Limited utility of number needed to treat and the polarity index for bipolar disorder to characterize treatment response

AbstractThe medical community increasingly supports the use of simplifying constructs or ratios to facilitate incorporation of evidence-based medicine into clinical practice such as number needed to treat (NNT) and polarity index (PI). Clinicians and teachers find them to be an appealing, easy-to remember integer that can be readily translated into clinical practice. However, serious questions have been raised with respect to the validity, reliability and value of these descriptors of response. This commentary identifies some of the specific limitations of the NNT and PI constructs when applied to treatments of bipolar disorder

Long-term efficacy and safety outcomes with OROS-MPH in adults with ADHD

Methylphenidate (MPH) is widely prescribed for adults with attention deficit hyperactivity disorder (ADHD), but data on long-term treatment and maintenance of effect are lacking. Osmotic release oral system-methylphenidate (OROS–MPH) was evaluated in a 52-wk open-label study in subjects who had previously completed a short-term placebo-controlled trial and short-term open-label extension. Efficacy was assessed using the investigator- and subject-rated Conners’ Adult ADHD Rating Scales (CAARS:O-SV and CAARS:S-S), and the Clinical Global Impression – Severity (CGI-S), Sheehan Disability Scale (SDS) and Quality of Life Enjoyment and Satisfaction Questionnaire (Q-LES-Q). Subjects completing ≥52 wk of treatment were eligible for a 4-wk randomized, placebo-controlled withdrawal phase in which loss of treatment effect was assessed using CAARS:O-SV and CGI-S. In the open-label phase (n=156), mean CAARS:O-SV score decreased from baseline by 1.9±7.8 (p<0.01), and small, statistically significant improvements from baseline were observed for CAARS:S-S, CGI-S and SDS. In the double-blind phase (OROS-MPH, n=23; placebo, n=22), CAARS:O-SV increased from double-blind baseline in the OROS-MPH and placebo arms (4.0±7.6 vs. 6.5±7.8, not statistically significant). Long-term OROS-MPH treatment was well tolerated, and there was no evidence of withdrawal or rebound after discontinuation. In conclusion, the short-term benefits of OROS-MPH continue during long-term open-label treatment. Maintenance of efficacy in a placebo-controlled withdrawal design remains to be confirmed in larger patient populations

Number needed to treat and number needed to harm with paliperidone palmitate relative to long-acting haloperidol, bromperidol, and fluphenazine decanoate for treatment of patients with schizophrenia

Srihari Gopal1, Joris Berwaerts1, Isaac Nuamah1, Kasem Akhras2, Danielle Coppola1, Ella Daly1, David Hough1, Joseph Palumbo11Johnson &amp;amp; Johnson Pharmaceutical Research &amp;amp; Development, LLC, Raritan, NJ, USA; 2Johnson &amp;amp; Johnson Pharmaceutical Services, LLC, Raritan, NJ, USABackground: We analyzed data retrieved through a PubMed search of randomized, placebo-controlled trials of first-generation antipsychotic long-acting injectables (haloperidol decanoate, bromperidol decanoate, and fluphenazine decanoate), and a company database of paliperidone palmitate, to compare the benefit-risk ratio in patients with schizophrenia.Methods: From the eight studies that met our selection criteria, two efficacy and six safety parameters were selected for calculation of number needed to treat (NNT), number needed to harm (NNH), and the likelihood of being helped or harmed (LHH) using comparisons of active drug relative to placebo. NNTs for prevention of relapse ranged from 2 to 5 for paliperidone palmitate, haloperidol decanoate, and fluphenazine decanoate, indicating a moderate to large effect size.Results: Among the selected maintenance studies, NNH varied considerably, but indicated a lower likelihood of encountering extrapyramidal side effects, such as akathisia, tremor, and tardive dyskinesia, with paliperidone palmitate versus placebo than with first-generation antipsychotic depot agents versus placebo. This was further supported by an overall higher NNH for paliperidone palmitate versus placebo with respect to anticholinergic use and Abnormal Involuntary Movement Scale positive score. LHH for preventing relapse versus use of anticholinergics was 15 for paliperidone palmitate and 3 for fluphenazine decanoate, favoring paliperidone palmitate.Conclusion: Overall, paliperidone palmitate had a similar NNT and a more favorable NNH compared with the first-generation long-acting injectables assessed.Keywords: long-acting injectables, first-generation antipsychotics, randomized, number needed to treat, number needed to harm, paliperidone palmitate, second-generation antipsychotic

Practical guidance for dosing and switching from paliperidone palmitate 1 monthly to 3 monthly formulation in schizophrenia

Objective: This commentary summarizes recommended dosing strategies for a recently developed 3 monthly long-acting injectable1 (LAI) formulation of paliperidone palmitate (PP3M) for the treatment of schizophrenia in adults. Methods: Recommendations for different dosing scenarios are based on the pharmacokinetic, efficacy and safety outcomes from phase 1 and phase 3 studies, population pharmacokinetic models, and model based simulations. Results: Switching to PP3M treatment is recommended only in patients previously treated with once monthly paliperidone palmitate LAI (PP1M) for at least 4 months. The first injection of PP3M (175 to 525mg equivalent [eq.]) should be given at the time of next scheduled injection of PP1M as a 3.5-fold multiple of the last PP1M dose (50-150mg eq.), with a dosing window of 1 week. Following that first injection of PP3M, once-every-three-months maintenance injections with PP3M are recommended, with a dosing window of 2 weeks. The doses of PP3M can be administered in either deltoid (90kg: 1.5inch22G needle; <90kg: 1.0inch22G needle) or gluteal muscles (1.5inch22G needle regardless of weight). In patients with mild renal impairment (creatinine clearance: 50-80mL/min), a 25% dose reduction in PP1M and subsequent switching to a corresponding 3.5-dose multiple of PP3M (but not exceeding 350mg eq.) is recommended. Appropriate dosing is recommended in elderly patients with diminished renal function not exceeding mild renal impairment. Similarly to PP1M, PP3M is not recommended in patients with moderate/severe renal impairment. Like PP1M, no dosage adjustment is required in patients with mild or moderate hepatic impairment or elderly patients with normal renal function. Conclusions: These data provide clinical guidelines for the optimum use of PP3M in patients with schizophrenia previously treated with PP1M for at least 4 months. Registration: ClinicalTrials.gov identifier: NCT01559272 and NCT01529515