Individual response to antidepressants for depression in adults-a meta-analysis and simulation study

BACKGROUND: The observation that some patients appear to respond better to antidepressants for depression than others encourages the assumption that the effect of antidepressants differs between individuals and that treatment can be personalized. OBJECTIVE: To compare the outcome variance in patients receiving antidepressants with the outcome variance in patients receiving placebo in randomized controlled trials (RCTs) of adults with major depressive disorder (MDD) and to illustrate, using simulated data, components of variation of RCTs. METHODS: From a dataset comprising 522 RCTs of antidepressants for adult MDD, we selected the placebo-controlled RCTs reporting outcomes on the 17 or 21 item Hamilton Depression Rating Scale or the Montgomery-Asberg Depression Rating Scale and extracted the means and SDs of raw endpoint scores or baseline to endpoint changes scores on eligible depression symptom rating scales. We conducted inverse variance random-effects meta-analysis with the variability ratio (VR), the ratio between the outcome variance in the group of patients receiving antidepressants and the outcome variance in the group receiving placebo, as the primary outcome. An increased variance in the antidepressant group would indicate individual differences in response to antidepressants. RESULTS: We analysed 222 RCTs that investigated 19 different antidepressants compared with placebo in 345 comparisons, comprising a total of 61144 adults with an MDD diagnosis. Across all comparisons, the VR for raw endpoint scores was 0.98 (95% CI 0.96 to 1.00, I2 = 0%) and 1.00 (95% CI 0.99 to 1.02, I2 = 0%) for baseline-to-endpoint change scores. CONCLUSION: Based on these data, we cannot reject the null hypothesis of equal variances in the antidepressant group and the placebo group. Given that RCTs cannot provide direct evidence for individual treatment effects, it may be most reasonable to assume that the average effect of antidepressants applies also to the individual patient

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

Metabolic profile in patients with newly diagnosed bipolar disorder and their unaffected first-degree relatives

Abstract Objective The prevalence of metabolic syndrome and insulin resistance is twice as high in patients with bipolar disorder compared with the general population, and possibly associated with a disabling illness trajectory of bipolar disorder, an increased risk of cardiovascular disease and premature death. Despite these detrimental effects, the prevalence of metabolic syndrome and insulin resistance in patients newly diagnosed with bipolar disorder and their unaffected first-degree relatives is largely unknown. Methods In a cross-sectional study of 206 patients with newly diagnosed bipolar disorder, 50 of their unaffected first-degree relatives and 109 healthy age- and sex-matched individuals, we compared the prevalence of metabolic syndrome and insulin resistance (HOMA-IR). In patients with bipolar disorder, we further investigated illness and medication variables associated with the metabolic syndrome and insulin resistance. Results Higher rates of metabolic syndrome (odds ratio = 3.529, 95% CI 1.378–9.041, P = 0.009) and levels of insulin resistance (B = 1.203, 95% CI 1.059–1.367, P = 0.005) were found in patients newly diagnosed with bipolar disorder, but not in their unaffected first-degree relatives compared with matched healthy individuals (data adjusted for sex and age). Most patients with bipolar disorder (94.7%) were diagnosed within the preceding 2 years, and the average illness duration, defined as time from first mood episode, was 10 years. Conclusion Our findings of elevated prevalence of metabolic syndrome and insulin resistance in patients with newly diagnosed bipolar disorder highlight the importance of screening for these conditions at an early stage to employ adequate and early care reducing the risk of cardiovascular disease and premature death

Tricyclic antidepressants versus ‘active placebo’, placebo or no intervention for adults with major depressive disorder : a protocol for a systematic review with meta-analysis and Trial Sequential Analysis

Background: Major depressive disorder is a common psychiatric disorder causing great burden on patients and societies. Tricyclic antidepressants are frequently used worldwide to treat patients with major depressive disorder. It has repeatedly been shown that tricyclic antidepressants reduce depressive symptoms with a statistically significant effect, but the effect is small and of questionable clinical importance. Moreover, the beneficial and harmful effects of all types of tricyclic antidepressants have not previously been systematically assessed. Therefore, we aim to investigate the beneficial and harmful effects of tricyclic antidepressants versus ‘active placebo’, placebo or no intervention for adults with major depressive disorder. Methods: This is a protocol for a systematic review with meta-analysis that will be reported as recommended by Preferred Reporting Items for Systematic Reviews and Meta-Analysis Protocols, bias will be assessed with the Cochrane Risk of Bias tool—version 2, our eight-step procedure will be used to assess if the thresholds for clinical significance are crossed, Trial Sequential Analysis will be conducted to control random errors and the certainty of the evidence will be assessed with the Grading of Recommendations Assessment, Development and Evaluation approach. To identify relevant trials, we will search both for published and unpublished trials in major medical databases and trial registers, such as CENTRAL, MEDLINE, EMBASE and ClinicalTrials.gov from their inception to 12 May 2021. Clinical study reports will be applied for from regulatory authorities and pharmaceutical companies. Two review authors will independently screen the results from the literature searches, extract data and perform risk of bias assessment. We will include any published or unpublished randomised clinical trial comparing tricyclic antidepressants with ‘active placebo’, placebo or no intervention for adults with major depressive disorder. The following interventions will be assessed: amineptine, amitriptyline, amoxapine, butriptyline, cianopramine, clomipramine, desipramine, demexiptiline, dibenzepin, dosulepin, dothiepin, doxepin, imipramine, iprindole, lofepramine, maprotiline, melitracen, metapramine, nortriptyline, noxiptiline, opipramol, protriptyline, tianeptine, trimipramine and quinupramine. Primary outcomes will be depressive symptoms, serious adverse events and quality of life. Secondary outcomes will be suicide or suicide-attempts and non-serious adverse events. If feasible, we will assess the intervention effects using random-effects and fixed-effect meta-analyses. Discussion: Tricyclic antidepressants are recommended by clinical guidelines and frequently used worldwide in the treatment of major depressive disorder. There is a need for a thorough systematic review to provide the necessary background for weighing the benefits against the harms. This review will ultimately inform best practice in the treatment of major depressive disorder

The risks of adverse events with venlafaxine and mirtazapine versus 'active placebo', placebo, or no intervention for adults with major depressive disorder : a protocol for two separate systematic reviews with meta-analysis and Trial Sequential Analysis

Background: Major depressive disorder causes a great burden on patients and societies. Venlafaxine and mirtazapine are commonly prescribed as second-line treatment for patients with major depressive disorder worldwide. Previous systematic reviews have concluded that venlafaxine and mirtazapine reduce depressive symptoms, but the effects seem small and may not be important to the average patient. Moreover, previous reviews have not systematically assessed the occurrence of adverse events. Therefore, we aim to investigate the risks of adverse events with venlafaxine or mirtazapine versus ‘active placebo’, placebo, or no intervention for adults with major depressive disorder in two separate systematic reviews. Methods: This is a protocol for two systematic reviews with meta-analysis and Trial Sequential Analysis. The assessments of the effects of venlafaxine or mirtazapine will be reported in two separate reviews. The protocol is reported as recommended by Preferred Reporting Items for Systematic Reviews and Meta-Analysis Protocols, risk of bias will be assessed with the Cochrane risk-of-bias tool version 2, clinical significance will be assessed using our eight-step procedure, and the certainty of the evidence will be assessed with the Grading of Recommendations Assessment, Development and Evaluation approach. We will search for published and unpublished trials in major medical databases and trial registers. Two review authors will independently screen the results from the literature searches, extract data, and assess risk of bias. We will include published or unpublished randomised clinical trial comparing venlafaxine or mirtazapine with ‘active placebo’, placebo, or no intervention for adults with major depressive disorder. The primary outcomes will be suicides or suicide attempts, serious adverse events, and non-serious adverse events. Exploratory outcomes will include depressive symptoms, quality of life, and individual adverse events. If feasible, we will assess the intervention effects using random-effects and fixed-effect meta-analyses. Discussion: Venlafaxine and mirtazapine are frequently used as second-line treatment of major depressive disorder worldwide. There is a need for a thorough systematic review to provide the necessary background for weighing the benefits against the harms. This review will ultimately inform best practice in the treatment of major depressive disorder

Individual response to antidepressants for depression in adults-a meta-analysis and simulation study.

BackgroundThe observation that some patients appear to respond better to antidepressants for depression than others encourages the assumption that the effect of antidepressants differs between individuals and that treatment can be personalized.ObjectiveTo compare the outcome variance in patients receiving antidepressants with the outcome variance in patients receiving placebo in randomized controlled trials (RCTs) of adults with major depressive disorder (MDD) and to illustrate, using simulated data, components of variation of RCTs.MethodsFrom a dataset comprising 522 RCTs of antidepressants for adult MDD, we selected the placebo-controlled RCTs reporting outcomes on the 17 or 21 item Hamilton Depression Rating Scale or the Montgomery-Asberg Depression Rating Scale and extracted the means and SDs of raw endpoint scores or baseline to endpoint changes scores on eligible depression symptom rating scales. We conducted inverse variance random-effects meta-analysis with the variability ratio (VR), the ratio between the outcome variance in the group of patients receiving antidepressants and the outcome variance in the group receiving placebo, as the primary outcome. An increased variance in the antidepressant group would indicate individual differences in response to antidepressants.ResultsWe analysed 222 RCTs that investigated 19 different antidepressants compared with placebo in 345 comparisons, comprising a total of 61144 adults with an MDD diagnosis. Across all comparisons, the VR for raw endpoint scores was 0.98 (95% CI 0.96 to 1.00, I2 = 0%) and 1.00 (95% CI 0.99 to 1.02, I2 = 0%) for baseline-to-endpoint change scores.ConclusionBased on these data, we cannot reject the null hypothesis of equal variances in the antidepressant group and the placebo group. Given that RCTs cannot provide direct evidence for individual treatment effects, it may be most reasonable to assume that the average effect of antidepressants applies also to the individual patient