Lisdexamfetamine Dimesylate in Residual Symptoms and Cognitive Impairment in Major Depressive Disorder.

NCT01148979 | Completed Phase 4 Results FDA Drug

• 1 other identifier: 2010-P-000871
• Study Type: interventional
• Target: 35
• Locations: 1 country
• Sites: 1

Brief Summary

This study aims to test the effect of a newly-approved stimulant medication, lisdexamfetamine dimesylate (Vyvanse), on specific residual symptoms of depression found in some patients who are undergoing treatment with, but have only partially responded to, a selective-serotonin reuptake inhibitor (SSRI) or selective-norepinephrine reuptake inhibitor (SNRI) antidepressant. Specifically, the investigators hypothesize that symptoms potentially related to deficient dopaminergic activity, such as lassitude, apathy, reduced positive affect and impaired executive function, in particular, will improve. This protocol is designed to test the hypothesis that this cluster of co-occurring residual symptoms sometimes found in treated depression will respond as a group to adjunctive psychostimulant therapy. The investigators propose to demonstrate this cluster of residual depressive symptoms and to measure the effect of stimulant therapy on it. The investigators hope to better understand the specific symptoms in this clinical population that are likely to improve with stimulant therapy.

Conditions

Major Depressive Disorder

Keywords

Major Depressive Disorder; Cognitive Impairment; Partial Response; Residual Symptoms

Outcome Measures

Primary Outcomes (1)

• Change From Baseline in the Dysphoric Apathy/Retardation Sub-factor (MDAR) of Montgomery-Asberg Depression Rating Scale (MADRS) at 4 Weeks.

  The Montgomery-Asberg Depression Rating Scale Dysphoric Apathy Retardation subfactor (MDAR) is a 5-item subscale of the clinician-administered 10-item Montgomery-Asberg Depression Rating Scale (MADRS). MDAR score can range from 0-30 with a higher score representing a greater severity of depressive symptoms.

  Baseline to 4 weeks of treatment

Study Arms (2)

Adjunct Lisdexamfetamine (Vyvanse)

EXPERIMENTAL

Participants receive Lisdexamfetamine Dimesylate 20-50 mg capsule each morning for 4 weeks. After a washout period of 2 weeks, they receive Placebo capsule (matching Lisdexamfetamine Dimesylate (Vyvanse) capsule) each morning for 4 weeks.

Drug: Lisdexamfetamine Dimesylate (Vyvanse)

Adjunct Placebo

PLACEBO COMPARATOR

Participants receive Placebo capsule (matching Lisdexamfetamine Dimesylate (Vyvanse) 20-50 mg capsule) each morning for 4 weeks. After a washout period of 2 weeks, they receive Lisdexamfetamine Dimesylate capsule each morning for 4 weeks.

Drug: Placebo

Interventions

Lisdexamfetamine Dimesylate (Vyvanse) DRUG

Lisdexamfetamine Dimesylate (Vyvanse) capsules dose ranging from 20mg to 50 mg.

Also known as: Vyvanse

Adjunct Lisdexamfetamine (Vyvanse)

Placebo DRUG

Lisdexamfetamine Dimesylate (Vyvanse)-matched placebo capsules.

Also known as: Sugar pill

Adjunct Placebo

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Meeting diagnostic criteria for major depression during the present episode of illness, currently with at least mild improvement by report (CGI-I ≥3) but with continuing residual symptoms.
• A score of ≥10 on MADRS items 1,2,6,7 and 8, (the MADRS Dysphoric Apathy/Retardation factor, Parker et al., 2003) at screening and randomization. These 5 items are: Apparent sadness, Reported sadness, Concentration difficulties, Lassitude, and Inability to feel. A score of ≥3 will be required for at least 2 of these items.
• A score of 3 or 4 on the Clinical Global Impression of Severity (CGI-S) at screening and randomization.
• At randomization subjects must have received therapeutic dosages of approved SSRI or SNRI agents for at least 8 weeks, with the last 4 weeks at a constant dosage.
• Females of Child-bearing Potential (FOCP) must have a negative serum beta Human Chorionic Gonadotropin (B-hCG) pregnancy test at the screening visit and a negative urine pregnancy test at the baseline visit, and agree to use one of the following methods of birth control: oral contraceptives, contraceptive implants, injectable contraceptives, IUDs, double-barrier contraception, sexual abstinence or vasectomized partner(s).

You may not qualify if:

• Treatment within 4 weeks of randomization with any non-SSRI/SNRI antidepressant (trazodone is permitted up to 100 mg at night for sleep); any antipsychotic agent; any mood stabilizer; any standing benzodiazepine regimen other than at low doses for sleep (≤ 1 mg lorazepam HS or the equivalent); or a standing regimen of any other agent that may affect cognitive function (e.g., psychostimulants, including modafinil or R-modafinil).
• Any current or past psychotic disorder, Bipolar I or II disorder, Current panic disorder, History of ADHD, Antisocial Personality Disorder or Borderline Personality Disorder, Mental retardation or any dementing disorder.
• Covi Anxiety Scale score greater than Raskin Depression Scale score at Screening, to exclude subjects with more prominent anxiety than depression
• MADRS Sleep (item 4), or Appetite (item 5) \>3 at screening or randomization
• Initial insomnia at screening that is not adequately controlled by sleep medication (trazodone up to 100 mg HS for sleep and/or ≤ 1 mg lorazepam HS or the equivalent).
• Medical conditions that might be exacerbated by Vyvanse treatment, such as uncontrolled hypertension or angina; or conditions that would make study findings hard to interpret, such as hyperthyroidism
• History of seizure (other than infantile febrile seizures), any tic disorder, or a current diagnosis and/or family history of Tourette's Disorder.
• Known cardiac structural abnormality or any other condition that may affect cardiac performance
• Any clinically significant ECG or laboratory abnormality at Screening
• Current abnormal thyroid function, as defined by abnormal TSH at Screening (Treatment with a stable dose of thyroid medication for at least 3 months is permitted if TSH is normal at screening).
• Suicide attempt within the past 2 years or a history of any homicidal behavior.
• MADRS Suicidal thoughts (item 10) \>4 at any study visit, or if a patient is considered by the investigator to be at clinical risk of suicide at any time in the course of the study.
• resting sitting systolic blood pressure \>149mmHg or diastolic blood pressure \> 95mmHg. Subjects may be on monotherapy with anti-hypertensive medication.
• documented allergy, hypersensitivity, intolerance, or non-responsivity to methylphenidate or amphetamines.
• Subject has a history of a substance use disorder (abuse or dependence, as defined by DSM-IV-TR™), with the exception of nicotine dependence, within 6 months prior to screening.

Sponsors & Collaborators

• Mclean Hospital: lead
• Shire: collaborator

Study Sites (1)

McLean Hospital

Belmont, Massachusetts, 02478, United States

Location

Related Publications (12)

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  PMID: 9164423 BACKGROUND

• Candy M, Jones L, Williams R, Tookman A, King M. Psychostimulants for depression. Cochrane Database Syst Rev. 2008 Apr 16;(2):CD006722. doi: 10.1002/14651858.CD006722.pub2.

  PMID: 18425966 BACKGROUND

• Dunkin JJ, Leuchter AF, Cook IA, Kasl-Godley JE, Abrams M, Rosenberg-Thompson S. Executive dysfunction predicts nonresponse to fluoxetine in major depression. J Affect Disord. 2000 Oct;60(1):13-23. doi: 10.1016/s0165-0327(99)00157-3.

  PMID: 10940443 BACKGROUND

• Edgar CJ, Pace-Schott EF, Wesnes KA. Approaches to measuring the effects of wake-promoting drugs: a focus on cognitive function. Hum Psychopharmacol. 2009 Jul;24(5):371-89. doi: 10.1002/hup.1034.

  PMID: 19565524 BACKGROUND

• Fava M, Graves LM, Benazzi F, Scalia MJ, Iosifescu DV, Alpert JE, Papakostas GI. A cross-sectional study of the prevalence of cognitive and physical symptoms during long-term antidepressant treatment. J Clin Psychiatry. 2006 Nov;67(11):1754-9. doi: 10.4088/jcp.v67n1113.

  PMID: 17196056 BACKGROUND

• Fava M, Thase ME, DeBattista C. A multicenter, placebo-controlled study of modafinil augmentation in partial responders to selective serotonin reuptake inhibitors with persistent fatigue and sleepiness. J Clin Psychiatry. 2005 Jan;66(1):85-93. doi: 10.4088/jcp.v66n0112.

  PMID: 15669893 BACKGROUND

• Fleurence R, Williamson R, Jing Y, Kim E, Tran QV, Pikalov AS, Thase ME. A systematic review of augmentation strategies for patients with major depressive disorder. Psychopharmacol Bull. 2009;42(3):57-90.

  PMID: 19752841 BACKGROUND

• Gorlyn M, Keilp JG, Grunebaum MF, Taylor BP, Oquendo MA, Bruder GE, Stewart JW, Zalsman G, Mann JJ. Neuropsychological characteristics as predictors of SSRI treatment response in depressed subjects. J Neural Transm (Vienna). 2008 Aug;115(8):1213-9. doi: 10.1007/s00702-008-0084-x. Epub 2008 Jul 16.

  PMID: 18629432 BACKGROUND

• Parker RD, Flint EP, Bosworth HB, Pieper CF, Steffens DC. A three-factor analytic model of the MADRS in geriatric depression. Int J Geriatr Psychiatry. 2003 Jan;18(1):73-7. doi: 10.1002/gps.776.

  PMID: 12497559 BACKGROUND

• Ravindran AV, Kennedy SH, O'Donovan MC, Fallu A, Camacho F, Binder CE. Osmotic-release oral system methylphenidate augmentation of antidepressant monotherapy in major depressive disorder: results of a double-blind, randomized, placebo-controlled trial. J Clin Psychiatry. 2008 Jan;69(1):87-94. doi: 10.4088/jcp.v69n0112.

  PMID: 18312042 BACKGROUND

• Taylor BP, Bruder GE, Stewart JW, McGrath PJ, Halperin J, Ehrlichman H, Quitkin FM. Psychomotor slowing as a predictor of fluoxetine nonresponse in depressed outpatients. Am J Psychiatry. 2006 Jan;163(1):73-8. doi: 10.1176/appi.ajp.163.1.73.

  PMID: 16390892 BACKGROUND

• Trivedi MH, Rush AJ, Wisniewski SR, Nierenberg AA, Warden D, Ritz L, Norquist G, Howland RH, Lebowitz B, McGrath PJ, Shores-Wilson K, Biggs MM, Balasubramani GK, Fava M; STAR*D Study Team. Evaluation of outcomes with citalopram for depression using measurement-based care in STAR*D: implications for clinical practice. Am J Psychiatry. 2006 Jan;163(1):28-40. doi: 10.1176/appi.ajp.163.1.28.

  PMID: 16390886 BACKGROUND

MeSH Terms

Conditions

Depressive Disorder, Major; Cognitive Dysfunction

Interventions

Lisdexamfetamine Dimesylate; Sugars

Condition Hierarchy (Ancestors)

Depressive Disorder; Mood Disorders; Mental Disorders; Cognition Disorders; Neurocognitive Disorders

Intervention Hierarchy (Ancestors)

Dextroamphetamine; Amphetamine; Amphetamines; Phenethylamines; Ethylamines; Amines; Organic Chemicals; Carbohydrates

Limitations and Caveats

The small sample size and crossover design both weaken group differences.

Results Point of Contact

• Title: J. Alexander Bodkin, MD
• Organization: McLean Hospital

abodkin@mclean.harvard.edu

617-855-3186

Study Officials

• J. Alexander Bodkin Bodkin, MD

  Mclean Hospital

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Masking Details: Both the study participant and the study investigators making evaluations are blinded to which treatment arm the participants are assigned to (i.e., whether they are receiving placebo or Vyvanse at any given point). Placebo and active medication capsules look identical.
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Director, Clinical Psychopharmacology Research Program

Model Details: This is a double-blind, placebo-controlled, crossover study in which each subject will act as their own control after being randomly assigned to placebo or Lisdexamfetamine Dimesylate (Vyvanse) for the first 4 weeks of study treatment, then receiving the other for the second 4 weeks of treatment. The two 4-week treatment periods are separated by a washout of 2 weeks.

Study Record Dates

• First Submitted: June 21, 2010
• First Posted: June 23, 2010
• Study Start: September 1, 2010
• Primary Completion: September 1, 2014
• Study Completion: October 1, 2014
• Last Updated: May 23, 2017
• Results First Posted: May 23, 2017

Record last verified: 2017-04

Locations

US (1)