Generic Name

Deutetrabenazine

Mechanism

• Selective, reversible inhibition of the vesicular monoamine transporter‑2 (VMAT2)
• ↓ dopamine uptake into synaptic vesicles → reduced vesicular dopamine release
• Decreases presynaptic dopamine turnover, diminishing hyperkinetic movements
• Deuterium atoms on the molecule slow oxidative metabolism, lowering plasma levels of toxic metabolites and potentially reducing side‑effect burden

Pharmacokinetics

• Route: Oral (capsule)
• Absorption: Peak plasma concentrations (tmax) ~ 1–2 h post‑dose
• Bioavailability: ~ 90 % (relative to tetrabenazine)
• Metabolism: Primarily CYP2D6 and CYP3A4 mediated to 3‑hydroxy‑deutetrabenazine, an active metabolite
• Half‑life: ~ 3.5–4 h (active metabolite) — steady state achieved in 2–3 weeks
• Protein binding: ~ 99 %
• Elimination: Renal and fecal routes; minimal hepatic clearance of parent drug due to deuteration

Indications

• Tardive dyskinesia (secondary to chronic antipsychotic use)
• Huntington disease chorea (movement disorder in Huntington disease)

Contraindications

• Contraindications:
• Severe hepatic impairment (Child‑Pugh C)
• Personal or family history of severe depression or suicidality without careful monitoring
• Warnings:
• Depression, suicidal ideation – assess risk at baseline and periodically; consider paroxetine or fluoxetine for co‑administration to mitigate risk
• Orthostatic hypotension or hypotension – screen for cardiovascular disease
• Exacerbation of parkinsonism – especially in Parkinson’s disease or patients on levodopa
• Drug interactions: CYP2D6 inducers/inhibitors alter serum levels; avoid concomitant MAO inhibitors or drugs that prolong QT interval

Dosing

• Initiate at low dose and titrate gradually to minimize emergent psychiatric effects
• If no benefit after 8–12 weeks at 20 mg BID, consider treatment withdrawal or switch to another agent
• Leave capsules whole – do not split or crush (manufacturer‑issued capsule strength)

Adverse Effects

• Incidence of depression: ~ 2–3 % at 4 weeks, higher in patients with pre‑existing psychiatric history
• Paradoxical hypokinesia can mimic Parkinson’s disease—monitor motor symptom progression

Monitoring

• Baseline:
• Complete metabolic panel, liver enzymes (AST, ALT, ALP, bilirubin)
• Weight, blood pressure, heart rate
• Depression screening (PHQ‑9) and suicidality assessment
• Genotype if available: CYP2D6 poor metabolizers → consider lower starting dose
• Follow‑up:
• LFTs at 2–4 weeks, then every 3–6 months if stable
• Weight check every 4 weeks during titration, then every 3 months
• Depression/suicidality screening at each visit
• Monitor for orthostatic vital signs if symptoms arise

Clinical Pearls

• Slow‑Titration Syllabus: Deutetrabenazine’s mild metabolic profile allows for weekly increments of 2.5 mg, but watch for *early* depressive symptoms—address promptly with CBT or adjunctive antidepressants.
• CYP2D6 Genetic Safety Net: Patients identified as *poor metabolizers* receive a **start dose of 2.5 mg BID even if tolerated*, as they may accumulate higher plasma levels.
• Deutetrabenazine vs Tetrabenazine: Deuterium substitution reduces formation of a toxic metabolite (3,4‑dihydroxy‑tetrabenazine), translating into a lower incidence of parkinsonism—particularly beneficial in older adults.
• Drug Interaction Check: Many antipsychotics are CYP2D6 substrates; co‑administration can increase or decrease deutetrabenazine levels. Maintain a watchful eye for cross‑reactivity.
• End‐to‑End Symptom Tracking: Use the Unified Huntington’s Disease Rating Scale (UHDRS) or Abnormal Involuntary Movement Scale (AIMS) pre‑treatment and monthly thereafter to objectively quantify benefit versus adverse motor interference.

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• Key Takeaway: *Deutetrabenazine* offers a safe, metabolically stable alternative for dyskinetic disorders, with a focus on gradual dosing, vigilant psychiatric monitoring, and individualized pharmacogenetic adjustments.