Deep transcranial magnetic stimulation for treatment-resistant depression: A systematic review and meta-analysis of randomized controlled studies.

The efficacy and safety of deep transcranial magnetic stimulation (dTMS) in treating treatment-resistant depression (TRD) are unknown. Up to June 21, 2023, we conducted a systematic search for RCTs, and then extracted and synthesized data using random effects models. Five RCTs involving 507 patients with TRD (243 in the active dTMS group and 264 in the control group) were included in the present study. The active dTMS group showed significantly higher study-defined response rate (45.3% versus 24.2%, n = 507, risk ratio [RR] = 1.87, 95% confidence interval [CI]: 1.21-2.91, I2 = 53%; P = 0.005) and study-defined remission rate (38.3% versus 14.4%, n = 507, RR = 2.37, 95%CI: 1.30-4.32, I2 = 58%; P = 0.005) and superiority in improving depressive symptoms (n = 507, standardized mean difference = -0.65, 95%CI: -1.11--0.18, I2 = 82%; P = 0.006) than the control group. In terms of cognitive functions, no significant differences were observed between the two groups. The two groups also showed similar rates of other adverse events and all-cause discontinuations (P > 0.05). dTMS is an effective and safe treatment strategy for the management of patients with TRD.

Adjunctive continuous theta burst stimulation for major depressive disorder or bipolar depression: A meta-analysis of randomized controlled studies.

OBJECTIVES: As a novel type of theta burst stimulation (TBS), continuous TBS (cTBS) has been shown to have mixed therapeutic effects for major depressive disorder (MDD) or bipolar depression (BD). Thus, we performed a meta-analysis of randomized controlled trials (RCTs) of cTBS for treating major depressive episodes in patients with MDD or BD. METHODS: A systematic search of four major bibliographic databases (PubMed, EMBASE, Cochrane Library, and PsycINFO) was conducted from inception dates to February 3, 2023 to identify eligible studies. The data were analyzed using a random-effects model. RESULTS: Three RCTs (n = 78, active cTBS = 37 and sham cTBS = 41) were included the meta-analysis. No significant differences were found in terms of change in Hamilton Depression Rating Scale (HAMD) scores (3 RCTs, n = 78, SMD = -0.09, 95 % CI: -0.53 to 0.36; I2 = 0 %; P = 0.71) and study-defined response (2 RCTs, n = 58, 26.7 % versus 21.4 %, RR = 1.20, 95 % CI: 0.48 to 2.96; I2 = 0 %; P = 0.70) between active and sham cTBS groups. Similarly, no group differences were found in the rates of adverse events and discontinuation due to any reason (P > 0.05). LIMITATIONS: Meta-analysis had small sample sizes and low number of included studies. CONCLUSIONS: Although cTBS appeared to be a safe and well-tolerated option for treating major depressive episodes in MDD or BD patients, no advantage in treatment effects was found in this meta-analysis. Future large-scale studies are warranted to assess the efficacy of cTBS for MDD or BD patients with a major depressive episode.

Efficacy and safety of intermittent theta burst stimulation versus high-frequency repetitive transcranial magnetic stimulation for patients with treatment-resistant depression: a systematic review.

Objective: Intermittent theta-burst stimulation (iTBS), which is a form of repetitive transcranial magnetic stimulation (rTMS), can produce 600 pulses to the left dorsolateral prefrontal cortex (DLPFC) in a stimulation time of just over 3 min. The objective of this systematic review was to compare the safety and efficacy of iTBS and high-frequency (≥ 5 Hz) rTMS (HF-rTMS) for patients with treatment-resistant depression (TRD). Methods: Randomized controlled trials (RCTs) comparing the efficacy and safety of iTBS and HF-rTMS were identified by searching English and Chinese databases. The primary outcomes were study-defined response and remission. Results: Two RCTs (n = 474) investigating the efficacy and safety of adjunctive iTBS (n = 239) versus HF-rTMS (n = 235) for adult patients with TRD met the inclusion criteria. Among the two included studies (Jadad score = 5), all were classified as high quality. No group differences were found regarding the overall rates of response (iTBS group: 48.0% versus HF-rTMS group: 45.5%) and remission (iTBS group: 30.0% versus HF-rTMS group: 25.2%; all Ps > 0.05). The rates of discontinuation and adverse events such as headache were similar between the two groups (all Ps > 0.05). Conclusion: The antidepressant effects and safety of iTBS and HF-rTMS appeared to be similar for patients with TRD, although additional RCTs with rigorous methodology are needed.

Accelerated intermittent theta burst stimulation for major depressive disorder or bipolar depression: A systematic review and meta-analysis.

We aimed to systematically evaluate the clinical efficacy and safety of accelerated intermittent theta burst stimulation (aiTBS) for patients with major depressive disorder (MDD) or bipolar depression (BD). A random-effects model was adopted to analyze the primary and secondary outcomes using the Review Manager, Version 5.3 software. This meta-analysis (MA) identified five double-blind randomized controlled trials (RCTs) comprising 239 MDD or BD patients with a major depressive episode. Active aiTBS overperformed sham stimulation in the study-defined response. This MA found preliminary evidence that active aiTBS resulted in a greater response in treating major depressive episodes in MDD or BD patients than sham stimulation.

Adjunctive transcranial alternating current stimulation for patients with major depressive disorder: A systematic review and meta-analysis.

Objective: We performed a meta-analysis of randomized, double-blind, controlled trials (RCTs) to systematically investigate the therapeutic effects and tolerability of transcranial alternating current stimulation (tACS) for the treatment of patients with major depressive disorder (MDD). Methods: Electronic search of PubMed, PsycINFO, EMBASE, Chinese National Knowledge Infrastructure, Wanfang database, and the Cochrane Library up to 1 April 2022. Double-blind RCTs examining the efficacy and safety of tACS for patients with MDD were included. The primary outcome was the improvement of depressive symptoms following a course of tACS treatment. Data were analyzed using Review Manager Version 5.3 (Cochrane IMS, Oxford, UK). Study quality was assessed using the Cochrane risk of bias and Jadad scale. Publication bias was assessed using a funnel plot and the Egger test. Results: We identified 883 articles, of which 4 RCTs with 5 active treatment arms covering 224 participants with MDD on active tACS (n = 117) and sham tACS (n = 107) were eligible for inclusion. Meta-analysis of depressive symptoms at post-tACS found an advantage of active tACS over sham tACS (n = 212, standard mean difference (SMD) = -1.14, 95% confidence interval (CI): -2.23, -0.06; I 2 = 90%, P = 0.04). The significant superiority of active tACS over sham tACS in improving depressive symptoms remained in a sensitivity analysis. Active tACS was significantly superior to sham tACS regarding depressive symptoms at the 4 week follow-up (SMD = -1.07, 95% CI: -2.05, -0.08; I 2 = 88%, P = 0.03) and study-defined remission [risk ratio (RR) = 2.07, 95% CI: 1.36, 3.14, I 2 = 9%, P = 0.0006]. The discontinuation rate due to any reason was similar between the two groups (P > 0.05). All included studies were rated as high quality (Jadad score ≥ 3), with funnel plots of primary outcome not suggestive of publication bias. Conclusion: tACS appeared to be modestly effective and safe for improving depressive symptoms in patients with MDD, although further studies are warranted.

Comparison of Efficacy and Safety of Magnetic Seizure Therapy and Electroconvulsive Therapy for Depression: A Systematic Review.

OBJECTIVES: As a new physical therapeutic technique, magnetic seizure therapy (MST) has established efficacy in the treatment of depression with few cognitive side effects, and thus appears to be a potential alternative to electroconvulsive therapy (ECT). The findings of randomized controlled trials (RCTs) examining the efficacy and safety of MST versus ECT for depression are inconsistent. This systematic review of RCTs was designed with the aim of assessing the safety and efficacy of MST versus ECT for patients with depression. METHODS: The WanFang, Chinese Journal Net (CNKI), EMBASE, PubMed, Cochrane Library, and PsycINFO databases were systematically searched by three independent investigators, from their inceptions to July 24, 2021. RESULTS: In total, four RCTs (n = 86) were included and analyzed. Meta-analyses of study-defined response (risk ratio (RR) = 1.36; 95% CI = 0.78 to 2.36; p = 0.28; I2 = 0%), study-defined remission (RR = 1.17; 95% CI = 0.61 to 2.23; p = 0.64; I2 = 0%), and the improvement in depressive symptoms (standardized mean difference (SMD) = 0.21; 95% CI = -0.29 to 0.71; p = 0.42; I2 = 0%) did not present significant differences between MST and ECT. Three RCTs evaluated the cognitive effects of MST compared with ECT using different cognitive measuring tools, but with mixed findings. Only two RCTs reported adverse drug reactions (ADRs), but these lacked specific data. Only one RCT reported discontinuation due to any reason. CONCLUSIONS: This preliminary study suggests that MST appears to have a similar antidepressant effect as ECT for depression, but mixed findings on adverse cognitive effects were reported.

Stanford neuromodulation therapy for treatment-resistant depression: a systematic review.

Objective: This systematic review of randomized controlled studies (RCTs) and observational studies evaluated the efficacy and safety of stanford neuromodulation therapy (SNT) for patients with treatment-resistant depression (TRD). Methods: A systematic search (up to 25 September, 2023) of RCTs and single-arm prospective studies was conducted. Results: One RCT (n = 29) and three single-arm prospective studies (n = 34) met the study entry criteria. In the RCT, compared to sham, active SNT was significantly associated with higher rates of antidepressant response (71.4% versus 13.3%) and remission (57.1% versus 0%). Two out of the three single-arm prospective studies reported the percentage of antidepressant response after completing SNT, ranging from 83.3% (5/6) to 90.5% (19/21). In the three single-arm prospective studies, the antidepressant remission rates ranged from 66.7% (4/6) to 90.5% (19/21). No severe adverse events occurred in all the four studies. Conclusion: This systematic review found SNT significantly improved depressive symptoms in patients with TRD within 5 days, without severe adverse events.

Adjunctive tDCS for treatment-refractory auditory hallucinations in schizophrenia: A meta-analysis of randomized, double-blinded, sham-controlled studies.

OBJECTIVE: Treatment-refractory auditory hallucinations (TRAH) in schizophrenia often do not improve with pharmacotherapy. We performed a meta-analysis of randomized, double-blind, sham-controlled clinical trials (RCTs) that systematically examined the therapeutic effects and tolerability of adjunctive active versus sham active transcranial direct current stimulation (tDCS) for auditory hallucinations as measured by the Auditory Hallucination Rating Scale (AHRS) in schizophrenia patients with TRAH. METHODS: Relevant data were extracted, checked and analyzed using the Review Manager, Version 5.3 by three independent investigators. RESULTS: Eight double-blind RCTs covering 329 schizophrenia patients (168 in active tDCS group, 161 in sham tDCS group) were included. Although no advantage of active tDCS on auditory hallucinations [7 RCTs, n = 224; standardized mean difference (SMD): - 0.33 (95% confidence interval (CI): - 0.71, 0.05), P = 0.09; I2 = 46%] was found compared to sham, subgroup analyses revealed that active tDCS with twice-daily stimulation [6 RCTs, n = 198; SMD: - 0.42 (95%CI: -0.82, -0.02), P = 0.04; I2 = 44%] and active tDCS with ≥ 10 stimulation sessions [6 RCTs, n = 198; SMD: - 0.42 (95%CI: -0.82, -0.02), P = 0.04; I2 = 44%] showed a significantly better therapeutic effect than sham in improving auditory hallucinations symptoms. Meta-analyses of total psychopathology and discontinuation due to any reason were not significantly different between the active and sham tDCS groups. CONCLUSION: This meta-analysis demonstrated that the effects of tDCS for auditory hallucinations symptoms were influenced by the tDCS parameters. Twice-daily stimulation and ≥ 10 stimulation sessions may be needed to improve auditory hallucinations symptoms in schizophrenia with TRAH.

Use of the RBANS to Evaluate Cognition in Patients with Schizophrenia and Metabolic Syndrome: a Meta-Analysis of Case-Control Studies.

Schizophrenia is associated with an increased risk of metabolic syndrome (MetS), which is an important risk factor for developing cognitive impairment in the general population. A few case-control studies have explored the relationship between MetS and cognitive deficits in individuals with schizophrenia but with inconsistent findings. This meta-analysis of case-control studies was carried out to explore the association between MetS and cognitive performance in patients with schizophrenia. Only case-control studies assessing the association of cognitive function and MetS in patients with schizophrenia were identified. Cognitive function was assessed using the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) scale. Six case-control studies (n = 992) comparing cognition between patients with schizophrenia with MetS (n = 426) and those without MetS (n = 566) using the RBANS were identified. Compared to patients with schizophrenia without MetS, patients with schizophrenia and MetS had significantly more impairments in RBANS total scores [standardized mean difference (SMD) = -0.26, 95% confidence interval (CI): -0.51 to -0.02; I2 = 72%; p = 0.03], immediate memory (SMD = -0.32, 95% CI: -0.54 to -0.10; I2 = 66%; p = 0.005), attention (SMD = -0.29, 95% CI: -0.56 to -0.02; I2 = 77%; p = 0.03), and delayed memory (SMD = -0.24, 95% CI: -0.46 to -0.03; I2 = 64%; p = 0.03). No group difference was found regarding visuospatial skills and language (p > 0.05). This meta-analysis found that schizophrenia patients with MetS had worse performance on certain cognitive tasks than non-MetS patients.

Adjunctive multi-session transcranial direct current stimulation for neurocognitive dysfunction in schizophrenia: A meta-analysis.

Findings of multi-session transcranial direct current stimulation (tDCS) as an adjunctive treatment of neurocognitive dysfunction in schizophrenia have been inconsistent. This meta-analysis of randomized controlled trials (RCTs) investigated the neurocognitive effects of adjunctive multi-session tDCS for schizophrenia. Twelve RCTs covering 418 schizophrenia patients were included and analyzed in this meta-analysis. The RevMan software (Version 5.3) was used to calculate risk ratios (RRs) and standardized mean differences (SMDs) with their 95% confidence intervals (CIs). Adjunctive tDCS outperformed the comparator in improving working memory deficits (SMD = 0.34, 95% CI: 0.03, 0.65; I2 = 52%; p = 0.03), but no significant effects were found in other cognitive domains. No group differences were found with regard to total psychopathology measured by the Brief Psychiatric Rating Scale and the Positive and Negative Symptom Scale (SMD =-0.29, 95%CI: -0.61, 0.03; I2 = 50%, p = 0.07) and discontinuation due to any reason (RR=0.80, 95%CI: 0.39, 1.66; I2 = 9%, p = 0.56). Adjunctive tDCS appears to have a significant therapeutic effect improving the working memory deficits in schizophrenia.

Efficacy and Safety of Adjunctive Aripiprazole, Metformin, and Paeoniae-Glycyrrhiza Decoction for Antipsychotic-Induced Hyperprolactinemia: A Network Meta-Analysis of Randomized Controlled Trials.

Aripiprazole, metformin, and paeoniae-glycyrrhiza decoction (PGD) have been widely used as adjunctive treatments to reduce antipsychotic (AP)-induced hyperprolactinemia in patients with schizophrenia. However, the comparative efficacy and safety of these medications have not been previously studied. A network meta-analysis of randomized controlled trials (RCTs) was conducted to compare the efficacy and safety between aripiprazole, metformin, and PGD as adjunctive medications in reducing AP-induced hyperprolactinemia in schizophrenia. Both international (PubMed, PsycINFO, EMBASE, and Cochrane Library databases) and Chinese (WanFang, Chinese Biomedical, and Chinese National Knowledge infrastructure) databases were searched from their inception until January 3, 2019. Data were analyzed using the Bayesian Markov Chain Monte Carlo simulations with the WinBUGS software. A total of 62 RCTs with 5,550 participants were included in the meta-analysis. Of the nine groups of treatments included, adjunctive aripiprazole (<5 mg/day) was associated with the most significant reduction in prolactin levels compared to placebo (posterior MD = -65.52, 95% CI = -104.91, -24.08) and the other eight treatment groups. Moreover, adjunctive PGD (>1:1) was associated with the lowest rate of all-cause discontinuation compared to placebo (posterior odds ratio = 0.45, 95% CI = 0.10, 3.13) and adjunctive aripiprazole (>10 mg/day) was associated with fewer total adverse drug events than placebo (posterior OR = 0.93, 95% CI = 0.65, 1.77) and other eight treatment groups. In addition, when risperidone, amisulpride, and olanzapine were the primary AP medications, adjunctive paeoniae/glycyrrhiza = 1:1, aripiprazole <5 mg/day, and aripiprazole >10 mg/day were the most effective treatments in reducing the prolactin levels, respectively. Adjunctive aripiprazole, metformin, and PGD showed beneficial effects in reducing AP-induced hyperprolactinemia in schizophrenia, with aripiprazole (<5 mg/day) being the most effective one.

Adjunctive Nonconvulsive Electrotherapy for Patients with Depression: a Systematic Review.

The efficacy and safety of adjunctive nonconvulsive electrotherapy (NET) for patients with depression are undetermined. This systematic review was conducted to examine the efficacy and safety of adjunctive NET for patients with depression. Chinese (WanFang and Chinese Journal Net) and English (PubMed, EMBASE, PsycINFO and the Cochrane Library) databases were systematically searched from their inception until Jan 27, 2021 by three independent investigators. One randomized controlled trial (RCT) with 3 treatment arms (n = 108) and two observational studies (single-group, before-after design, n = 31) were included. In the RCT, the antidepressant efficacy of NET on depression was similar to that of electroconvulsive therapy (ECT) (P > 0.05) but with significantly fewer neurocognitive impairments as measured by the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) (P < 0.05). In two observational studies, the 17-item Hamilton Depression Rating Scale (HAMD-17) scores decreased significantly from baseline to post-NET (all Ps < 0.05), without adverse neurocognitive effects. In the RCT, adverse drug reactions (ADRs) were not separately reported among the 3 treatment arms but a similar rate of discontinuation was reported. The currently available limited evidence from 3 studies suggests that NET as an adjunctive treatment may be a safe, well-tolerated, effective therapy for depression without serious neurocognitive impairments.

Adjunctive Magnetic Seizure Therapy for Schizophrenia: A Systematic Review.

Objective: The efficacy and safety of adjunctive magnetic seizure therapy (MST) for patients with schizophrenia are unclear. This systematic review was conducted to examine the efficacy and safety of adjunctive MST for schizophrenia. Methods: Chinese (WanFang and Chinese Journal Net) and English (PubMed, EMBASE, PsycINFO, and the Cochrane Library) databases were systematically searched. Results: Two open-label self-controlled studies (n = 16) were included and analyzed in this review. In these studies, the Positive and Negative Syndrome Scale (PANSS) total scores and Brief Psychiatric Rating Scale (BPRS) total scores significantly decreased from baseline to post-MST (all Ps < 0.05), without serious adverse neurocognitive effects. Mixed findings on the neurocognitive effects of adjunctive MST for schizophrenia were reported in the two studies. A discontinuation rate of treatment of up to 50% (4/8) was reported in both studies. The rate of adverse drug reactions (ADRs) was evaluated in only one study, where the most common ADRs were found to be dizziness (25%, 2/8) and subjective memory loss (12.5%, 1/8). Conclusion: There is inconsistent evidence for MST-related adverse neurocognitive effects and preliminary evidence for the alleviation of psychotic symptoms in schizophrenia.

Adjunctive Fluvoxamine for Schizophrenia: A Meta-analysis of Randomized Double-Blind, Placebo-Controlled Trials.

BACKGROUND: This was a meta-analysis of double-blind, randomized controlled trials that examined the therapeutic effects and tolerability of adjunctive fluvoxamine versus placebo for schizophrenia. METHODS: The Review Manager, Version 5.3, was used to analyze data. RESULTS: Five double-blind randomized controlled trials (N = 284) covering 145 patients on adjunctive fluvoxamine and 139 patients on placebo were included in the analyses. Meta-analyses of total psychopathology, and negative, positive, and depressive symptoms did not show significant differences between the fluvoxamine and placebo groups. Two studies examined the effects of adjunctive fluvoxamine on cognitive functioning with mixed findings. Fluvoxamine was superior over placebo in lessening weight gain and metabolic abnormalities. Although fluvoxamine led to more discontinuation, no significant group differences were found regarding adverse drug reactions. CONCLUSIONS: There was inconsistent evidence for the therapeutic effect of adjunctive fluvoxamine on cognitive functions and preliminary evidence for alleviating metabolic syndrome caused by clozapine. More studies are needed to explore further the effectiveness of adjunctive fluvoxamine for schizophrenia.

Adjunctive metformin for antipsychotic-induced dyslipidemia: a meta-analysis of randomized, double-blind, placebo-controlled trials.

Antipsychotic-induced dyslipidemia could increase the risk of cardiovascular diseases. This is a meta-analysis of randomized double-blind placebo-controlled trials to examine the efficacy and safety of adjunctive metformin for dyslipidemia induced by antipsychotics in schizophrenia. The standardized mean differences (SMDs) and risk ratios (RRs) with their 95% confidence intervals (CIs) were calculated using the random-effects model with the RevMan 5.3 version software. The primary outcome was the change of serum lipid level. Twelve studies with 1215 schizophrenia patients (592 in metformin group and 623 in placebo group) were included and analyzed. Adjunctive metformin was significantly superior to placebo with regards to low density lipoprotein cholesterol (LDL-C) [SMD: -0.37 (95%CI:-0.69, -0.05), P = 0.02; I2 = 78%], total cholesterol [SMD: -0.47 (95%CI:-0.66, -0.29), P < 0.00001; I2 = 49%], triglyceride [SMD: -0.33 (95%CI:-0.45, -0.20), P < 0.00001; I2 = 0%], and high density lipoprotein cholesterol [SMD: 0.29 (95%CI:0.02, 0.57), P = 0.03; I2 = 69%]. The superiority of metformin in improving LDL-C level disappeared in a sensitivity analysis and 80% (8/10) of subgroup analyses. Metformin was significantly superior to placebo with regards to decrease in body weight, body mass index, glycated hemoglobin A1c, fasting insulin, and homeostasis model assessment-insulin resistance (P = 0.002-0.01), but not regarding changes in waist circumference, waist-to-hip rate, leptin, fasting glucose, and blood pressure (P = 0.07-0.33). The rates of discontinuation due to any reason [RR: 0.97 (95%CI: 0.66, 1.43), P = 0.89; I2 = 0%] was similar between the two groups. Adjunctive metformin could be useful to improve total cholesterol and triglyceride levels, but it was not effective in improving LDL-C level in schizophrenia.

Cholesterol and triglyceride levels in first-episode patients with major depressive disorder: A meta-analysis of case-control studies.

BACKGROUND: Lipid profile disturbances are frequently observed in major depressive disorder (MDD) and constitute to high mortality rates. However, less is known about whether this risk is present in patients with first-episode MDD. Therefore, this meta-analysis was conducted to examine if lipid parameters differed between healthy controls and first-episode MDD patients. METHODS: Cochrane Library, PubMed, PsycINFO, EMBASE, Chinese Journal Net, and WanFang databases were searched from inception to October 23, 2018. The primary outcomes were triglycerides, high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol, and total cholesterol levels. RESULTS: A total of 11 case-control studies compared 690 subjects with first-episode MDD and 614 healthy controls were included and analyzed. Compared to healthy controls, patients with first-episode MDD were significantly associated with higher triglyceride (SMD = 0.29, 95% CI: 0.09, 0.48, P = 0.004) and lower HDL cholesterol levels (SMD = -0.54, 95% CI: -0.86, -0.22, P = 0.001). Subgroup analyses revealed that first-episode MDD patients with higher triglyceride and lower HDL levels were found only in Chinese and plasma group when compared to healthy controls (P < 0.05). Meta-regression analysis showed that the significant heterogeneity for triglyceride and HDL cholesterol was partly explained by the quality of study. No significant difference was found in LDL cholesterol and total cholesterol levels between the two groups. LIMITATIONS: Heterogeneity was relatively high among the included studies. CONCLUSIONS: Elevated triglyceride and decreased HDL cholesterol levels may be associated with first-episode MDD. Findings support early lipid monitoring and interventions targeting healthy lifestyle.

Minocycline for Depressive Symptoms: a Meta-Analysis of Randomized, Double-Blinded, Placebo-Controlled Trials.

Neuroinflammation appears to be associated with the neurobiology of depression, and treatments targeting inflammation have shown promising results in depression. This meta-analysis examined the efficacy and safety of minocycline, an anti-inflammatory drug, for the treatment of depressive symptoms. A systematic electronic literature search was independently conducted by two investigators. Standardized mean differences (SMDs) and risk ratio (RR) with their 95% confidence interval (CI) were calculated using a random-effect model. Four RCTs (n = 211) were identified for meta-analysis. Minocycline showed a significant trend of improvement in depressive symptoms compared to placebo [4 RCTs, n = 190, SMD: -0.54 (95%CI:-1.12, 0.04), P = 0.07; I2 = 73%]. Subgroup analyses showed that minocycline was superior to placebo in improving depressive symptoms in studies of unipolar depression (3 RCTs, n = 151, SMD: -0.77 (95%CI:-1.32, -0.22), P = 0.006; I2 = 60%) and in studies using minocycline monotherapy [SMD: -1.06 (95%CI:-1.68, -0.44), P = 0.0008]. The rates of discontinuation due to any reasons [RR: 1.48 (95%CI: 0.79, 2.77), P = 0.22, I2 = 0%] and adverse drug reactions [RR: 0.32 to 1.98 (95%CI: 0.03, 14.74), P = 0.19 to 0.84, I2 = 0% to 31%] were similar between minocycline and placebo. Minocycline appears to be effective and well-tolerated in ameliorating depressive symptoms in unipolar depression. Future large RCTs with sufficient duration is needed to confirm the positive effects of minocycline in treating depressive symptoms.

Adjunctive intranasal esketamine for major depressive disorder: A systematic review of randomized double-blind controlled-placebo studies.

OBJECTIVES: This is a meta-analysis of randomized double-blind controlled-placebo trials (RCTs) examining the effectiveness, tolerability, and safety of intranasal esketamine in treating major depressive disorder (MDD). METHODS: Standardized mean difference (SMD), risk ratio (RR) and their 95% confidence intervals (CIs) were calculated using RevMan version 5.3. RESULTS: Four RCTs with 7 active arms covering 708 patients with MDD on intranasal esketamine (n = 419) and placebo (n = 289) were included. Compared with placebo, adjunctive intranasal esketamine was associated with significantly greater study-defined response (RR=1.39, 95%CI: 1.18 to 1.64, P<0.0001) and remission (RR=1.42, 95%CI: 1.17 to 1.72, P = 0.0004) at endpoint assessment. Intranasal esketamine had greater study-defined response starting at 2 h (RR= 2.77, 95%CI: 1.62 to 4.76, P = 0.0002), peaking at 24 h (RR=5.42, 95%CI: 1.38 to 21.20, P = 0.02), and at least lasting for 28 days (RR=1.36, 95%CI: 1.16 to 1.58, P = 0.0001). Similarly, intranasal esketamine had significantly greater study-defined remission starting at 2 h (RR=7.71, 95%CI: 2.16 to 27.55, P = 0.002), peaking at 24 h (RR=6.87, 95%CI: 1.55 to 30.35, P = 0.01), and lasting for 28 days (RR=1.38, 95%CI: 1.11 to 1.72, P = 0.004). Intranasal esketamine had a significantly higher rate of discontinuation due to intolerability (RR=3.50, 95%CI: 1.38 to 8.86, P = 0.008). Discontinuation due to any reasons and inefficacy were similar between the two groups. CONCLUSION: Intranasal esketamine appears to have an ultra-rapid antidepressant effect for MDD, at least lasting for 28 days. The long-term therapeutic effect and safety of intranasal esketamine need to be further examined in large-scale RCTs.

Adjunctive Reboxetine for Schizophrenia: Meta-analysis of Randomized Double-blind, Placebo-controlled Trials.

BACKGROUND: Results of previous studies on the safety and efficacy of adjunctive reboxetine for schizophrenia have been inconsistent. AIM: The aim of this study was to examine the efficacy and tolerability of reboxetine as an adjunct medication to antipsychotic treatment in a meta-analysis of randomized controlled trials (RCTs). METHODS: Two independent investigators extracted data for a random effects meta-analysis and assessed the quality of studies using risk of bias and the Jadad scale. Weighted and standardized mean differences (WMDs/SMDs) and risk ratio (RR)±95% confidence intervals (CIs) were calculated. RESULTS: Nine RCTs (n=630) with double-blind design were identified. Reboxetine outperformed placebo in improving negative (9 RCTs, n=602, SMD: -0.47 [95% CI: -0.87, -0.07], p=0.02; I2=82%), but not the overall, positive, and general psychopathology scores. The significant therapeutic effect on negative symptoms disappeared in the sensitivity analysis after removing an outlying study and in 50% (6/12) of the subgroup analyses. Reboxetine outperformed placebo in reducing weight (3 RCTs, n=186, WMD: -3.83 kg, p=0.04; I2=92%) and body mass index (WMD: -2.23 kg/m2, p=0.04; I2=95%). Reboxetine caused dry mouth but was associated with less weight gain overall and weight gain of ≥7% of the initial weight. All-cause discontinuation and other adverse events were similar between reboxetine and placebo. CONCLUSION: Adjunctive reboxetine could be useful for attenuating antipsychotic-induced weight gain, but it was not effective in treating psychopathology including negative symptoms in schizophrenia.