Objective: This survey aims to explore the current medical treatment of major depressive disorder (MDD) in China and match its degree with Canadian Network for Mood and Anxiety Treatments (CANMAT). Methods: A total of 3275 patients were recruited from 16 mental health centers and 16 general hospitals in China. Descriptive statistics presented the total number and percentage of drugs, as well as all kinds of treatments. Results: Selective serotonin reuptake inhibitors (SSRIs) accounted for the largest proportion (57.2%), followed by serotonin-noradrenaline reuptake inhibitors (SNRIs) (22.8%) and mirtazapine (7.0%) in the first therapy, while that of SNRIs (53.9%) followed by SSRIs (39.2%) and mirtazapine (9.8%) in the follow-up therapy. An average of 1.85 medications was administered to each MDD patient. Conclusion: SSRIs were the first choice in the first therapy, while the proportion of those drugs decreased during the follow-up therapy and were replaced by SNRIs. Plenty of combined pharmacotherapies were directly selected as the first trial of patients, which was inconsistent with guideline recommendations.

Although data from adequately powered, high-quality randomized controlled trials are needed, existing research shows that depression prevention strategies can reduce risk of relapse/recurrence in youth. This includes SSRIs such as fluoxetine (ages 8 years and older) and escitalopram (ages 12 years and older)-the only antidepressants approved for use in the pediatric population by the Food and Drug Administration-and Cognifive-Behavioral Therapy or a combination of the two. Similar studies of relapse prevention are urgently needed in youth with anxiety disorders, as none currently exist.

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.
demonstrated benefit for combination treatment (CBT + fluoxetine), this finding was inconsistent with a British RCT (excluded from the AHRQ/RTI-UNC review because of ineligible population) that failed to find benefit of combination treatment (fluoxetine + CBT) over monotherapy in the context of routine specialist care of adolescents with MDD.
In the United States, expert consensus generally (but not universally) supports the prioritization of combination treatment, particularly if there is a need for acute symptom reduction in a severe, functionally impairing disorder, or partial response to either treatment alone.
Combination treatment typically involves concurrent administration of psychotherapy (CBT in the AHRQ-included study) and medication (fluoxetine in the AHRQ-included study). Optimally, combination treatment would be delivered in the same facility to enhance convenience for patient and family as well as communication between treatment providers. Typically, combination treatment would be more intense in the first months (eg, weekly psychotherapy visits for 3 to 4 months followed by booster sessions at variable intervals; weekly medication visits or contacts in the first month tapering to bi-monthly in the second month and monthly to quarterly thereafter). Parents would be involved initially in psychoeducation and intermittently thereafter as indicated.

Background: Major depressive disorder is one of the most common, burdensome, and costly psychiatric disorders worldwide in adults. Pharmacological and non-pharmacological treatments are available; however, because of inadequate resources, antidepressants are used more frequently than psychological interventions. Prescription of these agents should be informed by the best available evidence. Therefore, we aimed to update and expand our previous work to compare and rank antidepressants for the acute treatment of adults with unipolar major depressive disorder.

Methods: We did a systematic review and network meta-analysis. We searched Cochrane Central Register of Controlled Trials, CINAHL, Embase, LILACS database, MEDLINE, MEDLINE In-Process, PsycINFO, the websites of regulatory agencies, and international registers for published and unpublished, double-blind, randomised controlled trials from their inception to Jan 8, 2016. We included placebo-controlled and head-to-head trials of 21 antidepressants used for the acute treatment of adults (≥18 years old and of both sexes) with major depressive disorder diagnosed according to standard operationalised criteria. We excluded quasi-randomised trials and trials that were incomplete or included 20% or more of participants with bipolar disorder, psychotic depression, or treatment-resistant depression; or patients with a serious concomitant medical illness. We extracted data following a predefined hierarchy. In network meta-analysis, we used group-level data. We assessed the studies' risk of bias in accordance to the Cochrane Handbook for Systematic Reviews of Interventions, and certainty of evidence using the Grading of Recommendations Assessment, Development and Evaluation framework. Primary outcomes were efficacy (response rate) and acceptability (treatment discontinuations due to any cause). We estimated summary odds ratios (ORs) using pairwise and network meta-analysis with random effects. This study is registered with PROSPERO, number CRD42012002291.

Findings: We identified 28 552 citations and of these included 522 trials comprising 116 477 participants. In terms of efficacy, all antidepressants were more effective than placebo, with ORs ranging between 2·13 (95% credible interval [CrI] 1·89-2·41) for amitriptyline and 1·37 (1·16-1·63) for reboxetine. For acceptability, only agomelatine (OR 0·84, 95% CrI 0·72-0·97) and fluoxetine (0·88, 0·80-0·96) were associated with fewer dropouts than placebo, whereas clomipramine was worse than placebo (1·30, 1·01-1·68). When all trials were considered, differences in ORs between antidepressants ranged from 1·15 to 1·55 for efficacy and from 0·64 to 0·83 for acceptability, with wide CrIs on most of the comparative analyses. In head-to-head studies, agomelatine, amitriptyline, escitalopram, mirtazapine, paroxetine, venlafaxine, and vortioxetine were more effective than other antidepressants (range of ORs 1·19-1·96), whereas fluoxetine, fluvoxamine, reboxetine, and trazodone were the least efficacious drugs (0·51-0·84). For acceptability, agomelatine, citalopram, escitalopram, fluoxetine, sertraline, and vortioxetine were more tolerable than other antidepressants (range of ORs 0·43-0·77), whereas amitriptyline, clomipramine, duloxetine, fluvoxamine, reboxetine, trazodone, and venlafaxine had the highest dropout rates (1·30-2·32). 46 (9%) of 522 trials were rated as high risk of bias, 380 (73%) trials as moderate, and 96 (18%) as low; and the certainty of evidence was moderate to very low.

Interpretation: All antidepressants were more efficacious than placebo in adults with major depressive disorder. Smaller differences between active drugs were found when placebo-controlled trials were included in the analysis, whereas there was more variability in efficacy and acceptability in head-to-head trials. These results should serve evidence-based practice and inform patients, physicians, guideline developers, and policy makers on the relative merits of the different antidepressants.

Funding: National Institute for Health Research Oxford Health Biomedical Research Centre and the Japan Society for the Promotion of Science.

Background: Depressive disorders are common in children and adolescents. Antidepressants, psychotherapies, and their combination are often used in routine clinical practice; however, available evidence on the comparative efficacy and safety of these interventions is inconclusive. Therefore, we sought to compare and rank all available treatment interventions for the acute treatment of depressive disorders in children and adolescents.

Methods: We did a systematic review and network meta-analysis. We searched PubMed, Embase, the Cochrane Central Register of Controlled Trials, Web of Science, PsycINFO, ProQuest, CINAHL, LiLACS, international trial registries, and the websites of regulatory agencies for published and unpublished randomised controlled trials from database inception until Jan 1, 2019. We included placebo-controlled and head-to-head trials of 16 antidepressants, seven psychotherapies, and five combinations of antidepressant and psychotherapy that are used for the acute treatment of children and adolescents (≤18 years old and of both sexes) with depressive disorder diagnosed according to standard operationalised criteria. Trials recruiting participants with treatment-resistant depression, bipolar disorder, psychotic depression, treatment duration of less than 4 weeks, or an overall sample size of fewer than ten patients were excluded. We extracted data following a predefined hierarchy of outcome measures, and assessed risk of bias and certainty of evidence using validated methods. Primary outcomes were efficacy (change in depressive symptoms) and acceptability (treatment discontinuation due to any cause). We estimated summary standardised mean differences (SMDs) or odds ratios (ORs) with credible intervals (CrIs) using network meta-analysis with random effects. This study was registered with PROSPERO, number CRD42015020841.

Findings: From 20 366 publications, we included 71 trials (9510 participants). Depressive disorders in most studies were moderate to severe. In terms of efficacy, fluoxetine plus cognitive behavioural therapy (CBT) was more effective than CBT alone (-0·78, 95% CrI -1·55 to -0·01) and psychodynamic therapy (-1·14, -2·20 to -0·08), but not more effective than fluoxetine alone (-0·22, -0·86 to 0·42). No pharmacotherapy alone was more effective than psychotherapy alone. Only fluoxetine plus CBT and fluoxetine were significantly more effective than pill placebo or psychological controls (SMDs ranged from -1·73 to -0·51); and only interpersonal therapy was more effective than all psychological controls (-1·37 to -0·66). Nortriptyline (SMDs ranged from 1·04 to 2·22) and waiting list (SMDs ranged from 0·67 to 2·08) were less effective than most active interventions. In terms of acceptability, nefazodone and fluoxetine were associated with fewer dropouts than sertraline, imipramine, and desipramine (ORs ranged from 0·17 to 0·50); imipramine was associated with more dropouts than pill placebo, desvenlafaxine, fluoxetine plus CBT, and vilazodone (2·51 to 5·06). Most of the results were rated as "low" to "very low" in terms of confidence of evidence according to Confidence In Network Meta-Analysis.

Interpretation: 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.

Funding: National Key Research and Development Program of China.

Medications from the SSRI class currently marketed in the United States are citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline, and vilazodone. In the AHRQ/Mayo review, the SSRIs for which sufficient data were available for comparisons were fluoxetine, fluvoxamine, paroxetine, and sertraline. Although mechanisms of action vary somewhat across SSRIs (eg, effects on other neurotransmitter receptors affecting degree of serotonin selectivity), the primary mechanism was deemed in the AHRQ/Mayo review to be sufficiently similar across individual medications to warrant extension of the findings to the medication class.
Although there is substantial empirical support for the effectiveness and safety of the SSRI class of medications for the treatment of anxiety, no specific SSRIs have U.S. Food and Drug Administration (FDA) approval for this indication. The choice of a specific SSRI is governed by considerations such as pharmacokinetics, pharmacodynamics, tolerability, cost, insurance formularies, and unique risks leading to warnings or precautions.

Among the greatest unmet needs in major depressive disorder (MDD) is a lack of effective pharmacotherapies for patients who do not respond to first- and second-line antidepressant medications. After decades of muted progress, optimism regarding the future of MDD therapy rose after scientists serendipitously uncovered the antidepressant effects of ketamine. The discovery of ketamine's antidepressant effects inspired the search for related newer medications, such as -ketamine. Orally administered NMDA antagonists have also demonstrated considerable promise in recently concluded, late-stage clinical trials. Researchers evaluating an extended-release combination of bupropion (105 mg) and dextromethorphan (45 mg) found that recipients experienced a decline in MADRS total score. Neurosteroids, such as brexanolone and zuranolone, appear to represent another class of antidepressants. These drugs appear to modulate GABA neurotransmission, which has long been known to be a pathway for drugs that are used to treat insomnia and anxiety. After nearly 50 years of legal injunctions against their use, psychedelic drugs have attracted interest among researchers seeking alternative antidepressants. Psilocybin, derived from mushrooms, remains under investigation for its benefits in treatment-resistant depression.

Objectives: This systematic review aimed to evaluate the efficacy of B vitamins and vitamin D therapy in improving the standard treatment of depression and anxiety disorders. We also aimed to gather the evidence supporting the recommendations for supplementation in clinical practice.

Methods: Performed between March 2020 and September 2021, the main inclusion criteria were randomized controlled trials (RCTs), with patients ≥ 18 years old, both sexes, fulfilling target diagnoses of major depressive disorder (MDD), generalized anxiety disorder (GAD), or mild to severe depressive and anxiety symptoms. In addition, the RCTs were included if the scales to assess the severity of the symptoms were standardized rating scales in psychiatric. Trials that reported diagnoses of schizophrenia, perinatal depression, bipolar depression, sleep disorders, eating disorders, cancer, and multiple sclerosis in association with any of the mentioned diagnoses were excluded.

Results: We identified 20 RCTs that matched all eligibility criteria, totaling 2,256 subjects, diagnosed with MDD, GAD, and depressive or anxiety symptoms. Supplementation with folic acid or L-methylfolate, B1, B12 or methylcobalamin, and vitamin D (in different doses and study duration) significantly decreased depression score scales by increasing response to standard pharmacological treatment or as monotherapy, including partial or complete remission. As for anxiety symptoms, the availability of results is limited to adjuvant vitamin D therapy.

Discussion: B vitamins and vitamin D associated with other compounds also showed significant results, so the improvement in symptoms cannot be attributed strictly to those. Our results suggest that intervention with B vitamins and/or vitamin D may be an effective and well-tolerated adjuvant strategy for improving the symptoms of depression and anxiety, according to the patient's clinical status and nutritional biomarkers.

Objective: This survey aims to explore the current medical treatment of major depressive disorder (MDD) in China and match its degree with Canadian Network for Mood and Anxiety Treatments (CANMAT). Methods: A total of 3275 patients were recruited from 16 mental health centers and 16 general hospitals in China. Descriptive statistics presented the total number and percentage of drugs, as well as all kinds of treatments. Results: Selective serotonin reuptake inhibitors (SSRIs) accounted for the largest proportion (57.2%), followed by serotonin-noradrenaline reuptake inhibitors (SNRIs) (22.8%) and mirtazapine (7.0%) in the first therapy, while that of SNRIs (53.9%) followed by SSRIs (39.2%) and mirtazapine (9.8%) in the follow-up therapy. An average of 1.85 medications was administered to each MDD patient. Conclusion: SSRIs were the first choice in the first therapy, while the proportion of those drugs decreased during the follow-up therapy and were replaced by SNRIs. Plenty of combined pharmacotherapies were directly selected as the first trial of patients, which was inconsistent with guideline recommendations.

Although data from adequately powered, high-quality randomized controlled trials are needed, existing research shows that depression prevention strategies can reduce risk of relapse/recurrence in youth. This includes SSRIs such as fluoxetine (ages 8 years and older) and escitalopram (ages 12 years and older)-the only antidepressants approved for use in the pediatric population by the Food and Drug Administration-and Cognifive-Behavioral Therapy or a combination of the two. Similar studies of relapse prevention are urgently needed in youth with anxiety disorders, as none currently exist.

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.
demonstrated benefit for combination treatment (CBT + fluoxetine), this finding was inconsistent with a British RCT (excluded from the AHRQ/RTI-UNC review because of ineligible population) that failed to find benefit of combination treatment (fluoxetine + CBT) over monotherapy in the context of routine specialist care of adolescents with MDD.
In the United States, expert consensus generally (but not universally) supports the prioritization of combination treatment, particularly if there is a need for acute symptom reduction in a severe, functionally impairing disorder, or partial response to either treatment alone.
Combination treatment typically involves concurrent administration of psychotherapy (CBT in the AHRQ-included study) and medication (fluoxetine in the AHRQ-included study). Optimally, combination treatment would be delivered in the same facility to enhance convenience for patient and family as well as communication between treatment providers. Typically, combination treatment would be more intense in the first months (eg, weekly psychotherapy visits for 3 to 4 months followed by booster sessions at variable intervals; weekly medication visits or contacts in the first month tapering to bi-monthly in the second month and monthly to quarterly thereafter). Parents would be involved initially in psychoeducation and intermittently thereafter as indicated.

The SSRI medication class is a group of chemically and pharmacologically different compounds that inhibit the pre-synaptic reuptake of serotonin in the brain, thereby increasing availability of serotonin at the synaptic cleft. This blockade over time is believed to lead to a downregulation of inhibitory serotonin autoreceptors, which eventually heightens the serotonergic neuronal firing rate, which in turn leads to increased serotonin release. This multi-step process is hypothesized to be related to the delay in the full SSRI treatment effect. Suggested mechanisms of action for SSRIs include effects on brain plasticity, corticolimbic circuitry, and affective processing, and environmental interactions.
Medications from the SSRI class currently marketed in the United States are citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline, and vilazodone. Currently, only 2 SSRIs are approved by the US Food and Drug Administration (FDA) for the treatment of depression in youth: fluoxetine, for youth aged 8 years and older, and escitalopram, for youth aged 12 years and older.

Background: Major depressive disorder is one of the most common, burdensome, and costly psychiatric disorders worldwide in adults. Pharmacological and non-pharmacological treatments are available; however, because of inadequate resources, antidepressants are used more frequently than psychological interventions. Prescription of these agents should be informed by the best available evidence. Therefore, we aimed to update and expand our previous work to compare and rank antidepressants for the acute treatment of adults with unipolar major depressive disorder.

Methods: We did a systematic review and network meta-analysis. We searched Cochrane Central Register of Controlled Trials, CINAHL, Embase, LILACS database, MEDLINE, MEDLINE In-Process, PsycINFO, the websites of regulatory agencies, and international registers for published and unpublished, double-blind, randomised controlled trials from their inception to Jan 8, 2016. We included placebo-controlled and head-to-head trials of 21 antidepressants used for the acute treatment of adults (≥18 years old and of both sexes) with major depressive disorder diagnosed according to standard operationalised criteria. We excluded quasi-randomised trials and trials that were incomplete or included 20% or more of participants with bipolar disorder, psychotic depression, or treatment-resistant depression; or patients with a serious concomitant medical illness. We extracted data following a predefined hierarchy. In network meta-analysis, we used group-level data. We assessed the studies' risk of bias in accordance to the Cochrane Handbook for Systematic Reviews of Interventions, and certainty of evidence using the Grading of Recommendations Assessment, Development and Evaluation framework. Primary outcomes were efficacy (response rate) and acceptability (treatment discontinuations due to any cause). We estimated summary odds ratios (ORs) using pairwise and network meta-analysis with random effects. This study is registered with PROSPERO, number CRD42012002291.

Findings: We identified 28 552 citations and of these included 522 trials comprising 116 477 participants. In terms of efficacy, all antidepressants were more effective than placebo, with ORs ranging between 2·13 (95% credible interval [CrI] 1·89-2·41) for amitriptyline and 1·37 (1·16-1·63) for reboxetine. For acceptability, only agomelatine (OR 0·84, 95% CrI 0·72-0·97) and fluoxetine (0·88, 0·80-0·96) were associated with fewer dropouts than placebo, whereas clomipramine was worse than placebo (1·30, 1·01-1·68). When all trials were considered, differences in ORs between antidepressants ranged from 1·15 to 1·55 for efficacy and from 0·64 to 0·83 for acceptability, with wide CrIs on most of the comparative analyses. In head-to-head studies, agomelatine, amitriptyline, escitalopram, mirtazapine, paroxetine, venlafaxine, and vortioxetine were more effective than other antidepressants (range of ORs 1·19-1·96), whereas fluoxetine, fluvoxamine, reboxetine, and trazodone were the least efficacious drugs (0·51-0·84). For acceptability, agomelatine, citalopram, escitalopram, fluoxetine, sertraline, and vortioxetine were more tolerable than other antidepressants (range of ORs 0·43-0·77), whereas amitriptyline, clomipramine, duloxetine, fluvoxamine, reboxetine, trazodone, and venlafaxine had the highest dropout rates (1·30-2·32). 46 (9%) of 522 trials were rated as high risk of bias, 380 (73%) trials as moderate, and 96 (18%) as low; and the certainty of evidence was moderate to very low.

Interpretation: All antidepressants were more efficacious than placebo in adults with major depressive disorder. Smaller differences between active drugs were found when placebo-controlled trials were included in the analysis, whereas there was more variability in efficacy and acceptability in head-to-head trials. These results should serve evidence-based practice and inform patients, physicians, guideline developers, and policy makers on the relative merits of the different antidepressants.

Funding: National Institute for Health Research Oxford Health Biomedical Research Centre and the Japan Society for the Promotion of Science.

Background: Depressive disorders are common in children and adolescents. Antidepressants, psychotherapies, and their combination are often used in routine clinical practice; however, available evidence on the comparative efficacy and safety of these interventions is inconclusive. Therefore, we sought to compare and rank all available treatment interventions for the acute treatment of depressive disorders in children and adolescents.

Methods: We did a systematic review and network meta-analysis. We searched PubMed, Embase, the Cochrane Central Register of Controlled Trials, Web of Science, PsycINFO, ProQuest, CINAHL, LiLACS, international trial registries, and the websites of regulatory agencies for published and unpublished randomised controlled trials from database inception until Jan 1, 2019. We included placebo-controlled and head-to-head trials of 16 antidepressants, seven psychotherapies, and five combinations of antidepressant and psychotherapy that are used for the acute treatment of children and adolescents (≤18 years old and of both sexes) with depressive disorder diagnosed according to standard operationalised criteria. Trials recruiting participants with treatment-resistant depression, bipolar disorder, psychotic depression, treatment duration of less than 4 weeks, or an overall sample size of fewer than ten patients were excluded. We extracted data following a predefined hierarchy of outcome measures, and assessed risk of bias and certainty of evidence using validated methods. Primary outcomes were efficacy (change in depressive symptoms) and acceptability (treatment discontinuation due to any cause). We estimated summary standardised mean differences (SMDs) or odds ratios (ORs) with credible intervals (CrIs) using network meta-analysis with random effects. This study was registered with PROSPERO, number CRD42015020841.

Findings: From 20 366 publications, we included 71 trials (9510 participants). Depressive disorders in most studies were moderate to severe. In terms of efficacy, fluoxetine plus cognitive behavioural therapy (CBT) was more effective than CBT alone (-0·78, 95% CrI -1·55 to -0·01) and psychodynamic therapy (-1·14, -2·20 to -0·08), but not more effective than fluoxetine alone (-0·22, -0·86 to 0·42). No pharmacotherapy alone was more effective than psychotherapy alone. Only fluoxetine plus CBT and fluoxetine were significantly more effective than pill placebo or psychological controls (SMDs ranged from -1·73 to -0·51); and only interpersonal therapy was more effective than all psychological controls (-1·37 to -0·66). Nortriptyline (SMDs ranged from 1·04 to 2·22) and waiting list (SMDs ranged from 0·67 to 2·08) were less effective than most active interventions. In terms of acceptability, nefazodone and fluoxetine were associated with fewer dropouts than sertraline, imipramine, and desipramine (ORs ranged from 0·17 to 0·50); imipramine was associated with more dropouts than pill placebo, desvenlafaxine, fluoxetine plus CBT, and vilazodone (2·51 to 5·06). Most of the results were rated as "low" to "very low" in terms of confidence of evidence according to Confidence In Network Meta-Analysis.

Interpretation: 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.

Funding: National Key Research and Development Program of China.

Medications from the SSRI class currently marketed in the United States are citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline, and vilazodone. In the AHRQ/Mayo review, the SSRIs for which sufficient data were available for comparisons were fluoxetine, fluvoxamine, paroxetine, and sertraline. Although mechanisms of action vary somewhat across SSRIs (eg, effects on other neurotransmitter receptors affecting degree of serotonin selectivity), the primary mechanism was deemed in the AHRQ/Mayo review to be sufficiently similar across individual medications to warrant extension of the findings to the medication class.
Although there is substantial empirical support for the effectiveness and safety of the SSRI class of medications for the treatment of anxiety, no specific SSRIs have U.S. Food and Drug Administration (FDA) approval for this indication. The choice of a specific SSRI is governed by considerations such as pharmacokinetics, pharmacodynamics, tolerability, cost, insurance formularies, and unique risks leading to warnings or precautions.

This recommendation was supported by the findings from three meta-analyses published since the AHRQ/Mayo review.
Efficacy and safety of selective serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors, and placebo for common psychiatric disorders among children and adolescents—a systematic review and meta-analysis.
The SSRI medication class is a group of chemically and pharmacologically different compounds that inhibit the presynaptic reuptake of serotonin in the brain, thereby increasing availability of serotonin at the synaptic cleft. This blockade over time is believed to lead to a downregulation of inhibitory serotonin autoreceptors, which eventually heightens the serotonergic neuronal firing rate, which in turn leads to increased serotonin release. This multistep process is hypothesized to be related to the delay in onset of the SSRI treatment effect.
Medications from the SSRI class currently marketed in the United States are citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline, and vilazodone. In the AHRQ/Mayo review, the SSRIs for which sufficient data were available for comparisons were fluoxetine, fluvoxamine, paroxetine, and sertraline. Although mechanisms of action vary somewhat across SSRIs (eg, effects on other neurotransmitter receptors affecting degree of serotonin selectivity), the primary mechanism was deemed in the AHRQ/Mayo review to be sufficiently similar across individual medications to warrant extension of the findings to the medication class.

DRUG TREATMENT OF ANXIETY DISORDERS Three classes of drugs are available for the treatment of anxiety disorders: benzodiazepines, other anxiolytics, and serotonergic antidepressants. Except for acute anxiety and adjustment disorders, benzodiazepines are not recommended because of the risks associated with their chronic use (cognitive disorders, dependence, withdrawal syndromes). Other anxiolytics may be prescribed in generalized anxiety disorder but their effectiveness is generally poor. In contrast, several serotonergic antidepressants are indicated in generalized anxiety disorder, panic disorder and social phobia. These are long-term treatments, over at least 6 to 12 months, which can be very effective even in the absence of comorbid depression.

While some mild presentations of MDD may be managed successfully by only implementing the Actions outlined above, in particular the use of psychological interventions, many cases are likely to require antidepressant medication. Depending on locale, more than 20 antidepressant formulations, belonging to more than a dozen pharmacological classes, may be available for the treatment of major depression (see Table 10). The vast majority of these act via monoaminergic modulation and differ mainly in terms of tolerability and only somewhat in efficacy. Nevertheless, these differences are important and are useful for tailoring choice to the clinical profile of the depressed individual. Recent network meta-analyses (Cipriani et al., 2009, 2016, 2018) have shown that all antidepressants are effective (compared with placebo) and that some are more effective than others (head to head studies). Therefore, based on both evidence and clinical experience there are seven Choice antidepressants. It is noteworthy that each antidepressant is from a different class (see Table 10). The Choice antidepressants are shown in Figure 26 and they are positioned along an axis that reflects their differential tolerability and efficacy, comprising two groups of three antidepressants and with amitriptyline on its own. The two groups of three comprise escitalopram, vortioxetine and agomelatine (EVA) in one group, and venlafaxine, mirtazapine and bupropion (VMB) in the other. There is another subtle gradient of effectiveness favouring those agents that are listed higher. However, it is important to note that these differences are marginal and not as significant as the impact of tailoring choice to the patient’s unique profile. Nevertheless, it provides some indication of putative preferences (Figure 26).
Figure 26. The management of major depression.
This schematic summarises the treatment recommendations for the management of depression. It begins with measures that are necessary and form a foundation for specific treatment strategies. The primary focus here is on treating depression symptoms and achieving functional recovery in the acute phase, but we highlight elsewhere the importance of planning for long-term management (see Recommendation Box 3), and broader treatment aims (see section 5.1, ‘Aims of treatment’).

Background: Depression is the single largest contributor to non-fatal health loss worldwide. Second-generation antidepressants are the first-line option for pharmacological management of depression. Optimising their use is crucial in reducing the burden of depression; however, debate about their dose dependency and their optimal target dose is ongoing. We have aimed to summarise the currently available best evidence to inform this clinical question.

Methods: We did a systematic review and dose-response meta-analysis of double-blind, randomised controlled trials that examined fixed doses of five selective serotonin reuptake inhibitors (SSRIs; citalopram, escitalopram, fluoxetine, paroxetine, and sertraline), venlafaxine, or mirtazapine in the acute treatment of adults (aged 18 years or older) with major depression, identified from the Cochrane Central Register of Controlled Trials, CINAHL, Embase, LILACS, MEDLINE, PsycINFO, AMED, PSYNDEX, websites of drug licensing agencies and pharmaceutical companies, and trial registries. We imposed no language restrictions, and the search was updated until Jan 8, 2016. Doses of SSRIs were converted to fluoxetine equivalents. Trials of antidepressants for patients with depression and a serious concomitant physical illness were excluded. The main outcomes were efficacy (treatment response defined as 50% or greater reduction in depression severity), tolerability (dropouts due to adverse effects), and acceptability (dropouts for any reasons), all after a median of 8 weeks of treatment (range 4-12 weeks). We used a random-effects, dose-response meta-analysis model with flexible splines for SSRIs, venlafaxine, and mirtazapine.

Findings: 28 554 records were identified through our search (24 524 published and 4030 unpublished records). 561 published and 121 unpublished full-text records were assessed for eligibility, and 77 studies were included (19 364 participants; mean age 42·5 years, SD 11·0; 7156 [60·9%] of 11 749 reported were women). For SSRIs (99 treatment groups), the dose-efficacy curve showed a gradual increase up to doses between 20 mg and 40 mg fluoxetine equivalents, and a flat to decreasing trend through the higher licensed doses up to 80 mg fluoxetine equivalents. Dropouts due to adverse effects increased steeply through the examined range. The relationship between the dose and dropouts for any reason indicated optimal acceptability for the SSRIs in the lower licensed range between 20 mg and 40 mg fluoxetine equivalents. Venlafaxine (16 treatment groups) had an initially increasing dose-efficacy relationship up to around 75-150 mg, followed by a more modest increase, whereas for mirtazapine (11 treatment groups) efficacy increased up to a dose of about 30 mg and then decreased. Both venlafaxine and mirtazapine showed optimal acceptability in the lower range of their licensed dose. These results were robust to several sensitivity analyses.

Interpretation: For the most commonly used second-generation antidepressants, the lower range of the licensed dose achieves the optimal balance between efficacy, tolerability, and acceptability in the acute treatment of major depression.

Funding: Japan Society for the Promotion of Science, Swiss National Science Foundation, and National Institute for Health Research.

Background: Major depressive disorder is one of the most common, burdensome, and costly psychiatric disorders worldwide in adults. Pharmacological and non-pharmacological treatments are available; however, because of inadequate resources, antidepressants are used more frequently than psychological interventions. Prescription of these agents should be informed by the best available evidence. Therefore, we aimed to update and expand our previous work to compare and rank antidepressants for the acute treatment of adults with unipolar major depressive disorder.

Methods: We did a systematic review and network meta-analysis. We searched Cochrane Central Register of Controlled Trials, CINAHL, Embase, LILACS database, MEDLINE, MEDLINE In-Process, PsycINFO, the websites of regulatory agencies, and international registers for published and unpublished, double-blind, randomised controlled trials from their inception to Jan 8, 2016. We included placebo-controlled and head-to-head trials of 21 antidepressants used for the acute treatment of adults (≥18 years old and of both sexes) with major depressive disorder diagnosed according to standard operationalised criteria. We excluded quasi-randomised trials and trials that were incomplete or included 20% or more of participants with bipolar disorder, psychotic depression, or treatment-resistant depression; or patients with a serious concomitant medical illness. We extracted data following a predefined hierarchy. In network meta-analysis, we used group-level data. We assessed the studies' risk of bias in accordance to the Cochrane Handbook for Systematic Reviews of Interventions, and certainty of evidence using the Grading of Recommendations Assessment, Development and Evaluation framework. Primary outcomes were efficacy (response rate) and acceptability (treatment discontinuations due to any cause). We estimated summary odds ratios (ORs) using pairwise and network meta-analysis with random effects. This study is registered with PROSPERO, number CRD42012002291.

Findings: We identified 28 552 citations and of these included 522 trials comprising 116 477 participants. In terms of efficacy, all antidepressants were more effective than placebo, with ORs ranging between 2·13 (95% credible interval [CrI] 1·89-2·41) for amitriptyline and 1·37 (1·16-1·63) for reboxetine. For acceptability, only agomelatine (OR 0·84, 95% CrI 0·72-0·97) and fluoxetine (0·88, 0·80-0·96) were associated with fewer dropouts than placebo, whereas clomipramine was worse than placebo (1·30, 1·01-1·68). When all trials were considered, differences in ORs between antidepressants ranged from 1·15 to 1·55 for efficacy and from 0·64 to 0·83 for acceptability, with wide CrIs on most of the comparative analyses. In head-to-head studies, agomelatine, amitriptyline, escitalopram, mirtazapine, paroxetine, venlafaxine, and vortioxetine were more effective than other antidepressants (range of ORs 1·19-1·96), whereas fluoxetine, fluvoxamine, reboxetine, and trazodone were the least efficacious drugs (0·51-0·84). For acceptability, agomelatine, citalopram, escitalopram, fluoxetine, sertraline, and vortioxetine were more tolerable than other antidepressants (range of ORs 0·43-0·77), whereas amitriptyline, clomipramine, duloxetine, fluvoxamine, reboxetine, trazodone, and venlafaxine had the highest dropout rates (1·30-2·32). 46 (9%) of 522 trials were rated as high risk of bias, 380 (73%) trials as moderate, and 96 (18%) as low; and the certainty of evidence was moderate to very low.

Interpretation: All antidepressants were more efficacious than placebo in adults with major depressive disorder. Smaller differences between active drugs were found when placebo-controlled trials were included in the analysis, whereas there was more variability in efficacy and acceptability in head-to-head trials. These results should serve evidence-based practice and inform patients, physicians, guideline developers, and policy makers on the relative merits of the different antidepressants.

Funding: National Institute for Health Research Oxford Health Biomedical Research Centre and the Japan Society for the Promotion of Science.

Background: Depression is the single largest contributor to non-fatal health loss worldwide. Second-generation antidepressants are the first-line option for pharmacological management of depression. Optimising their use is crucial in reducing the burden of depression; however, debate about their dose dependency and their optimal target dose is ongoing. We have aimed to summarise the currently available best evidence to inform this clinical question.

Methods: We did a systematic review and dose-response meta-analysis of double-blind, randomised controlled trials that examined fixed doses of five selective serotonin reuptake inhibitors (SSRIs; citalopram, escitalopram, fluoxetine, paroxetine, and sertraline), venlafaxine, or mirtazapine in the acute treatment of adults (aged 18 years or older) with major depression, identified from the Cochrane Central Register of Controlled Trials, CINAHL, Embase, LILACS, MEDLINE, PsycINFO, AMED, PSYNDEX, websites of drug licensing agencies and pharmaceutical companies, and trial registries. We imposed no language restrictions, and the search was updated until Jan 8, 2016. Doses of SSRIs were converted to fluoxetine equivalents. Trials of antidepressants for patients with depression and a serious concomitant physical illness were excluded. The main outcomes were efficacy (treatment response defined as 50% or greater reduction in depression severity), tolerability (dropouts due to adverse effects), and acceptability (dropouts for any reasons), all after a median of 8 weeks of treatment (range 4-12 weeks). We used a random-effects, dose-response meta-analysis model with flexible splines for SSRIs, venlafaxine, and mirtazapine.

Findings: 28 554 records were identified through our search (24 524 published and 4030 unpublished records). 561 published and 121 unpublished full-text records were assessed for eligibility, and 77 studies were included (19 364 participants; mean age 42·5 years, SD 11·0; 7156 [60·9%] of 11 749 reported were women). For SSRIs (99 treatment groups), the dose-efficacy curve showed a gradual increase up to doses between 20 mg and 40 mg fluoxetine equivalents, and a flat to decreasing trend through the higher licensed doses up to 80 mg fluoxetine equivalents. Dropouts due to adverse effects increased steeply through the examined range. The relationship between the dose and dropouts for any reason indicated optimal acceptability for the SSRIs in the lower licensed range between 20 mg and 40 mg fluoxetine equivalents. Venlafaxine (16 treatment groups) had an initially increasing dose-efficacy relationship up to around 75-150 mg, followed by a more modest increase, whereas for mirtazapine (11 treatment groups) efficacy increased up to a dose of about 30 mg and then decreased. Both venlafaxine and mirtazapine showed optimal acceptability in the lower range of their licensed dose. These results were robust to several sensitivity analyses.

Interpretation: For the most commonly used second-generation antidepressants, the lower range of the licensed dose achieves the optimal balance between efficacy, tolerability, and acceptability in the acute treatment of major depression.

Funding: Japan Society for the Promotion of Science, Swiss National Science Foundation, and National Institute for Health Research.

While some mild presentations of MDD may be managed successfully by only implementing the Actions outlined above, in particular the use of psychological interventions, many cases are likely to require antidepressant medication. Depending on locale, more than 20 antidepressant formulations, belonging to more than a dozen pharmacological classes, may be available for the treatment of major depression (see Table 10). The vast majority of these act via monoaminergic modulation and differ mainly in terms of tolerability and only somewhat in efficacy. Nevertheless, these differences are important and are useful for tailoring choice to the clinical profile of the depressed individual. Recent network meta-analyses (Cipriani et al., 2009, 2016, 2018) have shown that all antidepressants are effective (compared with placebo) and that some are more effective than others (head to head studies). Therefore, based on both evidence and clinical experience there are seven Choice antidepressants. It is noteworthy that each antidepressant is from a different class (see Table 10). The Choice antidepressants are shown in Figure 26 and they are positioned along an axis that reflects their differential tolerability and efficacy, comprising two groups of three antidepressants and with amitriptyline on its own. The two groups of three comprise escitalopram, vortioxetine and agomelatine (EVA) in one group, and venlafaxine, mirtazapine and bupropion (VMB) in the other. There is another subtle gradient of effectiveness favouring those agents that are listed higher. However, it is important to note that these differences are marginal and not as significant as the impact of tailoring choice to the patient’s unique profile. Nevertheless, it provides some indication of putative preferences (Figure 26).
Figure 26. The management of major depression.
This schematic summarises the treatment recommendations for the management of depression. It begins with measures that are necessary and form a foundation for specific treatment strategies. The primary focus here is on treating depression symptoms and achieving functional recovery in the acute phase, but we highlight elsewhere the importance of planning for long-term management (see Recommendation Box 3), and broader treatment aims (see section 5.1, ‘Aims of treatment’).