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SummaryObjective To describe the efficacy and safety of lisdexamfetamine dimesylate (LDX) for the treatment of binge eating disorder (BED). Data sources The pivotal registration trials were accessed by querying http://www.ncbi.nlm.nih.gov/pubmed/, http://www.clinicaltrials.gov and http://www.clinicaltrialsregister.eu for the search terms ‘lisdexamfetamine’ and ‘binge’, and by also querying the Web of Science (Thomson Reuters) and Embase (Elsevier) commercial databases, 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 LDX is a central nervous system stimulant indicated for the treatment of moderate to severe BED. The recommended dose range is 50–70 mg/day. Approval for the treatment of BED was based on a clinical development programme that included an 11-week Phase II proof-of-concept, placebo-controlled study, testing fixed doses of LDX 30, 50 and 70 mg/day, and two 12-week Phase III placebo-controlled studies examining LDX 50–70 mg/day. Statistically significant reductions in binge eating days/week, the primary outcome measure, were observed for LDX doses of 50 and 70 mg/day, with effect sizes in the Phase III trials ranging from 0.83 to 0.97. The pooled NNT for response across all trials (as defined by a Clinical Global Impressions-Improvement score of ‘very much improved’ or ‘much improved’) for LDX vs. placebo was 3 (95% CI 3–4), and NNT for remission (as defined by 4-week cessation of binge eating) for LDX vs. placebo was 4 (95% CI 4–6). Reductions in weight ranged between 5.2% and 6.25% for LDX 50 or 70 mg/day. Discontinuation rates because of adverse events (AEs) were low; NNH for discontinuation because of an AE for LDX vs. placebo was 44 (95% CI 23–1971). The most commonly encountered AEs (incidence ≥ 10% and greater than the rate for placebo) were dry mouth, decreased appetite, insomnia and headache, with NNH values vs. placebo of 4 (95% CI 3–5), 11 (95% CI 8–17), 11 (95% CI 8–18) and 19 (95% CI 11–75), respectively. Conclusions LDX is the first pharmacological agent that has received regulatory approval for the treatment of BED. LDX 50 or 70 mg/day significantly reduced BED symptoms as measured by the number of binge eating days per week. Effect sizes were highly robust. Pending clinical trials include a long-term study examining maintenance of efficacy.

Summary Objective To describe the efficacy and safety of levomilnacipran (extended-release capsules) for the treatment of major depressive disorder (MDD). Data sources The pivotal registration trials were accessed by querying http://www.ncbi.nlm.nih.gov/pubmed/, http://www.clinicaltrialsregister.eu and http://www.clinicaltrials.gov for the search terms ‘levomilnacipran’ and ‘F2695’, and by obtaining 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 Levomilnacipran (1S, 2R-milnacipran) is a potent and selective serotonin–norepinephrine reuptake inhibitor with greater potency for inhibition of norepinephrine relative to serotonin reuptake. Approval for the treatment of MDD was based on a clinical development program that included one 10-week Phase II and four 8-week Phase III randomised placebo-controlled clinical trials in outpatients with MDD where levomilnacipran was titrated to target doses ranging from 40 to 120 mg taken once daily. Four of the five trials demonstrated efficacy as measured by the Montgomery Asberg Depression Rating Scale, with a NNT for response vs. placebo of 9 (95% CI 7–15), and for remission, 14 (95% CI 10–28). Levomilnacipran also demonstrated superiority over placebo as measured by improvement in the Sheehan Disability Scale functional impairment total score. NNH vs. placebo for discontinuation because an adverse event (AE) across all five trials was 19 (95% CI 14–28). The most commonly encountered AEs (incidence ≥ 5% and at least twice the rate of placebo) as identified in product labelling were nausea, hyperhidrosis, constipation, heart rate increased, erectile dysfunction in men, vomiting, tachycardia and palpitations, with NNH values vs. placebo of 10 (95% CI 8–12), 15 (95% CI 12–19), 17 (95% CI 13–24), 21 (95% CI 17–29), 20 (95% CI 14–36), 25 (95% CI 20–37), 25 (95% CI 19–40) and 30 (95% CI 22–49), respectively. Levomilnacipran was not associated with clinically relevant weight change in the short-term trials or in a 48-week open-label extension trial. Mean changes from baseline in systolic blood pressure (BP), diastolic BP and heart rate were +3.0 mmHg, +3.2 mm Hg and +7.4 bpm for levomilnacipran, and −0.4 mmHg, no change and −0.3 bpm for placebo, respectively. Categorical shift in BP from normal or prehypertension at baseline to stage 1 or stage 2 hypertension at end of study was 10.4% for levomilnacipran vs. 7.1% for placebo, for a NNH of 31 (95% CI 18–94). Conclusions Levomilnacipran represents another option for the treatment of MDD. Levomilnacipran appears to have a favourable weight-gain profile. Additional controlled data regarding long-term efficacy and comparative effectiveness will help characterise this new agent.

The objective of this systematic review was to describe the efficacy, tolerability, and safety of valbenazine for the treatment of tardive dyskinesia (TD).The pivotal registration trials were accessed by querying http://www.ncbi.nlm.nih.gov/pubmed/ and http://www.clinicaltrials.gov, for the search terms 'valbenazine' OR 'NBI-98854', 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 labeling provided additional information.All available clinical reports of studies were identified.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.Valbenazine, 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 three 6-week parallel group, randomised, placebo-controlled studies, including one Phase III trial described in product labeling. The recommended dose for valbenazine is 80 mg/d. The percentage of responders in the Phase III acute study, as defined by ≥50% reduction from baseline in the Abnormal Involuntary Movement Scale dyskinesia score was 40.0% for valbenazine 80 mg/d vs 8.7% for placebo, yielding a NNT of 4 (95% CI 3-6). As pooled from available data, discontinuation rates because of an adverse event were 2.9% for valbenazine-treated patients vs 1.6% for placebo-treated patients, resulting in a NNH of 76 (ns). The only adverse event that met the threshold of incidence ≥5% for valbenazine and a rate of ≥2 times than that observed with placebo was somnolence (somnolence, fatigue, sedation), with rates of 10.9% for valbenazine (all doses) vs 4.2% for placebo, resulting in a NNH of 15 (95% CI 9-52). An additional warning and precaution is that valbenazine can prolong the ECG QT interval, however, the valbenazine product label does not contain any bolded boxed warnings or contraindications.Valbenazine is presently the only US Food and Drug Administration-approved agent specifically indicated for the treatment of TD. Valbenazine is about 15 times more likely to result in a response than in a discontinuation because of an adverse event. Head-to-head comparisons with other VMAT2 inhibitors among patients with TD in the 'real world' are needed.

SummaryObjective 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.

To describe the efficacy and safety of levomilnacipran (extended-release capsules) for the treatment of major depressive disorder (MDD).The pivotal registration trials were accessed by querying http://www.ncbi.nlm.nih.gov/pubmed/, http://www.clinicaltrialsregister.eu and http://www.clinicaltrials.gov for the search terms 'levomilnacipran' and 'F2695', and by obtaining posters presented at congresses. Product labelling provided additional information.All available clinical reports of studies were identified.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.Levomilnacipran (1S, 2R-milnacipran) is a potent and selective serotonin-norepinephrine reuptake inhibitor with greater potency for inhibition of norepinephrine relative to serotonin reuptake. Approval for the treatment of MDD was based on a clinical development program that included one 10-week Phase II and four 8-week Phase III randomised placebo-controlled clinical trials in outpatients with MDD where levomilnacipran was titrated to target doses ranging from 40 to 120 mg taken once daily. Four of the five trials demonstrated efficacy as measured by the Montgomery Asberg Depression Rating Scale, with a NNT for response vs. placebo of 9 (95% CI 7-15), and for remission, 14 (95% CI 10-28). Levomilnacipran also demonstrated superiority over placebo as measured by improvement in the Sheehan Disability Scale functional impairment total score. NNH vs. placebo for discontinuation because an adverse event (AE) across all five trials was 19 (95% CI 14-28). The most commonly encountered AEs (incidence ≥ 5% and at least twice the rate of placebo) as identified in product labelling were nausea, hyperhidrosis, constipation, heart rate increased, erectile dysfunction in men, vomiting, tachycardia and palpitations, with NNH values vs. placebo of 10 (95% CI 8-12), 15 (95% CI 12-19), 17 (95% CI 13-24), 21 (95% CI 17-29), 20 (95% CI 14-36), 25 (95% CI 20-37), 25 (95% CI 19-40) and 30 (95% CI 22-49), respectively. Levomilnacipran was not associated with clinically relevant weight change in the short-term trials or in a 48-week open-label extension trial. Mean changes from baseline in systolic blood pressure (BP), diastolic BP and heart rate were +3.0 mmHg, +3.2 mm Hg and +7.4 bpm for levomilnacipran, and -0.4 mmHg, no change and -0.3 bpm for placebo, respectively. Categorical shift in BP from normal or prehypertension at baseline to stage 1 or stage 2 hypertension at end of study was 10.4% for levomilnacipran vs. 7.1% for placebo, for a NNH of 31 (95% CI 18-94).Levomilnacipran represents another option for the treatment of MDD. Levomilnacipran appears to have a favourable weight-gain profile. Additional controlled data regarding long-term efficacy and comparative effectiveness will help characterise this new agent.

Although great effort is made in clinical trials to demonstrate statistical superiority of one intervention vs. another, insufficient attention is paid regarding the clinical relevance or clinical significance of the observed outcomes. Effect sizes are not always reported. Available absolute effect size measures include Cohen's d, area under the curve, success rate difference, attributable risk and number needed to treat (NNT). Of all of these measures, NNT is arguably the most clinically intuitive and helps relate effect size difference back to real-world concerns of clinical practice. This commentary reviews the formula for NNT, and proposes acceptable values for NNT and its analogue, number needed to harm (NNH), using examples from the medical literature. The concept of likelihood to be helped or harmed (LHH), calculated as the ratio of NNH to NNT, is used to illustrate trade-offs between benefits and harms. Additional considerations in interpreting NNT are discussed, including the importance of defining acceptable response, adverse outcomes of interest, the effect of time, and the importance of individual baseline characteristics.

To describe the efficacy and safety of vilazodone for the treatment of major depressive disorder (MDD).The pivotal registration trials were accessed by querying http://www.ncbi.nlm.nih.gov/pubmed/, http://www.fda.gov and http://www.clinicaltrials.gov for the search term 'vilazodone'. Product labeling provided additional information. All available clinical reports of studies were identified.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.Vilazodone is a specific serotonin reuptake inhibitor and serotonin 5HT1A receptor partial agonist. In needs to be administered with food to ensure adequate bioavailability. Approval for the treatment of MDD was based on a clinical development programme that included two 8-week placebo-controlled randomised clinical trials in outpatients with MDD where vilazodone was titrated to a target dose of 40 mg/d over the first 2 weeks. Both trials evidenced efficacy for vilazodone as measured by the Montgomery Asberg Depression Rating Scale. NNT for response vs. placebo was 8 (95% CI 6-16) and for remission was 14 (95% CI 8-55). NNH vs. placebo for discontinuation because of an adverse event (AE) was 27 (95% CI 15-104). The most commonly encountered AEs (incidence ≥ 5% and at least twice the rate of placebo) were diarrhoea, nausea, vomiting and insomnia, with NNH values vs. placebo of 6 (95% CI 5-8), 6 (95% CI 5-8), 30 (95% CI 18-82) and 26 (95% CI 16-78), respectively. NNH vs. placebo for any sexual AE was 12 (95% CI 9-18), but systematically collected data using rating scales of sexual function did not reveal treatment associated effects. Vilazodone was not associated with clinically relevant weight change in the short-term trials. In an open-label 1-year study of vilazodone, mean weight increased by 1.7 kg among the observed cases.Vilazodone represents another option for the treatment of MDD. Vilazodone appears to have a favourable weight-gain profile based on short-term studies. Sexual side-effects were not consistently demonstrated when assessed using clinical rating scales but spontaneously reported AEs related to sexual functioning were observed. Additional controlled data regarding long-term efficacy and effectiveness will help characterise this new agent when used in maintenance treatment.