The 5 Biotypes of Depression

Born with epigenetic disorders, I struggled with depression for most of my life.

Over the years I’ve tried a variety of antidepressants such as anxiety medication and anxiety medication, as well as amino acid therapy (5-HTP, etc.), and other herbal remedies such as St. John’s Wort.

Some helped a bit, which was a clue to my undermethylation status, but they had nasty side-effects and over time, actually made me feel worse.

Since most psychiatrists believe that depression is caused by low levels of the neurotransmitter serotonin, SSRI anti-depressants (Selective Serotonin Reuptake Inhibitors) tend to be the standard of care because they inhibit the removal of serotonin from synapses by transport proteins called serotonin transporters (SERT). Unfortunately, this is a very flawed approach because it doesn’t take into account the unique biochemical imbalances and symptoms of the individual.

Thanks to the amazing 40-year research by William J. Walsh, Ph.D., president of the Walsh Research Institute, and clinical applications by Drs. Albert Mensah and Judith Bowman of Mensah Medical, I was finally able to get to the root cause of my suffering and eliminate my depression for good. Today, I partner with them on nutritional therapy programs.

Drawing on a database of 300,000 blood and urine chemistry test results and 200,000 medical history factors from approximately 2,800 patients diagnosed with depression, Dr. Walsh and his team identified five major depression biotypes. I’ve added four additional types that can also cause depressive symptoms. Even more fascinating, three of these forms of depression are not caused by fluctuating serotonin levels. 

Keep in mind that each imbalance can produce a wide range of symptoms and outcomes. For example, copper overload and undermethylation are the factors that contributed to my depression, high anxiety, disordered eating, digestive, menstrual, and other health problems. This is why my work is based on biochemical individuality, meaning what’s good for your best friend, is often not good for you too.

What Do “Depression Biotypes” Actually Mean?

Depression does not look the same in every person. Some people struggle mainly with low mood, while others notice sleep changes, anxiety, low energy, appetite shifts or trouble concentrating. That variety is one reason researchers and practitioners are interested in more personalized care. In a CDC survey from August 2021 through August 2023, 13.1% of people age 12 and older scored in the depression range during a two-week assessment period. That is a symptom-screening measure, not a claim that all respondents had the same diagnosis.

In this article, “the five biotypes” refers specifically to the biochemical framework developed by William J. Walsh, Ph.D. The five proposed patterns are undermethylation, pyrrole disorder, copper overload, overmethylation or folate deficiency, and toxic-metal overload. The Walsh Research Institute describes these patterns as part of its clinical nutrient-therapy model. They are not the five official diagnostic types of depression, and a nutrient or urine result alone cannot diagnose or classify a mood disorder.

The distinction matters. Personalizing nutrition can be valuable, especially when a real deficiency, medication interaction or medical condition is present. But depression still deserves a full assessment, and treatment decisions should reflect the whole person rather than a single proposed biochemical label.

The 5 Depression Biotypes

Here is a quick orientation before we look more closely at each of the five patterns. The names describe the Walsh model, not proven biological causes for every person with depression.

• Undermethylation: a pattern involving the body’s methylation processes and, in this model, histamine signaling.
•  Pyrrole disorder: a pattern linking urinary pyrrole compounds with zinc and vitamin B6 status.
•  Copper overload: a pattern focused on copper balance and related neurological or hormonal symptoms.
• Overmethylation (folate deficiency): a pattern connecting folate status and methylation-related symptoms.
• Toxic metal overload: a pattern concerning exposure to metals such as lead.

Undermethylation

The most common biotype, these folks tends to see improvement with SSRI’s. The problem in these cases is low activity at serotonin receptors due to rapid reabsorption after serotonin is released into a synapse; as well as high blood levels of histamine, another neurotransmitter. It’s actually not so much a serotonin deficiency, but an inability to keep serotonin in the synapse long enough. For more detailed information, see this post.

Methylation is a normal chemical process that helps cells regulate gene activity and handle certain molecules. Nutrients such as folate, vitamin B12 and methionine contribute to pathways involving methyl groups. That makes nutrition relevant to the discussion, but it does not mean that a person with low mood can be diagnosed as “undermethylated” by symptoms alone. Neither blood histamine nor response to an antidepressant is an established standalone diagnostic test for a depression biotype.

If persistent fatigue, restricted eating or possible deficiency is part of the picture, a clinician may reasonably check for nutritional and medical contributors. That question is different from predicting which psychiatric medicine someone will respond to.

Pyrrole Disorder

This biotype also tends to see improvement with SSRI’s. Pyrolurics exhibit a combination of impaired serotonin production and extreme oxidative stress. These individuals have elevated urine pyrroles coupled with severe zinc and vitamin B-6 deficiency. Omega 3 supplements create more inflammation for these folks. Sensitivity to noise and bright lights, poor short-term memory, no dream recall, frequent infections, extreme mood swings, high anxiety, alcoholism, tendency to skip breakfast, poor growth, an affinity for spicy food, fears, and dry skin are all symptoms. This type is the fastest to respond to treatment. Pyrrole disorder nutrition support can help address the underlying nutrient imbalances driving these symptoms.

Zinc and vitamin B6 are real nutrients with important roles in nervous-system function, and a documented deficiency deserves attention.

For readers who want to understand the practitioner perspective in more detail, my article on pyrrole disorder explains the nutritional approach and the questions it raises.

Copper Overload

High copper folks cannot properly metabolize metals. Most of these people say that SSRI’s do not have much of an effect either way, but they report benefits from normalizing their copper levels through nutrient therapy. High copper affects women who are also estrogen intolerant. In copper overload, it’s not so much a serotonin issue, but extreme blood and brain levels of copper that result in dopamine deficiency and norepinephrine overload. High copper is indicated in cases of postpartum depression. Andrea Yates who drowned her five children in 2001 is an extreme example. Addressing this imbalance often requires copper toxicity nutrition support to restore proper neurological and hormonal balance.

Copper is essential for health, but abnormal copper accumulation can also cause serious neurological and psychiatric symptoms in specific medical disorders. For example, Wilson disease affects copper handling and can involve the liver, brain and mental health. Diagnosis requires clinical evaluation and more than a single copper blood value; doctors may use ceruloplasmin, blood and urine studies, and other examinations. That established medical condition should not be confused with assuming that all postpartum depression or poor antidepressant response is caused by excess copper.

If mood symptoms arise during pregnancy or after childbirth, they should be assessed promptly as possible perinatal depression. Effective treatment may include therapy, medication, or both. Nutrition can be supportive, but it does not replace medical or mental-health care.

Overmethylation (folate deficiency)

This biotype tends to worsen on SSRIs, while folic acid supplements help. Nutritional support for overmethylation can help address the underlying biochemical imbalance. Folate plays a role in one-carbon metabolism and supports normal cell function. Folate deficiency is a real medical issue, but overmethylation and  folate deficiency are not interchangeable diagnoses. More importantly, neither a folate result nor a proposed methylation category can predict how an individual will respond to an antidepressant. People who experience troubling medication effects should contact their prescriber rather than stop or change their medication on their own.

The practical nutrition question is whether someone has a genuine deficiency, a restricted diet, or another health condition that requires individualized assessment. If so, the next step is targeted, supervised care, not guesswork based on a symptom list.

Toxic Metal Overload

This type of depression is caused by toxic metals (not including copper), usually, lead poisoning. Over the years, this type accounted for 5 percent of depressed patients, but removing lead from gasoline and paint has lowered the frequency of these cases.

Lead exposure deserves special attention because lead is toxic to the nervous system and can have important health effects. Yet a history of exposure must be evaluated in context, using an appropriate clinical history and testing when indicated. It is not accurate to assume that a fixed percentage of all depression cases is due to toxic metals or that a general “heavy metal detox” will treat depression.

Other Clinical Factors that May Also Cause Depression

Food Intolerances (gluten, dairy, and naturally occurring plant-based chemicals such as salicylates and oxalates, to name a few)
Blood Sugar Dysregulation (hypo or hyperglycemia)
Gut pathogens (such as yeast and bacterial overgrowth)
Thyroid diseases and imbalances

This section is worth expanding because readers often want to know what else may affect mood. Thyroid disorders, some medications, disrupted sleep, long-term illness and documented nutrient deficiencies can produce or worsen symptoms that resemble depression. A medical assessment can help identify these possibilities without assuming they explain every case. The National Institute of Mental Health specifically recommends evaluating medications and relevant physical conditions when diagnosing depression.

Vitamin B12 is one practical example. Deficiency can affect the nervous system and sometimes cause mood changes. A clinician may consider B12 evaluation when diet, medications, gastrointestinal history or neurological symptoms suggest a risk, rather than giving everyone the same supplement regimen.

Are These the Same as the Recognized Types of Depression?

No. The phrase “types of depression” usually refers to clinical presentations such as major depressive disorder, persistent depressive disorder, depression with seasonal patterns, and perinatal depression. Bipolar disorder can also include depressive episodes, but it requires a different assessment and treatment approach. These diagnoses depend on symptoms, duration, history and functioning, not the five Walsh biochemical categories.

You may also have read about a 2024 Stanford Medicine study that identified six “biotypes” using brain scans and machine learning. The researchers examined 801 people with depression or anxiety, then classified patterns of brain-circuit activity. This is interesting precision-psychiatry research, but it is not a validation of Walsh’s five nutrient-related biotypes. The two projects use different measurements, categories and evidence.

What Can Nutrition Contribute to Depression Care?

I care deeply about biochemical individuality because people do not have identical histories, diets or nutritional needs.

The Walsh Protocol draws on decades of biochemical research, extensive clinical databases, laboratory observations, and published work concerning methylation, copper regulation, oxidative stress, epigenetics, and psychiatric conditions.

Several of the biological factors it considers—including zinc and copper status, oxidative stress, methylation, and nutrient status—have been studied independently for their roles in brain function. Walsh and colleagues have also published research on some of the biochemical patterns associated with the model.

However, the Walsh Protocol as a whole has not been validated as a single treatment in the large, multicenter randomized controlled trials commonly used to establish medical therapies. A careful description is that it is a laboratory-informed biochemical framework combining published research with clinical pattern recognition, rather than a treatment proven to work for every psychiatric diagnosis.

A practical first step is to bring your symptoms, medications, supplement list, diet history and any previous test results to your health team. From there, you can ask which nutrition-related concerns are actually supported by your history and which deserve medical testing.

Frequently Asked Questions

Are the five biotypes of depression medically recognized diagnoses?

No. They refer to Dr. William Walsh’s biochemical framework. Most clinicians diagnose depression using a clinical assessment, not his five-category phenotype classification but his work is recognized by the American Psychiatric Association, so more clinicians are using it. Of note, Pyrrole disorder was once recognized in the Merck Manual — the physician’s reference guide — as a verified medical condition. Most doctors today have never heard of it.

Can a blood or urine test tell me which depression biotype I have?

Yes, but there is no established blood or urine panel that assigns one of these five biotypes as a validated psychiatric diagnosis.

How are the five biochemical biotypes different from Stanford’s six biotypes?

Walsh’s categories are based on a nutrient and biochemical model. Stanford’s six categories were developed from patterns of brain activity measured by functional MRI in research participants. They should not be treated as the same system.

Can vitamins or minerals treat depression?

The Walsh approach to nutrient therapy, which uses vitamins, minerals, and amino acids, has been shown to correct the underlying biochemistry that can cause depression. However, the complete protocol has not been validated as a unified treatment system in large, multicenter randomized trials. Speak with qualified health professionals about combining appropriate nutritional care with established treatment. 

What if antidepressants are not working for me?

Treatment response varies. Speak with your prescribing clinician about side effects, adequate time and dose, other conditions, psychotherapy and available alternatives. Do not stop a prescribed medication abruptly without professional guidance.

If you know of someone who struggles with depression, please share this post. If you struggle with depression, please share your experience in the comments below. It is through sharing your story that we create community, eliminate guilt and shame, and bring about healing.

If you feel hopeless, unsafe, or are thinking about suicide, seek immediate help through local emergency services or a crisis resource. In the United States, call or text 988. You deserve qualified care and support.

References

1. Walsh WJ. Nutrient Power: Heal Your Biochemistry and Heal Your Brain. Skyhorse Publishing; 2012. ISBN: 9781620873793.
2. Tozzi L, Zhang X, Pines A, et al. Personalized Brain Circuit Scores Identify Clinically Distinct Biotypes in Depression and Anxiety. Nature Medicine. 2024;30(7):2076–2087. doi: 10.1038/s41591-024-03057-9.
3. Jacka FN, O’Neil A, Opie R, et al. A Randomised Controlled Trial of Dietary Improvement for Adults with Major Depression (the SMILES Trial). BMC Medicine. 2017;15:23. doi: 10.1186/s12916-017-0791-y.
4. Firth J, Marx W, Dash S, et al. The Effects of Dietary Improvement on Symptoms of Depression and Anxiety: A Meta-Analysis of Randomized Controlled Trials. Psychosomatic Medicine. 2019;81(3):265–280. doi: 10.1097/PSY.0000000000000673.
5. Sarris J, Murphy J, Mischoulon D, et al. Adjunctive Nutraceuticals for Depression: A Systematic Review and Meta-Analyses. American Journal of Psychiatry. 2016;173(6):575–587. doi: 10.1176/appi.ajp.2016.15091228.