Brain Stimulation for Depression

(RAISE Trial)

Overseen By Ian Snyder, 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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests how brain stimulation might help treat depression. Researchers use two treatments, buprenorphine and naltrexone, to observe their effects on the brain's reward system, which can influence mood and depression. Participants may receive buprenorphine injections, naltrexone tablets, or placebos (inactive substances) to compare effects. Suitable candidates for this trial are adults who have experienced depression and have not responded well to one antidepressant treatment before. As a Phase 4 trial, this research aims to understand how these FDA-approved treatments can benefit more patients.

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 is the safety track record for these treatments?

Research has shown that both buprenorphine and naltrexone have been studied for their safety in humans.

For buprenorphine, most studies indicate it is well-tolerated. Strong evidence of misuse or dependency is lacking, suggesting people generally handle the treatment well without major issues. Some mild effects, such as slight euphoria or minor breathing problems, might occur, but these are less severe than with other similar drugs.

Naltrexone has also been examined for safety. Studies show that taking naltrexone does not commonly cause or worsen depression. The FDA has approved it for treating alcohol dependence, indicating its safety. This suggests naltrexone is generally considered safe and does not usually lead to serious side effects.

Overall, both buprenorphine and naltrexone have been tested and found safe for use in humans, with no major side effects reported in most people. ^{1 2 3 4 5}

Why are researchers enthusiastic about this study treatment?

Researchers are excited about these treatments because they explore new ways to manage depression by modulating reward learning signals in the brain. Buprenorphine, typically used for pain and opioid dependence, is being studied for its potential to alter these signals through its action as a μ-opioid partial agonist and kappa-opioid antagonist. This approach is different from most depression treatments, like SSRIs, which primarily focus on serotonin levels. On the other hand, Naltrexone, a μ-opioid receptor antagonist, is being investigated for its ability to block these signals, adding another layer of understanding to how depression might be managed. This study could open new avenues for treatments that work faster and target different aspects of brain function compared to conventional antidepressants.

What evidence suggests that this trial's treatments could be effective for depression?

In this trial, participants will be assigned to different treatment arms to evaluate the effects of buprenorphine and naltrexone on depression. Research has shown that buprenorphine might ease depression symptoms, though the effects are usually small. In several studies, patients noticed slight improvements in their depression when treated with buprenorphine. Participants in one arm of this trial will receive a buprenorphine injection along with an oral placebo pill.

Naltrexone, on the other hand, has been found to reduce depression when patients consistently follow their treatment plan. A small study suggested that low doses of naltrexone could decrease depression severity in some people. Participants in another arm of this trial will receive a naltrexone oral tablet along with an intramuscular saline injection. Both treatments show promise, but their effects on depression can differ from person to person. ^{1 2 3 6 7}

Who Is on the Research Team?

Marta Peciña, MD, PhD

Principal Investigator

University of Pittsburgh

Are You a Good Fit for This Trial?

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 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)

I have stopped taking antidepressants for at least 21 days, or 5 weeks for fluoxetine.

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 for a Trial Participant

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)

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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) 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]

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]

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]

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]

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]

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]

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]

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]

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]

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 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]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10970042/

Therapeutic Potential of Buprenorphine in Depression The results of our study suggest that buprenorphine may have the potential to improve depressive symptoms. Buprenorphine's therapeutic potential ...

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10149594/

The efficacy and safety of buprenorphine for the treatment ... Buprenorphine had a small effect on depressive symptoms (Hedges' g 0.17, 95%CI: 0.05 – 0.29). Results were driven by six trials of buprenorphine/samidorphan (N= ...

3. jamanetwork.com jamanetwork.com/journals/jamanetworkopen/fullarticle/2837787

Behavioral Therapy and Buprenorphine Treatment for ... Buprenorphine combined with low-intensity psychosocial support is a highly effective treatment for opioid use disorder (OUD). Studies of ...

4. sciencedirect.com sciencedirect.com/science/article/abs/pii/S0376871620302878

Depression history as a predictor of outcomes during ... Although depressive symptoms decreased significantly throughout treatment (p <.001), this improvement was not associated with opioid outcomes ( ...

5. sciencedirect.com sciencedirect.com/science/article/abs/pii/S0022395623001565

The efficacy and safety of buprenorphine for the treatment ... Conclusion. Buprenorphine may have a small benefit on depressive symptoms in patients with moderate or treatment resistant depression. Future studies should ...

6. samhsa.gov samhsa.gov/substance-use/treatment/options/buprenorphine

What is Buprenorphine? Side Effects, Treatment & Use It produces effects such as euphoria or respiratory depression at low to moderate doses. With buprenorphine, however, these effects are weaker ...

7. brixadihcp.com brixadihcp.com/safety/

Clinical Safety Profile Adverse reactions led to premature discontinuation in 10 (4.7%) patients in the group receiving BRIXADI compared to 5 (2.3%) patients in the sublingual ...