Initial Presentation

Adam was struggling more than usual. He was a 60-year-old contractor who had a long history of severe depression. For years, Adam had gotten by—even with the significant stress from his job—and managed to stay functional on bupropion XL 450 mg. However, more recently, he had become overwhelmed. His sleep was poor and fitful. In the mornings, he struggled to get out of bed, delaying his workday for hours. As such, he felt guilt over his job performance and struggled with significant fatigue. Due to his situation, Adam was feeling hopeless.

In desperation, he came to the clinic looking for help since his current medication was no longer providing adequate relief.

Initial Relevant Labs

• Vitamin B12 low normal at 239 pg/mL
• Homocysteine was elevated at 16.2 µmol/L
• Vitamin D was low at 21 ng/mL

Working Diagnosis

• Major depressive disorder, elevated homocysteine due to low vitamin B12, and low vitamin D

Initial Treatment for Depression

• Methylcobalamin  (vitamin B12) injections 1 mg three times per week
• Vitamin D 5000 iu
• Fish oil 2000 mg
• Inositol 1-4 grams at bedtime

Explanation

Low vitamin B12 is known to contribute to depression, with supplementation delaying depression onset and improving the efficacy of medication (Sangle 2020). Studies in older adults have found correlations between lower serum levels of the vitamin and depression status (Laird 2023). In addition, elevated homocysteine is most often due to low vitamin B12 and folate and can contribute to depressive symptoms (Moradi 2021). As a treatment, injections are a more rapid way to restore levels, and often lead to a more dramatic patient response, typically with improvements in both mood and energy levels.

Low vitamin D has also been associated with a number of different mental health conditions, including depression (Akpinar 2022). Vitamin D supplementation has been shown to improve depressive symptoms (Musazadeh 2023). Due to Adam’s low vitamin D, supplementation was initiated.

In general, patients with depression are known to have lower levels of omega-3 fatty acids that can act as a risk factor for the condition (Antao 2023). Supplementation with omega-3s has been shown to improve depression outcomes, potentially increasing remission rates by almost 20% (Norouziasl 2024).

Inositol is a compound often considered part of the B-vitamin family, even though it is not officially a vitamin. One of the essential functions of inositol is as a secondary messenger. Secondary messengers are compounds involved with relaying signals from the cell surface to the interior of a cell. Inositol plays a part in the secondary messenger system for several neurotransmitters, including serotonin (Vadnal 2012). While studies in mental health conditions have been somewhat mixed, clinical trials for panic disorder appear to show efficacy (Palatnik 2001). When stress or anxiety interfere with sleep, inositol may be a useful addition at bedtime. A study in pregnant women appears to confirm that inositol supplementation improves sleep quality and duration (Mashayekh-Amiri 2022).

Follow-up Presentation

At his two month follow up, Adam’s improvements with treatment were dramatic. The inositol had led to significant improvements in sleep. Adam’s mood also improved, and he felt hope again for his future. Due to his improvements, he was able to re-engage with work. In addition, his energy levels increased, and he reconnected with his wife and son, significantly improving family dynamics. Notably, all these benefits occurred without any change to his external stressors.

Follow-up Treatment

Continue supplementation as prescribed.

Case Summary

This case illustrates several important clinical principles. First, optimizing a person’s biochemistry may allow them to better deal with difficult situations that they are unable or unwilling to change. The work stress in Adam’s life that had contributed to his low mood remained, and yet Adam’s outlook improved significantly when his nutrient deficiencies were identified and addressed.

Second, this case demonstrates the importance of investigating underlying biochemical factors in treatment-resistant depression, particularly when conventional medication alone provides insufficient relief. The identification and treatment of suboptimal vitamin B12, vitamin D and elevated homocysteine levels, combined with targeted supplementation of inositol and omega-3s, led to meaningful improvements in Adam’s quality of life, family relationships and occupational functioning. This reinforces the value of looking beyond symptom management to address underlying biochemical imbalances.