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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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BDNF gene is a risk factor for schizophrenia in a Scottish population.
Neves-Pereira, M, Cheung, JK, Pasdar, A, Zhang, F, Breen, G, Yates, P, Sinclair, M, Crombie, C, Walker, N, St Clair, DM
Molecular psychiatry. 2005;(2):208-12
Abstract
Schizophrenia is a severe psychiatric disease with a strong genetic component. Brain-derived neurotrophic factor (BDNF) has been implicated in the pathogenesis of schizophrenia and bipolar (BP) disorders. The present study has examined two polymorphisms in linkage disequilibrium in the BDNF gene, which have been variously reported as associated with schizophrenia and BP. In our study, 321 probands with a primary diagnosis of schizophrenia or schizoaffective disorder, and 263 with a diagnosis of bipolar affective disorder, were examined together with 350 controls drawn from the same geographical region of Scotland. The val66met single-nucleotide polymorphism (SNP) showed significant (P = 0.005) association for valine (allele G) with schizophrenia but not bipolar disorder. Haplotype analysis of val/met SNP and a dinucleotide repeat polymorphism in the putative promoter region revealed highly significant (P < 1 x 10(-8)) under-representation of the methionine or met-1 haplotype in the schizophrenic but not the BP population. We conclude that, although the val66met polymorphism has been reported to alter gene function, the risk may depend upon the haplotypic background on which the val/met variant is carried.
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Association of mitochondrial complex I subunit gene NDUFV2 at 18p11 with bipolar disorder in Japanese and the National Institute of Mental Health pedigrees.
Washizuka, S, Iwamoto, K, Kazuno, AA, Kakiuchi, C, Mori, K, Kametani, M, Yamada, K, Kunugi, H, Tajima, O, Akiyama, T, et al
Biological psychiatry. 2004;(7):483-9
Abstract
BACKGROUND Linkage with 18p11 is one of the replicated findings in molecular genetics of bipolar disorder. Because mitochondrial dysfunction has been suggested in bipolar disorder, NDUFV2 at 18p11, encoding a subunit of the complex I, reduced nicotinamide adenine dinucleotide (NADH)ubiquinone oxidoreductase, is a candidate gene for this disorder. We previously reported that a polymorphism in the upstream region of NDUFV2, -602G> A, was associated with bipolar disorder in Japanese subjects; however, functional significance of -602G> A was not known. METHODS We screened the further upstream region of NDUFV2. We performed a case-control study in Japanese patients with bipolar disorder and control subjects and a transmission disequilibrium test in 104 parent and proband trios of the National Institute of Mental Health (NIMH) Genetics Initiative pedigrees. We also performed the promoter assay to examine functional consequence of the -602G> A polymorphism. RESULTS The -602G> A polymorphism was found to alter the promoter activity. We found that the other haplotype block surrounding -3542G> A was associated with bipolar disorder. The association of the haplotypes consisting of -602G> A and -3542G> A polymorphisms with bipolar disorder was seen both in Japanese case-control samples and NIMH trios. CONCLUSION Together these findings indicate that the polymorphisms in the promoter region of NDUFV2 are a genetic risk factor for bipolar disorder by affecting promoter activity.
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Acute antimanic efficacy and safety of oxcarbazepine in an open trial with an on-off-on design.
Hummel, B, Walden, J, Stampfer, R, Dittmann, S, Amann, B, Sterr, A, Schaefer, M, Frye, MA, Grunze, H
Bipolar disorders. 2002;(6):412-7
Abstract
RATIONALE AND OBJECTIVES Carbamazepine has shown reasonable antimanic properties, but its use has been limited because of enzyme-inducing effects. The keto-derivative oxcarbazepine (OXC) is very similar to carbamazepine, however, the metabolic pathway is different. OXC is not metabolized to the 10, 11-epoxide, which seems to be responsible for several undesirable side-effects of carbamazepine and furthermore OXC has less enzyme-inducing properties. METHODS In this non-random open label study, patients were treated with OXC for 14 days, crossed over to no OXC for 7 days, and then crossed back over to OXC for the remaining 14 days. OXC was titrated to a final dose in a range of 900-2100 mg due to individual response. Treatment success was defined as a reduction of the original Young Mania Rating Scale (YMRS) score of more than 50% at the end of study period. RESULTS Four of the 12 included patients (33%) met defined response criteria at the end of study period. Fifty percentage of the patients had to be prematurely excluded from the trial. The mean YMRS scores of the on-periods were obviously different from the off-period. Forty-two percentage of the patients experienced side-effects leading to premature discontinuation in two of 12 patients. CONCLUSION Antimanic activity of OXC was demonstrated in this pilot study only for patients with mild or moderate manic symptoms. Further studies are encouraged to clarify OXC's role as mood-stabilizer and assess whether it has a profile similar to that of carbamazepine.