Randomized, Proof-Of-Concept Trial of Augmentation of Antidepressants by Low Dose Naltrexone (LDN) for Patients With Breakthrough Symptoms of Major Depressive Disorder on Antidepressant Therapy
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 12
- 试验地点
- 1
- 主要终点
- Change in HAM-D-17 Total Score
研究概览
简要总结
The purpose of this pilot study is to determine if taking a low dose of naltrexone in addition to an antidepressant medication can help treat relapse or recurrence in people with Major Depressive Disorder (MDD). The U.S. Food and Drug Administration (FDA) has approved naltrexone for the treatment of alcohol dependence and opioid dependence, but the FDA has not approved naltrexone to treat depression. The investigators hypothesize that patients with breakthrough depression on an antidepressant regimen containing a pro-dopaminergic agent assigned to treatment with low dose naltrexone will demonstrate higher rates of response compared to those patients taking placebo.
详细描述
We carried out a pilot double-blind, randomized, controlled study of low-dose naltrexone (LDN) 1 mg b.i.d. versus placebo augmentation in MDD patients who relapsed on dopaminergic agents. The primary aim was to test the hypothesis that patients experiencing depressive breakthrough would demonstrate greater improvement in their depression when supplementing their current antidepressant regimen with LDN versus placebo, with no significant difference in side effects.
Boston area men and women with MDD were recruited from 01/13/2014-11/11/2014 via Institutional Review Board (IRB)-approved newspaper, television, internet, and radio ads initiated by Massachusetts General Hospital (MGH) and Boston Clinical Trials (BCT). Screened and eligible patients returned one week later for a baseline visit and were randomized consecutively to double-blind treatment with placebo or LDN 1 mg b.i.d. The randomization list was generated by an online randomization program and maintained by the research pharmacist. Subjects were treated for 3 weeks, with weekly assessments. All subjects were required to continue on their baseline antidepressant regimen without changes for the duration of the study; they were likewise asked not to modify any other allowed baseline medications that they had been taking prior to entering the study. Adherence was determined by weekly pill counts; protocol violation was defined as less than 80% adherence.
Side effects were assessed at every visit using the Systematic Assessment for Treatment Emergent Effects-Specific Inquiry (SAFTEE-SI) scale (Levine and Schooler, 1992) and categorized by severity as: 0-none, 1-mild, 2-moderate, 3-severe. Because some SAFTEE items could be present at baseline, particularly in a sample of subjects taking antidepressants that could themselves produce side effects, we defined as treatment-emergent any SAFTEE side effect for which severity increased by two or more levels (e.g. from none to moderate or from mild to severe) from baseline (Mischoulon et al., 2014). Frequency of side effect was based on the number of patients reporting the side effect at any time during the study.
Suicidal ideation was assessed at each visit using the Hamilton Depression Rating Scale (HAM-D). Subjects considered to be at high risk for suicide were discontinued and referred for further evaluation and hospitalization if clinically indicated. Subjects were also discontinued for any emergence of hypomania, mania, or psychosis; a Clinical Global Improvement (CGI-I) score greater than 5 (e.g., score of 6 or 7); evidence of illicit drug use or problematic alcohol use.
At the end of the double-blind study, both responders and non-responders who completed the double-blind phase had the option of receiving open-label adjunctive treatment with LDN for 3 more weeks.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
入排标准
- 年龄范围
- 18 Years 至 65 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Written informed consent.
- •Meet Diagnostic and Statistical Manual (DSM-IV) criteria by Structured Clinical Interview for DSM-IV (SCID-I/P) for Major Depressive Disorder (MDD), current.
- •Quick Inventory of Depressive Symptomatology - Self-Rated (QIDS-SR) score of at least 12 at both screen and baseline visits.
- •Received treatment with either an Selective serotonin re-uptake inhibitors (SSRI) in combination with a dopaminergic agent, or with an antidepressant with a dopaminergic mechanism of action in adequate doses, achieved remission per American College of Neuropsychopharmacology (ACNP) Task Force guidelines for ≥3 months, currently in relapse or recurrence without dose change for at least the past 4 weeks, based on meeting DSM-IV criteria for MDD.
- •Dopaminergic agents here include classical stimulants from the amphetamine or methylphenidate families; dopamine agonists (e.g. pramipexole); or dopamine active antidepressants like bupropion.
- •Additionally, low dose (< 2.5 mg) Abilify, a D2 partial agonist, is believed to exert pro-dopaminergic effects and will therefore be included as a dopamine agent.
- •Sertraline, although classified as an SSRI, has dopamine reuptake inhibiting properties believed to be relevant at higher doses (> 150 mg of sertraline), and will also therefore be considered a dopaminergic antidepressant at dose range above.
- •Based on the finding that the norepinephrine transporter is the reuptake inhibitor for dopamine in the prefrontal cortex and the robust sustained clinical response of a patient on duloxetine and low dose naltrexone, we include duloxetine, traditionally classed as an SNRI, among the dopamine acting antidepressants.)
- •During the baseline visit, patients must be on a stable dose of antidepressant regimen for the past 4 weeks.
排除标准
- •Pregnant women or women of child bearing potential who are not using a medically accepted means of contraception (to include oral contraceptive or implant, condom, diaphragm, spermicide, intrauterine device, tubal ligation, or partner with vasectomy).
- •Patients who no longer meet DSM-IV criteria for MDD during the baseline visit.
- •Patients who demonstrate a greater than 25% decrease in depressive symptoms as reflected by the QIDS-SR total score - screen to baseline.
- •Serious suicide or homicide risk, as assessed by evaluating clinician.
- •Unstable medical illness including cardiovascular, hepatic, renal, respiratory, endocrine, neurological, or hematological disease.
- •Substance use disorders active within the last six months, any bipolar disorder (current or past), any psychotic disorder (current or past).
- •History of a seizure disorder or clinical evidence of untreated hypothyroidism.
- •Patients requiring excluded medications (including but not limited to chronic or episodic use of anorexiants, episodic hormones, episodic benzodiazepines, episodic insulin, episodic and other episodic psychotropic medications).
- •Psychotic features in the current episode or a history of psychotic features, as assessed by SCID.
- •History of naltrexone intolerance at any dose.
- •Patients with a history of antidepressant-induced hypomania.
- •Inadequate exposure time or dose of current SSRI or Serotonin-norepinephrine reuptake inhibitor (SNRI); failure to comply with at least 80% of doses.
研究组 & 干预措施
Placebo
In this arm, patients will receive placebo for three weeks.
干预措施: Placebo (Drug)
Naltrexone
In this arm, patients will receive low dose naltrexone for three weeks.
干预措施: Naltrexone (Drug)
结局指标
主要结局
Change in HAM-D-17 Total Score
时间窗: Change from baseline to week 3
Hamilton Depression Scale-17 (HAM-D-17) item. The change in scores depends on the difference between the initial (baseline) score and the final score at the conclusion of the double blind treatment period. There is no formal range of score changes, since they depend on the initial and final score. A negative score represents a lowering in the score from baseline to end (improvement), and a positive score indicates an increase in score from baseline to end (worsening). A zero score would indicate no change. In theory, the maximum drop in score would be from 52 to zero, or -52. A maximum increase would be from 18 (the minimum score required for admission) to 52, or +34.
次要结局
- Remission Rate(Remission rate at 3 weeks.)
- Change in HAM-D28 Total Score(Change from baseline to week 3)
- Change in MADRS-10 Total Score(Change from baseline to week 3)
- Change in MADRS-15 Total Score(Change from baseline to week 3)
- Change in CGI-S Total Score(Change from baseline to week 3)
- Final CGI-I Score(From baseline to week 3)
- Response Rate(Response rate after 3 weeks)
研究者
David Mischoulon, MD
Staff Psychiatrist
Massachusetts General Hospital