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Expert Opinion on Drug Safety Oct 2018Currently, five pharmacotherapeutic options are available to treat Alzheimer's disease: memantine; the three cholinesterase inhibitors donepezil, galantamine, and... (Meta-Analysis)
Meta-Analysis Review
Currently, five pharmacotherapeutic options are available to treat Alzheimer's disease: memantine; the three cholinesterase inhibitors donepezil, galantamine, and rivastigmine; and combination treatments with memantine and one cholinesterase inhibitor. Selection of the best course of treatment is based upon the evidence gathered by systematic reviews and meta-analyses of randomized controlled trials. Areas covered: This article provides a risk-benefit analysis of these treatments using evidence from meta-analyses on their safety and their efficacy. Expert opinion: Memantine improves cognitive functions and behavioral disturbances more efficiently than the placebo, both as monotherapy and in combination with donepezil. Although memantine monotherapy and combination therapy are associated with a few individual adverse events such as somnolence, it is well-tolerated and its safety (all-cause discontinuation) is comparable or superior to that of the placebo (agitation). Pooled cholinesterase inhibitors are superior to the placebo in the improvement of cognitive functions, but not behavioral disturbances and they are not well-tolerated, as evaluated by the high discontinuation rate. Donepezil (10 mg/day) and oral rivastigmine and galantamine monotherapies carry the risk for some adverse events including gastrointestinal symptoms. Therefore, we consider that combined treatment with memantine and donepezil is the most useful treatment for Alzheimer's disease.
Topics: Alzheimer Disease; Cholinesterase Inhibitors; Cognition; Donepezil; Drug Therapy, Combination; Excitatory Amino Acid Antagonists; Humans; Indans; Memantine; Piperidines; Randomized Controlled Trials as Topic
PubMed: 30222469
DOI: 10.1080/14740338.2018.1524870 -
Archives of Physical Medicine and... Sep 2018To update the 1995 American Academy of Neurology (AAN) practice parameter on persistent vegetative state and the 2002 case definition for the minimally conscious state...
Comprehensive Systematic Review Update Summary: Disorders of Consciousness: Report of the Guideline Development, Dissemination, and Implementation Subcommittee of the American Academy of Neurology; the American Congress of Rehabilitation Medicine; and the National Institute on Disability,...
OBJECTIVE
To update the 1995 American Academy of Neurology (AAN) practice parameter on persistent vegetative state and the 2002 case definition for the minimally conscious state (MCS) by reviewing the literature on the diagnosis, natural history, prognosis, and treatment of disorders of consciousness lasting at least 28 days.
METHODS
Articles were classified per the AAN evidence-based classification system. Evidence synthesis occurred through a modified Grading of Recommendations Assessment, Development and Evaluation process. Recommendations were based on evidence, related evidence, care principles, and inferences according to the AAN 2011 process manual, as amended.
RESULTS
No diagnostic assessment procedure had moderate or strong evidence for use. It is possible that a positive EMG response to command, EEG reactivity to sensory stimuli, laser-evoked potentials, and the Perturbational Complexity Index can distinguish MCS from vegetative state/unresponsive wakefulness syndrome (VS/UWS). The natural history of recovery from prolonged VS/UWS is better in traumatic than nontraumatic cases. MCS is generally associated with a better prognosis than VS (conclusions of low to moderate confidence in adult populations), and traumatic injury is generally associated with a better prognosis than nontraumatic injury (conclusions of low to moderate confidence in adult and pediatric populations). Findings concerning other prognostic features are stratified by etiology of injury (traumatic vs nontraumatic) and diagnosis (VS/UWS vs MCS) with low to moderate degrees of confidence. Therapeutic evidence is sparse. Amantadine probably hastens functional recovery in patients with MCS or VS/UWS secondary to severe traumatic brain injury over 4 weeks of treatment. Recommendations are presented separately.
Topics: Adult; Child; Consciousness Disorders; Female; Humans; Independent Living; Male; Neurology; Persistent Vegetative State; Physical and Rehabilitation Medicine; Practice Guidelines as Topic; Prognosis; Rehabilitation Research
PubMed: 30098792
DOI: 10.1016/j.apmr.2018.07.002 -
Neurology Sep 2018To update the 1995 American Academy of Neurology (AAN) practice parameter on persistent vegetative state and the 2002 case definition for the minimally conscious state...
Comprehensive systematic review update summary: Disorders of consciousness: Report of the Guideline Development, Dissemination, and Implementation Subcommittee of the American Academy of Neurology; the American Congress of Rehabilitation Medicine; and the National Institute on Disability,...
OBJECTIVE
To update the 1995 American Academy of Neurology (AAN) practice parameter on persistent vegetative state and the 2002 case definition for the minimally conscious state (MCS) by reviewing the literature on the diagnosis, natural history, prognosis, and treatment of disorders of consciousness lasting at least 28 days.
METHODS
Articles were classified per the AAN evidence-based classification system. Evidence synthesis occurred through a modified Grading of Recommendations Assessment, Development and Evaluation process. Recommendations were based on evidence, related evidence, care principles, and inferences according to the AAN 2011 process manual, as amended.
RESULTS
No diagnostic assessment procedure had moderate or strong evidence for use. It is possible that a positive EMG response to command, EEG reactivity to sensory stimuli, laser-evoked potentials, and the Perturbational Complexity Index can distinguish MCS from vegetative state/unresponsive wakefulness syndrome (VS/UWS). The natural history of recovery from prolonged VS/UWS is better in traumatic than nontraumatic cases. MCS is generally associated with a better prognosis than VS (conclusions of low to moderate confidence in adult populations), and traumatic injury is generally associated with a better prognosis than nontraumatic injury (conclusions of low to moderate confidence in adult and pediatric populations). Findings concerning other prognostic features are stratified by etiology of injury (traumatic vs nontraumatic) and diagnosis (VS/UWS vs MCS) with low to moderate degrees of confidence. Therapeutic evidence is sparse. Amantadine probably hastens functional recovery in patients with MCS or VS/UWS secondary to severe traumatic brain injury over 4 weeks of treatment. Recommendations are presented separately.
Topics: Consciousness Disorders; Humans; Independent Living; Neurology; Physical and Rehabilitation Medicine; Practice Guidelines as Topic; Rehabilitation Research; United States
PubMed: 30089617
DOI: 10.1212/WNL.0000000000005928 -
BMC Geriatrics Jul 2018The risk-benefit relationship of memantine treatment for Alzheimer's disease (AD) remains unclear. In addition, variability between the results of clinical trials has... (Meta-Analysis)
Meta-Analysis
Predictors of discontinuation, efficacy, and safety of memantine treatment for Alzheimer's disease: meta-analysis and meta-regression of 18 randomized clinical trials involving 5004 patients.
BACKGROUND
The risk-benefit relationship of memantine treatment for Alzheimer's disease (AD) remains unclear. In addition, variability between the results of clinical trials has been observed. The aim of this study was to investigate the risk-benefit relationship of memantine treatment in patients with AD and to determine the predictor effect of patient, intervention, and study design related covariates.
METHODS
A systematic review and meta-analysis of double-blind, placebo controlled clinical trials was performed. Primary outcomes were all-cause discontinuation, discontinuation due to adverse events (AE) and efficacy on cognitive function. Odds ratio (OR) and standard mean difference (SMD) with 95% confidence intervals were calculated. Meta-regression was conducted to identify related covariates. Cochrane Collaboration tool was used to evaluate the risk of bias of included trials.
RESULTS
Eighteen studies involving 5004 patients were included. No differences between memantine and placebo were found for all-cause treatment discontinuation (OR=0.97 [0.82, 1.14]) and discontinuation due to AE (OR=1.18 [0.91, 1.53]). Memantine showed small improvement on cognitive function (SMD=0.15 [0.08, 0.22]). Baseline functional ability was positively associated with all-cause treatment discontinuation and discontinuation due to AE.
CONCLUSIONS
Our study suggests that memantine has a very small efficacy on AD symptomatology and its safety profile is similar to that of placebo. No evidence of treatment discontinuation improvement with memantine is found, indicating a dubious risk-benefit relationship. No intervention characteristic or subgroup of patients clearly shows a significantly better risk-benefit relationship.
PROSPERO REGISTRATION
CRD42014015696 .
Topics: Activities of Daily Living; Aged; Alzheimer Disease; Dopamine Agents; Double-Blind Method; Forecasting; Humans; Memantine; Randomized Controlled Trials as Topic; Regression Analysis; Treatment Outcome; Withholding Treatment
PubMed: 30041625
DOI: 10.1186/s12877-018-0857-5 -
CNS & Neurological Disorders Drug... 2018Aphasia is a common complication after stroke, and traditional speech and language therapy (SLT) has a limited effect on post-stroke aphasia (PSA). While there has been...
BACKGROUND
Aphasia is a common complication after stroke, and traditional speech and language therapy (SLT) has a limited effect on post-stroke aphasia (PSA). While there has been an increasing number of controlled clinical trials on the efficacy of drugs in the treatment of PSA, there have been very few systematic reviews on the efficacy and safety of pharmacological treatments in people with PSA.
OBJECTIVE
To evaluate the efficacy and safety of pharmacological interventions for PSA.
METHODS
The Cochrane Central Register of Controlled Trials (CENTRA), PubMed, Embase, Chinese Journal Full-text Database (CJFD), China Biology Medicine disc (CBMdisc), Wanfang Data and VIP Information System were searched for randomized controlled trials about pharmacological treatments for PSA. Literature screening using the inclusion and exclusion criteria, data extraction and methodological quality assessment of the included studies were completed by two independent reviewers. Methodological quality was considered high for modified Jadad quality scale scores of 4 to 7. RevMan 5.3 software was used to conduct a meta-analysis of high-quality studies.
RESULTS
Fifteen studies (578 participants) satisfied the eligibility criteria for this systematic review. Five trials (277 participants) assessed donepezil, four studies (124 participants) assessed memantine, three studies (72 participants) assessed bromocriptine, one trial (45 patients) evaluated galantamine, one study (21 patients) evaluated amphetamine, and one trial (39 patients) evaluated levodopa. The systematic review showed that donepezil achieved remarkable results in terms of the aphasia quotient (AQ) (SMD 0.82, 95% CI 0.48-1.17, P < 0.00001), repetition ability (SMD 0. 81, 95% CI 0.57-1.06, P < 0.00001), naming ability (SMD 0.56, 95% CI 0.29-0. 84, P < 0.00001), auditory comprehension (SMD 0.85, 95% CI 0.58-1. 13, P< 0.00001) and oral expression (SMD 0.90, 95% CI 0.54-1.26, P < 0.00001). Memantine showed no pronounced improvement in auditory comprehension (SMD 0.35, 95% CI -0.05-0.74, P = 0.09) but did improve the AQ (SMD 0.57, 95% CI 0.09-1.06, P = 0. 02), naming ability (SMD 0.81, 95% CI 0.38-1.25, P = 0.0002), spontaneous speech (SMD 0.76, 95% CI 0. 39- 1.13, P < 0.0001), and repetition ability (SMD 0.37, 95% CI 0.01-0.73, P = 0.04). Bromocriptine showed pronounced improvement in naming ability (SMD -0.20, 95% CI- 0.67-0.26, P = 0.39), verbal fluency (SMD 0.02, 95% CI 0.53-0.56, P = 0.95), and repetition ability (SMD 0.29, 95% CI -0.23-0. 81, P = 0.28). There is limited and inconclusive evidence for galantamine, amphetamine and levodopa.
CONCLUSION
Current evidence suggests that drugs, such as donepezil and memantine, can improve the prognosis of PSA. Donepezil has a significant effect in improving the ability of auditory comprehension, naming, repetition and oral expression. Memantine has a significant effect in improving the ability of naming, spontaneous speech and repetition. Bromocriptine showed no significant improvements in the treatment of aphasia after stroke. Data regarding galantamine, amphetamine and levodopa in the treatment of aphasia after stroke are limited and inconclusive.
Topics: Aphasia; Databases, Factual; Donepezil; Humans; Memantine; Nootropic Agents; Stroke
PubMed: 29984673
DOI: 10.2174/1871527317666180706143051 -
Journal of Neurotrauma Dec 2018Many individuals in post-traumatic amnesia (PTA) following traumatic brain injury (TBI) experience neurobehavioral symptoms (NBS) in addition to disorientation and...
Many individuals in post-traumatic amnesia (PTA) following traumatic brain injury (TBI) experience neurobehavioral symptoms (NBS) in addition to disorientation and amnesia. These symptoms are associated with low rehabilitation engagement, self-inflicted harm, and risk of violence. The aim of this systematic review was to evaluate the efficacy and harms of pharmacological interventions for NBS in PTA following TBI in adults. Studies in English published before December 2017 were reviewed. Six databases were searched, with additional hand searching of key journals, clinical trials registries, and international drug regulators. Evidence quality was assessed using Joanna Briggs Institute Critical Appraisal Instruments. Thirteen studies were identified: three randomized controlled trials (RCTs), three cohort studies, and seven case series. In the RCTs, neither amantadine nor sertraline reduced NBS. Less rigorous studies reported reduced NBS in patients administered haloperidol, ziprasidone, carbamazepine, amitriptyline, desipramine, and varied neuroleptics. There is a paucity of well-designed, adequately powered and controlled studies of pharmacological interventions for NBS in PTA. More research is needed to provide evidence-based treatment recommendations and improve care.
Topics: Amnesia; Brain Injuries, Traumatic; Central Nervous System Agents; Female; Humans; Male; Mental Disorders; Post-Concussion Syndrome
PubMed: 29969935
DOI: 10.1089/neu.2018.5738 -
The Cochrane Database of Systematic... Jun 2018Pharmacologic therapies for management of heroin withdrawal have been studied and reviewed widely. Opium dependence is generally associated with less severe dependence... (Review)
Review
BACKGROUND
Pharmacologic therapies for management of heroin withdrawal have been studied and reviewed widely. Opium dependence is generally associated with less severe dependence and milder withdrawal symptoms than heroin. The evidence on withdrawal management of heroin might therefore not be exactly applicable for opium.
OBJECTIVES
To assess the effectiveness and safety of various pharmacologic therapies for the management of the acute phase of opium withdrawal.
SEARCH METHODS
We searched the following sources up to September 2017: CENTRAL, MEDLINE, Embase, CINAHL, PsycINFO, regional and national databases (IMEMR, Iranmedex, and IranPsych), main electronic sources of ongoing trials, and reference lists of all relevant papers. In addition, we contacted known investigators to obtain missing data or incomplete trials.
SELECTION CRITERIA
Controlled clinical trials and randomised controlled trials on pharmacological therapies, compared with no intervention, placebo, other pharmacologic treatments, different doses of the same drug, and psychosocial intervention, to manage acute withdrawal from opium in a maximum duration of 30 days.
DATA COLLECTION AND ANALYSIS
We used the standard methodological procedures expected by Cochrane.
MAIN RESULTS
We included 13 trials involving 1096 participants. No pooled analysis was possible. Studies were carried out in three countries, Iran, India, and Thailand, in outpatient and inpatient settings. The quality of the evidence was generally very low.When the mean of withdrawal symptoms was provided for several days, we mainly focused on day 3. The reason for this was that the highest severity of opium withdrawal is in the second to fourth day.Comparing different pharmacological treatments with each other, clonidine was twice as good as methadone for completion of treatment (risk ratio (RR) 2.01, 95% confidence interval (CI) 1.69 to 2.38; 361 participants, 1 study, low-quality evidence). All the other results showed no differences between the considered drugs: baclofen versus clonidine (RR 1.06, 95% CI 0.63 to 1.80; 66 participants, 1 study, very low-quality evidence); clonidine versus clonidine plus amantadine (RR 1.03, 95% CI 0.86 to 1.24; 69 participants, 1 study); clonidine versus buprenorphine in an inpatient setting (RR 1.04, 95% CI 0.90 to 1.20; 1 study, 35 participants, very low-quality evidence); methadone versus tramadol (RR 0.95, 95% CI 0.65 to 1.37; 1 study, 72 participants, very low-quality evidence); methadone versus methadone plus gabapentin (RR 1.17, 95% CI 0.96 to 1.43; 1 study, 40 participants, low-quality evidence), and tincture of opium versus methadone (1 study, 74 participants, low-quality evidence).Comparing different pharmacological treatments with each other, adding amantadine to clonidine decreased withdrawal scores rated at day 3 (mean difference (MD) -3.56, 95% CI -5.97 to -1.15; 1 study, 60 participants, very low-quality evidence). Comparing clonidine with buprenorphine in an inpatient setting, we found no difference in withdrawal symptoms rated by a physician (MD -1.40, 95% CI -2.93 to 0.13; 1 study, 34 participants, very low-quality evidence), and results in favour of buprenorpine when rated by participants (MD -11.80, 95% CI -15.56 to -8.04). Buprenorphine was superior to clonidine in controlling severe withdrawal symptoms in an outpatient setting (RR 0.35, 95% CI 0.19 to 0.64; 1 study, 76 participants). We found no difference in the comparison of methadone versus tramadol (MD 0.04, 95% CI -2.68 to 2.76; 1 study, 72 participants) and in the comparison of methadone versus methadone plus gabapentin (MD -2.20, 95% CI -6.72 to 2.32; 1 study, 40 participants).Comparing clonidine versus buprenorphine in an outpatient setting, more adverse effects were reported in the clonidine group (1 study, 76 participants). Higher numbers of participants in the clonidine group experienced hypotension at days 5 to 8, headache at days 1 to 8, sedation at days 5 to 8, dizziness and dry mouth at days 1 to 10, and nausea at days 1 to 9. Sweating was reported in a significantly higher number of participants in the buprenorphine group at days 1 to 10. We found no difference between groups for all the other comparisons considering this outcome.Comparing different dosages of the same pharmacological detoxification treatment, a high dose of clonidine (1 to 1.2 mg/day) did not differ from a low dose of clonidine (0.5 to 0.6 mg/day) in completion of treatment in an inpatient setting (RR 1.00, 95% CI 0.84 to 1.19; 1 study, 68 participants), however a higher number of participants with hypotension was reported in the high-dose group (RR 3.25, 95% CI 1.77 to 5.98). Gradual reduction of methadone was associated with more adverse effects than abrupt withdrawal of methadone (RR 2.25, 95% CI 1.02 to 4.94; 1 study, 20 participants, very low-quality evidence).
AUTHORS' CONCLUSIONS
Results did not support using any specific pharmacological approach for the management of opium withdrawal due to generally very low-quality evidence and small or no differences between treatments. However, it seems that opium withdrawal symptoms are significant, especially at days 2 to 4 after discontinuation of opium. All of the assessed medications might be useful in alleviating symptoms. Those who receive clonidine might experience hypotension.
Topics: Amantadine; Amines; Baclofen; Buprenorphine; Clonidine; Cyclohexanecarboxylic Acids; Gabapentin; Humans; Methadone; Opioid-Related Disorders; Opium; Randomized Controlled Trials as Topic; Substance Withdrawal Syndrome; Tramadol; gamma-Aminobutyric Acid
PubMed: 29929212
DOI: 10.1002/14651858.CD007522.pub2 -
Revista Brasileira de Psiquiatria (Sao... 2018Amantadine blocks N-methyl-D-aspartate (NMDA) receptors and has dopaminergic and noradrenergic action, a neurochemical profile that suggests its potential as an... (Review)
Review
OBJECTIVE
Amantadine blocks N-methyl-D-aspartate (NMDA) receptors and has dopaminergic and noradrenergic action, a neurochemical profile that suggests its potential as an antidepressant drug. We conducted a systematic review of preclinical and clinical studies addressing the effects of amantadine in animal models of depression and in patients with depression.
METHODS
PubMed, Science Direct, and Web of Science were searched up to September 1, 2017 to identify clinical and preclinical studies. The following search terms were used: "amantadine AND depress*"; "amantadine AND mood"; "amantadine AND animal models AND antidepres*"; and "amantadine AND (forced swim, learned helplessness, reserpine, chronic mild stress, anhedonia, sucrose preference)."
RESULTS
Amantadine had antidepressant-like effects in animal models and appeared to potentiate the antidepressant effects of other antidepressants. These preclinical findings have received some support from the results of small open-label clinical trials, suggesting that amantadine can reduce depressive symptomatology and potentiate the antidepressant effects of monoaminergic drugs. In addition to its glutamatergic and dopaminergic effects, the potential antidepressant-like effects of amantadine have been linked to molecular and cellular actions, such as increased expression of neurotrophic factors (e.g., brain-derived neurotrophic factor), activation of σ1 receptors, decreased corticosterone levels, and decreased inflammatory response to stress.
CONCLUSION
Amantadine is an interesting candidate as new antidepressant drug for the treatment of depression.
Topics: Amantadine; Animals; Antidepressive Agents; Biogenic Monoamines; Clinical Trials as Topic; Depressive Disorder; Disease Models, Animal; Drug Evaluation, Preclinical; Humans
PubMed: 29898194
DOI: 10.1590/1516-4446-2017-2393 -
Dementia and Geriatric Cognitive... 2018Acetylcholinesterase inhibitors (AChEIs) and memantine are commonly used in the management of dementia. In routine clinical practice, dementia is often monitored via the... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Acetylcholinesterase inhibitors (AChEIs) and memantine are commonly used in the management of dementia. In routine clinical practice, dementia is often monitored via the Mini-Mental State Examination (MMSE). We conducted a systematic review and meta-analysis of the effects of these drugs on MMSE scores.
SUMMARY
Eighty trials were identified. Pooled effect estimates were in favour of both AChEIs and memantine at 6 months. Meta-regression indicated that dementia subtype was a moderator of AChEI treatment effect, with the effect of treatment versus control twice as high for patients with Parkinson disease dementia/ dementia with Lewy bodies (2.11 MMSE points at 6 months) as for patients with Alzheimer disease/vascular dementia (0.91 MMSE points at 6 months). Key Messages: AChEIs demonstrate a modest effect versus control on MMSE scores which is moderated by dementia subtype. For memantine the effect is smaller.
Topics: Alzheimer Disease; Cholinesterase Inhibitors; Cognition; Dementia, Vascular; Dopamine Agents; Humans; Memantine; Treatment Outcome
PubMed: 29734182
DOI: 10.1159/000486546 -
Clinical Pharmacology and Therapeutics Jan 2019Memantine and the Acetylcholinesterase inhibitors (AChEIs) are two classes of drugs that are used to treat patients with Alzheimer's disease. We conducted a network... (Meta-Analysis)
Meta-Analysis
Memantine and the Acetylcholinesterase inhibitors (AChEIs) are two classes of drugs that are used to treat patients with Alzheimer's disease. We conducted a network meta-analysis of randomized controlled trials to compare the treatment effectiveness of monotherapy or combination therapy A total of 23,707 AD patients in 76 randomized trials were identified. In patients with mild-to-moderate AD, monotherapy with donepezil, galantamine or rivastigmine were superior to placebo in enhancing cognitive functions and activities of daily living (ADL), whereas monotherapy with donepezil or memantine were superior to placebo in improving behavioral symptoms. However, combination therapy with AChEIs and memantine did not show additional benefit than monotherapy. In patients with moderate-to-severe AD, neither monotherapy nor combination therapy were superior to placebo in any domain measurement. Combination therapy with memantine and AChEIs is confirmed to have no additional benefits over monotherapy. This article is protected by copyright. All rights reserved.
Topics: Alzheimer Disease; Cholinesterase Inhibitors; Dopamine Agents; Humans; Memantine; Network Meta-Analysis; Nootropic Agents; Randomized Controlled Trials as Topic; Treatment Outcome
PubMed: 29717478
DOI: 10.1002/cpt.1104