Journal of Huntington’s Disease 2 (2013) 509–515 DOI 10.3233/JHD-130071 IOS Press
509
Research Report
Depressed Mood and Suicidality in Individuals Exposed to Tetrabenazine in a Large Huntington Disease Observational Study E. Ray Dorseya,∗ , Alicia F.D. Brochta , Paige E. Nicholsb , Kristin C. Darwinc , Karen E. Andersond , Christopher A. Becke , Sonal Singhf , Kevin M. Biglang and Ira Shoulsonh a Center
for Human Experimental Therapeutics, University of Rochester Medical Center, Rochester, NY, USA of Neurology, Johns Hopkins School of Medicine, Baltimore, MD, USA c School of Medicine, Johns Hopkins School of Medicine, Baltimore, MD, USA d Department of Psychiatry and Neurology, Georgetown University of Medical Center, Washington, DC, USA e Department of Biostatistics and Computational Biology, University of Rochester Medical Center, Rochester, NY, USA f Department of General Internal Medicine, Johns Hopkins School of Medicine, Baltimore, MD, USA g Department of Neurology, University of Rochester Medical Center, Rochester, NY, USA h Department of Neurology, Georgetown University of Medical Center, Washington, DC, USA b Department
Abstract. Background: Tetrabenazine, a treatment for chorea in Huntington disease, carries a boxed warning due to safety, especially related to suicidality. Objective: To compare the frequency of depressed mood and suicidality among a closely monitored cohort of individuals with Huntington disease who were exposed and not exposed to tetrabenazine. Methods: A longitudinal prospective study involving 1360 individuals with HD evaluated at 48 research centers in Australia, Canada, and the United States was examined for frequency of depressed mood that triggered a risk assessment, suicidal thoughts, suicide attempts, and completed suicide among individuals with prior, new, and no exposure to tetrabenazine.. Seventy-seven individuals were on tetrabenazine at study enrollment (prior exposure), 64 individuals were exposed to tetrabenazine during the study’s course (new exposure), and 1219 individuals had no exposure to tetrabenazine. Results: The hazard ratio for depressed mood among those with prior exposure to tetrabenazine compared to no exposure was 0.9 (95% CI, 0.5–1.6) and for those with new exposure compared to no exposure was 1.2 (95% CI, 0.8–1.9). One individual (1.3%) with prior exposure, one individual (1.6%) with new exposure, and 35 individuals (2.9%) with no exposure to tetrabenazine reported suicidal thoughts. The hazard ratio for suicidal ideation among those with prior exposure to tetrabenazine compared to no exposure was 0.5 (95% CI, 0.1–3.8) and for those with new exposure to tetrabenazine compared to no exposure was 0.6 (95% CI, 0.1–4.4). Among individuals with prior or new exposure to tetrabenazine, no suicide attempts or suicides occurred. Among those with no exposure to tetrabenazine 17 suicide attempts (1.4%) and four suicides (0.3%) occurred. Conclusions: In a large observational study with close clinical supervision, tetrabenazine treatment was not associated with an increased risk of depressed mood, suicidal ideation, suicide attempts, or suicide. Keywords: Depression, Huntington disease, suicide, tetrabenazine, U.S. Food and Drug Administration ∗ Correspondence to: Ray Dorsey, MD, MBA, 265 Crittenden Boulevard, CU 420694, Rochester, NY 14642, USA. Tel.: +1 585 276 6824; Fax: +1 585 461 4594; E-mail: ray.dorsey@ chet.rochester.edu.
ISSN 1879-6397/13/$27.50 © 2013 – IOS Press and the authors. All rights reserved
510
E.R. Dorsey et al. / Depressed Mood, Suicidality, and Tetrabenazine
INTRODUCTION Tetrabenazine is an efficacious drug for the treatment of chorea associated with Huntington disease [1, 2]. However, safety concerns, especially related to depression and suicide, are associated with the drug [3]. In 2008, the US Food and Drug Administration (FDA) approved tetrabenazine (brand name: Xenazine) with a boxed warning for depression and suicidality that states, “Xenazine can increase the risk of depression and suicidal thoughts and behavior (suicidality) in patients with Huntington’s disease”[4]. These safety concerns stem in part from the mechanism of tetrabenazine. The drug acts as a reversible inhibitor of human vesicular monoamine transporter 2, which leads to the depletion of monoamines including dopamine, norepinephrine, and serotonin from nerve terminals [5], and has the potential to worsen depression [6]. In the pivotal phase III study leading to the drug’s approval, depression scores as measured by the Hamilton Depression Scale improved in those randomized to placebo and those randomized to tetrabenazine, but the improvement in those randomized to tetrabenazine was significantly less than those randomized to placebo [7]. In addition, in the pivotal phase III study leading to the drug’s approval, one of the 54 participants randomized to tetrabenazine committed suicide [7]. However, given the small and short duration of the study, the frequency of suicide in HD, it remains unclear whether TBZ was causative. Depression and suicidality are both common in Huntington disease (HD). Compared to the general population, depression is twice as common [8], and suicide is more frequent [9–13], is attempted at least once by over 25% of individuals with HD, [6] and accounts for 5 to 7% of deaths [11, 12, 14]. In a recently completed, multi-center longitudinal observational study, we looked at the frequency of depressed mood, suicidal thought, suicide attempts, and suicides among individuals with HD in order to evaluate the effect of tetrabenazine on depressed mood and suicidality in that population.
MATERIALS AND METHODS Study We examined the safety of tetrabenazine in individuals with manifest Huntington disease who participated in the recently completed Cooperative Huntington Observational Research Trial (COHORT). COHORT
was a prospective longitudinal study of individuals from families affected by Huntington disease at 48 research centers in Australia (n = 2), Canada (n = 6), and the United States (n = 40) [15]. Data collection for the study began February 14, 2006 and ended June 30, 2011. Tetrabenazine was available from the onset of the study at study sites in Australia and Canada and became available for US COHORT participants in 2008 following its approval by the FDA. Study visits occurred annually and involved clinical assessments related to Huntington disease as measured by the Unified Huntington Disease Rating Scale (UHDRS) [16], the Mini-Mental State Examination [17], annually acquired lists of current medications, and reports of new clinical and mental health events. To help ensure the safety of the research participants, study investigators referred individuals who reported scores above a pre-specified threshold on the UHDRS for depressed mood or suicidal ideation to mental health professionals. In addition, study sites were required to report events that included suicide attempts, suicides, deaths other than suicide, and premature withdrawals, to the study’s leadership within three working days of the site becoming aware of the event. Participants For this analysis, we restricted the population to individuals who at any study visit had documentation of clinically manifest Huntington disease, which was determined by a study investigator’s affirmative response to question 80 on the UHDRS: “Based on the entire UHDRS, do you believe with a confidence level (greater than or equal to) 99% that this subject has manifest (Huntington disease)?”[16] and a CAG trinucleotide repeat length of greater than or equal to 36. From participants’ medication logs, we identified individuals who took tetrabenazine at some point during the course of the study. Based on the start and end date for the use of the drug, we quantified the number of years that participants were exposed to the drug (participant-years). If no end date was provided, we used the last date of observation for the research participant. We defined three groups of participants based on their history of exposure to tetrabenazine. Those who entered the COHORT study already on tetrabenazine were classified as having prior exposure (n = 77). Participants who had their first exposure to tetrabenazine during the course of the COHORT study were classified as having new exposure (n = 64) and those who never were exposed to tetrabenazine were classified as having no exposure (n = 1219).
E.R. Dorsey et al. / Depressed Mood, Suicidality, and Tetrabenazine
Assessments For this analysis, we focused on depressed mood, suicidality, and mortality outcomes associated with the use of tetrabenazine during the course of the study. As depression was not systematically assessed in the COHORT study, we focused on “depressed mood” as measured by the UHDRS question 25a, “Within the past month, how often have you been feeling sad, down, or ‘blue’?”. As part of the study, individuals who scored a 3 (“frequently, several times a week”) or greater on question 25a or 25b on the severity of the depressed mood were counseled to see a mental health professional. For this analysis, we used that same determination for identifying individuals with depressed mood. To measure suicidal ideation, we determined the frequency of suicidal thoughts as measured by the UHDRS question 28a, “Within the past month, how often have you thought about hurting yourself or ending it all?”. Participants who had a score of 2 (sometimes thought about suicide-at least once a month) or greater on Q28a (frequency of suicidal thoughts) were determined to have experienced suicidal thoughts [18]. We also examined the number of suicide attempts as reported and assessed by site investigators and completed suicides among individuals who reported exposure to tetrabenazine during or prior to the study’s conduct. For individuals who started tetrabenazine in between annual follow-up visits, we assigned all suicidal thoughts that were reported at their next visit as associated with an individual who was exposed to tetrabenazine. Analysis Baseline characteristics of individuals with Huntington disease with new exposure, prior exposure, and no exposure to tetrabenazine were compared using Fisher’s exact test for proportions and ANOVA for continuous outcomes. Cox proportional-hazards regression models were used to estimate the risk of depressed mood, suicidal thoughts, suicide attempts, suicide completion, and death. These models included adjustment for all baseline characteristics found to be imbalanced across the exposure groups at the 5% significance level. This included age, education, employment status, history of seeing a mental health professional, UHDRS motor and chorea scores, total functional capacity (an assessment of an individual’s ability to work, manage finances, conduct domestic chores, perform activities of daily living, and level of care required) [16], history of antipsychotic use, and
511
history of antidepressant use. Estimated hazard ratios (HR) with 95% confidence intervals (CI) and p-values were calculated for comparing the prior and new exposure groups to the unexposed group. RESULTS Participants During COHORT, 1360 individuals with manifest Huntington disease enrolled (Table 1). Of these 1360 individuals, 77 (5.7%) reported prior exposure to tetrabenazine accounting for 139 participant-years of observation and 64 (4.7%) reported new exposure to tetrabenazine accounting for 218 patient-years of observation. The average daily of dose of tetrabenazine on the initial assessment of those with prior exposure was 46.4 mg (SD 26.6) and for those with new exposure, the average daily dose was 32.9 mg (SD 16.5). The vast majority, 1219 participants (89.6%), reported no exposure to tetrabenazine during the course of the study, accounting for 3313 participant-years of observation. Baseline characteristics of the prior exposure, new exposure, and no exposure groups differed in important ways (Table 1). Among the important differences, those with prior exposure (before entering the study) to tetrabenazine were older, less likely to have completed high school, more impaired functionally, and more likely to have had a history of antipsychotic drug use. By contrast, those with new exposure to tetrabenazine were more educated and more likely to be employed than those with no exposure to tetrabenazine. Those with higher (worse) motor and maximal chorea scores were more likely to be exposed to tetrabenazine. Outcomes In the COHORT study, 15 individuals (19.5%) with prior exposure, 19 individuals (29.7%) with new exposure and 307 individuals (25.2%) with no exposure to tetrabenazine had a depressed mood. Compared to those with no exposure to tetrabenazine, the hazard ratio for depressed mood was (0.9 [95% CI, 0.5, 1.6]; P = 0.78) among those with prior exposure and (1.2 [95% CI, 0.8, 1.9]; P = 0.45) among those with new exposure to tetrabenazine (Table 2). During the COHORT study, one individual (1.3%) with prior exposure, one individual (1.6%) with new exposure, and 35 individuals (2.9%) with no exposure to tetrabenazine reported suicidal thoughts. The hazard ratio for suicidal ideation was not elevated among
512
E.R. Dorsey et al. / Depressed Mood, Suicidality, and Tetrabenazine Table 1 Baseline characteristics of individuals with Huntington disease who were exposed and not exposed to tetrabenazine
Characteristic
Prior exposure to tetrabenazine (N = 77)
New exposure to tetrabenazine (N = 64)
No exposure to tetrabenazine (N = 1219)
P-value
55.2 (11.9) 58.4 89.6 2.6 2.6 14.3 83.1 55.8 7.8 62.3
51.4 (11.8) 53.1 95.3 1.6 4.7 6.3 89.1 90.6 28.1 59.4
50.9 (12.2) 52.6 93.4 3.5 4.3 15.7 80.1 71.5 20.1 59.2
.0106 .6319 .3662 .9267 .8359 .1069 .1737
509
Research Report
Depressed Mood and Suicidality in Individuals Exposed to Tetrabenazine in a Large Huntington Disease Observational Study E. Ray Dorseya,∗ , Alicia F.D. Brochta , Paige E. Nicholsb , Kristin C. Darwinc , Karen E. Andersond , Christopher A. Becke , Sonal Singhf , Kevin M. Biglang and Ira Shoulsonh a Center
for Human Experimental Therapeutics, University of Rochester Medical Center, Rochester, NY, USA of Neurology, Johns Hopkins School of Medicine, Baltimore, MD, USA c School of Medicine, Johns Hopkins School of Medicine, Baltimore, MD, USA d Department of Psychiatry and Neurology, Georgetown University of Medical Center, Washington, DC, USA e Department of Biostatistics and Computational Biology, University of Rochester Medical Center, Rochester, NY, USA f Department of General Internal Medicine, Johns Hopkins School of Medicine, Baltimore, MD, USA g Department of Neurology, University of Rochester Medical Center, Rochester, NY, USA h Department of Neurology, Georgetown University of Medical Center, Washington, DC, USA b Department
Abstract. Background: Tetrabenazine, a treatment for chorea in Huntington disease, carries a boxed warning due to safety, especially related to suicidality. Objective: To compare the frequency of depressed mood and suicidality among a closely monitored cohort of individuals with Huntington disease who were exposed and not exposed to tetrabenazine. Methods: A longitudinal prospective study involving 1360 individuals with HD evaluated at 48 research centers in Australia, Canada, and the United States was examined for frequency of depressed mood that triggered a risk assessment, suicidal thoughts, suicide attempts, and completed suicide among individuals with prior, new, and no exposure to tetrabenazine.. Seventy-seven individuals were on tetrabenazine at study enrollment (prior exposure), 64 individuals were exposed to tetrabenazine during the study’s course (new exposure), and 1219 individuals had no exposure to tetrabenazine. Results: The hazard ratio for depressed mood among those with prior exposure to tetrabenazine compared to no exposure was 0.9 (95% CI, 0.5–1.6) and for those with new exposure compared to no exposure was 1.2 (95% CI, 0.8–1.9). One individual (1.3%) with prior exposure, one individual (1.6%) with new exposure, and 35 individuals (2.9%) with no exposure to tetrabenazine reported suicidal thoughts. The hazard ratio for suicidal ideation among those with prior exposure to tetrabenazine compared to no exposure was 0.5 (95% CI, 0.1–3.8) and for those with new exposure to tetrabenazine compared to no exposure was 0.6 (95% CI, 0.1–4.4). Among individuals with prior or new exposure to tetrabenazine, no suicide attempts or suicides occurred. Among those with no exposure to tetrabenazine 17 suicide attempts (1.4%) and four suicides (0.3%) occurred. Conclusions: In a large observational study with close clinical supervision, tetrabenazine treatment was not associated with an increased risk of depressed mood, suicidal ideation, suicide attempts, or suicide. Keywords: Depression, Huntington disease, suicide, tetrabenazine, U.S. Food and Drug Administration ∗ Correspondence to: Ray Dorsey, MD, MBA, 265 Crittenden Boulevard, CU 420694, Rochester, NY 14642, USA. Tel.: +1 585 276 6824; Fax: +1 585 461 4594; E-mail: ray.dorsey@ chet.rochester.edu.
ISSN 1879-6397/13/$27.50 © 2013 – IOS Press and the authors. All rights reserved
510
E.R. Dorsey et al. / Depressed Mood, Suicidality, and Tetrabenazine
INTRODUCTION Tetrabenazine is an efficacious drug for the treatment of chorea associated with Huntington disease [1, 2]. However, safety concerns, especially related to depression and suicide, are associated with the drug [3]. In 2008, the US Food and Drug Administration (FDA) approved tetrabenazine (brand name: Xenazine) with a boxed warning for depression and suicidality that states, “Xenazine can increase the risk of depression and suicidal thoughts and behavior (suicidality) in patients with Huntington’s disease”[4]. These safety concerns stem in part from the mechanism of tetrabenazine. The drug acts as a reversible inhibitor of human vesicular monoamine transporter 2, which leads to the depletion of monoamines including dopamine, norepinephrine, and serotonin from nerve terminals [5], and has the potential to worsen depression [6]. In the pivotal phase III study leading to the drug’s approval, depression scores as measured by the Hamilton Depression Scale improved in those randomized to placebo and those randomized to tetrabenazine, but the improvement in those randomized to tetrabenazine was significantly less than those randomized to placebo [7]. In addition, in the pivotal phase III study leading to the drug’s approval, one of the 54 participants randomized to tetrabenazine committed suicide [7]. However, given the small and short duration of the study, the frequency of suicide in HD, it remains unclear whether TBZ was causative. Depression and suicidality are both common in Huntington disease (HD). Compared to the general population, depression is twice as common [8], and suicide is more frequent [9–13], is attempted at least once by over 25% of individuals with HD, [6] and accounts for 5 to 7% of deaths [11, 12, 14]. In a recently completed, multi-center longitudinal observational study, we looked at the frequency of depressed mood, suicidal thought, suicide attempts, and suicides among individuals with HD in order to evaluate the effect of tetrabenazine on depressed mood and suicidality in that population.
MATERIALS AND METHODS Study We examined the safety of tetrabenazine in individuals with manifest Huntington disease who participated in the recently completed Cooperative Huntington Observational Research Trial (COHORT). COHORT
was a prospective longitudinal study of individuals from families affected by Huntington disease at 48 research centers in Australia (n = 2), Canada (n = 6), and the United States (n = 40) [15]. Data collection for the study began February 14, 2006 and ended June 30, 2011. Tetrabenazine was available from the onset of the study at study sites in Australia and Canada and became available for US COHORT participants in 2008 following its approval by the FDA. Study visits occurred annually and involved clinical assessments related to Huntington disease as measured by the Unified Huntington Disease Rating Scale (UHDRS) [16], the Mini-Mental State Examination [17], annually acquired lists of current medications, and reports of new clinical and mental health events. To help ensure the safety of the research participants, study investigators referred individuals who reported scores above a pre-specified threshold on the UHDRS for depressed mood or suicidal ideation to mental health professionals. In addition, study sites were required to report events that included suicide attempts, suicides, deaths other than suicide, and premature withdrawals, to the study’s leadership within three working days of the site becoming aware of the event. Participants For this analysis, we restricted the population to individuals who at any study visit had documentation of clinically manifest Huntington disease, which was determined by a study investigator’s affirmative response to question 80 on the UHDRS: “Based on the entire UHDRS, do you believe with a confidence level (greater than or equal to) 99% that this subject has manifest (Huntington disease)?”[16] and a CAG trinucleotide repeat length of greater than or equal to 36. From participants’ medication logs, we identified individuals who took tetrabenazine at some point during the course of the study. Based on the start and end date for the use of the drug, we quantified the number of years that participants were exposed to the drug (participant-years). If no end date was provided, we used the last date of observation for the research participant. We defined three groups of participants based on their history of exposure to tetrabenazine. Those who entered the COHORT study already on tetrabenazine were classified as having prior exposure (n = 77). Participants who had their first exposure to tetrabenazine during the course of the COHORT study were classified as having new exposure (n = 64) and those who never were exposed to tetrabenazine were classified as having no exposure (n = 1219).
E.R. Dorsey et al. / Depressed Mood, Suicidality, and Tetrabenazine
Assessments For this analysis, we focused on depressed mood, suicidality, and mortality outcomes associated with the use of tetrabenazine during the course of the study. As depression was not systematically assessed in the COHORT study, we focused on “depressed mood” as measured by the UHDRS question 25a, “Within the past month, how often have you been feeling sad, down, or ‘blue’?”. As part of the study, individuals who scored a 3 (“frequently, several times a week”) or greater on question 25a or 25b on the severity of the depressed mood were counseled to see a mental health professional. For this analysis, we used that same determination for identifying individuals with depressed mood. To measure suicidal ideation, we determined the frequency of suicidal thoughts as measured by the UHDRS question 28a, “Within the past month, how often have you thought about hurting yourself or ending it all?”. Participants who had a score of 2 (sometimes thought about suicide-at least once a month) or greater on Q28a (frequency of suicidal thoughts) were determined to have experienced suicidal thoughts [18]. We also examined the number of suicide attempts as reported and assessed by site investigators and completed suicides among individuals who reported exposure to tetrabenazine during or prior to the study’s conduct. For individuals who started tetrabenazine in between annual follow-up visits, we assigned all suicidal thoughts that were reported at their next visit as associated with an individual who was exposed to tetrabenazine. Analysis Baseline characteristics of individuals with Huntington disease with new exposure, prior exposure, and no exposure to tetrabenazine were compared using Fisher’s exact test for proportions and ANOVA for continuous outcomes. Cox proportional-hazards regression models were used to estimate the risk of depressed mood, suicidal thoughts, suicide attempts, suicide completion, and death. These models included adjustment for all baseline characteristics found to be imbalanced across the exposure groups at the 5% significance level. This included age, education, employment status, history of seeing a mental health professional, UHDRS motor and chorea scores, total functional capacity (an assessment of an individual’s ability to work, manage finances, conduct domestic chores, perform activities of daily living, and level of care required) [16], history of antipsychotic use, and
511
history of antidepressant use. Estimated hazard ratios (HR) with 95% confidence intervals (CI) and p-values were calculated for comparing the prior and new exposure groups to the unexposed group. RESULTS Participants During COHORT, 1360 individuals with manifest Huntington disease enrolled (Table 1). Of these 1360 individuals, 77 (5.7%) reported prior exposure to tetrabenazine accounting for 139 participant-years of observation and 64 (4.7%) reported new exposure to tetrabenazine accounting for 218 patient-years of observation. The average daily of dose of tetrabenazine on the initial assessment of those with prior exposure was 46.4 mg (SD 26.6) and for those with new exposure, the average daily dose was 32.9 mg (SD 16.5). The vast majority, 1219 participants (89.6%), reported no exposure to tetrabenazine during the course of the study, accounting for 3313 participant-years of observation. Baseline characteristics of the prior exposure, new exposure, and no exposure groups differed in important ways (Table 1). Among the important differences, those with prior exposure (before entering the study) to tetrabenazine were older, less likely to have completed high school, more impaired functionally, and more likely to have had a history of antipsychotic drug use. By contrast, those with new exposure to tetrabenazine were more educated and more likely to be employed than those with no exposure to tetrabenazine. Those with higher (worse) motor and maximal chorea scores were more likely to be exposed to tetrabenazine. Outcomes In the COHORT study, 15 individuals (19.5%) with prior exposure, 19 individuals (29.7%) with new exposure and 307 individuals (25.2%) with no exposure to tetrabenazine had a depressed mood. Compared to those with no exposure to tetrabenazine, the hazard ratio for depressed mood was (0.9 [95% CI, 0.5, 1.6]; P = 0.78) among those with prior exposure and (1.2 [95% CI, 0.8, 1.9]; P = 0.45) among those with new exposure to tetrabenazine (Table 2). During the COHORT study, one individual (1.3%) with prior exposure, one individual (1.6%) with new exposure, and 35 individuals (2.9%) with no exposure to tetrabenazine reported suicidal thoughts. The hazard ratio for suicidal ideation was not elevated among
512
E.R. Dorsey et al. / Depressed Mood, Suicidality, and Tetrabenazine Table 1 Baseline characteristics of individuals with Huntington disease who were exposed and not exposed to tetrabenazine
Characteristic
Prior exposure to tetrabenazine (N = 77)
New exposure to tetrabenazine (N = 64)
No exposure to tetrabenazine (N = 1219)
P-value
55.2 (11.9) 58.4 89.6 2.6 2.6 14.3 83.1 55.8 7.8 62.3
51.4 (11.8) 53.1 95.3 1.6 4.7 6.3 89.1 90.6 28.1 59.4
50.9 (12.2) 52.6 93.4 3.5 4.3 15.7 80.1 71.5 20.1 59.2
.0106 .6319 .3662 .9267 .8359 .1069 .1737
