Dose effects of tricyclic antidepressants in the treatment of acute depression - A systematic review and meta-analysis of randomized trials.

BACKGROUND: Tricyclic antidepressants (TCA) continue to be an important group of drugs, but it is unclear whether a dose-response relationship is supported by high-level evidence. METHODS: Systematic review in the Cochrane Collaboration's Central Register of Controlled Trials (CENTRAL) of studies randomizing patients to at least two doses of one TCA, complemented by searches in Medline, Embase, and PsycInfo. In multilevel regression, we calculated the standardized mean difference (SMD) in antidepressant efficacy per mg TCA dose increase, and we analyzed drop-outs due to adverse events. Finally, we computed random effects meta-analyses of all dose comparisons investigated in a minimum of two studies. RESULTS: Out of 5365 studies screened, we included 15 randomized trials on 24 comparisons of 14 different dose contrasts. We found a statistically non-significant positive effect of increasing the dose: 0.34 SMD with 100 mg/d dose increase ([-0.03; 0.70] p = 0.073). While several comparisons showed no clear signal of a dose gradient, 300 mg of imipramine/desipramine is statistically significantly superior to 150 mg (SMD: 0.80 [0.28; 1.33], p = 0.003, I2: 0%). Drop-outs increased with higher doses, albeit not statistically significantly: Odds ratio (OR) of 1.44 with 100 mg dose increase [0.54; 3.86]. Overall, risk of bias was high. LIMITATIONS: Limited number of studies with mainly high risk of bias. CONCLUSIONS: So far, data on a dose-response relationship in TCAs from direct dose comparisons are inconclusive. Clinically, escalation to high doses may be justified if side effects are bearable.

Dose-Response Relationship in Selective Serotonin and Norepinephrine Reuptake Inhibitors in the Treatment of Major Depressive Disorder: A Meta-Analysis and Network Meta-Analysis of Randomized Controlled Trials.

INTRODUCTION: Selective serotonin and norepinephrine reuptake inhibitors (SNRI) are among the most prescribed antidepressants, and dose escalation is a frequently applied strategy after non-response to an initially prescribed dose. OBJECTIVE: This meta-analysis aimed to find evidence of a dose-response relationship or to the contrary in direct comparisons of different SNRI doses in patients with major depressive disorder. METHODS: A systematic literature search for RCTs comparing at least two doses of SNRIs was carried out in CENTRAL, PubMed, PsycINFO, and EMBASE. Doses were classified as high, medium, and low according to manufacturers' product monographs and analyses at the level of SNRIs as a group and for single substances, accompanied by sensitivity network meta-analyses (Prospero CRD42018081031). RESULTS: From 2,070 studies screened, we included 26 studies with a total of 10,242 patients. Comparisons of medium versus low and high versus medium doses resulted in clinically and statistically non-significant standardized mean differences of -0.06 (-0.16 to 0.04) and -0.06 (-0.16 to 0.03) in favor of higher doses. In the analyses of single substances, no statistically significant results emerged, and many contrasts yielded very small effect sizes. Dropouts due to side effects tended to be more frequent with higher doses. Heterogeneity was low. Network meta-analyses of direct comparisons supported the findings, as did a risk of bias analysis. CONCLUSION: Based on the lack of positive evidence for a dose-response relationship in SNRIs as a group and in single SNRIs, we recommend prescribing medium doses. In case of insufficient response, we do not recommend increasing the dose of SNRIs.

Dose Increase Versus Unchanged Continuation of Antidepressants After Initial Antidepressant Treatment Failure in Patients With Major Depressive Disorder: A Systematic Review and Meta-Analysis of Randomized, Double-Blind Trials.

OBJECTIVE: To evaluate the efficacy and tolerability of dose increase compared to dose continuation of the initially prescribed antidepressant in antidepressant treatment failure (ATF). DATA SOURCES: We searched CENTRAL, PubMed, Embase, and PsycINFO using generic terms for depression, dose increase, and randomized controlled trials (RCTs), without date or language restrictions. STUDY SELECTION: Of 1,780 studies screened, 9 studies reporting on 1,273 patients were included for meta-analysis (PROSPERO Registration: CRD42017058389). Studies met the following predetermined inclusion criteria: randomized controlled trial, patients diagnosed with unipolar depression according to a standardized diagnostic instrument, ATF after a standard antidepressant trial (duration of ≥ 3 weeks at a standard dose), dose increase regimen, and control group of dose continuation. DATA EXTRACTION: Two authors extracted data independently according to the Cochrane Handbook for Systematic Reviews. Analyses are based on random effects models. RESULTS: All studies reported on selective serotonin reuptake inhibitors (SSRIs); 1 study also reported on maprotiline. Meta-analyses resulted in a statistically nonsignificant summary effect size of 0.053 standardized mean difference (95% CI, -0.143 to 0.248) in favor of antidepressant dose increase. Subgroup and sensitivity analyses and secondary outcome analyses resulted in similar effect estimates and supported the robustness of the results. CONCLUSIONS: With clinically and statistically nonsignificant effect estimates, there is evidence from RCTs against increasing the dose of SSRIs (with the possible exception of citalopram) in adult patients with major depression and ATF. Dose increase with other antidepressants (eg, tricyclic antidepressants, serotonin-norepinephrine reuptake inhibitors, monoamine oxidase inhibitors) and in other patient groups (minor depression, children and adolescents) or after long periods of first-line antidepressant therapy (ie, 8 weeks) have not been or not been sufficiently studied and, at this time, cannot be recommended in clinical practice.

Characteristics and heterogeneity of schizoaffective disorder compared with unipolar depression and schizophrenia - a systematic literature review and meta-analysis.

BACKGROUND: Comparisons of illness characteristics between patients with schizoaffective disorder (SAD) patients and unipolar depression (UD) are rare, even though UD is one of the most important differential diagnoses of SAD. Also, the variability of illness characteristics (heterogeneity) has not been compared. We compared illness characteristics and their heterogeneity among SAD, UD, and - as another important differential diagnosis - schizophrenia (S). METHODS: In order to reduce sampling bias we systematically searched for studies simultaneously comparing samples of patients with SAD, UD, and S. Using random effects and Mantel-Haenszel models we estimated and compared demographic, illness course and psychopathology parameters, using pooled standard deviations as a measurement of heterogeneity. RESULTS: Out of 155 articles found by an earlier meta-analysis, 765 screened in Medline, 2738 screened in EMBASE, and 855 screened in PsycINFO we selected 24 studies, covering 3714 patients diagnosed according to RDC, DSM-III, DSM-IIIR, DSM-IV, or ICD-10. In almost all key characteristics, samples with schizoaffective disorders fell between unipolar depression and schizophrenia, with a tendency towards schizophrenia. On average, UD patients were significantly older at illness onset (33.0 years, SAD: 25.2, S: 23.4), more often women (59% vs. 57% vs. 39%) and more often married (53% vs. 39% vs. 27%). Their psychopathology was also less severe, as measured by BPRS, GAS, and HAMD. In demographic and clinical variables heterogeneity was roughly 5% larger in UD than in SAD, and samples of patients with schizophrenia had the lowest pooled heterogeneity. A similar picture emerged in a sensitivity analysis with coefficient of variation as the measurement of heterogeneity. LIMITATIONS: Relative to bipolar disorder there are fewer studies including unipolar patients. No studies based on DSM-5 could be included. CONCLUSIONS: Regarding unipolar affective disorder this study confirms what we have shown for bipolar disorders in earlier studies: schizoaffective disorder falls between schizophrenia and affective disorders, and there are relevant quantitative differences in key illness characteristics, which supports the validity of the schizoaffective disorder concept. Contrary to our expectations heterogeneity is not larger in SAD than in UD and not substantially higher than in S. Lower reliability of the diagnosis of SAD therefore cannot be ascribed to higher variability of illness characteristics in SAD.