A composite immune and vascular stress marker in patients newly diagnosed with bipolar disorder and their unaffected first-degree relatives.

AIMS: Substantial evidence emphasizes immune dysregulation in patients with bipolar disorder (BD). However, whether immune dysregulation is present already in the early illness stages of BD or even precedes development of BD is largely unknown. In this study we compared immune and vascular stress markers in patients newly diagnosed with BD, their unaffected first-degree relatives (UR) and healthy control individuals (HC) and investigated the ability a composite immune and vascular stress marker to discriminate between the three groups of participants. METHODS: In a unique sample including 373 patients newly diagnosed with BD, 95 UR and 190 HC, we compared 47 immune and vascular stress markers at the baseline visit in the ongoing longitudinal Bipolar Illness Onset study. For comparison of individual immune and vascular stress markers between groups, we applied linear mixed models, whereas the composite immune and vascular stress marker was investigated using the SuperLearner ensemble-method. RESULTS: Compared with HC, patients newly diagnosed with BD had higher levels of the anti-inflammatory interleukin-1 receptor antagonist (IL-1RA) and IL-10, and of the pro-inflammatory IL-6, eotaxin, monocyte chemoattractant protein-1 (MCP-1), MCP-4, Macrophage Derived Chemokine (MDC), and Thymus and Activation-Regulated Chemokine (TARC) in analyses adjusted for sex and age ranging from 26 % higher levels of IL-6 (1.26, 95 %CI: [1.12-1.43], p < 0.001, adjusted p = 0.009) and IL-10 (1.26, 95 %CI: [1.09-1.46], p = 0.002, adjusted p = 0.049), respectively, to 9 % higher eotaxin levels (1.09, 95 %CI: [1.04-1.15], p = 0.001, adjusted p = 0.024). Of these, MDC levels were 12 % higher in BD compared with UR (1.12, 95 %CI: [1.02-1.22], p = 0.001, adjusted p = 0.024). For all other markers, UR showed no difference from patients with BD or HC. Based on a data-driven model, a composite marker including all 47 immune and vascular stress markers, sex, age, BMI, smoking status, and alcohol intake, discriminated patients with BD from HC with a with an area under the receiver operating curve (AUC) of 0.76 (95 % CI: 0.75-0.77) CONCLUSIONS: Higher levels of pro-inflammatory and anti-inflammatory immune markers are present in patients newly diagnosed with BD but not in UR compared with HC, supporting immune dysregulation playing a role in the pathophysiology of BD.

Early specialised treatment for bipolar disorder: Long-term follow-up from the early intervention in affective disorders (EIA) randomised controlled trial.

BACKGROUND: It is unclear whether treatment early after onset in bipolar disorder may improve the long-term illness course. The early intervention in affective disorders (EIA) randomised controlled trial found that 2-years treatment in a specialised mood disorder clinic combining evidence-based pharmacological treatment with group psychoeducation improved clinical outcomes compared with standard treatment in patients with bipolar disorder discharged after their 1st, 2nd, or 3rd hospital admission. We aimed to assess the 16 years long-term outcomes after randomisation of the participants in the EIA trial. METHODS: Data were obtained by linking nation-wide Danish population-based registers. All 158 participants of the EIA trial (Trial Registration Number NCT00253071) were followed from time of randomisation (2005-2009) to end of study (31 December 2021). The primary outcome was risk of psychiatric readmission. Secondary outcomes were total admissions and costs, medication use, intentional self-harm or suicide attempt or suicide, and socio-economic measures. RESULTS: The absolute mean risk of psychiatric readmission was 49.3% in the intervention group and 59.8% in the control group, with no statistically significant difference between the groups (b = -0.10, 95% CI: -0.26 to 0.047, p = 0.18). Compared with the control group, patients in the intervention group had numerically fewer total admission days (mean (SD) 44 (77) versus 62 (109)), lower total cost of psychiatric hospital admissions and hospital-based outpatient visits (mean (SD) 22,001 (36793) euros versus 29,822 (52671) euros) and higher use of lithium and antipsychotics, but the differences were not statistically significant. Fewer patients in the intervention group had an event of intentional self-harm or suicide attempt or suicide during follow-up (OR 0.25, 95% CI: 0.15-0.40, p < 0.001) compared with the control group and more patients in the intervention group used antiepileptics (OR 2.21, 95% CI: 1.08-4.60, p = 0.031). CONCLUSION: Analyses of very long-term outcomes of the EIA trial may potentially indicate a beneficial effect of the intervention at the long term but were likely underpowered to detect a more subtle effect and for most outcomes the differences between groups were not statistically significant.

Minor tranquillizers for short-term treatment of newly onset symptoms of anxiety and distress: a systematic review with network meta-analysis of randomized trials.

Unspecific symptoms of anxiety and distress are frequently encountered in patients in both general practice and acute psychiatric services. Minor tranquillizers may be a treatment option when non-pharmacological interventions are insufficient or unavailable. We conducted a systematic review with network meta-analysis of the evidence for short-term (1-4 weeks) pharmacological treatment of newly onset symptoms of anxiety and distress. We searched the PsycInfo, MEDLINE, EMBASE and Cochrane Library databases and extracted data following a predefined hierarchy of outcomes. We assessed risk of bias using the Cochrane Risk of Bias tool and the certainty of the evidence using the Grading of Recommendations Assessment, Development and Evaluation framework (GRADE). We included 34 randomized trials comprising a total of 7044 patients with adjustment disorders or anxiety spectrum disorders. The network meta-analysis showed that regarding the critical outcome symptoms of anxiety within 1-4 weeks benzodiazepines (SMD - 0.58, 95% CI - 0.77 to - 0.40), quetiapine (SMD - 0.51, 95% CI - 0.90 to - 0.13) and pregabalin (SMD - 0.58, 95% CI - 0.87 to - 0.28) all performed better than placebo with no statistically significant difference between the drugs. Data on other important outcomes were inconsistently reported. Adverse effects varied, but overall, it was uncertain whether adverse effects differed between interventions. The evidence regarding the risk of dependence was uncertain, but dependence may be a concern in susceptible individuals even with short-term treatment. Overall, the certainty of the evidence according to GRADE was rated as low to very low across outcomes. Despite the limitations in the evidence, the results of this review can inform treatment guidelines, supporting clinicians in the choice of minor tranquillizer in this prevalent and help-seeking, clinically heterogeneous population.

The relationship between dose and serotonin transporter occupancy of antidepressants-a systematic review.

Brain imaging techniques enable the visualization of serotonin transporter (SERT) occupancy as a measure of the proportion of SERT blocked by an antidepressant at a given dose. We aimed to systematically review the evidence on the relationship between antidepressant dose and SERT occupancy. We searched PubMed and Embase (last search 20 May 2021) for human in vivo, within-subject PET, or SPECT studies measuring SERT occupancy at any dose of any antidepressant with highly selective radioligands ([11C]-DASB, [123I]-ADAM, and [11C]-MADAM). We summarized and visualized the dose-occupancy relationship for antidepressants across studies, overlaying the plots with a curve based on predicted values of a standard 2-parameter Michaelis-Menten model fitted using the observed data. We included seventeen studies of 10 different SSRIs, SNRIs, and serotonin modulators comprising a total of 294 participants, involving 309 unique occupancy measures. Overall, following the Michaelis-Menten equation, SERT occupancy increased with a higher dose in a hyperbolic relationship, with occupancy increasing rapidly at lower doses and reaching a plateau at approximately 80% at the usual minimum recommended dose. All the studies were small, only a few investigated the same antidepressant, dose, and brain region, and few reported information on factors that may influence SERT occupancy. The hyperbolic dose-occupancy relationship may provide mechanistic insight of relevance to the limited clinical benefit of dose-escalation in antidepressant treatment and the potential emergence of withdrawal symptoms. The evidence is limited by non-transparent reporting, lack of standardized methods, small sample sizes, and short treatment duration. Future studies should standardize the imaging and reporting procedures, measure occupancy at lower antidepressant doses, and investigate the moderators of the dose-occupancy relationship.

Hand cleaning with ash for reducing the spread of viral and bacterial infections: a rapid review.

BACKGROUND: Handwashing is important to reduce the spread and transmission of infectious disease. Ash, the residue from stoves and fires, is a material used for cleaning hands in settings where soap is not widely available. OBJECTIVES: To assess the benefits and harms of hand cleaning with ash compared with hand cleaning using soap or other materials for reducing the spread of viral and bacterial infections. SEARCH METHODS: On 26 March 2020 we searched CENTRAL, MEDLINE, Embase, WHO Global Index Medicus, and the WHO International Clinical Trials Registry Platform. SELECTION CRITERIA: We included all types of studies, in any population, that examined hand cleaning with ash compared to hand cleaning with any other material. DATA COLLECTION AND ANALYSIS: Two review authors independently screened titles and full texts, and one review author extracted outcome data and assessed risk of bias, which another review author double-checked. We used the ROBINS-I tool for observational studies, we used RoB 2.0 for three interventional studies, and we used GRADE to assess the certainty of the evidence. We planned to synthesise data with random-effects meta-analyses. Our prespecified outcome measures were overall mortality, number of cases of infections (as defined in the individual studies), severity of infectious disease, harms (as reported in the individual studies), and adherence. MAIN RESULTS: We included 14 studies described in 19 records using eight different study designs, but only one randomised trial. The studies were primarily conducted in rural settings in low- and lower-middle-income countries. Six studies reported outcome data relevant to our review. A retrospective case-control study and a cohort study assessed diarrhoea in children under the age of five years and self-reported reproductive tract symptoms in women, respectively. It was very uncertain whether the rate of hospital contacts for moderate-to-severe diarrhoea in children differed between households that cleaned hands using ash compared with households cleaning hands using soap (RR 0.97, 95% CI 0.84 to 1.11; very low-certainty evidence). Similarly, it was very uncertain whether the rate of women experiencing symptoms of reproductive tract infection differed between women cleaning hands with ash compared with cleaning hands using soap (RR 0.48, 95% CI 0.12 to 1.86; very low-certainty evidence) or when compared with handwashing with water only or not washing hands (RR 0.50, 95% CI 0.13 to 1.96; very low-certainty evidence). Four studies reported on bacteriological counts after hand wash. We rated all four studies at high risk of bias, and we did not synthesise data due to methodological heterogeneity and unclear outcome reporting. AUTHORS' CONCLUSIONS: Based on the available evidence, the benefits and harms of hand cleaning with ash compared with soap or other materials for reducing the spread of viral or bacterial infections are uncertain.

Gut microbiota composition in patients with newly diagnosed bipolar disorder and their unaffected first-degree relatives.

OBJECTIVE: An aberrant gut microbiota may be associated with a broad spectrum of diseases including mental illness. The gut microbiota is scarcely studied in bipolar disorder (BD). We examined the gut microbiota composition in patients with newly diagnosed BD, their unaffected first-degree relatives and healthy individuals. METHODS: Stool samples were collected from 113 patients with BD, 39 unaffected first-degree relatives and 77 healthy individuals and the microbiota was profiled using 16S rRNA gene amplicon sequencing. RESULTS: The gut microbiota community membership of patients with BD differed from that of healthy individuals (R2 = 1.0%, P = 0.008), whereas the community membership of unaffected first-degree relatives did not. Flavonifractor was present in 61% of patients with BD, 42% of their unaffected relatives and 39% of healthy individuals. Presence of Flavonifractor was associated with an odds ratio of 2.9 (95%CI: 1.6-5.2, P = 5.8 × 10-4, Q = 0.036) for having BD. When excluding smokers, presence of Flavonifractor was associated with an odds ratio of 2.3 (95%CI: 1.1-5.3, P = 0.019) for having BD. However, when considering the subsample of non-smokers only, BD and presence of Flavonifractor were no longer associated when adjusted for all possible tests at genus level (Q = 0.6). Presence of Flavonifractor in patients with BD was associated with smoking and female sex, but not with age, waist circumference, exercise level, high-sensitive C-reactive protein, current affective state, subtype of BD, illness duration or psychotropic medication, respectively. CONCLUSION: Flavonifractor, a bacterial genus that may induce oxidative stress and inflammation in its host, was associated with BD. Higher prevalence of smoking among patients with BD contributed to our findings, and it cannot be excluded that findings are influenced by residual confounding.

Thirty-year cardiovascular risk score in patients with newly diagnosed bipolar disorder and their unaffected first-degree relatives.

OBJECTIVES: Bipolar disorder is associated with a decreased life expectancy of 8-12 years. Cardiovascular disease is the leading cause of excess mortality. For the first time, we investigated the Framingham 30-year risk score of cardiovascular disease in patients with newly diagnosed/first-episode bipolar disorder, their unaffected first-degree relatives and healthy individuals. METHODS: In a cross-sectional study, we compared the Framingham 30-year risk score of cardiovascular disease in 221 patients with newly diagnosed/first-episode bipolar disorder, 50 of their unaffected first-degree relatives and 119 healthy age- and sex-matched individuals with no personal or first-degree family history of affective disorder. Among patients with bipolar disorder, we further investigated medication- and illness-related variables associated with cardiovascular risk. RESULTS: The 30-year risk of cardiovascular disease was 98.5% higher in patients with bipolar disorder (p = 0.017) and 85.4% higher in unaffected first-degree relatives (p = 0.042) compared with healthy individuals in models adjusted for age and sex. When categorizing participants in low cardiovascular risk without considering age and sex distribution among participants, 81% of patients were at low risk, versus 92% of unaffected relatives and 89% of healthy individuals. Of the patients 209 (94.6%) were diagnosed within the preceding 2 years. Smoking was more prevalent among patients with bipolar disorder (45.2%) and their unaffected first-degree relatives (20.4%) compared with healthy individuals (12.8%). Similarly, dyslipidemia was more common among patients with bipolar disorder compared with healthy individuals. Treatment with psychotropic medication with metabolic adverse effects was associated with higher 30-year cardiovascular disease risk score, whereas we did not find illness-related variables associated with cardiovascular risk among patients with bipolar disorder. CONCLUSION: We found an enhanced cardiovascular disease risk score in patients with newly diagnosed bipolar disorder and their unaffected first-degree relatives, which points to a need for specific primary preventive interventions against smoking and dyslipidemia in these populations.

Glycogen synthase kinase-3ß in patients with bipolar I disorder: results from a prospective study.

OBJECTIVES: The enzyme glycogen synthase kinase-3ß (GSK3ß) is involved in the mechanisms of action of lithium and may play a role in relation to affective states in bipolar disorder. The objectives of the present study were to compare the activity of GSK-3ß (measured as levels of phosphorylated GSK-3ß [p-GSK-3ß]) between patients with bipolar disorder in the euthymic state and healthy control subjects, and to investigate whether GSK-3ß activity varies with affective states in patients with bipolar I disorder. METHODS: In a prospective 6-12-month follow-up study, we investigated state-specific, intraindividual alterations in the activity of GSK-3ß in 60 patients with bipolar I disorder with an acute severe manic index episode and in subsequent euthymic, depressive and manic states and compared this with repeated measurements in healthy control subjects. Data were analyzed using linear mixed-effects models. RESULTS: From baseline to the end of follow-up, blood samples were drawn from the 60 patients during 181 affective states, comprising 60 manic, 11 mixed, 23 depressive, and 87 states of euthymia. A total of 69 blood samples were drawn from 35 healthy control subjects, with two samples from the same subject taken three months apart. In mixed-model analysis, p-GSK-3ß was decreased in the euthymic state of subjects with bipolar disorder compared with healthy control subjects (b=0.63, 95% confidence interval [CI]: 0.42-0.96, P=.03). In addition, p-GSK-3ß varied with affective states, being increased in depressive (b=1.68, 95% CI: 1.08-2.62, P=.02) and mixed (b=2.07, 95% CI: 1.12-3.84, P=.02) states but not in mania compared with euthymia. CONCLUSIONS: The activity of GSK-3ß is altered in euthymic bipolar disorder compared with healthy control subjects and varies with affective states.

Glycogen Synthase Kinase-3ß: Variation over Time and the Possible Association with Mood and Cognition in Healthy Individuals.

Evidence indicates a role for glycogen synthase kinase-3ß (GSK-3ß) in the pathophysiology of mood disorders and in cognitive disturbances; however, the natural variation in GSK-3ß activity over time is unknown. We aimed to investigate GSK-3ß activity over time and its possible correlation with emotional lability, subjective mood fluctuations and cognitive function in healthy individuals. Thirty-seven healthy subjects were evaluated with neuropsychological tests and blood samples at baseline and 12-week follow-up. Total GSK-3ß and serine-9-phosphorylated GSK-3ß in peripheral blood mononuclear cells were quantitated using enzyme immunometric assays. The activity of GSK-3ß (serine-9-phosphorylated GSK-3ß/total GSK-3ß) was lower at baseline compared with follow-up. No significant mean change over time was observed in levels of total GSK-3ß and serine-9-phosphorylated GSK-3ß. Exploratory analysis revealed lower activity of GSK-3ß in spring and summer compared with the fall season. No correlation was observed between GSK-3ß activity and emotional lability, subjective mood fluctuations or cognitive function. The results suggest that intra- and interindividual variation in GSK-3ß activity over time could contribute to the heterogeneity of findings in clinical studies. The stability of GSK-3ß activity and the role of potential moderators of GSK-3ß activity warrant further investigation. Clinical studies of GSK-3ß should consider including repeated measures of both cases and healthy individuals.

Electronic self-monitoring of mood using IT platforms in adult patients with bipolar disorder: A systematic review of the validity and evidence.

BACKGROUND: Various paper-based mood charting instruments are used in the monitoring of symptoms in bipolar disorder. During recent years an increasing number of electronic self-monitoring tools have been developed. The objectives of this systematic review were 1) to evaluate the validity of electronic self-monitoring tools as a method of evaluating mood compared to clinical rating scales for depression and mania and 2) to investigate the effect of electronic self-monitoring tools on clinically relevant outcomes in bipolar disorder. METHODS: A systematic review of the scientific literature, reported according to the Preferred Reporting items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines was conducted. MEDLINE, Embase, PsycINFO and The Cochrane Library were searched and supplemented by hand search of reference lists. Databases were searched for 1) studies on electronic self-monitoring tools in patients with bipolar disorder reporting on validity of electronically self-reported mood ratings compared to clinical rating scales for depression and mania and 2) randomized controlled trials (RCT) evaluating electronic mood self-monitoring tools in patients with bipolar disorder. RESULTS: A total of 13 published articles were included. Seven articles were RCTs and six were longitudinal studies. Electronic self-monitoring of mood was considered valid compared to clinical rating scales for depression in six out of six studies, and in two out of seven studies compared to clinical rating scales for mania. The included RCTs primarily investigated the effect of heterogeneous electronically delivered interventions; none of the RCTs investigated the sole effect of electronic mood self-monitoring tools. Methodological issues with risk of bias at different levels limited the evidence in the majority of studies. CONCLUSIONS: Electronic self-monitoring of mood in depression appears to be a valid measure of mood in contrast to self-monitoring of mood in mania. There are yet few studies on the effect of electronic self-monitoring of mood in bipolar disorder. The evidence of electronic self-monitoring is limited by methodological issues and by a lack of RCTs. Although the idea of electronic self-monitoring of mood seems appealing, studies using rigorous methodology investigating the beneficial as well as possible harmful effects of electronic self-monitoring are needed.

Elevated levels of IL-6 and IL-18 in manic and hypomanic states in rapid cycling bipolar disorder patients.

Inflammatory system dysregulation may be involved in the pathophysiology of bipolar disorder with peripheral cytokine levels varying between affective states; however, the evidence is based primarily on case-control studies and limited by methodological issues. The objectives of the present study were to assess alterations of peripheral cytokine levels between affective states in rapid cycling bipolar disorder patients and to compare these with levels in healthy control subjects. In a longitudinal design, repeated measurements of plasma levels of IL-6, IL-10, IL-18, IL-1ß and TNF-α were obtained in affective states of varying polarity during 6-12 months in 37 rapid cycling bipolar disorder patients and compared with repeated measurements in 40 age- and gender matched healthy control subjects, using rigorous laboratory-, clinical- and statistical methodology. Adjusting for demographical, clinical- and lifestyle factors, levels of IL-6 (p<0.05) and IL-18 (p<0.005) were significantly elevated in rapid cycling bipolar disorder patients in a manic/hypomanic state, compared with a depressed and a euthymic state. Compared with healthy control subjects, unadjusted levels of IL-6 (p<0.05) and IL-18 (p<0.05) were elevated in manic/hypomanic bipolar disorder patients. Levels of IL-10 and IL-1ß were undetectable in the majority of samples; high TNF-α assay variability was found. The results support a role for altered peripheral immune response signaling in rapid cycling bipolar disorder and suggest that IL-6 and IL-18 could be markers of manic episodes.

Elevated levels of urinary markers of oxidatively generated DNA and RNA damage in bipolar disorder.

OBJECTIVES: The pathophysiological mechanisms underlying bipolar disorder and its multi-system nature are unclear. Oxidatively generated damage to nucleosides has been demonstrated in metabolic disorders; however, the extent to which this occurs in bipolar disorder in vivo is unknown. We investigated oxidatively generated damage to DNA and RNA in patients with bipolar disorder and its relationship with the affective phase compared with healthy control subjects. METHODS: Urinary excretion of 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG) and 8-oxo-7,8-dihydroguanosine (8-oxoGuo), markers of oxidatively generated DNA and RNA damage, respectively, was measured in 37 rapid cycling patients with bipolar disorder and in 40 age- and gender-matched healthy control subjects. Employing a longitudinal design, repeated measurements of both markers were evaluated in various affective phases in patients with bipolar disorder during a six- to 12-month period and compared with repeated measurements in healthy control subjects. RESULTS: In linear mixed models, adjusting for demographical, metabolic, and lifestyle factors, the excretion of 8-oxodG and 8-oxoGuo was significantly elevated in euthymic patients with bipolar disorder compared with healthy control subjects, with increases of 40% (p < 0.0005) and 43% (p < 0.0005), respectively. The increased oxidatively generated nucleoside damage was present through all affective phases of the illness, with no significant difference between affective states. CONCLUSIONS: Our results indicate that bipolar disorder is associated with increased oxidatively generated damage to nucleosides. The findings could suggest a role for oxidatively generated damage to DNA and RNA as a molecular mechanism contributing to the increased risk of medical disorders, shortened life expectancy, and the progressive course of illness observed in bipolar disorder.

Reduced mRNA expression of PTGDS in peripheral blood mononuclear cells of rapid-cycling bipolar disorder patients compared with healthy control subjects.

BACKGROUND: Disturbances related to the arachidonic acid cascade and prostaglandin metabolism may be involved in the pathophysiology of bipolar disorder, as supported by a recent genome-wide association study meta-analysis; however, evidence from clinical studies on a transcriptional level is lacking. Two enzymes in the arachidonic acid cascade are the prostaglandin D synthase (PTGDS), which catalyzes the conversion of prostaglandin H2 to prostaglandin D2 (PGD2), and the aldo-keto reductase family 1 member C3 (AKR1C3), which catalyzes the reduction of PGD2. We aimed to test the hypothesis that mRNA expression of PTGDS and AKR1C3 is deregulated in rapid-cycling disorder patients in a euthymic or current affective state compared with healthy control subjects, and that expression alters with affective states. METHODS: PTGDS and AKR1C3 mRNA expression in peripheral blood mononuclear cells was measured in 37 rapid-cycling bipolar disorder patients and 40 age- and gender-matched healthy control subjects using reverse transcription quantitative real-time polymerase chain reaction. Repeated measurements of PTGDS and AKR1C3 mRNA expression were obtained in various affective states during 6-12 months and compared with repeated measurements in healthy control subjects. RESULTS: Adjusted for age and gender, PTGDS mRNA expression was down-regulated in rapid-cycling bipolar disorder patients in a euthymic, depressive, and manic/hypomanic state compared with healthy control subjects. No difference in PTGDS mRNA expression was observed between affective states. AKR1C3 mRNA expression did not differ between bipolar disorder patients in any affective state or in comparison with healthy control subjects. CONCLUSIONS: The results suggest a role for aberrantly-regulated PTGDS mRNA expression in rapid-cycling bipolar disorder. The sample size was limited; replication of the findings in larger, independent samples is warranted to further explore the role of the arachidonic acid cascade and prostaglandin metabolism as a potential therapeutic target in bipolar disorder.

Functioning in patients with major depressive disorder in remission: A systematic review and meta-analysis.

BACKGROUND: Major depressive disorder (MDD) is one of the leading causes of burden of disease globally. We aimed to investigate whether global functioning is impaired in patients with MDD in full or partial remission compared to healthy control individuals (HC). METHODS: We conducted a systematic review and meta-analysis according to the PRISMA guideline. We searched the databases PubMed, EMBASE and PsycINFO from January 1st 1980 to February 1st 2023. We included studies of adults with a diagnosis/former diagnosis of MDD with assessment of global functioning performed during a state of full or partial remission. The methodological quality was assessed using the Joanna Briggs Institute (JBI) Critical Appraisal Checklist. Standardised mean differences (SMD) using random-effects models were calculated as the summary measure. We further performed meta-analyses of the mean raw score in patients with MDD for individual functioning scales. RESULTS: Forty-two studies, comprising 17,999 patients with MDD and 35,550 HC, were included, 14 of which included both patients with MDD in full or partial remission and HC. Global functioning was lower in patients with MDD in full or partial remission compared with HC (SMD -2.00, 95 % CI: -0.9 to -3.03, 15 comparisons, I2: 99.8 %). LIMITATIONS: Important information about the study participants and setting was not reported for most studies, or the reporting was unclear. CONCLUSION: Patients with MDD have lower levels of functioning compared with HC also when in full or partial remission. Assessment of functioning should be an essential component of managing patients with MDD, also during remission.