Psychiatric Presentations of Medical & Substance-Induced Illness
Before calling it psychiatric, rule out the body and the medicine cabinet
Red flags for a medical or substance cause
Why it matters. Psychiatric symptoms are often the first sign of endocrine, neurologic, infectious, autoimmune, or toxic disease. Labeling them primary psychiatric illness without a search delays treatment of conditions that are frequently reversible and sometimes fatal.
- First onset after age 40 with no psychiatric history
- Abrupt onset, or a new medication or substance shortly before
- Abnormal vital signs such as fever, tachycardia, or hypertension
- Fluctuating attention or consciousness, disorientation, or cognitive decline
- Visual, olfactory, gustatory, or tactile hallucinations
- Focal neurologic signs, headache, seizures, or recent head trauma
- Poor response to standard psychiatric treatment
| Modality | Suggests |
|---|---|
| Auditory | Primary psychotic or mood disorder: schizophrenia, mania, psychotic depression |
| Visual | Delirium, intoxication, Lewy body or Parkinson disease, occipital lesions, severe vision loss (Charles Bonnet syndrome, with insight preserved) |
| Olfactory or gustatory | Temporal lobe seizures or tumors |
| Tactile (formication) | Cocaine or amphetamines, alcohol withdrawal |
Delirium versus primary psychosis. Delirium develops over hours to days with fluctuating attention and consciousness, disorientation, visual hallucinations, and sleep-wake reversal. It is a medical emergency caused by infection, drugs (especially anticholinergics, sedatives, and opioids), metabolic disturbance, or withdrawal. Primary psychosis has a clear sensorium, intact orientation, and mainly auditory hallucinations. The EEG in delirium shows diffuse slowing, or fast activity in alcohol or benzodiazepine withdrawal; in schizophrenia it is normal.
Anxiety and depression mimics
| Condition | Psychiatric picture | Clues | Key test |
|---|---|---|---|
| Hyperthyroidism | Anxiety, insomnia, irritability | Tremor, heat intolerance, weight loss, tachycardia or AF | TSH (low) |
| Hypothyroidism | Depression, slowed thinking | Fatigue, weight gain, cold intolerance, constipation | TSH (high) |
| Pheochromocytoma | Panic-like spells, sense of doom | Headache, sweating, palpitations, tremor; severe paroxysmal or sustained hypertension | Plasma free or 24-hour urine fractionated metanephrines |
| Hypoglycemia | Anxiety, confusion | Sweating, tremor, hunger; insulin, sulfonylureas, insulinoma | Glucose during symptoms |
| Arrhythmia | Episodic panic | Palpitations from SVT or atrial fibrillation | ECG; ambulatory monitoring |
| Cushing syndrome | Depression, irritability, insomnia, cognitive complaints | Central obesity, striae, hypertension, hyperglycemia, hypokalemia | Late-night salivary cortisol or 1-mg dexamethasone test |
| Addison disease | Apathy, fatigue, depression | Weight loss, hyperpigmentation, hypotension, hyponatremia, hyperkalemia | Morning cortisol and ACTH; cosyntropin test |
| Pancreatic cancer | Depression preceding diagnosis | Age >50, weight loss, epigastric or back pain, new diabetes, painless jaundice | Pancreatic-protocol CT |
| B12 deficiency | Depression, irritability, cognitive decline, psychosis | Lost vibration and position sense, ataxia; anemia may be absent | B12; methylmalonic acid |
Thyroid. Check TSH in every new anxiety or depression workup. Older adults may have apathetic hyperthyroidism: depression, weight loss, and atrial fibrillation without hyperactivity.
Catching the spell. For episodic symptoms, obtain a fingerstick glucose and an ECG during the episode and use ambulatory ECG monitoring for intermittent palpitations. The Whipple triad confirms hypoglycemia: symptoms, a documented low glucose, and relief when glucose is raised. Pheochromocytoma is confirmed biochemically before any imaging; urine 5-HIAA is the test for carcinoid, which causes flushing and diarrhea rather than hypertension.
Depression with physical disease. Pancreatic cancer can present with depression months before physical signs, so first-episode depression after 50 with weight loss, pain, new-onset diabetes, or jaundice calls for imaging, not just an antidepressant. B12 deficiency adds subacute combined degeneration (loss of vibration and position sense, ataxia, spasticity); methylmalonic acid confirms a borderline level (homocysteine also rises in folate deficiency), and risks include pernicious anemia, metformin, PPIs, and vegan diets. Hypercalcemia and interferon-α therapy are other classic causes of depression.
Neurologic disease. About one-third of stroke survivors develop depression, which slows rehabilitation and responds to SSRIs. Depression is also common in Parkinson disease, multiple sclerosis, and Huntington disease, sometimes before motor signs. Apathy after frontal injury resembles depression but lacks sadness, and pseudobulbar affect (sudden crying or laughing out of proportion to mood after stroke, ALS, or MS) is treated with dextromethorphan-quinidine.
Medication- and substance-induced syndromes
Corticosteroids. Euphoria, insomnia, mania, or psychosis are dose-related, usually begin within the first 2 weeks, and are more common above 40 mg/day of prednisone; depression is more typical with long-term use or withdrawal. Lower or stop the steroid if possible; otherwise add an antipsychotic or mood stabilizer.
Dopaminergic drugs. Levodopa and dopamine agonists cause visual hallucinations, paranoia, and impulse-control disorders such as gambling or hypersexuality. In Parkinson disease, first exclude infection and metabolic causes, then reduce anticholinergics and dopamine agonists before levodopa. If psychosis persists, use pimavanserin, quetiapine, or clozapine; potent D2 blockers such as haloperidol worsen parkinsonism.
Other culprits. Stimulants (amphetamines, methylphenidate, cocaine) cause paranoid psychosis or mania; isoniazid can cause psychosis; efavirenz causes vivid dreams, depression, or psychosis; and anticholinergic drugs cause delirium, especially in older adults.
Substance-induced or independent? A substance- or medication-induced disorder requires symptoms that arise during or soon after intoxication, withdrawal, or drug exposure, a substance capable of causing them, and resolution within about 1 month of abstinence. Symptoms that began before use, persist beyond a month of abstinence, or recur without substances indicate an independent disorder.
Psychosis that persists well beyond a month of verified abstinence should be reclassified as an independent psychotic disorder, such as schizophreniform disorder if the total duration is 1–6 months.
Psychosis and personality change from systemic and brain disease
| Condition | Clues | Diagnosis and treatment |
|---|---|---|
| Anti-NMDAR encephalitis | Young woman; rapidly progressive psychosis, then seizures, dyskinesias, catatonia, dysautonomia | CSF antibodies; search for ovarian teratoma; tumor removal and immunotherapy |
| HIV | Psychosis, depression, cognitive decline from the virus, opportunistic infections, or drugs such as efavirenz | HIV test in every first psychosis |
| Neurosyphilis | General paresis: personality change, grandiosity, psychosis, dementia; Argyll Robertson pupils | Serum RPR plus treponemal test, then CSF VDRL; IV penicillin G |
| Neuropsychiatric lupus | Psychosis, depression, seizures, or cognitive change with systemic features | Lupus serologies; steroid-induced psychosis is the key differential |
| Wilson disease | Typically under 40; personality change, mood swings, psychosis plus liver disease, tremor, dystonia, dysarthria | Low ceruloplasmin, high 24-hour urine copper, Kayser-Fleischer rings; penicillamine, trientine, or zinc |
| Acute intermittent porphyria | Abdominal pain with benign exam, tachycardia, hypertension, motor neuropathy, hyponatremia, anxiety or psychosis, dark urine | Urine porphobilinogen during an attack; hemin and IV glucose |
| Temporal lobe epilepsy | Olfactory or gustatory auras, déjà vu, fear, lip-smacking automatisms; postictal or interictal psychosis | EEG and MRI |
| Frontal tumor | Gradual personality change, disinhibition or apathy, poor judgment, sometimes anosmia (meningioma) | Brain MRI |
Genetics and triggers. Wilson disease is autosomal recessive copper accumulation from ATP7B mutations. Acute intermittent porphyria is autosomal dominant porphobilinogen deaminase deficiency; attacks are triggered by barbiturates and other CYP inducers, alcohol, fasting, and progesterone, and the urine darkens on standing.
Bedside clues. Argyll Robertson pupils constrict to accommodation but not to light. Interictal personality change in temporal lobe epilepsy (Geschwind syndrome) includes hypergraphia, hyperreligiosity, altered sexuality, and "sticky" conversation.
Workup of a first psychotic episode
- History and examinationTimeline, medications and substances, family history, vital signs, cognitive screen, and neurologic examination for red flags.
- Core panel for everyoneCBC, CMP (electrolytes, calcium, renal and liver function), glucose, TSH, B12 and folate, RPR, HIV, urine drug screen, and a pregnancy test.
- MRI brainFocal neurologic signs, older age at onset, cognitive decline, or other atypical features.
- EEGFluctuating consciousness or seizure-like episodes.
- Lumbar punctureFever, meningismus, or suspected encephalitis, including anti-NMDAR antibodies.
Targeted tests. Add ceruloplasmin for a young patient with liver or movement abnormalities, urine porphobilinogen for abdominal pain with neuropathy or hyponatremia, and lupus serologies for systemic features. Neuroimaging is most useful when red flags are present; with a normal examination its yield is low.