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ObjectiveTo determine whether tetrabenazine (TBZ) use is associated with an increased incidence of depression and/or suicidal ideation.MethodsIn this retrospective cross-sectional study of the Enroll-HD database, we used multiple logistic regression analyses to determine whether TBZ use is associated with an increased incidence of depression and/or suicidal ideation. For both dependent variables (depression and suicidality), separate analyses were conducted on (1) all participants, (2) only participants with a history of depression, and (3) only participants with no history of depression. Adjustments were made for CAG repeat length, total motor score, total functional capacity, Symbol Digit Modalities Test score, sex, disease duration, history of depression (when applicable), antipsychotic use, and antidepressant use.ResultsCompared to participants who were not using TBZ (n = 3,548), TBZ users (n = 543) did not have an increased risk of depression (odds ratio [OR] = 0.78, p = 0.064). Participants taking TBZ actually had a relatively lower risk of suicidality (OR = 0.61, p = 0.043). Among only participants with a history of depression, those using TBZ had a lower incidence of depression (OR = 0.71, p = 0.016) and suicidal ideation (OR = 0.57, p = 0.028) compared to those not using TBZ. Finally, among only participants with no history of depression, TBZ use was not associated with a higher incidence of depression (OR = 1.59, p = 0.18) or suicidality (OR = 1.43, p = 0.66) compared to those who were not using TBZ.ConclusionsTBZ use was not associated with an increased incidence of depression or suicidality. These findings suggest that TBZ may be safe to use in patients with Huntington disease who have a history of depression.

We thank Sampaio et al. for the comment on our article.1 The Enroll-HD dataset does not contain information regarding why participants abandoned a particular therapy.2 Therefore, making the assumption that abandonment of tetrabenazine (TBZ) therapy occurs secondary to depression/suicidality could falsely induce a spurious positive association between TBZ and depression/suicidality that is equally dangerous. Furthermore, participants who abandoned TBZ prior to their baseline visit were included in the TBZ nonuser group.1 If the assumptions being made by Sampaio et al. are accurate, then it is reasonable to assume that an increased percentage of participants in the TBZ nonuser group have a history of depression. However, the percentage of participants with a history of depression is nearly identical between the 2 groups,1 indicating that few participants discontinued TBZ due to depression/suicidality.

Objectives: We aimed to describe the clinical phenotype conferred by the intermediate-length huntingtin allele CAG repeat expansion in a population-based study. Methods: The Prospective Huntington At Risk Observational Study (PHAROS) enrolled adults at risk for Huntington disease (HD). They were assessed approximately every 9 months with the Unified Huntington’s Disease Rating Scale (UHDRS) by investigators unaware of participants9 gene status. UHDRS scores were compared according to the Huntingtin gene CAG repeat number: expanded >36, intermediate 27–35, and nonexpanded controls Results: Fifty (5.1%) of the 983 participants had an intermediate allele (IA). They were similar to controls on UHDRS motor, cognitive, and functional measures, but significantly worse behaviorally on apathy and suicidal ideation. On 5 of the 9 other behavioral items and on total behavior, the IA group9s scores were worse than those of controls and expanded participants, who themselves scored significantly worse than controls on 6 behavioral measures. Retention rates at 4 years were 48% for the IA group compared to 58% and 60% for the expanded and control groups. Conclusions: In a cohort at risk for HD, the IA was associated with significant behavioral abnormalities but normal motor and cognition. This behavioral phenotype may represent a prodromal stage of HD, with the potential for subsequent clinical manifestations, or be part of a distinct phenotype conferred by pathology independent of the CAG expansion length.

Objective: To explore the behavioral phenotype of individuals with an intermediate CAGn expansion in a cohort of subjects at-risk for Huntington disease (HD). Background Recent reports suggest that some individuals with intermediate CAGn repeat expansions in the huntingtin gene develop manifest HD (Mov Disord 2007;22:127). We previously demonstrated that PHAROS participants with the intermediate alleles had behavioral scores on the Unified Huntington Disease Rating Scale 999 (UHDRS 999) similar to gene expanded participants. We now further explore the behavioral features associated with the intermediate CAGn expansion. Design/Methods: Subjects at-risk for HD in the Prospective Huntington At Risk Observational Study (PHAROS) were assessed in all domains of the UHDRS by investigators unaware of participant gene status. Data were analyzed according to CAG repeat length: expanded > 36, intermediate = 27- 35, and non-expanded 39). Pair-wise analyses compared individual behavioral items of the UHDRS. Results: Of the 983 participants analyzed, 50 (5.2%) had an intermediate repeat expansion, 346 (35.1%) were expanded, and 587 (59.7%) were non-expanded. Like those with an expanded allele, participants with an intermediate expansion scored high on the UHDRS measure of apathy.Low self esteem/guilt and irritability were also increased in the intermediate repeat group, and approached the gene expanded group in this regard. Conclusions: In a cohort of individuals at-risk for HD, those with an intermediate CAGn expansion were motorically, cognitively and functionally similar to those without the gene expansion. However, they exhibited apathy and a tendency towards other behavioral abnormalities comparable to the gene expanded group. Though traditionally considered non-pathologic, the intermediate repeat length may manifest as a distinctly behavioral phenotype. Future studies in larger populations of individuals with intermediate CAGn expansions are needed to confirm these findings. Supported by: Huntington Study Group. Disclosure: Dr. Killoran has nothing to disclose. Dr. Biglan has received personal compensation for activities with Lundbeck and Theravance Inc as a consultant. Dr. Biglan received research support from Presbyterian Home of Central New York, Susquehana Nursing and Rehabilitation Center, Marvell Inc, and Google. Dr. Jankovic has received personal compensation for activities with Allergan, Inc., Chelsea Therapeutics, Serono Inc., Merz Pharma, Lundbeck Research USA, Inc, Teva Neuroscience as a consultant. Dr. Jankovic has received personal compensation in an editorial capacity for Medlink: Neurology in Clinical Practice. Dr. Jankovic has received research support from Allergan, Inc, Allon Therapeutics, Ceregene, Inc., Chelsea Therapeutics; Diana Helis Henry Medical Research Foundation, Serono Inc., Huntington9s Disease Society of America, Huntington Study Group, Impax Pharmaceuticals, Ipsen Limited, Lundbeck Research USA, Inc. Dr. Eberly has nothing to disclose. Dr. Kayson has nothing to disclose. Dr. Oakes has received personal compensation in an editorial capacity for the journal "Lifetime Data Analysis". Dr. Young has received royalty payments from Novartis. Dr. Young has received research support from Novartis. Dr. Shoulson has received personal compensation for activities with AstraZeneca, Keryx Pharmaceuticals, Jazz Pharmaceuticals, Neurogen Corp, Alexa Molecular Delivery Corp, Nouvel Pharma, Novartis, and Westat. Dr. Shoulson has received personal compensation in an editorial capacity for Archives of Neurology. Dr. Shoulson has received research support from NIH, NHGRI, NINDS, Cephalon, Inc., Pharmacia and Upjohn, Inc. (Pfizer), Parallel Group, and Prestwick Pharmaceuticals, Inc.