Placebo effects in randomized trials of pharmacological and neurostimulation interventions for mental disorders: An umbrella review.

There is a growing literature exploring the placebo response within specific mental disorders, but no overarching quantitative synthesis of this research has analyzed evidence across mental disorders. We carried out an umbrella review of meta-analyses of randomized controlled trials (RCTs) of biological treatments (pharmacotherapy or neurostimulation) for mental disorders. We explored whether placebo effect size differs across distinct disorders, and the correlates of increased placebo effects. Based on a pre-registered protocol, we searched Medline, PsycInfo, EMBASE, and Web of Knowledge up to 23.10.2022 for systematic reviews and/or meta-analyses reporting placebo effect sizes in psychopharmacological or neurostimulation RCTs. Twenty meta-analyses, summarising 1,691 RCTs involving 261,730 patients, were included. Placebo effect size varied, and was large in alcohol use disorder (g = 0.90, 95% CI [0.70, 1.09]), depression (g = 1.10, 95% CI [1.06, 1.15]), restless legs syndrome (g = 1.41, 95% CI [1.25, 1.56]), and generalized anxiety disorder (d = 1.85, 95% CI [1.61, 2.09]). Placebo effect size was small-to-medium in obsessive-compulsive disorder (d = 0.32, 95% CI [0.22, 0.41]), primary insomnia (g = 0.35, 95% CI [0.28, 0.42]), and schizophrenia spectrum disorders (standardized mean change = 0.33, 95% CI [0.22, 0.44]). Correlates of larger placebo response in multiple mental disorders included later publication year (opposite finding for ADHD), younger age, more trial sites, larger sample size, increased baseline severity, and larger active treatment effect size. Most (18 of 20) meta-analyses were judged 'low' quality as per AMSTAR-2. Placebo effect sizes varied substantially across mental disorders. Future research should explore the sources of this variation. We identified important gaps in the literature, with no eligible systematic reviews/meta-analyses of placebo response in stress-related disorders, eating disorders, behavioural addictions, or bipolar mania.

Adverse childhood experiences and psychological functioning among women with schizophrenia or bipolar disorder: population-based study.

BACKGROUND: Adverse childhood experiences (ACEs) are well-known risk factors for schizophrenia and bipolar disorder. AIMS: The aim was to study the associations between specific ACEs and psychological functioning in women with schizophrenia or bipolar disorder. METHOD: Among 29 367 women (mean age 44 years) from the Icelandic Stress-And-Gene-Analysis (SAGA) study, 534 (1.8%, mean age 40) reported having been diagnosed with schizophrenia or bipolar disorder, which were combined to 'severe mental disorders'. Participants reported on 13 types of ACEs, childhood deprivation and psychological functioning (defined as coping ability and current symptoms of depression, anxiety and sleep disturbances). Adjusted Poisson regression calculated prevalence ratios (PRs) between ACEs and severe mental disorders. Linear regression assessed the association between ACEs and psychological functioning among women with a severe mental disorder. RESULTS: Women with a severe mental disorder reported more ACEs (mean 4.57, s.d. = 2.82) than women without (mean 2.51, s.d. = 2.34) in a dose-dependent manner (fully-adjusted PR = 1.23 per ACE, 95% CI 1.20-1.27). After mutual adjustment for other ACEs, emotional abuse, sexual abuse, mental illness of a household member, emotional neglect, bullying and collective violence were associated with severe mental disorders. Among women with severe mental disorders, a higher number of ACEs was associated with increased symptom burden of depression (ß = 2.79, 95% CI = 1.19-4.38) and anxiety (ß = 2.04, 95% CI = 0.99-3.09) including poorer sleep quality (ß = 0.83, 95% CI = 0.07-1.59). Findings were similar for schizophrenia and bipolar disorder separately. CONCLUSION: Women with schizophrenia or bipolar disorder show a strong history of ACEs, which may interfere with their psychological functioning and, therefore, need to be addressed as part of their treatment, for example, with trauma-focused psychotherapy.

Features of immunometabolic depression as predictors of antidepressant treatment outcomes: pooled analysis of four clinical trials.

BACKGROUND: Profiling patients on a proposed 'immunometabolic depression' (IMD) dimension, described as a cluster of atypical depressive symptoms related to energy regulation and immunometabolic dysregulations, may optimise personalised treatment. AIMS: To test the hypothesis that baseline IMD features predict poorer treatment outcomes with antidepressants. METHOD: Data on 2551 individuals with depression across the iSPOT-D (n = 967), CO-MED (n = 665), GENDEP (n = 773) and EMBARC (n = 146) clinical trials were used. Predictors included baseline severity of atypical energy-related symptoms (AES), body mass index (BMI) and C-reactive protein levels (CRP, three trials only) separately and aggregated into an IMD index. Mixed models on the primary outcome (change in depressive symptom severity) and logistic regressions on secondary outcomes (response and remission) were conducted for the individual trial data-sets and pooled using random-effects meta-analyses. RESULTS: Although AES severity and BMI did not predict changes in depressive symptom severity, higher baseline CRP predicted smaller reductions in depressive symptoms (n = 376, ßpooled = 0.06, P = 0.049, 95% CI 0.0001-0.12, I2 = 3.61%); this was also found for an IMD index combining these features (n = 372, ßpooled = 0.12, s.e. = 0.12, P = 0.031, 95% CI 0.01-0.22, I2= 23.91%), with a higher - but still small - effect size compared with CRP. Confining analyses to selective serotonin reuptake inhibitor users indicated larger effects of CRP (ßpooled = 0.16) and the IMD index (ßpooled = 0.20). Baseline IMD features, both separately and combined, did not predict response or remission. CONCLUSIONS: Depressive symptoms of people with more IMD features improved less when treated with antidepressants. However, clinical relevance is limited owing to small effect sizes in inconsistent associations. Whether these patients would benefit more from treatments targeting immunometabolic pathways remains to be investigated.

Levels of cytokines in the cerebrospinal fluid of patients with psychotic disorders compared to individually matched healthy controls.

BACKGROUND: Increased peripheral cytokine levels have been observed in patients with psychotic disorders; however, large high-quality studies with individually matched healthy controls have been lacking regarding cytokines in cerebrospinal fluid (CSF) of individuals with psychotic disorders. METHODS: Patients diagnosed with a non-organic, non-affective psychotic disorder (ICD-10: F20/22-29) within a year prior to inclusion and individually age- and sex-matched healthy controls were included by identical in- and exclusion criteria's except for the psychiatric diagnoses. All participants were aged 18-50 years and individuals with neurological or immunological disorders were excluded. CSF cytokines were analyzed with MesoScale V-PLEX neuroinflammation panel. Co-primary outcomes were CSF interleukin-6 (IL-6) and IL-8. RESULTS: We included 104 patients and 104 healthy controls, matching on age, sex and BMI. No significant differences were found for the primary outcomes IL-6 (relative mean difference (MD): 0.97, 95 %CI: 0.84-1.11, p = 0.637) or IL-8 (MD: 1.01, 95 %CI: 0.93-1.09, p = 0.895). Secondary analyses found patients to have higher IL-4 (MD: 1.30, 95 %CI: 1.04-1.61, p = 0.018), a trend towards higher IFN-γ (MD: 1.26, 95 %CI: 0.99-1.59, p = 0.056), and lower IL-16 (MD: 0.83, 95 %CI: 0.74-0.94, p = 0.004) than healthy controls, though not significant after correction for multiple testing. IL-8 and IL-16 were found positively associated with CSF white blood cells and CSF/serum albumin ratio. The study was limited by 77.9 % of the patients being on antipsychotic treatment at time of intervention, and that levels of nine of the 26 cytokines were below lower limit of detection (LLOD) in >50 % of samples; however, for the primary outcomes IL-6 and IL-8 more than 99.5 % of the samples were above LLOD and for IL-8 all samples exceeded the lower limit of quantification (LLOQ). CONCLUSIONS: We found no evidence of increased IL-6 and IL-8 in patients with recent-onset psychotic disorders in contrary to previous findings in meta-analyses of CSF cytokines. Secondary analyses found indication of higher IL-4, decreased IL-16, and borderline increased IFN-γ in patients, neither of which have previously been reported on in CSF analyses of individuals with psychotic disorders.

An umbrella review of candidate predictors of response, remission, recovery, and relapse across mental disorders.

We aimed to identify diagnosis-specific/transdiagnostic/transoutcome multivariable candidate predictors (MCPs) of key outcomes in mental disorders. We conducted an umbrella review (protocol  link ), searching MEDLINE/Embase (19/07/2022), including systematic reviews of studies reporting on MCPs of response, remission, recovery, or relapse, in DSM/ICD-defined mental disorders. From published predictors, we filtered MCPs, validating MCP criteria. AMSTAR2/PROBAST measured quality/risk of bias of systematic reviews/individual studies. We included 117 systematic reviews, 403 studies, 299,888 individuals with mental disorders, testing 796 prediction models. Only 4.3%/1.2% of the systematic reviews/individual studies were at low risk of bias. The most frequently targeted outcome was remission (36.9%), the least frequent was recovery (2.5%). Studies mainly focused on depressive (39.4%), substance-use (17.9%), and schizophrenia-spectrum (11.9%) disorders. We identified numerous MCPs within disorders for response, remission and relapse, but none for recovery. Transdiagnostic MCPs of remission included lower disease-specific symptoms (disorders = 5), female sex/higher education (disorders = 3), and quality of life/functioning (disorders = 2). Transdiagnostic MCPs of relapse included higher disease-specific symptoms (disorders = 5), higher depressive symptoms (disorders = 3), and younger age/higher anxiety symptoms/global illness severity/ number of previous episodes/negative life events (disorders = 2). Finally, positive trans-outcome MCPs for depression included less negative life events/depressive symptoms (response, remission, less relapse), female sex (response, remission) and better functioning (response, less relapse); for schizophrenia, less positive symptoms/higher depressive symptoms (remission, less relapse); for substance use disorder, marital status/higher education (remission, less relapse). Male sex, younger age, more clinical symptoms and comorbid mental/physical symptoms/disorders were poor prognostic factors, while positive factors included social contacts and employment, absent negative life events, higher education, early access/intervention, lower disease-specific and comorbid mental and physical symptoms/conditions, across mental disorders. Current data limitations include high risk of bias of studies and extraction of single predictors from multivariable models. Identified MCPs can inform future development, validation or refinement of prediction models of key outcomes in mental disorders.

Association between lithium treatment and renal, thyroid and parathyroid function: A cohort study of 6659 patients with bipolar disorder.

OBJECTIVES: Although potential adverse effects of lithium treatment on renal and endocrine systems have been extensively investigated, most prior studies are limited by selected populations and short follow-up. METHODS: Within the Psychiatric Services of the Central Denmark Region, we identified all patients with bipolar disorder and ≥1 serum-lithium (se-Li) measurements between January 1, 2013, and July 20, 2022, and reference patients with bipolar disorder matched on age, sex, and baseline creatinine. Outcomes were diagnoses of renal, thyroid and parathyroid disease, and blood tests measuring creatinine, estimated glomerular filtration rate (eGFR), thyroid-stimulating hormone (TSH), parathyroid hormone (PTH) and calcium. Analyses included unadjusted multilevel regression to describe changes in biochemical markers, and adjusted Cox regression to compare rates of disease/biochemical outcomes between lithium users and reference patients. RESULTS: Among 1646 lithium users (median age 36 years, 63% women) and 5013 reference patients, lithium users had decreasing TSH and eGFR, stable PTH, and increasing calcium levels over time. Lithium use was associated with increased rates of renal, thyroid and parathyroid disease, and levels of biochemical markers outside normal ranges (hazard rate ratios: 1.07-11.22), but the absolute number of severe outcomes was low (e.g., chronic kidney disease: N = 10, 0.6%). Notably, the rate of blood testing was substantially higher among lithium users than among reference patients (e.g., mean number of creatinine tests during the second year of follow-up: lithium users = 2.5, reference patients = 1.4). CONCLUSIONS: Severely adverse renal and endocrine outcomes are rare during lithium treatment. Observational studies of long-term lithium treatment are prone to detection bias.

Dimensions of temperament and character as predictors of antidepressant discontinuation, response and adverse reactions during treatment with nortriptyline and escitalopram.

BACKGROUND: Personality traits may predict antidepressant discontinuation and response. However, previous studies were rather small, only explored a few personality traits and did not include adverse drug effects nor the interdependency between antidepressant discontinuation patterns and response. METHODS: GENDEP included 589 patients with unipolar moderate-severe depression treated with escitalopram or nortriptyline for 12 weeks. Seven personality dimensions were measured using the self-reported 240-item Temperament and Character Inventory-Revised (TCI-R). We applied Cox proportional models to study discontinuation patterns, logistic and linear regression to investigate response and remission after 8 and 12 weeks, and mixed-effects linear models regarding time-varying treatment response and adverse drug reactions. RESULTS: Low harm avoidance, low cooperativeness, high self-transcendence and high novelty seeking were associated with higher risks for antidepressant discontinuation, independent of depressed mood, adverse drug reactions, drug, sex and age. Regression analyses showed that higher novelty seeking and cooperativeness scores were associated with a greater likelihood of response and remission after 8 and 12 weeks, respectively, but we found no correlations with response in the mixed-effects models. Only high harm avoidance was associated with more self-reported adverse effects. CONCLUSIONS: This study, representing the largest investigation between several personality traits and response to two different antidepressants, suggests that correlations between personality traits and antidepressant treatment response may be confounded by differential rates of discontinuation. Future trials on personality in the treatment of depression need to consider this interdependency and study whether interventions aiming at improving compliance for some personality types may improve response to antidepressants.

Pharmacological treatment of bipolar disorder and risk of diabetes mellitus: A nationwide study of 30,451 patients.

OBJECTIVE: While treatment with antipsychotics and antiepileptics have been associated with an increased risk of diabetes mellitus (DM), lithium may have the opposite effect via inhibition of glycogen synthase kinase-3. The aim of this study was to investigate whether treatment of bipolar disorder with lithium, antipsychotics, or antiepileptics is associated with the risk of DM in a real-world clinical setting. METHODS: Using nationwide registers, we identified all patients diagnosed with bipolar disorder in Danish Psychiatric Services from January 1, 1996, to January 1, 2019 (N = 30,451). The risk of developing DM was operationalized via hospital diagnoses and redeemed prescriptions for glucose-lowering drugs. For lithium, antipsychotics, valproate, and lamotrigine, we calculated hazard rate ratios (HRR) for developing DM via adjusted Cox proportional hazards models. Potential cumulative dose-response-like associations were examined using the log-rank test. RESULTS: During follow-up (245,181 person-years), 2107 (6.9%) patients developed DM. Compared with non-users of the respective drugs, we found no clinically or statistically significant difference in the risk of developing DM among patients receiving lithium (n = 11,690; incidence rate of DM/1000 person-years (IR) = 8.87, 95% CI: 8.02-9.90; HRR = 0.94, 95% CI: 0.84-1.06) or lamotrigine (n = 11,785; IR = 7.58, 95% CI: 6.69-8.59; HRR = 0.89, 95% CI: 0.77-1.02), respectively. Conversely, for patients receiving valproate (n = 5171; IR = 12.68, 95% CI: 10.87-14.80; HRR = 1.34, 95% CI: 1.14-1.58) and antipsychotics (n = 22,719; IR = 12.00, 95% CI: 11.14-12.94; HRR = 1.65, 95% CI: 1.45-1.88), respectively, there was increased risk of developing DM. For antipsychotics, we observed a clear cumulative dose-response-like association with the risk of DM. CONCLUSIONS: Treatment with valproate and antipsychotics-but not with lithium and lamotrigine-was associated with increased risk of DM in a real-world cohort of patients with bipolar disorder.

Schizophrenia spectrum disorders in Denmark between 2000 and 2018: Incidence and early diagnostic transition.

BACKGROUND: Schizophrenia spectrum disorders (SSD) comprise a group of related mental disorders, which share clinical features and common genetic disposition, but it is unknown if there is a diagnostic transition between these disorders over time. We aimed to study the incidence at the first SSD diagnosis between 2000 and 2018, defined as schizophrenia, schizotypal or schizoaffective disorder, and the early diagnostic transition between these disorders. METHODS: Using Danish nationwide healthcare registers, we identified all individuals aged 15-64 years during the period from 2000 to 2018 in Denmark and calculated the yearly incidence rates for the specific SSDs. We studied the diagnostic pathways from the first ever diagnosis of an SSD across the subsequent two treatment courses with an SSD diagnosis to evaluate early diagnostic stability, and explore potential changes over time. RESULTS: Among 21,538 patients, yearly incidence rates per 10,000 individuals were similar during the observation period for schizophrenia (2000: 1.8; 2018: 1.6), lower for schizoaffective disorder (2000: 0.3; 2018: 0.1) and increasing for schizotypal disorder (2000: 0.7; 2018: 1.3). Among the subgroup of 13,417 individuals with three separate treatment courses, early diagnostic stability was present among 89.9% which differed between the disorders (schizophrenia: 95.4%; schizotypal disorder: 78.0%; schizoaffective disorder: 80.5%). Among 1352 (10.1%) experiencing an early diagnostic transition, 398 (3.0%) were diagnosed with schizotypal disorder after a schizophrenia or schizoaffective disorder diagnosis. CONCLUSION: This study provides comprehensive incidence rates for SSDs. The majority of patients experienced early diagnostic stability, but sizable proportions of people with initial schizophrenia or schizoaffective disorder are subsequently diagnosed with schizotypal disorder.

Lithium plus antipsychotics or anticonvulsants for bipolar disorder: Comparing clinical response and metabolic changes.

OBJECTIVE: Patients with bipolar disorder treated with lithium often require additional antipsychotics or anticonvulsants. However, the comparative effectiveness and safety of these agents as add-on to lithium has not been studied. METHODS: This secondary analysis combined two similar 24-week trials on outpatients with bipolar disorder randomized to lithium (target serum level 0.4-0.6 mEq/L). Guideline-based adjunctive antipsychotics (Li+AP) and anticonvulsants (Li+AC) could be used if clinically indicated and was assessed at every study visit. Response was measured on the Clinical Global Impression scale and we performed adjusted mixed effects linear regression analyses. Analysis of variance tests compared metabolic measures including a binary diagnosis of metabolic syndrome before and after 24 weeks of treatment. RESULTS: Among 379 outpatients (57% female, mean age 38 years, mean Clinical Global Impression 4.4), users of Li+AP (N = 50, primarily quetiapine and aripiprazole) improved to a similar degree (mean Clinical Global Impression improvement = 1.6, standard deviation = 1.5) as those using lithium-only (i.e. without adjunctive antipsychotics or anticonvulsants, N = 149, mean Clinical Global Impression improvement = 1.7, standard deviation = 1.4) (p = 0.59). Users of Li+AC (N = 107, primarily lamotrigine and valproate, mean Clinical Global Impression improvement = 1.2, standard deviation = 1.3) and users of Li+AP+AC (N = 73, mean Clinical Global Impression improvement = 1.1, standard deviation = 1.3) showed worse response compared to lithium-only users (all p < 0.01). When comparing Li+AP to Li+AC, users of Li+AP improved slightly better on general (p = 0.05) and manic symptoms (p = 0.01), but showed a worse development of glucose, triglycerides, and metabolic syndrome. CONCLUSION: Despite treatment-by-indication confounding, these findings are relevant for real-world treatment settings and emphasize the need for randomized trials on this clinically important topic.

Diagnosis and Treatment of Bipolar Disorder: A Review.

Importance: Bipolar disorder affects approximately 8 million adults in the US and approximately 40 million individuals worldwide. Observations: Bipolar disorder is characterized by recurrent episodes of depression and mania or hypomania. Bipolar depressive episodes are similar to major depressive episodes. Manic and hypomanic episodes are characterized by a distinct change in mood and behavior during discrete time periods. The age of onset is usually between 15 and 25 years, and depression is the most frequent initial presentation. Approximately 75% of symptomatic time consists of depressive episodes or symptoms. Early diagnosis and treatment are associated with a more favorable prognosis. Diagnosis and optimal treatment are often delayed by a mean of approximately 9 years following an initial depressive episode. Long-term treatment consists of mood stabilizers, such as lithium, valproate, and lamotrigine. Antipsychotic agents, such as quetiapine, aripiprazole, asenapine, lurasidone, and cariprazine, are recommended, but some are associated with weight gain. Antidepressants are not recommended as monotherapy. More than 50% of patients with bipolar disorder are not adherent to treatment. Life expectancy is reduced by approximately 12 to 14 years in people with bipolar disorder, with a 1.6-fold to 2-fold increase in cardiovascular mortality occurring a mean of 17 years earlier compared with the general population. Prevalence rates of metabolic syndrome (37%), obesity (21%), cigarette smoking (45%), and type 2 diabetes (14%) are higher among people with bipolar disorder, contributing to the risk of early mortality. The annual suicide rate is approximately 0.9% among individuals with bipolar disorder, compared with 0.014% in the general population. Approximately 15% to 20% of people with bipolar disorder die by suicide. Conclusions and Relevance: Bipolar disorder affects approximately 8 million adults in the US. First-line therapy includes mood stabilizers, such as lithium, anticonvulsants, such as valproate and lamotrigine, and atypical antipsychotic drugs, such as quetiapine, aripiprazole, asenapine, lurasidone, and cariprazine.

Effect of mode of birth on development of mental disorders in the offspring.

OBJECTIVE: Increasing rates of caesarean sections has led to concerns about long-term effects on the offspring's health, and it has been hypothesised that caesarean section induced differences in the child's microbiota could potentially increase the risk of mental disorders. METHODS: Nationwide Danish cohort study of 2,196,687 births was conducted between 1980 and 2015, with 38.5 million observation-years. Exposure was 'Caesarean Section' and outcome was the child's risk of any mental disorder. Absolute and relative risks (RRs) were estimated using inverse probability weighting to adjust for age, calendar time and confounding variables while accounting for the competing risk of death. RESULTS: Caesarean section (n = 364,908, 16.6%), compared to vaginal birth, was associated with a small RR increase of 8% (RR, 1.08; 95% CI, 1.04-1.13; n = 44,352) for the development of any in-patient psychiatric admission at age 36 for the offspring and with a small absolute risk difference of 0.47% (95% CI, 0.23-0.76). When looking at all in-patient, out-patient and emergency room psychiatric contacts among people born after 1995, the effect was diminished (RR, 1.04; 95% CI, 0.99-1.09; n = 15,211). The risk was comparable when comparing prelabour versus intrapartum caesarean section (RR, 0.98; 95% CI, 0.90-1.08) and acute versus planned caesarean section (RR, 1.00; 95% CI, 0.80-1.29). CONCLUSION: Birth by caesarean section was associated with only a very slightly increased risk of any in-patient psychiatric admission for the offspring and diminished even further when including all psychiatric contacts. The very small associations observed may be explained by unmeasured confounding and is unlikely to be of substantial clinical relevance.

Childhood trauma and treatment outcomes during mood-stabilising treatment with lithium or quetiapine among outpatients with bipolar disorder.

BACKGROUND: Childhood trauma affects the course of mood disorders. Researchers are now considering childhood trauma as an influential factor in the treatment of mood disorders. However, the role of childhood trauma in the treatment of bipolar disorder remains understudied. METHODS: The effect of childhood trauma on treatment outcomes was evaluated among participants randomised to treatment with lithium or quetiapine in the Clinical and Health Outcomes Initiatives in Comparative Effectiveness for Bipolar Disorder (Bipolar CHOICE) study by clinician assessment. Mixed effects linear regression models were used to analyse rates of improvement in symptom severity (assessed with the Bipolar Inventory of Symptoms Scale and the Clinical Global Impression Scale for Bipolar Disorder) and functional impairment (assessed with the Longitudinal Interval Follow-up Evaluation-Range of Impaired Functioning Tool). RESULTS: A history of any childhood trauma was reported by 52.7% of the sample (N = 476). Although participants with a history of any childhood trauma presented with greater symptom severity and functional impairment at most study visits, participants with and without a history of any childhood trauma showed similar rates of improvement in symptom severity and functional impairment over the 24 weeks of treatment. CONCLUSION: This is the first study to explore the association between childhood trauma and treatment outcomes during treatment with lithium or quetiapine in the context of a randomised trial. In Bipolar CHOICE, a history of childhood trauma did not inhibit improvement in symptom severity or functional impairment. Nevertheless, these findings need replication across different settings.

Pre-diagnostic and post-diagnostic psychopharmacological treatment of 16 288 patients with bipolar disorder.

OBJECTIVES: The aim was to describe the pre-diagnostic and post-diagnostic psychopharmacological treatment of bipolar disorder over the past two decades. METHODS: We identified all 16 288 individuals aged ≥ 18 years, who received their first diagnosis of bipolar disorder at a psychiatric hospital in Denmark between 1997 and 2014. For each calendar year, we calculated the proportion of patients (with index date in the respective calendar years) who were prescribed psychopharmacological treatment in the 2 years preceding and the 2 years following the date of the first diagnosis of bipolar disorder. For patients diagnosed with bipolar disorder from 2007 to 2010 (n = 3949), we described the psychopharmacological treatment from 1995 to 2016, that is, from up to 16 years prior to and up to 10 years after the diagnosis. RESULTS: Concomitant use of ≥ 2 antidepressants in the 2 years preceding the bipolar disorder diagnosis increased over the study period. In the 2 years following the diagnosis, the use of lithium decreased, while use of atypical antipsychotics (particularly quetiapine), valproate, and lamotrigine increased over the study period. During the 10 years following the diagnosis, 53%-90% of the patients received any psychotropic drug while 12%-26% received treatment with an antidepressant without overlapping treatment with a mood-stabilizing drug. CONCLUSION: The increased use of two or more antidepressants suggests more focus on bipolar disorder as a differential diagnosis to treatment-resistant unipolar depression. The decreased use of lithium (consistent with international trends) and the prevalent use of antidepressants without overlapping treatment with a drug with mood-stabilizing properties are concerning.

Adjunctive antidepressant treatment among 763 outpatients with bipolar disorder: Findings from the Bipolar CHOICE and LiTMUS trials.

BACKGROUND: Adjunctive antidepressants are frequently used for bipolar depression but their clinical efficacy has been studied in few trials and little is known about how co-occurring manic symptoms affect treatment response. METHODS: Bipolar Clinical Health Outcomes Initiative in Comparative Effectiveness (N = 482) and Lithium Treatment Moderate-Dose Use Study (N = 281) were similar comparative effectiveness trials on outpatients with bipolar disorder comparing four different randomized treatment arms with adjunctive personalized guideline-based treatment for 24 weeks. Adjunctive antidepressant treatment could be used if clinically indicated and was assessed at every study visit. Adjusted mixed effects linear regression analyses compared users of antidepressants to nonusers overall and in different subcohorts. RESULTS: Of the 763 patients, 282 (37.0%) used antidepressant drugs during the study. Antidepressant users had less improvement compared to nonusers on the Clinical Global Impression Scale for Bipolar Disorder and on measures of depression. This was particularly true among patients with co-occurring manic symptoms. Exclusion of individuals begun on antidepressants late in the study (potentially due to overall worse response) resulted in no differences between users and nonusers. We found no differences in treatment effects on mania scales. CONCLUSIONS: In this large cohort of outpatients with bipolar disorder, clinically indicated and guideline-based adjunctive antidepressant treatment was not associated with lower depressive symptoms or higher mania symptoms. The treatment-by-indication confounding due to the nonrandomized design of the trials complicates causal interpretations, but no analyses indicated better treatment effects of adjunctive antidepressants.

Efficacy and safety of anti-inflammatory agents in treatment of psychotic disorders - A comprehensive systematic review and meta-analysis.

OBJECTIVE: Antipsychotic effects of immunomodulating drugs have been suggested; however, a thorough, comprehensive meta-analysis on the effect and safety of anti-inflammatory add-on treatment on psychotic disorders is lacking. METHOD: Multiple databases were searched up until February 2020. Only double-blinded, randomized, placebo-controlled clinical trials (RCTs) were included. Primary outcomes were change in total psychopathology and adverse events. Secondary outcomes included, amongst others, positive and negative symptoms, general psychopathology and cognitive domains. We performed random-effects meta-analyses estimating mean differences (MD) and standardized mean differences (SMD) for effect sizes. RESULTS: Seventy RCTs (N = 4104) were included, investigating either primarily anti-inflammatory drugs, i.e. drugs developed for immunomodulation, such as NSAIDs, minocycline and monoclonal antibodies (k = 15), or drugs with potential anti-inflammatory properties (k = 55), e.g. neurosteroids, N-acetyl cysteine, estrogens, fatty acids, statins, and glitazones. Antipsychotics plus anti-inflammatory treatment, compared to antipsychotics plus placebo, was associated with a PANSS scale MD improvement of -4.57 (95%CI = -5.93 to -3.20) points, corresponding to a SMD effect size of -0.29 (95%CI = -0.40 to -0.19). Trials on schizophrenia (MD = -6.80; 95%CI, -9.08 to -4.52) showed greater improvement (p < 0.01) than trials also including other psychotic disorders. However, primarily anti-inflammatory drugs (MD = 4.00; 95%CI = -7.19 to -0.80) were not superior (p = 0.69) to potential anti-inflammatory drugs (MD = 4.71; 95%CI = -6.26 to -3.17). Furthermore, meta-regression found that smaller studies showed significantly larger effect sizes than the larger studies (p = 0.0085), and only 2 studies had low risk of bias on all domains. Small but significant effects were found on negative symptoms (MD = -1.29), positive symptoms (MD = -0.53), general psychopathology (MD = -1.50) and working memory (SMD = 0.21). No differences were found regarding adverse events, but only 26 studies reported hereon. CONCLUSIONS: Anti-inflammatory add-on treatment to antipsychotics showed improvement of psychotic disorders; however, no superiority was found in primarily anti-inflammatory drugs, raising the question of the mechanism behind the effect, and treatment effect might be overestimated due to the large number of small studies.

Infections of the central nervous system as a risk factor for mental disorders and cognitive impairment: A nationwide register-based study.

BACKGROUND: CNS infections have been suggested as risk factors for cognitive decline and mental disorders; however, large-scale studies have been lacking regarding types and agents of CNS infections. METHODS: We utilized the unique personal registration number to create a cohort of 1,709,867 individuals born 1977-2010. CNS infection was exposure and data were analysed with 1) cox regression analyses estimating hazard ratios (HR) for developing mental disorders and 2) binomial regression estimating relative risk (RR) for completion of 9th grade including average grade score in a sub-cohort born 1988-1998. RESULTS: CNS infection increased the risk for developing mental disorders with a HR of 1.34 (95% CI 1.27-1.42). The highest risk observed was within the first 6 months after the CNS infection with a HR of 26.98 (95% CI 21.19-34.35). Viral CNS infections (HR 1.47, 95% CI 1.35-1.61) conferred a higher risk (p < 0.001) than bacterial (HR 1.24, 95% CI 1.15-1.35). Encephalitis (HR 1.64, 95% CI 1.41-1.90) conferred a higher risk (p < 0.001) than meningitis (HR 1.26, 95% CI 1.18-1.35). The risk was highest for organic mental disorders (HR 6.50, 95% CI 5.11-8.28) and disorders of intellectual development (HR 3.56, 95% CI 2.94-4.31), with a HR of 19.19 (95% CI 7.46-49.35) for profound disorder of intellectual development (IQ < 20). Furthermore, CNS infection decreased the RR of completing 9th grade of mandatory schooling (RR 0.89, 95% CI 0.88-0.91) and lowered average grade score for completers (p < 0.001). CONCLUSIONS: CNS infections increased the risk for mental disorders and decreased the likelihood of completing 9th grade, indicating long-term consequences of CNS infections.

Cerebrospinal fluid markers of inflammation and infections in schizophrenia and affective disorders: a systematic review and meta-analysis.

Infections and inflammatory processes have been associated with the development of schizophrenia and affective disorders; however, no study has yet systematically reviewed all available studies on cerebrospinal fluid (CSF) immune alterations. We aimed to systematically review the CSF immunological findings in schizophrenia spectrum and affective disorders. We identified all studies investigating CSF inflammatory markers in persons with schizophrenia or affective disorders published prior to March 23, 2017 searching PubMed, CENTRAL, EMBASE, Psychinfo, and LILACS. Literature search, data extraction and bias assessment were performed by two independent reviewers. Meta-analyses with standardized mean difference (SMD) including 95% confidence intervals (CI) were performed on case-healthy control studies. We identified 112 CSF studies published between 1942-2016, and 32 case-healthy control studies could be included in meta-analyses. Studies varied regarding gender distribution, age, disease duration, treatment, investigated biomarkers, and whether recruitment happened consecutively or based on clinical indication. The CSF/serum albumin ratio was increased in schizophrenia (1 study [54 patients]; SMD = 0.71; 95% CI 0.33-1.09) and affective disorders (4 studies [298 patients]; SMD = 0.41; 95% CI 0.23-0.60, I2 = 0%), compared to healthy controls. Total CSF protein was elevated in both schizophrenia (3 studies [97 patients]; SMD = 0.41; 95% CI 0.15-0.67, I2 = 0%) and affective disorders (2 studies [53 patients]; SMD = 0.80; 95% CI 0.39-1.21, I2 = 0%). The IgG ratio was increased in schizophrenia (1 study [54 patients]; SMD = 0.68; 95% CI 0.30-1.06), whereas the IgG Albumin ratio was decreased (1 study [32 patients]; SMD = -0.62; 95% CI -1.13 to -0.12). Interleukin-6 (IL-6) levels (7 studies [230 patients]; SMD = 0.55; 95% CI 0.35-0.76; I2 = 1%) and IL-8 levels (3 studies [95 patients]; SMD = 0.46; 95% CI 0.17-0.75, I2 = 0%) were increased in schizophrenia but not significantly increased in affective disorders. Most of the remaining inflammatory markers were not significantly different compared to healthy controls in the meta-analyses. However, in the studies which did not include healthy controls, CSF abnormalities were more common, and two studies found CSF dependent re-diagnosis in 3.2-6%. Current findings suggest that schizophrenia and affective disorders may have CSF abnormalities including signs of blood-brain barrier impairment and inflammation. However, the available evidence does not allow any firm conclusion since all studies showed at least some degree of bias and vastly lacked inclusion of confounding factors. Moreover, only few studies investigated the same parameters with healthy controls and high-quality longitudinal CSF studies are lacking, including impact of psychotropic medications, lifestyle factors and potential benefits of anti-inflammatory treatment in subgroups with CSF inflammation.

Correction: Cerebrospinal fluid markers of inflammation and infections in schizophrenia and affective disorders: a systematic review and meta-analysis.

Following publication of this paper, the authors realised that there were some errors in the reporting of the results on IL-6. This article has now been updated to include the correct values, following re-running of all analyses. For details of the changes made, please see the associated correction. This article was also originally published under standard licence, but has now been made available under a [CC BY 4.0] licence. The PDF and HTML versions of the paper have been modified accordingly.

Effect of antidepressant switching between nortriptyline and escitalopram after a failed first antidepressant treatment among patients with major depressive disorder.

BACKGROUND: For patients with major depressive disorder (MDD) experiencing side-effects or non-response to their first antidepressant, little is known regarding the effect of switching between a tricyclic antidepressant (TCA) and a selective serotonin reuptake inhibitor (SSRI).AimsTo compare the switch between the TCA nortriptyline and the SSRI escitalopram. METHOD: Among 811 adults with MDD treated with nortriptyline or escitalopram for up to 12 weeks, 108 individuals switched from nortriptyline to escitalopram or vice versa because of side-effects or non-response (trial registration: EudraCT No.2004-001723-38 (https://eudract.ema.europa.eu/) and ISRCTN No.03693000 (http://www.controlled-trials.com)). Patients were followed for up to 26 weeks after switching and response was measured with the Montgomery-Åsberg Depression Rating scale (MADRS). We performed adjusted mixed-effects linear regression models with full information maximum likelihood estimation reporting ß-coefficients with 95% CIs. RESULTS: Switching antidepressants resulted in a significant decrease in MADRS scores. This was present for switchers from escitalopram to nortriptyline (n = 36, ß = -0.38, 95% CI -0.51 to -0.25, P<0.001) and from nortriptyline to escitalopram (n = 72, ß = -0.34, 95% CI -0.41 to -0.26, P<0.001). Both switching options resulted in significant improvement among individuals who switched because of non-response or side-effects. The results were supported by analyses on other rating scales and symptom dimensions. CONCLUSIONS: These results suggest that switching from a TCA to an SSRI or vice versa after non-response or side-effects to the first antidepressant may be a viable approach to achieve response among patients with MDD.Declarations of interestK.J.A. holds an Alberta Centennial Addiction and Mental Health Research Chair, funded by the Government of Alberta. K.J.A. has been a member of various advisory boards, received consultancy fees and honoraria, and has received research grants from various companies including Johnson and Johnson Pharmaceuticals Research and Development and Bristol-Myers Squibb Pharmaceuticals Limited. D.S. has served on advisory boards for, and received unrestricted grants from, Lundbeck and AstraZeneca. A.F. and P.M. have received honoraria for participating in expert panels for Lundbeck and GlaxoSmithKline.