Despite considerable preclinical evidence, clinical trials assessing the effects of probiotics on individuals with major depressive disorder (MDD) are scarce. This study aimed to provide further evidence of the acceptability, tolerability and putative efficacy of probiotics in this patient group and to improve our understanding of the underlying mechanisms of action.

This double-blind randomised placebo-controlled pilot and mechanistic trial investigated the effects of an 8-week adjunctive multi-strain probiotic intervention in adults with MDD taking antidepressants. Psychiatric data and stool and blood samples were collected at baseline, week 4 and week 8. A computer-based emotion recognition task was also administered. Stool samples from 25 matched healthy controls were also obtained.

49 participants, randomised to probiotic (n = 24) or placebo (n = 25), were included in intent-to-treat analyses. Standardised effect sizes (SES) from linear mixed models demonstrated that the probiotic group attained greater improvements in depressive (HAMD week 4: SES [95%CI] = 0.70[0.01, 0.98]; IDS week 8: SES [95%CI] = 0.64 [0.03, 0.87]) and anxiety symptoms (HAMA week 4: SES [95%CI] = 0.67 [0.00, 0.95]; week 8: SES [95%CI] = 0.79 [0.06, 1.05]), compared to the placebo group. Attrition was 8% (n = 3 placebo, n = 1 probiotic), adherence was 97.2% and there were no serious adverse reactions. The probiotic modified the composition of the faecal microbiota by normalising richness and diversity towards healthy control levels. The probiotic also increased levels of specific taxa, including Bacillaceae (FDR p < 0.05), which correlated with reductions in anxiety scores (FDR p < 0.05). There was no impact of treatment on levels of inflammatory cytokines (CRP, TNFα, IL-1β, IL-6, IL-17) or BDNF. However, probiotics showed a tendency to increase positive affective bias and improved the accuracy of recognition of all emotions, except sadness.

Compared to placebo, the probiotic group had greater improvement in depressive and anxiety scores, from as early as 4 weeks. The acceptability, tolerability and estimated effect sizes on key clinical outcomes are promising and encourage further investigation of this probiotic as add-on treatment in MDD. The beneficial effects of probiotics in this patient group may be partially mediated by modification of the composition of the gut microbiota and improvement of affective biases, inherent to depressive disorders.

Major depressive disorder (MDD) is highly prevalent across Europe. While evidence-based treatments exist, many people with MDD have their condition undetected and/or untreated. This study aimed to assess the cost-effectiveness of reducing treatment gaps using a modeling approach.

A decision-tree model covering a 27-month time horizon was used. This followed a care pathway where MDD could be detected or not, and where different forms of treatment could be provided. Expected costs pertaining to Germany, Hungary, Italy, Portugal, Sweden, and the UK were calculated and quality-adjusted life years (QALYs) were estimated. The incremental costs per QALY of reducing detection and treatment gaps were estimated.

The expected costs with a detection gap of 69% and treatment gap of 50% were €1236 in Germany, €476 in Hungary, €1413 in Italy, €938 in Portugal, €2093 in Sweden, and €1496 in the UK. The incremental costs per QALY of reducing the detection gap to 50% ranged from €2429 in Hungary to €10,686 in Sweden. The figures for reducing the treatment gap to 25% ranged from €3146 in Hungary to €13,843 in Sweden.

Reducing detection and treatment gaps, and maintaining current patterns of care, is likely to increase healthcare costs in the short term. However, outcomes are improved, and reducing these gaps to 50 and 25%, respectively, appears to be a cost-effective use of resources.

Lithium has long been recognised as an effective treatment for bipolar disorder. Its relative efficacy has been measured with a diverse range of clinical outcomes, resulting in differences in efficacy reporting that have not been systematically reviewed.

We aimed to identify and compare the various measures of lithium efficacy employed in interventional studies for people with bipolar disorder.

Database (PubMed, Web of Science) and hand searches were performed to identify studies that assessed a clinical response in patients with bipolar disorder who received lithium, up to the end of 2021. We included primary human interventional studies without excluding specific study designs, bipolar disorder subtypes, duration or dosage of lithium treatment. Continuous outcome effects were meta-analysed; binary outcomes were synthesised visually and narratively. The Cochrane risk-of-bias tool was used to assess study-level risk of bias.

Seventy-one studies were included (N = 30 542). Approximately two-thirds of participants attained a clinically significant improvement in manic or depressive symptoms, and over 50% achieved remission. About a third required hospital admission (study length 2–12 years) and around 50% needed further treatment to stay well or had recurrence of symptoms; the latter two outcomes tended to be assessed over long-term maintenance periods.

An abundance of measurements have been used to assess lithium's clinical effects, across several study designs. Despite the resultant high heterogeneity, an overall picture of lithium's effects emerges that supports previous literature; between half and two-thirds of patients respond well to lithium across varying outcome measures, baseline mood states, study durations and bipolar disorder subtypes.

Major depressive disorder (MDD) is a leading cause of disability worldwide, and yet delivery of care for this illness is rife with gaps. The COVID-19 pandemic has had far reaching implications for every facet of healthcare, and MDD is no exception. This scoping review aimed to ascertain the impacts of COVID-19 on the delivery of MDD care in Europe, as well as to evaluate any novel MDD care strategies trialled in this period.

We searched the PubMed and PsycINFO databases up to January 2022 with a strategy centred around COVID-19 and MDD. Full texts of eligible studies examining working-age adults and conducted in Europe were evaluated against several criteria. All outcomes were then extracted and a narrative synthesis was constructed to summarise identified themes.

Of 1,744 records identified in our search, 11 articles were eligible for inclusion in the review. In general, these studies reported a decrease in treatment rates, access to care, and perceived access to care during the COVID-19 pandemic. In addition, digital interventions trialled during the pandemic were broadly well-received by users, though their efficacy in improving MDD care was ambiguous.

Despite a limited number of pertinent studies, this scoping review identified a trend of exacerbated treatment gaps in MDD care during the pandemic. Several of our pre-specified gaps, including delays to detection or treatment of depression and rates of follow-up contacts, remained unexplored in the context of COVID-19. This highlights the need for further investigation to obtain a full understanding of the relationship between COVID-19 and MDD care in Europe.

There has been increased interest in repurposing anti-inflammatories for the treatment of bipolar depression. Evidence from high-income countries suggests that these agents may work best for specific depressive symptoms in a subset of patients with biochemical evidence of inflammation but data from lower-middle income countries (LMICs) is scarce. This secondary analysis explored the relationship between pretreatment inflammatory markers and specific depressive symptoms, clinical measures, and demographic variables in participants with bipolar depression in Pakistan.

The current study is a cross-sectional secondary analysis of a randomized controlled trial of two anti-inflammatory medications (minocycline and celecoxib) for bipolar depression (n = 266). A series of logistic and linear regression models were completed to assess the relationship between C-reactive protein (CRP) (CRP > or < 3 mg/L and log10CRP) and clinical and demographic features of interest and symptoms of depression. Baseline clinical trial data was used to extract clinical and demographic features and symptoms of depression were assessed using the 24-item Hamilton Depression Rating Scale.

The prevalence of low-grade inflammation (CRP > 3 mg/L) in the sample was 70.9%. After adjusting for baseline body mass index, socioeconomic status, age, gender, symptoms related to anhedonia, fatigue, and motor retardation were most associated with low-grade inflammation.

Bipolar disorder (BD) patients from LMICs may experience higher rates of peripheral inflammation than have been reported in Western populations with BD. Future trials of repurposed anti-inflammatory agents that enrich for participants with these symptom profiles may inform the development of personalized treatment for bipolar depression in LMICs.

There is mounting interest in the potential efficacy of low carbohydrate and very low carbohydrate ketogenic diets in various neurological and psychiatric disorders.

To conduct a systematic review and narrative synthesis of low carbohydrate and ketogenic diets (LC/KD) in adults with mood and anxiety disorders.

MEDLINE, Embase, PsycINFO and Cochrane databases were systematically searched for articles from inception to 6 September 2022. Studies that included adults with any mood or anxiety disorder treated with a low carbohydrate or ketogenic intervention, reporting effects on mood or anxiety symptoms were eligible for inclusion. PROSPERO registration CRD42019116367.

The search yielded 1377 articles, of which 48 were assessed for full-text eligibility. Twelve heterogeneous studies (stated as ketogenic interventions, albeit with incomplete carbohydrate reporting and measurements of ketosis; diet duration: 2 weeks to 3 years; n = 389; age range 19 to 75 years) were included in the final analysis. This included nine case reports, two cohort studies and one observational study. Data quality was variable, with no high-quality evidence identified. Efficacy, adverse effects and discontinuation rates were not systematically reported. There was some evidence for efficacy of ketogenic diets in those with bipolar disorder, schizoaffective disorder and possibly unipolar depression/anxiety. Relapse after discontinuation of the diet was reported in some individuals.

Although there is no high-quality evidence of LC/KD efficacy in mood or anxiety disorders, several uncontrolled studies suggest possible beneficial effects. Robust studies are now needed to demonstrate efficacy, to identify clinical groups who may benefit and whether a ketogenic diet (beyond low carbohydrate) is required and to characterise adverse effects and the risk of relapse after diet discontinuation.

In difficult-to-treat depression (DTD) the outcome metrics historically used to evaluate treatment effectiveness may be suboptimal. Metrics based on remission status and on single end-point (SEP) assessment may be problematic given infrequent symptom remission, temporal instability, and poor durability of benefit in DTD.

Self-report and clinician assessment of depression symptom severity were regularly obtained over a 2-year period in a chronic and highly treatment-resistant registry sample (N = 406) receiving treatment as usual, with or without vagus nerve stimulation. Twenty alternative metrics for characterizing symptomatic improvement were evaluated, contrasting SEP metrics with integrative (INT) metrics that aggregated information over time. Metrics were compared in effect size and discriminating power when contrasting groups that did (N = 153) and did not (N = 253) achieve a threshold level of improvement in end-point quality-of-life (QoL) scores, and in their association with continuous QoL scores.

Metrics based on remission status had smaller effect size and poorer discrimination of the binary QoL outcome and weaker associations with the continuous end-point QoL scores than metrics based on partial response or response. The metrics with the strongest performance characteristics were the SEP measure of percentage change in symptom severity and the INT metric quantifying the proportion of the observation period in partial response or better. Both metrics contributed independent variance when predicting end-point QoL scores.

Revision is needed in the metrics used to quantify symptomatic change in DTD with consideration of INT time-based measures as primary or secondary outcomes. Metrics based on remission status may not be useful.

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.

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.

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 (F9704 = 1.113, p = 0.351).

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.

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. 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. 2. Recommend policies intending to better meet patient needs (i.e., minimize treatment gaps).

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.

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).

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.

A supply disruption alert in 2020, now rescinded, notified UK prescribers of the planned discontinuation of Priadel® (lithium carbonate) tablets. This service evaluation explored lithium dose and plasma levels before and after the switching of lithium brands, in order to determine the interchangeability of different brands of lithium from a pharmacokinetic perspective.

Data on the treatment of 37 patients switched from Priadel® tablets were analysed. Switching to Camcolit® controlled-release tablets at the same dose did not result in meaningful differences in plasma lithium levels. Dose adjustment and known or suspected poor medication adherence were associated with greater variability in plasma lithium levels on switching brands.

For comparable pre- and post-switch doses in adherent patients, the most common brands of lithium carbonate appear to produce similar plasma lithium levels. British National Formulary guidance relating to switching lithium brands may be unnecessarily complex.

Overgeneralised self-blame and worthlessness are key symptoms of major depressive disorder (MDD) and have previously been associated with self-blame-selective changes in connectivity between right superior anterior temporal lobe (rSATL) and subgenual frontal cortices. Another study showed that remitted MDD patients were able to modulate this neural signature using functional magnetic resonance imaging (fMRI) neurofeedback training, thereby increasing their self-esteem. The feasibility and potential of using this approach in symptomatic MDD were unknown.

This single-blind pre-registered randomised controlled pilot trial probed a novel self-guided psychological intervention with and without additional rSATL-posterior subgenual cortex (BA25) fMRI neurofeedback, targeting self-blaming emotions in people with insufficiently recovered MDD and early treatment-resistance (n = 43, n = 35 completers). Participants completed three weekly self-guided sessions to rebalance self-blaming biases.

As predicted, neurofeedback led to a training-induced reduction in rSATL-BA25 connectivity for self-blame v. other-blame. Both interventions were safe and resulted in a 46% reduction on the Beck Depression Inventory-II, our primary outcome, with no group differences. Secondary analyses, however, revealed that patients without DSM-5-defined anxious distress showed a superior response to neurofeedback compared with the psychological intervention, and the opposite pattern in anxious MDD. As predicted, symptom remission was associated with increases in self-esteem and this correlated with the frequency with which participants employed the psychological strategies in daily life.

These findings suggest that self-blame-rebalance neurofeedback may be superior over a solely psychological intervention in non-anxious MDD, although further confirmatory studies are needed. Simple self-guided strategies tackling self-blame were beneficial, but need to be compared against treatment-as-usual in further trials. https://doi.org/10.1186/ISRCTN10526888