With the increased prevalence of major depressive episodes with mixed features specifier (MDE-MFS), the pharmacological treatment for MDE-MFS has attracted great clinical attention. This study aimed to investigate the efficacy and safety of medication use for MDE-MFS.

Commonly used databases were searched for the meta-analysis. Primary efficacy outcomes included response rate and the change in the Young Mania Rating Scale scores; the primary safety outcome was the rate of treatment-emergent hypomania/mania. Effects were expressed as relative risk (RR) or standardized mean difference (SMD).

In patients with MDE-MFS, antipsychotics significantly improved depressive (RR = 1.46 [95% CI: 1.31, 1.61]) and manic (SMD = −0.35 [95% CI: −0.53, −0.17]) symptoms without increasing the risk of manic switch (RR = 0.91 [95% CI: 0.53, 1.55]). However, subgroup analysis of bipolar disorder (BD) patients with MDE-MFS indicated that antipsychotics had limited effects on manic symptoms. Mood stabilizers, especially valproate, demonstrated significant effects in BD patients with MDE-MFS by relieving depressive and manic symptoms. For MDE-MFS in patients with major depressive disorder, trazodone has shown potential effectiveness in retrospective studies, while the effectiveness of antidepressants on BD patients with MDE-MFS lacked evidence.

While antipsychotics are first options for MDE-MFS, their effect on manic symptoms in BD patients with MDE-MFS is still unclear. Mood stabilizers may also be considered, and the use of antidepressants remains a topic of controversy. Since our findings are mostly based on post-hoc analyses, the evidence remains preliminary, highlighting the need for further research to produce more conclusive evidence.

In the treatment of obsessive-compulsive disorder (OCD) with antidepressant medication, the earliest reliable indication of treatment failure remains uncertain. We investigated if non-improvement following 4 weeks of treatment predicts nonresponse at the end of the trial.

We conducted a random-effects bivariate diagnostic accuracy study using individual patient data from industry-sponsored short-term trials of adults with OCD receiving selective serotonin reuptake inhibitors or clomipramine, submitted for marketing approval. The primary outcome was accuracy of non-improvement (<25% reduction on the Yale–Brown Obsessive Compulsive Scale [YBOCS] after 4 weeks) in predicting nonresponse (<35% YBOCS reduction at trial endpoint [10–13 weeks]). Secondary outcomes were accuracy of non-improvement after 6 weeks, nonresponse after 8 weeks, and inclusion of Clinical Global Impression Scale – Improvement in definitions of improvement and response. We performed meta-regressions for sex, age, severity, trial duration, dosing regimen, and compound.

In 11 studies totaling 1,753 patients, non-improvement at week 4 predicted subsequent nonresponse (positive predictive value, PPV) in 86% of cases (95% confidence interval [CI] = 83–88%). Sensitivity was 78%, specificity was 70%, and the negative predictive value was 60%. Secondary outcomes showed similar PPV after 6 weeks and a PPV of 93% for nonresponse after 8 weeks. Predictive accuracy was significantly higher in men relative to women (β = −0.64, 95% CI = −1.12 to −0.16, p = 0.0089).

Patients with OCD who do not improve after 4 weeks of antidepressants will likely not respond to short-term treatment. Thus, a change in strategy should be considered after 4 weeks without treatment benefits.

Adults with mood and/or anxiety disorders have increased risks of comorbidities, chronic treatments and polypharmacy, increasing the risk of drug–drug interactions (DDIs) with antidepressants.

To use primary care records from the UK Biobank to assess DDIs with citalopram, the most widely prescribed antidepressant in UK primary care.

We classified drugs with pharmacokinetic or pharmacodynamic DDIs with citalopram, then identified prescription windows for these drugs that overlapped with citalopram prescriptions in UK Biobank participants with primary care records. We tested for associations of DDI status (yes/no) with sociodemographic and clinical characteristics and with cytochrome 2C19 activity, using univariate tests, then fitted multivariable models for variables that reached Bonferroni-corrected significance.

In UK Biobank primary care data, 25 508 participants received citalopram prescription(s), among which 11 941 (46.8%) had at least one DDI, with an average of 1.96 interacting drugs. The drugs most commonly involved were proton pump inhibitors (40% of co-prescription instances). Individuals with DDIs were more often female and older, had more severe and less treatment-responsive depression, and had higher rates of psychiatric and physical disorders. In the multivariable models, treatment resistance and markers of severity (e.g. history of suicidal and self-harm behaviours) were strongly associated with DDIs, as well as comorbidity with cardiovascular disorders. Cytochrome 2C19 activity was not associated with the occurrence of DDIs.

The high frequency of DDIs with citalopram in fragile groups confirms the need for careful consideration before prescribing and periodic re-evaluation.

Selective serotonin reuptake inhibitors (SSRIs) are the first-line treatment for major depressive disorder (MDD), but initial outcomes can be modest.

To compare SSRI dose optimisation with four alternative second-line strategies in MDD patients unresponsive to an SSRI.

Of 257 participants, 51 were randomised to SSRI dose optimisation (SSRI-Opt), 46 to lithium augmentation (SSRI+Li), 48 to nortriptyline combination (SSRI+NTP), 55 to switch to venlafaxine (VEN) and 57 to problem-solving therapy (SSRI+PST). Primary outcomes were week-6 response/remission rates, assessed by blinded evaluators using the 17-item Hamilton Depression Rating Scale (HDRS-17). Changes in HDRS-17 scores, global improvement and safety outcomes were also explored. EudraCT No. 2007-002130-11.

Alternative second-line strategies led to higher response (28.2% v. 14.3%, odds ratio = 2.36 [95% CI 1.0–5.6], p = 0.05) and remission (16.9% v. 12.2%, odds ratio = 1.46, [95% CI 0.57–3.71], p = 0.27) rates, with greater HDRS-17 score reductions (−2.6 [95% CI −4.9 to −0.4], p = 0.021]) than SSRI-Opt. Significant/marginally significant effects were only observed in both response rates and HDRS-17 decreases for VEN (odds ratio = 2.53 [95% CI 0.94–6.80], p = 0.067; HDRS-17 difference: −2.7 [95% CI −5.5 to 0.0], p = 0.054) and for SSRI+PST (odds ratio = 2.46 [95% CI 0.92 to 6.62], p = 0.074; HDRS-17 difference: −3.1 [95% CI −5.8 to −0.3], p = 0.032). The SSRI+PST group reported the fewest adverse effects, while SSRI+NTP experienced the most (28.1% v. 75%; p < 0.01), largely mild.

Patients with MDD and insufficient response to SSRIs would benefit from any other second-line strategy aside from dose optimisation. With limited statistical power, switching to venlafaxine and adding psychotherapy yielded the most consistent results in the DEPRE'5 study.

Common mental disorders (CMDs) are significant causes of work disability. Low socioeconomic status (SES) is a known risk factor for CMDs and work disability, one possible reason being poorer treatment adherence. We aimed to study the realization of pharmacological treatment and antidepressant adherence in patients with CMDs 3 years before and 3 years after being granted a disability pension (DP) and the role of SES in this. We also studied whether antidepressant adherence is associated with return to work (RTW) after a temporary DP.

Information on all persons granted a DP due to CMD between 2010 and 2012 in Finland (n = 12,388) was retrieved from national registers, which included medical, socioeconomic, and sociodemographic information of the subjects. We used the PRE2DUP method to estimate drug use periods and regression analyses to study associations between SES, taking medications, and RTW.

Prevalence of taking antidepressants increased towards the DP grant and decreased thereafter, but 14.6% of subjects did not take antidepressants or antipsychotics at all during the study period. Of SES factors, only income was positively associated with antidepressant adherence, lasting over a year. Antidepressant adherence was not associated with RTW.

An alarming result was the absence of recommended medication in fewer than every seventh patient estimated to be disabled due to pharmacologically treatable psychiatric disorders. Contrary to expectations, SES had only a minor predictive role in antidepressant adherence in this patient group. Contrary to taking antidepressants, rehabilitation was associated with RTW. The results adduced the importance of CMD treatment optimization regardless of SES.

Heterogeneous symptoms in major depression contribute to unsuccessful antidepressant treatment, termed treatment-resistant depression (TRD). Psychometric network modeling conceptualizes depression as interplay of symptoms with potential benefits for treatment; however, a knowledge gap exists regarding networks in TRD.

Symptoms from 1,385 depressed patients, assessed by the Montgomery-Åsberg-depression rating scale (MADRS) as part of the “TRD-III” cohort of the multinational research consortium “Group for the Studies of Resistant Depression,” were used for Gaussian graphical network modeling. Networks were estimated for two timepoints, pretreatment and posttreatment, after the establishment of outcomes response, non-response, and TRD. Applying the network-comparison test, edge weights, and symptom centrality was assessed by bootstrapping. Applying the network-comparison test, outcome groups were compared cross-sectionally and longitudinally regarding the networks’ global strength, invariance, and centrality.

Pretreatment networks did not differ in global strength, but outcome groups showed distinct symptom connections. For both response and TRD, global strength was reduced posttreatment, leading to significant differences between each pair of networks posttreatment. Sadness, lassitude, inability-to-feel, and pessimistic thoughts ranked most centrally in unfavorable outcomes, while reduced-appetite and suicidal thoughts were more densely connected in response. Connections between central symptoms increased in strength following unsuccessful treatment, particularly regarding links involving pessimistic thoughts in TRD.

Treatment reduced global network strength across outcome groups. However, distinct symptom networks were found in patients showing response to treatment, non-response, and TRD. More easily targetable symptoms such as reduced-appetite were central to networks in patients with response, while pessimistic thoughts may be a key symptom upholding disease burden in TRD.

Previous studies investigating the effectiveness of augmentation therapy have been limited.

To evaluate the effectiveness of antipsychotic augmentation therapies among patients with treatment-resistant depression.

We included patients diagnosed with depression receiving two antidepressant courses within 1 year between 2009 and 2020 and used the clone-censor-weight approach to address time-lag bias. Participants were assigned to either an antipsychotic or a third-line antidepressant. Primary outcomes were suicide attempt and suicide death. Cardiovascular death and all-cause mortality were considered as safety outcomes. Weighted pooled logistic regression and non-parametric bootstrapping were used to estimate approximate hazard ratios and 95% confidence intervals.

The cohort included 39 949 patients receiving antipsychotics and the same number of matched antidepressant patients. The mean age was 51.2 (standard deviation 16.0) years, and 37.3% of participants were male. Compared with patients who received third-line antidepressants, those receiving antipsychotics had reduced risk of suicide attempt (sub-distribution hazard ratio 0.77; 95% CI 0.72–0.83) but not suicide death (adjusted hazard ratio 1.08; 95% CI 0.93–1.27). After applying the clone-censor-weight approach, there was no association between antipsychotic augmentation and reduced risk of suicide attempt (hazard ratio 1.06; 95% CI 0.89–1.29) or suicide death (hazard ratio 1.22; 95% CI 0.91–1.71). However, antipsychotic users had increased risk of all-cause mortality (hazard ratio 1.21; 95% CI 1.07–1.33).

Antipsychotic augmentation was not associated with reduced risk of suicide-related outcomes when time-lag bias was addressed; however, it was associated with increased all-cause mortality. These findings do not support the use of antipsychotic augmentation in patients with treatment-resistant depression.

Antidepressants are effective for depression, but most evidence excludes individuals with comorbid physical conditions.

To assess antidepressants’ efficacy and tolerability in individuals with depression and comorbid physical conditions.

Systematic review and network meta-analysis of randomised controlled trials (RCTs). Co-primary outcomes were efficacy on depressive symptoms and tolerability (participants dropping out because of adverse events). Bias was assessed with the Cochrane Risk-of-Bias 2 tool and certainty of estimates with the Confidence in Network Meta-Analysis approach. A study protocol was registered in advance (https://osf.io/9cjhe/).

Of the 115 included RCTs, 104 contributed to efficacy (7714 participants) and 82 to tolerability (6083 participants). The mean age was 55.7 years and 51.9% of participants were female. Neurological and cardiocirculatory conditions were the most represented (26.1% and 18.3% of RCTs, respectively). The following antidepressants were more effective than placebo: imipramine, nortriptyline, amitriptyline, desipramine, sertraline, paroxetine, citalopram, fluoxetine, escitalopram, mianserin, mirtazapine and agomelatine, with standardised mean differences ranging from −1.01 (imipramine) to −0.34 (escitalopram). Sertraline and paroxetine were effective for the largest number of ICD-11 disease subgroups (four out of seven). In terms of tolerability, sertraline, imipramine and nortriptyline were less tolerated than placebo, with relative risks ranging from 1.47 (sertraline) to 3.41 (nortriptyline). For both outcomes, certainty of evidence was ‘low’ or ‘very low’ for most comparisons.

Antidepressants are effective in individuals with comorbid physical conditions, although tolerability is a relevant concern. Selective serotonin reuptake inhibitors (SSRIs) have the best benefit–risk profile, making them suitable as first-line treatments, while tricyclics are highly effective but less tolerated than SSRIs and placebo.