Sustained Treatment Response and Global Improvements With Long-term Valbenazine in Patients With Tardive Dyskinesia.

PURPOSE/BACKGROUND: Using data from KINECT® 4, a phase 3, 48-week study of valbenazine, post hoc analyses were conducted to assess long-term outcomes that are relevant to the real-world management of tardive dyskinesia (TD). METHODS/PROCEDURES: Post hoc analyses of the participants of the KINECT 4 study who completed 48 weeks of open-label valbenazine (40 or 80 mg) treatment were conducted. Valbenazine effects on TD were evaluated using the Abnormal Involuntary Movement Scale (AIMS), Clinical Global Impression of Change-TD (CGI-TD), and Patient Global Impression of Change (PGIC). FINDINGS/RESULTS: Of 103 participants completing 48 weeks of treatment, 55% experienced clinically meaningful improvement (defined as ≥2-point reduction in AIMS total score [sum of items 1 - 7, evaluated by site raters]) by week 4; at week 48, 97% met this threshold. The percentage of completers who achieved AIMS total score response thresholds of ≥10% to ≥90% increased over time, with 86% of completers reaching ≥50% improvement. Of the 40 (39%) completers with AIMS ≥50% response at week 8, 38 (95%) sustained this response at week 48; 81% of those who did not meet this threshold at week 8 had achieved it by week 48. At week 48, more than 85% of completers achieved CGI-TD and PGIC ratings of "much improved" or "very much improved." IMPLICATIONS/CONCLUSIONS: The majority of participants who completed 48 weeks of treatment with once-daily valbenazine experienced substantial clinically meaningful and sustained TD improvements. These findings indicate that valbenazine can be a highly effective long-term treatment in patients with TD.

Opioid antagonism mitigates antipsychotic-associated weight gain: focus on olanzapine.

BACKGROUND: The endogenous opioid system affects metabolism, including weight regulation. Evidence from preclinical and clinical studies provides a rationale for targeting this system to mitigate weight-related side effects of antipsychotics. This review describes the role of the opioid system in regulating weight and metabolism, examines the effects of opioid receptor antagonism on those functions, and explores the use of opioid antagonists to mitigate antipsychotic-associated weight gain and/or metabolic effects. METHODS: A PubMed literature search was conducted to identify representative opioid antagonists and associated preclinical and clinical studies examining their potential for the regulation of weight and metabolism. RESULTS: The mu opioid receptor (MOR), delta opioid receptor (DOR), and kappa opioid receptor (KOR) types have overlapping but distinct patterns of central and peripheral expression, and each contributes to the regulation of body weight and metabolism. Three representative opioid antagonists (eg, naltrexone, samidorphan, and LY255582) were identified for illustration. These opioid antagonists differed in their receptor binding and pharmacokinetic profiles, including oral bioavailability, systemic clearance, and half-life, and were associated with varying effects on food intake, energy utilization, and metabolic dysregulation. CONCLUSIONS: Preclinical and clinical data suggest that antagonism of the endogenous opioid system is a mechanism to address antipsychotic-associated weight gain and metabolic dysregulation. However, evidence suggests that the differing roles of MOR, DOR, and KOR in metabolism, together with the differences in receptor binding, pharmacokinetic, and functional activity profiles of the opioid receptor antagonists discussed in this review, likely contribute to their differential pharmacodynamic effects and clinical outcomes observed regarding antipsychotic-associated weight gain.

Good Publication Practice (GPP) Guidelines for Company-Sponsored Biomedical Research: 2022 Update.

These updated Good Publication Practice (GPP) guidelines include recommendations for publishing company-sponsored biomedical research. The GPP guidelines apply to peer-reviewed or peer-oriented biomedical publications, such as manuscripts, meeting presentations, posters, and abstracts, as well as enhanced content, such as plain-language summaries. The current GPP guidelines incorporate guidance on ethics and transparency as well as the planning, development, review, and approval of biomedical publications and policies and procedures that describe these practices. Supplemental materials lay out processes for steering committees, publication plans, publication working groups, determining authorship, and documentation. Information about new topics, such as alliances and working with patients, has been included where appropriate within these supplemental materials. Incorporating the principles and best practices presented in these GPP guidelines will result in increased transparency and a firm ethical footing. This guidance is also intended to enable the compliant incorporation of new and emerging publication tools for the ethical publication of company-sponsored research.

Effect of Sublingual Dexmedetomidine vs Placebo on Acute Agitation Associated With Bipolar Disorder: A Randomized Clinical Trial.

Importance: Acute agitation is common in patients with bipolar disorder and requires urgent management to relieve distress and to prevent escalation to aggressive behavior. Objective: To evaluate the effect of orally absorbed, sublingual dexmedetomidine, a selective α2A-adrenergic receptor agonist on symptoms of acute agitation in patients with bipolar disorder. Design, Setting, and Participants: Phase 3, randomized, double-blind, placebo-controlled trial conducted in 15 sites in the US with enrollment between February 24, 2020, and April 27, 2020, and final follow-up on May 21, 2020. A total of 380 adults with bipolar I or II disorder were randomized and 362 completed the study. Interventions: Participants were randomized to 3 groups: sublingual dexmedetomidine 180 µg (n = 127), sublingual dexmedetomidine 120 µg (n = 127), or placebo (n = 126). Main Outcomes and Measures: The primary efficacy end point was the mean change from baseline at 2 hours for the Positive and Negative Syndrome Scale-Excited Component (PEC) total score. The range of possible total scores is 5 (absence of agitation) to 35 (extremely severe). The secondary end point was the earliest time of a statistically significant change in PEC total score from baseline for the drug vs placebo. On the primary efficacy end point, to account for multiplicity associated with comparing 2 sublingual dexmedetomidine doses with placebo, the 2-sided significance level for each dose vs placebo was set at .025. Results: Of 380 patients randomized (mean age, 45.6 years; 54.8% women; and 56.1% Black individuals), 378 (99.5%) self-administered the study medication and completed the study. Baseline agitation was mild to moderate, with an overall mean PEC total score of 18.0. Two hours after taking the medication, the mean changes from baseline in PEC total score were -10.4 for sublingual dexmedetomidine 180 µg, -9.0 for sublingual dexmedetomidine 120 µg, and -4.9 for placebo. Least-square mean differences from placebo in the sublingual dexmedetomidine groups at 2 hours were -5.4 (97.5% CI, -6.6 to -4.2) for 180 µg and -4.1 (97.5% CI, -5.3 to -2.9) for 120 µg (both doses P < .001 vs placebo). Treatment effects began 20 minutes after taking the medication among patients in the sublingual dexmedetomidine groups (least-square mean difference for 180 µg, -1.1 [97.5% CI, -2.0 to -0.2]; P = .007; for 120 µg, -1.0 [97.5% CI, -1.9 to -0.1]; P = .009). Adverse events occurred in 35.7% of patients taking 180 µg of dexmedetomidine, 34.9% taking 120 µg, and 17.5% taking placebo. The most common adverse events (≥5%) in the respective 180 µg, 120 µg, and placebo groups were somnolence (21.4% and 20.6% vs 4.8%); dry mouth (4.8% and 7.1% vs 0.8%); hypotension (6.3% and 4.8% vs 0%); and dizziness (5.6% and 5.6% vs 0.8%). Conclusions and Relevance: Among patients with mild to moderate agitation associated with bipolar disorder, treatment with a sublingual film formulation of dexmedetomidine 120 µg or 180 µg, compared with placebo, resulted in significantly greater reduction in the agitation score at 2 hours. Further research is needed to understand the spectrum of patients for whom this treatment would be effective and feasible and to better understand the clinical importance of the observed effect size. Trial Registration: ClinicalTrials.gov Identifier: NCT04276883.

Pharmacokinetic Profile of the Asenapine Transdermal System (HP-3070).

PURPOSE/BACKGROUND: The asenapine transdermal system (HP-3070) is the first antipsychotic patch approved in the United States for treatment of adults with schizophrenia. METHODS/PROCEDURES: Three phase 1, open-label, randomized studies characterized the pharmacokinetic (PK) profile of HP-3070 by assessing its relative bioavailability compared with sublingual asenapine, its single-/multiple-dose PK and dose proportionality, and the effects of application site, ethnicity, and external heat on bioavailability. Two studies were conducted in healthy subjects, and 1 was conducted in adults with schizophrenia. FINDINGS/RESULTS: During single HP-3070 administration, asenapine concentrations increased gradually over approximately 12 hours and remained steady until the patch was removed 24 hours after application. Asenapine area under the curve values at HP-3070 3.8 and 7.6 mg/24 hours doses were similar to those for sublingual asenapine 5 and 10 mg twice-daily doses, respectively, whereas peak exposure (maximum observed plasma concentration) was significantly lower. During daily application of HP-3070, steady-state PK was reached within approximately 72 hours after initiating daily dosing and was characterized by peak-to-trough asenapine plasma concentration ratio of approximately 1.5. HP-3070 PK was dose proportional in the dose range studied, not affected by administration site, and similar across the studied ethnic groups. Application of external heat increased the rate of asenapine absorption (time to reach maximum observed plasma concentration) but did not significantly affect peak and total exposure. IMPLICATIONS/CONCLUSIONS: HP-3070 exhibited a dose-dependent PK profile unaffected by site of administration or ethnicity. HP-3070 showed a predictable absorption profile with limited variability, with an area under the curve similar to that of sublingual asenapine. Based on these PK metrics, HP-3070 steadily delivers asenapine with lower peaks and troughs than sublingual administration of asenapine.

Effect of Brexpiprazole on Agitation and Hostility in Patients With Schizophrenia: Post Hoc Analysis of Short- and Long-Term Studies.

BACKGROUND: Managing agitation and hostility represents a significant treatment challenge in schizophrenia. The aim of this analysis was to evaluate the short- and long-term efficacy of brexpiprazole for reducing agitation and hostility in schizophrenia. METHODS: This was a post hoc analysis of data from two 6-week, randomized, double-blind, placebo-controlled studies (ClinicalTrials.gov identifiers, NCT01396421 and NCT01393613) and a 52-week, open-label, extension study (NCT01397786). In the short-term studies, 1094 patients received placebo, 2 mg/d of brexpiprazole, or 4 mg/d of brexpiprazole; 346 brexpiprazole-treated patients rolled over into the long-term study and received 1 to 4 mg/d of brexpiprazole. Agitation was assessed using the Positive and Negative Syndrome Scale (PANSS) Excited Component (EC), and hostility was assessed using the PANSS hostility item (P7). RESULTS: Brexpiprazole improved PANSS-EC score over 6 weeks, with least squares mean differences versus placebo of -0.69 (95% confidence limits, -1.28, -0.11) for 2 mg/d (P = 0.020) and -1.11 (-1.70, -0.53) for 4 mg/d (P = 0.0002). In the subgroup with hostility at baseline (P7 score ≥3; 50.8% of the randomized sample), least squares mean differences versus placebo at week 6 on the PANSS-EC were -0.63 (-1.54, 0.28) for 2 mg/d (P = 0.18) and -1.03 (-1.92, -0.14) for 4 mg/d (P = 0.024), and on P7 (adjusted for positive symptoms) were -0.27 (-0.53, -0.01) for 2 mg/d (P = 0.038) and -0.34 (-0.59, -0.09) for 4 mg/d (P = 0.0080). The improvements were maintained over 58 weeks. Adverse events were generally comparable between treatment groups over 6 weeks; the incidence of akathisia among patients with hostility was 5.9% with placebo, 5.2% with 2 mg/d, and 8.6% with 4 mg/d. CONCLUSIONS: Brexpiprazole has the potential to be an efficacious and well-tolerated treatment for agitation and hostility among patients with schizophrenia.

Binge eating disorder revisited: what's new, what's different, what's next.

Binge eating disorder (BED) is the most common type of eating disorder. According to the most recent data available, the estimated lifetime prevalence of BED among US adults in the general population is 0.85% (men 0.42% and women 1.25%). Among psychiatric treatment populations, prevalence is several-fold higher. Although many people with BED are obese (BMI ≥ 30 kg/m2), roughly half are not. In the DSM-5, BED is defined by recurrent episodes of binge eating (eating in a discrete period of time, an amount of food larger than most people would eat in a similar amount of time under similar circumstances and a sense of lack of control over eating during the episode), occurring on average at least once a week for 3 months, and associated with marked distress. BED often goes unrecognized and thus untreated; in one study, 344 of 22,387 (1.5%) survey respondents met DSM-5 criteria for BED, but only 11 out of the 344 had ever been diagnosed with BED by a health-care provider. Psychiatric comorbidities are very common, with most adults with BED also experiencing anxiety disorders, mood disorders, impulse control disorders, or substance use disorders, suggesting that clinicians have patients in their practice with unrecognized BED. Multiple neurobiological explanations have been suggested for BED, including dysregulation in reward center and impulse control circuitry. Additionally, there is interplay between genetic influences and environmental stressors. Psychological treatments such as cognitive behavioral interventions have been recommended as first line and are supported by meta-analytic reviews; however, access to such treatments may be limited because of local availability and/or cost, and these treatments generally lead to little to no weight loss, although successfully eliminating binge eating can protect against future weight gain. Routine medication treatments for anxiety and depression do not necessarily ameliorate the symptoms of BED, but there are approved and emerging medication options, lisdexamfetamine and dasotraline, respectively, that specifically address the core drivers behind binge eating, namely obsessive thoughts and compulsive behaviors regarding food, resulting in marked decreases in binge eating behaviors as well as weight loss.

Cariprazine for bipolar depression: What is the number needed to treat, number needed to harm and likelihood to be helped or harmed?

OBJECTIVE: Cariprazine is an oral antipsychotic approved in the US for the treatment of schizophrenia, acute bipolar mania, and most recently, bipolar depression. The aim of this systematic review is to describe the efficacy, tolerability and safety of cariprazine for the treatment of depressive episodes associated with bipolar I disorder (bipolar depression) in adults. DATA SOURCES: The pivotal registration trials were accessed by querying http://www.ncbi.nlm.nih.gov/pubmed/ and http://www.clinicaltrials.gov, for the search terms "cariprazine" AND "bipolar" AND "depression," and by also querying the Web of Science commercial database for clinical poster abstracts, and by asking the manufacturer for copies of posters presented at congresses. Product labelling provided additional information. STUDY SELECTION: Double-blind placebo-controlled studies in adults with bipolar depression. DATA EXTRACTION: Descriptions of the principal results and calculation of number needed to treat (NNT) and number needed to harm (NNH) for relevant dichotomous outcomes were calculated from the available study reports and other sources of information. DATA SYNTHESIS: Cariprazine differs from other antipsychotics in that it has a 10-fold higher affinity for dopamine D3 receptors than for D2 receptors. Cariprazine's principal active metabolite, didesmethyl-cariprazine (DDCAR), has a half-life of 1-3 weeks and at steady state DDCAR is the predominant circulating moiety. Four double-blind placebo-controlled studies of cariprazine for bipolar depression were found of which three were considered positive and provided data on efficacy; all four studies were used to assess tolerability. Rates of treatment response, defined by a ≥50% reduction from baseline on the Montgomery-Asburg Depression Ratting Scale (MADRS) total score at study endpoint, for the approved doses of 1.5 and 3.0 mg/d (pooled) vs placebo were 46.3% vs 35.9% (NNT 10, 95% CI 7-21). Corresponding rates for remission (defined as MADRS total score ≤10 at endpoint) were 30.2% vs 20.9% (NNT 11, 95% CI 8-22). Discontinuation rates because of an adverse event (AE) were 6.7% for cariprazine (all doses pooled) vs 4.8% for placebo (NNH 51, ns). Product labelling lists the most common AEs as nausea, akathisia, restlessness and extrapyramidal symptoms. Patients receiving cariprazine 3.0 vs 1.5 mg/d were more likely to experience AEs and discontinue the trials because of an AE. CONCLUSIONS: Cariprazine is the fourth agent approved for bipolar depression in the US. The likelihood to experience a benefit (response or remission) is substantially greater than the likelihood to encounter a discontinuation because of an AE. Direct, head-to-head comparisons with the other approved choices for bipolar depression in the "real world" are needed.

Testing, Testing. 1, 2, 3. Is This Mic On?

This issue of the International Journal of Clinical Practice includes 4 articles regarding testing in medicine. Our Associate Editor for Cardiovascular Disease Prevention and Metabolic Diseases, Anthony Wierzbicki, together with Timothy Reynolds, start us off with a thoughtful extended editorial/perspective with the title (translated) "first, do no harm.". This article is protected by copyright. All rights reserved.

Psychiatric commentary addressing the article titled "Guidance for switching from off-label antipsychotics to pimavanserin for Parkinson's disease psychosis: an expert consensus".

Pimavanserin is not curative, but can improve the quality of life remaining for the person with Parkinson's disease who typically has been suffering from this relentless neurodegenerative disease for years. Using pimavanserin effectively requires knowledge not only about the product itself, but also about the treatments pimavanserin is replacing.

Pimavanserin for the treatment of Parkinson's disease psychosis: number needed to treat, number needed to harm, and likelihood to be helped or harmed.

OBJECTIVE: Our aim was to describe the efficacy and tolerability of pimavanserin, a highly selective serotonin 5-HT2A receptor inverse agonist/antagonist indicated for the treatment of hallucinations and delusions associated with Parkinson's disease psychosis (PDP), using the metrics of number needed to treat (NNT) and number needed to harm (NNH). METHODS: Categorical efficacy and tolerability data were extracted from the clinical trial databases of the double-blind placebo-controlled studies of pimavanserin in persons with PDP. NNT and NNH values were calculated with their respective 95% confidence intervals. The likelihood to be helped or harmed (LHH) was then calculated contrasting therapeutic response versus discontinuation because of an adverse event. RESULTS: NNT values for pimavanserin 34 mg/d versus placebo for several definitions of clinical response are 10, and/or are not statistically significant, and/or show an advantage for pimavanserin over placebo (such as for postural hypotension). In terms of LHH, pimavanserin 34 mg/d is about five times more likely to result in clinical response (as measured by a ≥3 point decrease from baseline on the Scale for the Assessment of Positive Symptoms adapted for Parkinson's disease) versus discontinuation due to an adverse event. CONCLUSIONS: Using the metrics of NNT, NNH, and LHH, pimavanserin 34 mg/d for the treatment of PDP appears to have a compelling benefit/risk profile.

Effect of aripiprazole lauroxil in patients with acute schizophrenia as assessed by the Positive and Negative Syndrome Scale-supportive analyses from a Phase 3 study.

OBJECTIVE: Aripiprazole lauroxil (AL) is a long-acting injectable atypical antipsychotic that was evaluated for the treatment of schizophrenia in a randomized, placebo-controlled, Phase 3 study. Here, we present exploratory analyses of supportive efficacy endpoints. METHODS: Patients experiencing an acute exacerbation of schizophrenia received AL 441 mg intramuscularly (IM), AL 882 mg IM, or matching placebo IM monthly. Supportive endpoints included changes from baseline at subsequent time points in Clinical Global Impression-Severity (CGI-S) scale score; Positive and Negative Syndrome Scale (PANSS) Total score; PANSS Positive, Negative, and General Psychopathology subscale scores; PANSS Marder factors (post hoc); and PANSS responder rate. Overall response rate, based on PANSS Total score and Clinical Global Impression-Improvement (CGI-I) scale score, was also analyzed. RESULTS: Of 622 patients who were randomized, 596 had ≥1 post-baseline PANSS score. Patients were markedly ill at baseline (mean PANSS Total scores 92-94). Compared with placebo, CGI-S scores; PANSS Positive, Negative, and General Psychopathology subscale scores; and PANSS Marder factors were all significantly (p<0.001) improved by Day 85 with both AL doses, with significantly lower scores starting from Day 8 in most instances. Treatment response rates were significantly (p<0.001) greater with both doses of AL vs placebo. CONCLUSION: AL demonstrated robust efficacy on CGI-S score, PANSS subscale scores, PANSS Marder factors, and response rates. Study limitations included use of a fixed dose for initial oral aripiprazole and fixed monthly AL doses without the option to individualize the oral initiation dosing or injection frequency for efficacy, tolerability, or safety.

Activating and Sedating Adverse Effects of Second-Generation Antipsychotics in the Treatment of Schizophrenia and Major Depressive Disorder: Absolute Risk Increase and Number Needed to Harm.

PURPOSE/BACKGROUND: Activating and sedating adverse effects of antipsychotics can be obstacles to their use. METHODS/PROCEDURES: This study quantified the activating and sedating properties of first-line oral second-generation antipsychotics by examining the rates of adverse reactions as reported in product labeling for the indications of schizophrenia and adjunctive treatment of major depressive disorder. Additional data sources included regulatory documents, study synopses, and published study reports. Attributable risk increase and number needed to harm (NNH) were calculated for each agent versus placebo. FINDINGS/RESULTS: Heterogeneity among the different antipsychotics regarding activating or sedating adverse events was observed, with some agents displaying the potential for both activating and sedating properties. For agents indicated for the treatment of schizophrenia, predominantly activating medications include lurasidone (NNH, 11 for akathisia vs 20 for somnolence) and cariprazine (NNH, 15 for akathisia vs 65 for somnolence-combined terms). Similarly activating and sedating are risperidone (NNH, 15 for akathisia vs 13 for sedation) and aripiprazole (NNH, 31 for akathisia vs 34 for somnolence). Predominantly sedating are olanzapine, quetiapine immediate and extended release, ziprasidone, asenapine, and iloperidone. Agents that are neither activating nor sedating are paliperidone and brexpiprazole. For major depressive disorder, the overall findings regarding activation and sedation appear similar to those seen with schizophrenia. Data extracted were limited to those available from registrational studies that contributed to the adverse event tables contained in the product labels. Postregistrational comparative studies may yield different outcomes. IMPLICATIONS/CONCLUSIONS: Differences in tolerability profiles regarding activation and sedation have implications in terms of selecting the optimal antipsychotic for a given individual.

Aripiprazole Lauroxil: Pharmacokinetic Profile of This Long-Acting Injectable Antipsychotic in Persons With Schizophrenia.

BACKGROUND: Aripiprazole lauroxil is an extended-release prodrug of aripiprazole for intramuscular injection, approved for schizophrenia treatment. We developed a population pharmacokinetic (PopPK) model to characterize aripiprazole lauroxil PK and evaluate dosing scenarios likely to be encountered in clinical practice. METHODS: Data from 616 patients with schizophrenia, collected from 5 clinical studies, were used to construct the PopPK model. The model was subsequently used to evaluate various dose levels and frequency and the impact of dosing delay on aripiprazole concentrations. FINDINGS: The results of the model indicate that aripiprazole is released into the systemic circulation after 5 to 6 days, and release continues for an additional 36 days. The slow increase in aripiprazole concentration after injection necessitates the coadministration of oral aripiprazole for 21 days with the first injection. Based on the PopPK model simulations, a dosing interval of 882 mg every 6 weeks results in aripiprazole concentrations that fall within the concentration range associated with the efficacious aripiprazole lauroxil dose range (441-882 mg dosed monthly). A 662-mg monthly dose also resulted in aripiprazole concentrations within the efficacious dose range. Aripiprazole lauroxil administration results in prolonged exposure, such that dose delays of 2 to 4 weeks, depending on the dose regimen, do not require oral aripiprazole supplementation upon resumption of dosing. CONCLUSIONS: This PopPK model and model-based simulations were effective means for evaluating aripiprazole lauroxil dosing regimens and management of missed doses. Such analyses play an important role in determining the use of this long-acting antipsychotic in clinical practice.

Measurement of agitation and aggression in adult and aged neuropsychiatric patients: review of definitions and frequently used measurement scales.

Agitation and aggression in adult psychiatric patients with psychoses and in persons with dementia increase the burden of disease and frequently cause hospitalization. The implementation of currently available management strategies and the development of new ones is hindered by inconsistent terminology that confuses agitation with aggression. This confusion is maintained by many rating scales that fail to distinguish between these two syndromes. We review the frequently used rating scales with a particular focus on their ability to separate agitation from aggression. Agitation and aggression are two different syndromes. For example, reactive aggression is often precipitated by rejection of care and may not be associated with agitation per se. We propose, in treatment studies of behavioral symptoms of dementia and challenging behaviors in psychoses, that outcomes should be evaluated separately for agitation and aggression. This is important for investigation of drug effectiveness since the medication may be effective against one syndrome but not the other. Separate assessments of agitation and aggression should be a general principle of trial design with particular salience for registration studies of medications proposed for approval by the U.S. Food and Drug Administration and other regulatory bodies.

Deutetrabenazine for tardive dyskinesia: A systematic review of the efficacy and safety profile for this newly approved novel medication-What is the number needed to treat, number needed to harm and likelihood to be helped or harmed?

OBJECTIVE: Deutetrabenazine is a deuterated formulation of tetrabenazine. The aim of this systematic review is to describe the efficacy, tolerability and safety of deutetrabenazine for the treatment of tardive dyskinesia (TD). DATA SOURCES: The pivotal registration trials were accessed by querying http://www.ncbi.nlm.nih.gov/pubmed/ and http://www.clinicaltrials.gov, for the search terms 'deutetrabenazine' OR 'SD-809', and by also querying the EMBASE (Elsevier) commercial database for clinical poster abstracts, and by asking the manufacturer for copies of posters presented at congresses. Product labelling provided additional information. STUDY SELECTION: All available clinical reports of studies were identified. DATA EXTRACTION: Descriptions of the principal results and calculation of number needed to treat (NNT) and number needed to harm (NNH) for relevant dichotomous outcomes were extracted from the available study reports and other sources of information. DATA SYNTHESIS: Deutetrabenazine, a reversible inhibitor of vesicular monoamine transporter type 2 (VMAT2), received approval for the treatment of TD in adults based on a clinical trial development programme that included two 12-week parallel group, randomised and placebo-controlled studies. Deutetrabenazine dose is determined individually for each patient based on reduction of TD and tolerability. The recommended starting dose of deutetrabenazine for TD is 6 mg BID, administered with food, and can be increased at weekly intervals in increments of 6 mg/day to a maximum recommended daily dosage of 24 mg BID. The percentage of responders in the fixed-dose Phase III acute study, as defined by a rating of "much improved" or "very much improved" on the clinical global impression of change, was 46% for deutetrabenazine (pooled dose groups 12 and 18 mg BID) vs 26% for placebo, yielding a NNT of 5 (95% CI 3-19); the percentage of responders as defined by an improvement in Abnormal Involuntary Movement Scale (AIMS) severity score (sum of items 1-7) of 50% or more, was 34% for deutetrabenazine (pooled dose groups 12 and 18 mg BID) vs 12% for placebo, yielding a NNT of 5 (95% CI 3-11). Pooling the data across both short-term studies, NNT for AIMS response for the therapeutic doses of deutetrabenazine vs placebo was 7 (95% CI 4-18). Discontinuation because of an adverse event occurred among 3.6% of patients randomised to deutetrabenazine (any dose) vs 3.1% for placebo, yielding a NNH of 189 (not significant). The Likelihood to be Helped or Harmed comparing success (AIMS response) vs discontinuation because of an adverse event is 27. The most common adverse reactions (that occurred in ≥4% of deutetrabenazine-treated patients with TD and greater than placebo) were nasopharyngitis and insomnia, with NNH values of 50 (not significant) and 34 (95% CI 18-725), respectively. CONCLUSIONS: Deutetrabenazine is the second FDA-approved agent specifically indicated for the treatment of TD. Head-to-head comparisons with other VMAT2 inhibitors among patients with TD in the "real world" are needed.