Low-Dose Naltrexone for Breakthrough Depression
To learn more about the relationship between low-dose naltrexone and mood and to view the results of this proof-of-concept protocol, click here.
Author: David P Soskin
Mentor: Maurizio Fava
Title: Randomized, Proof-Of-Concept Trial of Low Dose and Ultra-Low Dose Naltrexone for Patients with Breakthrough Symptoms of Major Depressive Disorder on Antidepressant Therapy
I. Background
Major depressive disorder (MDD) has the highest lifetime prevalence rate of any psychiatric disorder (Kessler et al., 2005), and is associated with significant medical co-morbidity and functional disability (Kessler et al., 2003). Current pharmacological treatments are considered to be suboptimal (American Psychiatric Association, 2000): only approximately 50% of outpatients starting treatment with a selective serotonin reuptake inhibitor (SSRI) will respond (Agency for Health Care Policy and Research, 1993) and fewer will remit (Trivedi et al., 2006). Perhaps more problematic, between 40% and 60% of responders will relapse within one year (Ramana et al., 1995; Rush et al., 2006). Given the limited efficacy of existing treatments, the high rates of relapse, and the historical decline in the development of antidepressants (Shorter & Tyrer, 2003), there is increasing clinical urgency to develop novel approaches to enhancing the long-term efficacy of antidepressant therapies.
The Inflammatory Hypothesis of Depression
There is growing evidence that inflammatory processes contribute to the pathophysiology of MDD. Pro-inflammatory cytokines, including interleukin-1 (IL-1), tumor necrosis factor-alpha (TNF-alpha), and interleukin-6 (IL-6) have been shown to be increased in individuals with MDD (Mossner et al., 2007; Simon et al., 2008; Zorrilla et al., 2001) or to be associated with established risk factors for MDD (e.g, stress, medical illness, obesity, sedentary lifestyle, diet, insomnia, social isolation, low socioeconomic status) (Raison, Lowry, & Rook, 2010) compared to healthy controls. In animal models, administration of pro-inflammatory cytokines or cytokine inducers have been associated with depression-like behavioral changes, including increased immobility time on the forced swim test, anhedonia, sleep disruption, and anorexia (Miller, Maletic, & Raison, 2009). These symptoms can be reversed through acute treatment with an anti-inflammatory cytokine (IL-10) or cytokine antagonist (IL-1RA), or chronic treatment with a serotonergic antidepressant (Dantzer, O'Connor, Freund, Johnson, & Kelley, 2008).
In humans, similar links between cytokine activity and mood changes have been established. Approximately 20% to 50% of patients treated with the pro-inflammatory cytokine, interferon-alpha, for hepatits C or malignant melanoma will develop a clinical depression (Miller et al., 2009), and these rates can be dramatically reduced (approximately fourfold) following pre-treatment with the antidepressant, paroxetine (Musselman et al., 2001). In a study of patients with psoriasis, Tyring and colleagues found that individuals randomized to treatment with the tumor necrosis factor (TNF)-alpha antagonist, etanercept, had significantly greater improvements in depressive symptoms (measured by the HAM-D-17) compared to controls; changes in core features of depression were only weakly correlated with objective measures of skin clearance and joint pain (Tyring et al., 2006). In a proof-of-concept study, Muller and colleagues found that depressed patients randomized to treatment with reboxetine combined with the cyclooxygenase-2 (COX-2) inhibitor, celecoxib, showed greater improvements in depression (measured by the HAM-D-17) compared to controls treated with reboxetine alone (Muller et al., 2006).
Another recent discovery is that peripheral cytokine networks can affect molecular and cellular pathways in the central nervous system. Cytokines are able to penetrate the blood brain barrier through leaky regions, active transport systems, and efferent nerve conduction, and can then be converted to centrally released cytokines by microglial cells (Capuron & Miller, 2011). Within the CNS, pro-inflammatory cytokines have been shown to modulate neurotransmitter systems, neurotrophic factors, and neurocircuitry associated with mood regulation. Serotonin and dopamine neurotransmissions appear to be reduced through downregulation of presynaptic synthesis and upregulation of postsynaptic transporters (Dantzer et al., 2008; Kitagami et al., 2003; Zhu et al., 2010). Pro-inflammatory cytokines induce the enzyme, indoleamine 2,3-dioxygenase (IDO), which shunts tryptophan metabolism toward the production of kynurenine and quinolinic acid rather than serotonin (Lestage, Verrier, Palin, & Dantzer, 2002). Kynurenine and quinolinic acid have opposing actions on glutamatergic NMDA receptors, and quinolinic acid has been shown to increase release of glutamate by astrocytes, possibly contributing to excitotoxicity and loss of glial elements. Other pro-inflammatory cytokine-induced changes associated with the pathophysiology of MDD include decreases in BDNF levels; hypoactivity in prefrontal regions and hyperactivity in the basal ganglia (thought to represent increased oscillatory bursts from depleted DA neurons); acute HPA hyperactivity; and chronic glucocorticod resistance (Capuron & Miller, 2011).
Low Dose and Ultra-Low Dose Naltrexone
Naltrexone hydrochloride is a competitive antagonist of mu and delta opioid receptors, which has historically been used for the treatment of opioid addiction. More recently, naltrexone at low (2-4.5 mg/day) and ultra-low doses (100-200 mcg/day) has been shown to inhibit the production of pro-inflammatory cytokines and neurotoxic superoxides via suppression of microglia cell activation in the central nervous system (Greeneltch et al., 2004; Greeneltch, Haudenschild, Keegan, & Shi, 2004; Lin et al., 2012; B. Liu & Hong, 2003; Y. Liu et al., 2002; Tsai et al., 2008). These effects appear to be independent of naltrexone’s opioid receptor activity, and may be mediated by activation of toll-like receptor 4 (Hutchinson et al., 2008). Recent studies have also found that ultra-low dose naltrexone (ULDN) binds filamin A, which may reduce release of inflammatory cytokines (Burns & Wang, 2010); and modulate opioid receptor activity to potentiate analgesia and prevent tolerance and dependence (Wang, Frankfurt, & Burns, 2008).
In addition to these anti-inflammatory properties, low dose naltrexone (LDN) temporarily blocks opioid receptors, which may induce upregulation of mood enhancing endorphins and increase dopamine activity (Sharafaddinzadeh, Moghtaderi, Kashipazha, Majdinasab, & Shalbafan, 2010). Finally, there is evidence that naltrexone exerts neuroprotective effects via modulation of mitochronical apoptotic pathways (San-Emeterio & Hurle, 2006).
Multiple clinical trials of LDN have now suggested beneficial mood effects. LDN was found to reduce symptoms of fibromyalgia, many of which overlap with core symptoms of major depressive disorder (MDD) (Younger & Mackey, 2009). Similarly, in cancer patients, naltrexone reduced the depression-like side effects of treatment with interferon-alpha (Valentine, Meyers, & Talpaz, 1995). Additionally, open-label pilot studies of LDN for immune-mediated disorders, including Crohn’s disease (Smith et al., 2007) and multiple sclerosis (Gironi et al., 2008), indicate that LDN is safe, well-tolerated, and independently associated with improvements in quality of life.
At the Massachusetts General Hospital’s (MGH’s) Depression Clinical and Research Program (DCRP), we have also observed anecdotally that LDN or ULDN may have specific efficacy for the treatment of “breakthrough depression,” an umbrella term, which encompasses depressive relapse (a depressive episode within 6 months of antidepressant response) and recurrence (a depressive episode after 6 months of response). Here is an example:
“A 29-year-old man suffered severe depression with recurrent major depressive episodes. He had responded briefly to complex polypharmacy and electroconvulsive therapy, but his depression usually returned within 3 weeks of these interventions.
In addition to restarting Abilify, which he had transiently responded to in the past, the patient was instructed to pulverize a tablet of naltrexone 50 mg, and take the smallest fragment with water. A sample of these fragments was later weighed, indicating he was taking on the average about 1 mg of naltrexone daily. The former pharmacologic regimen was otherwise unchanged.
About one week after initiating low dose naltrexone, the patient experienced marked remission. Despite minor variation in mood, he has maintained the remission for more than 6 months (continuing to present). He has remained on adjunctive naltrexone 1 mg daily”
(e-mail communication from a Senior Researcher at MGH, August 26, 2012).
***Note that all patient-sensitive information was changed to ensure anonymity for the patient and to comply with HIPAA.
Catalyzed by this report, several members of the DCRP used LDN and ULDN to treat breakthrough depressive episodes, also with dramatic results. For a particularly treatment-resistant patient with a depressive recurrence, another Senior Researcher at MGH added approximately 1 mg daily of naltrexone to a complex antidepressant regimen, which included duloxetine and riluzole. His patient demonstrated a robust response within 2 weeks, which has now been maintained for over 2 years (e-mail communication, August 7, 2012). At a DCRP staff meeting on July 25th of 2012, several additional cases of positive responses to LDN or ULDN for depressive breakthrough were reviewed by the group.
The Treatment of Depressive Breakthrough
The treatment of depressive breakthrough is a particularly challenging and understudied area in psychiatric research. Since the publication of Kraepelin’s classic textbook of psychiatry in the early twentieth century (Kraepelin & Diefendorf, 1907), mood disorders have been characterized as quintessentially “relapsing and remitting” phenomena. Double-blind discontinuation studies indicate that continued antidepressant therapy lowers the risk of MDD relapse and recurrence compared to placebo substitution (Geddes et al., 2003). However, even among MDD patients taking long-term antidepressants for prophylaxis, recurrence rates range from 20% to 80% within one to five years after an acute response (Montgomery et al., 1988; Peselow, Dunner, Fieve, & DiFiglia, 1991; Ramana et al., 1995). In an NIMH-sponsored, naturalistic study of 350 patients who recovered from an index episode of MDD, the cumulative rate of recurrence was 85% at 15 years (Mueller et al., 1999).
Despite the ubiquity of "depressive breakthroughs," few treatment studies are available to guide clinicians. The extant literature consists predominantly of case series, surveys and open trials, which have been limited by heterogeneous study samples and non-rigorous methodologies (Alpert & Fava, 2004). Remarkably, our literature review found no randomized controlled trials examining the efficacy of medication augmentation after depressive breakthrough.
Given the biological mechanisms, clinical trial findings, and case-reports reviewed above, there is reason to believe that LDN or ULDN could represent a novel augmentation strategy for depressive breakthrough. Although the pathophysiology of “tachyphylaxis” (i.e. tolerance to antidepressants) is not yet fully understood, serotonergic antidepressant "apathy syndrome" has been hypothesized to arise from the inhibitory effects of serotonin upregulation on dopamine transmission in the prefrontal cortex (Dunlop & Nemeroff, 2007). Therefore, it is also possible that antidepressant tolerance could be reversed by LDN or ULDN via enhancement of the dopaminergic system (above), or activation of "hedonic hotspots" in the mesolimbic reward circuitry involving G-coupled excitatory opioid receptors (Roshanpour et al., 2009). Naltrexone’s low cost (< $40 per month), history of safe use at much higher doses, and relatively mild side effect profile, also make it an attractive candidate for a proof-of-concept study (Younger & Mackey, 2009).
II. Hypotheses and Aims
Primary Aims
Hypothesis 1: Patients with breakthrough depression (BTD) assigned to treatment with LDN (1 mg bid) or ULDN (100 mcg bid) will demonstrate higher rates of response (HAM-D-17 score reduction > 50%) compared to placebo controls
Secondary Aims
Hypothesis 1: Patients with BTD assigned to treatment with LDN or ULDN will demonstrate higher rates of remission (HAM-D-17 score < 8) compared to placebo controls.
Hypothesis 2: Patients with BTD assigned to treatment with LDN or ULDN will experience no significant differences in the number of adverse events, as measured by the SAFTEE-SI, compared to placebo controls.
Hypothesis 3: Patients assigned to LDN and ULDN will experience greater improvement in Quality of Life, Enjoyment, and Satisfaction Questionnaire (Q-LES-Q) and Sheehan Disability Scale (SDS) scores compared to placebo controls.
Exploratory Aim: To assess the efficacy of LDN on symptom response, as measured by change on the HAM-D-17, compared to ULDN.
III. Design and Methodology
Overview of Design
In accordance with a modified sequential parallel comparison design (SCPD) (Fava, Evins, Dorer, & Schoenfeld, 2003), the trial will be conducted over 6 weeks, with double-blind treatment divided into two phases of 3 weeks each; this interval of 3 weeks was chosen based on the rapid course of recovery described in the case reports above. The first phase will consist of an unbalanced randomization between placebo and active treatment with more patients randomized to placebo in a 2 (LDN): 2 (ULDN): 8 (placebo) ratio. Entering phase 2, all placebo non-responders will then be randomized to placebo or LDN or ULDN in a 1:1:1 ratio; since these patients have already failed placebo, their placebo response should be reduced. Additionally, all drug non-responders entering phase 2 will be crossed-over to the alternative dose group (LDN or ULDN). This crossover design for non-responders is similar to the one that we employed in our successfully completed investigation of St. John’s Wort, citalopram, and placebo for Minor Depression (Rapaport et al., 2011); non-responders switched to the alternative dose will provide preliminary dose response data for future trials. Phase 1 responders to both drug and placebo will continue to receive the same intervention in phase 2. Our analysis will pool data from both phases to maximize power and reduce the required sample size. A recent report from FDA statisticians supports these enriched designs (Chen, Yang, Hung, & Wang, 2011).
Selection of Patients
12 men and women ages 18 to 65 who have received adequately dosed SSRI or SNRI for a major depressive episode, achieved remission for at least 3 months, and then had a relapse or recurrence (defined above), will be recruited from the greater Boston area. Participants will be recruited through advertisements and referrals and diagnosed with MDD by the SCID. All ethnicities will be included.
Recruitment and Retention
Sources of recruitment will include the following: 1) Patients who have completed DCRP studies and have a relapse or recurrence. 2) Patients in DCRP clinical practices. 3) Referrals from psychiatry practices of MGH (600 clinicians) and primary care physicians at both institutions, to whom we will present informational talks about MDD recurrence and this study. 4) IRB-approved newspaper, television, internet, and radio ads targeting individuals having a recurrence while on antidepressants.
Retention is always of concern in clinical trials. At the DCRP, our depression trials demonstrate average attrition rates of 20%, near the nationwide average. However, we expect a lower attrition rate in this study because: 1) Nonresponders in Phase 1 will receive an active treatment in Phase 2. Thus every subject (except for placebo responders) is guaranteed at least one active intervention. 2) Participants who have recently benefited from antidepressants may be optimistic about re-establishing improvement, and more likely to stay in the study. 3) Free follow-up will be offered after the study; participants will therefore be invested in remaining with us since we are demonstrating a commitment beyond the clinical trial.
Inclusion Criteria
1. Age 18-65;
2. Written informed consent;
3. Meet DSM-IV criteria (by Structured Clinical Interview for DSM-IV SCID-I/P) for MDD, current;
4. Quick Inventory of Depressive Symptomatology – Self-Rated (QIDS-SR) score of at least 12 at both screen and baseline visits
5. Received treatment with SSRI or SNRI in adequate doses (per MGH ATRQ) (Chandler, Iosifescu, Pollack, Targum, & Fava, 2010), achieved remission per ACNP Task Force guidelines (REF) 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
6. During the baseline visit, patients must be on a stable dose of SSRI or SNRI for the past 4 weeks
Exclusion Criteria
1. 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);
2. Patients who no longer meet DSM-IV criteria for MDD during the baseline visit;
3. Patients who demonstrate a greater than 25% decrease in depressive symptoms as reflected by the QIDS-SR total score - screen to baseline;
4. Serious suicide or homicide risk, as assessed by evaluating clinician;
5. Unstable medical illness including cardiovascular, hepatic, renal, respiratory, endocrine, neurological, or hematological disease;
6. The following DSM-IV diagnoses: substance use disorders active within the last six months, any bipolar disorder (current or past), any psychotic disorder (current or past);
7. History of a seizure disorder or clinical evidence of untreated hypothyroidism;
8. Patients requiring excluded medications (see Table 1 for details);
9. Psychotic features in the current episode or a history of psychotic features, as assessed by SCID;
10. History of naltrexone intolerance at any dose;
11. Patients with a history of antidepressant-induced hypomania.
12. Inadequate exposure time or dose of current SSRI or SNRI; failure to comply with at least 80% of doses.
13. Specified concomitant medications.
Drugs that may be given to the patient include any prescription or OTC medication such as aspirin, acetaminophen and cold preparations not specifically excluded by the protocol. Patients requiring concomitant therapy with excluded drugs will be discontinued from the study. The following list is a list of drugs allowed and not allowed as concomitant medications (for brevity, many of the drugs from our original list have not been included here).
(1) Benzodiazepine anxiolytics and non-benzodiazepine sedative-hypnotics noted above will be allowed only if subjects are on a stable regimen for at least 2 weeks prior to baseline at doses no greater than the following or their equivalent: clonazepam 1.0 qd and zolpidem 10 mg qhs.
(2) Reserpine will be excluded.
(3) Adequate thyroid replacement which has been stable for 6 months or more is acceptable as is estrogen replacement for post-menopausal women or the use of oral contraceptives, the initiation of which does not coincide with the onset or exacerbation of depression.
(4) Dietary supplements with putative CNS activity will be excluded including SAMe, St. John's Wort, DHEA, Inositol, Ginko biloba and psychotropic doses of Omega-3-fatty acids including DHA and Flax Seed Oil.
IV. Treatment of Subjects
Once patients agree to participate in the study by signing the informed consent document, a full medical and psychiatric history will be taken and a physical examination will be performed by a board-certified psychiatrist. Screen rating scales will be performed. Screened and eligible patients will be asked to return one week later for a baseline visit when they will be randomized to double-blind treatment with placebo, LDN, or ULDN with the study design outlined above. The study will last six weeks, during which patients will be assesssed weekly. Subjects will be assigned randomization numbers in consecutive order. The randomization list will be provided by a computer-generated random-number list and will be maintained by the research pharmacist. In addition, the presence of any side effect or adverse event will be carefully documented with the SAFTEE-SI (Levine & Schooler, 1992). Reasons for premature discontinuation, including intolerable side effects, will be recorded.
All concomitant medications taken during the study will be recorded in the case report form, along with dosage information and start and stop dates. Patients requiring excluded drugs (above) will be discontinued from the study. Medication management and clinical ratings will be performed by the study clinicians.
Every effort will be made to encourage patients to comply with this dosage regimen and to take all medications as instructed. All patients will be instructed to return any excess medication at each visit. A pill count will be done to corroborate the study drug record. Protocol violation will be defined as less than 80% compliance by pill count.
Follow-up
At the end of the double-blind study, both responders and non-responders who have completed the double-blind phase will have the option of receiving open-label adjunctive treatment with LDN or ULDN. Subjects who agree to receive open-label treatment with LDN or ULDN for 3 months will be seen monthly by a board-certified psychiatrist until the end of the follow-up phase. Subjects who complete or refuse follow-up will then be offered a referral to a psychiatrist.
V. Efficacy and Safety Assessments
Efficacy Data
The primary efficacy measure will be the change in 17-item Hamilton Rating Scale for Depression (HAM-D-17) [55] score. Response will be defined as a 50% or greater reduction in HAM-D-17 score from baseline. Remission will be defined as a HAM-D-17 score < 8 at endpoint. Secondary measures of efficacy include change in CGI-severity, with “clinical response defined” as CGI-S of 1 or 2 at endpoint. The following instruments will be administered according to the study schedule:
1) Structured Clinical Interview for DSM-IV: The SCID-I/P, administered by the clinician, proceeds by modules to diagnose the different Axis I disorders. Questions here are asked exactly as written, and each is based on the individual criteria from DSM-IV. Answers are generally rated on a scale of 1-3 (1= doubtful, 2= probable, 3= definite), and, based on the number of positive answers, a diagnosis is determined. While the entire SCID-I/P is administered at screen, the mood module will be administered at each follow up visit.
2) The MGH Antidepressant Treatment History Questionnaire: (MGH-ATR) (Fava, 2003). The MGH-ATR provides specific criteria for the adequate dose and adequate length of a trial for it to be considered a failure, thus allowing clinicians to systematically collect data aimed at assessing the degree of treatment-resistance of the current major depressive episode.
3) The 28-item Hamilton Depression Scale (HAM-D-28) (Hamilton, 1960): this version allows scoring of the HAM-D-17, 21-, 25-, and 28-item scales. This instrument is completed by the clinician by using a structured interview and defined anchor points, and aims to quantify the degree of depression over the past 7 days. The HAM-D is the most widely studied instrument for depression, and its reliability and validity are high.
4) Clinical Global Impressions - Severity and Improvement (CGI-S, CGI-I): These two instruments are scored 1-7 by the clinician based on assessment of the patient's clinical status. They measure, based on history and scores on other instruments: a) Depressive severity (CGI-S) and b) Clinical Improvement (CGI-I). Patient rated versions of both scales will also be utilized (the PGI-S/I).
5) QIDS-SR (Trivedi et al., 2004): This is a brief (16-item) self-report inventory of core depressive symptoms such as sleep, depressed mood, appetite, concentration, suicidal ideation, interest, energy, psychomotor retardation or agitation.
6) The Massachusetts General Hospital Cognitive and Physical Functioning Questionnaire. This is a brief (7-item) self-report inventory to assess rates of significant cognitive symptoms, sleepiness, and fatigue (Fava, Iosifescu, Pedrelli, & Baer, 2009).
7) The Massachusetts General Hospital Sexual Functioning Questionnaire (Fava, Rankin, Alpert, Nierenberg, & Worthington, 1998): this is a self-rating scale that measures common symptoms of sexual dysfunction, such as reduced libido and orgasm difficulties.
8) The Quality of Life Satisfaction Questionnaire-short form (Q-LES-Q) (Endicott, Nee, Harrison, & Blumenthal, 1993) is a patient-administered instrument that rates satisfaction on a 1-5 scale, with 13 specific areas of life, as well as medication, and overall life satisfaction over the past week.
9) The Sheehan Disability Scale (Leon, Shear, Portera, & Klerman, 1992) is a 3-item self-measure of disability and impairment.
Safety Data
Once the patient has agreed to participate in the study by signing the informed consent document, vital signs (weight, and standing and supine pulse and blood pressure) will be recorded at each visit and a physical exam will be performed at screen. Consumptive habits (smoking, alcohol, and caffeinated beverages) will be recorded at baseline, Day 21, and Day 42. A urine pregnancy test (for women of childbearing potential) will also be administered at the screen visit; urine drug testing will be conducted at screening to ensure that patients are not using prohibited agents. Because changes in liver function enzymes have not been found with LDN, LFTs will be monitored only at screening and day 42 (Younger & Mackey, 2009).
Adverse Events
Documentation of the presence of any side effect or adverse event will be completed at every visit using the SAFTEE-SI. Subjects will be encouraged to contact (page) the principal investigator or a member of his staff at any time between visits concerning adverse events or worsening of symptoms. Suicidal ideation will be assessed at each visit using the HAM-D interview. Subjects who are felt by the study clinician to be at high risk for suicide will be discontinued from the study and referred for hospitalization and further treatment if clinically indicated.
Termination
Every effort will be made to keep patients in the study for the full six weeks of treatment. Acceptable reasons for early discontinuation include the following: 1) request of patient, 2) decision of physician, 3) serious adverse event, 4) protocol violation, 5) worsening of depression or clinical deterioration requiring hospitalization.
Data Management
Clinical data at each visit will be recorded using a standardized clinician assessment form and a set of patient rating scales. Edited and corrected data will be added to a database that is ready to be used as input to statistical software (STATA), which will be the primary software used for data development and analysis. All data will be stored in locked file cabinets. No identifiers other than study ID’s will be included in the data. Study staff and subjects may have the option to enter clinical data into the database directly, using Red-Cap, a platform for electronic data capture that streamlines data collection and management, and ensures data integrity, resulting in improved data quality. Subjects and/or research staff enter survey responses into electronic assessment forms, and the responses are then transmitted securely via encrypted connection and stored in a secured database.
VI. Statistical Methodology
General Considerations
Data will be entered and error-checked by DCRP staff involved in the conduct of the study. Once the data set is entered and checked, analyses will be conducted. Both a completer analysis of all patients finishing the trial and an intent-to-treat analysis examining all patients enrolled into the trial will be used to define the severity of depression at endpoint. Examination of both study completers and all patients randomized provides the broadest assessment of the effects of treatment in trials of this kind. We plan to pool the data from the proposed study with the modified sequential parallel comparison design, to provide an estimate of the placebo response based on a larger sample size. As per the sequential parallel comparison design analytical plan, the effect of the active treatment is assessed using a z-score. Under the null hypothesis of no drug-placebo difference, the z score has a mean of 0. Let p1, q1 be the response rates to the first administration of drug and placebo respectively and let p2, q2 by the responses to the second treatment. To analyze these data we use a statistic based on h = w(p1 - q1) + (1 - w)(p2 - q2). The weight, w and the randomization fraction, a are chosen to maximize the power of the test, based on the alternative hypothesis. The standard error for h requires a special formula because some of the same patients who are included in the estimation of p2, q2 are included in the estimation of p1, q1. The computation is facilitated by considering a table of outcomes, where in this case p1, p2, q1, q2 are the theoretical probabilities rather than the observed relative frequencies. A more detailed description of the analyses is included in the enclosed copy of the paper by Fava et al on the sequential parallel comparison design (Fava, Evins, Dorer, & Schoenfeld, 2003).
Sample Size Determination
Patient retention rates during phase 1 and phase 2 of the trial are assumed to be 90% and 90%, respectively, based on previous studies for the treatment of breakthrough depression (CIT needed). The treatment differences from phase 1 and phase 2 will be combined with equal weights to estimate the overall treatment effect. To test the hypothesis that the combined treatment difference of 47.5% or greater (the underlying hypothesis: response rates of 70% and 25% at phase 1, and 55% and 10% at phase 2 for combined drug groups and placebo, respectively), a total of 12 patients will be randomized in the study to have 80% power at the 10% significance level.
The study is powered for a medium to large effect size (ES) difference (Cohen’s d>0.5 – 0.8) to detect a clinically meaningful difference between two active treatments. Although this increases the risk of a type II error, we believe it is justified given the dramatic responses - from severe depression to full recovery - in the case-reports above.
VII Risks and Benefits
Risks and Discomforts
1. Risks to the Subjects
a. Human Subjects Involvement and Characteristics:
This study will recruit a total of 12 individuals age 18-65 with MDD. Subjects must be medically stable as defined in the protocol. We also specifically exclude patients at acute risk for suicide, active substance abuse or dependence, and those with psychosis or bipolar illness. Rationale for exclusions is discussed in the study protocol. We exclude patients below the age of 18 or over the age of 65.
b. Sources of materials: eesearch data acquired will include a diagnosis from the SCID, and all administered rating scales.
c. Potential risks: preliminary investigations of LDN have raised no safety concerns. Patients will be carefully monitored by clinicians for side effects and potential toxicities. Blood sampling is performed in the study during the baseline (45 mls total) and day 42 visits (30 mls total) and there is always a very minor risk of infection, bruising, or syncope during a blood draw. There is also the discomfort of having one’s blood drawn. Answering detailed questionnaires may create some inconvenience for subjects.
2. Adequacy of protection against risks
a. Recruitment and informed consent: ll materials used to recruit subjects for this protocol will be reviewed and approved by the IRB prior to their use. All subjects will receive the consent form for the study. These documents will be read by the patients and also reviewed by the patient with a psychiatrist or psychologist on the research staff prior to participating in the study. Any questions, concerns, or ambiguities will be clarified by the site’s PI or another study clinician prior to the patient signing consent. Patients will sign informed consent and only then will begin participation in the study.
b. Protection against risk: The procedures to protect against or minimize potential risks include the following: (1) the assignment of unique study subject numbers to patients, (2) the use of these primary identifiers throughout the study, (3) storage of information in locked file cabinets, and (4) access limited to study personnel for these file cabinets and data. Data will be entered into password protected computer files. The blood draws will be performed by trained staff who have certificates documenting their ability to draw blood. We are performing a physical examination prior to allowing anyone to enter the randomized phase of the protocol to ensure that subjects are medically stable. Close monitoring of patients throughout the study will ensure that adverse effects from treatment, exacerbation of symptoms, or emergence of suicidality, mania or psychosis will be promptly recognized so that patients can be treated appropriately following study discontinuation. All patients will be instructed on how to contact study clinicians in the case of an emergency.
Potential Benefits
1a. Benefits to the Patient: the study may provide relief of depressive symptoms for some patients who participate.
1b. Benefits to Others: the study may benefit other people with depression, by furthering our understanding of the potential antidepressant properties of LDN or ULDN. The study will also systematically test the safety, tolerability and efficacy of LDN or ULDN as an adjunct to SSRIs or SNRIs for the treatment of breakthrough depression.
Serious Adverse Events
Expedited review will occur for all events meeting the FDA definiton of Serious Adverse Events (SAEs) i.e., any fatal event, immediately life-threatening event, permanently or substantially disabling event, event requiring or prolonging inpatient hospitalization, or any congenital anomaly. For purposes of this study, all SAEs will be required to be reported immediately (within 24 hours) to the site’s IRB and to the Co-PIs (Dr. Fava and Dr. Soskin), regardless of any judgment of their relatedness to the study drug. Information will be reviewed by the study PIs and a determination made of whether there was any possible relevance to the study drug. Additional reporting to the FDA will be made according to the regulations governing SAE reporting.
A serious adverse event is one that meets any one of the following criteria:
a. Death;
b. Life threatening;
c. Requires inpatient hospitalization or prolongation of exisiting hospitalization;
d. Results in persistent or significant disability or incapacity;
e. Congenital anomaly or birth defect;
g. Overdose;
h. Results in development of drug dependency or drug use.
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Mentor: Maurizio Fava
Title: Randomized, Proof-Of-Concept Trial of Low Dose and Ultra-Low Dose Naltrexone for Patients with Breakthrough Symptoms of Major Depressive Disorder on Antidepressant Therapy
I. Background
Major depressive disorder (MDD) has the highest lifetime prevalence rate of any psychiatric disorder (Kessler et al., 2005), and is associated with significant medical co-morbidity and functional disability (Kessler et al., 2003). Current pharmacological treatments are considered to be suboptimal (American Psychiatric Association, 2000): only approximately 50% of outpatients starting treatment with a selective serotonin reuptake inhibitor (SSRI) will respond (Agency for Health Care Policy and Research, 1993) and fewer will remit (Trivedi et al., 2006). Perhaps more problematic, between 40% and 60% of responders will relapse within one year (Ramana et al., 1995; Rush et al., 2006). Given the limited efficacy of existing treatments, the high rates of relapse, and the historical decline in the development of antidepressants (Shorter & Tyrer, 2003), there is increasing clinical urgency to develop novel approaches to enhancing the long-term efficacy of antidepressant therapies.
The Inflammatory Hypothesis of Depression
There is growing evidence that inflammatory processes contribute to the pathophysiology of MDD. Pro-inflammatory cytokines, including interleukin-1 (IL-1), tumor necrosis factor-alpha (TNF-alpha), and interleukin-6 (IL-6) have been shown to be increased in individuals with MDD (Mossner et al., 2007; Simon et al., 2008; Zorrilla et al., 2001) or to be associated with established risk factors for MDD (e.g, stress, medical illness, obesity, sedentary lifestyle, diet, insomnia, social isolation, low socioeconomic status) (Raison, Lowry, & Rook, 2010) compared to healthy controls. In animal models, administration of pro-inflammatory cytokines or cytokine inducers have been associated with depression-like behavioral changes, including increased immobility time on the forced swim test, anhedonia, sleep disruption, and anorexia (Miller, Maletic, & Raison, 2009). These symptoms can be reversed through acute treatment with an anti-inflammatory cytokine (IL-10) or cytokine antagonist (IL-1RA), or chronic treatment with a serotonergic antidepressant (Dantzer, O'Connor, Freund, Johnson, & Kelley, 2008).
In humans, similar links between cytokine activity and mood changes have been established. Approximately 20% to 50% of patients treated with the pro-inflammatory cytokine, interferon-alpha, for hepatits C or malignant melanoma will develop a clinical depression (Miller et al., 2009), and these rates can be dramatically reduced (approximately fourfold) following pre-treatment with the antidepressant, paroxetine (Musselman et al., 2001). In a study of patients with psoriasis, Tyring and colleagues found that individuals randomized to treatment with the tumor necrosis factor (TNF)-alpha antagonist, etanercept, had significantly greater improvements in depressive symptoms (measured by the HAM-D-17) compared to controls; changes in core features of depression were only weakly correlated with objective measures of skin clearance and joint pain (Tyring et al., 2006). In a proof-of-concept study, Muller and colleagues found that depressed patients randomized to treatment with reboxetine combined with the cyclooxygenase-2 (COX-2) inhibitor, celecoxib, showed greater improvements in depression (measured by the HAM-D-17) compared to controls treated with reboxetine alone (Muller et al., 2006).
Another recent discovery is that peripheral cytokine networks can affect molecular and cellular pathways in the central nervous system. Cytokines are able to penetrate the blood brain barrier through leaky regions, active transport systems, and efferent nerve conduction, and can then be converted to centrally released cytokines by microglial cells (Capuron & Miller, 2011). Within the CNS, pro-inflammatory cytokines have been shown to modulate neurotransmitter systems, neurotrophic factors, and neurocircuitry associated with mood regulation. Serotonin and dopamine neurotransmissions appear to be reduced through downregulation of presynaptic synthesis and upregulation of postsynaptic transporters (Dantzer et al., 2008; Kitagami et al., 2003; Zhu et al., 2010). Pro-inflammatory cytokines induce the enzyme, indoleamine 2,3-dioxygenase (IDO), which shunts tryptophan metabolism toward the production of kynurenine and quinolinic acid rather than serotonin (Lestage, Verrier, Palin, & Dantzer, 2002). Kynurenine and quinolinic acid have opposing actions on glutamatergic NMDA receptors, and quinolinic acid has been shown to increase release of glutamate by astrocytes, possibly contributing to excitotoxicity and loss of glial elements. Other pro-inflammatory cytokine-induced changes associated with the pathophysiology of MDD include decreases in BDNF levels; hypoactivity in prefrontal regions and hyperactivity in the basal ganglia (thought to represent increased oscillatory bursts from depleted DA neurons); acute HPA hyperactivity; and chronic glucocorticod resistance (Capuron & Miller, 2011).
Low Dose and Ultra-Low Dose Naltrexone
Naltrexone hydrochloride is a competitive antagonist of mu and delta opioid receptors, which has historically been used for the treatment of opioid addiction. More recently, naltrexone at low (2-4.5 mg/day) and ultra-low doses (100-200 mcg/day) has been shown to inhibit the production of pro-inflammatory cytokines and neurotoxic superoxides via suppression of microglia cell activation in the central nervous system (Greeneltch et al., 2004; Greeneltch, Haudenschild, Keegan, & Shi, 2004; Lin et al., 2012; B. Liu & Hong, 2003; Y. Liu et al., 2002; Tsai et al., 2008). These effects appear to be independent of naltrexone’s opioid receptor activity, and may be mediated by activation of toll-like receptor 4 (Hutchinson et al., 2008). Recent studies have also found that ultra-low dose naltrexone (ULDN) binds filamin A, which may reduce release of inflammatory cytokines (Burns & Wang, 2010); and modulate opioid receptor activity to potentiate analgesia and prevent tolerance and dependence (Wang, Frankfurt, & Burns, 2008).
In addition to these anti-inflammatory properties, low dose naltrexone (LDN) temporarily blocks opioid receptors, which may induce upregulation of mood enhancing endorphins and increase dopamine activity (Sharafaddinzadeh, Moghtaderi, Kashipazha, Majdinasab, & Shalbafan, 2010). Finally, there is evidence that naltrexone exerts neuroprotective effects via modulation of mitochronical apoptotic pathways (San-Emeterio & Hurle, 2006).
Multiple clinical trials of LDN have now suggested beneficial mood effects. LDN was found to reduce symptoms of fibromyalgia, many of which overlap with core symptoms of major depressive disorder (MDD) (Younger & Mackey, 2009). Similarly, in cancer patients, naltrexone reduced the depression-like side effects of treatment with interferon-alpha (Valentine, Meyers, & Talpaz, 1995). Additionally, open-label pilot studies of LDN for immune-mediated disorders, including Crohn’s disease (Smith et al., 2007) and multiple sclerosis (Gironi et al., 2008), indicate that LDN is safe, well-tolerated, and independently associated with improvements in quality of life.
At the Massachusetts General Hospital’s (MGH’s) Depression Clinical and Research Program (DCRP), we have also observed anecdotally that LDN or ULDN may have specific efficacy for the treatment of “breakthrough depression,” an umbrella term, which encompasses depressive relapse (a depressive episode within 6 months of antidepressant response) and recurrence (a depressive episode after 6 months of response). Here is an example:
“A 29-year-old man suffered severe depression with recurrent major depressive episodes. He had responded briefly to complex polypharmacy and electroconvulsive therapy, but his depression usually returned within 3 weeks of these interventions.
In addition to restarting Abilify, which he had transiently responded to in the past, the patient was instructed to pulverize a tablet of naltrexone 50 mg, and take the smallest fragment with water. A sample of these fragments was later weighed, indicating he was taking on the average about 1 mg of naltrexone daily. The former pharmacologic regimen was otherwise unchanged.
About one week after initiating low dose naltrexone, the patient experienced marked remission. Despite minor variation in mood, he has maintained the remission for more than 6 months (continuing to present). He has remained on adjunctive naltrexone 1 mg daily”
(e-mail communication from a Senior Researcher at MGH, August 26, 2012).
***Note that all patient-sensitive information was changed to ensure anonymity for the patient and to comply with HIPAA.
Catalyzed by this report, several members of the DCRP used LDN and ULDN to treat breakthrough depressive episodes, also with dramatic results. For a particularly treatment-resistant patient with a depressive recurrence, another Senior Researcher at MGH added approximately 1 mg daily of naltrexone to a complex antidepressant regimen, which included duloxetine and riluzole. His patient demonstrated a robust response within 2 weeks, which has now been maintained for over 2 years (e-mail communication, August 7, 2012). At a DCRP staff meeting on July 25th of 2012, several additional cases of positive responses to LDN or ULDN for depressive breakthrough were reviewed by the group.
The Treatment of Depressive Breakthrough
The treatment of depressive breakthrough is a particularly challenging and understudied area in psychiatric research. Since the publication of Kraepelin’s classic textbook of psychiatry in the early twentieth century (Kraepelin & Diefendorf, 1907), mood disorders have been characterized as quintessentially “relapsing and remitting” phenomena. Double-blind discontinuation studies indicate that continued antidepressant therapy lowers the risk of MDD relapse and recurrence compared to placebo substitution (Geddes et al., 2003). However, even among MDD patients taking long-term antidepressants for prophylaxis, recurrence rates range from 20% to 80% within one to five years after an acute response (Montgomery et al., 1988; Peselow, Dunner, Fieve, & DiFiglia, 1991; Ramana et al., 1995). In an NIMH-sponsored, naturalistic study of 350 patients who recovered from an index episode of MDD, the cumulative rate of recurrence was 85% at 15 years (Mueller et al., 1999).
Despite the ubiquity of "depressive breakthroughs," few treatment studies are available to guide clinicians. The extant literature consists predominantly of case series, surveys and open trials, which have been limited by heterogeneous study samples and non-rigorous methodologies (Alpert & Fava, 2004). Remarkably, our literature review found no randomized controlled trials examining the efficacy of medication augmentation after depressive breakthrough.
Given the biological mechanisms, clinical trial findings, and case-reports reviewed above, there is reason to believe that LDN or ULDN could represent a novel augmentation strategy for depressive breakthrough. Although the pathophysiology of “tachyphylaxis” (i.e. tolerance to antidepressants) is not yet fully understood, serotonergic antidepressant "apathy syndrome" has been hypothesized to arise from the inhibitory effects of serotonin upregulation on dopamine transmission in the prefrontal cortex (Dunlop & Nemeroff, 2007). Therefore, it is also possible that antidepressant tolerance could be reversed by LDN or ULDN via enhancement of the dopaminergic system (above), or activation of "hedonic hotspots" in the mesolimbic reward circuitry involving G-coupled excitatory opioid receptors (Roshanpour et al., 2009). Naltrexone’s low cost (< $40 per month), history of safe use at much higher doses, and relatively mild side effect profile, also make it an attractive candidate for a proof-of-concept study (Younger & Mackey, 2009).
II. Hypotheses and Aims
Primary Aims
Hypothesis 1: Patients with breakthrough depression (BTD) assigned to treatment with LDN (1 mg bid) or ULDN (100 mcg bid) will demonstrate higher rates of response (HAM-D-17 score reduction > 50%) compared to placebo controls
Secondary Aims
Hypothesis 1: Patients with BTD assigned to treatment with LDN or ULDN will demonstrate higher rates of remission (HAM-D-17 score < 8) compared to placebo controls.
Hypothesis 2: Patients with BTD assigned to treatment with LDN or ULDN will experience no significant differences in the number of adverse events, as measured by the SAFTEE-SI, compared to placebo controls.
Hypothesis 3: Patients assigned to LDN and ULDN will experience greater improvement in Quality of Life, Enjoyment, and Satisfaction Questionnaire (Q-LES-Q) and Sheehan Disability Scale (SDS) scores compared to placebo controls.
Exploratory Aim: To assess the efficacy of LDN on symptom response, as measured by change on the HAM-D-17, compared to ULDN.
III. Design and Methodology
Overview of Design
In accordance with a modified sequential parallel comparison design (SCPD) (Fava, Evins, Dorer, & Schoenfeld, 2003), the trial will be conducted over 6 weeks, with double-blind treatment divided into two phases of 3 weeks each; this interval of 3 weeks was chosen based on the rapid course of recovery described in the case reports above. The first phase will consist of an unbalanced randomization between placebo and active treatment with more patients randomized to placebo in a 2 (LDN): 2 (ULDN): 8 (placebo) ratio. Entering phase 2, all placebo non-responders will then be randomized to placebo or LDN or ULDN in a 1:1:1 ratio; since these patients have already failed placebo, their placebo response should be reduced. Additionally, all drug non-responders entering phase 2 will be crossed-over to the alternative dose group (LDN or ULDN). This crossover design for non-responders is similar to the one that we employed in our successfully completed investigation of St. John’s Wort, citalopram, and placebo for Minor Depression (Rapaport et al., 2011); non-responders switched to the alternative dose will provide preliminary dose response data for future trials. Phase 1 responders to both drug and placebo will continue to receive the same intervention in phase 2. Our analysis will pool data from both phases to maximize power and reduce the required sample size. A recent report from FDA statisticians supports these enriched designs (Chen, Yang, Hung, & Wang, 2011).
Selection of Patients
12 men and women ages 18 to 65 who have received adequately dosed SSRI or SNRI for a major depressive episode, achieved remission for at least 3 months, and then had a relapse or recurrence (defined above), will be recruited from the greater Boston area. Participants will be recruited through advertisements and referrals and diagnosed with MDD by the SCID. All ethnicities will be included.
Recruitment and Retention
Sources of recruitment will include the following: 1) Patients who have completed DCRP studies and have a relapse or recurrence. 2) Patients in DCRP clinical practices. 3) Referrals from psychiatry practices of MGH (600 clinicians) and primary care physicians at both institutions, to whom we will present informational talks about MDD recurrence and this study. 4) IRB-approved newspaper, television, internet, and radio ads targeting individuals having a recurrence while on antidepressants.
Retention is always of concern in clinical trials. At the DCRP, our depression trials demonstrate average attrition rates of 20%, near the nationwide average. However, we expect a lower attrition rate in this study because: 1) Nonresponders in Phase 1 will receive an active treatment in Phase 2. Thus every subject (except for placebo responders) is guaranteed at least one active intervention. 2) Participants who have recently benefited from antidepressants may be optimistic about re-establishing improvement, and more likely to stay in the study. 3) Free follow-up will be offered after the study; participants will therefore be invested in remaining with us since we are demonstrating a commitment beyond the clinical trial.
Inclusion Criteria
1. Age 18-65;
2. Written informed consent;
3. Meet DSM-IV criteria (by Structured Clinical Interview for DSM-IV SCID-I/P) for MDD, current;
4. Quick Inventory of Depressive Symptomatology – Self-Rated (QIDS-SR) score of at least 12 at both screen and baseline visits
5. Received treatment with SSRI or SNRI in adequate doses (per MGH ATRQ) (Chandler, Iosifescu, Pollack, Targum, & Fava, 2010), achieved remission per ACNP Task Force guidelines (REF) 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
6. During the baseline visit, patients must be on a stable dose of SSRI or SNRI for the past 4 weeks
Exclusion Criteria
1. 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);
2. Patients who no longer meet DSM-IV criteria for MDD during the baseline visit;
3. Patients who demonstrate a greater than 25% decrease in depressive symptoms as reflected by the QIDS-SR total score - screen to baseline;
4. Serious suicide or homicide risk, as assessed by evaluating clinician;
5. Unstable medical illness including cardiovascular, hepatic, renal, respiratory, endocrine, neurological, or hematological disease;
6. The following DSM-IV diagnoses: substance use disorders active within the last six months, any bipolar disorder (current or past), any psychotic disorder (current or past);
7. History of a seizure disorder or clinical evidence of untreated hypothyroidism;
8. Patients requiring excluded medications (see Table 1 for details);
9. Psychotic features in the current episode or a history of psychotic features, as assessed by SCID;
10. History of naltrexone intolerance at any dose;
11. Patients with a history of antidepressant-induced hypomania.
12. Inadequate exposure time or dose of current SSRI or SNRI; failure to comply with at least 80% of doses.
13. Specified concomitant medications.
Drugs that may be given to the patient include any prescription or OTC medication such as aspirin, acetaminophen and cold preparations not specifically excluded by the protocol. Patients requiring concomitant therapy with excluded drugs will be discontinued from the study. The following list is a list of drugs allowed and not allowed as concomitant medications (for brevity, many of the drugs from our original list have not been included here).
(1) Benzodiazepine anxiolytics and non-benzodiazepine sedative-hypnotics noted above will be allowed only if subjects are on a stable regimen for at least 2 weeks prior to baseline at doses no greater than the following or their equivalent: clonazepam 1.0 qd and zolpidem 10 mg qhs.
(2) Reserpine will be excluded.
(3) Adequate thyroid replacement which has been stable for 6 months or more is acceptable as is estrogen replacement for post-menopausal women or the use of oral contraceptives, the initiation of which does not coincide with the onset or exacerbation of depression.
(4) Dietary supplements with putative CNS activity will be excluded including SAMe, St. John's Wort, DHEA, Inositol, Ginko biloba and psychotropic doses of Omega-3-fatty acids including DHA and Flax Seed Oil.
IV. Treatment of Subjects
Once patients agree to participate in the study by signing the informed consent document, a full medical and psychiatric history will be taken and a physical examination will be performed by a board-certified psychiatrist. Screen rating scales will be performed. Screened and eligible patients will be asked to return one week later for a baseline visit when they will be randomized to double-blind treatment with placebo, LDN, or ULDN with the study design outlined above. The study will last six weeks, during which patients will be assesssed weekly. Subjects will be assigned randomization numbers in consecutive order. The randomization list will be provided by a computer-generated random-number list and will be maintained by the research pharmacist. In addition, the presence of any side effect or adverse event will be carefully documented with the SAFTEE-SI (Levine & Schooler, 1992). Reasons for premature discontinuation, including intolerable side effects, will be recorded.
All concomitant medications taken during the study will be recorded in the case report form, along with dosage information and start and stop dates. Patients requiring excluded drugs (above) will be discontinued from the study. Medication management and clinical ratings will be performed by the study clinicians.
Every effort will be made to encourage patients to comply with this dosage regimen and to take all medications as instructed. All patients will be instructed to return any excess medication at each visit. A pill count will be done to corroborate the study drug record. Protocol violation will be defined as less than 80% compliance by pill count.
Follow-up
At the end of the double-blind study, both responders and non-responders who have completed the double-blind phase will have the option of receiving open-label adjunctive treatment with LDN or ULDN. Subjects who agree to receive open-label treatment with LDN or ULDN for 3 months will be seen monthly by a board-certified psychiatrist until the end of the follow-up phase. Subjects who complete or refuse follow-up will then be offered a referral to a psychiatrist.
V. Efficacy and Safety Assessments
Efficacy Data
The primary efficacy measure will be the change in 17-item Hamilton Rating Scale for Depression (HAM-D-17) [55] score. Response will be defined as a 50% or greater reduction in HAM-D-17 score from baseline. Remission will be defined as a HAM-D-17 score < 8 at endpoint. Secondary measures of efficacy include change in CGI-severity, with “clinical response defined” as CGI-S of 1 or 2 at endpoint. The following instruments will be administered according to the study schedule:
1) Structured Clinical Interview for DSM-IV: The SCID-I/P, administered by the clinician, proceeds by modules to diagnose the different Axis I disorders. Questions here are asked exactly as written, and each is based on the individual criteria from DSM-IV. Answers are generally rated on a scale of 1-3 (1= doubtful, 2= probable, 3= definite), and, based on the number of positive answers, a diagnosis is determined. While the entire SCID-I/P is administered at screen, the mood module will be administered at each follow up visit.
2) The MGH Antidepressant Treatment History Questionnaire: (MGH-ATR) (Fava, 2003). The MGH-ATR provides specific criteria for the adequate dose and adequate length of a trial for it to be considered a failure, thus allowing clinicians to systematically collect data aimed at assessing the degree of treatment-resistance of the current major depressive episode.
3) The 28-item Hamilton Depression Scale (HAM-D-28) (Hamilton, 1960): this version allows scoring of the HAM-D-17, 21-, 25-, and 28-item scales. This instrument is completed by the clinician by using a structured interview and defined anchor points, and aims to quantify the degree of depression over the past 7 days. The HAM-D is the most widely studied instrument for depression, and its reliability and validity are high.
4) Clinical Global Impressions - Severity and Improvement (CGI-S, CGI-I): These two instruments are scored 1-7 by the clinician based on assessment of the patient's clinical status. They measure, based on history and scores on other instruments: a) Depressive severity (CGI-S) and b) Clinical Improvement (CGI-I). Patient rated versions of both scales will also be utilized (the PGI-S/I).
5) QIDS-SR (Trivedi et al., 2004): This is a brief (16-item) self-report inventory of core depressive symptoms such as sleep, depressed mood, appetite, concentration, suicidal ideation, interest, energy, psychomotor retardation or agitation.
6) The Massachusetts General Hospital Cognitive and Physical Functioning Questionnaire. This is a brief (7-item) self-report inventory to assess rates of significant cognitive symptoms, sleepiness, and fatigue (Fava, Iosifescu, Pedrelli, & Baer, 2009).
7) The Massachusetts General Hospital Sexual Functioning Questionnaire (Fava, Rankin, Alpert, Nierenberg, & Worthington, 1998): this is a self-rating scale that measures common symptoms of sexual dysfunction, such as reduced libido and orgasm difficulties.
8) The Quality of Life Satisfaction Questionnaire-short form (Q-LES-Q) (Endicott, Nee, Harrison, & Blumenthal, 1993) is a patient-administered instrument that rates satisfaction on a 1-5 scale, with 13 specific areas of life, as well as medication, and overall life satisfaction over the past week.
9) The Sheehan Disability Scale (Leon, Shear, Portera, & Klerman, 1992) is a 3-item self-measure of disability and impairment.
Safety Data
Once the patient has agreed to participate in the study by signing the informed consent document, vital signs (weight, and standing and supine pulse and blood pressure) will be recorded at each visit and a physical exam will be performed at screen. Consumptive habits (smoking, alcohol, and caffeinated beverages) will be recorded at baseline, Day 21, and Day 42. A urine pregnancy test (for women of childbearing potential) will also be administered at the screen visit; urine drug testing will be conducted at screening to ensure that patients are not using prohibited agents. Because changes in liver function enzymes have not been found with LDN, LFTs will be monitored only at screening and day 42 (Younger & Mackey, 2009).
Adverse Events
Documentation of the presence of any side effect or adverse event will be completed at every visit using the SAFTEE-SI. Subjects will be encouraged to contact (page) the principal investigator or a member of his staff at any time between visits concerning adverse events or worsening of symptoms. Suicidal ideation will be assessed at each visit using the HAM-D interview. Subjects who are felt by the study clinician to be at high risk for suicide will be discontinued from the study and referred for hospitalization and further treatment if clinically indicated.
Termination
Every effort will be made to keep patients in the study for the full six weeks of treatment. Acceptable reasons for early discontinuation include the following: 1) request of patient, 2) decision of physician, 3) serious adverse event, 4) protocol violation, 5) worsening of depression or clinical deterioration requiring hospitalization.
Data Management
Clinical data at each visit will be recorded using a standardized clinician assessment form and a set of patient rating scales. Edited and corrected data will be added to a database that is ready to be used as input to statistical software (STATA), which will be the primary software used for data development and analysis. All data will be stored in locked file cabinets. No identifiers other than study ID’s will be included in the data. Study staff and subjects may have the option to enter clinical data into the database directly, using Red-Cap, a platform for electronic data capture that streamlines data collection and management, and ensures data integrity, resulting in improved data quality. Subjects and/or research staff enter survey responses into electronic assessment forms, and the responses are then transmitted securely via encrypted connection and stored in a secured database.
VI. Statistical Methodology
General Considerations
Data will be entered and error-checked by DCRP staff involved in the conduct of the study. Once the data set is entered and checked, analyses will be conducted. Both a completer analysis of all patients finishing the trial and an intent-to-treat analysis examining all patients enrolled into the trial will be used to define the severity of depression at endpoint. Examination of both study completers and all patients randomized provides the broadest assessment of the effects of treatment in trials of this kind. We plan to pool the data from the proposed study with the modified sequential parallel comparison design, to provide an estimate of the placebo response based on a larger sample size. As per the sequential parallel comparison design analytical plan, the effect of the active treatment is assessed using a z-score. Under the null hypothesis of no drug-placebo difference, the z score has a mean of 0. Let p1, q1 be the response rates to the first administration of drug and placebo respectively and let p2, q2 by the responses to the second treatment. To analyze these data we use a statistic based on h = w(p1 - q1) + (1 - w)(p2 - q2). The weight, w and the randomization fraction, a are chosen to maximize the power of the test, based on the alternative hypothesis. The standard error for h requires a special formula because some of the same patients who are included in the estimation of p2, q2 are included in the estimation of p1, q1. The computation is facilitated by considering a table of outcomes, where in this case p1, p2, q1, q2 are the theoretical probabilities rather than the observed relative frequencies. A more detailed description of the analyses is included in the enclosed copy of the paper by Fava et al on the sequential parallel comparison design (Fava, Evins, Dorer, & Schoenfeld, 2003).
Sample Size Determination
Patient retention rates during phase 1 and phase 2 of the trial are assumed to be 90% and 90%, respectively, based on previous studies for the treatment of breakthrough depression (CIT needed). The treatment differences from phase 1 and phase 2 will be combined with equal weights to estimate the overall treatment effect. To test the hypothesis that the combined treatment difference of 47.5% or greater (the underlying hypothesis: response rates of 70% and 25% at phase 1, and 55% and 10% at phase 2 for combined drug groups and placebo, respectively), a total of 12 patients will be randomized in the study to have 80% power at the 10% significance level.
The study is powered for a medium to large effect size (ES) difference (Cohen’s d>0.5 – 0.8) to detect a clinically meaningful difference between two active treatments. Although this increases the risk of a type II error, we believe it is justified given the dramatic responses - from severe depression to full recovery - in the case-reports above.
VII Risks and Benefits
Risks and Discomforts
1. Risks to the Subjects
a. Human Subjects Involvement and Characteristics:
This study will recruit a total of 12 individuals age 18-65 with MDD. Subjects must be medically stable as defined in the protocol. We also specifically exclude patients at acute risk for suicide, active substance abuse or dependence, and those with psychosis or bipolar illness. Rationale for exclusions is discussed in the study protocol. We exclude patients below the age of 18 or over the age of 65.
b. Sources of materials: eesearch data acquired will include a diagnosis from the SCID, and all administered rating scales.
c. Potential risks: preliminary investigations of LDN have raised no safety concerns. Patients will be carefully monitored by clinicians for side effects and potential toxicities. Blood sampling is performed in the study during the baseline (45 mls total) and day 42 visits (30 mls total) and there is always a very minor risk of infection, bruising, or syncope during a blood draw. There is also the discomfort of having one’s blood drawn. Answering detailed questionnaires may create some inconvenience for subjects.
2. Adequacy of protection against risks
a. Recruitment and informed consent: ll materials used to recruit subjects for this protocol will be reviewed and approved by the IRB prior to their use. All subjects will receive the consent form for the study. These documents will be read by the patients and also reviewed by the patient with a psychiatrist or psychologist on the research staff prior to participating in the study. Any questions, concerns, or ambiguities will be clarified by the site’s PI or another study clinician prior to the patient signing consent. Patients will sign informed consent and only then will begin participation in the study.
b. Protection against risk: The procedures to protect against or minimize potential risks include the following: (1) the assignment of unique study subject numbers to patients, (2) the use of these primary identifiers throughout the study, (3) storage of information in locked file cabinets, and (4) access limited to study personnel for these file cabinets and data. Data will be entered into password protected computer files. The blood draws will be performed by trained staff who have certificates documenting their ability to draw blood. We are performing a physical examination prior to allowing anyone to enter the randomized phase of the protocol to ensure that subjects are medically stable. Close monitoring of patients throughout the study will ensure that adverse effects from treatment, exacerbation of symptoms, or emergence of suicidality, mania or psychosis will be promptly recognized so that patients can be treated appropriately following study discontinuation. All patients will be instructed on how to contact study clinicians in the case of an emergency.
Potential Benefits
1a. Benefits to the Patient: the study may provide relief of depressive symptoms for some patients who participate.
1b. Benefits to Others: the study may benefit other people with depression, by furthering our understanding of the potential antidepressant properties of LDN or ULDN. The study will also systematically test the safety, tolerability and efficacy of LDN or ULDN as an adjunct to SSRIs or SNRIs for the treatment of breakthrough depression.
Serious Adverse Events
Expedited review will occur for all events meeting the FDA definiton of Serious Adverse Events (SAEs) i.e., any fatal event, immediately life-threatening event, permanently or substantially disabling event, event requiring or prolonging inpatient hospitalization, or any congenital anomaly. For purposes of this study, all SAEs will be required to be reported immediately (within 24 hours) to the site’s IRB and to the Co-PIs (Dr. Fava and Dr. Soskin), regardless of any judgment of their relatedness to the study drug. Information will be reviewed by the study PIs and a determination made of whether there was any possible relevance to the study drug. Additional reporting to the FDA will be made according to the regulations governing SAE reporting.
A serious adverse event is one that meets any one of the following criteria:
a. Death;
b. Life threatening;
c. Requires inpatient hospitalization or prolongation of exisiting hospitalization;
d. Results in persistent or significant disability or incapacity;
e. Congenital anomaly or birth defect;
g. Overdose;
h. Results in development of drug dependency or drug use.
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