Buspirone + Melatonin for Depression After Traumatic Brain Injury

Recruiting at1 trial location

Age: 18 - 65

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 4

Recruiting

Sponsor: Massachusetts General Hospital

Must be taking: Buspirone, Melatonin

Must not be taking: Antidepressants, Psychostimulants

Disqualifiers: Neurological disorders, Bipolar, Schizophrenia, others

No Placebo Group

Prior Safety Data

Approved in 4 Jurisdictions

Trial Summary

What is the purpose of this trial?

Traumatic brain injuries (TBIs) are common. Post-TBI depression is associated with anxiety, aggression, fatigue, distractibility, anger, irritability, and rumination. The current research group conducted a pilot clinical trial, which investigated the novel treatment combination of buspirone and melatonin (B+MEL) in outpatients with clinical depression. Compared to placebo, B+MEL was associated with a significant improvement in depressive symptoms. Depression following TBI may be different from clinical depression. The B+MEL combination has never been studied in patients with post-TBI depression. The B+MEL has shown promise in ameliorating cognitive difficulties in people with depression. Because cognitive problems are typical in people with post-TBI depression, we plan to measure the effect of the B+MEL combination on cognitive ability in post-TBI depression. Additionally, we are interested in measuring functional magnetic resonance imaging changes before and after treatment with B+MEL in order to gain insight into the brain mechanisms of our hypothesized clinical symptom changes. The goals of the proposed pilot research project are to assess changes in symptoms in patients with post-TBI depression following Buspirone + Melatonin combination (B+MEL), and the corresponding brain mechanisms underlying these hypothesized changes by measuring: 1) depressive symptoms; 2) cognitive symptoms; 3) functional magnetic resonance imaging.

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 evidence supports the effectiveness of the drug combination of Buspirone and Melatonin for depression after traumatic brain injury?

Research shows that Buspirone can improve cognitive performance after a brain injury, and Melatonin has neuroprotective properties that may help with brain recovery. While these findings are promising, more studies are needed to confirm their combined effectiveness for depression after traumatic brain injury. ^{1 2 3 4 5}

Is the combination of Buspirone and Melatonin safe for humans?

Melatonin has been shown to have low toxicity and is generally well-tolerated in humans, with no serious adverse events reported in studies for sleep disturbances and other conditions. However, specific safety data for the combination of Buspirone and Melatonin is not available in the provided research. ^{2 3 5 6 7}

How does the drug Buspirone + Melatonin differ from other treatments for depression after traumatic brain injury?

The combination of Buspirone and Melatonin is unique because it targets both depression and sleep disturbances, which are common after traumatic brain injury. Melatonin is known for its neuroprotective properties and ability to regulate sleep, while Buspirone is used to treat anxiety and depression, making this combination potentially effective for addressing multiple symptoms associated with brain injury. ^{2 3 5 6 8}

Research Team

Eligibility Criteria

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 am between 18 and 64 years old.

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.

Trial Timeline

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

Treatment Details

Interventions

• Buspirone and Melatonin Combination (Other)

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.

Participant Groups

Group I: Buspirone and Melatonin Experimental Treatment 2 Interventions

Buspirone 15mg and Melatonin 3mg

Who Is Running the Clinical Trial?

Massachusetts General Hospital

Lead Sponsor

Trials

3,066

Recruited

13,430,000+

Dr. William Curry

Massachusetts General Hospital

Chief Medical Officer

MD from Harvard Medical School

Dr. Anne Klibanski

Massachusetts General Hospital

Chief Executive Officer since 2019

MD from Harvard Medical School

Findings from Research

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]

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]

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]

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]

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]

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]

References

1. United States 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. [2021]

2. England pubmed.ncbi.nlm.nih.gov

The value of melatonin for sleep disorders occurring post-head injury: a pilot RCT. [2015]

3. Russia (Federation) pubmed.ncbi.nlm.nih.gov

[Treatment of sleep disorders in patients with mild cranial-brain injury in the early rehabilitation period]. [2016]

4. United States 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. [2021]

5. Switzerland pubmed.ncbi.nlm.nih.gov

Melatonin as a Therapy for Traumatic Brain Injury: A Review of Published Evidence. [2018]

6. United States 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. [2022]

7. Israel 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]. [2013]

8. Poland pubmed.ncbi.nlm.nih.gov

[Circadian rhythms of melatonin of patients with severe traumatic brain injury]. [2015]