Lithium is the most effective mood stabilizer for the treatment of bipolar disorder, but it is toxic at only twice the therapeutic dosage and has many undesirable side effects. It is likely that a small molecule could be found with lithium-like efficacy but without toxicity through target-based drug discovery; however, therapeutic target of lithium remains equivocal. Inositol monophosphatase is a possible target but no bioavailable inhibitors exist. Here we report that the antioxidant ebselen inhibits inositol monophosphatase and induces lithium-like effects on mouse behaviour, which are reversed with inositol, consistent with a mechanism involving inhibition of inositol recycling. Ebselen is part of the National Institutes of Health Clinical Collection, a chemical library of bioavailable drugs considered clinically safe but without proven use. Therefore, ebselen represents a lithium mimetic with the potential both to validate inositol monophosphatase inhibition as a treatment for bipolar disorder and to serve as a treatment itself.A safe lithium mimetic for bipolar disorder.
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пятница, 11 января 2013 г.
Эбселен как потенциальная замена литию
четверг, 6 октября 2011 г.
Метиленовый синий как нормотимик
Methylene Blue Studied for Bipolar as FDA Issues Warning
The investigators administered methylene blue to 37 subjects meeting criteria for bipolar disorder, while maintaining lamotrigine(Drug information on lamotrigine) as their primary mood stabilizer. Patients were randomized to receive 13 weeks treatment with either 195 mg methylene blue daily, or 15 mg as a putative subtherapeutic dose in lieu of a placebo that mimics the color in urine; with groups switching the regimen for an additional 13 weeks.
Alda reported that the active dose was associated with statistically significantly improved mood symptom scores from baseline on multiple measures, including the Montgomery-Asberg Depression Rating Scale (MADRS). There was no therapeutic effect apparent on cognitive performance, but no decrement observed with its use.
пятница, 23 сентября 2011 г.
понедельник, 4 апреля 2011 г.
пятница, 11 июня 2010 г.
вторник, 25 мая 2010 г.
Антиконвульсанты в терапии поведенческих и психологических симптомов деменции
"INTRODUCTION: Dementia, besides the dominant cognitive disorders that define it, is associated with behavioral disturbances, the consequences of which are, on various levels, a determining factor for the handling of these patients. The treatment of behavioral and psychological symptoms is essential and although, to date, no therapeutic solution is satisfactory, it is necessary to look for an alternative to the neuroleptics usually employed, which raise real problems of tolerance in this geriatric population. BACKGROUND: For several years, anticonvulsants, among which some have shown mood stabilizing activity, have been the object of research in this indication. The purpose of this review of the literature is to assess the interest and the limits of anticonvulsant mood stabilizers (carbamazepine, valproic acid, gabapentin, lamotrigine, topiramate, oxcarbazepine) in the treatment of the so-called "noncognitive" symptoms of dementia. Their mechanism of action in mood disorders is not well known, but it would appear to be via the modulation of glutamate-mediated excitatory synaptic transmission and gamma-aminobutyric acid (GABA)-mediated inhibitory synaptic transmission that anticonvulsants might reduce behavioral symptoms in demented patients. METHODS: The method employed in this work was a systematic bibliographic review, in which only the double-blind placebo-controlled studies or the clinically detailed enough open-labelled studies using validated scales were retained. RESULTS: Among these medications, only carbamazepine demonstrated its efficacy in behavioral and psychological symptoms of dementia (BPSD) in controlled studies, notably that of Tariot et al. [J Am Geriatr Soc 42 (1994) 1160-1166 and Am J Psychiatry 155 (1998) 54-61] and Olin et al. [Am J Geriatr Psychiatry 9 (2001) 400-405], but with significant adverse events (sedation, hyponatremia, cardiac toxicity), particularly in the elderly and, being a strong enzymatic inducer, with a high likelihood of drug-drug interactions. Valproic acid showed some interesting results in BPSD within a large number of open studies and case reports. However, among the five controlled studies that have been published [Curr Ther Res 62 (2001) 51-67; Am J Geriatr Psychiatry 9 (2001) 58-66; Int J Geriatr Psychiatry 17 (2002) 579-585; Curr Alzheimer Res 2 (2005) 553-558 and Am J Geraitr Psychiatry 13 (2005) 942-945], none confirmed its efficacy on these symptoms. Regarding its tolerability in the geriatric population, no notable major side effect was reported (haematologic and hepatic effects are not more frequent than in the general population), except possible excessive sedation. Moreover, it appears that valproic acid could have neuroprotective effects, even if the contrary has been observed in a recent study. More studies need to be (and are being) conducted, notably on the interest of valproic acid in prophylaxis of BPSD. Gabapentin seems to be worthwhile and well tolerated in this indication, but no controlled study has been conducted to prove its efficacy, even if a quite important number of case reports and open studies have shown encouraging results. Concerning lamotrigine, which may potentially induce severe cutaneous side effects when administered with valproic acid, this drug has shown its efficacy in bipolar disorders and two recent case reports seem to indicate some interest in BPSD. Furthermore, lamotrigine appears to have neuroprotective effects. Although topiramate has shown interesting results in one open study in BPSD, its use in demented patients cannot be recommended because of its deleterious effect on cognitive functions. Oxcarbazepine, theoretically, could be an alternative to carbamazepine, which is, as aforesaid, the only anticonvulsant that proved its interest in BPSD. However, no clinical study has yet been published to support this hypothesis. This drug is better tolerated than carbamazepine, but induces severe and more frequent hyponatremia. DISCUSSION AND CONCLUSION: Finally, although we all know that antipsychotics should no longer be prescribed in the elderly, the treatment of behavioral and psychological symptoms of dementia remains a difficult problem, considering the lack of a real alternative to these medications. Anticonvulsant mood stabilizers are an interesting solution but none of them, other than carbamazepine, which did, but which is not better tolerated than the usual drugs in this population - was able to prove its efficacy in this indication. Among these medications, valproic acid, gabapentin and lamotrigine should be studied further, and the neuroprotective effect of some of them is an interesting route for research."
Anticonvulsant mood stabilizers in the treatment of behavioral and psychological symptoms of dementia (BPSD)
Anticonvulsant mood stabilizers in the treatment of behavioral and psychological symptoms of dementia (BPSD)
Влияние современных антиконвульсантов на когнитивные функции
"BACKGROUND: Antiepileptic drugs (AEDs) can be associated with neurotoxic side effects including cognitive dysfunction, a problem of considerable importance given the usual long-term course of treatment. Pregabalin is a relatively new AED widely used for the treatment of seizures and some types of chronic pain including fibromyalgia. We measured the cognitive effects of 12 weeks of pregabalin in healthy volunteers. METHODS: Thirty-two healthy volunteers were randomized in a double-blind parallel study to receive pregabalin or placebo (1:1). Pregabalin was titrated over 8 weeks to 600 mg/d. At baseline, and after 12 weeks of treatment, all subjects underwent cognitive testing. Test-retest changes in all cognitive and subjective measures were Z scored against test-retest regressions previously developed from 90 healthy volunteers. Z scores from the placebo and pregabalin groups were compared using Wilcoxon tests. RESULTS: Thirty subjects completed the study (94%). Three of 6 target cognitive measures (Digit Symbol, Stroop, Controlled Oral Word Association) revealed significant test-retest differences between the pregabalin and placebo groups, all showing negative effects with pregabalin (p < 0.05). These cognitive effects were paralleled by complaints on the Portland Neurotoxicity Scale, a subjective measure of neurotoxicity (p < 0.01). CONCLUSION: At conventional doses and titration, pregabalin induced mild negative cognitive effects and neurotoxicity complaints in healthy volunteers. These effects are one factor to be considered in the selection and monitoring of chronic AED therapy. Class of Evidence: This study provides Class I evidence that pregabalin 300 mg BID negatively impacts cognition on some tasks in healthy volunteers."
Cognitive effects of pregabalin in healthy volunteers: a double-blind, placebo-controlled trial.
"OBJECTIVE: To evaluate the cognitive effects of topiramate (TPM) and gabapentin (GBP). METHODS: Forty healthy volunteers were randomized to a 12-week course of TPM, GBP, or placebo. Doses were gradually escalated over 10 weeks to a maximum of 400 mg/day of TPM or 3,600 mg/day of GBP or to the highest tolerated dose. Subjects were interviewed and examined biweekly. Cognitive testing was performed prior to initiating the drug and again 12 weeks later, at least 2 weeks after achieving plateau dosing. For each subject and cognitive measure, test-retest Z scores were calculated based on regression equations derived from 73 healthy volunteers. Group comparisons utilized the Wilcoxon test. RESULTS: There were significant TPM vs GBP and TPM vs placebo differences in test-retest Z scores for four of six target cognitive measures (Digit Symbol, Story Recall, Selective Reminding, Controlled Oral Word Association), always indicating worse retest performance for subjects receiving TPM. Overall, 12 of 24 cognitive measures were similarly affected. TPM effects were large, and several target measures averaged >2 SD of negative change. One measure was significantly affected by GBP. CONCLUSIONS: Topiramate (TPM) impaired cognitive test performance, whereas gabapentin had minimal effects. The effects of TPM were of sufficient magnitude potentially to affect daily and occupational function."
Effects of topiramate and gabapentin on cognitive abilities in healthy volunteers.
Cognitive effects of pregabalin in healthy volunteers: a double-blind, placebo-controlled trial.
"OBJECTIVE: To evaluate the cognitive effects of topiramate (TPM) and gabapentin (GBP). METHODS: Forty healthy volunteers were randomized to a 12-week course of TPM, GBP, or placebo. Doses were gradually escalated over 10 weeks to a maximum of 400 mg/day of TPM or 3,600 mg/day of GBP or to the highest tolerated dose. Subjects were interviewed and examined biweekly. Cognitive testing was performed prior to initiating the drug and again 12 weeks later, at least 2 weeks after achieving plateau dosing. For each subject and cognitive measure, test-retest Z scores were calculated based on regression equations derived from 73 healthy volunteers. Group comparisons utilized the Wilcoxon test. RESULTS: There were significant TPM vs GBP and TPM vs placebo differences in test-retest Z scores for four of six target cognitive measures (Digit Symbol, Story Recall, Selective Reminding, Controlled Oral Word Association), always indicating worse retest performance for subjects receiving TPM. Overall, 12 of 24 cognitive measures were similarly affected. TPM effects were large, and several target measures averaged >2 SD of negative change. One measure was significantly affected by GBP. CONCLUSIONS: Topiramate (TPM) impaired cognitive test performance, whereas gabapentin had minimal effects. The effects of TPM were of sufficient magnitude potentially to affect daily and occupational function."
Effects of topiramate and gabapentin on cognitive abilities in healthy volunteers.
четверг, 6 мая 2010 г.
Антидепрессанты при БАР
"Although some might argue that the precise relative risk of antidepressant-induced mania or hypomania is unknown (eg, considering intervening factors such as the natural illness course), recent literature suggests that the emergence of mania or hypomania can be reasonably attributed to antidepressant use in no more than 10% to 25% of patients with bipolar disorder"
"One large randomized trial showed comparable antidepressant efficacy with a mood stabilizer plus adjunctive venlafaxine (43%) vs sertraline (55%) vs bupropion (49%) over 10 weeks,14 but the lack of a mood stabilizer monotherapy comparison group limits the ability to anticipate whether adjunctive antidepressants increase response or remission rates more than mood stabilizers alone. Adjunctive imipramine,13 paroxetine,12,13,15 and bupropion12 yield no greater improvement in depressive symptoms than is seen with optimally dosed mood stabilizers alone."
"The largest dataset on this topic—the randomized controlled data from Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD)12—found that the risk for treatment-emergent manic switch with paroxetine or bupropion was almost identical (about 10%) with or without an FDA-approved antimanic agent.
In a retrospective study, Henry et al6 found that cotherapy with lithium but not divalproex or carbamazepine protects against antidepressant-induced mania, and that switch rates to mania were the same whether or not an antidepressant was taken with an anticonvulsant. In a naturalistic retrospective study (n=158), Bottlender et al24 revealed that mood stabilizers (lithium, carbamazepine, or divalproex) prevented switches from depression to mania during treatment with TCAs but not SSRIs or MAOIs.
I favor incorporating lithium or other antimanic agents in the regimens of patients with bipolar depression not primarily to guard against antidepressant-induced mania but more for pharmacodynamic synergy—complementary mechanisms of action that collectively may produce more substantial antidepressant effects—especially when the patient’s illness course has included manic or hypomanic features in the preceding year."
"Wehr et al25 reported that antidepressants may accelerate cycling frequency (ie, inter-episode durations become shorter) in a small subgroup (N=10) of patients. By contrast, use of TCAs was not more likely in the weeks preceding shifts from depression to mania or hypomania in a 14-year follow-up study of bipolar rapid cycling from the NIMH Collaborative Depression Study.26 In fact, rapid-cycling patients spent more weeks depressed when taking lithium without a TCA than with."
Antidepressants in bipolar disorder: 7 myths and realities
"One large randomized trial showed comparable antidepressant efficacy with a mood stabilizer plus adjunctive venlafaxine (43%) vs sertraline (55%) vs bupropion (49%) over 10 weeks,14 but the lack of a mood stabilizer monotherapy comparison group limits the ability to anticipate whether adjunctive antidepressants increase response or remission rates more than mood stabilizers alone. Adjunctive imipramine,13 paroxetine,12,13,15 and bupropion12 yield no greater improvement in depressive symptoms than is seen with optimally dosed mood stabilizers alone."
"The largest dataset on this topic—the randomized controlled data from Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD)12—found that the risk for treatment-emergent manic switch with paroxetine or bupropion was almost identical (about 10%) with or without an FDA-approved antimanic agent.
In a retrospective study, Henry et al6 found that cotherapy with lithium but not divalproex or carbamazepine protects against antidepressant-induced mania, and that switch rates to mania were the same whether or not an antidepressant was taken with an anticonvulsant. In a naturalistic retrospective study (n=158), Bottlender et al24 revealed that mood stabilizers (lithium, carbamazepine, or divalproex) prevented switches from depression to mania during treatment with TCAs but not SSRIs or MAOIs.
I favor incorporating lithium or other antimanic agents in the regimens of patients with bipolar depression not primarily to guard against antidepressant-induced mania but more for pharmacodynamic synergy—complementary mechanisms of action that collectively may produce more substantial antidepressant effects—especially when the patient’s illness course has included manic or hypomanic features in the preceding year."
"Wehr et al25 reported that antidepressants may accelerate cycling frequency (ie, inter-episode durations become shorter) in a small subgroup (N=10) of patients. By contrast, use of TCAs was not more likely in the weeks preceding shifts from depression to mania or hypomania in a 14-year follow-up study of bipolar rapid cycling from the NIMH Collaborative Depression Study.26 In fact, rapid-cycling patients spent more weeks depressed when taking lithium without a TCA than with."
Antidepressants in bipolar disorder: 7 myths and realities
понедельник, 15 июня 2009 г.
вторник, 26 мая 2009 г.
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