5-HTP and Creatine for Depression R33 Phase

Sponsor

University of Utah (Other)

Overall Status

Not yet recruiting

CT.gov ID

NCT05895747

Collaborator

(none)

109

Enrollment

Arms

36.9

Anticipated Duration (Months)

Study Details

Study Description

Brief Summary

This is a three-armed clinical trial examining the effect of 5-hydroxytryptophan and creatine monohydrate as augmenting agents for the treatment of depression. Subjects will be randomized between 5-HTP 100mg BID + creatine 5g daily, 5-HTP 200mg BID + creatine 10g daily, vs double placebo, for 8 weeks. The ability of the interventions to affect biomarkers associated with depression will be assessed using brain phosphorus magnetic resonance spectroscopy, functional connectivity imaging, and plasma serotonin levels.

Condition or Disease	Intervention/Treatment	Phase
Major Depressive Disorder	Drug: Low Dose 5-hydroxytryptophan Drug: High Dose 5-hydroxytryptophan Drug: Low Dose Creatine Monohydrate Drug: High Dose Creatine Monohydrate Drug: Placebo	Phase 2

Detailed Description

Major depressive disorder (MDD) has a lifetime prevalence of over 16% and is associated with reduced work productivity, disability, increased mortality, and increased rates of suicide attempts and completed suicides. Unfortunately, ~34% fail to respond to standard ADs (ADs). Environmental and patient-level factors that increase the risk of MDD could pinpoint novel mechanisms underlying the disorder. One such factor may be relative hypoxia. Persons with hypoxic medical conditions, such as asthma and chronic obstructive pulmonary disease, are at higher risk of depression and suicide compared to those with other chronic medical conditions. Smoking also promotes hypoxia and is linked to increased risks of suicide and depression. Of special relevance to this study, living at high altitude produces relative hypoxia even after months, and is linked to increased risks of suicide and depression. Hypoxia could contribute to MDD in at least two ways. First, brain bioenergetics are altered in both hypoxia and MDD. Hypoxia reduces several neurochemical markers of brain activity, including phosphocreatine (PCr) and n-acetylaspartate (NAA), and alters mitochondrial dynamics in the hippocampus. Proton magnetic resonance spectroscopy (1H-MRS) shows that high-altitude residents have altered whole brain pH and reduced inorganic phosphate to total phosphate (tP) ratios compared to persons dwelling at sea-level. In depressed patients, phosphorus MRS (31P-MRS) shows reduced nucleotide triphosphate (NTP) concentrations and decreased PCr concentrations; AD response is associated with increases in PCr and NTP. Hypoxia could also promote MDD by altering serotonin (5-HT) production. Chronic hypoxia reduces 5-HT in the forebrain and brainstem in rodents. The conversion of tryptophan to 5-hydroxytryptophan (5-HTP) by tryptophan hydroxylase is oxygen-dependent and slowed by hypoxia. Animal studies have shown that selective serotonin reuptake inhibitors (SSRIs) are not as effective at altitude, possibly because of inadequate 5-HT production. Reductions in 5-HT synthesis and inefficiencies in bioenergetics could both contribute to altered brain functional connectivity. MDD may disrupt cortical emotion regulation, and resting state functional connectivity (fcMRI) studies suggest that depression involves reduced connectivity between frontal cortical regions and the amygdala, while AD response correlates with normalization of those connections. Alterations in connectivity associated with AD response are correlated with changes in brain metabolites, suggesting a link to brain bioenergetics.

This suggests two natural supplements as interventions for depression. Oral creatine monohydrate (Cr) could improve bioenergetics in MDD, as Cr alters brain tCr, PCr, and NTP levels. Moreover, Cr produces improvements in mood correlated with normalization of PCr levels and structural connectivity. Alterations in 5-HT synthesis due to hypoxia could be rectified by 5-HTP, as its conversion to 5-HT is not oxygen-dependent. 5-HTP elevates brain 5-HT levels and has AD efficacy in clinical trials. The proposed study is a two-phase, three-armed trial to evaluate whether SSRI/SNRI augmentation with the supplements Cr, 5-HTP, or their combination (5-HTP+Cr) can enhance AD response in treatment-resistant MDD. In the R61 phase, the study will assess the ability of the interventions to alter biological signatures associated with depression, as measured by 31P-MRS, fcMRI, and changes in whole blood 5-HT. In the R33 phase, the study will attempt to replicate the above findings with dose variation and evaluate their correlation with clinical outcomes. The study will have the following aims:

Aim 1. Replicate the clinically meaningful changes in biological signatures (PCr:tP ratios as measured by 31P-MRS, sgACC connectivity as measured by fcMRI, and whole blood serotonin) demonstrated in the R61 phase, following the decision rule noted above.

Aim 2. Demonstrate that the changes in each of the above markers that is carried over from the R61 phase are correlated with changes in depression as measured by the 17-item Hamilton Depression Rating Scale, which would be studied in a subsequent efficacy trial.

Study results will help elucidate the potential efficacy of a novel combination of nutritional supplements in persons with MDD, given strong epidemiologic and physiologic evidence suggesting that relative hypoxia can contribute to depression through alterations in brain bioenergetics and 5-HT synthesis. Target engagement will be indicated by improvements in functional connectivity and frontal cortical energy metabolism.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

109 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)

Primary Purpose:

Treatment

Official Title:

31P-MRS and Resting State Functional Connectivity Analysis of the Effects of 5-hydroxytryptophan and Creatine for Antidepressant Augmentation in Patients With SSRI/SNRI-resistant Major Depressive Disorder

Anticipated Study Start Date :

Jul 3, 2023

Anticipated Primary Completion Date :

Jun 30, 2026

Anticipated Study Completion Date :

Jul 31, 2026

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Low Dose 5-hydroxytryptophan and Creatine Monohydrate 5-HTP 100mg PO BID plus creatine 5g PO Qday	Drug: Low Dose 5-hydroxytryptophan 5-hydroxytryptophan 100mg PO BID Other Names: 5-HTP Drug: Low Dose Creatine Monohydrate Creatine monohydrate 5g PO qday Other Names: creatine Drug: Placebo Creatine-matched placebo and 5-HTP-matched placebo; Placebo will be dextrose either encapsulated (5-HTP matched) or as loose powder (creatine matched) Other Names: dextrose
Experimental: High Dose 5-hydroxytryptophan and Creatine Monohydrate 5-HTP 200mg PO BID plus creatine 10mg PO Qday	Drug: High Dose 5-hydroxytryptophan 5-hydroxytryptophan 200mg PO BID Other Names: 5-HTP Drug: High Dose Creatine Monohydrate Creatine monohydrate 10g PO qday Other Names: creatine
Placebo Comparator: Double Placebo Creatine-matched placebo and 5-HTP-matched placebo	Drug: Placebo Creatine-matched placebo and 5-HTP-matched placebo; Placebo will be dextrose either encapsulated (5-HTP matched) or as loose powder (creatine matched) Other Names: dextrose

Arm

Intervention/Treatment

Experimental: Low Dose 5-hydroxytryptophan and Creatine Monohydrate

5-HTP 100mg PO BID plus creatine 5g PO Qday

Drug: Low Dose 5-hydroxytryptophan

5-hydroxytryptophan 100mg PO BID

Other Names:

5-HTP

Drug: Low Dose Creatine Monohydrate

Creatine monohydrate 5g PO qday

Other Names:

creatine

Drug: Placebo

Creatine-matched placebo and 5-HTP-matched placebo; Placebo will be dextrose either encapsulated (5-HTP matched) or as loose powder (creatine matched)

Other Names:

dextrose

Experimental: High Dose 5-hydroxytryptophan and Creatine Monohydrate

5-HTP 200mg PO BID plus creatine 10mg PO Qday

Drug: High Dose 5-hydroxytryptophan

5-hydroxytryptophan 200mg PO BID

Other Names:

5-HTP

Drug: High Dose Creatine Monohydrate

Creatine monohydrate 10g PO qday

Other Names:

creatine

Placebo Comparator: Double Placebo

Creatine-matched placebo and 5-HTP-matched placebo

Drug: Placebo

Creatine-matched placebo and 5-HTP-matched placebo; Placebo will be dextrose either encapsulated (5-HTP matched) or as loose powder (creatine matched)

Other Names:

dextrose

Outcome Measures

Primary Outcome Measures

17-Item Hamilton Depression Rating Scale [8 weeks]
Hamilton Depression Rating Scale response: >=50% reduction in baseline score; maximum possible score is 52, minimum possible score is 0. Higher scores suggest more severe depression.

Secondary Outcome Measures

Montgomery Asberg Depression Rating Scale [8 weeks]
Montgomery Asberg Depression Rating Scale; Response is a >=50% reduction in baseline score; minimum score 0; maximum score 60; higher scores suggest more severe depression

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 65 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Adults age 18-65 years inclusive
Current diagnosis of MDD identified by the MINI (Mini Neuropsychiatric Interview)
Current HAM-D17 score of >= 16
Adequate adherence to any FDA approved SSRI or SNRI for at least 8 weeks
Right-handed
Residing at > 4000 ft for at least 12 weeks

Exclusion Criteria:

Any non-MDD and non-anxiety psychiatric diagnosis, as identified by the MINI
History of or current diagnosis of renal disease, such as chronic renal failure, acute renal failure or end stage renal disease
Current colitis or diverticulitis
History of or current pulmonary disease (except well controlled asthma)
Current smoking
History of cardiac disease or QTc > 500ms
History of fibromyalgia or any rheumatological condition
History of or current seizure disorder
Current serious suicide risk identified by the Columbia Severity Suicide Rating Scale
Current treatment with an antipsychotic, mood stabilizer, or non-SSRI/SNRI antidepressant except for bupropion at FDA-approved doses or trazodone up to 200mg, or use of any supplements apart from standard multivitamins
Positive pregnancy test, pregnancy, failure to use adequate birth control method
Previous diagnosis of serotonin syndrome or evidence of serotonin syndrome
Pre-existing eosinophilia (absolute eosinophil count > 500/uL)
Contraindications to MRI: ferromagnetic implants, implanted devices, claustrophobia

Contacts and Locations

Locations

No locations specified.

Sponsors and Collaborators

University of Utah

Investigators

None specified.

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

Responsible Party:

Brent Michael Kious, MD, PhD, Assistant Professor, University of Utah

ClinicalTrials.gov Identifier:

NCT05895747

Other Study ID Numbers:

IRB_00132830_R33

First Posted:

Jun 9, 2023

Last Update Posted:

Jun 12, 2023

Last Verified:

Jun 1, 2023

Individual Participant Data (IPD) Sharing Statement:

Plan to Share IPD:

Studies a U.S. FDA-regulated Drug Product:

Yes

Studies a U.S. FDA-regulated Device Product:

Additional relevant MeSH terms:

Depressive Disorder

Depression

Depressive Disorder, Major

5-Hydroxytryptophan

Study Results

No Results Posted as of Jun 12, 2023