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[Possibilities of pharmacological modulation of brain glutamatergic system in the treatment of vascular cognitive impairment].
Litvinenko, IV, Vorob'ev, SV, Lobzin, VY, Lupanov, IA
Zhurnal nevrologii i psikhiatrii imeni S.S. Korsakova. 2013;(9):29-35
Abstract
An aim of the study was to investigate the efficacy and safety of noojerone (memantine) in patients with cognitive impairment comorbid to brain ischemia, stages II-III. The main group (30 patients, aged 64-86 years) was treated with noojerone in addition to standard therapy according to dosage scheme during 6 months. The control group (15 patients, aged 61-78 years) received standard therapy only. Patients underwent somatic and neurological examinations, along with neuropsychological testing (MMSE, FAB and other tests). The use of noojerone in complex treatment decreased cognitive impairment in the main group compared to the control one. The most distinct changes were noted on MMSE. Statistically significant changes appeared during the 12th week. The maximal effect was observed when the drug was applied during 6 months. Noojerone was well-tolerated by the patients.
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Ketamine aggravates symptoms of acute stress disorder in a naturalistic sample of accident victims.
Schönenberg, M, Reichwald, U, Domes, G, Badke, A, Hautzinger, M
Journal of psychopharmacology (Oxford, England). 2008;(5):493-7
Abstract
The glutamatergic N-methyl-D-aspartate receptor antagonist ketamine produces transient dissociative states and alters cognitive functioning in healthy humans, thus resembling the core symptoms of acute and chronic post-traumatic stress disorder (PTSD). First evidence exists that the common use of the analgesic and sedative properties of ketamine during emergency care correlates with sustained symptoms of PTSD in accident victims. The aim of the present study was to examine whether ketamine administration after moderate accidental trauma modulates dissociation and other symptoms of acute stress disorder (ASD) in the direct aftermath of the event. Accident victims were screened within the third day after admission to hospital for symptoms of ASD (Peritraumatic Dissociative Experiences Questionnaire, ASD Scale) and prior stressful life events (Traumatic Life Events Questionnaire). Subjects had received a single or fractionated dose of either racemic ketamine (n=13), opioids (n=24) or non-opioid analgesics (n=13) during initial emergency treatment. There were no significant differences between medication groups in demographic and clinical characteristics such as injury severity or prior traumatization. With respect to ASD symptomatology three days post-event there were significant associations between ketamine analgosedation and increased symptoms of dissociation, reexperiencing, hyperarousal and avoidance relative to the comparison groups.Growing evidence exists that ketamine might modulate or aggravate early post-traumatic stress reactions when given in the acute trauma phase, which in turn might contribute to long-lasting symptomatology.
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An open-label trial of the glutamate-modulating agent riluzole in combination with lithium for the treatment of bipolar depression.
Zarate, CA, Quiroz, JA, Singh, JB, Denicoff, KD, De Jesus, G, Luckenbaugh, DA, Charney, DS, Manji, HK
Biological psychiatry. 2005;(4):430-2
Abstract
BACKGROUND Preclinical and clinical evidence indicate that the glutamatergic system might play a role in the pathophysiology of mood disorders. This study was conducted to determine the efficacy and safety of riluzole, a glutamate-modulating agent, in bipolar depression. METHODS This was an 8-week add-on study of riluzole in combination with lithium in acutely depressed bipolar patients aged 18 years and older. After open treatment with lithium for a minimum period of 4 weeks, subjects who continued to have a Montgomery-Asberg Depression Rating Scale (MADRS) score of ≥20 received riluzole (50-200 mg/day) for 8 weeks. RESULTS Fourteen bipolar depressed patients entered the study. The linear mixed models for total MADRS score showed a significant treatment effect. No switch into hypomania or mania was observed. Overall, riluzole was well tolerated. CONCLUSIONS Although preliminary, these results suggest that riluzole might indeed have antidepressant efficacy in subjects with bipolar depression.
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Preliminary evidence of attenuation of the disruptive effects of the NMDA glutamate receptor antagonist, ketamine, on working memory by pretreatment with the group II metabotropic glutamate receptor agonist, LY354740, in healthy human subjects.
Krystal, JH, Abi-Saab, W, Perry, E, D'Souza, DC, Liu, N, Gueorguieva, R, McDougall, L, Hunsberger, T, Belger, A, Levine, L, et al
Psychopharmacology. 2005;(1):303-9
Abstract
RATIONALE Some of the behavioral consequences of deficits in N-methyl-D-aspartate (NMDA) glutamate receptor function are thought to arise from the disinhibition of cortical glutamatergic circuitry. OBJECTIVE This study evaluated whether pretreatment with a drug that reduces glutamatergic activation, the group II metabotropic glutamate receptor (mGluR) agonist, LY354740, reduced the cognitive effects of the NMDA glutamate receptor antagonist, ketamine, in healthy human subjects. METHODS Nineteen healthy human subjects completed 3 test days during which LY354740 (matched placebo, 100 mg, 400 mg) was administered under double-blind conditions 4 h prior to the single-blind intravenous administration of saline and 5.7 h prior to ketamine administration (bolus of 0.26 mg/kg over 1 min, infusion of 0.65 mg/kg per hour for 100 min). Thus on each test day each subject received a single dose of LY354740 (or its matched placebo) and both saline and ketamine infusions. RESULTS Ketamine impaired attention, working memory, and delayed recall. It also produced positive and negative symptoms, perceptual changes, and dysphoric mood. LY354740 did not have a significant effect on working memory on the placebo day; however, it produced a significant dose-related improvement in working memory during ketamine infusion. CONCLUSIONS These data provide preliminary and suggestive evidence that LY354740 or other group II mGluR agonists might play a role in treating working memory impairment related to deficits in NMDA receptor function.
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5.
Riluzole and blood pressure in multiple system atrophy.
Lipp, A, Tank, J, Stoffels, M, Arnold, G, Luft, FC, Jordan, J
Clinical autonomic research : official journal of the Clinical Autonomic Research Society. 2003;(4):271-4
Abstract
Riluzole is a neuroprotective agent that is currently tested for the treatment of multiple system atrophy (MSA). Riluzole may influence afferent and efferent parts of the baroreflex due to glutamate antagonistic effects. The effect of riluzole on the efferent part may be unmasked in MSA patients with dysfunction of afferent structures of the baroreflex. We compared the effect of a single dose of 200 mg riluzole with placebo in 10 patients with probable MSA. Brachial blood pressure and heart rate were recorded at baseline and for 120 minutes every 5 minutes after ingestion of riluzole. For determination of spontaneous baroreflex sensitivity, continuous finger blood pressure and ECG were recorded. Cardiac stroke volume was monitored using impedance cardiography. The change in blood pressure over a two hour period was significantly greater with riluzole than with placebo (5 +/- 5/2 +/- 3 mmHg with placebo, 16 +/- 6/10 +/- 2 mmHg with riluzole, p < 0.001 by ANOVA). Systemic vascular resistance increased 32 +/- 6% with riluzole. Baroreflex sensitivity, the high and low frequency components of heart rate variability, and the low frequency component of systolic blood pressure variability were not different between placebo and riluzole treatment. We conclude that in MSA patients, manipulation of glutamatergic transmission with riluzole elicits a moderate pressor response. The response is explained by a marked increase in systemic vascular resistance. We propose that decreased inhibition of efferent sympathetic neurons may contribute to the response.