Autoimmune Differential: Treatment Resistant Depression or Anxiety?

Authors:

Dr. Jon Weingarden, PsyD

Dr. Brittany Panico, DO - Rheumatologist, medical editor and co-author

Certain autoimmune syndromes may take years before diagnosis (5). This may be due to an often prolonged stage of early symptom presentation, diffuse symptoms that either confuse care providers or mimic other conditions resulting in incorrect diagnosis and incorrect treatment or no treatment (7). Often worst of all, there can be a sense that providers judge or neglect to see early symptoms the individual describes. All the while, the condition worsens. Visits to the doctor with inaccurate or no results leads to avoidance of treatment and shame or stigma - an implication it is “all in your mind,” which was a common refrain for conditions like fibromyalgia and Myalgic Encephalomyelitis / Chronic Fatigue Syndrome (ME / CFS).

Prior to diagnosis of an autoimmune disorder, patients may go through periods of seeking help for diffuse symptoms, and giving up on hope for medical care.

However, this can also impact care providers. Especially early in our careers, we may be sensitive to true or perceived “failures” and imposter syndrome. Facing unknown presentations, difficulty determining a disease presentation among lifestyle challenges,  or lack of treatment response can be difficult. This can create a social-interpersonal loop between the patient and provider that, in the mental health field, we might call an enactment or transference-countertransference.

Autoimmune diseases often cause diffuse systems that can include mental health symptoms and mimic psychiatric disorders. Stress response is a major overlap between both categories.

This article focuses on basic information on autoimmune syndromes that may overlap Generalized Anxiety Disorder (GAD) and Major Depressive Disorder (MDD), differential diagnostic considerations and some treatment considerations. Additionally, it includes a differential diagnostic tool for practitioners and autoimmune symptom tracking or journaling for patients.

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The Broad Categories of Autoimmune Illness

Autoimmune diseases are generally classified by the specific tissues, organs, or systems they target:

1. Systemic Connective Tissue / Rheumatic Diseases: (e.g., MCTD, Lupus, Scleroderma, Rheumatoid Arthritis, Sjögren’s syndrome). These target widespread collagen, blood vessels, and joint linings (5).

2. Endocrine (Hormonal) Autoimmune Diseases: (e.g., Hashimoto’s thyroiditis, Graves’ disease, Type 1 diabetes, Addison’s disease). These attack hormone-producing glands.

3. Neurological / Central Nervous System Autoimmune Diseases: (e.g., Multiple Sclerosis, Autoimmune Encephalitis, Myasthenia Gravis). These target the brain, spinal cord, or nerve-muscle junctions.

4. Gastrointestinal (Gut) Autoimmune Diseases: (e.g., Celiac disease, Crohn’s disease, Ulcerative colitis, Autoimmune Gastritis). These target the digestive tract linings.

5. Dermatological (Skin) Autoimmune Diseases: (e.g., Psoriasis, Vitiligo, Alopecia Areata). These target skin cells or hair follicles. Least likely to mimic psychiatric conditions.

6. Neurological / Neuroimmune Diseases or Central Sensitivity Syndromes: (e.g., Chronic Fatigue Syndrome (CFS) or myalgic encephalomyelitis and fibromyalgia). These aren’t always lumped in with autoimmune diseases as they do not have current medical tests to confirm their diagnosis.

   
   

Of note - non-autoimmune conditions to also consider: Excessive Daytime Sleepiness secondary to Obstructive Sleep Apnea (OSA), Endometriosis and other conditions that may have diffuse symptoms.

1. Example: The Anatomy of an Overlap Syndrome

An overlap syndrome occurs when a patient simultaneously exhibits diagnostic features of more than one distinct systemic autoimmune disease (5). Some clinicians do not recognize these conditions as definitive for a specific disease, and thus they may be more difficult to diagnose, and with potentially more subtle  or less overt presentations.  Many times  psychiatric symptoms may overshadow the autoimmune symptoms, which can contribute to delayed diagnosis of the underlying disorder or misdiagnosis entirely(7).

• Mixed Connective Tissue Disease (MCTD): Also known as Systemic Overlap Syndrome, is a specific, distinct overlap condition combining clinical features of lupus, systemic sclerosis (scleroderma), and polymyositis. Clinically, this is defined by the presence of a positive blood test for anti-U1 RNP antibodies (1, 2). Symptoms are often related to autonomic dysfunction and vascular abnormalities. 

• Rhupus: A highly precise overlap subtype describing individuals who concurrently meet strict diagnostic criteria for both Rheumatoid Arthritis (RA) and Systemic Lupus Erythematosus (SLE) (7).

  
  

As these conditions have diffuse symptoms and diagnosis may be difficult or delayed, symptoms may be misdiagnosed as GAD or MDD. We discuss stress response below, in relation to “sickness behavior”. MDD symptoms also can follow chronic stress response, and may be a reaction to decreased physical ability caused by physical and mental fatigue, as well as objective muscle weakness when there are polymyositis symptoms present (5).

Muscle weakness related to polymyositis can result in esophageal dysmotility, and consequently GERD or acid reflux (8). This, along with other aspects of autoimmune illness such as systemic inflammation can precipitate or worsen Obstructive Sleep Apnea (OSA) (9). OSA can contribute to fatigue, a symptom referred to as Excessive Daytime Sleepiness, as well as chronic stress response. This occurs as the  body responds to each apnea-hypoxia episode as a threat, therefore activating the sympathetic nervous system, and in turn, worsening the underlying autoimmune disorder (9).

2. Neuroinflammation and the "Sickness Behavior" Loop

Physical symptoms of anxiety anxiety, heightened stress responses, and cognitive symptoms are not merely emotional reactions to a chronic illness. These features are direct, organic manifestations of neuroinflammation (10). This is an evolutionary, hard-wired survival strategy triggered by any form of significant tissue damage or prolonged immune system activation (10).

This stress-inflammation response can trigger sickness behavior multiple ways:

• Physical injuries (broken bones, deep cuts, motor vehicle accident)

• Surgical trauma

• Infections (viral or bacterial)

• The physical tissue and cellular damage of autoimmune diseases

Dying and damaged cells release distress signals called Damage-Associated Molecular Patterns (DAMPs). Immune cells detect these DAMPs and immediately release the exact same inflammatory cytokines (like IL-1 and TNF-alpha) that breach the blood-brain barrier (10, 11). The brain receives these signals and instantly forces the organism into "sickness behavior" (10).

The body’s natural response to injury is to conserve as much metabolic energy as possible to heal and ward off threats of further bodily injury (infection of wounds, physical threats when already vulnerable, etc). This occurs in nature as an injured animal or human with an infection decreases physical movement to conserve energy to allow the body’s natural immune system to heal that injury. The brain intentionally induces lethargy, social withdrawal (hiding), loss of appetite, and hyper-vigilance (anxiety) to keep the body isolated, still, and safe from predators while cellular repairs take place (10, 11).

Sickness Behavior: akin to withdrawal or hiding of a wounded animal

Autoimmune illnesses cause chronic, low-grade cellular damage. This is analogous to a slow-growing infection or chronic wound with delayed healing. Consequently, the brain is receiving a constant, unbroken stream of inflammation-producing  DAMPs and cytokines (10). This often manifests as profound or debilitating  fatigue and urge to withdraw.  This is not a matter of willpower and these signals are difficult to turn off by mindset alone. This is the brain’s way of executing a primitive biological command to hide and heal (10).

Breach of the Blood-Brain Barrier 

When an autoimmune syndrome flares, hyperactive immune cells pump out pro-inflammatory signaling proteins called cytokines, such as IL-1, IL-6, and TNF-alpha (10). Over time, this chronic systemic inflammation weakens the blood-brain barrier, allowing these cytokines to leak directly into the central nervous system (11).

Once inside, these signals trigger microglia, the resident immune cells of the brain. Microglia switch them from gentle housecleaners to a more aggressive, inflammatory state (11).

Biological Sickness Behavior

Activation of these microglial cells alters the  brain's primary stress control axis, called the HPA axis. This in turn signals to the body’s autonomic nervous system a state of "fight-or-flight" in which the sympathetic hyper-arousal loop is chronically turned on (10). Typically, this mechanism is intended for brief periods of activation, then relaxation. With a chronic illness, the sympathetic nervous system component is turned on and remains turned on, leaving the body in a constant state of perceived threat. 

Furthermore, inflammation activates an enzyme called IDO, which steals the amino acid tryptophan to fight peripheral inflammation (10, 11). This directly starves the brain of the raw ingredients required to manufacture serotonin. Serotonin is an essential neurotransmitter responsible for controlling mood and stress response including anxiety which according to polyvagal theory moderates mammals ability to engage socially, as well as regulating sleep and affecting alertness, and digestion. Symptoms then manifest  as physical panic and severe cognitive fatigue (11).

Due to the body’s way of processing trauma, both physical and emotional, there is a strong link between autoimmune illnesses and Posttraumatic Stress Disorder (PTSD). Each of these conditions independently provide feedback to the nervous system and in turn, increase the likelihood of developing the other.

3. The Neurovascular Medication Tightrope

Managing the psychiatric and vascular or autonomic symptoms of an overlap syndrome requires a delicate pharmaceutical balance, as drugs that treat one system can frequently aggravate another.

Current  medical literature focuses heavily on how anxiety can cause blood vessel constriction. This can manifest as Raynaud's syndrome, as stress causes a spike in adrenaline, which then constricts blood vessels and can change the color of the skin (typically of the hands, toes, and face) (6). However, the presence of Raynaud's can also trigger  anxiety as this can be an alarming process when the skin changes color or becomes numb without conscious control  (12). This can manifest as a feedback loop involving vascular interoception and the sensation of dissociation. 

• Vascular Interoception: the brain constantly monitors the internal state of the body through a process called interoception (12). When the body senses a threat, the blood vessels in extremities such as fingers can rapidly spasm and constrict , which severely restricts blood flow and oxygen delivery to the tissue. (6). When this occurs, the tiny nerve endings in the body region instantly send urgent, high-priority threat signals to the insular cortex in the brain, which is responsible for interoception, or perception of internal body states, like heartrate, breathing, digestion and hunger, pain, taste, and emotions, self-awareness and social empathy (12). Even during periods without physical threat, the brain registers this sudden lack of blood flow in the extremities as a severe physical crisis, which then automatically triggers a surge of panic and anxiety (12).

• The Sensation of Dissociation: The feeling of being disconnected to oneself can be a direct result of this sudden drop in blood flow and neurological feedback (12). When an individual’s fingers turn white, cold, and numb, the brain can lose its normal proprioceptive map, or the awareness of where body parts are in relation to space (6). This is exacerbated as  the sensory nerves are starved of oxygen, and they send further dysregulated  signals back to the brain. This sudden sensory dysfunction creates a profound mismatch between the mind and the body, which can manifest as the psychological feeling of depersonalization or dissociation. You may be looking at your hands, but they don't quite feel like they are part of your body(12).

  

  The dopamine-serotonin seesaw: serotonin promotes calmness and potentially vasodilation with the risk of worsening brain-fog or lethargy and suppressing dopamine which can result in movement disorder, while dopamine promotes alertness at the potential cost of worsening anxiety and vasoconstriction.

The SSRI and Sleep Movement Paradox

Selective Serotonin Reuptake Inhibitors (SSRIs), like sertraline or lexapro serve an excellent dual purpose at moderate doses. These medications preserve scarce serotonin to help calm the sympathetic stress response and act as peripheral smooth-muscle relaxants to prevent the intense vascular spasms of Raynaud’s phenomenon (4).

However, elevated serotonin levels can indirectly suppress dopamine pathways in the brain's movement-control centers (11). This dopamine-serotonin imbalance can trigger or even worsen sleep-related movement disorders, such as Restless Legs Syndrome (RLS), Periodic Limb Movement Disorder (PLMD), and sleep bruxism (teeth grinding) (4, 11).

The Dopamine Dilemma

Conversely, dopaminergic and noradrenergic medications, such as stimulants or the NDRI Wellbutrin (bupropion), can drastically improve cognitive symptoms like brain fog and autoimmune-related fatigue (13). However, these medications that act as dopamine and norepinephrine agonists can also over stimulate the sympathetic nervous system, which in turn can induce intense vasoconstriction (vascular narrowing) (6). In a patient with an overlap syndrome in which  Raynaud's or small-vessel vasculitis is present, this vasoconstriction can starve the extremities and inner ear of microcirculation (6). This can then cause a secondary wave of physical anxiety, positional vertigo, and potentially motion-induced dizziness (11, 13).

Vascular beyond neurostimulants - Dizziness as a Sign

Neuroinflammation and vascular permeability changes can also result in increased motion sensitivity and consequently dizziness (10). Activated microglia can contribute to inflammation of  the vestibulocochlear nerve, which is responsible for balance and spatial orientation (10). When this is combined with additional cognitive energy requirements that  tax our brain’s bandwidth, dizziness and the sensation of loss of balance can be a result(11). Additionally, vascular spasms in the labyrinthine artery, a singular tiny blood vessel that supplies the inner ear, can disrupt  the fluid mechanics that our brain relies on to maintain balance and sense of equilibrium.

4. Fatigue and Addressing the Cellular Energy Problem

Chronic autoimmune inflammation can cause damage to mitochondria, the internal engines that produce energy for all our cells. This perpetually depletes the natural intracellular energy pools, particularly NAD+, a molecule that helps recharge our cellular batteries, ATP (adenosine triphosphate). This depletion is most often counterbalanced with central nervous system stimulants. However, the use of stimulants often results in a systemic crash and the opposite of the desired physiologic effect (12, 13). A more sustainable clinical approach focuses on non-stimulant, cellular-level interventions that function like a synchronized metabolic assembly line.  This can be achieved with several non-stimulant substitutes:  

• Acetyl-L-Carnitine (ALCAR): Unlike standard L-carnitine, ALCAR possesses an acetyl group that allows it to readily cross the blood-brain barrier (12). Once inside the central nervous system, it fuels neuronal mitochondria and provides the raw materials to produce acetylcholine, which is the core neurotransmitter responsible for working memory, focus, and rapid word-finding (12). ALCAR moves “fuel” into the cell for energy (12, 13).

• Coenzyme Q10 (CoQ10): Functions as the essential "spark plug" within the mitochondrial electron transport chain (13). CoQ10 is responsible for shuttling electrons down the line to ultimately synthesize ATP (13). When systemic autoimmune inflammation induces widespread oxidative stress, it rapidly depletes the body's natural CoQ10 stores (13). Supplementing with CoQ10, particularly in its highly bioavailable ubiquinol form, helps keep this vital energy pipeline open. This can dampen cellular fatigue and provide muscular antioxidant protection against free-radical damage (13).

• NAD+ Precursors (Nicotinamide Riboside / NR): Directly fuels the mitochondria to generate ATP, helping cells bypass the energy depletion imposed by chronic immune activation (12). [Note: Alcohol (ethanol) forces cells to convert NAD+ into NADH, which cancels out the benefits of NR supplementation]

• Creatine Monohydrate: Functions as a physical energy reserve (14). It stores high-energy phosphate molecules directly inside muscle and brain tissues, and can instantly regenerate ATP during physical tasks without drawing from already depleted NAD+ pools (14). This can directly combat the heavy, muscular weakness that can be associated with autoimmune overlap disorders (14).

• Low-Dose Naltrexone (LDN): Acts as a neurologic immunomodulator. At low doses (1.5mg – 4.5mg), naltrexone binds to receptors on hyper-reactive microglia, which then decreases  inflammation within and around the brain that is responsible for symptoms like  fatigue and pain. [Not directly related to cellular energy assembly].

The Krebs cycle is part of the cellular energy assembly process that occurs in the mitochondria, an organelle inside of animal cells, also known as the cellular powerplant.

Interaction with Alcohol

Not only does NAD+ depletion and mitochondrial damage contribute to cellular fatigue, this process can also increase the nervous system’s sensitivity to CNS depressants. When alcohol is ingested, large  amounts of NAD+ are required to fuel alcohol dehydrogenase (ADH), the  enzyme that breaks down alcohol (12). Due to NAD+ depletion, the liver’s ability to metabolize alcohol is significantly diminished, and this increases alcohol’s intoxicating effects during periods of chronic inflammation. This can exacerbate the effects of chemical hangover, leading to worsening and prolonged flare symptoms, fatigue, mental fog and pain  (12). The use of alcohol to combat social withdrawal and autonomic arousal related to “sickness behavior” described above, can ultimately inhibit cellular recovery and contribute to longer flare periods. Additionally, the autonomic nervous system is particularly sensitive to the effects of alcohol: while alcohol initially reduces anxiety, the bodies natural physiological homeostatic mechanisms can overcompensate resulting in an anxiety rebound. In turn, there can be increased urges to consume alcohol in response to these worsened symptoms (anxiety, social withdrawal, prolonged flare ups including pain and fatigue), creating a feedback loop.

5. How the GI Tract Responds to Inflammation

The intestinal wall is lined with epithelial cells that are held together by microscopic "gatekeepers" called tight junction proteins. When these epithelial cells are damaged, the result is often referred to as  Leaky gut because the body's ability to digest nutrients is compromised and symptoms often result in digestive issues, change in bowel pattern, and even mood changes.  (3). Systemic inflammation, by definition, has broad effects throughout our body, and the GI system is not excluded (3). Autoimmune illness can increase gut permeability, which in turn increases inflammation as our immune system reacts to foreign bodies that typically would not pass through the tight junction proteins of the digestive tract (3). Additionally, alcohol contributes to damage of the GI cells and causes these cells to pull apart, creating literal gaps in the gut barrier. Once these gaps open, toxins from gut bacteria,  particularly a highly inflammatory endotoxin molecule called Lipopolysaccharide (LPS), leak directly into the bloodstream from the damaged barrier. The immune system recognizes LPS as an immediate threat and something that should not be present in the blood and thus triggers  further release of  inflammatory cytokines.

Dysbiosis and the Milk/Wheat Overlap: Alcohol acts as a selective fuel source for pro-inflammatory gut bacteria, causing a rapid shift in the gut microbiome (dysbiosis). If you have food sensitivities, such as to milk or wheat, further compromise in the GI membrane caused by alcohol can mean that any trace exposures to these foods will cross the gut barrier much more readily. This in turn amplifies symptoms of acid reflux and inflammation, which can manifest as bloating,  stomach distension, and change in bowel patterns(3).

Note: Akin to sensitivity to foods, other sensitivities may present on the skin as rashes or sensitivity to chemicals that were otherwise tolerated like detergents, soaps and sunscreens. 

More from an interview between Dr. Brittany Panico and Dr. Jon Weingarden

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📚 ARTICLE REFERENCES

1. Alarcón-Segovia, M., et al. Comparison Between 3 Diagnostic Criteria for Mixed Connective Tissue Disease: Study of 593 Patients. PubMed (National Center for Biotechnology Information).

2. ARUP Laboratories Technical Bulletin. Mixed Connective Tissue Disease - MCTD: Choose the Right Test Diagnostic Criteria. ARUP Consult.

3. Cleveland Clinic Health Library. Mixed Connective Tissue Disease (MCTD): Systemic Management, Extranodal Overlaps, and Longitudinal Survival Profiles. Cleveland Clinic.

4. Harvard Medical School Health Publishing. A Major Change for Restless Legs Treatment: Strategic Adjustments on Antidepressants and Iron Status. Harvard Health.

5. Hospital for Special Surgery (HSS) Rheumatic Disease Center. Mixed Connective Tissue Disease and Overlap Syndromes: Defining Anti-RNP Antibody Clinical Phenotypes. HSS Health Library.

6. Mayo Clinic Clinical Reference. Raynaud's Disease: Secondary Etiologies, Connective Tissue Overlaps, and Vasoconstrictive Medication Contraindications. Mayo Clinic.

7. Medscape Drugs & Diseases Reference. Mixed Connective-Tissue Disease (MCTD) Differential Diagnoses, Kahn and Alarcón-Segovia Criteria Frameworks. Medscape Reference.

8. The Myositis Association (TMA) Reference Library. Treating Swallowing Problems and Esophageal Smooth-Muscle Dysfunction in People with Myositis.

9. Journal of Clinical Sleep Medicine / Sleep Research Online. Bidirectional Mechanisms of Gastroesophageal Reflux Disease (GERD) and Obstructive Sleep Apnea (OSA).

10. Elsevier / Brain, Behavior, and Immunity. Cytokine-Induced Sickness Behavior and the Regulation of the Hypothalamic-Pituitary-Adrenal (HPA) Axis.

11. The Journal of Neuroscience. Microglial Activation and Indoleamine 2,3-Dioxygenase (IDO) Pathways in Inflammation-Induced Depressive Behavior.

12. Harvard Medical School News / Neurobiology. How Immune Activity Altering Cytokine Pathways Can Change Mood and Fuel Neuroinflammatory Cognitive Fatigue.

13. Cleveland Clinic / Mitochondrial Disease Center. Comprehensive Supplement Support Frameworks: Roles of Coenzyme Q10, Acetyl-L-Carnitine, and NAD+ Precursors in Addressing Intracellular Bioenergetic Deficits.

14. National Institutes of Health (NIH) / PubMed Central. Role of Creatine Supplementation in Conditions Involving Mitochondrial Energy Depletion and Chronic Cellular Fatigue.

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Medical Disclaimer

The clinical toolkits and blog article contained herein are designed strictly for educational and self-tracking optimization purposes. They do not replace formal clinical assessment, personalized medical advice, or psychiatric diagnosis. All therapeutic changes, supplement introductions (such as creatine), and specialist referrals must be authorized and coordinated directly through a licensed healthcare provider.