Initial Presentation

David presented to our clinic with severe, long-standing depression that had not responded to treatment with a number of antidepressants, including fluoxetine, cymbalta or lexapro. His current regimen included extended release quetiapine 150 mg, sertraline 100 mg and bupropion 150 mg. While the medications had initially seemed to “take the edge off” of his symptoms, they were no longer providing good control.

David had a positive family history for depression on both sides of his family but denied any personal history of trauma. One of his treatment goals was to decrease his medications, especially since their efficacy had declined over time and he had gained weight while taking them.

Initial relevant labs

• RBC magnesium was low at 3.4 mg/dL
• MTHFR heterozygous C/T
• Kryptopyrrole was high at 61.3 µg/dL
• OAT testing found multiple elevated yeast and bacterial markers indicating problems with the gastrointestinal microbiome

Initial Treatment

• Magnesium citrate 450 mg per day
• 50 billion CFUs Probiotic and Saccharomyces boulardii, 1 cap each twice daily for 3 months
• B-complex with methylfolate and a total of ~100 mg vitamin B6 per day
• Zinc 30 mg per day

Explanation

Magnesium deficiencies can contribute to depression. Studies have found reduced levels in depressed patients and improved symptoms with magnesium supplementation (Botturi 2021).

Methylfolate has also been shown to help improve depressive symptoms as an adjunctive treatment (Maruf 2022). David was heterozygous for a methylenetetrahydrofolate reductase (MTHFR) single nucleotide polymorphism (SNP). MTHFR converts folic acid to active folate. SNPs of the MTHFR enzyme at position 677 with a single C to T substitution have almost 50% reduced enzymatic activity (van der Put 1998) indicating a potential need for supplementing active folate.

Kryptopyrrole testing identifies levels of hydroxyhemopyrrolin-2-one (HPL) in the urine, a compound that shows correlations with mental illness and certain nutrient deficiencies (Mikirova 2015). While typically associated with lower zinc and vitamin B6, levels of niacin and vitamin C may also need to be considered for some individuals. For David, B-complex and zinc were prescribed to address the elevation of HPL levels.

Urinary organic acid testing (OAT) also uncovered signs of both yeast and bacterial overgrowth in the gastrointestinal tract. A comprehensive probiotic regimen, including a high-dose, 50-billion-colony-forming-units probiotic and Saccharomyces boulardii were prescribed to support a healthier gastrointestinal microbiome.

Follow-up Presentation

After three months, his symptoms had slowly but steadily improved. With his mood symptoms more stable, David asked about reducing or eliminating some of his medications.

Follow-up Testing

• Kryptopyrrole was within the normal range at 6.3 µg/dL
• OAT testing markers for both bacteria and yeast had mostly normalized

Follow-up Treatment

Vitamin B6 was reduced to approximately 50 mg total per day. The quetiapine was tapered and discontinued over the next month. While David had some increased insomnia during the taper, six milligrams of melatonin one-half hour before bed helped him fall asleep until the quetiapine was eliminated.

Explanation for Follow-up Treatment

Kryptopyrrole elevations are not fully understood, although associations with microbiome disturbances have been observed (Mikirova 2015). Due to improvements in kryptopyrrole levels with treatment, his Vitamin B6 levels were reduced to a maintenance level at 50 mg per day. As David’s symptoms stabilized, a slow taper of the quetiapine was prescribed and followed carefully for any signs of increased depression. Other than transient insomnia, the taper was completed without major side effects.

Additional Follow-up

At the six-month mark, David was happy with his progress. Work had become more manageable and his marriage had improved. His wife even commented that she had rediscovered the man that she had originally fallen in love with.

Case Summary

Many patients only receive minimal benefits with standard antidepressant treatment. It’s quite common to find nutrient deficiencies, genetic markers and gastrointestinal microbiome disturbances that are keeping depressive symptoms entrenched. By addressing these components, many cases of treatment-resistant depression improve.