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Journal of Psychiatric Research Apr 2021It remains unclear whether the dopaminergic and noradrenergic systems may be implied in suicide attempt risk. In addition, although the serotonergic system has been... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
It remains unclear whether the dopaminergic and noradrenergic systems may be implied in suicide attempt risk. In addition, although the serotonergic system has been extensively studied, no formal meta-analysis has been performed to examine its association with suicide attempt.
METHODS
Using PRISMA methodology, we performed a systematic literature review and random-effects meta-analyses of the differences in cerebrospinal fluid (CSF) levels of 5-HIAA, HVA and MHPG between suicide attempters and individuals who never attempted suicide.
RESULTS
We identified 30 studies including 937 suicide attempters and 1128 non-attempters; 29 of them measured CSF levels of 5-HIAA, 22 measured CSF levels of HVA and 14 measured CSF levels of MHPG. CSF levels of 5-HIAA and HVA were significantly lower in suicide attempters than in non-attempters [SMD = -0.43 (95% CI: -0.71 to -0.15; p < 0.01) and SMD = -0.45 (95% CI: -0.72 to -0.19; p < 0.01), respectively]. We did not find a significant association between CSF MHPG levels and suicide attempt.
LIMITATIONS
Our analyses relied on a limited number of studies of good quality and most studies included small sample sizes.
CONCLUSION
Both serotonin and dopamine systems may play a role in suicide attempt risk. Our findings suggest that a silo approach to biomarkers should be phased out in favor of the study of multiple systems in parallel and in the same populations to progress in the identification of the biological components independently associated with suicide risk, with the goal of identifying new treatment targets and improving suicide risk prediction.
Topics: Dopamine; Homovanillic Acid; Humans; Hydroxyindoleacetic Acid; Serotonin; Suicide, Attempted; Violence
PubMed: 33618064
DOI: 10.1016/j.jpsychires.2021.01.045 -
The Cochrane Database of Systematic... Feb 2022Attention deficit hyperactivity disorder (ADHD) is a psychiatric diagnosis increasingly used in adults. The recommended first-line pharmacological treatment is central... (Review)
Review
BACKGROUND
Attention deficit hyperactivity disorder (ADHD) is a psychiatric diagnosis increasingly used in adults. The recommended first-line pharmacological treatment is central nervous system (CNS) stimulants, such as methylphenidate, but uncertainty remains about its benefits and harms.
OBJECTIVES
To assess the beneficial and harmful effects of extended-release formulations of methylphenidate in adults diagnosed with ADHD.
SEARCH METHODS
We searched CENTRAL, MEDLINE, Embase, nine other databases and four clinical trial registries up to February 2021. We searched 12 drug regulatory databases for clinical trial data up to 13 May 2020. In addition, we cross-referenced all available trial identifiers, handsearched reference lists, searched pharmaceutical company databases, and contacted trial authors.
SELECTION CRITERIA
Randomised, double-blind, parallel-group trials comparing extended-release methylphenidate formulations at any dose versus placebo and other ADHD medications in adults diagnosed with ADHD.
DATA COLLECTION AND ANALYSIS
Two review authors independently extracted data. We assessed dichotomous outcomes as risk ratios (RRs), and rating scales and continuous outcomes as mean differences (MDs) or standardised mean differences (SMDs). We used the Cochrane risk of bias tool to assess risks of bias, and GRADE to assess the certainty of the evidence. We meta-analysed the data using a random-effects model. We assessed three design characteristics that may impair the trial results' 'generalisability'; exclusion of participants with psychiatric comorbidity; responder selection based on previous experience with CNS stimulants; and risk of withdrawal effects. Our prespecified primary outcomes were functional outcomes, self-rated ADHD symptoms, and serious adverse events. Our secondary outcomes included quality of life, ADHD symptoms rated by investigators and by peers such as family members, cardiovascular variables, severe psychiatric adverse events, and other adverse events.
MAIN RESULTS
We included 24 trials (5066 participants), of which 21 reported outcome data for this review. We also identified one ongoing study. We included documents from six drug regulatory agencies covering eight trials. Twenty-one trials had an outpatient setting and three were conducted in prisons. They were primarily conducted in North America and Europe. The median participant age was 36 years. Twelve trials (76% of participants) were industry-sponsored, four (14% of participants) were publicly funded with industry involvement, seven (10% of participants) were publicly funded, and one had unclear funding. The median trial duration was eight weeks. One trial was rated at overall unclear risk of bias and 20 trials were rated at overall high risk of bias, primarily due to unclear blinding of participants and investigators, attrition bias, and selective outcome reporting. All trials were impaired in at least one of the three design characteristics related to 'generalisability'; for example, they excluded participants with psychiatric comorbidity such as depression or anxiety, or included participants only with a previous positive response to methylphenidate, or similar drugs. This may limit the trials' usefulness for clinical practice, as they may overestimate the benefits and underestimate the harms. Extended-release methylphenidate versus placebo (up to 26 weeks) For the primary outcomes, we found very low-certainty evidence that methylphenidate had no effect on 'days missed at work' at 13-week follow-up (mean difference (MD) -0.15 days, 95% confidence interval (CI) -2.11 to 1.81; 1 trial, 409 participants) or serious adverse events (risk ratio (RR) 1.43, CI 95% CI 0.85 to 2.43; 14 trials, 4078 participants), whereas methylphenidate improved self-rated ADHD symptoms (small-to-moderate effect; SMD -0.37, 95% CI -0.43 to -0.30; 16 trials, 3799 participants). For secondary outcomes, we found very low-certainty evidence that methylphenidate improved self-rated quality of life (small effect; SMD -0.15, 95% CI -0.25 to -0.05; 6 trials, 1888 participants), investigator-rated ADHD symptoms (small-to-moderate effect; SMD -0.42, 95% CI -0.49 to -0.36; 18 trials, 4183 participants), ADHD symptoms rated by peers such as family members (small-to-moderate effect; SMD -0.31, 95% CI -0.48 to -0.14; 3 trials, 1005 participants), and increased the risk of experiencing any adverse event (RR 1.27, 95% CI 1.19 to 1.37; 14 trials, 4214 participants). We rated the certainty of the evidence as 'very low' for all outcomes, primarily due to high risk of bias and 'indirectness of the evidence'. One trial (419 participants) had follow-up at 52 weeks and two trials (314 participants) included active comparators, hence long-term and comparative evidence is limited.
AUTHORS' CONCLUSIONS
We found very low-certainty evidence that extended-release methylphenidate compared to placebo improved ADHD symptoms (small-to-moderate effects) measured on rating scales reported by participants, investigators, and peers such as family members. Methylphenidate had no effect on 'days missed at work' or serious adverse events, the effect on quality of life was small, and it increased the risk of several adverse effects. We rated the certainty of the evidence as 'very low' for all outcomes, due to high risk of bias, short trial durations, and limitations to the generalisability of the results. The benefits and harms of extended-release methylphenidate therefore remain uncertain.
Topics: Adult; Anxiety Disorders; Attention Deficit Disorder with Hyperactivity; Central Nervous System Stimulants; Humans; Methylphenidate; Quality of Life; Randomized Controlled Trials as Topic
PubMed: 35201607
DOI: 10.1002/14651858.CD012857.pub2 -
The Cochrane Database of Systematic... Jan 2021Attention deficit hyperactivity disorder (ADHD) is characterized by symptoms of inattention or impulsivity or both, and hyperactivity, which affect children,... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Attention deficit hyperactivity disorder (ADHD) is characterized by symptoms of inattention or impulsivity or both, and hyperactivity, which affect children, adolescents, and adults. In some countries, methylphenidate is the first option to treat adults with moderate or severe ADHD. However, evidence on the efficacy and adverse events of immediate-release (IR) methylphenidate in the treatment of ADHD in adults is limited and controversial.
OBJECTIVES
To evaluate the efficacy and harms (adverse events) of IR methylphenidate for treating ADHD in adults.
SEARCH METHODS
In January 2020, we searched CENTRAL, MEDLINE, Embase, eight additional databases and three trial registers. We also searched internal reports on the European Medicines Agency and the US Food and Drug Administration websites. We checked citations of included trials to identify additional trials not captured by the electronic searches.
SELECTION CRITERIA
Randomized controlled trials (RCTs) comparing IR methylphenidate, at any dose, with placebo or other pharmacological interventions (including extended-release formulations of methylphenidate) for ADHD in adults. Primary outcomes comprised changes in the symptoms of ADHD (efficacy) and harms. Secondary outcomes included changes in the clinical impression of severity and improvement, level of functioning, depression, anxiety and quality of life. Outcomes could have been rated by investigators or participants.
DATA COLLECTION AND ANALYSIS
Two review authors extracted data independently on the characteristics of the trials, participants, interventions; outcomes and financial conflict of interests. We resolved disagreements by discussion or consulting a third review author. We obtained additional, unpublished information from the authors of one included trial that had reported efficacy data in a graph. We calculated mean differences (MDs) or standardized MDs (SMDs) with 95% confidence intervals (CIs) for continuous data reported on the same or different scales, respectively. We summarized dichotomous variables as risk ratios (RRs) with 95% CI.
MAIN RESULTS
We included 10 trials published between 2001 and 2016 involving 497 adults with ADHD. Three trials were conducted in Europe and one in Argentina; the remaining trials did not report their location. The RCTs compared IR methylphenidate with placebo, an osmotic-release oral system (OROS) of methylphenidate (an extended-release formulation), an extended-release formulation of bupropion, lithium, and Pycnogenol® (maritime pine bark extract). Participants comprised outpatients, inpatients in addiction treatment, and adults willing to attend an intensive outpatient program for cocaine dependence. The duration of the follow-up ranged from 6 to 18 weeks. IR methylphenidate versus placebo We found very low-certainty evidence that, compared with placebo, IR methylphenidate may reduce symptoms of ADHD when measured with investigator-rated scales (MD -20.70, 95% CI -23.97 to -17.43; 1 trial, 146 participants; end scores; Adult ADHD Investigator Symptom Report Scale (AISRS), scored from 0 to 54), but the evidence is uncertain. The effect of IR methylphenidate on ADHD symptoms when measured with participant-rated scales was moderate, but the certainty of the evidence is very low (SMD -0.59, 95% CI -1.25 to 0.06; I = 69%; 2 trials, 138 participants; end scores). There is very low-certainty evidence that, compared with placebo, IR methylphenidate may reduce the clinical impression of the severity of ADHD symptoms (MD -0.57, 95% CI -0.85 to -0.28; 2 trials, 139 participants; I = 0%; change and end scores; Clinical Global Impression (CGI)-Severity scale (scored from 1 (very much improved) to 7 (very much worse))). There is low-certainty evidence that, compared with placebo, IR methylphenidate may slightly impact the clinical impression of an improvement in symptoms of ADHD (MD -0.94, 95% CI -1.37 to -0.51; 1 trial, 49 participants; end scores; CGI-Improvement scale (scored from 1 (very much improved) to 7 (very much worse))). There is no clear evidence of an effect on anxiety (MD -0.20, 95% CI -4.84 to 4.44; 1 trial, 19 participants; change scores; Hamilton Anxiety Scale (HAM-A; scored from 0 to 56); very low-certainty evidence) or depression (MD 2.80, 95% CI -0.09 to 5.69; 1 trial, 19 participants; change scores; Hamilton Depression Scale (HAM-D; scored from 0 to 52); very low-certainty evidence) in analyses comparing IR methylphenidate with placebo. IR methylphenidate versus lithium Compared with lithium, it is uncertain whether IR methylphenidate increases or decreases symptoms of ADHD (MD 0.60, 95% CI -3.11 to 4.31; 1 trial, 46 participants; end scores; Conners' Adult ADHD Rating Scale (scored from 0 to 198); very low-certainty evidence); anxiety (MD -0.80, 95% CI -4.49 to 2.89; 1 trial, 46 participants; end scores; HAM-A; very low-certainty evidence); or depression (MD -1.20, 95% CI -3.81 to 1.41, 1 trial, 46 participants; end scores; HAM-D scale; very low-certainty evidence). None of the included trials assessed participant-rated changes in symptoms of ADHD, or clinical impression of severity or improvement in participants treated with IR methylphenidate compared with lithium. Adverse events were poorly assessed and reported. We rated all trials at high risk of bias due to selective outcome reporting of harms and masking of outcome assessors (failure to blind outcome assessor to measure adverse events). Overall, four trials with 203 participants who received IR methylphenidate and 141 participants who received placebo described the occurrence of harms. The use of IR methylphenidate in these trials increased the risk of gastrointestinal complications (RR 1.96, 95% CI 1.13 to 2.95) and loss of appetite (RR 1.77, 95% CI 1.06 to 2.96). Cardiovascular adverse events were reported inconsistently, preventing a comprehensive analysis. One trial comparing IR methylphenidate to lithium reported five and nine adverse events, respectively. We considered four trials to have notable concerns of vested interests influencing the evidence, and authors from two trials omitted information related to the sources of funding and conflicts of interest.
AUTHORS' CONCLUSIONS
We found no certain evidence that IR methylphenidate compared with placebo or lithium can reduce symptoms of ADHD in adults (low- and very low-certainty evidence). Adults treated with IR methylphenidate are at increased risk of gastrointestinal and metabolic-related harms compared with placebo. Clinicians should consider whether it is appropriate to prescribe IR methylphenidate, given its limited efficacy and increased risk of harms. Future RCTs should explore the long-term efficacy and risks of IR methylphenidate, and the influence of conflicts of interest on reported effects.
Topics: Adult; Antidepressive Agents, Second-Generation; Anxiety; Attention Deficit Disorder with Hyperactivity; Bias; Bupropion; Central Nervous System Stimulants; Depression; Drug Delivery Systems; Female; Flavonoids; Humans; Lithium Compounds; Male; Methylphenidate; Middle Aged; Placebos; Plant Extracts; Randomized Controlled Trials as Topic; Young Adult
PubMed: 33460048
DOI: 10.1002/14651858.CD013011.pub2 -
The Cochrane Database of Systematic... Dec 2022Cataract surgery is the most common ambulatory incisional surgery performed in the USA. Cystoid macular edema (CME), the accumulation of fluid in the central retina due... (Review)
Review
BACKGROUND
Cataract surgery is the most common ambulatory incisional surgery performed in the USA. Cystoid macular edema (CME), the accumulation of fluid in the central retina due to leakage from dilated capillaries, is the most common cause of vision impairment following cataract surgery. Acute CME, defined as CME of less than four months' duration, often resolves spontaneously. CME that persists for four months or longer is termed chronic CME. Non-steroidal anti-inflammatory drugs (NSAIDs) have been used to treat CME. This update adds new evidence and analyses to the previously published review.
OBJECTIVES
To examine the effectiveness of NSAIDs in the treatment of CME following cataract surgery.
SEARCH METHODS
We searched the CENTRAL (2022, Issue 3); Ovid MEDLINE; Embase; PubMed; LILACS; mRCT (discontinued in 2014, last searched August 2011), ClinicalTrials.gov, and WHO ICTRP databases. We did not use any date or language restrictions in the electronic search for trials. We last searched the electronic databases on 20 March 2022. SELECTION CRITERIA: We included randomized controlled trials evaluating the effects of NSAIDs for CME following cataract surgery.
DATA COLLECTION AND ANALYSIS
Two review authors independently screened all titles and abstracts, reviewed full-text publications against eligibility criteria, independently extracted data from newly included trials and assessed risk of bias for each included trial. We contacted trial authors for clarification or to request missing information. We provided a narrative synthesis of all included trials and their results. For continuous and dichotomous outcomes, we separately performed pooled analysis and reported mean difference (MD) and risk ratio (RR) as well as the associated 95% confidence interval (CI) whenever feasible. Two review authors independently graded the overall certainty of the evidence for each outcome using the GRADE approach.
MAIN RESULTS
We included nine trials with a total of 390 participants (393 eyes). Study participants' mean age was 72.2 years (interquartile range [IQR] 68.8 to 73.6) and 72% were women (IQR 69% to 74%). Three trials included participants with acute CME, and four included participants with chronic CME; the remaining two trials enrolled both participants with acute and chronic CME or participants with unknown CME duration. We assessed trials as having unclear (33%) or high risk of bias (67%). Visual improvement of two or more lines at the end of treatment Data from one trial in participants with acute CME show no treatment effect of topical ketorolac compared to placebo (RR 2.00, 95% CI 0.46 to 8.76; 22 participants). Data from a three-arm trial in participants with acute CME demonstrate that, when compared with topical prednisolone, topical ketorolac (RR 1.33, 95% CI 0.58 to 3.07; 17 participants) or topical ketorolac and prednisolone combination therapy (RR 1.78, 95% CI 0.86 to 3.69; 17 participants) may have little or no effect on visual improvement. Results of subgroup analysis from two studies in participants with chronic CME suggest that, after treatment for 90 days or longer, NSAIDs may increase participants' likelihood of visual improvement by 1.87 fold (RR 2.87, 95% CI 1.58 to 5.22; I = 33%; 2 trials, 121 participants) relative to placebo. However, there was no evidence of treatment effects in the subgroup with two months of treatment or less (RR 0.72, 95% CI 0.30 to 1.73; P = 0.19, I = 41%; 2 trials, 34 participants). Overall, this evidence is very low certainty. A single-study estimate in patients with mixed CME indicates that topical diclofenac may increase the likelihood of visual improvement by 40% when compared to topical ketorolac (RR 1.40, 95% CI 1.02 to 1.94; 68 participants). However, the same trial reported no difference between the groups in mean final visual acuity in Snellen lines (MD 0.40, 95% CI -0.93 to 1.73). A three-arm trial in patients with mixed CME reporting visual changes in ETDRS letters in comparisons between ketorolac and diclofenac (34 participants) or bromfenac (34 participants) suggests no evidence of effects. Overall, NSAIDs may slightly improve visual acuity in participants with mixed CME but the evidence is very uncertain. Persistence of improvement of vision one month after discontinuation of treatment One trial of participants with chronic CME tested oral indomethacin (RR 0.40, 95% CI 0.10 to 1.60; 20 participants) and the other compared topical ketorolac to placebo (RR 4.00, 95% CI 0.51 to 31.1; 26 participants). While there is no evidence of treatment effects, evidence suggests substantial between-group heterogeneity (P = 0.07, I = 69.9%; very low-certainty evidence). None of the trials in patients with acute or mixed CME reported this outcome. Proportion of participants with improvement in leakage on fundus fluorescein angiography One three-arm trial in participants with acute CME shows that, when compared with topical prednisolone, there is no treatment benefit of topical ketorolac (RR 1.11, 95% CI 0.45 to 2.75; 17 participants) or topical ketorolac and topical prednisolone combination therapy (RR 1.56, 95% CI 0.72 to 3.38; 17 participants). This evidence is very low certainty. The combined estimate from two trials in participants with chronic CME indicates NSAIDs have little to no effect over placebo on improving leakage (RR 1.93, 95% CI 0.62 to 6.02; 40 participants; very low-certainty evidence). Neither of the trials in patients with mixed CME reported this outcome. Proportion of participants with improved contrast sensitivity Very low-certainty evidence from one trial in participants with acute CME shows no treatment benefit of ketorolac (RR 1.11, 95% CI 0.45 to 2.75; 17 participants) or ketorolac and prednisolone combination therapy (RR 1.78, 95% CI 0.86 to 3.69; 17 participants) compared with topical prednisolone. None of the trials in patients with chronic or mixed CME reported this outcome. Proportion of participants with improved central macular thickness on optical coherence tomography; measures of quality of life No included trial reported these outcomes. Adverse effects Most trials observed no differences in ocular adverse events, such as corneal toxicity or elevated intraocular pressure, between comparison groups.
AUTHORS' CONCLUSIONS
Evidence on effects of NSAIDs in patients with CME is very uncertain and further investigation is warranted. Our findings are limited by small sample sizes, and heterogeneity in interventions, assessments, and reporting of clinically important outcomes.
Topics: Humans; Female; Aged; Male; Macular Edema; Anti-Inflammatory Agents, Non-Steroidal; Ketorolac; Diclofenac; Quality of Life; Cataract; Prednisolone
PubMed: 36520144
DOI: 10.1002/14651858.CD004239.pub4 -
Bipolar Disorders May 2024Abnormalities in dopamine and norepinephrine signaling are implicated in cognitive impairments in bipolar disorder (BD) and attention-deficit hyperactivity disorder... (Review)
Review
Efficacy and safety of established and off-label ADHD drug therapies for cognitive impairment or attention-deficit hyperactivity disorder symptoms in bipolar disorder: A systematic review by the ISBD Targeting Cognition Task Force.
BACKGROUND
Abnormalities in dopamine and norepinephrine signaling are implicated in cognitive impairments in bipolar disorder (BD) and attention-deficit hyperactivity disorder (ADHD). This systematic review by the ISBD Targeting Cognition Task Force therefore aimed to investigate the possible benefits on cognition and/or ADHD symptoms and safety of established and off-label ADHD therapies in BD.
METHODS
We included studies of ADHD medications in BD patients, which involved cognitive and/or safety measures. We followed the procedures of the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) 2020 statement. Searches were conducted on PubMed, Embase and PsycINFO from inception until June 2023. Two authors reviewed the studies independently using the Revised Cochrane Collaboration's Risk of Bias tool for Randomized trials.
RESULTS
Seventeen studies were identified (N = 2136), investigating armodafinil (k = 4, N = 1581), methylphenidate (k = 4, N = 84), bupropion (k = 4, n = 249), clonidine (k = 1, n = 70), lisdexamphetamine (k = 1, n = 25), mixed amphetamine salts (k = 1, n = 30), or modafinil (k = 2, n = 97). Three studies investigated cognition, four ADHD symptoms, and 10 the safety. Three studies found treatment-related ADHD symptom reduction: two involved methylphenidate and one amphetamine salts. One study found a trend towards pro-cognitive effects of modafinil on some cognitive domains. No increased risk of (hypo)mania was observed. Five studies had low risk of bias, eleven a moderate risk, and one a serious risk of bias.
CONCLUSIONS
Methylphenidate or mixed amphetamine salts may improve ADHD symptoms in BD. However, there is limited evidence regarding the effectiveness on cognition. The medications produced no increased mania risk when used alongside mood stabilizers. Further robust studies are needed to assess cognition in BD patients receiving psychostimulant treatment alongside mood stabilizers.
Topics: Humans; Attention Deficit Disorder with Hyperactivity; Bipolar Disorder; Cognitive Dysfunction; Central Nervous System Stimulants; Off-Label Use; Methylphenidate
PubMed: 38433530
DOI: 10.1111/bdi.13414 -
Minerva Anestesiologica Oct 2023Shivering is a common side effect after general anesthesia. Risk factors are hypothermia, young age and postoperative pain. Severe complications of shivering are rare... (Meta-Analysis)
Meta-Analysis
INTRODUCTION
Shivering is a common side effect after general anesthesia. Risk factors are hypothermia, young age and postoperative pain. Severe complications of shivering are rare but can occur due to increased oxygen consumption. Previous systematic reviews are outdated and have summarized the evidence on the topic using only pairwise comparisons. The objective of this manuscript was a quantitative synthesis of evidence on pharmacological interventions to treat postanesthetic shivering.
EVIDENCE ACQUSITION
Systematic review and frequentist network meta-analysis using the R package netmeta. Endpoints were the risk ratio (RR) of persistent shivering at one, five and 10 minutes after treatment with saline/placebo as the comparator. Data were retrieved from Medline, Embase, Central and Web of Science up to January 2022. Eligibility criteria were: randomized, controlled, and blinded trials comparing pharmacological interventions to treat shivering after general anesthesia. Studies on shivering during or after any type of regional anesthesia were excluded as well as sedated patients after cardiac surgery.
EVIDENCE SYNTHESIS
Thirty-two trials were eligible for data synthesis, including 28 pharmacological interventions. The largest network included 1431 patients. The network geometry was two-centered with most comparisons linked to saline/placebo or pethidine. The best interventions were after one minute: doxapram 2 mg/kg, tramadol 2 mg/kg and nefopam 10 mg, after 5 minutes: tramadol 2 mg/kg, nefopam 10 mg and clonidine 150 µg and after 10 minutes: nefopam 10 mg, methylphenidate 20 mg and tramadol 1 mg/kg, all reaching statistical significance. Pethidine 25 mg and clonidine 75 µg also performed well and with statistical significance in all networks.
CONCLUSIONS
Nefopam, tramadol, pethidine and clonidine are the most effective treatments to stop postanesthetic shivering. The efficacy of doxapram is uncertain since different doses showed contradictory effects and the evidence for methylphenidate is based on a single comparison in only one network. Furthermore, both lack data on side effects. Further studies are needed to clarify the efficacy of dexmedetomidine to treat postanesthetic shivering.
Topics: Humans; Adult; Shivering; Nefopam; Clonidine; Tramadol; Network Meta-Analysis; Doxapram; Meperidine; Methylphenidate
PubMed: 37458681
DOI: 10.23736/S0375-9393.23.17410-4 -
Journal of Affective Disorders Sep 2021Globally, depression impacts nearly 300 million people, and roughly half do not achieve remission with standard first-line therapies. For such individuals, augmentation... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Globally, depression impacts nearly 300 million people, and roughly half do not achieve remission with standard first-line therapies. For such individuals, augmentation strategies are often helpful at reducing the severity of depression. While there are many potential adjunctive medication choices, psychostimulants are among the more controversial options.
OBJECTIVES
The present review sought to clarify the comparative efficacy and safety of different stimulant-like medications to treat depression.
METHODS
We conducted a systematic review and network meta-analysis of randomized, controlled trials (RCTs) using psychostimulant medications to treat adults with depression. Outcomes were pooled using rate ratios (RRs) for dichotomous outcomes (e.g., response, adverse events) and standardized mean differences (SMDs) for continuous outcomes (e.g., change in depression scores).
RESULTS
We identified 37 eligible studies (ranging from 1958 to 2016). We assessed nine psychostimulants: methylphenidate (n=14), dextroamphetamine (n=9), modafinil (n=6), lisdexamphetamine (n=3), methylamphetamine (n=3), pemoline (n=2), atomoxetine (n=1), desipramine (n=1), and imipramine (n=1). Overall, psychostimulants demonstrated efficacy for depression, reduced fatigue and sleepiness, and appeared well-tolerated. However, there was inconsistent evidence across particular psychostimulants. For example, the only psychostimulant which demonstrated efficacy for depression-in terms of both symptom severity and response rates-was methylphenidate.
CONCLUSIONS
While our review suggests that some psychostimulants-particularly methylphenidate-appear well-tolerated and demonstrate some efficacy for depression, as well as fatigue and sleepiness, the strength of evidence in our estimates was low to very low for most agents given the small sample sizes, few RCTs, and imprecision in most estimates. A lack of consistent evidence precludes a definitive hierarchy of treatments and points to a need for additional, high-quality RCTs.
Topics: Adult; Central Nervous System Stimulants; Depression; Fatigue; Humans; Methylphenidate; Network Meta-Analysis
PubMed: 34144366
DOI: 10.1016/j.jad.2021.05.119 -
Neuroscience and Biobehavioral Reviews Jul 2024Attention-Deficit/Hyperactivity Disorder (ADHD) is associated with executive function deficits that are improved with medications. However, meta-analyses of stimulant... (Meta-Analysis)
Meta-Analysis Review
Attention-Deficit/Hyperactivity Disorder (ADHD) is associated with executive function deficits that are improved with medications. However, meta-analyses of stimulant effects on cognition have mostly tested single-dose effects, and there is no meta-analysis of non-stimulant effects. This systematic review and meta-analysis tested the clinically more relevant longer-term effects of Methylphenidate (20 studies; minimum 1 week) and Atomoxetine (8 studies; minimum 3 weeks) on reaction time, attention, inhibition, and working memory, searching papers on PubMed, Embase, Ovid MEDLINE, and PsycINFO. The meta-analysis of 18 studies in 1667 subjects showed that methylphenidate was superior to placebo in all cognitive domains with small to medium effect sizes (Hedges g of 0.34-0.59). The meta-analysis of atomoxetine included 7 studies in 829 subjects and showed no effects in working memory, but superior effects in the other domains with medium to large effect sizes (Hedge's g of 0.36-0.64). Meta-regression analysis showed no drug differences on cognitive effects. The meta-analyses show for the first time that chronic Methylphenidate and Atomoxetine have comparable effects of improving executive functions in people with ADHD.
Topics: Humans; Attention Deficit Disorder with Hyperactivity; Executive Function; Central Nervous System Stimulants; Methylphenidate; Atomoxetine Hydrochloride; Memory, Short-Term
PubMed: 38718988
DOI: 10.1016/j.neubiorev.2024.105703 -
Drug Metabolism and Disposition: the... Oct 2020Carboxylesterase (CES) 1 is the predominant esterase expressed in the human liver and is capable of catalyzing the hydrolysis of a wide range of therapeutic agents,...
Carboxylesterase (CES) 1 is the predominant esterase expressed in the human liver and is capable of catalyzing the hydrolysis of a wide range of therapeutic agents, toxins, and endogenous compounds. Accumulating studies have demonstrated associations between the expression and activity of CES1 and the pharmacokinetics and/or pharmacodynamics of CES1 substrate medications (e.g., methylphenidate, clopidogrel, oseltamivir). Therefore, any perturbation of CES1 by coingested xenobiotics could potentially compromise treatment. Natural products are known to alter drug disposition by modulating cytochrome P450 and UDP-glucuronosyltransferase enzymes, but this issue is less thoroughly explored with CES1. We report the results of a systematic literature search and discuss natural products as potential modulators of CES1 activity. The majority of research reports reviewed were in vitro investigations that require further confirmation through clinical study. Cannabis products ( -tetrahydrocannabinol, cannabidiol, cannabinol); supplements from various plant sources containing naringenin, quercetin, luteolin, oleanolic acid, and asiatic acid; and certain traditional medicines (danshen and zhizhuwan) appear to pose the highest inhibition potential. In addition, ursolic acid, gambogic acid, and glycyrrhetic acid, if delivered intravenously, may attain high enough systemic concentrations to significantly inhibit CES1. The provision of a translational interpretation of in vitro assessments of natural product actions and interactions is limited by the dearth of basic pharmacokinetic data of the natural compounds exhibiting potent in vitro influences on CES1 activity. This is a major impediment to assigning even potential clinical significance. The modulatory effects on CES1 expression after chronic exposure to natural products warrants further investigation. SIGNIFICANCE STATEMENT: Modulation of CES1 activity by natural products may alter the course of treatment and clinical outcome. In this review, we have summarized the natural products that can potentially interact with CES1 substrate medications. We have also noted the limitations of existing reports and outlined challenges and future directions in this field.
Topics: Administration, Intravenous; Administration, Oral; Biological Products; Carboxylic Ester Hydrolases; Clopidogrel; Drug Evaluation, Preclinical; Drug Interactions; Humans; Methylphenidate; Oseltamivir
PubMed: 32591414
DOI: 10.1124/dmd.120.000065 -
Clinical NeuropharmacologyFatigue is a chronic and debilitating symptom of many long-term neurological conditions (LTNCs). Although methylphenidate provides some promise in alleviating fatigue in... (Meta-Analysis)
Meta-Analysis
OBJECTIVE
Fatigue is a chronic and debilitating symptom of many long-term neurological conditions (LTNCs). Although methylphenidate provides some promise in alleviating fatigue in other clinical groups, little work has explored its potential utility within LTNCs. The current systematic review and meta-analysis evaluates the utility of methylphenidate for symptoms of fatigue in LTNCs.
METHODS
Five databases (PsycINFO, MEDLINE, Embase, Scopus, and Cochrane Library) were searched for relevant articles from their inception to February 2022. A purpose-developed evaluation tool was used to assess each study's research quality (QuEST:F).
RESULTS
Of the 1698 articles identified, 11 articles were included within this review (n = 370). Meta-analytical findings reported an overall significant benefit of methylphenidate for symptoms of fatigue across a mixed neurological sample ( g = -0.44; 95% confidence interval, -0.77 to -0.11). Subgroup analyses identified a significantly greater benefit ( P < 0.001) of methylphenidate for fatigue in LTNCs with static pathogenic trajectories (eg, traumatic brain injury) (number needed to treat = 2.5) compared with progressive conditions (eg, multiple sclerosis) (number needed to treat = 40.2).
CONCLUSIONS
Methylphenidate may pose an effective intervention for the treatment of fatigue in a number of LTNCs. Nonetheless, given the quality of the current evidence base, there exists a clear need for further robust assessment of the utility of methylphenidate-with a focus on subgroup-specific variability.
Topics: Humans; Methylphenidate; Neoplasms; Fatigue; Multiple Sclerosis; Central Nervous System Stimulants
PubMed: 37962311
DOI: 10.1097/WNF.0000000000000572