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Frontiers in Pharmacology 2023We compared and ranked the efficacy and tolerability of multiple prophylactic treatments for vestibular migraine (VM), including β-blockers, calcium channel blockers,...
We compared and ranked the efficacy and tolerability of multiple prophylactic treatments for vestibular migraine (VM), including β-blockers, calcium channel blockers, antiseizure medications, and antidepressants such as tricyclics and serotonin-noradrenaline reuptake inhibitors. PubMed, Web of Science, Embase, and Cochrane Center for Clinical Trials were systematically searched for relevant randomized clinical trials (RCTs) from March 2023 to May 2023. Studies on the efficacy and tolerability of prophylactic treatments for VM were included. Efficacy was measured using the average vertigo frequency per month and dizziness handicap inventory (DHI) improvement after 3-6 months of treatment. Tolerability was measured by the number of patients reporting at least one adverse event (AE). Network meta-analyses were performed according to a Bayesian framework and a random-effects model based on odds ratios or mean differences (MDs) and 95% confidence intervals (CIs). A sequence of ranking probability was calculated according to the surface under the cumulative ranking (SUCRA) curve. This network meta-analysis was previously registered with PROSPERO (CRD42023422258). Five RCTs comprising 334 patients were analyzed by synthesizing the published evidence. Considering the examined prophylactic therapies, there is significant evidence that valproate acid (VPA) is superior to placebo or abortive treatment alone (MD = -4.12, 95% CI = -8.09, -0.15) in reducing the frequency of vertigo. Flunarizine (MD = 20.00, 95% CI = 10.90, 29.10), valproate acid (MD = 18.88, 95% CI = 10.42, 27.34), and venlafaxine (MD = 11.48, 95% CI = 9.84, 13.12) were significantly more effective than placebo or abortive treatment in reducing DHI. VPA most strongly reduced the frequency of vertigo according to SUCRA, but it ranked third-to-last in tolerability. Flunarizine ranked best in DHI improvement but worst in tolerability. Metoprolol ranked worst for efficacy but best for tolerability. VPA and flunarizine reduced the frequency of vertigo and improved DHI, but they had unfavorable tolerability. The effects of metoprolol on vertigo require further study. Given the low certainty and limited sample, additional head-to-head RCTs are warranted to further confirm efficacy. https://www.crd.york.ac.uk/PROSPERO/; Identifier CRD42023422258.
PubMed: 38186654
DOI: 10.3389/fphar.2023.1332973 -
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 -
Psychopharmacology Feb 2024The selective serotonin and norepinephrine reuptake inhibitor venlafaxine is among the most prescribed antidepressant drugs worldwide and, according to guidelines, its... (Meta-Analysis)
Meta-Analysis
INTRODUCTION
The selective serotonin and norepinephrine reuptake inhibitor venlafaxine is among the most prescribed antidepressant drugs worldwide and, according to guidelines, its dose titration should be guided by drug-level monitoring of its active moiety (AM) which consists of venlafaxine (VEN) plus active metabolite O-desmethylvenlafaxine (ODV). This indication of therapeutic drug monitoring (TDM), however, assumes a clear concentration/effect relationship for a drug, which for VEN has not been systematically explored yet.
OBJECTIVES
We performed a systematic review and meta-analysis to investigate the relationship between blood levels, efficacy, and adverse reactions in order to suggest an optimal target concentration range for VEN oral formulations for the treatment of depression.
METHODS
Four databases (MEDLINE (PubMed), PsycINFO, Web of Science Core Collection, and Cochrane Library) were systematically searched in March 2022 for relevant articles according to a previously published protocol. Reviewers independently screened references and performed data extraction and critical appraisal.
RESULTS
High-quality randomized controlled trials investigating concentration/efficacy relationships and studies using a placebo lead-in phase were not found. Sixty-eight articles, consisting mostly of naturalistic TDM studies or small noncontrolled studies, met the eligibility criteria. Of them, five cohort studies reported a positive correlation between blood levels and antidepressant effects after VEN treatment. Our meta-analyses showed (i) higher AM and (ii) higher ODV concentrations in patients responding to VEN treatment when compared to non-responders (n = 360, k = 5). AM concentration-dependent occurrence of tremor was reported in one study. We found a linear relationship between daily dose and AM concentration within guideline recommended doses (75-225 mg/day). The population-based concentration ranges (25-75% interquartile) among 11 studies (n = 3200) using flexible dosing were (i) 225-450 ng/ml for the AM and (ii) 144-302 ng/ml for ODV. One PET study reported an occupancy of 80% serotonin transporters for ODV serum levels above 85 ng/ml. Based on our findings, we propose a therapeutic reference range for AM of 140-600 ng/ml.
CONCLUSION
VEN TDM within a range of 140 to 600 ng/ml (AM) will increase the probability of response in nonresponders. A titration within the proposed reference range is recommended in case of non-response at lower drug concentrations as a consequence of VEN's dual mechanism of action via combined serotonin and norepinephrine reuptake inhibition. Drug titration towards higher concentrations will, however, increase the risk for ADRs, in particular with supratherapeutic drug concentrations.
Topics: Humans; Antidepressive Agents; Depression; Desvenlafaxine Succinate; Norepinephrine; Reference Values; Serotonin; Venlafaxine Hydrochloride
PubMed: 37857898
DOI: 10.1007/s00213-023-06484-7 -
The Annals of Pharmacotherapy Jul 2024Ketamine has been used in anesthesia, pain management, and major depressive disorder. It has recently been studied in patients with post-traumatic stress disorder (PTSD). (Meta-Analysis)
Meta-Analysis
BACKGROUND
Ketamine has been used in anesthesia, pain management, and major depressive disorder. It has recently been studied in patients with post-traumatic stress disorder (PTSD).
OBJECTIVE
To determine the impact of ketamine on PTSD symptomatology and depression scores.
METHODS
We conducted a literature search of Medline 1960 to May 20, 2023, and found 6 randomized controlled trials that met our inclusion criteria. We extracted data on the Clinician-Administered PTSD (CAPS), PTSD Checklist (PCL), or Montgomery-Asberg Depression Rating (MADRS) scales.
RESULTS
The use of ketamine significantly reduced CAPS scores (n = 5, MD: -10.63 [95% CI -14.95 to -6.32]), PCL scores (n = 3, MD: -6.13 [95% CI -8.61 to -3.64]), and MADRS scores (n = 3, MD: -6.33 [95% CI -8.97 to -3.69]) at the maximal follow-up times versus control. Significant benefits were found at day 1 and weeks 1, 2, and 4 for CAPS and PCL scores as well as MADRS scores at day 1, week 1, and week 4 for ketamine versus control. The time to PTSD relapse was prolonged in the patients receiving ketamine versus control (n = 2, 15.74 days [95% CI 3.57 to 29.91 days]). More dry mouth (n = 2, OR 5.85 [95% CI 1.32 to 25.95]), dizziness (n = 2, OR 3.83 [95% CI 1.28 to 11.41]), and blurred vision (n = 2, OR 7.57 [1.00 to 57.10]) occurred with ketamine than control therapy.
CONCLUSIONS AND RELEVANCE
Ketamine modestly reduced PTSD and depression scores as early as 1 day of therapy, but the longevity of effect needs to be determined. Given similar magnitude of benefit with SSRIs and venlafaxine, ketamine would not supplant these traditional options for chronic use.
Topics: Ketamine; Humans; Stress Disorders, Post-Traumatic; Randomized Controlled Trials as Topic; Psychiatric Status Rating Scales
PubMed: 37776285
DOI: 10.1177/10600280231199666 -
CNS Drugs Sep 2023Although one of the major presentations of vestibular migraine is dizziness with/without unsteady gait, it is still classified as one of the migraine categories.... (Meta-Analysis)
Meta-Analysis
INTRODUCTION
Although one of the major presentations of vestibular migraine is dizziness with/without unsteady gait, it is still classified as one of the migraine categories. However, in contrast to ordinary migraine, vestibular migraine patients have distinct characteristics, and the detailed treatment strategy for vestibular migraine is different and more challenging than ordinary migraine treatment. Currently, there is no conclusive evidence regarding its management, including vestibular migraine prophylaxis.
AIM
The objective of this current network meta-analysis (NMA) was to compare the efficacy and acceptability of individual treatment strategies in patients with vestibular migraine.
METHODS
The PubMed, Embase, ScienceDirect, ProQuest, Web of Science, ClinicalKey, Cochrane Central, and ClinicalTrials.gov databases were systematically searched for randomized controlled trials (RCTs), with a final literature search date of 30 December 2022. Patients diagnosed with vestibular migraine were included. The PICO of the current study included (1) patients with vestibular migraine; (2) intervention: any active pharmacologic or non-pharmacologic intervention; (3) comparator: placebo-control, active control, or waiting list; and (4) outcome: changes in migraine frequency or severity. This NMA of RCTs of vestibular migraine treatment was conducted using a frequentist model. We arranged inconsistency and similarity tests to re-examine the assumption of NMA, and also conducted a subgroup analysis focusing on RCTs of pharmacological treatment for vestibular migraine management. The primary outcome was changes in the frequency of vestibular migraines, while the secondary outcomes were changes in vestibular migraine severity and acceptability. Acceptability was set as the dropout rate, which was defined as the participant leaving the study before the end of the trial for any reason. Two authors independently evaluated the risk of bias for each domain using the Cochrane risk-of-bias tool.
RESULTS
Seven randomized controlled trials (N = 828, mean age 37.6 years, 78.4% female) and seven active regimens were included. We determined that only valproic acid (standardized mean difference [SMD] -1.61, 95% confidence interval [CI] -2.69, -0.54), propranolol (SMD -1.36, 95% CI -2.55, -0.17), and venlafaxine (SMD -1.25, 95% CI -2.32, -0.18) were significantly associated with better improvement in vestibular migraine frequency than the placebo/control groups. Furthermore, among all the investigated pharmacologic/non-pharmacologic treatments, valproic acid yielded the greatest decrease in vestibular migraine frequency among all the interventions. In addition, most pharmacologic/non-pharmacologic treatments were associated with similar acceptability (i.e. dropout rate) as those of the placebo/control groups.
CONCLUSIONS
The current study provides evidence that only valproic acid, propranolol, and venlafaxine might be associated with beneficial efficacy in vestibular migraine treatment.
TRIAL REGISTRATION
CRD42023388343.
Topics: Adult; Female; Humans; Male; Migraine Disorders; Network Meta-Analysis; Propranolol; Valproic Acid; Venlafaxine Hydrochloride
PubMed: 37676473
DOI: 10.1007/s40263-023-01037-0 -
The Journal of Maternal-fetal &... Dec 2023Antidepressant medications are used by increasing numbers of pregnant women. The evidence on the relationship between antidepressant use during pregnancy and the risk... (Meta-Analysis)
Meta-Analysis
OBJECTIVE
Antidepressant medications are used by increasing numbers of pregnant women. The evidence on the relationship between antidepressant use during pregnancy and the risk for gestational diabetes mellitus (GDM) is inconsistent. We perform a systematic review and meta-analysis to assess the GDM risk associated with antidepressant exposure during pregnancy.
METHODS
We systematically searched the PubMed and EMBASE databases until December 2021. We sought observational studies assessing the association between gestational antidepressant use and GDM.
RESULTS
Five observational studies were included in the analysis. Mothers exposed to antidepressants during pregnancy were at a significantly increased risk for GDM (relative risk [RR] 1.20, 95% confidence interval [CI] 1.11-1.30; < .001). However, after considering confounding by indication, we observed no significant effect of antidepressant use during pregnancy on the risk of GDM (RR 1.13, 95% CI 1-1.28; = .054; = 0%). Independent of clinical indication, subgroup analysis based on individual antidepressants suggested that the risk was increased by venlafaxine or amitriptyline use, but not by selective serotonin reuptake inhibitors.
CONCLUSIONS
The significant association between antidepressant exposure during pregnancy and GDM may be overestimated due to confounding by indication. However, the evidence remains insufficient, particularly for specific drug classes.
Topics: Pregnancy; Female; Humans; Diabetes, Gestational; Antidepressive Agents; Selective Serotonin Reuptake Inhibitors; Venlafaxine Hydrochloride; Amitriptyline
PubMed: 36599445
DOI: 10.1080/14767058.2022.2162817 -
The Journal of Laryngology and Otology Sep 2023Vestibular migraine is in the process of recognition as an individual clinical entity. At present, no guidelines exist for its management. This study aimed to conduct a... (Meta-Analysis)
Meta-Analysis Review
OBJECTIVE
Vestibular migraine is in the process of recognition as an individual clinical entity. At present, no guidelines exist for its management. This study aimed to conduct a systematic review and meta-analysis to determine the effectiveness of available prophylactic medication.
METHOD
literature search was performed using PubMed, Ovid and Embase databases. Qualitative and quantitative analysis were performed as well as risk of bias analysis. Meta-analysis for the mean differences for pre- and post-treatment impact based on Dizziness Handicap Inventory and Vertigo Symptom Scale were performed. Proportionate transformation meta-analysis for the successful event rate based on complete symptoms control was explored.
RESULTS
Thirteen publications were identified: 3 were randomised, controlled trials and 10 were non-randomised, controlled trials. Propranolol and venlafaxine improved the Vertigo Symptom Scale score by -13.31 points and -4.16 points, respectively, and the Dizziness Handicap Inventory score by -32.24 and -21.24, respectively. Only propranolol achieved statistically significant impact with 60 per cent of patients achieving complete symptom control.
CONCLUSION
Propranolol should be offered as the first-line treatment for vestibular migraine followed by venlafaxine. Amitriptyline, flunarizine and cinnarizine showed a trend for symptom improvement, but this was not statistically significant.
Topics: Humans; Dizziness; Propranolol; Venlafaxine Hydrochloride; Vertigo; Migraine Disorders
PubMed: 36200521
DOI: 10.1017/S0022215122001979