Brain Stimulation for Depression

(RAISE Trial)

Overseen By Eli Strohecker, BS

Age: 18 - 65

Sex: Any

Trial Phase: Phase 4

Sponsor: Marta Peciña, MD PhD

Must not be taking: Psychiatric medications, Opioid analgesics

Disqualifiers: Pregnancy, Psychotic disorders, Substance dependence, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: 6

Duration: 3 weeks

120 Participants Needed

Trial Summary

What is the purpose of this trial?

The central goal of this application is to demonstrate the causal contribution of reward learning signals (expected values and reward prediction errors \[RPE\]) to antidepressant responses (Aim1) by experimentally manipulating expected values using transcranial magnetic stimulation (TMS) targeting the vmPFC (Aim 2) and μ-opioid striatal RPE signal using pharmacological approaches (Aim 3).

Will I have to stop taking my current medications?

Yes, you will need to stop taking antidepressant medications at least 21 days before the imaging data collection (five weeks for fluoxetine). Additionally, you cannot be taking any psychiatric medications or other potential augmenting agents.

What data supports the effectiveness of the drug Buprenorphine for depression?

Research shows that low doses of Buprenorphine can effectively reduce depressive symptoms and serious suicidal thoughts, even in patients who don't respond to other antidepressants. However, more studies are needed to understand its long-term effects and the best way to use it with other treatments. ^{1 2 3 4 5}

Is brain stimulation for depression safe for humans?

Buprenorphine, used in various forms for depression and opioid dependence, is generally considered safe and well-tolerated at low doses, though more studies are needed to understand long-term effects. It has been shown to reduce depressive symptoms and is effective in opioid dependence treatment, with some formulations designed to minimize misuse. ^{1 3 6 7 8}

How does the treatment of brain stimulation with Buprenorphine and Naltrexone for depression differ from other treatments?

This treatment is unique because it combines brain stimulation, which directly targets brain areas involved in mood regulation, with Buprenorphine and Naltrexone, drugs typically used for addiction treatment, potentially offering a novel approach for treatment-resistant depression by addressing both mood and reward system dysfunctions. ^{9 10 11 12 13}

Research Team

Marta Peciña, MD, PhD

Principal Investigator

University of Pittsburgh

Eligibility Criteria

Adults aged 18-55 with major depression, who have tried at most one antidepressant without success, can join this trial. They must be fluent in English and off antidepressants for at least 21 days. People with a history of psychotic disorders, substance dependence (except nicotine), or those currently suicidal or on certain psychiatric medications cannot participate.

Inclusion Criteria

I am between 18 and 55 years old, speak English, and can understand and consent to the study.

I have tried only one antidepressant without success, as per the MGH-ATRQ standards.

A score on the Mood and Anxiety Symptom Questionnaire- Anhedonic Depression (MASQ-AD) ≥ 23 (2/3 sample) and MASQ-AD < 23 (1/3 sample) with or without certain anxiety disorders (e.g., generalized anxiety, panic, agoraphobia, social phobia, and specific phobia)

Exclusion Criteria

I have been on a stable dose of thyroid medication for hypothyroidism for 3 months.

Requiring immediate hospitalization for psychiatric disorder or have an unstable general medical condition (GMC) that will likely require hospitalization or to be deemed terminal (life expectancy < 6 months after study entry)

Currently enrolled in another study, and participation in that study contraindicates participation in this study

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive TMS sessions and pharmacological interventions to modulate reward learning signals

3 weeks

3 sessions (in-person)

Follow-up

Participants are monitored for changes in BOLD signal during the Antidepressant fMRI Task

3 weeks

3 visits (in-person)

Treatment Details

Interventions

• Buprenorphine
• Naltrexone
• Theta Burst Stimulation

Trial Overview The study tests if stimulating the brain's reward system using TMS and altering opioid signals with buprenorphine/naltrexone can improve depression symptoms. Participants will receive either real treatments or placebos to compare effects.

Participant Groups

Group I: Oral Placebo Pill + Intramuscular Saline Injection Experimental Treatment 3 Interventions

Inert pill and saline injection that have no inherent power to produce an effect. In the inert pill condition, participants will receive one IM arm injection of saline (1ML) and an oral placebo tablet.

Group II: Naltrexone Oral Tablet + Intramuscular Saline Injection Experimental Treatment 3 Interventions

Naltrexone is thought to strongly block μ-opioid receptors. Oral (pill) opioid antagonist which will be used to modulate reward learning signals to understand placebo effects in participants with depression. In the naltrexone condition, participants will receive one tablet of 50mg Naltrexone hydrochloride (ReVia®. Toronto, ON: Teva Canada Limited; 2015) (onset of action: ≥15 minutes; peak effect: \~1 hour; duration: \~24 hours) and a saline IM injection.

Group III: Buprenorphine Injection + Oral Placebo Pill Experimental Treatment 3 Interventions

Buprenorphine is a μ-opioid partial agonist and kappa-opioid antagonist that is used to treat moderate to severe pain and opioid dependence. The intramuscular administered opioid agonist which will be used to modulate reward learning signals to understand placebo effects in patients with depression. In the buprenorphine condition, participants will receive one IM injection of 0.3mg/1ML buprenorphine hydrochloride (Buprenex®. Richmond, VA: Reckitt Benckiser Pharmaceuticals Inc.; 2006) (onset of action: ≥15 minutes; peak effect: \~1 hour; duration: \~6 hours) and an oral placebo tablet.

Buprenorphine is already approved in United States, European Union for the following indications:

Approved in United States as Buprenorphine for:

• Moderate to severe opioid addiction (dependence)

Approved in European Union as Buprenorphine for:

• Opioid dependence

Who Is Running the Clinical Trial?

Marta Peciña, MD PhD

Lead Sponsor

Trials

3

Recruited

210+

Findings from Research

Buprenorphine (BUP) has been found to be an effective and safe treatment option for reducing depressive symptoms, suicidal ideation, and non-suicidal self-injury, particularly in patients with treatment-resistant depression (TRD).

The study highlights the need for further research to explore the long-term effects of BUP and the efficacy of various combinations with other medications, as well as to establish optimal dosing guidelines.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The Efficacy of Buprenorphine in Major Depression, Treatment-Resistant Depression and Suicidal Behavior: A Systematic Review. Serafini, G., Adavastro, G., Canepa, G., et al.[2023]

Buprenorphine, a partial mu-opioid receptor agonist, is an effective and well-tolerated treatment for opioid dependence, comparable to methadone, and can now be prescribed by all physicians in office-based settings due to the Drug Addiction Treatment Act of 2000.

It is available in two formulations: Subutex (buprenorphine only) and Suboxone (buprenorphine with naloxone), but physicians must obtain a special waiver to prescribe it and are limited to 30 patients at a time.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Buprenorphine: a (relatively) new treatment for opioid dependence. Welsh, C., Valadez-Meltzer, A.[2021]

Buprenorphine is a safe and effective treatment for opioid dependence, particularly when combined with naloxone, which reduces its potential for abuse.

New regulations enable certified physicians to prescribe buprenorphine in their offices, significantly improving patient access to this important treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Buprenorphine maintenance: a new treatment for opioid dependence. Collins, GB., McAllister, MS.[2019]

In a study of 5,529 patients with chronic pain and prescription opioid dependence, depression did not affect the initiation of buprenorphine (BUP) treatment, indicating that patients with depression are just as likely to start BUP as those without depression.

However, among those who started BUP, patients with depression received 29% fewer prescriptions and had a higher risk of treatment gaps lasting over 30 days, suggesting that depression may lead to challenges in maintaining consistent BUP treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Depression and Buprenorphine Treatment in Patients with Non-cancer Pain and Prescription Opioid Dependence without Comorbid Substance Use Disorders. Scherrer, JF., Salas, J., Grucza, R., et al.[2021]

In a study of 32 veterans over three years, those receiving buprenorphine/naloxone in a group setting had a significantly higher retention rate in treatment after one year (69%) compared to those treated individually (27%).

The study also found that 94% of urine samples from participants were negative for opioids, indicating effective management of opioid use disorder with buprenorphine/naloxone in a group format.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Group medication management for buprenorphine/naloxone in opioid-dependent veterans. Berger, R., Pulido, C., Lacro, J., et al.[2014]

A study involving 53 opioid-dependent patients showed that switching from buprenorphine to buprenorphine/naloxone was well-tolerated, with no significant issues reported during the transition.

Patients expressed a preference for buprenorphine/naloxone over buprenorphine, with 54% favoring the combination formulation due to its taste and ease of use, indicating it may be a more acceptable option for maintenance treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Preference for buprenorphine/naloxone and buprenorphine among patients receiving buprenorphine maintenance therapy in France: a prospective, multicenter study. Daulouède, JP., Caer, Y., Galland, P., et al.[2015]

A survey of intravenous drug users in Helsinki revealed that 73% used buprenorphine as their primary drug, primarily for self-treating addiction or withdrawal symptoms.

The combination of buprenorphine and naloxone (Suboxone) was tried by 68% of respondents, but 80% reported negative experiences, suggesting that while it may help reduce buprenorphine abuse, its acceptance among users is low.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Abuse liability of buprenorphine-naloxone tablets in untreated IV drug users. Alho, H., Sinclair, D., Vuori, E., et al.[2015]

New prolonged-release formulations of buprenorphine, including a six-month implant and two subcutaneous injection depots, aim to improve patient comfort and safety by reducing the need for daily intake and minimizing risks associated with sublingual forms.

These formulations have shown promise in addressing concerns about treatment adherence, particularly for stabilized patients, while also raising some apprehensions about potential coercive use among opioid users.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Prolonged-release buprenorphine formulations: Perspectives for clinical practice]. Chappuy, M., Trojak, B., Nubukpo, P., et al.[2022]

Deep brain stimulation (DBS) targeting the nucleus accumbens showed sustained antidepressant and anxiolytic effects in 45% of the 11 patients with treatment-resistant depression over a follow-up period of up to 4 years.

All patients reported improvements in quality of life, and there were no severe adverse events related to the treatment, indicating that NAcc-DBS is a safe and potentially effective long-term intervention for TRD.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Long-term effects of nucleus accumbens deep brain stimulation in treatment-resistant depression: evidence for sustained efficacy. Bewernick, BH., Kayser, S., Sturm, V., et al.[2021]

Deep brain stimulation (DBS) of the ventromedial prefrontal cortex (vmPFC) significantly reduces immobility in rats, indicating an antidepressant-like effect in the forced swim test, which is a common model for studying depression.

However, the addition of augmentative drugs like buspirone, risperidone, or pindolol did not enhance the antidepressant effects of vmPFC DBS, suggesting that these therapies may not work synergistically in this context.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Augmentative therapies do not potentiate the antidepressant-like effects of deep brain stimulation in rats. Laver, B., Diwan, M., Nobrega, JN., et al.[2021]

Deep brain stimulation of the ventral tegmental area (VTA) significantly alleviates depressive behaviors more quickly and effectively than traditional chemical antidepressants or electroconvulsive therapy, based on a series of behavioral tests.

The positive effects of VTA stimulation are linked to increased levels of brain-derived neurotrophic factor (BDNF) mRNA in the prefrontal cortex, suggesting a potential mechanism of action that enhances motivation and pleasure.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Programmed acute electrical stimulation of ventral tegmental area alleviates depressive-like behavior. Friedman, A., Frankel, M., Flaumenhaft, Y., et al.[2022]

Deep brain stimulation of the NAcore region significantly reduced cue-induced reinstatement of heroin seeking and decreased motivation for heroin taking, suggesting its potential as a treatment for substance use dependence.

In contrast, stimulation of the NAshell region did not affect heroin seeking or self-administration, highlighting the distinct roles of these brain sub-regions in addiction behavior.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Deep brain stimulation of the nucleus accumbens core but not shell reduces motivational components of heroin taking and seeking in rats. Schippers, MC., Gaastra, M., Mesman, T., et al.[2022]

Deep brain stimulation (DBS) targeting the nucleus accumbens showed immediate clinical improvement in all three patients with treatment-resistant depression, indicating its potential efficacy in alleviating depressive symptoms.

No significant side effects were reported from the DBS procedure, aside from minor surgical-related discomfort, suggesting that this intervention may be a safe option for patients who have not responded to other treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Deep brain stimulation to reward circuitry alleviates anhedonia in refractory major depression. Schlaepfer, TE., Cohen, MX., Frick, C., et al.[2023]

References

1. Switzerland pubmed.ncbi.nlm.nih.gov

The Efficacy of Buprenorphine in Major Depression, Treatment-Resistant Depression and Suicidal Behavior: A Systematic Review. [2023]

2. United States pubmed.ncbi.nlm.nih.gov

Buprenorphine: a (relatively) new treatment for opioid dependence. [2021]

3. United States pubmed.ncbi.nlm.nih.gov

Buprenorphine maintenance: a new treatment for opioid dependence. [2019]

4. Netherlands pubmed.ncbi.nlm.nih.gov

Depression and Buprenorphine Treatment in Patients with Non-cancer Pain and Prescription Opioid Dependence without Comorbid Substance Use Disorders. [2021]

5. Netherlands pubmed.ncbi.nlm.nih.gov

Group medication management for buprenorphine/naloxone in opioid-dependent veterans. [2014]

6. United States pubmed.ncbi.nlm.nih.gov

Preference for buprenorphine/naloxone and buprenorphine among patients receiving buprenorphine maintenance therapy in France: a prospective, multicenter study. [2015]

7. Ireland pubmed.ncbi.nlm.nih.gov

Abuse liability of buprenorphine-naloxone tablets in untreated IV drug users. [2015]

8. France pubmed.ncbi.nlm.nih.gov

[Prolonged-release buprenorphine formulations: Perspectives for clinical practice]. [2022]

9. England pubmed.ncbi.nlm.nih.gov

Long-term effects of nucleus accumbens deep brain stimulation in treatment-resistant depression: evidence for sustained efficacy. [2021]

10. Netherlands pubmed.ncbi.nlm.nih.gov

Augmentative therapies do not potentiate the antidepressant-like effects of deep brain stimulation in rats. [2021]

11. England pubmed.ncbi.nlm.nih.gov

Programmed acute electrical stimulation of ventral tegmental area alleviates depressive-like behavior. [2022]

12. United States pubmed.ncbi.nlm.nih.gov

Deep brain stimulation of the nucleus accumbens core but not shell reduces motivational components of heroin taking and seeking in rats. [2022]

13. England pubmed.ncbi.nlm.nih.gov

Deep brain stimulation to reward circuitry alleviates anhedonia in refractory major depression. [2023]