A randomized, double-blind, placebo-controlled trial of 5-hydroxytryptophan and creatine for SSRI or SNRI augmentation in treatment resistant depression associated with hypobaric hypoxia in females

Principal Investigator: Brent Kious
Keywords: Depression , Treatment resistence , 5-hydroxytryptophan , Creatine Monohydrate , altitude Department: Psychiatry
IRB Number: 00094176 Co Investigator: Younghoon Sung
Specialty: Psychiatry
Sub Specialties: Mood Disorders
Recruitment Status: Recruiting

Contact Information

Hana  Sabic
hana.sabic@utah.edu
801-587-0332

Brief Summary

We propose to determine if 8 weeks of dietary augmentation with oral 5g creatine monohydrate daily and 100 mg of 5-hydroxytryptophan (5-HTP) twice daily reduces hypoxia-related depressive symptoms measured by the 17-item Hamilton Depression Rating Scale (HAM-D) in women with SSRI- or SNRI-resistant depression, combined with the examination of changes in functional connectivity based on resting-state fMRI and changes in brain metabolism inferred from phosphorus-31 magnetic resonance spectroscopy.  

Specific Aims

Aim 1: To describe changes in HAM-D scores over the course of 8 weeks of creatine and 5-HTP supplementation in women compared to placebo. A clinical trial of creatine augmentation in SSRI-treated females with major depressive disorder found that creatine significantly improved HAM-D scores compared to placebo (Lyoo, Yoon et al. 2012). There are also reports of preclinical studies demonstrating antidepressant effects of creatine in female, but not male rats (Allen, D'Anci et al. 2010). Therapeutic administration of 5-HTP has also been shown to be beneficial in the treatment of depression (Birdsall 1998). We hypothesize that subjects’ HAM-D scores will improve over 8 weeks with 5-HTP + creatine supplementation compared to placebo.  

Aim 2: To identify functional neuroimaging correlates of treatment response in the aforementioned study.  Resting-state functional magnetic resonance imaging can be used to demonstrate alterations in brain connectivity in depression and to describe how they evolve with antidepressant treatment.  To that end, we will examine the correlation between clinical response in the study proposed and changes in functional connectivity over 8 weeks.  We hypothesize that abnormalities in functional connectivity associated with depression will normalize over 8 weeks of treatment in a fashion correlated with clinical improvement in those receiving active treatment, but will remain unchanged in those receiving placebo.

Aim 3: To identify neurochemical correlates of treatment response in the aforementioned study.  We will examine the correlation between clinical response in the aforementioned subjects and changes in frontal cortical energy metabolism over 8 weeks, as measured by phosphorus magnetic resonance spectroscopy (31P-MRS). We hypothesize that deficits in frontal cortical energy metabolism will normalize over 8 weeks of treatment in a fashion correlated with clinical improvement in those receiving active treatment.

Inclusion Criteria

  • Female gender, ages 25-40 years inclusive**
  • Current diagnosis of Major Depressive Disorder identified by the SCID-I
  • At least moderate depression (Current HAM-D17 score of > 16) despite adequate adherence  to any FDA approved SSRI or SNRI for at least 8 weeks
  • Right-handed

**The age range of the study is dictated primarily by the period of maximal cerebral anatomic stability to improve our imaging findings; below age 25, there is excessive brain development which could make results harder to interpret; above age 40, there is often the onset of mild neurodegeneration which can also complicate imaging interpretation.

 

Healthy Controls Inclusion criteria:

  • Female gender, ages 25-40 inclusive
  • No current or past DSM-5 diagnosis, as determined by clinical and structured interviews
  • Right handed

Exclusion Criteria

  • Any non-MDD and non-anxiety psychiatric diagnosis, as identified by the SCID-I
  • History of or current diagnosis of renal disease, such as chronic renal failure, acute renal failure or end stage renal disease
  • Diabetes type I or II
  • Current colitis or diverticulitis
  • History of or current pulmonary disease
  • History of cardiac disease or QTc > 500ms
  • History of fibromyalgia, lupus, eosinophilia-myalgia syndrome, dermatomyositis, polymyositis, rheumatoid arthritis, psoriatic arthritis, mixed connective tissue disease, ankylosing spondylitis, or other related 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 antidepressant except for bupropion as an augmenting agent
  • Positive pregnancy test, pregnancy, failure to use adequate birth control method
  • Previous diagnosis of serotonin syndrome or evidence of serotonin syndrome
  • Use of any excluded drugs or medications including serotonergic drugs or medications
  • Pre-existing eosinophilia (absolute eosinophil count > 500/uL)
  • Contraindications to MRI: ferromagnetic implants, implanted devices, claustrophobia
  • Left-handed (handedness affects neural localization of different brain functions, and to keep imaging interpretation consistent we are excluding all left-handed individuals)