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NMDA antagonists for treating the non-motor symptoms in Parkinson's disease.
Vanle, B, Olcott, W, Jimenez, J, Bashmi, L, Danovitch, I, IsHak, WW
Translational psychiatry. 2018;(1):117
Abstract
Among patients with Parkinson's disease (PD), depression is prevalent and disabling, impacting both health outcomes and quality of life. There is a critical need for alternative pharmacological methods to treat PD depression, as mainstream antidepressant drugs are largely ineffective in this population. Currently, there are no recommendations for the optimal treatment of PD neuropsychiatric symptoms. Given the dual antidepressant and anti-dyskinetic effects of ketamine and other N-methyl-D-aspartate (NMDA) antagonists for PD, this review aims to examine the current evidence of NMDA antagonists for treating neuropsychiatric symptoms, including memantine, amantadine, ketamine, dizoclopine, and d-cycloserine. A comprehensive literature search was conducted using the PubMed database. We also searched the following databases up to March 1, 2018: Ovid MEDLINE, PsycINFO, CINAHL, Google Scholar, Cochrane Central Register of Controlled Trials, and Cochrane Database of Systematic Reviews. The following keywords were used: NMDA antagonist and Parkinson's disease. Two authors independently reviewed the articles identified from the search using specific selection criteria, focusing on studies of mood, psychiatric condition, depression, cognition, and quality of life, and the consensus was reached on the 20 studies included. There is a preliminary evidence that NMDA antagonists may modulate psychiatric symptoms in PD. However, current evidence of psychiatric symptom-modifying effects is inconclusive and requires that further trials be conducted in PD. The repurposing of old NMDA antagonists, such as ketamine for depression and newer therapies, such as rapastinel, suggests that there is an emerging place for modulating the glutamatergic system for treating non-motor symptoms in PD.
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Serum and plasma brain-derived neurotrophic factor and response in a randomized controlled trial of riluzole for treatment resistant depression.
Wilkinson, ST, Kiselycznyk, C, Banasr, M, Webler, RD, Haile, C, Mathew, SJ
Journal of affective disorders. 2018;:514-518
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Abstract
BACKGROUND Serum brain-derived neurotrophic factor (BDNF) is decreased in individuals with major depressive disorder (MDD). Pre-clinical and clinical reports suggest that the glutamate release inhibitor riluzole increases BDNF and may have antidepressant properties. Here we report serum (sBDNF) and plasma (pBDNF) levels from a randomized controlled, adjunctive, sequential parallel comparison design trial of riluzole in MDD. METHODS Serum and plasma BDNF samples were drawn at baseline and weeks 6 and 8 from 55 subjects randomized to adjunctive treatment with riluzole or placebo for 8 weeks. RESULTS Riluzole responders had lower baseline serum (19.08 ng/ml [SD 9.22] v. 28.80 ng/ml [9.63], p = 0.08) and plasma (2.72 ng/ml [1.07] v. 4.60 ng/ml [1.69], p = 0.06) BDNF compared to non-responders at a trend level. This pattern was nominally seen in placebo responders for baseline pBDNF to some degree (1.21 ng/ml [SD 1.29] v. 3.58 ng/ml [SD 1.67], p = 0.12) but not in baseline sBDNF. LIMITATIONS A number of limitations warrant comment, including the small sample size of viable BDNF samples and the small number of riluzole responders. CONCLUSIONS Preliminary evidence reported here suggests that lower baseline BDNF may be associated with better clinical response to riluzole.
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Combination Therapy of Serotonin Reuptake Inhibitors and Memantine for Obsessive- Compulsive Disorder: A Meta-Analysis of Double-Blind, Randomized, Placebo-Controlled Trials.
Kishi, T, Matsuda, Y, Iwata, N
Journal of Alzheimer's disease : JAD. 2018;(1):43-48
Abstract
We performed a meta-analysis to determine whether combination therapy with serotonin reuptake inhibitors (SRIs) and memantine (MEM) was beneficial for the treatment of obsessive- compulsive disorder. This study included three double-blind, randomized, placebo-controlled trials. MEM+SRI was superior to placebo+SRI with regard to response rate [primary outcome, n = 97; risk ratio = 0.22; 95% confidence intervals (CI) = 0.12-0.42; p < 0.00001; I2 = 0%; number needed to treat = 2], the Yale- Brown Obsessive- Compulsive Scale total [standardized mean difference (SMD) = - 4.56; 95% CI = - 8.50, - 0.62; p = 0.02], obsession subscale (SMD = - 4.39; 95% CI = - 5.94, - 2.85; p < 0.00001), and compulsion subscale score (SMD = - 4.60; 95% CI = - 7.64, - 1.55; p = 0.003). No significant differences in any safety outcome were found between the groups.
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Predictors of Response to Ketamine in Treatment Resistant Major Depressive Disorder and Bipolar Disorder.
Rong, C, Park, C, Rosenblat, JD, Subramaniapillai, M, Zuckerman, H, Fus, D, Lee, YL, Pan, Z, Brietzke, E, Mansur, RB, et al
International journal of environmental research and public health. 2018;(4)
Abstract
OBJECTIVES Extant evidence indicates that ketamine exerts rapid antidepressant effects in treatment-resistant depressive (TRD) symptoms as a part of major depressive disorder (MDD) and bipolar disorder (BD). The identification of depressed sub-populations that are more likely to benefit from ketamine treatment remains a priority. In keeping with this view, the present narrative review aims to identify the pretreatment predictors of response to ketamine in TRD as part of MDD and BD. METHOD Electronic search engines PubMed/MEDLINE, ClinicalTrials.gov, and Scopus were searched for relevant articles from inception to January 2018. The search term ketamine was cross-referenced with the terms depression, major depressive disorder, bipolar disorder, predictors, and response and/or remission. RESULTS Multiple baseline pretreatment predictors of response were identified, including clinical (i.e., Body Mass Index (BMI), history of suicide, family history of alcohol use disorder), peripheral biochemistry (i.e., adiponectin levels, vitamin B12 levels), polysomnography (abnormalities in delta sleep ratio), neurochemistry (i.e., glutamine/glutamate ratio), neuroimaging (i.e., anterior cingulate cortex activity), genetic variation (i.e., Val66Met BDNF allele), and cognitive functioning (i.e., processing speed). High BMI and a positive family history of alcohol use disorder were the most replicated predictors. CONCLUSIONS A pheno-biotype of depression more, or less likely, to benefit with ketamine treatment is far from complete. Notwithstanding, metabolic-inflammatory alterations are emerging as possible pretreatment response predictors of depressive symptom improvement, most notably being cognitive impairment. Sophisticated data-driven computational methods that are iterative and agnostic are more likely to provide actionable baseline pretreatment predictive information.
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What is in the Myopathy Literature?
Lacomis, D
Journal of clinical neuromuscular disease. 2018;(4):217-223
Abstract
This update covers the results of a randomized, placebo-controlled study that provides evidence that lamotrigine is effective in treating nondystrophic myotonias. Next, an overview of adverse effects of immune checkpoint inhibitors is provided, and the association of autoimmune myopathy and these monoclonal antibody therapies is discussed in light of recent reports. Last, the utility of electrodiagnostic testing in patients with intensive care unit weakness is addressed with emphasis on the high sensitivity and specificity of prolonged compound muscle action potential amplitudes in diagnosing critical illness myopathy.
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Auditory System Target Engagement During Plasticity-Based Interventions in Schizophrenia: A Focus on Modulation of N-Methyl-D-Aspartate-Type Glutamate Receptor Function.
Kantrowitz, JT, Swerdlow, NR, Dunn, W, Vinogradov, S
Biological psychiatry. Cognitive neuroscience and neuroimaging. 2018;(7):581-590
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Abstract
Cognitive deficits are predictive of long-term social and occupational functional deficits in schizophrenia but are currently without gold-standard treatments. In particular, augmentation of auditory cortical neuroplasticity may represent a rate-limiting first step before addressing higher-order cognitive deficits. We review the rationale for N-methyl-d-aspartate-type glutamate receptor (NMDAR) modulators as treatments for auditory plasticity deficits in schizophrenia, along with potential serum and electroencephalographic target engagement biomarkers for NMDAR function. Several recently published NMDAR-modulating treatment studies are covered, involving D-serine, memantine, and transcranial direct current stimulation. While all three interventions appear to modulate auditory plasticity, direct agonists (D-serine) appear to have the largest and most consistent effects on plasticity, at least acutely. We hypothesize that there may be synergistic effects of combining procognitive NMDAR-modulating approaches with auditory cortical neuroplasticity cognitive training interventions. Future studies should assess biomarkers for target engagement and patient stratification, along with head-to-head studies comparing putative interventions and potential long-term versus acute effects.
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Characterizing the course of suicidal ideation response to ketamine.
Ballard, ED, Yarrington, JS, Farmer, CA, Richards, E, Machado-Vieira, R, Kadriu, B, Niciu, MJ, Yuan, P, Park, L, Zarate, CA
Journal of affective disorders. 2018;:86-93
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Abstract
BACKGROUND No pharmacological treatments exist for active suicidal ideation (SI), but the glutamatergic modulator ketamine elicits rapid changes in SI. We developed data-driven subgroups of SI trajectories after ketamine administration, then evaluated clinical, demographic, and neurobiological factors that might predict SI response to ketamine. METHODS Data were pooled from five clinical ketamine trials. Treatment-resistant inpatients (n = 128) with DSM-IV-TR-diagnosed major depressive disorder (MDD) or bipolar depression received one subanesthetic (0.5 mg/kg) ketamine infusion over 40 min. Composite SI variable scores were analyzed using growth mixture modeling to generate SI response classes, and class membership predictors were evaluated using multinomial logistic regressions. Putative predictors included demographic variables and various peripheral plasma markers. RESULTS The best-fitting growth mixture model comprised three classes: Non-Responders (29%), Responders (44%), and Remitters (27%). For Responders and Remitters, maximal improvements were achieved by Day 1. Improvements in SI occurred independently of improvements in a composite Depressed Mood variable for Responders, and partially independently for Remitters. Indicators of chronic SI and self-injury were associated with belonging to the Non-Responder group. Higher levels of baseline plasma interleukin-5 (IL-5) were linked to Remitters rather than Responders. LIMITATIONS Subjects were not selected for active suicidal thoughts; findings only extend to Day 3; and plasma, rather than CSF, markers were used. CONCLUSION The results underscore the heterogeneity of SI response to ketamine and its potential independence from changes in Depressed Mood. Individuals reporting symptoms suggesting a longstanding history of chronic SI were less likely to respond or remit post-ketamine.
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Effect of the Glutamate NMDA Receptor Antagonist Memantine as Adjunctive Treatment in Borderline Personality Disorder: An Exploratory, Randomised, Double-Blind, Placebo-Controlled Trial.
Kulkarni, J, Thomas, N, Hudaib, AR, Gavrilidis, E, Grigg, J, Tan, R, Cheng, J, Arnold, A, Gurvich, C
CNS drugs. 2018;(2):179-187
Abstract
BACKGROUND Borderline personality disorder (BPD) is a complex, severe and highly stigmatised psychiatric illness. Several lines of evidence highlight the causal link between chronic stress, glucocorticoid response to stress and glutamatergic overactivity as a key event in the pathophysiology of BPD. Therefore, molecular mechanisms capable of regulating glutamate excitotoxicity represent novel and potentially promising treatment targets. Memantine-HCl is a voltage-dependent N-methyl-D-aspartate (NMDA) receptor 'channel blocker' that selectively blocks pathological glutamate overactivity. OBJECTIVE The aim of the current study was to determine if memantine can improve BPD symptoms. METHOD An 8-week, double-blind, placebo-controlled trial of adjunctive memantine to treatment as usual was conducted. Treatment as usual comprised antidepressants (selective serotonin reuptake inhibitors, tricyclic antidepressants, monoamine oxidase inhibitors, noradrenergic and specific serotonin antagonists and serotonin noradrenaline reuptake inhibitors), mood stabilisers and antipsychotics, as well as psychotherapy and other psychosocial interventions. Sixteen participants received oral placebo while 17 participants received daily oral memantine 10 mg for 7 days, with subsequent titration to daily oral memantine 20 mg. Eligibility criteria included men and women aged between 16-65 years, with a diagnosis of BPD according to the Diagnostic Interview for Borderline Patients. Primary outcome measures included the Zanarini Rating Scale for Borderline Personality Disorder (ZAN-BPD), assessed fortnightly. Secondary measures included an adverse effect questionnaire administered fortnightly to assess adverse effects known to be related to memantine use. RESULTS According to intention-to-treat, latent growth curve analyses, a significant change in total score of ZAN-BPD symptom severity was observed in the memantine group at 20 mg/daily across time, compared with placebo (p = 0.02). No adverse effects were significantly more frequent among participants receiving active memantine than among those receiving placebo. CONCLUSION Memantine at a 20-mg daily dose is a well tolerated drug that can improve BPD symptomatology and may be a promising novel therapeutic for its treatment. Further studies are needed to explore the efficacy of memantine versus placebo, as well as in comparison with other potential treatments for BPD. ClinicalTrials.gov identifier: NCT02097706.
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Memantine in Japanese patients with moderate to severe Alzheimer's disease: meta-analysis of multiple-index responder analyses.
Okuizumi, K, Kamata, T, Matsui, D, Saito, K, Matsumoto, T, Fukuchi, Y
Expert opinion on pharmacotherapy. 2018;(5):425-430
Abstract
BACKGROUND Responder analyses assessing clinical worsening have attempted to clarify clinically meaningful drug efficacy enhancements in patients with Alzheimer's disease (AD). RESEARCH DESIGN AND METHODS This was a meta-analysis of two multicenter, randomized, double-blind, parallel-group, 24-week studies of 633 Japanese patients with moderate to severe AD receiving memantine 20 mg/day (n = 318) or placebo (n = 315). The clinical trial registration number is UMIN000026013. RESULTS Overall odds ratios (OR) for a reduced likelihood of clinical worsening (memantine versus placebo) were statistically significant on the following individual and combined rating scales: Severe Impairment Battery-Japanese version (SIB-J, OR 0.52; 95% CI: 0.37, 0.73; p = 0.0001); Behavioral Pathology in AD Rating Scale (BEHAVE-AD, OR 0.53; 95% CI: 0.37, 0.75; p = 0.0003); and SIB-J + Clinician's Interview-Based Impression of Change-plus-Japanese version (SIB-J + CIBIC-plus-J; OR 0.53; 95% CI: 0.37, 0.77; p = 0.0009). A significantly reduced risk of triple worsening was evident in the memantine versus placebo group on the combined SIB-J + CIBIC-plus-J + BEHAVE-AD rating scales (OR 0.38; 95% CI: 0.22, 0.65; p = 0.0003). CONCLUSIONS Memantine is a viable treatment option for patients with AD presenting not only with cognitive impairment, but also with a broader range of symptoms, including the behavioral and psychological symptoms of dementia.
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Does oral administration of ketamine accelerate response to treatment in major depressive disorder? Results of a double-blind controlled trial.
Arabzadeh, S, Hakkikazazi, E, Shahmansouri, N, Tafakhori, A, Ghajar, A, Jafarinia, M, Akhondzadeh, S
Journal of affective disorders. 2018;:236-241
Abstract
BACKGROUND Major depressive disorder (MDD) exerts a high health and financial burden on society. The conventional pharmacotherapies for MDD are partially effective and the response to medication often starts with some delay. There are recent reports of antidepressant effects for oral ketamine. METHODS We employed a double-blind controlled trial to examine the time course of the therapeutic effect of ketamine when combined with the conventional administration of sertraline. A total of 81 patients participated in the study and were scored with the Hamilton Depression Rating Scale (HDRS) at baseline and at 2, 4 and 6 weeks after the start of the trial RESULTS General linear model repeated measures demonstrated significant effect for time × treatment interaction on the HDRS scores, with significant difference at all time points post treatment. Early improvement was significantly greater in the ketamine group (85.4%) compared to the placebo group (42.5%). We did not observe any side effects for ketamine administration. LIMITATIONS Our follow up was limited to 6 weeks post initiation of treatment and cannot reveal the potential long-term adverse effects of oral ketamine and the sustainability of its benefit. CONCLUSION Altogether, our results suggest that oral ketamine may be considered as suitable adjuvant to sertraline in relieving depressive symptoms.