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Molecular Psychiatry Jan 2023A systematic review and random-effects model network meta-analysis were conducted to compare the efficacy, acceptability, tolerability, and safety of antidepressants to... (Meta-Analysis)
Meta-Analysis
A systematic review and random-effects model network meta-analysis were conducted to compare the efficacy, acceptability, tolerability, and safety of antidepressants to treat adults with major depressive disorder (MDD) in the maintenance phase. This study searched the PubMed, Cochrane Library, and Embase databases and included only double-blind, randomized, placebo-controlled trials with an enrichment design: patients were stabilized on the antidepressant of interest during the open-label study and then randomized to receive the same antidepressant or placebo. The outcomes were the 6-month relapse rate (primary outcome, efficacy), all-cause discontinuation (acceptability), discontinuation due to adverse events (tolerability), and the incidence of individual adverse events. The risk ratio with a 95% credible interval was calculated. The meta-analysis comprised 34 studies (n = 9384, mean age = 43.80 years, and %females = 68.10%) on 20 antidepressants (agomelatine, amitriptyline, bupropion, citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, levomilnacipran, milnacipran, mirtazapine, nefazodone, paroxetine, reboxetine, sertraline, tianeptine, venlafaxine, vilazodone, and vortioxetine) and a placebo. In terms of the 6-month relapse rate, amitriptyline, citalopram, desvenlafaxine, duloxetine, fluoxetine, fluvoxamine, mirtazapine, nefazodone, paroxetine, reboxetine, sertraline, tianeptine, venlafaxine, and vortioxetine outperformed placebo. Compared to placebo, desvenlafaxine, paroxetine, sertraline, venlafaxine, and vortioxetine had lower all-cause discontinuation; however, sertraline had a higher discontinuation rate due to adverse events. Compared to placebo, venlafaxine was associated with a lower incidence of dizziness, while desvenlafaxine, sertraline, and vortioxetine were associated with a higher incidence of nausea/vomiting. In conclusion, desvenlafaxine, paroxetine, venlafaxine, and vortioxetine had reasonable efficacy, acceptability, and tolerability in the treatment of adults with stable MDD.
Topics: Female; Humans; Adult; Depressive Disorder, Major; Duloxetine Hydrochloride; Sertraline; Citalopram; Venlafaxine Hydrochloride; Vortioxetine; Fluoxetine; Paroxetine; Mirtazapine; Amitriptyline; Desvenlafaxine Succinate; Fluvoxamine; Reboxetine; Network Meta-Analysis; Antidepressive Agents; Randomized Controlled Trials as Topic
PubMed: 36253442
DOI: 10.1038/s41380-022-01824-z -
The Lancet. Psychiatry Jul 2019Depression is the single largest contributor to non-fatal health loss worldwide. Second-generation antidepressants are the first-line option for pharmacological... (Meta-Analysis)
Meta-Analysis
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.
Topics: Depressive Disorder, Major; Dose-Response Relationship, Drug; Double-Blind Method; Humans; Mirtazapine; Randomized Controlled Trials as Topic; Serotonin Agents; Selective Serotonin Reuptake Inhibitors; Venlafaxine Hydrochloride
PubMed: 31178367
DOI: 10.1016/S2215-0366(19)30217-2 -
Journal of Affective Disorders May 2020We investigated the comparative efficacy and tolerability of pharmacological treatment strategies for the treatment of acute bipolar depression. (Meta-Analysis)
Meta-Analysis Review
OBJECTIVE
We investigated the comparative efficacy and tolerability of pharmacological treatment strategies for the treatment of acute bipolar depression.
DATA SOURCES
A systematic review and network meta-analysis was conducted by searching eight registries for published and unpublished, double-blind, randomized controlled trials of pharmacotherapies for the acute treatment of bipolar depression.
DATA EXTRACTION AND SYNTHESIS
PRISMA guidelines were used for abstracting data, while the Cochrane Risk of Bias Tool was used to assess data quality. Data extraction was done independently by two reviewers, with discrepancies resolved by consensus. Data were pooled using a random-effects model.
MAIN OUTCOMES AND MEASURES
Primary outcomes were efficacy (response and remission rate) and acceptability (completion of treatment and dropouts due to adverse events). Summary odds ratios (ORs) were estimated using pairwise and network meta-analysis with random effects.
RESULTS
Identified citations (4,404) included 50 trials comprising 11,448 participants. Escitalopram, phenelzine, moclobemide, carbamazepine, sertraline, lithium, paroxetine, aripiprazole, gabapentin and ziprasidone appear to be ineffective as compared to placebo in treatment of bipolar depression. Divalproex, olanzapine/fluoxetine, olanzapine, quetiapine, cariprazine, and lamotrigine, appear to be effective as compared to placebo in treatment of bipolar depression according to the network meta-analysis. Aripiprazole showed higher discontinuation rates versus placebo due to the appearance of any adverse event. Quetiapine was better than placebo at reducing treatment-emergent affective switches. For Bipolar I Disorder, cariprazine, fluoxetine, imipramine, lamotrigine, lurasidone, olanzapine-fluoxetine, and olanzapine were significantly better than placebo at response, while fluoxetine, imipramine, cariprazine, lurasidone, olanzapine-fluoxetine, and olanzapine were significantly better than placebo at remission.
CONCLUSIONS AND RELEVANCE
These results could serve evidence-based practice and inform patients, physicians, guideline developers, and policymakers on the relative benefits of the different antidepressants, antipsychotics, and mood-stabilizing agents for the treatment of bipolar depression.
REGISTRATION
PROSPERO (CRD42019122172).
Topics: Antipsychotic Agents; Bipolar Disorder; Humans; Lurasidone Hydrochloride; Network Meta-Analysis; Olanzapine
PubMed: 32339131
DOI: 10.1016/j.jad.2020.03.030 -
The Cochrane Database of Systematic... Mar 2022Posttraumatic stress disorder (PTSD) is a prevalent and disabling disorder. Evidence that PTSD is characterised by specific psychobiological dysfunctions has contributed... (Review)
Review
BACKGROUND
Posttraumatic stress disorder (PTSD) is a prevalent and disabling disorder. Evidence that PTSD is characterised by specific psychobiological dysfunctions has contributed to a growing interest in the use of medication in its treatment.
OBJECTIVES
To assess the effects of medication for reducing PTSD symptoms in adults with PTSD.
SEARCH METHODS
We searched the Cochrane Central Register of Controlled Trials (CENTRAL; Issue 11, November 2020); MEDLINE (1946-), Embase (1974-), PsycINFO (1967-) and PTSDPubs (all available years) either directly or via the Cochrane Common Mental Disorders Controlled Trials Register (CCMDCTR). We also searched international trial registers. The date of the latest search was 13 November 2020.
SELECTION CRITERIA
All randomised controlled trials (RCTs) of pharmacotherapy for adults with PTSD.
DATA COLLECTION AND ANALYSIS
Three review authors (TW, JI, and NP) independently assessed RCTs for inclusion in the review, collated trial data, and assessed trial quality. We contacted investigators to obtain missing data. We stratified summary statistics by medication class, and by medication agent for all medications. We calculated dichotomous and continuous measures using a random-effects model, and assessed heterogeneity.
MAIN RESULTS
We include 66 RCTs in the review (range: 13 days to 28 weeks; 7442 participants; age range 18 to 85 years) and 54 in the meta-analysis. For the primary outcome of treatment response, we found evidence of beneficial effect for selective serotonin reuptake inhibitors (SSRIs) compared with placebo (risk ratio (RR) 0.66, 95% confidence interval (CI) 0.59 to 0.74; 8 studies, 1078 participants), which improved PTSD symptoms in 58% of SSRI participants compared with 35% of placebo participants, based on moderate-certainty evidence. For this outcome we also found evidence of beneficial effect for the noradrenergic and specific serotonergic antidepressant (NaSSA) mirtazapine: (RR 0.45, 95% CI 0.22 to 0.94; 1 study, 26 participants) in 65% of people on mirtazapine compared with 22% of placebo participants, and for the tricyclic antidepressant (TCA) amitriptyline (RR 0.60, 95% CI 0.38 to 0.96; 1 study, 40 participants) in 50% of amitriptyline participants compared with 17% of placebo participants, which improved PTSD symptoms. These outcomes are based on low-certainty evidence. There was however no evidence of beneficial effect for the number of participants who improved with the antipsychotics (RR 0.51, 95% CI 0.16 to 1.67; 2 studies, 43 participants) compared to placebo, based on very low-certainty evidence. For the outcome of treatment withdrawal, we found evidence of a harm for the individual SSRI agents compared with placebo (RR 1.41, 95% CI 1.07 to 1.87; 14 studies, 2399 participants). Withdrawals were also higher for the separate SSRI paroxetine group compared to the placebo group (RR 1.55, 95% CI 1.05 to 2.29; 5 studies, 1101 participants). Nonetheless, the absolute proportion of individuals dropping out from treatment due to adverse events in the SSRI groups was low (9%), based on moderate-certainty evidence. For the rest of the medications compared to placebo, we did not find evidence of harm for individuals dropping out from treatment due to adverse events.
AUTHORS' CONCLUSIONS
The findings of this review support the conclusion that SSRIs improve PTSD symptoms; they are first-line agents for the pharmacotherapy of PTSD, based on moderate-certainty evidence. The NaSSA mirtazapine and the TCA amitriptyline may also improve PTSD symptoms, but this is based on low-certainty evidence. In addition, we found no evidence of benefit for the number of participants who improved following treatment with the antipsychotic group compared to placebo, based on very low-certainty evidence. There remain important gaps in the evidence base, and a continued need for more effective agents in the management of PTSD.
Topics: Adolescent; Adult; Aged; Aged, 80 and over; Amitriptyline; Antidepressive Agents; Antidepressive Agents, Tricyclic; Antipsychotic Agents; Humans; Middle Aged; Mirtazapine; Paroxetine; Selective Serotonin Reuptake Inhibitors; Stress Disorders, Post-Traumatic; Young Adult
PubMed: 35234292
DOI: 10.1002/14651858.CD002795.pub3 -
Progress in Neuro-psychopharmacology &... Jul 2021Gastrointestinal side effects (SEs) are frequently observed in patients with major depressive disorder (MDD) while taking antidepressants and may lead to treatment... (Meta-Analysis)
Meta-Analysis
Gastrointestinal side effects (SEs) are frequently observed in patients with major depressive disorder (MDD) while taking antidepressants and may lead to treatment discontinuation. The aim of this meta-analysis is to provide quantitative measures on short-term rates of gastrointestinal SEs in MDD patients treated with second-generation antidepressants. An electronic search of the literature was conducted by using MEDLINE, ISI Web of Science - Web of Science Core Collection, and Cochrane Library databases. Eligible studies had to focus on the use of at least one of 15 antidepressants commonly used in MDD (i.e., agomelatine, bupropion, citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, levomilnacipran, mirtazapine, paroxetine, reboxetine, sertraline, venlafaxine, and vortioxetine) and report data on treatment-emergent gastrointestinal SEs (i.e. nausea/vomiting, diarrhoea, constipation, abdominal pain, dyspepsia, anorexia, increased appetite and dry mouth) within 12 weeks of treatment. Overall, 304 studies were included in the meta-analyses. All the considered antidepressants showed higher rates of gastrointestinal SEs than placebo. Escitalopram and sertraline were shown to be the least tolerated antidepressants on the gastrointestinal tract, being associated with all the considered SEs with the exception of constipation and increased appetite, while mirtazapine was shown to be the antidepressant with fewer side effects on the gut, being only associated with increased appetite. In conclusion, commonly used antidepressants showed different profiles of gastrointestinal SEs, possibly related to their mechanisms of action. The specific tolerability profile of each compound should be considered by clinicians when prescribing antidepressants in order to improve adherence to treatment and increase positive outcomes in patients with MDD.
Topics: Antidepressive Agents; Constipation; Depressive Disorder, Major; Diarrhea; Humans; Nausea; Vomiting
PubMed: 33549697
DOI: 10.1016/j.pnpbp.2021.110266 -
JAMA Psychiatry Mar 2021Precise estimation of the drug metabolism capacity for individual patients is crucial for adequate dose personalization. (Meta-Analysis)
Meta-Analysis
IMPORTANCE
Precise estimation of the drug metabolism capacity for individual patients is crucial for adequate dose personalization.
OBJECTIVE
To quantify the difference in the antipsychotic and antidepressant exposure among patients with genetically associated CYP2C19 and CYP2D6 poor (PM), intermediate (IM), and normal (NM) metabolizers.
DATA SOURCES
PubMed, Clinicaltrialsregister.eu, ClinicalTrials.gov, International Clinical Trials Registry Platform, and CENTRAL databases were screened for studies from January 1, 1990, to June 30, 2020, with no language restrictions.
STUDY SELECTION
Two independent reviewers performed study screening and assessed the following inclusion criteria: (1) appropriate CYP2C19 or CYP2D6 genotyping was performed, (2) genotype-based classification into CYP2C19 or CYP2D6 NM, IM, and PM categories was possible, and (3) 3 patients per metabolizer category were available.
DATA EXTRACTION AND SYNTHESIS
The Meta-analysis of Observational Studies in Epidemiology (MOOSE) guidelines were followed for extracting data and quality, validity, and risk of bias assessments. A fixed-effects model was used for pooling the effect sizes of the included studies.
MAIN OUTCOMES AND MEASURES
Drug exposure was measured as (1) dose-normalized area under the plasma level (time) curve, (2) dose-normalized steady-state plasma level, or (3) reciprocal apparent total drug clearance. The ratio of means (RoM) was calculated by dividing the mean drug exposure for PM, IM, or pooled PM plus IM categories by the mean drug exposure for the NM category.
RESULTS
Based on the data derived from 94 unique studies and 8379 unique individuals, the most profound differences were observed in the patients treated with aripiprazole (CYP2D6 PM plus IM vs NM RoM, 1.48; 95% CI, 1.41-1.57; 12 studies; 1038 patients), haloperidol lactate (CYP2D6 PM vs NM RoM, 1.68; 95% CI, 1.40-2.02; 9 studies; 423 patients), risperidone (CYP2D6 PM plus IM vs NM RoM, 1.36; 95% CI, 1.28-1.44; 23 studies; 1492 patients), escitalopram oxalate (CYP2C19 PM vs NM, RoM, 2.63; 95% CI, 2.40-2.89; 4 studies; 1262 patients), and sertraline hydrochloride (CYP2C19 IM vs NM RoM, 1.38; 95% CI, 1.27-1.51; 3 studies; 917 patients). Exposure differences were also observed for clozapine, quetiapine fumarate, amitriptyline hydrochloride, mirtazapine, nortriptyline hydrochloride, fluoxetine hydrochloride, fluvoxamine maleate, paroxetine hydrochloride, and venlafaxine hydrochloride; however, these differences were marginal, ambiguous, or based on less than 3 independent studies.
CONCLUSIONS AND RELEVANCE
In this systematic review and meta-analysis, the association between CYP2C19/CYP2D6 genotype and drug levels of several psychiatric drugs was quantified with sufficient precision as to be useful as a scientific foundation for CYP2D6/CYP2C19 genotype-based dosing recommendations.
Topics: Antidepressive Agents; Antipsychotic Agents; Cytochrome P-450 CYP2C19; Cytochrome P-450 CYP2D6; Humans; Pharmacogenomic Variants
PubMed: 33237321
DOI: 10.1001/jamapsychiatry.2020.3643 -
World Psychiatry : Official Journal of... Jun 2020Mental disorders frequently begin in childhood or adolescence. Psychotropic medications have various indications for the treatment of mental dis-orders in this age...
Safety of 80 antidepressants, antipsychotics, anti-attention-deficit/hyperactivity medications and mood stabilizers in children and adolescents with psychiatric disorders: a large scale systematic meta-review of 78 adverse effects.
Mental disorders frequently begin in childhood or adolescence. Psychotropic medications have various indications for the treatment of mental dis-orders in this age group and are used not infrequently off-label. However, the adverse effects of these medications require special attention during developmentally sensitive periods of life. For this meta-review, we systematically searched network meta-analyses and meta-analyses of randomized controlled trials (RCTs), individual RCTs, and cohort studies reporting on 78 a priori selected adverse events across 19 categories of 80 psychotropic medications - including antidepressants, antipsychotics, anti-attention-deficit/hyperactivity disorder (ADHD) medications and mood stabilizers - in children and adolescents with mental disorders. We included data from nine network meta-analyses, 39 meta-analyses, 90 individual RCTs, and eight cohort studies, including 337,686 children and adolescents. Data on ≥20% of the 78 adverse events were available for six antidepressants (sertraline, escitalopram, paroxetine, fluoxetine, venlafaxine and vilazodone), eight antipsychotics (risperidone, quetiapine, aripiprazole, lurasidone, paliperidone, ziprasidone, olanzapine and asenapine), three anti-ADHD medications (methylphenidate, atomoxetine and guanfacine), and two mood stabilizers (valproate and lithium). Among these medications with data on ≥20% of the 78 adverse events, a safer profile emerged for escitalopram and fluoxetine among antidepressants, lurasidone for antipsychotics, methylphenidate among anti-ADHD medications, and lithium among mood stabilizers. The available literature raised most concerns about the safety of venlafaxine, olanzapine, atomoxetine, guanfacine and valproate. Nausea/vomiting and discontinuation due to adverse event were most frequently associated with antidepressants; sedation, extrapyramidal side effects, and weight gain with antipsychotics; anorexia and insomnia with anti-ADHD medications; sedation and weight gain with mood stabilizers. The results of this comprehensive and updated quantitative systematic meta-review of top-tier evidence regarding the safety of antidepressants, antipsychotics, anti-ADHD medications and mood stabilizers in children and adolescents can inform clinical practice, research and treatment guidelines.
PubMed: 32394557
DOI: 10.1002/wps.20765 -
The Cochrane Database of Systematic... Nov 2023A panic attack is a discrete period of fear or anxiety that has a rapid onset and reaches a peak within 10 minutes. The main symptoms involve bodily systems, such as... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
A panic attack is a discrete period of fear or anxiety that has a rapid onset and reaches a peak within 10 minutes. The main symptoms involve bodily systems, such as racing heart, chest pain, sweating, shaking, dizziness, flushing, churning stomach, faintness and breathlessness. Other recognised panic attack symptoms involve fearful cognitions, such as the fear of collapse, going mad or dying, and derealisation (the sensation that the world is unreal). Panic disorder is common in the general population with a prevalence of 1% to 4%. The treatment of panic disorder includes psychological and pharmacological interventions, including antidepressants and benzodiazepines.
OBJECTIVES
To compare, via network meta-analysis, individual drugs (antidepressants and benzodiazepines) or placebo in terms of efficacy and acceptability in the acute treatment of panic disorder, with or without agoraphobia. To rank individual active drugs for panic disorder (antidepressants, benzodiazepines and placebo) according to their effectiveness and acceptability. To rank drug classes for panic disorder (selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), mono-amine oxidase inhibitors (MAOIs) and benzodiazepines (BDZs) and placebo) according to their effectiveness and acceptability. To explore heterogeneity and inconsistency between direct and indirect evidence in a network meta-analysis.
SEARCH METHODS
We searched the Cochrane Common Mental Disorders Specialised Register, CENTRAL, CDSR, MEDLINE, Ovid Embase and PsycINFO to 26 May 2022.
SELECTION CRITERIA
We included randomised controlled trials (RCTs) of people aged 18 years or older of either sex and any ethnicity with clinically diagnosed panic disorder, with or without agoraphobia. We included trials that compared the effectiveness of antidepressants and benzodiazepines with each other or with a placebo.
DATA COLLECTION AND ANALYSIS
Two authors independently screened titles/abstracts and full texts, extracted data and assessed risk of bias. We analysed dichotomous data and continuous data as risk ratios (RRs), mean differences (MD) or standardised mean differences (SMD): response to treatment (i.e. substantial improvement from baseline as defined by the original investigators: dichotomous outcome), total number of dropouts due to any reason (as a proxy measure of treatment acceptability: dichotomous outcome), remission (i.e. satisfactory end state as defined by global judgement of the original investigators: dichotomous outcome), panic symptom scales and global judgement (continuous outcome), frequency of panic attacks (as recorded, for example, by a panic diary; continuous outcome), agoraphobia (dichotomous outcome). We assessed the certainty of evidence using threshold analyses.
MAIN RESULTS
Overall, we included 70 trials in this review. Sample sizes ranged between 5 and 445 participants in each arm, and the total sample size per study ranged from 10 to 1168. Thirty-five studies included sample sizes of over 100 participants. There is evidence from 48 RCTs (N = 10,118) that most medications are more effective in the response outcome than placebo. In particular, diazepam, alprazolam, clonazepam, paroxetine, venlafaxine, clomipramine, fluoxetine and adinazolam showed the strongest effect, with diazepam, alprazolam and clonazepam ranking as the most effective. We found heterogeneity in most of the comparisons, but our threshold analyses suggest that this is unlikely to impact the findings of the network meta-analysis. Results from 64 RCTs (N = 12,310) suggest that most medications are associated with either a reduced or similar risk of dropouts to placebo. Alprazolam and diazepam were associated with a lower dropout rate compared to placebo and were ranked as the most tolerated of all the medications examined. Thirty-two RCTs (N = 8569) were included in the remission outcome. Most medications were more effective than placebo, namely desipramine, fluoxetine, clonazepam, diazepam, fluvoxamine, imipramine, venlafaxine and paroxetine, and their effects were clinically meaningful. Amongst these medications, desipramine and alprazolam were ranked highest. Thirty-five RCTs (N = 8826) are included in the continuous outcome reduction in panic scale scores. Brofaromine, clonazepam and reboxetine had the strongest reductions in panic symptoms compared to placebo, but results were based on either one trial or very small trials. Forty-one RCTs (N = 7853) are included in the frequency of panic attack outcome. Only clonazepam and alprazolam showed a strong reduction in the frequency of panic attacks compared to placebo, and were ranked highest. Twenty-six RCTs (N = 7044) provided data for agoraphobia. The strongest reductions in agoraphobia symptoms were found for citalopram, reboxetine, escitalopram, clomipramine and diazepam, compared to placebo. For the pooled intervention classes, we examined the two primary outcomes (response and dropout). The classes of medication were: SSRIs, SNRIs, TCAs, MAOIs and BDZs. For the response outcome, all classes of medications examined were more effective than placebo. TCAs as a class ranked as the most effective, followed by BDZs and MAOIs. SSRIs as a class ranked fifth on average, while SNRIs were ranked lowest. When we compared classes of medication with each other for the response outcome, we found no difference between classes. Comparisons between MAOIs and TCAs and between BDZs and TCAs also suggested no differences between these medications, but the results were imprecise. For the dropout outcome, BDZs were the only class associated with a lower dropout compared to placebo and were ranked first in terms of tolerability. The other classes did not show any difference in dropouts compared to placebo. In terms of ranking, TCAs are on average second to BDZs, followed by SNRIs, then by SSRIs and lastly by MAOIs. BDZs were associated with lower dropout rates compared to SSRIs, SNRIs and TCAs. The quality of the studies comparing antidepressants with placebo was moderate, while the quality of the studies comparing BDZs with placebo and antidepressants was low.
AUTHORS' CONCLUSIONS
In terms of efficacy, SSRIs, SNRIs (venlafaxine), TCAs, MAOIs and BDZs may be effective, with little difference between classes. However, it is important to note that the reliability of these findings may be limited due to the overall low quality of the studies, with all having unclear or high risk of bias across multiple domains. Within classes, some differences emerged. For example, amongst the SSRIs paroxetine and fluoxetine seem to have stronger evidence of efficacy than sertraline. Benzodiazepines appear to have a small but significant advantage in terms of tolerability (incidence of dropouts) over other classes.
Topics: Adult; Humans; Panic Disorder; Selective Serotonin Reuptake Inhibitors; Paroxetine; Fluoxetine; Venlafaxine Hydrochloride; Serotonin and Noradrenaline Reuptake Inhibitors; Alprazolam; Clomipramine; Reboxetine; Clonazepam; Desipramine; Network Meta-Analysis; Antidepressive Agents; Antidepressive Agents, Tricyclic; Benzodiazepines; Diazepam
PubMed: 38014714
DOI: 10.1002/14651858.CD012729.pub3 -
Frontiers in Pharmacology 2020: Generalized anxiety disorder (GAD) is one of the most common psychiatric disorders associated with substantial dysfunction and socioeconomic burden. Pharmacotherapy is... (Review)
Review
Comparative Remission Rates and Tolerability of Drugs for Generalised Anxiety Disorder: A Systematic Review and Network Meta-analysis of Double-Blind Randomized Controlled Trials.
: Generalized anxiety disorder (GAD) is one of the most common psychiatric disorders associated with substantial dysfunction and socioeconomic burden. Pharmacotherapy is the first choice for GAD. Remission [Hamilton Anxiety Scale (HAM-A) score ≤7] is regarded as a crucial treatment goal for patients with GAD. There is no up-to-date evidence to compare remission rate and tolerability of all available drugs by using network meta-analysis. Therefore, the goal of our study is to update evidence and determine the best advantageous drugs for GAD in remission rate and tolerability profiles. : We performed a systematic review and network meta-analysis of double-blind randomized controlled trials (RCTs). We searched PubMed, EMBASE, Cochrane Central Register of Controlled Trials, Chinese National Knowledge Infrastructure, wanfang data, China Biology Medicine and ClinicalTrials.gov from their inception to March 2020 to identify eligible double-blind, RCTs reporting the outcome of remission in adult patients who received any pharmacological treatment for GAD. Two reviewers independently assessed quality of included studies utilizing the Cochrane Collaboration's risk of bias tool as described in Cochrane Collaboration Handbook and extracted data from all manuscripts. Our outcomes were remission rate (proportion of participants with a final score of seven or less on HAM-A) and tolerability (treatments discontinuations due to adverse events). We calculated summary odds ratios (ORs) and 95% confidence intervals (CIs) of each outcome via pairwise and network meta-analysis with random effects. : Overall, 30 studies were included, comprising 32 double-blind RCTs, involving 13,338 participants diagnosed as GAD by DSM-IV criteria. Twenty-eight trials were rated as moderate risk of bias, four trials as low. For remission rate, agomelatine (OR 2.70, 95% CI 1.74-4.19), duloxetine (OR 1.88, 95% CI 1.47-2.40), escitalopram (OR 2.03, 95% CI 1.48-2.78), paroxetine (OR 1.74, 95% CI 1.25-2.42), quetiapine (OR 1.88, 95% CI 1.39-2.55), and venlafaxine (OR 2.28, 95% CI 1.69-3.07) were superior to placebo. For tolerability, sertraline, agomelatine, vortioxetine, and pregabalin were found to be comparable to placebo. However, the others were worse than placebo in terms of tolerability, with ORs ranging between 1.86 (95% CI 1.25-2.75) for tiagabine and 5.98 (95% CI 2.41-14.87) for lorazepam. In head-to-head comparisons, agomelatine, duloxetine, escitalopram, quetiapine, and venlafaxine were more efficacious than tiagabine in terms of remission rate, ORs from 1.66 (95% CI 1.04-2.65) for duloxetine to 2.38 (95% CI 1.32-4.31) for agomelatine. We also found that agomelatine (OR 2.08, 95% CI 1.15-3.75) and venlafaxine (OR 1.76, 95% CI 1.08-2.86) were superior to vortioxetine. Lorazepam and quetiapine were poorly tolerated when compared with other drugs. : Of these interventions, only agomelatine manifested better remission with relatively good tolerability but these results were limited by small sample sizes. Duloxetine, escitalopram, venlafaxine, paroxetine, and quetiapine showed better remission but were poorly tolerated.
PubMed: 33343351
DOI: 10.3389/fphar.2020.580858