The Clinician Detective: Investigation Begins with Careful Observation

Dr. Ronald Swatzyna, Director and Chief Scientist of the Houston Neuroscience Brain Center, inspired our Clinician Detective series. In his Association for Applied Psychophysiology and Biofeedback (AAPB) Distinguished Scientist address, he reminded his audience that the DSM-5 advises systematically ruling out general medical conditions before assigning a psychiatric diagnosis to ensure diagnostic validity and appropriate treatment planning. He argued that in abrupt onset and refractory cases, EEG biomarkers should challenge neurofeedback providers and their medical colleagues to become detectives to identify their causes. This collaborative approach allows each professional to contribute to assessment while "staying in their lane."

Dr. Swatzyna generously mentors professionals in his investigative method, including raw EEG interpretation, to train the next generation of neurofeedback clinicians.

We based this post on his ADDA-R ethics webinar, "Meeting the Ethical Requirements for Diagnosing Mental Health Disorders: A Neuroscience Approach."

Introduction

As clinicians trained in neuroscience and neurofeedback (a therapeutic technique that uses real-time displays of brain activity to teach self-regulation of brain function), we often see what others miss.

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Patients come to us with symptoms—anxiety, hallucinations, panic, fatigue—but these symptoms do not arrive with a clear label. Too often, diagnoses are assigned quickly, based on surface-level behavioral observations. But we are not mere cataloguers of symptoms. We are diagnosticians, and if we are to honor the ethical responsibilities of our role, we must go beyond the DSM checklist. We must ask what lies beneath the symptoms. We must ask why now and why this person, not merely what this is called (Giedd et al., 2024; Kendler, 2019).

This ethos—the approach of the “Clinician Detective”—is rooted in the principle that behavior is biology in disguise. Emotional disturbances, disorganized thought, inattention, and mood instability are often consequences of disrupted neural function, systemic illness, environmental toxicity, or unrecognized trauma (Campbell & Kendler, 2013; Mandal et al., 2022; Vadodaria et al., 2019).

Ethically, we are obligated to rule out these root causes before assigning psychiatric labels. The DSM-5 itself mandates that clinicians first rule out substance use, medical conditions, and environmental factors before a mental disorder diagnosis can be ethically made (Giedd et al., 2024; Kendler, 2019).

In DSM-5's Use of Manual section, it states:

Before a diagnosis of a mental disorder can be made, the clinician must rule out that the symptoms are not attributable to the physiological effects of a substance or another medical condition (p. 19).

Mental Illness as Circuit Dysfunction: From DSM to RDoC

The DSM-5 remains the dominant diagnostic system in clinical psychiatry, but it is not grounded in neuroscience. In fact, Dr. Thomas Insel, during his tenure as Director of the National Institute of Mental Health, publicly stated that the DSM lacks scientific validity. He emphasized that it is a tool of consensus, not evidence—a system of naming, not explaining (Giedd et al., 2024; Kendler, 2019).

In response, the NIMH launched the Research Domain Criteria (RDoC, a research framework for studying mental disorders based on dimensions of observable behavior and neurobiological measures), which reframes mental illness as circuit dysfunction.

This model views psychiatric disorders as problems in specific brain systems that can be measured using tools such as electroencephalography, functional magnetic resonance imaging, and genetic analysis (Giedd et al., 2024; Mandal et al., 2022; Vadodaria et al., 2019).

Rather than asking whether a patient fits the criteria for major depressive disorder, the RDoC model asks: which brain networks are failing? Is the prefrontal cortex under-regulating the limbic system? Is the default mode network hyperactive? Are the attentional circuits fragmented? These are not academic questions; they are clinically essential.

The Diagnostic Value of Physical Examination

A patient’s appearance speaks volumes. Before a single symptom is described, a careful clinician can gather meaningful clues by observing skin color, weight, posture, and eye clarity. Pale skin—known as pallor—can signal anemia. Anemia can cause fatigue, irritability, and poor concentration—symptoms easily mistaken for depression (Mandal et al., 2022). Likewise, the presence of bulging eyes or a tremulous appearance may point to hyperthyroidism. This can cause anxiety, agitation, and insomnia, and in some cases, even psychosis (Mandal et al., 2022).

Cold hands are not a trivial finding. They may indicate vasoconstriction due to anemia, autoimmune disease, or thyroid dysfunction (Mandal et al., 2022). Dry, brittle nails and thinning hair are outward signs of internal endocrine or nutritional disorders. The body reveals what the mind cannot articulate (Mandal et al., 2022).

In children, growth metrics can indicate hidden physiological stress. Short stature—defined as below the 3rd percentile—can result from chronic illness, malnutrition, or genetic conditions like Turner syndrome (a genetic disorder affecting females). Tall stature may suggest syndromes such as Marfan (a genetic disorder affecting connective tissue) or Klinefelter (a genetic condition in males with an extra X chromosome), each with its own neurological and behavioral implications (Mandal et al., 2022; Vadodaria et al., 2019). Stature is not just a pediatric concern; it’s a signal that the system may be developmentally compromised (Vadodaria et al., 2019).

Chronic vs. Acute Onset: Timing is Everything

When did the symptoms begin? This simple question can distinguish between a primary psychiatric disorder and a medical emergency. Chronic symptoms often point toward developmental, genetic, or cumulative stress-related processes (Giedd et al., 2024; Mandal et al., 2022; Vadodaria et al., 2019).

Genetic polymorphisms (variations in DNA sequence) such as MTHFR, COMT, FOXP1, and FOXP2 (genes involved in brain function and development) can affect how the brain processes neurotransmitters and regulates gene expression (Mandal et al., 2022; Vadodaria et al., 2019).

MTHFR mutations, for instance, impair the methylation process needed to convert folate (a B vitamin) into its active form. This can lead to elevated homocysteine (an amino acid in the blood), a compound linked to mood disorders, cognitive impairment, and cardiovascular disease (Mandal et al., 2022; Vadodaria et al., 2019).

Acute symptoms often have a trigger. Infections, head trauma, exposure to environmental toxins, or sudden psychosocial stress can precipitate dramatic changes in cognition and behavior (Campbell & Kendler, 2013; Mandal et al., 2022; Vadodaria et al., 2019).

A new psychiatric presentation following travel should raise concerns about infectious diseases; recent head injury suggests a possible mild traumatic brain injury (Mandal et al., 2022). The key is to look for change points in the patient’s narrative—what changed just before the mind unraveled? (Giedd et al., 2024; Mandal et al., 2022)

Refractoriness as a Diagnostic Clue

When patients fail to respond to psychiatric treatment, this is not a clinical dead-end—it is a diagnostic opportunity. Treatment resistance often signals that the diagnosis is incomplete or incorrect (Giedd et al., 2024; Mandal et al., 2022; Vadodaria et al., 2019).

Patients may have been misdiagnosed, or the underlying condition may be biological rather than psychiatric (Mandal et al., 2022; Vadodaria et al., 2019). If SSRIs induce mania, bipolar disorder may have been missed. If neurofeedback fails to improve attention, the clinician should explore whether the patient has a history of previous mild traumatic brain injury (mTBI) or is suffering from chronic inflammation (Campbell & Kendler, 2013; Mandal et al., 2022; Vadodaria et al., 2019).

Nonresponse should never be dismissed. It is the brain’s way of saying, “you are not treating the right problem” (Giedd et al., 2024; Mandal et al., 2022; Vadodaria et al., 2019).

Substance Use and Medication Side Effects: Hidden Causes of Psychiatric Symptoms

Substances alter the brain’s chemistry and circuitry. Chronic cannabis use, for example, has been linked to anxiety, depression, and, in vulnerable individuals, psychosis (Mandal et al., 2022). Cannabinoid Hyperemesis Syndrome (CHS, a condition of repeated vomiting due to heavy cannabis use), is often misdiagnosed as anxiety or gastrointestinal illness (Mandal et al., 2022). The paradoxical feature of CHS—symptom relief from hot showers—is a key diagnostic clue (Mandal et al., 2022).

Medication-induced psychiatric symptoms are equally important. Diphenhydramine (Benadryl, an antihistamine used for allergies), a common antihistamine, possesses anticholinergic properties that can cause delirium, particularly in the elderly (Mandal et al., 2022). Methadone and Suboxone (medications for opioid addiction), while effective for opioid dependence, can produce mood blunting and anxiety (Mandal et al., 2022). Polypharmacy (use of multiple medications) must always be examined with suspicion. Each molecule a patient ingests can disrupt neurotransmission (Mandal et al., 2022).

Genetic and Laboratory Investigation: Revealing the Unseen

Laboratory testing is not supplementary—it is essential.

A basic panel may uncover thyroid dysfunction, anemia, electrolyte imbalances, or markers of systemic inflammation such as elevated C-reactive protein (Mandal et al., 2022; Vadodaria et al., 2019). A urinalysis can detect infection, which in older adults may present solely as delirium or hallucinations (Mandal et al., 2022).

Genetic analysis can provide deeper insight. The COMT gene (codes for an enzyme that breaks down dopamine and other neurotransmitters) influences how quickly the brain clears dopamine, epinephrine, and norepinephrine. Low-activity variants of this gene are associated with increased stress sensitivity, pain, and mood instability (Mandal et al., 2022; Vadodaria et al., 2019).

FOXP2, a gene involved in language processing and speech development, has been associated with neurodevelopmental disorders, and abnormalities can manifest as behavioral dysregulation mistaken for psychiatric illness (Mandal et al., 2022; Vadodaria et al., 2019).

Neuroimaging must be considered in cases of refractory (hard-to-treat) or unusual symptoms. Structural brain anomalies, such as Chiari malformations (brain tissue extends into the spinal canal) or arachnoid cysts (fluid-filled sacs in the brain), may cause symptoms of ADHD, depression, or even psychosis, depending on their location and size (Mandal et al., 2022).

The Unseen Injury: Mild Traumatic Brain Injury (mTBI)

A blow to the head does not need to cause loss of consciousness to result in significant brain dysfunction. Mild traumatic brain injury, also called concussion, often leads to disruption in attention, working memory, emotional regulation, and sleep (Mandal et al., 2022). Symptoms may appear weeks or months after the injury and are often mistaken for depression, anxiety, or even personality disorders (Mandal et al., 2022).

Children are particularly vulnerable, as their brains are still developing. A child who begins acting out in school 6 months after a fall from a bicycle may not be defiant—they may be struggling with a disrupted executive network (Mandal et al., 2022). mTBI may also lead to vestibular disturbances, tinnitus, hormonal imbalance, and visual strain. All of these contribute to emotional instability and cognitive fatigue (Mandal et al., 2022).

Environmental Toxins and Electromagnetic Exposure

Environmental exposures can create profound neuropsychiatric symptoms. Heavy metals such as lead, mercury, and arsenic have been linked to cognitive decline, irritability, mood disorders, and even psychosis (Mandal et al., 2022; Vadodaria et al., 2019).

Pesticides disrupt neurodevelopment and are associated with decreased executive function, increased impulsivity, and mood instability (Mandal et al., 2022; Vadodaria et al., 2019).

Mold toxicity is another overlooked factor. Mycotoxins released by indoor mold exposure can impair memory, concentration, and sleep, and may cause emotional blunting, paranoia, or panic attacks (Mandal et al., 2022).

These symptoms are not “all in the patient’s head”—they are in the environment, affecting the brain through inflammatory and oxidative pathways (Campbell & Kendler, 2013; Mandal et al., 2022; Vadodaria et al., 2019).

Emerging research into electromagnetic hypersensitivity suggests that some individuals experience neurologically mediated symptoms—such as headaches, insomnia, anxiety, and sensory disturbances—when exposed to Wi-Fi, Bluetooth, or smart meter radiation. While these reports are controversial, they are increasing, especially in adolescents, whose brains are more susceptible to electromagnetic influences during specific developmental windows (Giedd et al., 2024; Vadodaria et al., 2019).

Mrs. J: A Case of Hallucinations, Infection, and Misleading Appearances

Mrs. J was 75 years old when her daughter brought her to the emergency room in a panic. Over the past 2 days, her mother had become confused, frightened, and accusatory. She claimed that strangers were in the house, that her food had been poisoned, and that her family was plotting to harm her. This loving, coherent woman was suddenly delusional and agitated.

The initial thought, as it too often is in geriatric psychiatry, was dementia or late-onset schizophrenia. But Mrs. J had no psychiatric history, and she had been managing her affairs independently just a week earlier.

Upon examination, she was dehydrated and had a low-grade fever. A urinalysis revealed pyuria (the presence of white blood cells in the urine, indicating an infection) and positive nitrites (a sign of bacterial infection), consistent with a urinary tract infection. Her blood work showed an elevated white blood count and C-reactive protein (CRP), confirming systemic inflammation. The diagnosis was urosepsis-induced delirium—a brain reaction to systemic infection (Mandal et al., 2022).

Delirium is an acute neuropsychiatric syndrome marked by fluctuating attention, disorientation, and sometimes hallucinations. It is caused by disruption of neurotransmitters, particularly acetylcholine, in response to infection, metabolic stress, or toxic insults (Campbell & Kendler, 2013; Mandal et al., 2022). In elderly patients, UTIs are among the most common culprits (Mandal et al., 2022).

With antibiotics and supportive care, Mrs. J returned to baseline in 48 hours. Her hallucinations stopped. Her fear lifted. Had she been misdiagnosed, she could have been unnecessarily institutionalized, medicated with antipsychotics, and labeled with a psychiatric illness she did not have (Mandal et al., 2022).

Conclusion: Investigating the Origin, Not Just the Outcome

Mrs. J’s case is not rare. Every day, psychiatric symptoms are misinterpreted as primary disorders when they are signs of medical, environmental, or iatrogenic distress (Campbell & Kendler, 2013; Giedd et al., 2024; Mandal et al., 2022; Vadodaria et al., 2019).

As clinicians committed to ethical, neuroscience-informed care, we must look beyond behavior and into biology. Diagnosis begins not with naming, but with understanding.

We must ask what is driving the dysfunction. We must examine what the brain is trying to tell us—not in symptoms, but in systems. That is the work of the clinician detective. That is the ethical mandate of our profession.

Key Takeaways

1. Neuroinflammation and autoimmunity are significant root causes of psychiatric symptoms, often under-recognized in clinical practice.

2. Mitochondrial dysfunction and metabolic disturbances contribute to the development and progression of psychiatric disorders.

3. Noradrenergic system imbalances can lead to symptoms such as anxiety, insomnia, irritability, and emotional instability.

4. Infectious diseases can directly cause psychiatric symptoms through mechanisms like neuroinflammation and central nervous system infection.

5. Current psychiatric diagnosis often focuses on symptoms rather than root causes, highlighting the need for causal, biologically informed approaches.

Glossary

acetylcholine: a neurotransmitter (chemical messenger) in the brain important for memory, learning, and muscle activation.

ADHD (Attention-Deficit/Hyperactivity Disorder): a neurodevelopmental disorder characterized by problems with attention, hyperactivity, and impulsiveness.

anemia: a condition in which the blood lacks enough healthy red blood cells to carry adequate oxygen to the body’s tissues.

anticholinergic: substances that block the action of acetylcholine, a neurotransmitter, which can affect memory and cognition.

anxiety: a feeling of worry, nervousness, or unease, often about an imminent event or something with an uncertain outcome.

autoimmune disease: a condition in which the immune system mistakenly attacks the body’s own tissues.

bipolar disorder: a mental health condition marked by extreme mood swings, including emotional highs (mania) and lows (depression).

cannabinoid hyperemesis syndrome (CHS): a condition caused by chronic cannabis use, leading to repeated episodes of severe nausea and vomiting.

cardiovascular disease: a group of disorders of the heart and blood vessels, such as heart attacks and strokes.

Chiari malformation: a structural defect in the base of the skull and cerebellum, part of the brain that controls balance.

chronic inflammation: long-term activation of the immune system, which can damage tissues and organs.

cognitive impairment: difficulty with thinking skills such as memory, learning, concentration, or decision making.

COMT Gene: a gene that codes for an enzyme involved in breaking down certain neurotransmitters in the brain.

concussion (mTBI, Mild Traumatic Brain Injury): a mild brain injury caused by a blow or jolt to the head, often resulting in temporary cognitive and emotional symptoms.

CRP (C-reactive Protein): a protein produced by the liver in response to inflammation.

delirium: a sudden, severe confusion and rapid changes in brain function, often caused by illness or medication.

default mode network: a network of interacting brain regions that is active when a person is not focused on the outside world, such as during daydreaming or self-reflection.

depression: a mood disorder causing persistent feelings of sadness and loss of interest.

developmental windows: critical periods during brain development when the brain is especially sensitive to environmental influences.

diphenhydramine: an antihistamine medication commonly used for allergies and as a sleep aid, known by the brand name Benadryl.

DSM-5 (Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition): the standard classification of mental disorders used by mental health professionals.

electromagnetic hypersensitivity (EHS): a reported sensitivity to electromagnetic fields, such as those from Wi-Fi or cell phones, resulting in various symptoms.

endocrine disorders: medical conditions involving the glands that produce hormones.

epigenetics: the study of changes in gene expression that do not involve alterations to the underlying DNA sequence.

executive functions: mental skills that include working memory, flexible thinking, and self-control.

folate: a B-vitamin important for cell growth and metabolism.

FOXP1/FOXP2 genes: genes involved in brain development, especially language and speech.

functional magnetic resonance imaging (fMRI): a brain imaging technique that measures brain activity by detecting changes in blood flow.

genetic polymorphism: a variation in DNA sequence among individuals.

hallucination: a perception of having seen, heard, touched, tasted, or smelled something that wasn't actually there.

homocysteine: an amino acid in the blood that, at high levels, is associated with an increased risk of cardiovascular diseases.

hyperthyroidism: a condition in which the thyroid gland produces too much thyroid hormone, affecting metabolism.

insomnia: difficulty falling or staying asleep.

Irritability: a feeling of agitation or frustration.

Klinefelter Syndrome: a genetic condition in males caused by an extra X chromosome, often associated with learning difficulties and tall stature.

limbic system: a group of brain structures involved in emotion, motivation, and memory.

malnutrition: a condition that results from eating a diet lacking in nutrients.

mania: a state of abnormally elevated mood, arousal, and energy levels.

Marfan syndrome: a genetic disorder affecting connective tissue, often resulting in tall stature and long limbs.

methylation: a chemical process that modifies DNA and affects gene expression.

methadone/suboxone: medications used to treat opioid dependence.

mitochondrial dysfunction: problems with the mitochondria, the energy-producing structures in cells, which can affect brain and body function.

mood instability: rapid and extreme changes in mood.

mycotoxins: toxic substances produced by certain types of mold.

neurodevelopmental disorders: disorders that affect brain development and function.

neuroimaging: techniques used to visualize the structure or function of the brain.

neuroinflammation: inflammation of the nervous tissue, often associated with psychiatric and neurological disorders.

neuropsychiatric: relating to disorders that have both neurological and psychiatric features.

neurotransmitter: chemicals that transmit signals across a synapse from one neuron to another.

noradrenergic system: the part of the nervous system that uses norepinephrine as a neurotransmitter, involved in arousal and stress.

Obsessive-Compulsive Disorder (OCD): a mental health disorder characterized by unwanted repetitive thoughts and behaviors.

oxidative stress: damage to cells caused by free radicals, which are unstable molecules produced during normal metabolism.

pallor: unusual paleness of the skin.

paranoia: unfounded or exaggerated distrust of others.

pesticides: chemicals used to kill pests, which can be toxic to humans.

polypharmacy: the use of multiple medications by a patient, often leading to adverse effects.

posture: how someone holds their body when standing or sitting.

prefrontal cortex: the front part of the brain involved in complex behaviors, decision making, and moderating social behavior.

psychosis: a mental disorder characterized by a disconnection from reality, often including hallucinations or delusions.

psychosocial stress: stress resulting from social interaction and life events.

refractory: resistant to treatment.

RDoC (Research Domain Criteria): a research framework for studying mental disorders based on dimensions of observable behavior and neurobiological measures.

redox balance: the balance between oxidation and reduction reactions in the body, important for cellular health.

selective serotonin reuptake inhibitors (SSRIs): a class of drugs commonly used to treat depression and anxiety by increasing serotonin levels in the brain.

short stature: height significantly below the average for age and sex.

stature: a person’s natural height.

substance use: the consumption of alcohol, drugs, or other substances that can affect mental and physical health.

systemic illness: a disease that affects the entire body, rather than a single organ or part.

thyroid dysfunction: abnormal function of the thyroid gland, which regulates metabolism.

tinnitus: the perception of noise or ringing in the ears.

Turner Syndrome: a genetic disorder affecting females, characterized by short stature and lack of ovarian development.

urinalysis: a test of urine used to detect and manage a wide range of disorders.

urosepsis: a severe infection that starts in the urinary tract and spreads to the bloodstream, causing systemic illness.

vasoconstriction: narrowing of the blood vessels, which can reduce blood flow.

vestibular disturbances: problems with balance and spatial orientation, often related to the inner ear or brain.

working memory: the ability to hold and manipulate information in the mind over short periods.

References

Giedd, J., Maxwell, B., Bala, J., Thiagarajan, T. C., & Newson, J. (2024). Leveraging big data for causal understanding in mental health: a research framework. Frontiers in Psychiatry, 15, 1331722. https://doi.org/10.3389/fpsyt.2024.1331722

Hocaoglu Cicek Erdogan, A. (2020). Psychiatric aspect of infectious diseases and pandemic: A review (tur). Journal of Clinical Psychiatry, 23(1), 1–8. https://doi.org/10.5505/kpd.2020.66944

Kendler, K. (2019). From many to one to many-the search for causes of psychiatric Illness. JAMA Psychiatry, 76(10), 1085–1091. https://doi.org/10.1001/jamapsychiatry.2019.1538

Mandal, P., Guha Roy, R., Ingole, R., Samkaria, A., Gaur, S., & Goel, A. (2022). Schizophrenia, bipolar and major depressive disorders: Overview of clinical features, neurotransmitter alterations, pharmacological interventions, and impact of oxidative stress in the disease process. ACS Chemical Neuroscience, 13(18), 2622–2637. https://doi.org/10.1021/acschemneuro.2c00397

Paolini Paoletti, F., Nigro, P., Tambasco, N., Gaetani, L., Chipi, E., Simoni, S., Menculini, G., Di Filippo, M., Parnetti, L., Tortorella, A., & Mancini, A. (2021). Insights into the pathophysiology of psychiatric symptoms in central nervous system disorders: Implications for early and differential diagnosis. International Journal of Molecular Sciences, 22(9), 4531. https://doi.org/10.3390/ijms22094531

Siow, Y.-H., Cardaci, J., Henderson, T. A., Uszler, J., Thornton, J. F., McLean, M., van Lierop, M. J., Pavel, D., & Cohen, P. (2020). Functional neuroimaging in psychiatry—Aiding in diagnosis and guiding treatment. What the American Psychiatric Association does not know. Frontiers in Psychiatry, 11, 312. https://doi.org/10.3389/fpsyt.2020.00312

Vanek, J., Nesnidal, V., Sova, M., Ociskova, M., Genzor, S., Holubová, M., Prasko, J., Kolek, A., Šlepecký, M., & Kantor, K. (2020). Obstructive sleep apnea, depression and cognitive impairment. Sleep Medicine, 70, 124–129. https://doi.org/10.1016/j.sleep.2020.03.023

Vadodaria, K., Kim, Y., Lenkei, Z., Marchetto, M. C., Kato, T., Santos, R., & Gage, F. (2019). Mitochondria, metabolism, and redox mechanisms in psychiatric disorders. Antioxidants & Redox Signaling, 31(4), 275–317. https://doi.org/10.1089/ars.2018.7606

About the Author

Fred Shaffer earned his PhD in Psychology from Oklahoma State University. He earned BCIA certifications in Biofeedback and HRV Biofeedback. Fred is an Allen Fellow and Professor of Psychology at Truman State University, where has has taught for 50 years. He is a Biological Psychologist who consults and lectures in heart rate variability biofeedback, Physiological Psychology, and Psychopharmacology. Fred helped to edit Evidence-Based Practice in Biofeedback and Neurofeedback (3rd and 4th eds.) and helped to maintain BCIA's certification programs.

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