Antidepressant Medications: 33 Recent Meta-Analyses—Ken Pope, PHD, ABPP

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Antidepressant Medications: 33 Meta-Analytic Studies Published in 2018-2022


Kenneth S. Pope, Ph.D., ABPP

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For each brand name and generic antidepressant medication, I searched out meta-analytic studies on its uses, effectiveness, risks, side effects, differential effects on different populations, etc.—to help clinicians, expert witnesses, researchers, and others to stay abreast of the evolving research in this area. I focused on studies published in 2018-2022, and included both the citation and a brief excerpt for each study.

  1. Biffi, A., et al. (2020). "Use of antidepressants during pregnancy and neonatal outcomes: An umbrella review of meta-analyses of observational studies." Journal of Psychiatric Research 124: 99-108.

    EXCERPT: " Our review included 22 meta-analyses investigating 69 associations. However, none were supported by convincing evidence. Highly suggestive evidence regarded the associations between (i) any time AD exposure and the risk of preterm birth (relative risk, 1.68; 95% confidence interval 1.52, 1.86), (ii) any time exposure to selective serotonin reuptake inhibitors (SSRIs) and the risk of preterm birth (1.43; 1.22, 1.37) and (iii) respiratory distress (1.33; 1.14, 1.55), and (iv) SSRI exposure during the first trimester of pregnancy and the risk of cardiovascular malformations (1.25; 1.13, 1.39). Suggestive evidence was obtained for any time AD exposure on 1-min low Apgar score (absolute average difference, −0.34; −0.53, −0.14).... Overall, the effects of AD exposure during pregnancy on neonatal outcomes have been extensively studied, but few of the associations are graded as high quality evidence. More prospective studies and large collaborations with comprehensive standardised reporting of analyses are needed."

  2. Boschloo, L., et al. (2019). "The symptom-specific efficacy of antidepressant medication vs. cognitive behavioral therapy in the treatment of depression: Results from an individual patient data meta-analysis." World Psychiatry 18(2): 183-191.

    EXCERPT: "Five symptoms (i.e., “depressed mood” , “feelings of guilt” , “suicidal thoughts” , “psychic anxiety” and “general somatic symptoms”) showed larger improvements in the medication compared to the CBT condition (effect sizes ranging from .13 to .16), whereas no differences were found for the twelve other symptoms. In addition, network estimation techniques revealed that all effects, except that on “depressed mood” , were direct and could not be explained by any of the other direct or indirect treatment effects. Exploratory analyses showed that information about the symptom-specific efficacy could help in identifying those patients who, based on their pre-treatment symptomatology, are likely to benefit more from antidepressant medication than from CBT (effect size of .30) versus those for whom both treatments are likely to be equally efficacious. Overall, our symptom-oriented approach results in a more thorough evaluation of the efficacy of antidepressant medication over CBT and shows potential in 'precision psychiatry'"

  3. Ciprianim A., et al. (2018). "Comparative efficacy and acceptability of 21 antidepressant drugs for the acute treatment of adults with major depressive disorder: a systematic review and network meta-analysis." The Lancet 391(10128): 1357-1366

    EXCERPT: "We found that all antidepressants included in the meta-analysis were more efficacious than placebo in adults with major depressive disorder and the summary effect sizes were mostly modest. Some antidepressants, such as escitalopram, mirtazapine, paroxetine, agomelatine, and sertraline had a relatively higher response and lower dropout rate than the other antidepressants. By contrast, reboxetine, trazodone, and fluvoxamine were associated with generally inferior efficacy and acceptability profiles compared with the other antidepressants, making them less favourable options. To make our results as relevant and robust as possible to inform clinical practice, we decided to focus on head-to-head studies and at the same time emphasise the certainty of the retrieved evidence. Our assessment overall found few differences between antidepressants when all data were considered, while there was more diversity in the range of efficacy and dropout patterns seen across the head-to-head comparisons than the meta-analysis of antidepressants versus placebo. The present findings in adults contrast with the efficacy of antidepressants in children and adolescents, for which fluoxetine is probably the only antidepressant that might reduce depressive symptoms.21 This differential efficacy across age groups might reflect heterogeneous mechanisms and causes of depression,22 smaller number of studies in young people, or different methodological issues affecting adult and paediatric trials.23 The effect sizes were also smaller in more recent and larger placebo-controlled trials than in older and smaller ones, which might be an indicator of bias."

  4. Dinoff, A., et al. (2020). "A meta-analysis of the potential antidepressant effects of buprenorphine versus placebo as an adjunctive pharmacotherapy for treatment-resistant depression." J Affect Disord 271: 91-99.

    EXCERPT: "This meta-analysis did not reveal a significant reduction in depression symptom severity in individuals with TRD after an adjunctive intervention with buprenorphine when compared to placebo."

  5. Fornaro, M., et al. (2018). "Incidence, prevalence and clinical correlates of antidepressant-emergent mania in bipolar depression: A systematic review and meta-analysis." Bipolar Disorders.

    EXCERPT: "Overall, concurrent lithium therapy predicted the lowest TEM rates. Inconsistent operational definitions of TEM were recorded, and the lack of information about age, sex, co-occurring anxiety, and other clinically relevant moderators precluded further stratification of the results....  Rates of TEM vary primarily depending on study setting, which is concordant with the high degree of heterogeneity of the included records."

  6. Furukawa, T. A., et al. (2018). "Initial severity of major depression and efficacy of new generation antidepressants: Individual participant data meta-analysis." Acta Psychiatrica Scandinavicas (Online in advance of print publication)

    EXCERPT: The best-fitting model revealed that the interaction between baseline severity and treatment was not statistically significant.... Several sensitivity analyses confirmed the robustness of the findings.... We may expect as much benefit from antidepressant treatments for mild, moderate or severe major depression. Clinical practice guidelines will need to take these findings into consideration.

  7. Geoffroy, P. A., et al. (2019). "Efficacy of light therapy versus antidepressant drugs, and of the combination versus monotherapy, in major depressive episodes: A systematic review and meta-analysis." Sleep Medicine Reviews 48.

    EXCERPT: " No differences were observed between LT and AD, with a clear superiority of the combination, thus both LT monotherapy and combination may be proposed as a first line treatment in seasonal and non-seasonal depression."

  8. Giacobbe, P., et al. (2018). "Efficacy and tolerability of lisdexamfetamine as an antidepressant augmentation strategy: A meta-analysis of randomized controlled trials." Journal of Affective Disorders 226: 294-300.

    EXCERPT: "LDX did not demonstrate superiority in efficacy relative to placebo as indicated by a Hedges' g score of 0.126 (95% CI −0.040–0.291; p = 0.136) for mean change in Montgomery-Asberg Depression Rating Scale. Odds ratios of 1.206 (95% CI 0.745–1.954; p = 0.446) and 1.244 (95% CI 0.959–1.614; p = 0.1) were found for remission and response rates respectively. Risk differences of −0.1 (95% CI −0.155–(−0.045); p < 0.001) indicated a 10% increase chance of developing treatment-emergent adverse events (TEAE) in the LDX group. There was no significant difference in risk for developing serious or severe TEAE and discontinuing treatment due to TEAE."

  9. He, H., et al. (2018). "Efficacy and tolerability of different doses of three new antidepressants for treating major depressive disorder: A PRISMA-compliant meta-analysis." Journal of Psychiatric Research 96: 247-259.

    EXCERPT: "The changes in the MADRS total score were significantly higher for vortioxetine at 5, 10, 20, and 10–20 mg/day than for placebo. The tolerability was significantly worse for 20 mg/day vortioxetine than for placebo (RR = 1.84, 95% confidence interval = 1.13 to 3.02). In addition, increasing the dosage improved the efficacy of vortioxetine but worsened the tolerability. Levomilnacipran and vilazodone at any dosage produced a significantly higher mean change from baseline in the MADRS total score and a worse tolerability than for placebo.... Considering both efficacy and tolerability, 10 mg/day vortioxetine might be optimal for the treatment of MDD."

  10. Holper, L. and M. P. Hengartner (2020). "Comparative efficacy of placebos in short-term antidepressant trials for major depression: A secondary meta-analysis of placebo-controlled trials." BMC Psychiatry 20.

    EXCERPT: "The present exploratory NMA indicates that distinguishable side effects of older drugs may unblind outcome-assessors thus resulting in overestimation of the average drug-placebo difference and underrating bias in placebo-arms, particularly for the older antidepressant drugs amitriptyline and trazodone. If confirmed in prospective studies, these findings suggest that efficacy rankings for antidepressants are susceptible to bias and should be considered unreliable or misleading."

  11. Hsu, T.-W., et al. (2022). "The efficacy and tolerability of memantine for depressive symptoms in major mental diseases: A systematic review and updated meta-analysis of double-blind randomized controlled trials." Journal of Affective Disorders 306: 182-189.

    EXCERPT: "The present meta-analysis indicates that memantine effectively alleviates depressive symptoms in patients with mood disorders with a small effect size. Furthermore, memantine is well-tolerated and acceptable."Í

  12. Kato, M., et al. (2021). "Discontinuation of antidepressants after remission with antidepressant medication in major depressive disorder: A systematic review and meta-analysis." Molecular Psychiatry 26(1): 118-133.

    EXCERPT: " To prevent relapse and treatment failure, maintenance therapy, and careful attention for at least 6 months after remission is recommended. SSRIs are well-balanced agents, and flexible dose adjustments are more effective for relapse prevention."

  13. Kim, H. K., et al. (2021). "Antidepressant treatment outcomes in patients with and without comorbid physical or psychiatric disorders: A systematic review and meta-analysis." Journal of Affective Disorders 295: 225-234.

    EXCERPT: "Our review provides updated evidence demonstrating that patients with MDD and physical or psychiatric comorbidities experience worse antidepressant outcomes."

  14. Kreitzer, N., et al. (2019). "The effect of antidepressants on depression after traumatic brain injury: A meta-analysis." The Journal of Head Trauma Rehabilitation 34(3): E47-E54.

    EXCERPT: " This meta-analysis found no significant benefit of antidepressant over placebo in the treatment of MDD following TBI. Pooled estimates showed a high degree of bias and heterogeneity. Prospective studies on the impact of antidepressants in well-defined cohorts of TBI patients are warranted."

  15. Leung, M. T. Y., et al. (2021). "Gestational exposure to antidepressants and risk of seizure in offspring: A systematic review and meta-analysis." Neuroscience and Biobehavioral Reviews 131: 345-359.

    EXCERPT: "We found that gestational antidepressant exposure is associated with a 2.3-fold higher incidence of seizure in offspring. Although a causal relationship cannot be confirmed in view of other potential confounders, our findings warrant future research on related clinical aspects, and possibly more careful monitoring of foetal neurodevelopment in pregnant women taking antidepressants during pregnancy. However, this does not suggest the abrupt withdrawal of antidepressants during pregnancy for all cases at risk of seizure in offspring as this must be balanced with the risk of negative consequences caused by untreated maternal depression, and decision-making should be individualised for each patient."

  16. Li, X. and C. Zhang (2020). "Comparative efficacy of nine antidepressants in treating Chinese patients with post-stroke depression: A network meta-analysis." J Affect Disord 266: 540-548.

    EXCERPT: "Escitalopram was associated with a quicker relief of depression, but mirtazapine was probably the best option when it comes to the efficacy of 8-week treatment duration. Amitriptyline and doxepin were nearly the worst choice regardless of the duration (2, 4 or 8 weeks)."

  17. Man, K. K. C., et al. (2018). "Prenatal antidepressant exposure and the risk of attention-deficit hyperactivity disorder in children: A systematic review and meta-analysis." Neuroscience and Biobehavioral Reviews 86: 1-11.

    EXCERPT: "These data suggest that the observed association between prenatal use of antidepressants and risk of ADHD in offspring can be partially explained by confounding by indication because the results from sibling-matched analyses do not support an increased risk of ADHD in discordant exposed siblings."

  18. Mills, K. A., et al. (2018). "Efficacy and tolerability of antidepressants in Parkinson's disease: A systematic review and network meta-analysis." International Journal of Geriatric Psychiatry 33(4): 642-651.

    EXCERPT: "Pairwise meta-analysis suggested that type B-selective monoamine oxidase inhibitors (SMD = −1.28, CI = −1.68, −0.88), selective serotonin reuptake inhibitors (SMD = −0.49, CI = −0.93, −0.05), and tricyclics (SMD = −0.83, CI = −1.53, −0.13) are effective antidepressants in PD. Network meta-analysis showed that monoamine oxidase inhibitors had the largest effect on depression in PD (SMD (vs selective serotonin reuptake inhibitors) = −0.78, CI = −1.55, −0.01), but these might not be considered traditional antidepressants given their type B selectivity. Conclusions: Although limited by few data, this review suggests that multiple antidepressant classes are potentially efficacious in the treatment of depression in PD, but that further comparative efficacy and tolerability research is needed."

  19. Monden, R., et al. (2018). "The comparative evidence basis for the efficacy of second-generation antidepressants in the treatment of depression in the US: A Bayesian meta-analysis of Food and Drug Administration reviews." Journal of Affective Disorders 235: 393-398.

    EXCERPT: "The resulted Bayes factors showed that the evidence load for efficacy varied strongly across antidepressants. However, all tested drugs except for bupropion and vilazodone showed strong evidence for their efficacy. The posterior effect-size distributions showed variation across antidepressants, with the highest pooled estimated effect size for venlafaxine followed by paroxetine, and the lowest for bupropion and vilazodone.... The results illustrate the importance of considering both the effect size and the evidence-load when judging the efficacy of a treatment. In doing so, the currently employed Bayesian approach provided clear insights on top of those gained with traditional approaches."

  20. Nord, C. L., et al. (2021). "Neural effects of antidepressant medication and psychological treatments: A quantitative synthesis across three meta-analyses." The British Journal of Psychiatry: publ;ishjed online in advance of print publication.

    EXCERPT: Neural changes from psychotherapy and antidepressant medication did not significantly converge on any region. Antidepressants evoked neural changes in the amygdala, whereas psychotherapy evoked anatomically distinct changes in the medial prefrontal cortex. Both psychotherapy- and antidepressant-related changes separately converged on regions of the affect network.... This supports the notion of treatment-specific brain effects of antidepressants and psychotherapy. Both treatments induce changes in the affect network, but our results suggest that their effects on affect processing occur via distinct proximal neurocognitive mechanisms of action."

  21. Olgiati, P., et al. (2018). "Early improvement and response to antidepressant medications in adults with major depressive disorder. Meta-analysis and study of a sample with treatment-resistant depression." Journal of Affective Disorders 227: 777-786.

    EXCERPT: "Our meta-analysis (9 studies; N = 6185) showed significant associations between early improvement, response (OR: 3.28 95% C.I: 2.06–5.20) and remission (OR: 2.10 95% C.I: 1.53–2.87). 24.6% of TRD sample remitted. VEI was a poor outcome predictor: sensitivity = 0.52 (0.40–0.63); specificity=0.82 (0.76–0.86); AUC = 0.67 (0.62–0.71). EI had a moderate predictive power: sensitivity = 0.87 (0.77–0.93); specificity = 0.71 (0.66–0.77); AUC = 0.76 (0.71–0.80). The best treatment scenario was Algorithm C (switch after 4 weeks) in which remission rate was marginally increased (35.1% vs 33.7% of Algorithm A). Algorithm B (switch after 2 weeks) led to a 4.3% decrease in remission compared to Algorithm A.... Although literature data suggest a correlation between an initial improvement of depressive symptoms and later response and remission during AD treatment, our analysis shows that such an early improvement is not a reliable outcome predictor in TRD. The nature of TRD is complex and different biological mechanisms and treatments might be necessary for TRD patients."

  22. Ostuzzi, G., et al. (2019). "Efficacy and acceptability of antidepressants in people with ischemic heart disease: A systematic review and meta-analysis." International Clinical Psychopharmacology 34(2): 65-75.

    EXCERPT: "Antidepressants appeared to be more effective than placebo in reducing depressive symptoms (11 comparisons; 1685 participants; standardized mean difference, −0.71; 95% confidence interval, −1.11 to −0.30; GRADE quality, moderate). This result was confirmed in the subgroup of serotonin selective reuptake inhibitors, and for the single drugs sertraline and citalopram, with a greater magnitude of effect and a higher quality of evidence for the former. No differences between antidepressants and placebo emerged in terms of acceptability and tolerability, quality of life, mortality, and cardiovascular events. Only two small head-to-head studies were identified. Sertraline is a reasonable first-line choice in patients with ischemic heart disease and depression, while the role of citalopram as first-line agent should be reconsidered."

  23. Prado, C. E., et al. (2018). "A meta-analysis of the effects of antidepressants on cognitive functioning in depressed and non-depressed samples." Neuropsychology Review.

    EXCERPT: "Results revealed that overall, antidepressants have a modest, positive effect on divided attention, executive function, immediate memory, processing speed, recent memory and sustained attention for depressed participants. Selective serotonin reuptake inhibitors (SSRI's) were found to have the greatest positive effect on cognition for depressed participants, as compared to the other classes of antidepressants analysed. Antidepressants did not significantly affect cognitive function in non-depressed participants."

  24. Stefánsdóttir, Í. H., et al. (2022). "Efficacy and safety of serotonin reuptake inhibitors (ssri) and serotonin noradrenaline reuptake inhibitors (snri) for children and adolescents with anxiety disorders: A systematic review and meta-analysis." Nordic Journal of Psychiatry—published online in advance of print publication.

    EXCERPT: "SSRIs and SNRIs are an effective treatment of childhood anxiety disorders and are superior to pill placebo. While the risk of serious adverse events was low with SSRI/SNRI treatment, there was an increased risk of experiencing behavioral activation with SSRI/SNRI treatment.... SSRI and SNRI treatment is effective for childhood anxiety disorders, with positive effect of treatment outweighing the negative effects."

  25. Suchting, R., et al. (2021). "Revisiting monoamine oxidase inhibitors for the treatment of depressive disorders: A systematic review and network meta-analysis." Journal of Affective Disorders 282: 1153-1160.

    EXCERPT: "Except fluvoxamine, all antidepressants demonstrated superior efficacy to placebo, and none demonstrated substantially better or worse all-cause dropout rates. Phenelzine demonstrated superior evidence for efficacy compared to all other treatments, and clomipramine demonstrated superior evidence for acceptability compared to all other treatments.... The results of this analysis largely support the re-evaluation of the use of MAOIs as antidepressant agents in the treatment algorithm of depression."

  26. Telang, S., et al. (2018). "Meta-analysis: Second generation antidepressants and headache." Journal of Affective Disorders 236: 60-68.

    EXCERPT: "SSRIs were associated with a significantly increased risk of headache (RR = 1.06, 95%CI = 1.00–1.13, z = 2.0, p = 0.045) when compared to placebo. There was no significant difference (test for subgroup differences χ² = 2.2, df = 1, p = 0.14) in the risk of headache between SSRIs and SNRIs (RR = 0.97, 95%CI = 0.88–1.06, p = 0.63). There was no significant difference in the relative risk of headache with second generation antidepressants based on diagnostic indication, pharmacological properties and dosage of medications. The only antidepressants that were found to be significantly associated with increased risk of headache compared to placebo were bupropion (RR = 1.22, 95%CI = 1.06–1.41, z = 2.73, p = 0.006) and escitalopram (RR = 1.18, 95%CI = 1.01–1.37, z = 2.11, p = 0.04).... Headaches reported after the initiation of second generation antidepressant medications are more likely to be coincidental than a treatment-emergent side effect of these medications.

  27. Ulrich, S., et al. (2020). "Efficacy and adverse effects of tranylcypromine and tricyclic antidepressants in the treatment of depression: A systematic review and comprehensive meta-analysis." Journal of Clinical Psychopharmacology 40(1): 63-74.

    EXCERPT: "Tranylcypromine and TCAs have an equal antidepressant effect in a mean sample of depressed patients with mixed psychomotor symptoms. Tranylcypromine might be superior to TCAs in depression with predominant psychomotor retardation."

  28. Wang, Y.-C., et al. (2018). "Increased risk of dementia in patients with antidepressants: A meta-analysis of observational studies." Behavioural Neurology 2018.

    EXCERPT: "Our findings indicate that antidepressant use is significantly associated with an increased risk of developing dementia. Therefore, we suggest physicians to carefully prescribe antidepressants, especially in elder patients. Additionally, treatment should be stopped if any symptoms related to dementia are to be noticed."

  29. Wang, S.-M., et al. (2021). "Rapid onset of intranasal esketamine in patients with treatment resistant depression and major depression with suicide ideation: A meta-analysis." Clinical Psychopharmacology and Neuroscience 19(2): 341-354.

    EXCERPT: "Esketamine showed rapid antidepressant effects in patients with MDD, including TRD and MDSI. The study also suggested that esketamine might be associated with rapid anti-suicidal effects for patients with MDSI."

  30. Watanabe, N., et al. (2020). "Predicting antidepressant response through early improvement of individual symptoms of depression incorporating baseline characteristics of patients: An individual patient data meta-analysis." Journal of Psychiatric Research 125: 85-90.

    EXCERPT: "Primary and secondary outcomes were response and remission at week 6, respectively. We compared models that only included improvement in the overall depression severity at week 2 with models that also included improvement in individual symptoms and baseline characteristics, by conducting an individual patient data meta-analysis. We obtained data from three trials comprising 997 participants. For the response outcome, the model incorporating individual symptoms and baseline characteristics demonstrated better predictive values than those in the model including early improvement in overall depression only. However, the area under the receiver operating characteristic curve, and positive and negative predictive values were 0.65, 0.70, and 0.64, respectively, suggesting that 30% and 36% of the participants still had false-negative and false-positive predictions, respectively. For the remission outcome, the corresponding values in the latter model were 0.72, 0.62, and 0.68, respectively. We suggest that clinical judgement on early discontinuation of antidepressant from non-early improvement at week 2 should be carefully made."

  31. Zhao, X., et al. (2018). "A meta-analysis of selective serotonin reuptake inhibitors (SSRIs) use during prenatal depression and risk of low birth weight and small for gestational age." Journal of Affective Disorders 241: 563-570

    EXCERPT: "Fifteen articles involved 1,977,446 subjects were identified that tested the relationship between the SSRIs use, LBW and SGA outcomes. Statistical analyses revealed a significant association between SSRIs use and suboptimal fetal growth (RR = 1.45, 95% CI = 1.18 − 1.76, Z = 3.62, p = 0.00 for SGA; RR = 1.38, 95% CI = 1.13 − 1.69, Z = 3.14, p = 0.00 for LBW).... Our findings suggested that SSRIs use for prenatal depression is associated with suboptimal fetal growth."

  32. Zheng, W., et al. (2019). "Adjunctive ketamine and electroconvulsive therapy for major depressive disorder: A meta-analysis of randomized controlled trials." Journal of Affective Disorders 250: 123-131.

    EXCERPT: "Eleven RCTs testing the effects of ketamine on neurocognitive functions with various test batteries found mixed results. Ketamine alone significantly increased blood pressure more than other anesthetic drugs in MDD treated with ECT.... Compared to other anesthetic agents, ketamine alone does not appear to improve the efficacy of ECT. However, ketamine+other anesthetic combinations may confer a short-term advantage in improving depressive symptom at the early stages of ECT."

  33. Zhou, X., et al. (2020). "Comparative efficacy and acceptability of antidepressants, psychotherapies, and their combination for acute treatment of children and adolescents with depressive disorder: A systematic review and network meta-analysis." The Lancet Psychiatry 7(7): 581-601.

    EXCERPT: "Despite the scarcity of high-quality evidence, fluoxetine (alone or in combination with CBT) seems to be the best choice for the acute treatment of moderate-to-severe depressive disorder in children and adolescents. However, the effects of these interventions might vary between individuals, so patients, carers, and clinicians should carefully balance the risk-benefit profile of efficacy, acceptability, and suicide risk of all active interventions in young patients with depression on a case-by-case basis. "


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