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About 20% of major depressive episodes become chronic and medication-refractory and also appear to be less responsive to standard cognitive-behavioural therapy (CBT). To test whether CBT developed from behavioural activation principles that explicitly and exclusively targets depressive rumination enhances treatment as usual (TAU) in reducing residual depression. Forty-two consecutively recruited participants meeting criteria for medication-refractory residual depression were randomly allocated to TAU v. TAU plus up to 12 sessions of individual rumination-focused CBT. The trial has been registered (ISRCTN22782150). Adding rumination-focused CBT to TAU significantly improved residual symptoms and remission rates. Treatment effects were mediated by change in rumination. This is the first randomised controlled trial providing evidence of benefits of rumination-focused CBT in persistent depression. Although suggesting the internal validity of rumination-focused CBT for residual depression, the trial lacked an attentional control group so cannot test whether the effects were as a result of the specific content of rumination-focused CBT v. non-specific therapy effects.

Despite established clinical associations among major depression (MD), alcohol dependence (AD), and alcohol consumption (AC), the nature of the causal relationship between them is not completely understood. We leveraged genome-wide data from the Psychiatric Genomics Consortium (PGC) and UK Biobank to test for the presence of shared genetic mechanisms and causal relationships among MD, AD, and AC. Linkage disequilibrium score regression and Mendelian randomization (MR) were performed using genome-wide data from the PGC (MD: 135 458 cases and 344 901 controls; AD: 10 206 cases and 28 480 controls) and UK Biobank (AC-frequency: 438 308 individuals; AC-quantity: 307 098 individuals). Positive genetic correlation was observed between MD and AD (rgMD-AD = + 0.47, P = 6.6 × 10-10). AC-quantity showed positive genetic correlation with both AD (rgAD-AC quantity = + 0.75, P = 1.8 × 10-14) and MD (rgMD-AC quantity = + 0.14, P = 2.9 × 10-7), while there was negative correlation of AC-frequency with MD (rgMD-AC frequency = -0.17, P = 1.5 × 10-10) and a non-significant result with AD. MR analyses confirmed the presence of pleiotropy among these four traits. However, the MD-AD results reflect a mediated-pleiotropy mechanism (i.e. causal relationship) with an effect of MD on AD (beta = 0.28, P = 1.29 × 10-6). There was no evidence for reverse causation. This study supports a causal role for genetic liability of MD on AD based on genetic datasets including thousands of individuals. Understanding mechanisms underlying MD-AD comorbidity addresses important public health concerns and has the potential to facilitate prevention and intervention efforts.

Postpartum depression and anxiety are under-addressed public health problems with numerous treatment access barriers, including insufficiently available mental health specialist providers. To examine the effectiveness of nurse-delivered telephone interpersonal psychotherapy (IPT) for postpartum depression. Trial registration ISRCTN88987377. Postpartum women (n = 241) with major depression (on the Structured Clinical Interview for DSM-IV (SCID-I)) from 36 Canadian public health regions in rural and urban settings were randomly assigned to 12 weekly 60 min nurse-delivered telephone-IPT sessions or standard locally available care. The primary outcome was the proportion of women clinically depressed at 12 weeks post-randomisation, with masked intention-to-treat analysis. Secondary outcomes examined included comorbid anxiety, self-reported attachment and partner relationship quality. At 12 weeks, 10.6% of women in the IPT group (11/104) and 35% in the control group (35/100) remained depressed (OR = 0.22, 95% CI 0.10-0.46), with the IPT group 4.5 times less likely to be clinically depressed (SCID); 21.2% in the IPT group and 51% in the control group had an Edinburgh Postnatal Depression Scale (EPDS) score >12 (OR = 0.26, 95% CI 0.14-0.48), and attachment avoidance decreased more in the IPT group than in the control group (P = 0.02). Significant differences favoured the IPT group for comorbid anxiety and partner relationship quality at all time points, with no differences in health service or antidepressant use. None of the IPT responders relapsed by 36 weeks. Between-group SCID differences were sustained at 24 weeks, but not at 36 weeks. Nurse-delivered telephone IPT is an effective treatment for diverse urban and rural women with postpartum depression and anxiety that can improve treatment access disparities.

Suicide is a devastating public health problem and very few biological treatments have been found to be effective for quickly reducing the intensity of suicidal ideation (SI). We have previously shown that a single dose of ketamine, a glutamate N-methyl-d-aspartate (NMDA) receptor antagonist, is associated with a rapid reduction in depressive symptom severity and SI in patients with treatment-resistant depression. We conducted a randomized, controlled trial of ketamine in patients with mood and anxiety spectrum disorders who presented with clinically significant SI (n = 24). Patients received a single infusion of ketamine or midazolam (as an active placebo) in addition to standard of care. SI measured using the Beck Scale for Suicidal Ideation (BSI) 24 h post-treatment represented the primary outcome. Secondary outcomes included the Montgomery-Asberg Depression Rating Scale--Suicidal Ideation (MADRS-SI) score at 24 h and additional measures beyond the 24-h time-point. The intervention was well tolerated and no dropouts occurred during the primary 7-day assessment period. BSI score was not different between the treatment groups at 24 h (p = 0.32); however, a significant difference emerged at 48 h (p = 0.047). MADRS-SI score was lower in the ketamine group compared to midazolam group at 24 h (p = 0.05). The treatment effect was no longer significant at the end of the 7-day assessment period. The current findings provide initial support for the safety and tolerability of ketamine as an intervention for SI in patients who are at elevated risk for suicidal behavior. Larger, well-powered studies are warranted.

Both posttraumatic stress disorder (PTSD) and depression are highly comorbid with chronic pain and have deleterious effects on pain and treatment outcomes, but the nature of the relationships among chronic pain, PTSD, and depression has not been fully elucidated. This study examined 250 Veterans Affairs primary care patients with moderate to severe chronic musculoskeletal pain who participated in a randomized controlled pain treatment trial. Baseline data were analyzed to examine the independent associations of PTSD and major depression with multiple domains of pain, psychological status, quality of life, and disability. PTSD was strongly associated with these variables and in multivariate models, PTSD and major depression each had strong independent associations with these domains. PTSD demonstrated similar relationships as major depression with psychological, quality of life, and disability outcomes and significant but somewhat smaller associations with pain. Because PTSD and major depression have independent negative associations with pain, psychological status, quality of life, and disability, it is important for clinicians to recognize and treat both mental disorders in patients with chronic pain.

Major depressive disorder (MDD) and generalized anxiety disorder (GAD) have the highest co-morbidity rates within the internalizing disorders cluster, yet no Internet-based cognitive behavioural therapy (iCBT) programme exists for their combined treatment. We designed a six-lesson therapist-assisted iCBT programme for mixed anxiety and depression. Study 1 was a randomized controlled trial (RCT) comparing the iCBT programme (n = 46) versus wait-list control (WLC; n = 53) for patients diagnosed by structured clinical interview with MDD, GAD or co-morbid GAD/MDD. Primary outcome measures were the Patient Health Questionnaire nine-item scale (depression), Generalized Anxiety Disorder seven-item scale (generalized anxiety), Kessler 10-item Psychological Distress scale (distress) and 12-item World Health Organization Disability Assessment Schedule II (disability). The iCBT group was followed up at 3 months post-treatment. In study 2, we investigated the adherence to, and efficacy of the same programme in a primary care setting, where patients (n = 136) completed the programme under the supervision of primary care clinicians. The RCT showed that the iCBT programme was more effective than WLC, with large within- and between-groups effect sizes found (>0.8). Adherence was also high (89%), and gains were maintained at 3-month follow-up. In study 2 in primary care, adherence to the iCBT programme was low (41%), yet effect sizes were large (>0.8). Of the non-completers, 30% experienced benefit. Together, the results show that iCBT is effective and adherence is high in research settings, but there is a problem of adherence when translated into the 'real world'. Future efforts need to be placed on developing improved adherence to iCBT in primary care settings.

Background Generalized anxiety disorder (GAD) and major depressive disorder (MDD) are highly comorbid. A possible explanation is that they share four symptoms according to the Diagnostic and Statistical Manual of Mental Disorders—Fourth Edition—Text Revision (DSM‐IV‐TR). The present study addressed the symptom overlap of people meeting DSM‐IV‐TR diagnostic criteria for GAD, MDD, or both to investigate whether comorbidity might be explained by overlapping diagnostic criteria. Methods Participants (N = 1,218) were enrolled in the Coordinated Anxiety Learning and Management study (a randomized effectiveness clinical trial in primary care). Hypotheses were (1) the comorbid GAD/MDD group endorses the overlapping symptoms more than the nonoverlapping symptoms, and (2) the comorbid GAD/MDD group endorses the overlapping symptoms more than GAD only or MDD only groups, whereas differences would not occur for nonoverlapping symptoms. Results The overlapping GAD/MDD symptoms were endorsed more by the comorbid group than the MDD group but not the GAD group when covarying for total symptom endorsement. Similarly, the comorbid group endorsed the overlapping symptoms more than the nonoverlapping symptoms and did not endorse the nonoverlapping symptoms more than the GAD or MDD groups when covarying for total symptom endorsement. Conclusions The results suggest that comorbidity of GAD and MDD is strongly influenced by diagnostic overlap. Results are discussed in terms of errors of diagnostic criteria, as well as models of shared psychopathology that account for diagnostic criteria overlap.

Studies investigating the long-term effect of attention bias modification (ABM) in clinical samples are lacking. This study investigates the 6-months follow-up effect of ABM on depressive symptoms in participant with major depressive disorder with and without comorbid disorders. We conducted a double-blind randomized sham-controlled trial in 101 participants between 19 November 2019, and 17 August 2021. Follow-up ended 3 April 2022. Participants were allocated to ABM or sham condition twice daily for 14 consecutive days. Primary outcomes were the total score on the Beck Depression Inventory-II (BDI-II) at 6 months, mean Brief State Rumination Inventory (BSRI) score post-treatment and reduction in BSRI post-treatment. Secondary outcome was change in attentional bias (AB). The trial was preregistered in ClinicalTrials.gov (#NCT04137367). A total of 118 patients aged 18-65 years were assessed for eligibility, and 101 were randomized and subjected to intention-to-treat analyses. At 6 months, ABM had no effect on depression and anxiety compared to a sham condition. While rumination decreased during the intervention, there was no effect of condition on rumination and AB. Predictor analysis did not reveal differences between participants with ongoing major depressive episode or comorbid anxiety. Compared to sham training, there was no effect of ABM on depressive symptoms at 6-months follow-up. Since the intervention failed at modifying AB, it is unclear whether changes in AB are related to long-term outcomes.

In low-income and middle-income countries, individuals with major depressive disorder often do not receive screening and treatment. We assessed effectiveness and cost-effectiveness of an integrated care model for treating major depressive disorder in Malawi, accounting for two sets of positive externalities: household benefits and improvements in comorbidities. In this stepped-wedge, cluster-randomised, controlled trial, 14 health facilities in Neno District, Malawi, introduced screening, diagnosis, and treatment for people with major depressive disorder, using a stepped-care model of group Problem Management Plus and antidepressant therapy. Adults (ie, aged ≥18 years) residing in facility catchment areas, newly diagnosed with major depressive disorder, and actively enrolled in an integrated chronic care clinic were eligible for inclusion. People identified with high suicidal risk or psychotic symptoms were excluded. Health facilities were categorised into two strata (ie, health centres or secondary hospitals) and randomly allocated to one of five trial sequences, with intervention initiation staggered across sequences in 3-month periods. Participants were masked to trial sequence, data collectors were masked to treatment assignment, and the chief statistician was masked to treatment assignment until analysis. Services were delivered by counsellors and clinical officers at integrated chronic care clinics, and assessments took place at 3-month intervals over 27 months. Primary outcomes were changes in depressive symptom severity (measured with the Patient Health Questionnaire-9 [PHQ-9]), current depressive episode (PHQ-9 score of >10), and functioning (measured with the WHO Disability Assessment Schedule 2.0) over the 27-month period. Longitudinal mixed-effects regression analyses assessed outcomes from an intention-to-treat perspective. The trial was registered with ClinicalTrials.gov (NCT04777006) and is completed. Between Sept 1, 2021, and April 28, 2022, we conducted 15 562 screenings, resulting in 506 (3%) adults identified with major depressive disorder and 487 (3%) enrolled (395 [81%] women and 92 [19%] men). Assignment to IC3D corresponded to a 2·60-point (95% CI –3·35 to –1·86; d –0·61) reduction in depressive symptoms and 1·69-point (–2·73 to –0·65; –0·27) improvement in functioning, reflecting a reduced odds of depression after treatment roll-out (adjusted odds ratio 0·62, 95% CI 0·51 to 0·74). Integrated care for people with major depressive disorder and chronic health conditions is effective at reducing depressive symptoms, improving functioning, and reducing the odds of depression, and facilitates expansion of services through existing infrastructure. National Institute of Mental Health.

Background Metabolic disturbances have been correlated with suicidality, but little is known about the association between suicide risk and metabolic disturbances among individuals with depression. This study was to evaluate the prevalence and clinical correlations, especially cardio-metabolic associated factors of recent suicide attempts in Chinese patients with major depressive disorder (MDD). Methods A total of 288 MDD inpatients were recruited. Their clinical and demographic data together with plasma glucose, lipid and thyroid function parameters were collected. Self-Rating Depression Scale (SDS), Self-Rating Anxiety Scale (SAS) and Eysenck Personality Questionnaire (EPQ) were rated for most of the patients. Results Of these MDD inpatients, 20.14% had attempted suicide during the past 1 month. Compared to those who had not attempted suicide, the suicide attempters had a significantly longer duration of illness, lower low-density lipoprotein (LDL) cholesterol, lower total cholesterol, and more psychotic symptoms. However, all these significant results did not survive after the bonferroni correction (all p  > 0.05). A logistic regression analysis indicated that suicide attempts were associated with the lower total cholesterol and more psychotic symptoms. Conclusions Our findings support the hypothesis of the association of low plasma cholesterol level and recent suicidal attempts in patients with MDD.