Tetrabenazine augmentation in treatment-resistant schizophrenia: a 12-week, double-blind, placebo-controlled trial.

Evidence linking schizophrenia to alterations in presynaptic dopamine (DA) grows, although treatments to date have largely focused on postsynaptic D2 receptor blockade. This study examined augmenting response in treatment-resistant schizophrenia through the addition of tetrabenazine (TBZ), a presynaptic vesicular monoamine transporter (VMAT2) inhibitor. Participants included 41 outpatients (mean age, 43.5 years) with treatment-refractory schizophrenia, stabilized on their present antipsychotic treatment (clozapine, 73%) for more than 3 months. Individuals were randomly assigned to TBZ augmentation (12.5-75 mg/d), titrated according to a fixed, flexible schedule, or placebo over 12 weeks. Twenty subjects received TBZ, and 21 received placebo; doses of 18 of the 20 TBZ-treated individuals were titrated up to the maximum of 75 mg/d, and 16 (80%) of them completed the trial. Tetrabenazine was well tolerated and not linked to increased adverse effects, including those that have been reported more frequently (eg, parkinsonism, depression, and sedation) with higher doses (>100 mg/d) used in the treatment of hyperkinetic movement disorders. However, there was no indication of clinical improvement as measured using the Brief Psychiatric Rating Scale, the Clinical Global Impression scale, and the Global Assessment of Functioning scale. In examining those receiving TBZ-clozapine specifically, there was no indication of drug-drug interactions or difference in response compared to the overall sample. Tetrabenazine was not effective, as used here, in augmenting clinical response in treatment-resistant schizophrenia. It may be premature, however, to discount the potential benefits of VMAT2 inhibitors in treating psychosis in light of what is presently understood regarding presynaptic DA's role and evidence that "endogenous sensitization" may occur over the course of the illness.

Age at onset in Canadian OCD patients: mixture analysis and systematic comparison with other studies.

OBJECTIVE: This study aimed to determine the distributions of the age at onset (AAO) using mixture analysis and better develop the understanding of AAO as a clinical feature of obsessive-compulsive disorder. METHOD: Mixture analysis was used to identify sub-groups characterized by differences in AAO. Clinical features were analyzed for differences in AAO sub-groups using mixture analysis. Comparisons were made with AAO cut-offs used in previous studies using the 2-Sample Kolmogorov-Smirnov Test. RESULTS: Mixture analysis of our sample (n=196) yielded a combination of 2 normal theoretical distributions with means (SD) of 9.66 (3.12) for the early-onset sub-group and 21.1 (8.36) years for the late-onset sub-group. The sub-groups were divided by a cut-off of 15 years. As expected, a negative correlation was found between AAO and duration of illness. The early-onset subjects had significantly lower age at the time of the assessment and they tended to have more often panic attacks but were treated less often with benzodiazepines and other anti-anxiety medications. The comparison analysis showed significant difference in the AAO distribution between our sample and four other study samples. CONCLUSIONS: Our findings support the notion that different AAO sub-groups correspond with differences in clinical presentations of obsessive-compulsive disorder.

Parent of origin effect and differential allelic expression of BDNF Val66Met in suicidal behaviour.

OBJECTIVES: Brain-derived neurotrophic factor (BDNF) plays an important role in the pathophysiology of mood disorders and may also be involved in suicidal behaviour since BDNF levels are decreased in brain and plasma of suicide victims. Because the differential allelic expression of Val66Met BDNF gene on suicidal behaviour has not been investigated, we analyzed the parent-of-origin effect (POE) in suicide attempters and the differential expression of BDNF Val66Met alleles in suicide victims. METHODS: We performed a family-based association study and ETDT analyses of the Val66Met polymorphism in nuclear families with at least one subject affected by major psychosis with suicidal behaviour, and compared allele-specific mRNA levels in post-mortem brain samples from suicide and non-suicide victims. The subjects included in this study have diagnosis of schizophrenia, bipolar disorder type I and type II. RESULTS: Allele 3 in the GT repeat polymorphism was transmitted significantly more often to patients who attempted suicide (maternal transmissions: 46/22, P = 0.003; paternal transmissions: 55/30, P = 0.006). There was no significant difference between maternal and paternal transmission ratios. Furthermore, there was no significant difference in the ratio of Val/Met-specific mRNA expression between suicide victims and controls. CONCLUSIONS: These data do not support a role for allelic imbalance or POE of BDNF for suicidal behaviour in major psychoses.

Ethnicity and age at onset in bipolar spectrum disorders.

UNLABELLED: IntroductionTo determine the influence of ethnicity on the age at onset (AAO) and further understand the significance of AAO as a clinical marker of bipolar and schizoaffective disorders. METHODS: Admixture analysis was used to identify sub-groups characterized by differences in AAO. Differences in clinical features were analyzed for these sub-groups using multivariate logistic regression. Comparisons were made with previous studies using the 2-Sample Kolmogorov-Smirnov Test. RESULTS: Admixture analysis yielded a combination of 2 normal theoretical distributions with means (SD) of 16.9 (3.6) for the early-onset sub-group and 24.4 (9.2) years for the late-onset sub-group. The sub-groups were divided by a cut-off of 22 years. There were significant differences between the early and late onset bipolar patient populations regarding substance abuse comorbidity (P=.044) and psychotic features (P=.015). Ethnicity did not have a significant influence on the AAO.DiscussionThe associations between early-onset and higher incidence of psychosis and substance abuse in our sample are consistent with other studies exploring the AAO in bipolar disorder. CONCLUSION: Our findings support the notion of AAO as a clinical marker for the underlying heterogeneity of bipolar spectrum disorders. In particular, we found a strong overlap of early AAO with clinical features associated with greater severity and poor outcome.