenia, major depressive disorder and bipolar disorder.

There is considerable debate as to whether the continuum of major psychiatric disorders exists and to what extent the boundaries extend. Converging evidence suggests that alterations in hippocampal volume are a common sign in psychiatric disorders; however, there is still no consensus on the nature and extent of hippocampal atrophy in schizophrenia (SZ), major depressive disorder (MDD) and bipolar disorder (BD). The aim of this study was to verify the continuum of SZ - BD - MDD at the level of hippocampal subfield volume and to compare the volume differences in hippocampal subfields in the continuum. A total of 412 participants (204 SZ, 98 MDD, and 110 BD) underwent 3 T MRI scans, structured clinical interviews, and clinical scales. We segmented the hippocampal subfields with FreeSurfer 7.1.1 and compared subfields volumes across the three diagnostic groups by controlling for age, gender, education, and intracranial volumes. The results showed a gradual increase in hippocampal subfield volumes from SZ to MDD to BD. Significant volume differences in the total hippocampus and 13 of 26 hippocampal subfields, including CA1, CA3, CA4, GC-ML-DG, molecular layer and the whole hippocampus, bilaterally, and parasubiculum in the right hemisphere, were observed among diagnostic groups. Medication treatment had the most effect on subfields of MDD compared to SZ and BD. Subfield volumes were negatively correlated with illness duration of MDD. Positive correlations were found between subfield volumes and drug dose in SZ and MDD. There was no significant difference in laterality between diagnostic groups. The pattern of hippocampal volume reduction in SZ, MDD and BD suggests that there may be a continuum of the three disorders at the hippocampal level. The hippocampus represents a phenotype that is distinct from traditional diagnostic strategies. Combined with illness duration and drug intervention, it may better reflect shared pathophysiology and mechanisms across psychiatric disorders.

Early maladaptive schema domains and suicide risk in major depressive disorder: the mediating role of patients’ illness-related self-regulation processes and symptom severity

AbstractEarly maladaptive schemas (EMS), illness representations, and coping are associated with clinical outcomes of patients with major depressive disorder (MDD). However, the pathways that link these factors are largely unknown. The present prospective study aimed at investigating the possible mediating role of illness representations and coping in the associations among schema domains, symptom severity, and suicide risk in MDD. Participants were 135 patients diagnosed with MDD, aged 48.13 ± 14.12 (84.4% females). The Young Schema Questionnaire-Short Form 3 was used to measure schema domains at baseline. Illness representations and coping were measured at approximately five months later (mean = 5.04 ± 1.16 months) with the Illness Perception Questionnaire-Mental Health and the Brief COPE Inventory, respectively. MDD outcomes were measured about 10 months after the baseline assessment (mean = 9.44 ± 2.36 months) with the Beck Depression Inventory and the Risk Assessment Suicidality Scale. SPSS AMOS 27 was used to conduct path analysis. Serial mediation Structural Equation Modelling, controlling for age, education, marital status, working status, MDD duration, pharmacotherapy, and psychotherapy, revealed that Impaired Autonomy and Performance was positively linked to suicide risk. Negative MDD impact representations and symptom severity serially mediated the aforementioned association. Finally, problem-focused coping was negatively related to symptom severity and suicide risk. This study’s main limitation was modest sample size. Representations regarding the impact and severity of MDD mediate the effects of Impaired Autonomy and Performance on future suicide risk in MDD. Healing Impaired Autonomy and Performance domain of EMS, restructuring patients’ representations of high MDD impact, and enhancing problem-focused coping could significantly reduce symptom severity and suicide risk in Schema Therapy with MDD individuals.

Regionally decreased cortical gyrification in patients with major depressive disorder

IntroductionEarly neurodevelopmental deviations, such as abnormal cortical folding patterns, are a candidate biomarker for major depressive disorder (MDD). Previous studies on patterns of abnormal cortical gyrification in MDD have provided valuable insights; however, the findings on cortical folding are controversial.ObjectivesWe aimed to investigate the association of MDD with the local gyrification index (LGI) in each cortical region at the whole-brain level and the association of the LGI with clinical characteristics of MDD, including recurrence, remission status, illness duration, severity of depression, and medication status of patients with MDD.MethodsWe obtained T1-weighted images of 234 patients with MDD and 215 healthy controls (HCs). LGI values were automatically calculated using the FreeSurfer software according to the Desikan–Killiany atlas. LGI values from 66 cortical regions in the bilateral hemispheres were analyzed. We compared the LGI values between the MDD and HC groups using the analysis of covariance, including patients’ age, sex, and years of education as covariates. The association between clinical characteristics and LGI values was investigated in the MDD group.ResultsCompared with HCs, patients with MDD showed significantly decreased LGI values in the cortical regions, including the bilateral ventrolateral and dorsolateral prefrontal cortices, medial and lateral orbitofrontal cortices, insula, right rostral anterior cingulate cortex, and several temporal and parietal regions, with the highest effect size in the left pars triangularis (Cohen’s f = 0.361; P = 1.78 × 10-13). As for the association of clinical characteristics with LGIs within the MDD group, recurrence and longer illness duration of MDD were associated with increased gyrification in several occipital and temporal regions, which showed no significant difference in LGIs between MDD and HC groups.ConclusionsConsidering that the aforementioned cortical regions are involved in emotion regulation, abnormal cortical folding patterns in such regions may be associated with the dysfunction of emotion regulation-related neural circuits, which may lead to MDD. These findings suggest that LGI may be a relatively stable neuroimaging marker associated with the trait of MDD predisposition.Disclosure of InterestNone Declared

Clinical correlates of autoimmune thyroiditis and non-autoimmune hypothyroidism in treatment-naïve patients with major depressive disorders

BackgroundThyroid autoimmunity is a potentially critical factor that is often neglected in the association between subclinical hypothyroidism (SCH) and depressive disorders. This study aimed to investigate the clinical correlates of autoimmune thyroiditis (AIT) and non-autoimmune hypothyroidism (NAIH) in treatment-naïve patients with major depressive disorder (MDD). MethodUsing a cross-sectional design, we recruited a total of 1718 outpatients with treatment-naïve MDD. Demographic and relevant clinical information including duration of MDD, severity of depression and anxiety, psychotic symptoms, suicide attempts, thyroid function parameters, etc. were collected. According to thyroid function parameters, patients were classified as AIT, NAIH, latent Hashimoto's thyroiditis (LH) and euthyroidism (ET). ResultsPatients with SCH (including AIT and NAIH) had older age at onset, and were more likely to have psychotic symptoms compared to those with ET. Multiple linear regression analysis showed that SCH was associated with duration of MDD and HAMD scores. Logistic regression analysis showed that the odds of having more severe anxiety and metabolic syndrome were greater among patients with SCH compared to those with ET. The odds of having suicide attempts were greater among patients with AIT than among those with ET. LimitationBecause of the cross-sectional design of this study, we were unable to sort out causality between MDD and SCH. ConclusionOur findings suggested that AIT and NAIH were associated with duration of MDD, HAMD scores, severity of anxiety, and metabolic syndrome. However, only AIT in SCH was associated with suicide attempts.

Aberrant frontolimbic circuit in female depressed adolescents with and without suicidal attempts: A resting-state functional magnetic resonance imaging study.

The neurobiological basis of suicidal behaviors among female adolescents with major depressive disorder (MDD) remains largely unclear. Fifty-eight drug-naïve, first-episode female adolescent MDD [including 31 patients with suicidal attempt (SA group) and 27 patients without SA (non-SA group)], and 36 matched healthy controls (HCs) participated in the present study. Resting-state functional magnetic resonance imaging (MRI) was performed on each subject. The metrics of the amplitude of low-frequency fluctuation (ALFF), fractional ALFF (fALFF), and regional homogeneity (ReHo) were compared among the three groups. Then seed-based functional connectivity (FC) was conducted based on the ALFF/fALFF and ReHo results, which were then correlated to clinical variables. Compared with the non-SA group, the SA group exhibited increased fALFF in the bilateral insula and right precentral gyrus, and enhanced ReHo in the left superior temporal gyrus, left middle cingulate cortex, right insula, and right precentral gyrus. Relative to the HCs, the SA group demonstrated additionally reduced fALFF and ReHo in the left middle frontal gyrus. Moreover, the SA group showed increased FC between the right precentral gyrus and the left middle frontal gyrus and left insula, and between the right insula and anterior/middle cingulate cortex compared to the non-SA and HC groups. In addition, the fALFF in the left middle frontal gyrus was positively correlated with the 17-item Hamilton Depression Rating Scale scores, and the values in the fALFF/ReHo in the right insula were positively correlated with the duration of MDD within the patient group. These findings highlight the multiple abnormalities of the frontolimbic circuit, which may enhance our understanding of the neurobiological basis underlying female MDD with SA during adolescence.

Educational inequalities in major depressive disorder over the adult life course: a microsimulation

Abstract Background Educational inequalities in major depressive disorder (MDD) pose a major challenge. Tackling this issue requires evidence on the long-term impact of intervening on modifiable factors, e.g. behavioural and psychosocial factors. Therefore, we aim to simulate the development of educational inequalities in MDD across the life course, and to assess the impact of intervening on the modifiable factors that contribute to these inequalities. Methods We used data from the prospective Dutch Lifelines Cohort Study to estimate the required input for a continuous-time microsimulation. The microsimulation allowed us to estimate the development of educational inequalities in MDD with a synthetic cohort of 500,000 individuals followed from ages 18 to 65, and to assess the potential benefit of intervening on quality of social contacts, health literacy, and smoking. Results On average, an additional 19.1% of individuals with low education will ever experience MDD between ages 18 and 65 compared to those with high education (32.0% vs 12.9%, respectively). Additionally, individuals with low education generally will develop MDD 0.9 years earlier (35.6 years vs 36.5 years, respectively) and spend 1.2 years more with MDD (6.2 years vs 5 years, respectively), than individuals with high education. Improving the quality of social contacts in individuals with low education would have the largest impact; it would reduce the inequalities in the prevalence, onset, and duration of MDD by an average of 18.4%, 18.3%, and 28.6%, respectively. Conclusions Intervening on modifiable factors, especially quality of social contacts, in individuals with low education could help reduce the large estimated educational inequalities in MDD over the life course. Key messages • There are large educational inequalities in major depressive disorder (MDD) over the life course, especially with regard to the life course prevalence of MDD. • Improving quality of social contacts, and to a lesser extent health literacy and smoking behaviours, amongst individuals with low education may help reduce the inequalities in MDD.

Development and Clinical Application of Positron Emission Tomography Imaging Agents for Monoamine Oxidase B.

Monoamine oxidase B (MAO-B) is a high-density protein in the brain mainly found on outer mitochondrial membranes, primarily in astroglia, but additionally in serotonergic neurons and in the substantia nigra in the midbrain. It is an enzyme that participates in the oxidative metabolism of important monoamines including dopamine, norepinephrine, benzylamine, and phenylethylamine. Elevated MAO-B density may be associated with astrogliosis and inhibiting MAO-B may reduce astrogliosis. MAO-B density is elevated in postmortem sampling of pathology for many neuropsychiatric diseases including Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, amyotrophic lateral sclerosis, and alcohol use disorder. Initial development of positron emission tomography (PET) imaging agents focused on analogs of [11C]L-deprenyl, with the most commonly applied being the deuterium substituted [11C]L-deprenyl-D2. This latter radiotracer was modeled with an irreversible trapping compartment reflecting its irreversible binding to MAO-B. Subsequently, [11C]SL25.1188, a reversible binding MAO-B radioligand with outstanding properties including high specific binding and excellent reversibility was developed. [11C]SL25.1188 PET was applied to discover a substantive elevation of MAO-B binding in the prefrontal cortex in major depressive disorder (MDD) with an effect size of more than 1.5. Longer duration of MDD was associated with greater MAO-B binding throughout most gray matter regions in the brain, suggesting progressive astrogliosis. Important applications of [11C]L-deprenyl-D2 PET are detecting a 40% loss in radiotracer accumulation in cigarette smokers, and substantial occupancy of novel therapeutics like EVT301 and sembragiline. Given the number of diseases with elevations of MAO-B density and astrogliosis, and the advance of [11C]SL25.1188, clinical applications of MAO-B imaging are still at an early stage.

Severe insomnia is associated with metabolic syndrome in women over 50 years with major depression treated in psychiatry settings: a METADAP report

IntroductionMajor depression is associated with metabolic syndrome and cardiovascular risk. We have previously shown that severe insomnia, a core symptom of major depression episode (MDE), is associated with hypertriglyceridemia, a component of metabolic syndrome, in women but not in men with major depression. Since insomnia is related to cardiovascular morbidity in the general population and major depression also, our objective was to assess the link between insomnia and metabolic syndrome, a marker syndrome of cardiovascular risk, during MDE, in women and in men. MethodsIn 624 patients with a current MDE cohort, both insomnia and metabolic syndrome were assessed in women and men. Insomnia was rated from 0 to 6 based on the HDRS corresponding items, severe insomnia being defined by a total insomnia score ≥4. Resultssevere insomnia was associated with metabolic syndrome in women but not in men. In multivariate logistic regressions, these results in women were independent from age, educational level, major depressive disorder duration and current smoking. These results were only significant in women aged ≥50 years, a cut-off age for menopausal status but not in women under 50 years. ConclusionWomen aged ≥50 years with a severe insomnia during MDE have an increased risk of metabolic syndrome. Severe insomnia may be a clinical marker of metabolic risk in this population. They should be particularly monitored for metabolic syndrome and may benefit from sleep recommendations and cardiovascular prevention.

Effectiveness of trauma-focused treatment for adolescents with major depressive disorder

ABSTRACT Background: Major Depressive Disorder (MDD) in adolescence has a high prevalence and risk of disability, but current treatments show limited effectiveness and high drop-out and relapse rates. Although the role of distressing experiences that relate to the development and maintenance of MDD has been recognized for decades, the efficacy of a trauma-focused treatment approach for MDD has hardly been studied. Objective: To determine the effectiveness of eye movement desensitization and reprocessing (EMDR) therapy as a stand-alone intervention in adolescents diagnosed with MDD. We hypothesized that reprocessing core memories related to the onset and maintenance of MDD using EMDR therapy would be associated with a significant decrease in depressive and comorbid symptoms. Method: We recruited 32 adolescents (12–18 years) fulfilling DSM-IV criteria for mild to moderate-severe MDD from an outpatient youth mental health care unit. Treatment consisted of six weekly 60-min individual sessions. Presence or absence of MDD classification (ADIS-C), symptoms of depression (CDI), symptoms of posttraumatic stress (UCLA), anxiety (SCARED), somatic complaints (CSI), and overall social-emotional functioning (SDQ) were assessed pre and post-treatment and 3 months after treatment. Results: 60.9% of the adolescents completing treatment no longer met DSM-IV criteria for MDD after treatment anymore, and 69.8% at follow-up. Multilevel analyses demonstrated significant posttreatment reductions of depressive symptoms (CDI: Cohen’s d = 0.72), comorbid posttraumatic stress, anxiety and somatic complaints, while overall social-emotional functioning improved. These gains were maintained at 3-month follow-up (Cohen’s d = 1.11). Severity of posttraumatic stress reactions significantly predicted the posttreatment outcome; however, duration of MDD, number of comorbid disorders, or having a history of emotional abuse, emotional neglect or physical neglect were not predictive for outcome. Conclusions: This is the first study suggesting that EMDR therapy is associated with a significant reduction of depressive symptoms and comorbid psychiatric problems in adolescents with mild to moderate-severe MDD.

Reduced default mode network functional connectivity in patients with recurrent major depressive disorder.

Major depressive disorder (MDD) is common and disabling, but its neuropathophysiology remains unclear. Most studies of functional brain networks in MDD have had limited statistical power and data analysis approaches have varied widely. The REST-meta-MDD Project of resting-state fMRI (R-fMRI) addresses these issues. Twenty-five research groups in China established the REST-meta-MDD Consortium by contributing R-fMRI data from 1,300 patients with MDD and 1,128 normal controls (NCs). Data were preprocessed locally with a standardized protocol before aggregated group analyses. We focused on functional connectivity (FC) within the default mode network (DMN), frequently reported to be increased in MDD. Instead, we found decreased DMN FC when we compared 848 patients with MDD to 794 NCs from 17 sites after data exclusion. We found FC reduction only in recurrent MDD, not in first-episode drug-naïve MDD. Decreased DMN FC was associated with medication usage but not with MDD duration. DMN FC was also positively related to symptom severity but only in recurrent MDD. Exploratory analyses also revealed alterations in FC of visual, sensory-motor, and dorsal attention networks in MDD. We confirmed the key role of DMN in MDD but found reduced rather than increased FC within the DMN. Future studies should test whether decreased DMN FC mediates response to treatment. All R-fMRI indices of data contributed by the REST-meta-MDD consortium are being shared publicly via the R-fMRI Maps Project.

Monoamine Oxidase B Total Distribution Volume in the Prefrontal Cortex of Major Depressive Disorder

Monoamine oxidase B (MAO-B) is an important, high-density enzyme in the brain that generates oxidative stress by hydrogen peroxide production, alters mitochondrial function, and metabolizes nonserotonergic monoamines. Recent advances in positron emission tomography radioligand development for MAO-B in humans enable highly quantitative measurement of MAO-B distribution volume (MAO-B VT), an index of MAO-B density. To date, this is the first investigation of MAO-B in the brain of major depressive disorder that evaluates regions beyond the raphe and amygdala. To investigate whether MAO-B VT is elevated in the prefrontal cortex in major depressive episodes (MDEs) of major depressive disorder. This case-control study was performed at a tertiary care psychiatric hospital from April 1, 2014, to August 30, 2018. Twenty patients with MDEs without current psychiatric comorbidities and 20 age-matched controls underwent carbon 11-labeled [11C]SL25.1188 positron emission tomography scanning to measure MAO-B VT. All participants were drug and medication free, nonsmoking, and otherwise healthy. The MAO-B VT in the prefrontal cortex (PFC). The second main outcome was to evaluate the association between MAO-B VT in the PFC and duration of major depressive disorder illness. Twenty patients with MDEs (mean [SD] age, 34.2 [13.2] years; 11 women) and 20 healthy controls (mean [SD] age, 33.7 [13.1] years; 10 women) were recruited. Patients with MDEs had significantly greater MAO-B VT in the PFC (mean, 26%; analysis of variance, F1,38 = 19.6, P < .001). In individuals with MDEs, duration of illness covaried positively with MAO-B VT in the PFC (analysis of covariance, F1,18 = 15.2, P = .001), as well as most other cortex regions and the thalamus. Fifty percent (10 of 20) of patients with MDEs had MAO-B VT values in the PFC exceeding those of healthy controls. Greater MAO-B VT is an index of MAO-B overexpression, which may contribute to pathologies of mitochondrial dysfunction, elevated synthesis of neurotoxic products, and increased metabolism of nonserotonergic monoamines. Hence, this study identifies a common pathological marker associated with downstream consequences poorly targeted by the common selective serotonin reuptake inhibitor treatments. It is also recommended that the highly selective MAO-B inhibitor medications that are compatible for use with other antidepressants and have low risk for hypertensive crisis should be developed or repurposed as adjunctive treatment for MDEs.

Early weight gain predicts later metabolic syndrome in depressed patients treated with antidepressants: Findings from the METADAP cohort

BackgroundMetabolic syndrome (MetS) is a major public health issue. We assessed whether early weight gain predicts later MetS in depressed patients treated with antidepressants. MethodsIn the 6-month prospective METADAP cohort, 260 non-overweight patients with a Major Depressive Disorder (MDD) and a current Major Depressive Episode (MDE) were assessed for early weight gain (>5%) after one month of treatment, and for the later incidence of MetS after three and six months of treatment. Outcome variables were MetS, the number of MetS criteria, and each MetS criterion (high Waist Circumference (WC), high Blood Pressure (BP), high triglyceridemia (TG), low HDL-Cholesterolemia, and high Fasting Plasma Glucose (FPG). Multivariate models were adjusted for age, sex, previous MDD duration, severity of current MDE, and antidepressants. Results24.6% of patients had early weight gain. Compared to those without weight gain, patients with early weight gain had higher MetS incidence: 16.7% vs. 6.9% after 3 months (p = 0.07), and 23.8% vs. 7.1% after 6 months (p = 0.02). Among completers (n = 120), early weight gain was significantly associated with later MetS incidence (OR: 5.5) and a higher number of MetS criteria (IRR: 1.7). This effect was driven by the WC, TG, and HDL-C criteria. ConclusionCompared to Non-early weight gainers, patients with early weight gain in the first month of antidepressant treatment have a significant higher risk of developing MetS during the 6 months of treatment. Early weight monitoring is recommended in order to set preventive measures to avoid new metabolic syndromes in depressed patients treated with antidepressants.

The Hippocampus in Depression: More Than the Sum of Its Parts? Advanced Hippocampal Substructure Segmentation in Depression

BackgroundHippocampal volume reduction is the most replicated finding in neuroimaging studies of major depressive disorder (MDD). Varying hippocampal volume definition is a well-established problem in this field. Given that hippocampal function can be mapped onto anatomically defined substructures and that detailed examination of substructure volumes is now possible, we examined different hippocampal composite measures in MDD to look for hippocampal markers of MDD. MethodsMagnetic resonance imaging brain scans were compared between 80 patients with a range of MDD duration and 83 healthy control subjects. High-resolution T1-weighted and T2-weighted–fluid-attenuated inversion recovery magnetic resonance images were examined using the automated hippocampal substructure module in FreeSurfer 6.0. Between-group volumetric assessments were performed at substructure and composite substructures levels. ResultsPatients with MDD showed a bilateral pattern of volume reduction in principal hippocampal substructures: the cornu ammonis (CA1–CA4), dentate gyrus, and subiculum. Changes were more pronounced on the left of these structures and in recurrent depression. CA2 to CA4 were the only substructures reduced in first-presentation depression. Overall changes were most marked in the left CA1, and CA1 volume was a predictor of illness duration. ConclusionsHippocampal involvement in MDD is confined to principal substructures only. Differences between patients with MDD and healthy control subjects increased with progressively restricted hippocampal definitions, with the left CA1 emerging as a potential marker of MDD. Changes were more extensive in patients with recurrent, as opposed to first-presentation, MDD, suggesting a hippocampal disease process. These findings identify core hippocampal regions in the pathology of MDD, suggesting a potential marker of disease progression in MDD.

Twenty-Five Cohorts of Major Depressive Disorder in China: Evidence for Reduced But Not Enhanced Default Mode Network Functional Connectivity

Background: Major Depressive Disorder (MDD) is common and disabling, but its neural pathophysiology remains unclear. Functional brain network studies in MDD have largely had limited statistical power and data analysis approaches have varied widely. The REST-meta-MDD Project of resting-state fMRI (R-fMRI) addresses these issues. Methods: The 25 research groups in China composing the REST-meta-MDD Project contributed R-fMRI data of 1,300 patients with MDD and 1,128 normal controls (NCs). The data were preprocessed locally with a standardized protocol prior to aggregated group analyses. We focused on functional connectivity (FC) within the default mode network (DMN), frequently reported to show increased FC in MDD. Outcomes: We found decreased instead of increased DMN FC in MDD compared to NCs. We found FC reduction only in recurrent MDD, not in first-episode drug-naive MDD. Decreased DMN FC was associated with medication usage but not with MDD duration or severity. Exploratory analyses also revealed alterations of local intrinsic activity in MDD. Interpretation: We confirmed the key role of DMN in MDD but found reduced rather than increased FC within the DMN. Future studies should test whether decreased DMN FC mediates treatment response. All the R-fMRI indices have been made publicly available via the R-fMRI Maps Project. The REST-meta-MDD model can be generalized to longitudinal MDD studies and to other psychiatric disorders. Funding Statement: This work was supported by the National Key R&D Program of China (2017YFC1309902), the National Natural Science Foundation of China (81671774, 81630031 and 81371488), the Hundred Talents Program of the Chinese Academy of Sciences, Beijing Municipal Science & Technology Commission (Z161100000216152 and Z171100000117016), Department of Science and Technology, Zhejiang Province (2015C03037). Declaration of Interests: All the authors declare no competing financial interests. Ethics Approval Statement: All contributed data were from studies approved by local Institutional Review Boards. Data submitted to the consortium were fully deidentified and anonymized.

Vilazodone efficacy in subgroups of patients with major depressive disorder

The efficacy of antidepressants to treat major depressive disorder (MDD) varies by patient characteristics. This post-hoc analysis evaluated the effects of vilazodone across patient subgroups in adults with MDD. Data were pooled from four trials of vilazodone (NCT00285376, NCT00683592, NCT01473394, and NCT01473381). Mean change from baseline to week 8 in Montgomery-Åsberg Depression Rating Scale (MADRS) total score, MADRS response (≥50% total score improvement), and MADRS remission (total score≤10) were analyzed in the pooled intent-to-treat population (vilazodone=1254, placebo=964) and in subgroups of patients categorized by sex, age, MDD duration, recurrent episodes, baseline MADRS total score, and current episode duration. MADRS total score improvement was significantly greater with vilazodone versus placebo in the intent-to-treat population and in all patient subgroups (P<0.001). MADRS response and remission rates significantly separated from placebo (P<0.05) regardless of age, sex, MDD duration, recurrent MDD, and baseline symptom severity [except remission in patients with very severe baseline symptoms (MADRS score≥35)] and in patients with a shorter current episode duration (≤12 months). Despite the limitations associated with analyzing uncommon outcomes (e.g. MADRS remission) in small subgroups, vilazodone was an effective treatment in multiple patient populations, including those where reduced efficacy has previously been reported: males, older individuals, patients with a longer duration of MDD, and patients with recurrent depression.

Factors impacting the efficacy of venlafaxine extended release 75-225 mg/day in patients with major depressive disorder: exploratory post hoc subgroup analyses of a randomized, double-blind, placebo-controlled study in Japan.

PurposeTo explore the potential factors impacting the efficacy of venlafaxine extended release (ER) and treatment differences between 75 mg/day and 75–225 mg/day dose in patients with major depressive disorder (MDD).MethodsWe performed exploratory post hoc subgroup analyses of a randomized, double-blind, placebo-controlled study conducted in Japan. A total of 538 outpatients aged 20 years or older with a primary diagnosis of MDD who experienced single or recurrent episodes were randomized into three groups: fixed-dose, flexible-dose, or placebo. Venlafaxine ER was initiated at 37.5 mg/day and titrated to 75 mg/day for both fixed-dose and flexible-dose group, and to 225 mg/day for flexible-dose group (if well tolerated). Efficacy endpoints were changes from baseline at Week 8 using the Hamilton Rating Scale for Depression–17 items (HAM-D17) total score, Hamilton Rating Scale for Depression–6 items score, and Montgomery–Asberg Depression Rating Scale total score. The following factors were considered in the subgroup analyses: sex, age, HAM-D17 total score at baseline, duration of MDD, duration of current depressive episode, history of previous depressive episodes, history of previous medications for MDD, and CYP2D6 phenotype. For each subgroup, an analysis of covariance model was fitted and the adjusted mean of the treatment effect and corresponding 95% CI were computed. Due to the exploratory nature of the investigation, no statistical hypothesis testing was used.ResultsVenlafaxine ER improved symptoms of MDD compared with placebo in most subgroups. The subgroup with a long duration of MDD (>22 months) consistently showed greater treatment benefits in the flexible-dose group than in the fixed-dose group.ConclusionThese results suggest that a greater treatment response to venlafaxine ER (up to 225 mg/day) can be seen in patients with a longer duration of MDD. Further investigations are needed to identify additional factors impacting the efficacy of venlafaxine ER.

Autonomic dysfunction of gastric motility in major depression

BackgroundPatients suffering from major depressive disorder (MDD) often complain about somatic symptoms. Cardiac complaints have been examined predominantly. However, gastrointestinal complaints are also reported frequently and are associated with worse outcomes. The research concerning changes in gastric motility of these patients is rather sparse. The aim of our study was to determine dysfunction of gastric motility and gastrointestinal symptoms in MDD. The duration and severity of MDD were examined regarding its influence over gastric emptying. MethodsGastric emptying was determined by a 13C-acetate breath test in patients with MDD (n = 29) and healthy control subjects (n = 51). Prior to this, depressive illness was operationalized using external and self-assessment scales (HAMD-21, MADRS, BDI, CGI). Whether the severity or duration of MDD influenced the gastric emptying parameters was examined using Spearman's correlation. In addition, autonomic complaints were recorded by means of an ANS score. Each ANS score item was determined using a Mann-Whitney U or Kruskal-Wallis test concerning the gastric emptying parameters. ResultsThere was a significant difference in the parameters of the maximum gastric emptying rate (Tmax) and gastric half emptying time T1/2b between patients with MDD and healthy control subjects (Tmax 66.21min vs 53.35min, p < 0.006, T1/2b 207.59min vs 133.27min, p < 0.005).There was a significant negative correlation between Tmax and the severity of MDD determined with the depression rating scales BDI (Spearman's rank − 0.521, p = 0.013) and HAMD-21 (r − 0.384, p = 0.048).No correlation was found between the duration of MDD and the maximum gastric emptying rate (r − 0.125, p = 0.519) and gastric half emptying time (r − 0.62, p = 0.749). ConclusionGastrointestinal motility is significantly impaired in patients with MDD compared to healthy control subjects. Autonomic complaints were indicated frequently in MDD patients. The duration of MDD had no influence over the time of gastric emptying. There was a significant negative correlation between the severity of MDD and Tmax, indicating that the Tmax was reached earlier with the progression of MDD. The slowing of gastric motility in MDD patients is likely a result of a dysfunction of the autonomic nervous system.