Buspirone + Melatonin for Depression After Traumatic Brain Injury

Recruiting at 1 trial location

Overseen By Kaloyan S Tanev, MD

Age: 18 - 65

Sex: Any

Trial Phase: Phase 4

Sponsor: Massachusetts General Hospital

Must be taking: Buspirone, Melatonin

Must not be taking: Antidepressants, Psychostimulants

Disqualifiers: Neurological disorders, Bipolar, Schizophrenia, 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

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

Duration: 6 weeks

10 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores a new treatment combination of buspirone (an anti-anxiety medication) and melatonin (a hormone that regulates sleep) for individuals dealing with depression after a traumatic brain injury (TBI). The goal is to determine if this combination can improve mood and cognitive issues, such as memory and focus, in these patients. Researchers use brain scans to understand how the treatment affects brain activity. Individuals who experienced a mild or moderate TBI at least three months ago and have been diagnosed with major depression might be suitable candidates. As a Phase 4 trial, this research aims to understand how this already FDA-approved and effective treatment can benefit more patients.

Will I have to stop taking my current medications?

Yes, if you are currently taking an antidepressant, you will need to stop, as the trial excludes those who have been on antidepressants in the past 4 weeks. Also, you cannot participate if you are using buspirone, any psychostimulant, or modafinil/armodafinil.

What is the safety track record for the Buspirone and Melatonin combination?

Research has shown that combining buspirone and melatonin (B+MEL) significantly improves depression symptoms compared to a placebo. Patients with depression tolerate this combination well, indicating general safety. These studies reported no major side effects. The FDA has already approved buspirone for treating anxiety, supporting its safety profile. Melatonin, commonly used as a sleep aid, is also generally considered safe. This combination might also aid thinking-related issues, offering promise for individuals with depression after a traumatic brain injury (TBI). ^{1 2 3 4 5}

Why are researchers enthusiastic about this study treatment?

Unlike the standard treatments for depression, which often include medications like SSRIs or SNRIs, the combination of Buspirone and Melatonin offers a unique approach by targeting serotonin receptors and regulating the sleep-wake cycle. Buspirone is an anxiolytic that modulates serotonin without the typical side effects of antidepressants, while Melatonin is a natural hormone that aids in sleep. Researchers are excited because this combination could not only alleviate depressive symptoms more holistically but also potentially improve sleep patterns, a common issue in depression after traumatic brain injury.

What evidence suggests that the Buspirone and Melatonin combination might be an effective treatment for post-TBI depression?

Research has shown that a combination of buspirone and melatonin (B+MEL) can help treat depression. In earlier studies, participants taking B+MEL showed noticeable improvement in depression symptoms compared to those taking a placebo, which contains no active medicine. Although depression after a traumatic brain injury (TBI) may differ from regular depression, this trial will assess the effectiveness of B+MEL in alleviating general thinking and memory problems often associated with depression. These findings suggest that B+MEL could improve both mood and cognitive issues in individuals with depression following a TBI. ^{1 2 3 4 6}

Are You a Good Fit for This Trial?

This trial is for adults aged 18-64 who have had a non-penetrating mild or moderate traumatic brain injury at least 3 months ago, with specific scores on the Glasgow Coma Scale and experiences of loss of consciousness and post-traumatic amnesia. They must be experiencing depression as diagnosed by medical records, speak English, and have a certain score indicating depression severity.

Inclusion Criteria

I had a mild or moderate brain injury over 3 months ago.

Patients with mild or moderate TBI

I have had a head injury with specific symptoms and am willing to start treatment with Buspirone and Melatonin.

Exclusion Criteria

Evidence of TBI severity greater than moderate, inability to attend regular appointments, imminent risk of suicide, lifetime history of schizophrenia or other primary psychotic disorders, history of bipolar disorder, alcohol or substance dependence in the past 3 months, pregnancy or breast-feeding, concomitant use of buspirone, any psychostimulant, or modafinil/armodafinil, current use or recent use of antidepressants, prior intolerances to buspirone or melatonin, conditions precluding subject from participating in MRI procedures.

I do not have any neurological disorders or unstable medical conditions.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive Buspirone 15mg and Melatonin 3mg for post-TBI depression

6 weeks

Weekly visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Buspirone and Melatonin Combination

Trial Overview The study tests Buspirone combined with Melatonin (B+MEL) in outpatients suffering from depression after a traumatic brain injury. It aims to see if this combination improves depressive and cognitive symptoms while also looking at changes in brain function through imaging before and after treatment.

How Is the Trial Designed?

Group I: Buspirone and Melatonin Experimental Treatment 2 Interventions

Buspirone 15mg and Melatonin 3mg

Buspirone and Melatonin Combination is already approved in United States, European Union for the following indications:

Approved in United States as Buspar for:

• Generalized Anxiety Disorder

Approved in European Union as Buspirone for:

• Anxiety disorders

Approved in European Union as Circadin for:

• Insomnia characterized by difficulties with sleep initiation

Approved in United States as Melatonin for:

• Sleep disorders
• Insomnia

Who Is Running the Clinical Trial?

Massachusetts General Hospital

Lead Sponsor

Trials

3,066

Recruited

13,430,000+

Published Research Related to This Trial

In a randomized double-blind controlled trial involving TBI patients with chronic sleep disturbances, Melatonin (5 mg) and Amitriptyline (25 mg) were compared, showing no significant differences in sleep metrics but some positive trends in patient-reported outcomes.

Patients taking Melatonin reported improved daytime alertness, while those on Amitriptyline experienced increased sleep duration, indicating potential benefits of both medications without adverse effects, warranting further research.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The value of melatonin for sleep disorders occurring post-head injury: a pilot RCT. Kemp, S., Biswas, R., Neumann, V., et al.[2015]

Melatonin treatment (3 mg) significantly reduced sleep-related problems in youth with persistent post-concussion symptoms (PPCS) after mild traumatic brain injury (mTBI), showing a notable improvement compared to placebo.

Short-term melatonin use was well-tolerated and also associated with a decrease in depressive symptoms, indicating potential benefits beyond just sleep improvement.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy of Melatonin for Sleep Disturbance in Children with Persistent Post-Concussion Symptoms: Secondary Analysis of a Randomized Controlled Trial. Barlow, KM., Kirk, V., Brooks, B., et al.[2022]

Circadin, a prolonged-release melatonin formulation, effectively improves sleep quality and reduces sleep latency in patients aged 55 and over with primary insomnia, showing benefits in next-day alertness and overall quality of life.

Unlike traditional sedative hypnotics, Circadin does not impair cognitive or psychomotor skills, has no risk of dependence or abuse, and has a favorable safety profile with no significant adverse events compared to placebo.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Controlled release melatonin (Circadin) in the treatment of insomnia in older patients: efficacy and safety in patients with history of use and non-use of hypnotic drugs]. Zisapel, N.[2013]

In a study involving 5 patients with severe traumatic brain injury and 2 healthy controls, it was found that the patients exhibited significant disruptions in melatonin secretion, lacking the normal circadian rhythm seen in healthy individuals.

These findings suggest that severe brain injury can severely impact melatonin levels shortly after the injury, indicating a need for further research to understand the implications for recovery and treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Circadian rhythms of melatonin of patients with severe traumatic brain injury]. Moskała, M., Krupa, M., Gościński, I., et al.[2015]

Combining environmental enrichment (EE) with the serotonin(1A) receptor agonist buspirone did not produce greater benefits after traumatic brain injury (TBI) than either treatment alone, suggesting that EE alone may provide significant recovery benefits.

Both EE and buspirone improved motor recovery and cognitive functions like spatial learning and memory retention in rats after TBI, but the combination did not enhance these effects, possibly due to a ceiling effect from the EE treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Evaluation of a combined treatment paradigm consisting of environmental enrichment and the 5-HT1A receptor agonist buspirone after experimental traumatic brain injury. Kline, AE., Olsen, AS., Sozda, CN., et al.[2021]

In a study involving 96 male rats with traumatic brain injury (TBI), the serotonin(1A) receptor agonist buspirone (BUS) at a dose of 0.3 mg/kg significantly improved cognitive performance and provided histological protection by reducing cortical lesion size, compared to a saline control.

The results suggest that buspirone has a narrow therapeutic window, with the 0.3 mg/kg dose being optimal for enhancing spatial learning and memory after TBI, indicating its potential as a new treatment option for clinical TBI.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Traumatic brain injury-induced cognitive and histological deficits are attenuated by delayed and chronic treatment with the 5-HT1A-receptor agonist buspirone. Olsen, AS., Sozda, CN., Cheng, JP., et al.[2021]

Melatonin (MEL) shows promising neuroprotective properties after traumatic brain injury (TBI) with low toxicity, making it a potential treatment option, especially since there are currently no FDA-approved therapies for TBI.

The evidence reviewed comes from 22 preclinical studies primarily involving adult male rats, highlighting the need for more diverse research including female, pediatric, and geriatric subjects, as well as longer-term studies beyond the initial injury period.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Melatonin as a Therapy for Traumatic Brain Injury: A Review of Published Evidence. Osier, N., McGreevy, E., Pham, L., et al.[2018]

In a study of 60 patients with mild cranial-brain injury, melatonin (melaxen) significantly improved sleep quality, reducing sleep latency and the number of awakenings per night.

Melatonin treatment also led to a decrease in depression severity during the early rehabilitation period, suggesting it may be beneficial for both sleep and mood in these patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Treatment of sleep disorders in patients with mild cranial-brain injury in the early rehabilitation period]. Ivanova, DS., Kulikova, IS., Vinogradov, OI., et al.[2016]

Citations

1. trialx.com trialx.com/clinical-trials/listings/288012/buspirone-and-melatonin-for-depression-following-traumatic-brain-injury/

Buspirone and Melatonin for Depression Following ... Compared to placebo, B+MEL was associated with a significant improvement in depressive symptoms. Depression following TBI may be different from ...

2. rally.massgeneralbrigham.org rally.massgeneralbrigham.org/study/buspirone_melantonin_tbi

Buspirone and Melatonin for Depression following ... Compared to placebo, B+MEL was associated with a significant improvement in depressive symptoms. Depression following TBI may be different from clinical ...

3. withpower.com withpower.com/trial/phase-4-brain-injuries-traumatic-7-2020-c7740

Buspirone + Melatonin for Depression After Traumatic Brain Injury Compared to placebo, B+MEL was associated with a significant improvement in depressive symptoms. Depression following TBI may be different from clinical ...

4. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC4914431/

Combination therapies for neurobehavioral and cognitive ... Summary of neurobehavioral and cognitive outcomes induced by combination therapies after traumatic brain injury. Model, Treatments, Assessments and outcomes ...

5. connect.careboxhealth.com connect.careboxhealth.com/en-US/trial/listing/473856

Buspirone and Melatonin for Depression Following ... Compared to placebo, B+MEL was associated with a significant improvement in depressive symptoms. Depression following TBI may be different from ...

6. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/26025562/

Changes in cognitive symptoms after a buspirone ... These preliminary findings suggest that a combination of buspirone with melatonin may benefit cognitive function distinct from mood symptoms.