Personalized Depression Approaches

Depression is one of the most common mental health conditions and in psychiatry, we are aware that depression can present differently amongst people. Major depressive disorder is a clinical diagnosis, as we do not yet have a lab test or biomarker indicating depression. With the help of personalized medicine and ongoing research, there is a greater understanding of the heterogenicity of depression which allows us to better target treatment. In this post, I’ll explore how identifying symptom subtypes and using inflammatory biomarkers like CRP can help us choose more effective, personalized treatments for depression.

Why the "Trial and Error" Approach in Psychiatry Falls Short

Unfortunately in conventional psychiatry, we have been placated to using a trial and error approach for treatments that is frustrating for patients and for us as psychiatrists. The good news is, we can start applying what we understand in regards to symptom clusters and personalize treatment approaches. Symptom clusters are patterns of symptoms that tend to occur together, suggesting different underlying biological or psychological processes within depression.

The Netherlands Study: Subtypes of Depression Symptoms

In results from the Netherlands Study of Depression and Anxiety (2010), researchers found three distinct clusters of depression symptoms: mild/moderate, severe atypical, and severe typical. Severe typical depression symptoms include depression, poor sleep, decreased appetite, less sleep, weight loss, and early morning waking. Researchers found childhood trauma and negative life events, as well as smoking to be correlated with typical depression symptoms.

What I find to be most intriguing is that the severe atypical depression cluster that had have symptoms such as increased appetite, increased sleep, and lower energy/fatigue were more common in women and also from a biomarker standpoint, had greater leptin resistance and higher inflammatory markers (CRP and IL-6, specifically). C-reactive protein (CRP) is a blood marker of systemic inflammation. Elevated CRP levels are often seen in people with atypical depression and can help guide treatment choices. Leptin resistance is a condition where the brain stops responding to the hormone leptin, leading to persistent hunger, reduced metabolism, and difficulty losing weight—even when the body has plenty of fat stores.

Based on these findings, we can start to be more specific, intentional, and targeted with treatment. Atypical depression is an immuno-metabolic subtype of depression driven by underlying metabolic dysregulation. Typical depression, conversely, seems to have an underlying pathophysiology to some extent driven by HPA dysfunction and high cortisol. This may help explain why those with typical depression have more difficulties with sleep and early morning waking, as high cortisol can disrupt sleep.

Integrative Psychiatry Approaches to Treat Atypical Depression

1. Diet: From a lifestyle/behavioral change perspective, ketogenic diets (high fat/protein and low carbohydrates), Mediterranean diets, and intermittent fasting can be effective. Cutting down on sugar and grains can be effective. Continuous glucose monitors are a helpful tool to teach you how your body responds to certain foods by monitoring changes in blood sugar levels.

2. Cold and hot therapies: Use of contrast therapy with saunas and cold, or somewhat cold if female, water immersion have anti-inflammatory benefits.

   
   

3. Supplements: Anti-inflammatory approaches can also be considered including omega 3 fatty acids, L-methylfolate, curcumin from turmeric, and saffron are supplements that have anti-inflammatory properties.

   
   

4. Medications: Inflammation may influence how people respond to antidepressants. Those with higher CRP levels (and therefore higher levels of inflammation) often do better with medications that boost dopamine, like bupropion or nortriptyline, while those with lower CRP respond better to SSRIs. People with increased BMI and increased levels of inflammation may also have a better response to ketamine. GLP-1 agonists like semaglutide, originally used for diabetes and obesity, also have anti-inflammatory and mood-enhancing effects, making them an emerging option for people with both metabolic and mood challenges.

   
   
   
   

Key Takeaways:

• Depression presents in different ways, and not all cases respond to the same treatments.

• Atypical depression often involves inflammation and metabolic issues, and may respond better to dopamine-targeting meds, lifestyle changes, and anti-inflammatory supplements.

• Measuring CRP and getting details on specific symptoms can help guide more personalized, effective care.

  
  

My inspiration for this post: Watching this presentation from the Precision Mental Health at Stanford from 2023.

References:

Flux, M. C., Smith, D. G., Allen, J. J. B., et al. (2023). Association of plasma cytokines and antidepressant response following mild-intensity whole-body hyperthermia in major depressive disorder. Translational Psychiatry, 13(1), 132. https://doi.org/10.1038/s41398-023-02402-9

Freeman, M. P., Hock, R. S., Papakostas, G. I., et al. (2020). Body mass index as a moderator of treatment response to ketamine for major depressive disorder. Journal of Clinical Psychopharmacology, 40(3), 287-292. https://doi.org/10.1097/JCP.0000000000001209

Hamer, M., Batty, G. D., Marmot, M. G., Singh-Manoux, A., & Kivimäki, M. (2011). Anti-depressant medication use and C-reactive protein: Results from two population-based studies. Brain, Behavior, and Immunity, 25(1), 168-173. https://doi.org/10.1016/j.bbi.2010.09.013

Jha, M. K., Minhajuddin, A., Gadad, B. S., et al. (2017). Can C-reactive protein inform antidepressant medication selection in depressed outpatients? Findings from the CO-MED trial. Psychoneuroendocrinology, 78, 105-113. https://doi.org/10.1016/j.psyneuen.2017.01.023

Lamers, F., de Jonge, P., Nolen, W. A., Smit, J. H., Zitman, F. G., Beekman, A. T. F., & Penninx, B. W. J. H. (2010). Identifying depressive subtypes in a large cohort study: Results from the Netherlands Study of Depression and Anxiety (NESDA). The Journal of Clinical Psychiatry, 71(12), 1582–1589. https://doi.org/10.4088/JCP.09m05398blu