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Background: England's primary care service for psychological therapy (Improving Access to Psychological Therapies [IAPT]) treats anxiety and depression, with a target recovery rate of 50%. Identifying the characteristics of patients who achieve recovery may assist in optimizing future treatment. This naturalistic cohort study investigated pre-therapy characteristics as predictors of recovery and improvement after IAPT therapy. Methods: In a cohort of patients attending an IAPT service in South London, we recruited 263 participants and conducted a baseline interview to gather extensive pre-therapy characteristics. Bayesian prediction models and variable selection were used to identify baseline variables prognostic of good clinical outcomes. Recovery (primary outcome) was defined using (IAPT) service-defined score thresholds for both depression (Patient Health Questionnaire [PHQ-9]) and anxiety (Generalized Anxiety Disorder [GAD-7]). Depression and anxiety outcomes were also evaluated as standalone (PHQ-9/GAD-7) scores after therapy. Prediction model performance metrics were estimated using cross-validation. Results: Predictor variables explained 26% (recovery), 37% (depression), and 31% (anxiety) of the variance in outcomes, respectively. Variables prognostic of recovery were lower pre-treatment depression severity and not meeting criteria for obsessive compulsive disorder. Post-therapy depression and anxiety severity scores were predicted by lower symptom severity and higher ratings of health-related quality of life (EuroQol questionnaire [EQ5D]) at baseline. Conclusion: Almost a third of the variance in clinical outcomes was explained by pre-treatment symptom severity scores. These constructs benefit from being rapidly accessible in healthcare services. If replicated in external samples, the early identification of patients who are less likely to recover may facilitate earlier triage to alternative interventions. [ABSTRACT FROM AUTHOR]

Background: Improving Access to Psychological Therapies (IAPT) is a primary care therapy service commissioned by England's National Health Service (NHS) for people with unipolar depression and anxiety-related disorders. Its scope does not extend to 'severe mental illness', including bipolar disorders (BD), but evidence suggests there is a high BD prevalence in ostensibly unipolar major depressive disorder (uMDD) samples. This study aimed to indicate the prevalence and characteristics of people with BD in a naturalistic cohort of IAPT patients. Methods: 371 participants were assessed before initiating therapy. Participants were categorised by indicated diagnoses: BD type-I (BD-I) or type-II (BD-II) as defined using a DSM diagnostic interview, bipolar spectrum (BSp, not meeting diagnostic criteria but exceeding BD screening thresholds), lifetime uMDD or other. Information about psychiatric history and co-morbidities was examined, along with symptoms before and after therapy. Results: 368 patients provided sufficient data to enable classification. 10% of participants were grouped as having BD-I, 20% BD-II, 40% BSp, 25% uMDD and 5% other. BD and uMDD participants had similar demographic characteristics, but patients meeting criteria for BD-I/BD-II had more complex psychiatric presentations. All three 'bipolar' groups had particularly high rates of anxiety disorders. IAPT therapy receipt was comparable between groups, as was therapy response (F 9704 = 1.113, p = 0.351). Conclusions: Notwithstanding the possibility that bipolar diathesis was overestimated, findings illustrate a high prevalence of BD in groups of people notionally with uMDD or anxiety. As well as improving the detection of BD, further substantive investigation is required to establish whether individuals affected by BD should be eligible for primary care psychological intervention. [ABSTRACT FROM AUTHOR]

Castro Menezes et al. examine factors differentiating bipolar and unipolar depression [[3]], which has translational potential given the well-documented, persistently high rates of mis- and delayed-diagnosis for BD, where the most frequent misdiagnosis is unipolar major depression [[4]]. Of the 154 participants with BD, 10% had an existing thyroid disorder prior to lithium therapy and almost one third of the remaining sample developed a thyroid disorder during lithium treatment. Despite the clear uncertainty, given the outstanding treatment challenges in BD, it was concluded that acetazolamide should be further examined for its putative role in managing BD [[15]]. [Extracted from the article]

Background: Ketamine may be effective in treating symptoms of anxiety, but the time profile of ketamine's anxiolytic effect is ill-defined. This systematic review and meta-analysis investigated the anxiolytic effect of ketamine at different time points across a range of clinical settings. Methods: Electronic databases were searched to capture randomised control trials measuring the anxiolytic effects of ketamine in contexts including mood disorders, anxiety disorders and chronic pain. Meta-analyses were conducted using a random-effects model. The correlations between (1) improvements in mean anxiety and depression scores, and (2) peak dissociation and improvements in mean anxiety scores were also assessed. Results: In all, 14 studies met inclusion criteria. Risk of bias was high in 11 studies. Ketamine significantly reduced anxiety scores compared to placebo at acute (<12 h; standard mean difference (SMD): −1.17, 95% confidence interval (CI) [−1.89, −0.44], p < 0.01), subacute (24 h; SMD: −0.44, 95% CI [−0.65, −0.22], p < 0.01) and sustained (7–14 days; SMD: −0.40, 95% CI [−0.63, −0.17], p < 0.01) time points. Exploratory analyses revealed improvements in anxiety and depression symptoms correlated at both subacute (R 2 = 0.621, p = 0.035) and sustained time points (R 2 = 0.773, p = 0.021). The relationship between peak dissociation and improvement in anxiety was not significant. Conclusions: Ketamine appears to offer rapid and sustained anxiety symptom relief across a range of clinical settings, with anxiolytic effects occurring within the first 12 h of administration and remaining effective for 1–2 weeks. Future studies could explore the effects of ketamine maintenance therapy on anxiety symptoms. [ABSTRACT FROM AUTHOR]

Background: Reserpine is an effective antihypertensive drug, but its role in routine practice has declined such that it is rarely used. This is largely based on the assumption that reserpine causes depression. This assumption was a foundation for the original monoamine hypothesis of depression. However, there remains conflicting evidence as to whether reserpine causes depression, and no systematic review of available evidence. Aims: We systematically reviewed evidence on effects of reserpine on depressive and related symptoms (e.g. anxiety, suicidal ideation). Method: Electronic searches of MEDLINE, Embase and PsycINFO were conducted to identify studies up to 14 February 2021. Studies of any methodological design involving reserpine-treated and reserpine-untreated conditions, in any adult human population, were included and a narrative synthesis of findings was undertaken. Risk of bias (RoB) was examined using ROBINS-I. Results: Of the 35 studies meeting inclusion criteria, 9 were randomised controlled trials. Eleven studies reported some depressogenic effects, 13 reported no effect and 11 reported putative antidepressant effects. Studies identifying depressive effects were more likely to examine people without psychiatric disorders at baseline, while studies identifying a potential antidepressant effect tended to treat fewer participants for shorter durations, at higher doses. Around one-third of studies conducted in people with psychiatric disorders showed beneficial effects on depression symptoms. 30/35 studies were at high RoB. Conclusions: Associations between reserpine and depression are inconsistent and limited by a lack of high-quality evidence. Due to reserpine's apparently complex effects, we urge nuance rather than simplicity surrounding the monoamine hypothesis of depression. [ABSTRACT FROM AUTHOR]

Background: Major depressive disorder (MDD) is a highly burdensome health condition, for which there are numerous accepted pharmacological and psychological interventions. Adjunctive treatment (augmentation/combination) is recommended for the ~50% of MDD patients who do not adequately respond to first-line treatment. We aimed to evaluate the current evidence for concomitant approaches for people with early-stage treatment-resistant depression (TRD; defined below). Methods: We systematically searched Medline and Institute for Scientific Information Web of Science to identify randomised controlled trials of adjunctive treatment of ⩾10 adults with MDD who had not responded to ⩾1 adequate antidepressant. The cochrane risk of bias (RoB) tool was used to assess study quality. Pre-post treatment meta-analyses were performed, allowing for comparison across heterogeneous study designs independent of comparator interventions. Results: In total, 115 trials investigating 48 treatments were synthesised. The mean intervention duration was 9 weeks (range 5 days to 18 months) with most studies assessed to have low (n = 57) or moderate (n = 51) RoB. The highest effect sizes (ESs) were from cognitive behavioural therapy (ES = 1.58, 95% confidence interval (CI): 1.09–2.07), (es)ketamine (ES = 1.48, 95% CI: 1.23–1.73) and risperidone (ES = 1.42, 95% CI: 1.29–1.61). Only aripiprazole and lithium were examined in ⩾10 studies. Pill placebo (ES = 0.89, 95% CI: 0.81–0.98) had a not inconsiderable ES, and only six treatments' 95% CIs did not overlap with pill placebo's (aripiprazole, (es)ketamine, mirtazapine, olanzapine, quetiapine and risperidone). We report marked heterogeneity between studies for almost all analyses. Conclusions: Our findings support cautious optimism for several augmentation strategies; although considering the high prevalence of TRD, evidence remains inadequate for each treatment option. [ABSTRACT FROM AUTHOR]

Background. Despite well-established guidelines for managing major depressive disorder, its extensive disability burden persists. This Value of Treatment mission from the European Brain Council aimed to elucidate the nature and extent of “gaps” between best-practice and current-practice care, specifically to: 1. Identify current treatment gaps along the care pathway and determine the extent of these gaps in comparison with the stepped-care model and 2. Recommend policies intending to better meet patient needs (i.e., minimize treatment gaps). Methods. After agreement upon a set of relevant treatment gaps, data pertaining to each gap were gathered and synthesized from several sources across six European countries. Subsequently, a modified Delphi approach was undertaken to attain consensus among an expert panel on proposed recommendations for minimizing treatment gaps. Results. Four recommendations were made to increase the depression diagnosis rate (from ~50% episodes), aiming to both increase the number of patients seeking help, and the likelihood of a practitioner to correctly detect depression. These should reduce time to treatment (from ~1 to ~8 years after illness onset) and increase rates of treatment; nine further recommendations aimed to increase rates of treatment (from ~25 to ~50% of patients currently treated), mainly focused on targeting the best treatment to each patient. To improve follow-up after treatment initiation (from ~30 to ~65% followed up within 3 months), seven recommendations focused on increasing continuity of care. For those not responding, 10 recommendations focused on ensuring access to more specialist care (currently at rates of ~5–25% of patients). Conclusions. The treatment gaps in depression care are substantial and concerning, from the proportion of people not entering care pathways to those stagnating in primary care with impairing and persistent illness. A wide range of recommendations can be made to enhance care throughout the pathway. [ABSTRACT FROM AUTHOR]

Threat avoidance is a prominent symptom of affective disorders, yet its biological basis remains poorly understood. Here, we used a validated task, the Joystick Operated Runway Task (JORT), combined with fMRI, to explore whether abnormal function in neural circuits responsible for avoidance underlies these symptoms. Eighteen individuals with major depressive disorder (MDD) and 17 unaffected controls underwent the task, which involved using physical effort to avoid threatening stimuli, paired with mild electric shocks on certain trials. Activity during anticipation and avoidance of threats was explored and compared between groups. Anticipation of aversive stimuli was associated with significant activation in the dorsal anterior cingulate cortex, superior frontal gyrus, and striatum, while active avoidance of aversive stimuli was associated with activity in dorsal anterior cingulate cortex, insula, and prefrontal cortex. There were no significant group differences in neural activity or behavioral performance on the JORT; however, participants with depression reported more dread while being chased on the task. The JORT effectively identified neural systems involved in avoidance and anticipation of aversive stimuli. However, the absence of significant differences in behavioral performance and activation between depressed and non-depressed groups suggests that MDD is not associated with abnormal function in these networks. Future research should investigate the basis of passive avoidance in major depression. Further, the JORT should be explored in patients with anxiety disorders, where threat avoidance may be a more prominent characteristic of the disorder. [ABSTRACT FROM AUTHOR]

Functional impairment is a major target in the treatment of bipolar disorder (BD), but the magnitude and type of functional difficulties differ across patients. Findings on predictors of overall functioning and specific functional areas are inconsistent. We aimed to characterize functional difficulties and identify factors associated with global functioning and individual domains in euthymic patients. The Functional Assessment Short Test (FAST) was used to assess overall psychosocial functioning and specific functional domains in 80 euthymic participants with BD. Participants also completed a clinical interview and a cognitive assessment. Model selection with elastic net regression was performed to identify predictors of global functioning. We then examined the association of these predictors with individual functional domains using correlation. FAST scores indicated moderate or severe impairment for 54% of the sample, with occupational functioning showing the highest impairment rate. Elastic net regression selected a model with three variables (higher residual depressive symptoms, lower executive functioning, more perceived cognitive deficits) as predictors of overall functioning. No significant associations were found between these predictors. Depressive symptoms were associated with interpersonal relationships and leisure time, executive skills with occupational functioning, and perceived deficits with cognitive functioning. Residual depressive symptoms were the strongest predictor of overall functioning which highlights the importance of assessing and targeting subthreshold symptoms for recovery. Executive difficulties were associated with functioning, particularly occupational skills, independently of depressive symptoms. Interventions targeting these difficulties, such as cognitive and functional remediation, may be key treatment options towards facilitating functional recovery. [ABSTRACT FROM AUTHOR]

Aims: Low mood and anhedonia are the core symptoms of major depressive disorder (MDD). However, there is no established visual analogue scale that measures pervasiveness of both symptoms. We aimed to validate the Maudsley 3-item Visual Analogue Scale (M3VAS) as a measure of core depressive symptoms and suicidality.Methods: This is a cross-sectional secondary analysis combining data from two randomised controlled trials covering a broad range of depression severity from euthymia to severe depression. We validated the M3VAS by testing: 1) latent construct domains using factor analysis; 2) internal consistency using Cronbach's alpha; and 3) convergent validity by correlating M3VAS scores against scores on the Quick Inventory of Depressive Symptomatology-16 item (QIDS-SR-16), which is validated for use in clinical trials.Results: Of 180 patients in the combined cohort, 177 (98.3%) provided complete data on the M3VAS and QIDS-SR-16. The mean (SD) age was 41.6 (13.0) years and 59.3% were female. Using factor analysis, one eigenvalue above 1 was produced (2.39) that explained 79.6% of the variance, indicating a one-factor model. Cronbach's alpha was 0.87, demonstrating good internal consistency. Total M3VAS scores correlated strongly (r = 0.72, p<0.001) with QIDS-SR-16 scores, indicating good convergent validity.Limitations: This was a cross-sectional study and was not validated against a clinician-rated assessment for depression.Conclusion: The M3VAS is a simple, valid instrument for the assessment of core depressive symptoms and suicidality across the depression spectrum. Future studies should test the longitudinal validity of the M3VAS in detecting changes in core depressive symptoms and suicidality over time. [ABSTRACT FROM AUTHOR]

Most interventions for treatment-resistant depression (TRD) are added as augmenters. We aimed to determine the relative effectiveness of augmentation treatments for TRD. This systematic review and network meta-analysis (NMA) sought all randomized trials of pharmacological and psychological augmentation interventions for adults meeting the most common clinical criteria for TRD. The NMA compared the intervention effectiveness of depressive symptoms for TRD augmentation. Of 36 included trials, 27 were suitable for inclusion in NMA, and no psychological trials could be included in the absence of a common comparator. Antipsychotics (13 trials), mood stabilizers (three trials), NMDA-targeting medications (five trials), and other mechanisms (3 trials) were compared against placebo. NMDA treatments were markedly superior to placebo (ES = 0.91, 95% CI 0.67 to 1.16) and head-to-head NMA suggested that NMDA therapies had the highest chance of being an effective treatment option compared to other pharmacological classes. This study provides the most comprehensive evidence of augmenters' effectiveness for TRD, and our GRADE recommendations can be used to guide guidelines to optimize treatment choices. Although conclusions are limited by paucity of, and heterogeneity between, trials as well as inconsistent reports of treatment safety. This work supports the use of NMDA-targeting medications such as ketamine. [ABSTRACT FROM AUTHOR]

Background: Treatment-resistant depression is an important contributor to the global burden of depression. Antidepressant augmentation is a recommended treatment strategy for treatment-resistant patients, but outcomes remain poor. Identifying factors that are predictive of response to augmentation treatments may improve outcomes.Aims: This review aimed to synthesise the existing literature examining predictors of response to augmentation treatments in patients who had insufficiently responded to initial treatment.Methods: A systematic search was conducted identifying 2241 unique manuscripts. 24 examining predictors of outcome to pharmacological or psychological augmentation treatment were included in this review.Results: Atypical antipsychotics were the most frequently assessed treatment class (nine studies), closely followed by mood stabilisers (eight studies). Only one eligible psychological augmentation study was identified. Early response to treatment (week 2) was the best-supported predictor of subsequent treatment outcome, reported by six studies. Many predictor variables were only assessed by one report and others such as pre-treatment severity yielded contradictory results, both within and across treatment classes.Conclusions: This review highlights the importance of early response as a predictor of pharmacological augmentation outcome, with implications for both the monitoring and treatment of resistant unipolar patients. Further replication is needed across specific interventions to fully assess the generalisability of this finding. However, the clear lack of consistent evidence for other predictive factors both within and across treatments, and the scarce examination of psychological augmentation, demonstrates the need for much more research of a high quality if response prediction is to improve outcomes for patients with treatment-resistant depression. [ABSTRACT FROM AUTHOR]

Background: Treatment-resistant depression (TRD) contributes substantially to the burden of mood disorders and is undoubtedly an important subpopulation in whom there are clear unmet treatment needs. Despite a paucity of research focusing specifically on TRD, recent studies indicate that inflammatory activity may be particularly elevated in these patients.Methods: 36 patients with TRD were investigated longitudinally before and after undertaking a specialist inpatient treatment program. 27 inflammatory proteins were compared between patients and a matched sample of non-depressed controls, as well as between treatment responders and non-responders. Treatment outcomes were calculated from depression severity scores before and after admission, and at a long-term follow-up 3-12 months after discharge.Results: TRD patients had higher levels of numerous inflammatory proteins than controls, and elevated interleukins 6 and 8, tumour necrosis factor, c-reactive protein and macrophage inflammatory protein-1 were associated with poorer treatment outcomes. A separate set of proteins (either anti-inflammatory in nature or attenuated at baseline) showed increases during treatment, regardless of clinical response. Participants with the greatest elevations in inflammation tended to be older, more cognitively impaired and more treatment-resistant at baseline.Limitations: The small sample and large number of comparisons examined in this study must be taken into account when interpreting these results.Conclusions: However, this study provides empirical support for theories that more severe, chronic or treatment-resistant depressive disorders are associated with dysregulated inflammatory activity. If a predictor or predictors of response in TRD are established, improved and targeted care might be more reliably provided to this vulnerable population. [ABSTRACT FROM AUTHOR]

Background: Depression is considered to have the highest disability burden of all conditions. Although treatment-resistant depression (TRD) is a key contributor to that burden, there is little understanding of the best treatment approaches for it and specifically the effectiveness of available augmentation approaches.AimsWe conducted a systematic review and meta-analysis to search and quantify the evidence of psychological and pharmacological augmentation interventions for TRD.Method: Participants with TRD (defined as insufficient response to at least two antidepressants) were randomised to at least one augmentation treatment in the trial. Pre-post analysis assessed treatment effectiveness, providing an effect size (ES) independent of comparator interventions.Results: Of 28 trials, 3 investigated psychological treatments and 25 examined pharmacological interventions. Pre-post analyses demonstrated N-methyl-d-aspartate-targeting drugs to have the highest ES (ES = 1.48, 95% CI 1.25-1.71). Other than aripiprazole (four studies, ES = 1.33, 95% CI 1.23-1.44) and lithium (three studies, ES = 1.00, 95% CI 0.81-1.20), treatments were each investigated in less than three studies. Overall, pharmacological (ES = 1.19, 95% CI 1.80-1.30) and psychological (ES = 1.43, 95% CI 0.50-2.36) therapies yielded higher ESs than pill placebo (ES = 0.78, 95% CI 0.66-0.91) and psychological control (ES = 0.94, 95% CI 0.36-1.52).Conclusions: Despite being used widely in clinical practice, the evidence for augmentation treatments in TRD is sparse. Although pre-post meta-analyses are limited by the absence of direct comparison, this work finds promising evidence across treatment modalities.Declaration of interestIn the past 3 years, A.H.Y. received honoraria for speaking from AstraZeneca, Lundbeck, Eli Lilly and Sunovion; honoraria for consulting from Allergan, Livanova and Lundbeck, Sunovion and Janssen; and research grant support from Janssen. In the past 3 years, A.J.C. received honoraria for speaking from AstraZeneca and Lundbeck; honoraria for consulting with Allergan, Janssen, Livanova, Lundbeck and Sandoz; support for conference attendance from Janssen; and research grant support from Lundbeck. B.B. has recently been (soon to be) on the speakers/advisory board for Hexal, Lilly, Lundbeck, Mundipharma, Pfizer, and Servier. No other conflicts of interest. [ABSTRACT FROM AUTHOR]

Background: Recent studies suggest that anti-inflammatory medication may play a role in the treatment of mood disorders.Aims: The purpose of this study was to determine the efficacy of anti-inflammatory drugs in patients with major depressive disorder and bipolar disorder.Method: The Cochrane Central Register of Controlled Trials, PubMed, EMBASE, PsychINFO and Clinicaltrials.gov were searched from inception until 15 April 2017 for completed and on-going randomized controlled trials of anti-inflammatory agents for major depressive disorder and bipolar disorder. Data from randomized controlled trials assessing the antidepressant and anti-manic effect of adjunctive mechanistically diverse anti-inflammatory agents were pooled to determine standard mean differences (SMDs) compared with placebo and/or treatment as usual.Results: Patients receiving anti-inflammatory agents showed lower post-treatment depressive symptom scores compared with those receiving placebo with a standard mean difference of -0.71 (six randomized controlled trials, n=214, 95% CI -1.24 to -0.17, p=0.009). Anti-inflammatory treatment was found to reduce post-treatment manic symptom scores with a standard mean difference of -0.72 (three randomized controlled trials, n=96, 95% CI -1.31 to -0.13, p=0.02). Anti-inflammatories did not show a statistically significant improvement in the secondary outcome measure (change in symptom scores from baseline to outcome).Conclusions: Further high quality trials are needed before making recommendations for the routine clinical use of anti-inflammatories in the treatment of mood disorders. [ABSTRACT FROM AUTHOR]

A plethora of research has implicated hundreds of putative biomarkers for depression, but has not yet fully elucidated their roles in depressive illness or established what is abnormal in which patients and how biologic information can be used to enhance diagnosis, treatment and prognosis. This lack of progress is partially due to the nature and heterogeneity of depression, in conjunction with methodological heterogeneity within the research literature and the large array of biomarkers with potential, the expression of which often varies according to many factors. We review the available literature, which indicates that markers involved in inflammatory, neurotrophic and metabolic processes, as well as neurotransmitter and neuroendocrine system components, represent highly promising candidates. These may be measured through genetic and epigenetic, transcriptomic and proteomic, metabolomic and neuroimaging assessments. The use of novel approaches and systematic research programs is now required to determine whether, and which, biomarkers can be used to predict response to treatment, stratify patients to specific treatments and develop targets for new interventions. We conclude that there is much promise for reducing the burden of depression through further developing and expanding these research avenues. [ABSTRACT FROM AUTHOR]

Background Many patients with depressive disorders demonstrate resistance to psychological therapy. A frequent finding is hypothalamic-pituitary-adrenal (HPA) axis alterations. As cortisol is known to modulate cognitive processes, those patients may be less likely to profit from psychological therapy. Aims To conduct a systematic review and meta-analysis on cortisol as a predictor of psychological therapy response. Method The Cochrane Library, EMBASE, MEDLINE and PsycINFO databases were searched. Records were included if they looked at patients with any depressive disorder engaging in psychological therapy, with a pre-treatment cortisol and a post-treatment symptom measure. Results Eight articles satisfied our selection criteria. The higher the cortisol levels before starting psychological therapy, the more symptoms patients with depression experienced at the end of treatment and/or the smaller their symptom change. Conclusions Our findings suggest that patients with depression with elevated HPA functioning are less responsive to psychological therapy. [ABSTRACT FROM AUTHOR]

The article offers information on Reynolds argues for a trial of methylfolate treatment that used before using a label of treatment-resistant depression. Topics discussed include one-carbon metabolism which refers to a complex network of biochemical reactions, including the folate cycle; and mentions methylenetetrahydrofolate reductase (MHTFR) that required in the reduction of folate.

Background: Optimising treatments for patients with treatment-resistant depression (TRD) is key to reducing the burden of this severe illness. The anti-glucocorticoid medication metyrapone has mixed evidence supporting a role as a possible augmentation treatment in TRD. The degree of treatment resistance in depression has been associated prospectively and retrospectively with elevated inflammation, and inflammatory activity may influence responses to antidepressant treatments. Aims: To investigate whether levels of pro-inflammatory cytokines are associated with clinical outcomes to metyrapone or placebo. Methods: A double-blind RCT randomised patients with TRD to 3 weeks of placebo or metyrapone augmentation to ongoing serotonergic antidepressants. No benefit of metyrapone was reported in the primary analysis. The current study assessed levels of pro-inflammatory proteins interleukin-6 (IL-6), tumour necrosis factor (TNFα), c-reactive protein (CRP) and interleukin-10 (IL-10) before randomisation and after treatment as potential moderators and/or mediators of clinical outcomes. Results: The three pro-inflammatory proteins (but not IL-10) were elevated in this sample of patients with TRD compared to a non-affected control group. High pre-treatment IL-6 levels predicted a poorer response in the trial overall but did not moderate response to metyrapone versus placebo. Changes in IL-6 indirectly mediated depression outcome, with metyrapone increasing IL-6 levels and IL-6 increase associated with a poorer outcome on depression. Other inflammatory proteins did not mediate or moderate treatment outcomes. Interpretation: Metyrapone is hypothesised to have a therapeutic effect in depression on the basis of inhibiting the synthesis of cortisol. In this study, metyrapone did not reduce cortisol, possibly due to glucocorticoid system overcompensation). The mediation effect of IL-6 may support this and perhaps help to indicate why the treatment was not effective. [ABSTRACT FROM AUTHOR]

In people with depression, immune dysfunctions have been linked with treatment non-response, but examinations of psychological therapy outcomes, particularly longitudinal biomarker studies, are rare. This study investigated relationships between inflammation, depressive subtypes and clinical outcomes to psychological therapy. Adults with depression (n = 96) were assessed before and after a course of naturalistically-delivered psychological therapy. In total, 32 serum inflammatory proteins were examined alongside therapy outcomes and depressive subtypes (somatic/cognitive symptom subtype, and bipolar/unipolar depression). Overall, 49% of participants responded to treatment. High levels of tumour necrosis factor (TNFα), interleukin-6 (IL-6) and soluble intracellular adhesion molecule-1 (sICAM1), and low interferon-γ (IFNγ), preceded a poorer response to therapy. After therapy, non-responders had elevated c-reactive protein (CRP), thymus and activation-regulated chemokine (TARC) and macrophage chemoattractant protein-4 (MCP4), and attenuated IFNy. Non-somatic depressive symptoms were universally not associated with proteins, while somatic-depressive symptom severity was positively correlated with several pro-inflammatory markers. In the somatic subgroup only, IL-6 and serum amyloid alpha (SAA) decreased between pre- and post-therapy timepoints. Regardless of treatment response, IL-7, IL-8, IL-15 and IL-17 increased over time. These results suggest that inflammation is associated with somatic symptoms of depression and non-response to psychological therapy. Future work may enhance the prospective prediction of treatment-response by examining larger samples of individuals undertaking standardised treatment programmes. [ABSTRACT FROM AUTHOR]

The article discusses research evidence on the use of precision medicine for the treatment of depression and looks at the barriers to the effective utilization of therapeutic markers (TM) in practice. Topics mentioned include the findings of a study by A. Cattaneo and colleagues about macrophage migration inhibitory factor and interleukin-1ß, the types of TM including prognostic biomarkers, and the search for homogeneous subtypes of depression.

Background: Many patients with depressive disorders demonstrate resistance to psychological therapy. A frequent finding is hypothalamic-pituitary-adrenal (HPA) axis alterations. As cortisol is known to modulate cognitive processes, those patients may be less likely to profit from psychological therapy.Aims: To conduct a systematic review and meta-analysis on cortisol as a predictor of psychological therapy response.Method: The Cochrane Library, EMBASE, MEDLINE and PsycINFO databases were searched. Records were included if they looked at patients with any depressive disorder engaging in psychological therapy, with a pre-treatment cortisol and a post-treatment symptom measure.Results: Eight articles satisfied our selection criteria. The higher the cortisol levels before starting psychological therapy, the more symptoms patients with depression experienced at the end of treatment and/or the smaller their symptom change.Conclusions: Our findings suggest that patients with depression with elevated HPA functioning are less responsive to psychological therapy. [ABSTRACT FROM AUTHOR]

Biological factors are known to be important in understanding the pathogenesis of Major Depressive Disorder (MDD). Oxidative stress and neuroinflammation pathways are likely to play a critical role here. We undertook a study to investigate two novel biomarkers - serum NADPH oxidase 1 (NOX1) and Raftlin levels - in treatment-naive, smoking-free first episode patients with MDD compared to healthy controls (HCs) matched for age, sex and body mass index. We found increased NOX1 and Raftlin levels in MDD patients compared to HCs. Both parameters showed very good diagnostic performance in the MDD group. In addition, we found a significant positive correlation between depression severity (HAM D) scores and both biomarker levels in the patient group. To the best of our knowledge, this is the first human study to evaluate serum NOX1 and Raftlin levels in depression. NOX1, an important source of reactive oxygen species (ROS), and Raftlin, which may play a role in the inflammatory process, represent novel potential biomarkers of MDD. These findings support the implication of oxidative stress and inflammatory processes in patients with MDD, and indicate that the deteriorated ROS-antioxidant balance can be regulated via NOX1 in patients with depression. • We investigated the levels of NOX1 and Raftlin in patients with major depressive disorder. • We found that patients had increased serum NOX1 and raftlin levels compared to healthy controls. • Both parameters showed very good diagnostic performance in patients with major depressive disorder. • We concluded that the deteriorated ROS-antioxidant balance can be regulated via NOX1 in patients with depression. [ABSTRACT FROM AUTHOR]

Background: Treatment resistant depression (TRD) poses a significant clinical challenge, despite a range of efficacious specialist treatments. Accurately predicting response a priori may help to alleviate the burden of TRD. This study sought to determine whether outcome prediction can be achieved in a specialist inpatient setting.Methods: Patients at the Affective Disorders Unit of the Bethlam Royal Hospital, with current depression and established TRD were included (N = 174). Patients were treated with an individualised combination of pharmacotherapy and specialist psychological therapies. Predictors included clinical and sociodemographic characteristics, and polygenic risk scores for depression and related traits. Logistic regression models examined associations with outcome, and predictive potential was assessed using elastic net regularised logistic regressions with 10-fold nested cross-validation.Results: 47% of patients responded (50% reduction in HAMD-21 score at discharge). Age at onset and number of depressive episodes were positively associated with response, while degree of resistance was negatively associated. All elastic net models had poor performance (AUC<0.6). Illness history characteristics were commonly retained, and the addition of genetic risk scores did not improve performance.Limitations: The patient sample was heterogeneous and received a variety of treatments. Some variable associations may be non-linear and therefore not captured.Conclusions: This treatment may be most effective for recurrent patients and those with a later age of onset, while patients more severely treatment resistant at admission remain amongst the most difficult to treat. Individual level prediction remains elusive for this complex group. The assessment of homogenous subgroups should be one focus of future investigations. [ABSTRACT FROM AUTHOR]

Childhood maltreatment is widely reported across the world and the incidence of child cruelty and neglect offences is reportedly on the rise. Childhood maltreatment is strongly associated with a range of negative health outcomes in adulthood and represents the strongest environmental risk factor for Major Depressive Disorder (MDD). Immuno-inflammatory activation is one biological mechanism activated in response to maltreatment, and a possible mediator of this increased risk for MDD. Immune modulators, such as the inflammatory cytokines are reported to be increased in patients with MDD and play a role in brain development, neurogenesis and synaptic remodelling. We hypothesize that: (i) maltreatment subtypes will have effects on specific inflammatory markers in adulthood; and (ii) maltreatment will have differential effects on inflammatory markers in adulthood depending on whether or not an individual develops MDD. 616 U.K. participants (276 MDD cases and 340 controls) were recruited as part the South East London Community Health Study (SELCoH) and the Antiglucocorticoid augmentation (metyrapone) of antiDepressants in Depression (ADD) Study. MDD status was defined using either DSM-IV, or the Clinical Interview Schedule-Revised (which generates ICD-10 diagnoses). Childhood maltreatment was determined using the Childhood Trauma Questionnaire and ordinal measures of maltreatment subtype severity were generated. The expression of 41 inflammatory markers were quantified using multiplex electrochemiluminescence methods applied to participant serum samples. General linear models were used to investigate the main effects of maltreatment severity on immune marker expression, and MDD case-control by maltreatment interactions whilst covarying for a broad range of potential confounders. Within each test we performed, we corrected for the number of inflammatory markers assessed using the False Discovery Rate (q<0.1). 34 out of 41 inflammatory markers were expressed in over 70% of our sample, and these were carried forward into downstream analyses. Main effect analyses showed that a higher severity of emotional neglect in childhood was associated with higher Vascular Endothelial Growth Factor D (VEGF-D) levels in adulthood (q<0.1). Interaction analyses revealed that higher childhood emotional and physical neglect in childhood was associated with higher Interleukin 12 heterodimer (IL-12p70) levels in controls only, with lower levels found in MDD subjects (q<0.1). VEGF-D is a cytokine responsible for vascularisation and angiogenesis. The effect we observed was irrespective of MDD case-control status, suggesting that if higher levels of VEGF-D levels do have a long-lasting impact on health, this may relate to disorders other than MDD, or it requires interaction with other factors to lead to MDD. Our MDD case-control by maltreatment interaction analyses revealed heightened levels of IL-12p70 in control subjects relative to depressed cases in association with emotional and physical neglect severity. IL-12p70 has been shown to have neuroprotective properties and we hypothesise that this marker may be involved in a mechanism which confers resilience to MDD in response to childhood neglect, or that it represents a biological proxy for a protective environmental factor (e.g. social support). Further work is now needed to understand if IL12p70 represents a novel drug target to treat MDD in those who have experienced childhood neglect. [ABSTRACT FROM AUTHOR]