Lisdexamfetamine Dimesylate in Residual Symptoms and Cognitive Impairment in Major Depressive Disorder.
Lisdexamfetamine Dimesylate in Residual Symptoms and Cognitive Impairment in Major Depressive Disorder.
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.
This protocol is designed to test the hypothesis that a cluster of co-occurring residual
 symptoms sometimes found in treated depression will respond as a group to psychostimulant
 therapy. This cluster includes apathy, reduced drive, fatigue, impaired executive function
 and other cognitive measures, and low positive affect. We propose to measure this cluster of
 symptoms in a population of residually depressed subjects demonstrating them, and then to
 measure the effect of stimulant therapy on this cluster, and each constituent symptom, as
 well as to measure its effect on subjects' overall functional impairment, and to document
 treatment emergent adverse effects. The goal is to gather data about the response of these
 residual symptoms to stimulant therapy. Since each subject will be exposed to active
 treatment and matched placebo, a benefit to individual participants will be to learn if their
 specific symptom burden is ameliorated by stimulant therapy, and what adverse effects may
 emerge for them. We hope to develop an understanding of the specific symptoms in this
 clinical population that are likely to improve with stimulant therapy. We also hope to be
 able to characterize the side effect burden of stimulant therapy in this clinical population.
Inclusion Criteria:

 1. 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.

 2. 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.

 3. A score of 3 or 4 on the Clinical Global Impression of Severity (CGI-S) at screening
 and randomization.

 4. 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.

 5. 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).

 Exclusion Criteria:

 1. 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).

 2. 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.

 3. Covi Anxiety Scale score greater than Raskin Depression Scale score at Screening, to
 exclude subjects with more prominent anxiety than depression

 4. MADRS Sleep (item 4), or Appetite (item 5) >3 at screening or randomization

 5. 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).

 6. 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

 7. History of seizure (other than infantile febrile seizures), any tic disorder, or a
 current diagnosis and/or family history of Tourette's Disorder.

 8. Known cardiac structural abnormality or any other condition that may affect cardiac
 performance

 9. Any clinically significant ECG or laboratory abnormality at Screening

 10. 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).

 11. Suicide attempt within the past 2 years or a history of any homicidal behavior.

 12. 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.

 13. resting sitting systolic blood pressure >149mmHg or diastolic blood pressure > 95mmHg.
 Subjects may be on monotherapy with anti-hypertensive medication.

 14. documented allergy, hypersensitivity, intolerance, or non-responsivity to
 methylphenidate or amphetamines.

 15. 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.

 16. Subject has glaucoma

 17. Subject is taking other medications that have central nervous system (CNS) effects or
 affect performance, such as sedating antihistamines and decongestant