Major Depressive DisorderPhase 2NCT04395183
5-HTP and Creatine for Depression
A Phase 2 study testing 5-Hydroxytryptophan 100 MG and Creatine monohydrate in people with Major Depressive Disorder, run by University of Utah at 1 site in United States.
Trial 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 + placebo, creatine + placebo, and 5-HTP + creatine, for 8 weeks. Read more about this study
- Who is it for?
- Ages 25 to 40 years
- Conditions the study is for
- Major Depressive Disorder
- What is being tested?
- 5-Hydroxytryptophan 100 MG and Creatine monohydrate
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 43 participants
- Where
- 1 siteUnited States
- Study dates
- 1 Mar 2021to 1 Mar 2024
- Phase
- Phase 2
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 25 to 40 years
- All sexes
- No healthy volunteers
- Adult
Who may be able to join
- Adults age 25-40 years inclusive
- Current diagnosis of MDD identified by the SCID-5
- 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
Who cannot join
- Any non-MDD and non-anxiety psychiatric diagnosis, as identified by the SCID-5
- 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
- Current smoking
- History of cardiac disease or QTc > 500ms
Show all 14Show fewer
- 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 or 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
Trial locations and contacts
1 site in 1 country.
United States1 site
University of Utah Department of Psychiatry
Salt Lake City, Utah, 84108
About this study
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
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 + placebo, creatine + placebo, and 5-HTP + creatine, 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.
Read the detailed description
Major depressive disorder (MDD) has a lifetime prevalence of over 16%1 and is associated with reduced work productivity,2 disability,3 increased mortality,4 and increased rates of suicide attempts5 and completed suicides.6 Unfortunately, ~34% fail to respond to standard ADs (ADs).7 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.8-12 Smoking also promotes hypoxia13 and is linked to increased risks of suicide and depression.14-16 Of special relevance to this study, living at high altitude produces relative hypoxia even after months,17 and is linked to increased risks of suicide18-22 and depression.23,24 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),25 and alters mitochondrial dynamics in the hippocampus.26,27 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.28 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.29 Hypoxia could also promote MDD by altering serotonin (5-HT) production. Chronic hypoxia reduces 5-HT in the forebrain and brainstem in rodents.30 The conversion of tryptophan to 5-hydroxytryptophan (5-HTP) by tryptophan hydroxylase is oxygen-dependent and slowed by hypoxia.31,32 Animal studies have shown that selective serotonin reuptake inhibitors (SSRIs) are not as effective at altitude,33 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,34 and resting state functional connectivity (fcMRI) studies suggest that depression involves reduced connectivity between frontal cortical regions and the amygdala,35 while AD response correlates with normalization of those connections.36 Alterations in connectivity associated with AD response are correlated with changes in brain metabolites,37 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.38 Moreover, Cr produces improvements in mood39 correlated with normalization of PCr levels40 and structural connectivity.41 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.42 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 and evaluate their correlation with clinical outcomes. The study will have the following aims:
- Aim 1 (R61+R33): To identify 31P-MRS correlates of AD response in subjects with MDD receiving Cr, 5-HTP, or 5-HTP+Cr. It is hypothesized that subjects' frontal cortical metabolism will normalize compared to controls over 8 weeks in those receiving Cr or 5-HTP+Cr but not those receiving only 5-HTP.
- Aim 2 (R61+R33): To identify resting state fcMRI correlates of AD response in subjects with MDD receiving Cr, 5-HTP, or 5-HTP+Cr. It is hypothesized that resting functional connectivity in prefrontal regions will normalize (with improvement in hypoconnectivity between subgenual cingulate cortex and the remaining brain) over 8 weeks in all treatment groups compared to controls, with the greatest changes in the 5-HTP+Cr group.
- Aim 3 (R61+R33: To characterize changes in whole blood 5-HT levels in study participants. It is hypothesized that whole blood 5-HT will increase over 8 weeks in subjects receiving 5-HTP or 5-HTP+Cr, but not those receiving only Cr.
- Aim 4 (R33): To describe changes in HAM-D scores in study participants randomized between SSRI/SNRI augmentation with 5-HTP, Cr, or 5-HTP+Cr. It is hypothesized that HAM-D scores will improve over 8 weeks in all treatment groups, with the greatest changes in the 5-HTP+Cr group.
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.
- Conditions
- Major Depressive Disorder
- Being tested
- 5-Hydroxytryptophan 100 MG, Creatine monohydrate, placebo matched to 5-HTP, Placebo
- Medical subject headings
- Depressive Disorder, Major
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
5-Hydroxytryptophan 100 MGDrug
Also called creatine monohydrate
5-HTP 100mg PO BID
Creatine monohydrateDrug
Creatine monohydrate 5g PO qday
placebo matched to 5-HTPDrug
placebo matched to 5-HTP
PlaceboDrug
Dextrose either as loose powder (matched to creatine) or encapsulated (matched to 5-HTP)
| Study group | Role | What they receive |
|---|---|---|
| 5-HTP + Placebo | Active comparator | 5-hydroxytryptophan 100mg PO BID plus placebo matched to creatine monohydrate Receives: Drug: 5-Hydroxytryptophan 100 MG; Drug: placebo matched to 5-HTP |
| Creatine + Placebo | Active comparator | Creatine 5g PO qday plus placebo matched to 5-HTP Receives: Drug: Creatine monohydrate; Drug: placebo matched to 5-HTP |
| Creatine + 5-HTP | Active comparator | Creatine 5g PO qday plus 5-hydroxytryptophan 100mg PO BID Receives: Drug: 5-Hydroxytryptophan 100 MG; Drug: Creatine monohydrate |
| Double Placebo | Placebo comparator | Creatine-matched placebo and 5-HTP-matched placebo Receives: Drug: Placebo |
What is being measured
The primary outcome is the main question the study is designed to answer.
17-Item Hamilton Depression Rating Scale Responders
Hamilton Depression Rating Scale response rate: proportion of participants exhibiting >=50% reduction in baseline score; maximum possible score is 52, minimum possible score is 0. Higher scores suggest more severe depression.
Measured: 8 weeks
Secondary outcomes (1)
Montgomery Asberg Depression Rating Scale Response Rate
Montgomery Asberg Depression Rating Scale Response Rate. Proportion of responders. Response is a >=50% reduction in baseline score; minimum score 0; maximum score 60; higher scores suggest more severe depression
Measured: 8 weeks
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted20 May 2020
- Study start1 Mar 2021
- Primary completion1 Aug 2023
- Study completion1 Mar 2024
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Other trials for Major Depressive DisorderStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Double blind
- Who is masked
- Participant, Investigator
- Enrolment
- 43 participants (actual)
Sponsor and investigators
- Lead sponsor
- University of Utah
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, Brent Michael Kious, MD, PhD, University of Utah
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT04395183
- Sponsor's protocol ID
- IRB_00132830
- Status last verified
- Jul 2024
- First submitted
- 15 May 2020
- Last updated
- 23 Jul 2024
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- No
Study at a glance
From the registry record, last updated by the sponsor on 23 Jul 2024. Recruitment status is as the sponsor reported it: confirm with the study team.
- 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
- ClinicalTrials.gov ID
- NCT04395183
- Acronym / sponsor ID
- IRB_00132830
- Conditions
- Major Depressive Disorder
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 43 participants (actual)
- Lead sponsor
- University of UtahUniversity, hospital or other
- Study start
- 1 Mar 2021 (actual)
- Primary completion
- 1 Aug 2023 (actual)
- Study completion
- 1 Mar 2024 (actual)
- First posted
- 20 May 2020 (actual)
- Results
- Posted 23 Jul 2024
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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 + placebo, creatine + placebo, and 5-HTP + creatine, 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.
Detailed description
Major depressive disorder (MDD) has a lifetime prevalence of over 16%1 and is associated with reduced work productivity,2 disability,3 increased mortality,4 and increased rates of suicide attempts5 and completed suicides.6 Unfortunately, ~34% fail to respond to standard ADs (ADs).7 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.8-12 Smoking also promotes hypoxia13 and is linked to increased risks of suicide and depression.14-16 Of special relevance to this study, living at high altitude produces relative hypoxia even after months,17 and is linked to increased risks of suicide18-22 and depression.23,24 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),25 and alters mitochondrial dynamics in the hippocampus.26,27 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.28 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.29 Hypoxia could also promote MDD by altering serotonin (5-HT) production. Chronic hypoxia reduces 5-HT in the forebrain and brainstem in rodents.30 The conversion of tryptophan to 5-hydroxytryptophan (5-HTP) by tryptophan hydroxylase is oxygen-dependent and slowed by hypoxia.31,32 Animal studies have shown that selective serotonin reuptake inhibitors (SSRIs) are not as effective at altitude,33 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,34 and resting state functional connectivity (fcMRI) studies suggest that depression involves reduced connectivity between frontal cortical regions and the amygdala,35 while AD response correlates with normalization of those connections.36 Alterations in connectivity associated with AD response are correlated with changes in brain metabolites,37 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.38 Moreover, Cr produces improvements in mood39 correlated with normalization of PCr levels40 and structural connectivity.41 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.42 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 and evaluate their correlation with clinical outcomes. The study will have the following aims:
- Aim 1 (R61+R33): To identify 31P-MRS correlates of AD response in subjects with MDD receiving Cr, 5-HTP, or 5-HTP+Cr. It is hypothesized that subjects' frontal cortical metabolism will normalize compared to controls over 8 weeks in those receiving Cr or 5-HTP+Cr but not those receiving only 5-HTP.
- Aim 2 (R61+R33): To identify resting state fcMRI correlates of AD response in subjects with MDD receiving Cr, 5-HTP, or 5-HTP+Cr. It is hypothesized that resting functional connectivity in prefrontal regions will normalize (with improvement in hypoconnectivity between subgenual cingulate cortex and the remaining brain) over 8 weeks in all treatment groups compared to controls, with the greatest changes in the 5-HTP+Cr group.
- Aim 3 (R61+R33: To characterize changes in whole blood 5-HT levels in study participants. It is hypothesized that whole blood 5-HT will increase over 8 weeks in subjects receiving 5-HTP or 5-HTP+Cr, but not those receiving only Cr.
- Aim 4 (R33): To describe changes in HAM-D scores in study participants randomized between SSRI/SNRI augmentation with 5-HTP, Cr, or 5-HTP+Cr. It is hypothesized that HAM-D scores will improve over 8 weeks in all treatment groups, with the greatest changes in the 5-HTP+Cr group.
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
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Double blind (participant, investigator)
- Number of arms
- 4
| Arm | Type | Receives |
|---|---|---|
| 5-HTP + Placebo | Active comparator | Drug: 5-Hydroxytryptophan 100 MG, Drug: placebo matched to 5-HTP5-hydroxytryptophan 100mg PO BID plus placebo matched to creatine monohydrate |
| Creatine + Placebo | Active comparator | Drug: Creatine monohydrate, Drug: placebo matched to 5-HTPCreatine 5g PO qday plus placebo matched to 5-HTP |
| Creatine + 5-HTP | Active comparator | Drug: 5-Hydroxytryptophan 100 MG, Drug: Creatine monohydrateCreatine 5g PO qday plus 5-hydroxytryptophan 100mg PO BID |
| Double Placebo | Placebo comparator | Drug: PlaceboCreatine-matched placebo and 5-HTP-matched placebo |
Who may qualify
- Ages
- 25 to 40 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult
Key inclusion criteria (6 listed)
- Adults age 25-40 years inclusive
- Current diagnosis of MDD identified by the SCID-5
- Current HAM-D17 score of > 16
- Adequate adherence to any FDA approved SSRI or SNRI for at least 8 weeks
- Right-handed
Key exclusion criteria (14 listed)
- Any non-MDD and non-anxiety psychiatric diagnosis, as identified by the SCID-5
- 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
- Current smoking
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| 5-Hydroxytryptophan 100 MGAlso: creatine monohydrate5-HTP 100mg PO BID | Drug | 5-HTP + Placebo, Creatine + 5-HTP |
| Creatine monohydrateCreatine monohydrate 5g PO qday | Drug | Creatine + 5-HTP, Creatine + Placebo |
| placebo matched to 5-HTPplacebo matched to 5-HTP | Drug | 5-HTP + Placebo, Creatine + Placebo |
| PlaceboDextrose either as loose powder (matched to creatine) or encapsulated (matched to 5-HTP) | Drug | Double Placebo |
Primary outcome
17-Item Hamilton Depression Rating Scale Responders
Time frame: 8 weeks
Hamilton Depression Rating Scale response rate: proportion of participants exhibiting >=50% reduction in baseline score; maximum possible score is 52, minimum possible score is 0. Higher scores suggest more severe depression.
1 secondary outcome
Montgomery Asberg Depression Rating Scale Response Rate
Time frame: 8 weeks
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 23 Jul 2024.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
The record lists no contact. Use the official record to reach the sponsor.
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing 5-Hydroxytryptophan 100 MG and Creatine monohydrate in people with Major Depressive Disorder, run by University of Utah at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 6 inclusion and 14 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 23 Jul 2024. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 23 Jul 2024). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
17-Item Hamilton Depression Rating Scale Responders (time frame: 8 weeks). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 23 Jul 2024.