Bipolar Disorder Linked with More Somatic Symptoms
June 23, 2016
Dr. Meyer is a Psychopharmacology Consultant, California Department of State Hospitals, Sacramento, California; Assistant Clinical Professor of Psychiatry, University of California, San Diego, San Diego, California; and Deputy Editor of Current Psychiatry.
Dr. Meyer is a consultant to Acadia Pharmaceuticals, Neurocrine Biosciences, Inc., and Teva Pharmaceutical Industries; and is a speaker for Acadia Pharmaceuticals, Alkermes, Allergan, Merck, Otsuka America, Inc., and Sunovion Pharmaceuticals.
Tetrabenazine is the only agent that has demonstrated significant efficacy for TD management, but its use involves slow titration, multiple daily dosing, CYP2D6 genotyping for doses >50 mg/d, and tolerability issues. For example, the most common adverse effects in the pivotal tetrabenazine Huntington’s disease trial were sedation/somnolence (tetrabenazine 31% vs 3% for placebo), insomnia (tetrabenazine 22% vs 0% for placebo), depression (tetrabenazine 19% vs 0% for placebo), fatigue (tetrabenazine 22% vs 13% for placebo), and akathisia (tetrabenazine 19% vs 0% for placebo).2 For comparison, the only adverse event occurring in ≥5% of deutetrabenazine participants and at a rate ≥2 times that of placebo in the pivotal Huntington’s disease trial was somnolence (11.1% for deutetrabenazine vs 4.4% for placebo).4
Deutetrabenazine has 80% oral bioavailability, and is rapidly converted to its active metabolites after oral dosing (Table 2).5 Linear dose dependence of Cmax and area under the curve (AUC) was observed for the active metabolites following single or multiple doses of deutetrabenazine (6 to 24 mg and 7.5 to 22.5 mg, twice daily).15 Cmax of deuterated α-DHTBZ and β-DHTBZ is reached within 3 to 4 hours after dosing, with a steady state ratio of 3:1 for the α-DHTBZ vs the β-DHTBZ form. Food had no effect on AUC, but did increase Cmax by 50%.5
Deutetrabenazine is metabolized through carbonyl reductase enzymes to its active metabolites, and these are further metabolized through multiple CYP pathways, predominantly 2D6 and to a lesser extent 3A4. The effect of CYP2D6 inhibition on the pharmacokinetics of deutetrabenazine and its α-DHTBZ and β-DHTBZ metabolites was studied in 24 healthy participants following a single 22.5 mg dose of deutetrabenazine given after 8 days of administration of the strong CYP2D6 inhibitor paroxetine, 20 mg/d. In the presence of paroxetine, systemic exposure (AUC) of α-DHTBZ was 1.9-fold higher and β-DHTBZ was 6.5-fold higher, resulting in an approximately 3-fold increase in AUC for total (α+β)-DHTBZ, with corresponding increases in mean half-life of approximately 1.5-fold and 2.7-fold, respectively.5 Neither deutetrabenazine or its metabolites are inhibitors or inducers of major CYP enzymes. Aside from VMAT2, the results of in vitro studies suggest that deutetrabenazine and its active metabolites are unlikely to inhibit most major drug transporters at clinically relevant concentrations.
Efficacy was established in two 12-week, double-blind, placebo-controlled trials of adult patients with TD (ages 18 to 80).6,7 Eligible participants had:
Exclusion criteria included treatment with tetrabenazine, reserpine, α-methyl-p-tyrosine, strong anticholinergic medications, dopamine antagonizing antiemetics (eg, metoclopramide, prochlorperazine, promethazine), dopamine agonists, levodopa, stimulants, or a monoamine oxidase inhibitor (MAOI) within 30 days of screening or baseline, or treatment with botulinum toxin within 3 months of screening; and presence of a neurologic condition that could confound TD assessments, serious untreated or undertreated psychiatric illness, or unstable medical illness. Patients with a history of or active suicidal ideation or behavior within 6 months of screening or score ≥11 on the depression subscale of the Hospital Anxiety and Depression Scale were excluded. Those participants with Fridericia-corrected QT interval values >450 milliseconds in men, >460 milliseconds in women, or >480 milliseconds in patients with a right bundle branch block on electrocardiography at screening also were excluded.
The flexible-dose TD study was performed in 117 participants randomized in a 1:1 manner to deutetrabenazine or placebo, both administered twice daily, titrated to optimal dosage (12 to 48 mg/d) over 6 weeks, and then administered at that dose for another 6 weeks.7 The population demographics were: mean age, 54.6 ± 10.3 years, 52.1% female, 69.2% white, and 80.3% receiving ongoing dopamine antagonists, with a mean TD duration of 74.7 ± 81.5 months. Sixty-eight percent had schizophrenia spectrum disorders, and 30% had mood disorders. The primary outcome was change in total AIMS score (items 1 to 7) assessed by central, independent raters. The mean baseline AIMS score for items 1 to 7 was 9.6 ± 3.9, with 82.9% of participants with baseline AIMS scores ≥6. Study treatment retention was high: placebo 88.1%, deutetrabenazine 89.7%.7 There was a mean 3 point decrease in AIMS score for deutetrabenazine compared with 1.4 for placebo (P = .019). Among those with baseline AIMS scores ≥6, there was a 3.4 point decrease in AIMS scores for deutetrabenazine compared with a 1.9 point decrease for placebo (P = .027). The only adverse effects that occurred in ≥5% of deutetrabenazine participants and at a rate ≥2 times the rate in placebo were insomnia (deutetrabenazine 6.9% vs placebo 1.7%) and akathisia (deutetrabenazine 5.2% vs placebo 0%).
The fixed-dose TD study was performed in 293 participants randomized in 1:1:1:1 manner to 1 of 3 fixed doses of deutetrabenazine (12 mg/d, 24 mg/d, or 36 mg/d) or placebo, both administered twice daily.6 The starting dose of deutetrabenazine was 6 mg twice daily. During the dose escalation period (through Week 4), the dose of study drug was increased weekly in increments of 6 mg/d until the randomized dose was achieved. Patients continued to receive the dose they were assigned to over a maintenance period of 8 weeks.6 The population demographics were: mean age, 56.4 ± 11.3 years, 55% female, 79% white, 76% receiving ongoing dopamine antagonists, with a mean TD duration of 67.2 ± 66 months. Sixty percent had schizophrenia spectrum disorders, and 36% had mood disorders. The primary outcome was change in AIMS total score (items 1 to 7) assessed by central, independent raters. The mean AIMS score at baseline was 9.5 ± 2.7 in the placebo group, and for deutetrabenazine: 9.6 ± 2.4 in the 12 mg/d group, 9.4 ± 2.9 in the 24 mg/d group, and 10.1 ± 3.2 in the 36 mg/d group. The 24 mg/d and 36 mg/d doses significantly reduced AIMS scores from baseline vs placebo: 36 mg: −3.3 (0.42) vs −1.4 (0.41) (P = .001); 24 mg: −3.2 (0.45) vs −1.4 (0.41) (P = .003). Study treatment retention rates were high: placebo 90.5%, deutetrabenazine 88%. Across all doses, only 1 adverse effect occurred in ≥5% of deutetrabenazine participants: headache (5% deutetrabenazine vs 6% placebo). At the highest dose, 36 mg/d, the only adverse effects that occurred in ≥5% of participants were diarrhea (7% deutetrabenazine vs 3% placebo) and headache (7% deutetrabenazine vs 6% placebo).
Outcome. In the flexible-dose study (mean dose 38.8 ± 7.92 mg/d), the deutetrabenazine arm experienced a mean 30% reduction in AIMS scores from baseline at the Week 12 endpoint. Compared with placebo, the mean reduction in AIMS scores (standard error) was: −3.0 (0.45) deutetrabenazine vs −1.6 (0.46) placebo (P = .019).7 For the fixed-dose study, the 24 mg/d and 36 mg/d doses significantly reduced AIMS scores from baseline vs placebo: 36 mg: −3.3 (0.42) vs −1.4 (0.41) (P = .001); 24 mg: −3.2 (0.45) vs −1.4 (0.41) (P = .003). In addition to these mean changes from baseline, 35% of the 24 mg/d group and 33% of the 36 mg/d group demonstrated ≥50% reduction in AIMS scores.6
In the 2 phase 3 trials, there were no adverse effects occurring with an incidence ≥5% and at least twice the rate of placebo.5 Discontinuations because of adverse events were low in both pivotal studies across all treatment groups: 3.4% for placebo vs 1.7% for deutetrabenazine in the flexible-dose trial,7 and 3% for placebo vs 4% for deutetrabenazine in the fixed-dose study.6 In neither trial were there clinically significant changes in ratings of depression, suicidality, parkinsonism, or schizophrenia symptoms. The mean QT prolongation in healthy volunteers is described above.
Unique properties. Deutetrabenazine utilizes the greater bond strength of the carbon–deuterium bond to slow CYP metabolism, resulting in prolonged duration of action that is well tolerated, and provides significant efficacy.
Why Rx? The reasons to prescribe deutetrabenazine for TD patients include:
The recommended starting dosage of deutetrabenazine is 6 mg twice daily taken with food, increasing by 6 mg/d weekly as needed, with a maximum dose of 48 mg/d or 36 mg/d in those taking strong CYP2D6 inhibitors or who are 2D6 poor metabolizers. Deutetrabenazine is contraindicated in patients with hepatic impairment (as determined by Child-Pugh criteria16). There are no data in patients with renal impairment. The combined efficacy and tolerability of dosages >48 mg/d has not been evaluated. Overdoses of tetrabenazine ranging from 100 to 1,000 mg have been reported in the literature and were associated with acute dystonia, oculogyric crisis, nausea and vomiting, sweating, sedation, hypotension, confusion, diarrhea, hallucinations, rubor, and tremor.5
When used for TD, deutetrabenazine is contraindicated for patients taking reserpine, tetrabenazine, valbenazine, or MAOIs, and for patients with hepatic impairment. As with most medications, there are no data on deutetrabenazine use in pregnant women; however, oral administration of deutetrabenazine (5, 10, or 30 mg/kg/d) or tetrabenazine (30 mg/kg/d) to pregnant rats during organogenesis had no clear effect on embryofetal development. The highest dose tested was 6 times the maximum recommended human dose of 48 mg/d on a body surface area (mg/m2) basis. There are no data on the presence of deutetrabenazine or its metabolites in human milk, the effects on the breastfed infant, or the effects of the drug on milk production.
Deutetrabenazine is the second agent approved to treat tardive dyskinesia (TD) in the United States. Deutetrabenazine is well tolerated, with completion rates of 88% to 90% in two 12-week pivotal trials. At the recommended dosages deutetrabenazine is not associated with development of depression or suicidality, insomnia, or parkinsonism when used for managing TD. Deutetrabenazine has metabolites that are vesicular monoamine transporter type 2 antagonists, a feature that appears to be effective for the treatment of TD.
Drug Brand Names
Amantadine • Symmetrel
Clonazepam • Klonopin
Deutetrabenazine • Austedo
Metoclopramide • Reglan
Prochlorperazine • Compro
Promethazine • Phenergan
Reserpine • Serpasil
Tetrabenazine • Xenazine
Valbenazine • Ingrezza
Immunizations for psychiatric patients, Pt 2
June 23, 2016