Before TMS: Ruling Out Medical Causes of "Treatment-Resistant" Depression

Before depression is labeled treatment-resistant and a course of TMS is planned, it is worth confirming that nothing else is keeping it going. Common contributors to apparent treatment resistance are not exotic: an incorrect diagnosis (especially unrecognized bipolar disorder), medication trials that were too short or too low in dose, missed doses, untreated sleep apnea, thyroid disease, anemia, alcohol or other substances, and medications that can themselves lower mood.

Guidelines support a focused medical workup rather than a large battery of tests. The 2023 CANMAT guidelines recommend a detailed history and targeted examination, name a complete blood count and thyroid-stimulating hormone (TSH) as reasonable low-cost tests, and advise ordering other tests only when the history points to them. This article explains what is worth checking, how strong the evidence is for each item, and how the results bear on a decision about TMS.

Why "treatment-resistant" deserves a second look

Treatment-resistant depression is most often defined as an inadequate response to at least two antidepressants given at an adequate dose and duration and taken as prescribed. A 2023 review in World Psychiatry estimated that at least 30% of people with depression meet that definition, and noted that a significant percentage are "pseudo-resistant" because earlier trials were inadequate or the medication was not taken as prescribed.

CANMAT's list of factors behind a poor response to initial treatment is a useful checklist in itself: incorrect diagnosis, psychiatric comorbidities such as anxiety disorders, personality disorders, ADHD and substance use disorders, non-psychiatric conditions such as anemia, obesity, sleep apnea and thyroid disease, inadequate dose or duration, side effects that look like symptoms, poor adherence, and differences in drug metabolism. Its first recommended step is to re-evaluate the diagnosis, comorbidities and adherence, and to consider laboratory investigations for medical factors that need their own treatment.

Payers ask for the same thing. New York Medicaid's TMS policy says providers "must confirm the diagnosis and rule out other etiologies of depressive symptoms that can interfere with medication effectiveness."

What to check, and how strong the evidence is

Diagnosis first: bipolarity and other look-alikes

The single most consequential finding in a workup is often a diagnostic one. A review of studies published between 1998 and 2008 concluded that treatment-resistant depression populations show high rates of previously unrecognized bipolar disorder, and gave "at least moderate support" to the idea that hidden bipolarity contributes to apparent resistance, while noting that none of the individual studies had been designed to test that question. No laboratory test detects it. It is found by asking about past periods of unusually elevated or irritable mood, reduced need for sleep, and family history, ideally with input from someone who knows the patient well.

This matters for TMS specifically. FDA's guidance for TMS devices lists bipolar disorder among the conditions where evidence of safety and efficacy is lacking, and major insurers including Aetna and Optum classify TMS for bipolar disorder as experimental or unproven. TMS for bipolar depression reviews that evidence, and the site's article on why bipolar disorder gets misdiagnosed explains how it is missed.

Other conditions on CANMAT's list, including ADHD, PTSD, anxiety disorders and personality disorders, do not rule out TMS but change what a realistic plan looks like. If you are thinking about suicide or are in crisis, call or text 988 (the 988 Suicide & Crisis Lifeline) or go to the nearest emergency room.

The basic blood tests guidelines support

Thyroid

Hypothyroidism has long been considered a classic medical cause of depression. The best current estimate is more measured: a 2021 meta-analysis in JAMA Psychiatry (25 studies, 348,014 participants) found an odds ratio of 1.30 for clinical depression with hypothyroidism overall, 1.77 for overt hypothyroidism and 1.13 for the subclinical form. The authors concluded the association was considerably weaker than previously assumed. A TSH is still worth having, because overt thyroid disease is cheap to detect and treatable, but a mildly abnormal result should not be assumed to explain a severe depression.

Complete blood count and iron

CANMAT names the complete blood count alongside TSH as a low-cost test that can rule out anemia as a treatable cause of low mood and energy. Iron deficiency without anemia is a grayer area. A 2025 meta-analysis of iron supplementation in non-anemic children, adolescents and menstruating adults found improvements in fatigue and anxiety in randomized trials but not in depression scores, and the effects were absent in analyses that excluded iron-deficient participants. Correcting low iron is reasonable medicine; expecting it to resolve a major depressive episode is not supported.

Vitamin B12 and folate

Vitamin B12 deficiency affects roughly 2% to 3% of US adults, with higher risk in older age, restricted diets, malabsorption, and long-term use of metformin or acid-suppressing drugs. Its symptoms include fatigue, brain fog and depression. Universal screening is not recommended, but testing is advised when a person has at least one risk factor and one clinical feature; a serum level under 180 pg/mL is diagnostic, and a borderline level of 180 to 350 pg/mL calls for a methylmalonic acid test. More on this is in the site's article on depression and vitamin B12 deficiency.

Folate is relevant mainly as a treatment question. In two randomized trials of L-methylfolate added to an SSRI, the first found no significant benefit, and the second (75 patients, 15 mg a day) found a higher response rate than placebo, with a number needed to treat of about six. That is a mixed and modest evidence base for an adjunct, not a reason to delay other treatment.

Sleep apnea: a contributor that is easy to miss

CANMAT singles out undiagnosed sleep apnea as a possible driver of persistent insomnia, fatigue and low motivation after antidepressant treatment. In a clinical trial sample of 125 adults with major depression and suicidal thoughts, none of whom were suspected of having sleep apnea, 14% met diagnostic criteria on testing. Neither daytime sleepiness nor insomnia severity predicted who had it; age, male sex and higher body mass index did.

Treatment appears to help mood. A meta-analysis of 19 randomized trials in people with obstructive sleep apnea found that CPAP improved depressive symptoms compared with control, with a much larger effect in the two trials that enrolled people with more depression at baseline; results varied widely between trials. Loud snoring, witnessed pauses in breathing, morning headaches or unrefreshing sleep justify a sleep study before concluding that depression is resistant. The site's article on sleep and depression covers insomnia, which is a separate and equally treatable problem.

Medications, alcohol and other substances

A national survey analysis in JAMA (2018; 26,192 adults) found that 37.2% used at least one prescription medication listing depression as a potential adverse effect. Among adults not taking antidepressants, an estimated 15% of those using three or more such drugs had depression, compared with 4.7% of those using none. This was a cross-sectional study and cannot show that the drugs caused the depression, but it justifies reading the whole medication list, not only the psychiatric part.

Alcohol deserves a direct question. In a 24-week study of 138 outpatients with both alcohol dependence and major depression, greater reductions in drinking were associated with better depression outcomes whether the depression was classed as independent or substance-induced, while the antidepressant studied had no effect on depression in either group.

Substances also bear on TMS safety. International safety guidance lists alcohol withdrawal and stimulants such as cocaine among factors that lower seizure threshold. In the pivotal deep TMS trial, the one seizure occurred in a patient who had been drinking heavily the night before and had not disclosed it. Some insurers also write substance use into their TMS criteria; Aetna, for example, does not cover TMS when there has been substance abuse in the previous 90 days.

Hormones and vitamin D: targeted, not routine

CANMAT advises testing testosterone or vitamin D only when the history and examination suggest deficiency. The trial evidence explains the caution.

• Vitamin D: in VITAL-DEP, 18,353 adults aged 50 and older took 2,000 IU a day or placebo for a median of 5.3 years, with no significant difference in the risk of depression or clinically relevant depressive symptoms. A 2024 meta-analysis of 31 trials did find a short-term reduction in depressive symptoms with supplementation, larger in people who already had symptoms and fading in longer trials. See the site's vitamin D and depression page.
• Testosterone: a meta-analysis of 27 randomized trials in 1,890 men found a small reduction in depressive symptoms with testosterone treatment (effect size 0.21).
• Perimenopause: CANMAT identifies the perinatal and perimenopausal periods as times of higher risk for depression. Perimenopause, depression and TMS discusses this group.

Inflammatory markers such as C-reactive protein are sometimes ordered as well. Their role is still a research question, covered in inflammation and treatment-resistant depression. Genetic testing of drug metabolism is a separate topic with its own evidence, in pharmacogenomic testing and where TMS fits.

What does not need routine testing

CANMAT states that there is no supportive evidence for routine electrocardiography, EEG or brain imaging in people presenting with major depression, and that these should be ordered only when there is a clinical reason. Standard TMS is positioned using scalp measurements and does not require an MRI. Specialized panels that claim to diagnose depression from blood, urine or stool have not been validated for that purpose, and a normal result on them does not change the treatment options.

How the workup feeds into a TMS decision

A workup before TMS does three jobs. It occasionally finds a treatable contributor that deserves treatment in its own right and may change the plan; correcting one has not been shown to improve the response to TMS. It screens for safety: FDA guidance asks for closer monitoring of patients with a history of seizure, stroke or head injury, those taking medications that lower seizure threshold, and those with conditions that alter electrolyte balance, and it contraindicates TMS when conductive or magnetic metal is implanted in or near the head. And it produces the documentation insurers ask for, including the list of medication trials with doses and dates. TMS safety and seizure risk covers the screening questions in detail.

A workup should not become a reason for indefinite delay. For many people the medical evaluation turns up nothing remarkable, and for them the appropriate conclusion is that the depression itself needs a different treatment. The basic tests take days, not months, and can run alongside the insurance authorization process. Every treatment-resistant depression option compared sets out what comes next.

How an integrative practice approaches this

Dr. Lewis's practice describes its functional medicine work as examining how inflammation, metabolism, hormones, nutrition, sleep and gut health may influence mental well-being, and its lab testing as a way to rule out medical contributors alongside a careful clinical evaluation. Its published panels include an anemia panel, a thyroid panel and inflammation markers. The practice also states plainly that some functional tests are validated and others are investigational, that functional testing is optional, and that it is not validated for diagnosing a mental health condition. Details are on the functional medicine and psychiatry and lab testing pages.

That distinction is the right one to hold onto. The guideline-supported core is small: history, medication review, CBC, TSH, and targeted tests driven by symptoms and risk factors. Anything beyond that is optional, and its results should be weighed as hypotheses, not diagnoses. TMS in an integrative, precision psychiatry practice discusses how the two approaches fit together. The full series is in the TMS guide, and the TMS service page explains how to start a conversation about whether TMS is an option.

Frequently asked questions

What blood tests should be done before TMS?

There is no TMS-specific required panel. Guidelines for depression support a complete blood count and TSH as inexpensive basics, with other tests such as B12, vitamin D or testosterone ordered when your history or symptoms point to them.

Can a thyroid problem make antidepressants stop working?

Overt hypothyroidism is associated with depression and can cause fatigue, slowed thinking and low mood that overlap with it. Treating it is necessary, but a mildly abnormal thyroid test rarely explains a severe depressive episode by itself.

Do I need a brain MRI or EEG before TMS?

Not routinely. Guidelines find no evidence for routine imaging or EEG in depression, and standard TMS is positioned with scalp measurements. Some specialized protocols use MRI for targeting, and your psychiatrist may order imaging if your neurological history calls for it.

If my labs are all normal, does that mean TMS will work?

No. Normal results mean there is no obvious medical contributor to correct first. They do not predict response to TMS, which no blood test currently does.

Should I have a sleep study before starting TMS?

Only if there are signs of sleep apnea, such as loud snoring, witnessed pauses in breathing, morning headaches or unrefreshing sleep. Sleep apnea can go unsuspected in people with depression, so the screening questions are worth asking.

Sources

1. Canadian Network for Mood and Anxiety Treatments (CANMAT) 2023 Update on Clinical Guidelines for Management of Major Depressive Disorder in Adults. Canadian Journal of Psychiatry, 2024. pmc.ncbi.nlm.nih.gov
2. Treatment-resistant depression: definition, prevalence, detection, management, and investigational interventions. World Psychiatry, 2023. pubmed.ncbi.nlm.nih.gov
3. Is unrecognized bipolar disorder a frequent contributor to apparent treatment resistant depression?. Journal of Affective Disorders, 2010. pubmed.ncbi.nlm.nih.gov
4. Association of Hypothyroidism and Clinical Depression: A Systematic Review and Meta-analysis. JAMA Psychiatry, 2021. pubmed.ncbi.nlm.nih.gov
5. Psychiatric and cognitive outcomes of iron supplementation in non-anemic children, adolescents, and menstruating adults: A meta-analysis and systematic review. Neuroscience & Biobehavioral Reviews, 2025. pubmed.ncbi.nlm.nih.gov
6. Vitamin B12 Deficiency: Common Questions and Answers. American Family Physician, 2025. pubmed.ncbi.nlm.nih.gov
7. L-methylfolate as adjunctive therapy for SSRI-resistant major depression: results of two randomized, double-blind, parallel-sequential trials. American Journal of Psychiatry, 2012. pubmed.ncbi.nlm.nih.gov
8. Prevalence of obstructive sleep apnea in suicidal patients with major depressive disorder. Journal of Psychiatric Research, 2019. pubmed.ncbi.nlm.nih.gov
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10. Prevalence of Prescription Medications With Depression as a Potential Adverse Effect Among Adults in the United States. JAMA, 2018. pubmed.ncbi.nlm.nih.gov
11. Depression outcome in alcohol dependent patients: an evaluation of the role of independent and substance-induced depression and other predictors. Journal of Affective Disorders, 2015. pubmed.ncbi.nlm.nih.gov
12. Effect of Long-term Vitamin D3 Supplementation vs Placebo on Risk of Depression or Clinically Relevant Depressive Symptoms and on Change in Mood Scores: A Randomized Clinical Trial. JAMA, 2020. pubmed.ncbi.nlm.nih.gov
13. The effect of vitamin D supplementation on depression: a systematic review and dose-response meta-analysis of randomized controlled trials. Psychological Medicine, 2024. pubmed.ncbi.nlm.nih.gov
14. Association of Testosterone Treatment With Alleviation of Depressive Symptoms in Men: A Systematic Review and Meta-analysis. JAMA Psychiatry, 2019. pubmed.ncbi.nlm.nih.gov
15. 510(k) Summary K231926 – NeuroStar Advanced Therapy System. U.S. FDA, 2024. accessdata.fda.gov
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17. Class II Special Controls Guidance Document: Repetitive Transcranial Magnetic Stimulation (rTMS) Systems. U.S. FDA, 2011. fda.gov
18. Safety and recommendations for TMS use in healthy subjects and patient populations, with updates on training, ethical and regulatory issues: Expert Guidelines. Clinical Neurophysiology, 2021. europepmc.org
19. New York State Medicaid Coverage of Therapeutic Transcranial Magnetic Stimulation (Medicaid Update, July 2025, Vol. 41 No. 7). NYS Department of Health, 2025. healthweb-back.health.ny.gov
20. Transcranial Magnetic Stimulation and Cranial Electrical Stimulation (Clinical Policy Bulletin 0469). Aetna, 2026. aetna.com
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Educational information, not medical advice. Whether TMS or any treatment fits you is a decision to make with a psychiatrist who knows your history.