1 Boring Old Man

So, I was watching this movie on television on a channel with commercials and that lady on the right was moping around trying to avoid falling in a hole [her "depression"]. Apparently, her antidepressant was helping, but she still had some very hard days. Then along comes Abilify, and she is able not to fall in the hole and looked like a new woman. Then we heard about adjunctive treatment with atypical antipsychotics, a list of possible side effects that ought to scare away anyone, then back to Masters and Commanders: The Far Side of the World. It looks like atypical antipsychotic augmentation is following me wherever I go. After the movie, I googled Abilify and there she was, same lady, fit as a fiddle, right on their web site. So I thought as long as I was looking at Seroquel, I might as well take a peek at Abilify‘s approval in Major Depressive Disorder. After all, Abilify was the first such FDA approval [though that’s the first television ad for augmentation I’ve seen]. But before I go through the studies, I thought I’d look up the published articles. That approval was based on two identical studies summarized here:

Adjunctive aripiprazole in major depressive disorder:
Analysis of efficacy and safety in patients with anxious and atypical features.
by Trivedi MH, Thase ME, Fava M, Nelson CJ, Yang H, Qi Y, Tran QV, Pikalov A, Carlson BX, Marcus RN, Berman RM.
Journal of Clinical Psychiatry. 2008 Dec;69(12):1928-36.

^{Abstract
OBJECTIVE: To evaluate the efficacy of adjunctive aripiprazole to standard antidepressant therapy (ADT) for patients with DSM-IV major depressive disorder with anxious/atypical features at baseline.
METHOD: Data from 2 identical 14-week studies (an 8-week prospective ADT treatment phase and a 6-week randomized, double-blind phase) of aripiprazole augmentation were pooled to evaluate efficacy and safety in the 2 subgroups. The primary efficacy endpoint was mean change in Montgomery-Asberg Depression Rating Scale (MADRS) total score from end of ADT treatment to end of randomized treatment (last observation carried forward). Anxious depression was defined by a Hamilton Rating Scale for Depression anxiety/somatization factor score > or = 7, and atypical depression was defined by previously described criteria on the Inventory of Depressive Symptomatology-Self-Report. Both anxious and atypical subtypes were defined based on symptoms at entry into prospective ADT (week 0). Patients were enrolled between June 2004 and April 2006 in one study and from September 2004 to December 2006 in the other (total randomized population, N = 742; anxious/nonanxious population, N = 740; atypical/nonatypical population, N = 737).
RESULTS: Completion rates were between 84% and 90% and comparable across all subgroups, with low discontinuations due to adverse events. Patients receiving adjunctive aripiprazole demonstrated significantly greater improvement in MADRS total score versus patients receiving adjunctive placebo, starting at week 1 or week 2 and continuing through to endpoint (anxious: -8.72 vs. -6.17, p < or = .001; nonanxious: -8.61 vs. -4.97, p < or = .001; atypical: -9.31 vs. -5.15, p < or = .001; nonatypical: -8.08 vs. -6.22, p < .05). At endpoint, remission rates were also significantly higher with adjunctive aripiprazole versus adjunctive placebo (p < .05) in all subgroups. Treatment emergent adverse event profile was similar in all subgroups and comparable to the total population. Reporting of akathisia and weight gain on aripiprazole treatment did not differ between subgroups.
CONCLUSION: Adjunctive aripiprazole is an effective treatment for patients with major depression presenting with either anxious or atypical features.
TRIAL REGISTRATION: clinicaltrials.gov Identifiers: NCT00095823 and NCT00095758.}

The Efficacy and Safety of Aripiprazole as Adjunctive Therapy in Major Depressive Disorder:
A Second Multicenter, Randomized, Double-Blind, Placebo-Controlled Study
by Marcus, Ronald N.; McQuade, Robert D.; Carson, William H.; Hennicken, Delphine; Fava, Maurizio; Simon, Jeffrey S.; Trivedi, Madhukar H.; Thase, Michael E.; Berman, Robert M.

Journal of Clinical Psychopharmacology. 2008 Apr;28(2):156-165.

^{AUTHOR DISCLOSURE INFORMATION: Robert M. Berman, Ronald N. Marcus, and Delphine Hennicken are employees of Bristol-Myers Squibb. Drs Berman and Marcus are also Bristol-Myers Squibb shareholders. Robert D. McQuade and William H. Carson are employees of Otsuka Pharmaceutical Development & Commercialization Inc. Robert D. McQuade is an ex-employee of Bristol-Myers Squibb and is a Bristol-Myers Squibb shareholder. Maurizio Fava receives research support from Abbott Laboratories, Alkermes, Aspect Medical Systems, Astra-Zeneca, Bristol-Myers Squibb, Cephalon, Eli Lilly &Co, Forest Pharmaceuticals Inc, GlaxoSmithkline, J&J Pharmaceuticals, Lichtwer Pharma GmbH, Lorex Pharmaceuticals, Novartis, Organon Inc, PamLab LLC, Pfizer Inc, Pharmavite, Roche, Sanofi/Synthelabo, Solvay Pharmaceuticals Inc, Wyeth-Ayerst Laboratories; is an advisor/consultant for Aspect Medical Systems, AstraZeneca, Bayer AG, Best Practice Project Management Inc, Biovail Pharmaceuticals Inc, BrainCells Inc, Bristol-Myers Squibb, Cephalon, Compellis, Cypress Pharmaceuticals, Dov Pharmaceuticals, Eli Lilly & Co, EPIX Pharmaceuticals, Fabre-Kramer Pharmaceuticals Inc, Forest Pharmaceuticals Inc, GlaxoSmithkline, Grunenthal GmBH, Janssen Pharmaceutica, Jazz Pharmaceuticals, J&J Pharmaceuticals, Knoll Pharmaceutical Co, Lundbeck, MedAvante Inc, Merck, Neuronetics, Novartis, Nutrition 21, Organon Inc, PamLab LLC, Pfizer Inc, PharmaStar, Pharmavite, Roche, Sanofi/Synthelabo, Sepracor, Solvay Pharmaceuticals Inc, Somaxon, Somerset Pharmaceuticals, Takeda, Wyeth-Ayerst Laboratories; participates in speakers’ bureau for AstraZeneca, Boehringer-Ingelheim, Bristol-Myers Squibb, Cephalon, Eli Lilly & Co, Forest Pharmaceuticals Inc, GlaxoSmithkline, Novartis, Organon Inc, Pfizer Inc, PharmaStar, Wyeth-Ayerst Laboratories; and has equity holdings with Compellis, MedAvante. Jeffrey S. Simon has been a consultant for Pfizer, Bristol-Meyers Squibb, Wyeth Research, Abbott, Tap, and Cephalon. He has received research/grant support from Bristol-Meyers Squibb, Pfizer, Wyeth Research, Sanofi, Lilly, Cephalon, Forest, GlaxoSmithKline, Otsuka, AstraZeneca, and Organon, and he is on the speakers’ bureau of Wyeth Research and GlaxoSmithKline. Madhukar Trivedi has received research support from, or served as a consultant to, or has been on the speakers’ boards of the following: Abdi Brahim; Abbott Laboratories Inc; Akzo (Organon Pharmaceuticals Inc); AstraZeneca; Bayer; Bristol-Myers Squibb; Cephalon Inc; Corcept Therapeutics Inc; Cyberonics Inc; Eli Lilly & Co; Fabre Kramer Pharmaceuticals Inc; Forest Pharmaceuticals; GlaxoSmithKline; Janssen Pharmaceutica Products, LP; Johnson & Johnson PRD; Meade Johnson; Merck; National Institute of Mental Health; National Alliance for Research in Schizophrenia and Depression; Neuronetics; Novartis; Parke-Davis Pharmaceuticals Inc; Pfizer Inc; Pharmacia & Upjohn; Predix Pharmaceuticals; Sepracor; Solvay Pharmaceuticals Inc; VantagePoint; and Wyeth-Ayerst Laboratories. Michael E. Thase is an advisor/consultant for: AstraZeneca, Bristol-Myers Squibb, Cephalon Inc, Cyberonics Inc, Eli Lilly & Co, GlaxoSmithKline; Janssen Pharmaceutica, MedAvante Inc, Neuronetics Inc, Novartis; Organon Inc, Sepracor Inc, Shire US Inc, and Wyeth Pharmacueticals. Dr Thase participates in speakers’ bureaus for AstraZeneca, Bristol-Myers Squibb, Cyberonics Inc, Eli Lilly & Co, GlazoSmithKline, Organon Inc, Sanofi Aventis, and Wyeth Pharmacueticals. Dr Thase does not receive any grants from pharmaceutical companies. He has equity holdings in MedAvante Inc and receives income from royalties, patents, or other sources from American Psychiatric Publishing Inc, Guildford Publications, and Herald House.}

^{SUPPORT: This study was supported by Bristol-Myers Squibb (Princeton, NJ) and Otsuka Pharmaceutical Co, Ltd (Tokyo, Japan). Editorial support for the preparation of this manuscript was provided by Michelle O’Donovan, PhD, Ogilvy Healthworld Medical Education (London, UK); funding was provided by Bristol-Myers Squibb.}

^Abstract

^{Nonresponse to one or more antidepressants is common and an important public health problem. This study evaluated the efficacy and safety of adjunctive aripiprazole or placebo to standard antidepressant therapy (ADT) in patients with major depressive disorder who showed an inadequate response to at least 1 and up to 3 historical and 1 additional prospective ADT. The study comprised a 7-28-day screening, an 8-week prospective treatment, and a 6-week randomization phase. During prospective treatment, patients experiencing a major depressive episode (17-item Hamilton Rating Scale for Depression total score >=18) received single-blind adjunctive placebo plus clinicians’ choice of ADT (escitalopram, fluoxetine, paroxetine controlled-release, sertraline, or venlafaxine extended-release). Subjects with inadequate response were randomized to adjunctive placebo (n = 190) or adjunctive aripiprazole (n = 191) (starting dose 5 mg/d, dose adjustments 2-20 mg/d, mean end-point dose of 11.0 mg/d). The primary efficacy endpoint was the mean change in Montgomery-Åsberg Depression Rating Scale total score from end of prospective treatment phase to end of randomized treatment phase (last observation carried forward). Mean change in Montgomery-Åsberg Depression Rating Scale total score was significantly greater with adjunctive aripiprazole than placebo (-8.5 vs -5.7; P> = 0.001). Remission rates were significantly greater with adjunctive aripiprazole than placebo (25.4% vs 15.2%; P = 0.016) as were response rates (32.4% vs 17.4%; P < 0.001). Adverse events occurring in 10% of patients or more with adjunctive placebo or aripiprazole were akathisia (4.2% vs 25.9%), headache (10.5% vs 9.0%), and fatigue (3.7% vs 10.1%). Incidence of adverse events leading to discontinuation was low (adjunctive placebo [1.1%] vs adjunctive aripiprazole [3.7%]). Aripiprazole is an effective and safe adjunctive therapy as demonstrated in this short-term study for patients who are nonresponsive to standard ADT.}