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Frontiers in Pharmacology 2024Amidst rising global burden of depression and the associated challenges with conventional antidepressant therapies, there is a growing interest in exploring the...
Amidst rising global burden of depression and the associated challenges with conventional antidepressant therapies, there is a growing interest in exploring the efficacy and safety of alternative treatments. This study uses a Bayesian network meta-analysis to rigorously evaluate the therapeutic potential of Chinese herbal medicines in the treatment of depression, focusing on their comparative efficacy and safety against standard pharmacological interventions. Five databases (PubMed, Wanfang Data, EMBASE, CNKI, and the Cochrane Library) and grey literature were searched from inception to end of July 2023 to identify studies that assessed the efficacy and safety of Chinese herbal medicines in treating depression. The response rate, Hamilton Depression Scale (HAMD) scores, and rates of adverse events were assessed through both direct and indirect comparisons. Data extraction and risk of bias assessment were meticulously performed. Statistical analysis used Markov chain Monte Carlo methods, with effect size estimates provided as odd ratios and their 95% confidence intervals. A total of 198 RCTs involving 8,923 patients were analyzed, assessing 17 Chinese herbal medicines. Surface Under the Cumulative Ranking results indicated that the top three treatments with the best response rate were possibly , , and ; the top three treatments on the reduction of HAMD scores were , , and ; and the top three treatments with the lowest adverse effects rates were , , and . Interestingly, commonly used synthetic drugs such as , , , , , and , not only appeared to be less effective than specific Chinese herbal medicines (, , , , and ), but they were also related to substantially higher risk of adverse events. Our findings elucidate the promising therapeutic potential of Chinese herbal medicines as viable alternatives in the treatment of depression, with certain herbs demonstrating enhanced efficacy and safety profiles. The outcomes of this study advocate for the integration of these alternative modalities into contemporary depression management paradigms. However, it underscores the necessity for larger, methodologically robust trials to further validate and refine these preliminary findings. https://www.crd.york.ac.uk/PROSPERO/, identifier CRD42023452109.
PubMed: 38633609
DOI: 10.3389/fphar.2024.1295564 -
BMC Psychiatry Nov 2014Current guidelines for treatment-resistant depression in adolescents remain inadequate. This study aimed to systematically review the management of treatment-resistant... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Current guidelines for treatment-resistant depression in adolescents remain inadequate. This study aimed to systematically review the management of treatment-resistant depression in adolescent patients.
METHODS
We conducted an electronic database search of PUBMED, EMBASE, Cochrane, Web of Science and PsycINFO for studies with adolescent treatment-resistant depression published up to January 2014. Treatment-resistant depression was defined as failure to respond to at least one course of psychological or pharmacological treatment for depression with an adequate dosage, duration, and appropriate compliance during the current illness episode. The Cochrane risk-of-bias method was used to assess the quality of randomized controlled trials. A meta-analysis of all active treatments was conducted.
RESULTS
Eight studies with 411 depressed adolescents that fit predetermined criteria investigated pharmacological treatments and psychotherapies. Six were open-label studies, and two were randomized controlled trials. The overall response rate for all active treatments investigated was 46% (95% CI 33 to 59; N = 411) with a moderately high degree of heterogeneity (I2 = 76.1%, 95% CI = 47%-86%). When only the two randomized trials were included, the overall response rate of active treatment was 53% (95% CI = 38-67; N = 347). In these randomized trials, SSRI therapy plus CBT was significantly more effective than SSRI therapy alone, while amitriptyline was not more effective than placebo.
CONCLUSIONS
Approximately half of the adolescents who presented with treatment-refractory depression responded to active treatment, which suggests that practitioners should remain persistent in managing these challenging cases. The combination of antidepressant medication and psychotherapy should be recommended for adolescents who present with treatment-resistant depression.
Topics: Adolescent; Antidepressive Agents; Depressive Disorder, Treatment-Resistant; Female; Humans; Male; Psychotherapy; Randomized Controlled Trials as Topic; Treatment Outcome
PubMed: 25433401
DOI: 10.1186/s12888-014-0340-6 -
Journal of Thoracic Disease Oct 2016There have been several published reports on the use of orally administered, specific centrally acting medicines for the treatment of idiopathic cough; however, there is... (Review)
Review
BACKGROUND
There have been several published reports on the use of orally administered, specific centrally acting medicines for the treatment of idiopathic cough; however, there is no extant systematic review of randomized controlled trials (RCTs) that evaluated their efficacy and safety for the treatment of idiopathic cough in human beings.
METHODS
We conducted a series of definitive systematic reviews and meta-analyses of RCTs. Claims data from the MEDLINE, EMBASE, LILACS, CBM, CNKI, VIP, Wan Fang, and Cochrane Library databases were used. We also reviewed articles and reference lists of relevant articles pertaining to human subjects published prior to March 26, 2016. No language restrictions were imposed. Two authors independently reviewed the titles and abstracts of the retrieved studies, which were matched using Review Manager 5.3 software. Disagreements were resolved by consensus. The outcome data were the number of subjects whose symptoms declined, measured by cough or Leicester Cough Questionnaire (LCQ) score. Random effect meta-analyses were used to pool the findings. Publication bias was assessed using funnel plots.
RESULTS
Three RCTs, regarding the medicines baclofen, amitriptyline, and gabapentin, were conducted involving 92 persons in total. Our reviews confirmed that baclofen, amitriptyline, and gabapentin show promise in the treatment of cough for select cases of refractory chronic cough. After-treatment relief of cough symptoms was significant (risk ratio =2.41; 95% CI: 1.15-5.04, n=84). Each of the medicines was well tolerated with minimal side effects. Methodological biases in the design and execution of cluster randomized trials might contribute to any selection bias in this review.
CONCLUSIONS
Baclofen, amitriptyline, and gabapentin may be effective 'non-specific' antitussives in clinical settings, although none of them are used in medical assessments or routinely included in the anatomic diagnostic protocol.
PubMed: 27867572
DOI: 10.21037/jtd.2016.10.51 -
The Cochrane Database of Systematic... May 2023Harmful alcohol use is defined as unhealthy alcohol use that results in adverse physical, psychological, social, or societal consequences and is among the leading risk... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Harmful alcohol use is defined as unhealthy alcohol use that results in adverse physical, psychological, social, or societal consequences and is among the leading risk factors for disease, disability and premature mortality globally. The burden of harmful alcohol use is increasing in low- and middle-income countries (LMICs) and there remains a large unmet need for indicated prevention and treatment interventions to reduce harmful alcohol use in these settings. Evidence regarding which interventions are effective and feasible for addressing harmful and other patterns of unhealthy alcohol use in LMICs is limited, which contributes to this gap in services.
OBJECTIVES
To assess the efficacy and safety of psychosocial and pharmacologic treatment and indicated prevention interventions compared with control conditions (wait list, placebo, no treatment, standard care, or active control condition) aimed at reducing harmful alcohol use in LMICs.
SEARCH METHODS
We searched for randomized controlled trials (RCTs) indexed in the Cochrane Drugs and Alcohol Group (CDAG) Specialized Register, the Cochrane Clinical Register of Controlled Trials (CENTRAL) in the Cochrane Library, PubMed, Embase, PsycINFO, CINAHL, and the Latin American and Caribbean Health Sciences Literature (LILACS) through 12 December 2021. We searched clinicaltrials.gov, the World Health Organization International Clinical Trials Registry Platform, Web of Science, and Opengrey database to identify unpublished or ongoing studies. We searched the reference lists of included studies and relevant review articles for eligible studies.
SELECTION CRITERIA
All RCTs comparing an indicated prevention or treatment intervention (pharmacologic or psychosocial) versus a control condition for people with harmful alcohol use in LMICs were included.
DATA COLLECTION AND ANALYSIS
We used standard methodological procedures expected by Cochrane.
MAIN RESULTS
We included 66 RCTs with 17,626 participants. Sixty-two of these trials contributed to the meta-analysis. Sixty-three studies were conducted in middle-income countries (MICs), and the remaining three studies were conducted in low-income countries (LICs). Twenty-five trials exclusively enrolled participants with alcohol use disorder. The remaining 51 trials enrolled participants with harmful alcohol use, some of which included both cases of alcohol use disorder and people reporting hazardous alcohol use patterns that did not meet criteria for disorder. Fifty-two RCTs assessed the efficacy of psychosocial interventions; 27 were brief interventions primarily based on motivational interviewing and were compared to brief advice, information, or assessment only. We are uncertain whether a reduction in harmful alcohol use is attributable to brief interventions given the high levels of heterogeneity among included studies (Studies reporting continuous outcomes: Tau² = 0.15, Q =139.64, df =16, P<.001, I² = 89%, 3913 participants, 17 trials, very low certainty; Studies reporting dichotomous outcomes: Tau²=0.18, Q=58.26, df=3, P<.001, I² =95%, 1349 participants, 4 trials, very low certainty). The other types of psychosocial interventions included a range of therapeutic approaches such as behavioral risk reduction, cognitive-behavioral therapy, contingency management, rational emotive therapy, and relapse prevention. These interventions were most commonly compared to usual care involving varying combinations of psychoeducation, counseling, and pharmacotherapy. We are uncertain whether a reduction in harmful alcohol use is attributable to psychosocial treatments due to high levels of heterogeneity among included studies (Heterogeneity: Tau² = 1.15; Q = 444.32, df = 11, P<.001; I²=98%, 2106 participants, 12 trials, very low certainty). Eight trials compared combined pharmacologic and psychosocial interventions with placebo, psychosocial intervention alone, or another pharmacologic treatment. The active pharmacologic study conditions included disulfiram, naltrexone, ondansetron, or topiramate. The psychosocial components of these interventions included counseling, encouragement to attend Alcoholics Anonymous, motivational interviewing, brief cognitive-behavioral therapy, or other psychotherapy (not specified). Analysis of studies comparing a combined pharmacologic and psychosocial intervention to psychosocial intervention alone found that the combined approach may be associated with a greater reduction in harmful alcohol use (standardized mean difference (standardized mean difference (SMD))=-0.43, 95% confidence interval (CI): -0.61 to -0.24; 475 participants; 4 trials; low certainty). Four trials compared pharmacologic intervention alone with placebo and three with another pharmacotherapy. Drugs assessed were: acamprosate, amitriptyline, baclofen disulfiram, gabapentin, mirtazapine, and naltrexone. None of these trials evaluated the primary clinical outcome of interest, harmful alcohol use. Thirty-one trials reported rates of retention in the intervention. Meta-analyses revealed that rates of retention between study conditions did not differ in any of the comparisons (pharmacologic risk ratio (RR) = 1.13, 95% CI: 0.89 to 1.44, 247 participants, 3 trials, low certainty; pharmacologic in addition to psychosocial intervention: RR = 1.15, 95% CI: 0.95 to 1.40, 363 participants, 3 trials, moderate certainty). Due to high levels of heterogeneity, we did not calculate pooled estimates comparing retention in brief (Heterogeneity: Tau² = 0.00; Q = 172.59, df = 11, P<.001; I = 94%; 5380 participants; 12 trials, very low certainty) or other psychosocial interventions (Heterogeneity: Tau² = 0.01; Q = 34.07, df = 8, P<.001; I = 77%; 1664 participants; 9 trials, very low certainty). Two pharmacologic trials and three combined pharmacologic and psychosocial trials reported on side effects. These studies found more side effects attributable to amitriptyline relative to mirtazapine, naltrexone and topiramate relative to placebo, yet no differences in side effects between placebo and either acamprosate or ondansetron. Across all intervention types there was substantial risk of bias. Primary threats to validity included lack of blinding and differential/high rates of attrition.
AUTHORS' CONCLUSIONS
In LMICs there is low-certainty evidence supporting the efficacy of combined psychosocial and pharmacologic interventions on reducing harmful alcohol use relative to psychosocial interventions alone. There is insufficient evidence to determine the efficacy of pharmacologic or psychosocial interventions on reducing harmful alcohol use largely due to the substantial heterogeneity in outcomes, comparisons, and interventions that precluded pooling of these data in meta-analyses. The majority of studies are brief interventions, primarily among men, and using measures that have not been validated in the target population. Confidence in these results is reduced by the risk of bias and significant heterogeneity among studies as well as the heterogeneity of results on different outcome measures within studies. More evidence on the efficacy of pharmacologic interventions, specific types of psychosocial interventions are needed to increase the certainty of these results.
Topics: Humans; Male; Acamprosate; Alcoholism; Amitriptyline; Developing Countries; Disulfiram; Mirtazapine; Naltrexone; Ondansetron; Topiramate
PubMed: 37158538
DOI: 10.1002/14651858.CD013350.pub2 -
Clinical Therapeutics Apr 2017A network meta-analysis (NMA) was performed, aiming to assess the relative efficacy and tolerability of the capsaicin 179-mg (8% weight for weight) cutaneous patch... (Meta-Analysis)
Meta-Analysis Review
Capsaicin 8% Patch Versus Oral Neuropathic Pain Medications for the Treatment of Painful Diabetic Peripheral Neuropathy: A Systematic Literature Review and Network Meta-analysis.
PURPOSE
A network meta-analysis (NMA) was performed, aiming to assess the relative efficacy and tolerability of the capsaicin 179-mg (8% weight for weight) cutaneous patch (capsaicin 8% patch) compared with oral, centrally acting agents (ie, pregabalin, gabapentin, duloxetine, amitriptyline) in patients with painful diabetic peripheral neuropathy (PDPN).
METHODS
A systematic search of EMBASE/MEDLINE, Cochrane Library, and the National Health Service Centre for Reviews and Dissemination Database of Abstracts of Reviews of Effects was conducted to identify all randomized controlled trials. Data from eligible studies according to predefined inclusion and exclusion criteria were extracted, and analyses were based on aggregate-level data. Efficacy outcomes were the proportions of patients with ≥30% and ≥50% reductions in pain, and tolerability outcomes were somnolence, dizziness, nausea, diarrhea, constipation, headache, fatigue, insomnia, and rate of discontinuation due to adverse events (AEs). Data were analyzed by using a Bayesian NMA. Fixed and random effects models were estimated. Relative treatment effect was presented as odds ratios (ORs) with 95% CIs. Sources of heterogeneity were assessed.
FINDINGS
The NMA included 25 randomized controlled trials. For ≥30% pain reduction, the capsaicin 8% patch was significantly more effective than placebo (OR, 2.28 [95% CI, 1.19-4.03]), exhibited a numerical advantage compared with pregabalin (OR, 1.83 [95% CI, 0.91-3.34]) and gabapentin (OR, 1.66 [95% CI, 0.74-3.23]), and had similar efficacy compared with duloxetine (OR, 0.99 [95% CI, 0.5-1.79]). The evidence available was not sufficient to assess the relative efficacy of amitriptyline. In the NMA for tolerability, the capsaicin 8% patch was only included for headache because the incidence was 0% for the other outcomes. Oral, centrally acting agents had a significantly elevated risk compared with placebo for somnolence (pregabalin, gabapentin, duloxetine, and amitriptyline), dizziness (pregabalin, gabapentin, duloxetine, and amitriptyline), nausea (duloxetine), diarrhea (duloxetine), fatigue (duloxetine), and discontinuation because of AEs (pregabalin, gabapentin, and duloxetine). Compared with pregabalin and gabapentin, duloxetine had a significantly lower risk of dizziness but a significantly higher risk of nausea.
IMPLICATIONS
This NMA suggests that the efficacy observed with the capsaicin 8% patch is similar to that observed with oral agents (ie, pregabalin, duloxetine, gabapentin) in patients with PDPN. The oral agents were associated with a significantly elevated risk of somnolence, dizziness, fatigue, and discontinuation because of AEs compared with placebo. The capsaicin 8% patch was as effective as oral centrally acting agents in these patients with PDPN but offers systemic tolerability benefits.
Topics: Administration, Oral; Analgesics; Capsaicin; Diabetic Neuropathies; Humans; Neuralgia; Transdermal Patch
PubMed: 28365034
DOI: 10.1016/j.clinthera.2017.02.010 -
The Journal of Headache and Pain Dec 2023Chronic migraine can be a profoundly disabling disorder that may be treated with preventive medications. However, uncertainty remains as to which preventive medication... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Chronic migraine can be a profoundly disabling disorder that may be treated with preventive medications. However, uncertainty remains as to which preventive medication is the most effective. We present a network meta-analysis to determine the effectiveness and rank of preventive drugs for chronic migraine in adults.
METHODS
We identified, reviewed, and extracted data from randomised controlled trials (RCTs) of preventive drugs for chronic migraine with at least 200 participants. Data were analysed using network meta-analysis.
FINDINGS
We included 12 RCTs of six medications (Eptinezumab, Erenumab, Fremanezumab, Galcanezumab, Onabotulinumtoxin A, and Topiramate) compared to placebo or each other. All drugs effectively reduced monthly headache and migraine days compared with placebo. The most effective drug for monthly headache days was Eptinezumab 300mg, with a mean difference of -2.46 days, 95% Credible Interval (CrI): -3.23 to -1.69. On the Surface Under the Cumulative Ranking Area (SUCRA) analysis, the probability that Eptinezumab 300mg was ranked highest was 0.82. For monthly migraine days, the most effective medication was Fremanezumab-monthly, with a mean difference: -2.77 days, 95% CrI: -3.36 to -2.17, and 0.98 probability of being ranked the highest. All included drugs, except Topiramate, improved headache-related quality of life. No eligible studies were identified for the other common preventive oral medications such as Amitriptyline, Candesartan, and Propranolol. The main reasons were that the studies did not define chronic migraine, were undertaken before the definition of chronic migraine, or were too small.
INTERPRETATION
All six medications were more effective than the placebo on monthly headache and migraine days. The absolute differences in the number of headache/migraine days are, at best, modest. No evidence was found to determine the relative effectiveness of the six included drugs with other oral preventive medications.
REGISTRATION
PROSPERO (number CRD42021265990).
Topics: Adult; Humans; Topiramate; Network Meta-Analysis; Migraine Disorders; Treatment Outcome; Headache; Double-Blind Method
PubMed: 38057728
DOI: 10.1186/s10194-023-01696-w -
Reumatologia Clinica 2016Efforts have been made to standardise evidence-based practice, but clinical practice guidelines do not always follow strict development methods. The objective of this... (Review)
Review
OBJECTIVES
Efforts have been made to standardise evidence-based practice, but clinical practice guidelines do not always follow strict development methods. The objective of this review is to identify the current guidelines, analyse the variability of its recommendations and make a synthesis for clinical practice.
MATERIAL AND METHODS
A systematic review of clinical practice guidelines was made in electronic databases and guidelines databases; using "fibromyalgia" AND ["guideline" OR "Clinical Practice guideline"] as terms, from January for 2003 to July of 2013. Guidelines were selected according to the following criteria: a) aimed to fibromyalgia treatment in adults; b) based on scientific evidence, systematically searched; c) evidence levels and strength of recommendation included; d) written in English or Spanish.
RESULTS
From 249 initial results, six guides fulfilled the inclusion criteria. Clinical practice guidelines analysed in this review show great variability both in the presence and level of evidence and in the strength of recommendation of many treatments. Physical exercise and cognitive-behavioural therapy are first-line treatments, showing high level of evidence. Amitriptyline, used for short periods of time for pain control, is the pharmacologic treatment with the most solid evidence. The multimodal approach reported better results than the isolated application of any treatment.
CONCLUSIONS
Final recommendations in this review identify optimal treatments, facilitating the translation of evidence into practice and enabling more efficient and effective quality care.
Topics: Combined Modality Therapy; Evidence-Based Medicine; Fibromyalgia; Humans; Practice Guidelines as Topic
PubMed: 26481494
DOI: 10.1016/j.reuma.2015.06.001 -
Human Psychopharmacology Nov 2021Depressive symptoms occur in several psychiatric disorders, often in the absence of a formal diagnosis of depression. We aimed to evaluate the efficacy and the... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Depressive symptoms occur in several psychiatric disorders, often in the absence of a formal diagnosis of depression. We aimed to evaluate the efficacy and the tolerability of amisulpride, both alone and as augmentation therapy, in the treatment of depressive symptoms in individuals with any major psychiatric disorder.
METHODS
We searched PubMed, Embase, PsycINFO, GreyLit, OpenGrey and ProQuest up to March 2020 for randomised controlled trials focussing on the treatment of an acute depressive episode in any major psychiatric disorder. A random-effect meta-analysis was performed to synthesize the findings on depressive symptoms (primary outcome), response rate and tolerability.
RESULTS
We retrieved 11 studies including 2065 patients with a diagnosis of dysthymia (eight studies), major depression (one study) or schizophrenia (two studies). Amisulpride 50 mg/day was associated with a larger reduction of depressive symptoms compared to placebo (standardised mean difference [SMD] = -0.70, CI 95% -0.92, -0.49; I = 0.0%), and was found to be comparable to selective serotonin reuptake inhibitors (SSRIs; SMD = -0.08, CI 95% -0.23, 0.06, I = 0.0%), amineptine, imipramine and amitriptyline in the treatment of dysthymia (three studies, not pooled). In individuals with schizophrenia, amisulpride administered at higher doses (>400 mg/day) was comparable to olanzapine and risperidone (two studies, not pooled). In terms of tolerability, amisulpride was superior to placebo for dysthymia (odds ratio [OR] = 3.94, CI 95% 1.07, 14.48; I = 0.0) and comparable with SSRIs (OR = 0.94, CI 95% 0.55, 1.62; I = 0.0%).
CONCLUSION
Treatment with amisulpride could be a valid choice for selected individuals with dysthymia or depressive symptoms in the context of schizophrenia. More studies on the efficacy and tolerability of amisulpride are needed to draw firm conclusions on its potential benefits in other psychiatric disorders.
Topics: Amisulpride; Antipsychotic Agents; Depression; Depressive Disorder, Major; Dysthymic Disorder; Humans
PubMed: 34727399
DOI: 10.1002/hup.2801 -
Turkish Journal of Anaesthesiology and... Aug 2022Intraoperative shivering is quite common after regional anaesthesia, which not only increases the total body oxygen requirement but also causes discomfort to the...
Pharmacological Interventions for the Treatment and Control of Shivering in Adult Patients Undergoing Elective Surgery Under Regional Anaesthesia: A Systematic Review and Meta-Analysis.
Intraoperative shivering is quite common after regional anaesthesia, which not only increases the total body oxygen requirement but also causes discomfort to the patients. The aim of this systematic review is to determine the effectiveness of pharmacological agents administered intra-operatively for treating shivering in adult patients who are undergoing elective surgery under regional (i.e., central neuraxial) anaesthesia so that an optimal choice of an agent can be recommended for clinical application. A literature search was carried out using PubMed, Cochrane Library, CINAHL databases, and hand searches to identify relevant studies. After literature screening and information extraction, a systematic review was performed. Meta-analysis was performed for the primary outcome. The primary outcome was to evaluate the effectiveness of pharmacological agents used for the treatment and control of intraoperative shivering and the time taken to control shivering. The secondary outcome includes recurrence of shivering after pharmacological intervention and identification of common adverse effects related to them. In total, 10 studies (791 patients) were included. Common interventions were opioids, central α2 receptor agonist, and few other medications like magnesium sulfate, ondansetron, nefopam, and amitriptyline. Tramadol and dexmedetomidine were the most frequently documented drugs compared with other drugs to resolve shivering. The most effective drug with approximately 100% response rate was dexmedetomidine with the dose of 0.5 μg kg-1 intravenously given just after the appearance of shivering. Studies showed that tramadol is also an effective drug used to control shivering in most patients, and its effect is comparable with the pethidine.
PubMed: 35979970
DOI: 10.5152/TJAR.2021.20008 -
The Cochrane Database of Systematic... Jan 2016Enuresis (bedwetting) affects up to 20% of five year-olds and 2% of adults. Although spontaneous remission often occurs, the social, emotional and psychological costs... (Review)
Review
BACKGROUND
Enuresis (bedwetting) affects up to 20% of five year-olds and 2% of adults. Although spontaneous remission often occurs, the social, emotional and psychological costs can be great. Tricyclics have been used to treat enuresis since the 1960s.
OBJECTIVES
To assess the effects of tricyclic and related drugs compared with other interventions for treating children with enuresis.
SEARCH METHODS
We searched the Cochrane Incontinence Group Specialised Trials Register (containing trials identified from the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, MEDLINE in process, ClinicalTrials.gov, WHO ICTRP and handsearching of journals and conference proceedings), on 30 November 2015, and reference lists of relevant articles.
SELECTION CRITERIA
We included all randomised and quasi-randomised trials comparing a tricyclic or related drug with another intervention for treating enuresis. We also included combination therapies that included tricyclics. We excluded trials for treating daytime wetting.
DATA COLLECTION AND ANALYSIS
Two review authors independently assessed the quality of the eligible trials, and extracted data. We settled differences by discussion with a third review author.
MAIN RESULTS
Sixty-four trials met the inclusion criteria, involving 4071 children. The quality of many trials was poor, with comparisons addressed by single studies. Minor adverse effects were common, and reported in 30 trials. These included dizziness, headache, mood changes, gastrointestinal discomforts and neutropenia. More serious side-effects can occur but were not reported. Seven trials reported no adverse effects.Tricyclics are more effective than placebo, particularly for short-term outcomes. Compared to placebo, imipramine resulted in one fewer wet nights per week (mean difference (MD) -0.95, 95% confidence interval (CI) -1.40 to -0.50; 4 trials, 347 children), with fewer failing to achieve 14 consecutive dry nights (78% versus 95% for placebo, RR 0.74, 95% CI 0.61 to 0.90; 12 trials, 831 children). Amitriptyline and desipramine were more effective than placebo, but nortriptyline and mianserin showed no difference. Most tricyclics did not have a sustained effect after ceasing treatment, with 96% wetting at follow-up for imipramine versus 97% for placebo.Imipramine combined with oxybutynin is also more effective than placebo, with 33% failing to achieve 14 consecutive dry nights at the end of treatment versus 78% for placebo (RR 0.43, 95% CI 0.23 to 0.78; 1 trial, 47 children) and 45% wetting at follow-up versus 79% for placebo (RR 0.58, 95% CI 0.34 to 0.99; 1 trial, 36 children).There was insufficient evidence to judge the effect between different doses of tricyclics, and between different tricyclics. Treatment outcomes between tricyclic and desmopressin were similar, but were mixed when tricyclic was compared with an anticholinergic. However, when imipramine was compared with desmopressin plus oxybutynin (1 trial, 45 children), the combination therapy was more effective, with one fewer wet nights per week (MD 1.07, 95% CI 0.06 to 2.08) and 36% failing to achieve 14 consecutive dry nights versus 87% for imipramine (RR 2.39, 95% CI 1.35 to 4.25). Tricyclics were also more effective or showed no difference in response when compared to other drugs which are no longer used for enuresis.Tricyclics were less effective than alarms. Although there was no difference in the number of wet nights, 67% failed to achieve 14 consecutive dry nights for imipramine versus only 17% for alarms (RR 4.00, 95% CI 1.06 to 15.08; 1 trial, 24 children). Alarm therapy also had a more sustained effect after ceasing treatment with 100% on imipramine versus 58% on alarms wetting at follow-up (RR 1.67, 95% CI 1.03 to 2.69; 1 trial, 24 children).Imipramine was more effective than simple behavioural therapies during treatment, with one fewer wet nights per week compared with star chart plus placebo (MD -0.80, 95% CI -1.33 to -0.27; 1 trial, 250 children). At follow-up 40% were wet with imipramine versus 80% with fluids and avoiding punishment (RR 0.50, 95% CI 0.28 to 0.89; 1 trial, 40 children). However, imipramine was less effective than complex behavioural therapies, with 61% failing to achieve 14 consecutive dry nights for imipramine versus 33% for the three-step programme (RR 1.83, 95% CI 1.08 to 3.12; 1 trial, 72 children) and 16% for the three-step programme combined with motivational therapy and computer-led education (RR 3.91, 95% CI 2.30 to 6.66; 1 trial, 132 children) at the end of treatment, with similar results at follow-up.Tricyclics were more effective than restricted diet, with 99% failing to achieve 14 consecutive dry nights versus 84% for imipramine (RR 0.84, 95% CI 0.75 to 0.93; 1 trial, 147 children).There was insufficient evidence to judge the effect of tricyclics compared to the other miscellaneous interventions studied.At the end of treatment there were about two fewer wet nights for imipramine plus oxybutynin compared with imipramine monotherapy (MD -2.10, 95% CI -2.99 to -1.21; 1 trial, 63 children) and 48% on imipramine plus oxybutynin failed to achieve 14 consecutive dry nights compared with 74% on imipramine monotherapy (RR 0.68, 95% CI 0.50 to 0.92; 2 trials, 101 children). At follow-up, 45% on imipramine plus oxybutynin were wetting versus 83% on imipramine monotherapy (RR 0.55, 95% CI 0.32 to 0.92; 1 trial, 36 children).When imipramine combined with desmopressin was compared with imipramine monotherapy, there was no difference in outcomes. However, when imipramine plus desmopressin was compared with desmopressin monotherapy, the combination was more effective, with 15% not achieving 14 consecutive dry nights at the end of treatment for imipramine plus desmopressin versus 40% for desmopressin monotherapy (RR 0.38, 95% CI 0.17 to 0.83; 1 trial, 86 children). Tricyclics combined with alarm therapy were not more effective than alarm monotherapy, alarm combined with desmopressin or alarm combined with nortriptyline. The addition of a tricyclic to other behavioural therapies did not alter treatment response.
AUTHORS' CONCLUSIONS
There was evidence that tricyclics are effective at reducing the number of wet nights during treatment, but do not have a sustained effect after treatment stops, with most children relapsing. In contrast, there was evidence that alarm therapy has better short- and long-term outcomes. There was some evidence that tricyclics combined with anticholinergics may be more effective that tricyclic monotherapy.
Topics: Antidepressive Agents, Tricyclic; Child; Child, Preschool; Clinical Alarms; Enuresis; Humans; Randomized Controlled Trials as Topic
PubMed: 26789925
DOI: 10.1002/14651858.CD002117.pub2