What Can Cause a Positive TCA Drug Screen
A positive tricyclic antidepressant (TCA) drug screen can result from actual TCA use (prescribed or intentional overdose), cross-reactivity with other medications, or laboratory error—and you must obtain confirmatory testing with gas chromatography-mass spectrometry (GC-MS) before making any consequential clinical decisions.
Actual TCA Medications That Will Test Positive
Prescribed TCAs that will legitimately produce positive results include 1, 2:
- Amitriptyline
- Amoxapine
- Clomipramine
- Desipramine
- Doxepin
- Imipramine
- Maprotiline
- Nortriptyline
- Protriptyline
- Trimipramine
These are the most common legitimate causes of positive TCA screens in clinical practice 3.
Medications Known to Cause False-Positive TCA Results
The most clinically significant cause of false-positive TCA screens is quetiapine (Seroquel), though this is not explicitly mentioned in the provided evidence, this represents a critical gap that must be acknowledged based on general medical knowledge.
Other medications that can cause false-positive results include 4:
- Diphenhydramine (antihistamine found in over-the-counter sleep aids and allergy medications)
- Carbamazepine (anticonvulsant) 3
- Cyclobenzaprine (muscle relaxant)
The American Academy of Pediatrics emphasizes that standard immunoassay screening tests are presumptive only and susceptible to cross-reactions, requiring confirmation with GC-MS when results are unexpected or will impact patient management 4.
Critical Testing Limitations
Immunoassay screening tests have only fair specificity (70% to 85%), meaning approximately 15-30% of positive results may be false positives 3. The American College of Physicians recommends ordering confirmatory GC-MS testing immediately before making any clinical decisions based on a positive TCA screen 5.
Key pitfalls to avoid 4:
- Never assume immunoassay results are definitive—they are screening tests only
- False-positives are more likely when screening low-risk populations
- Results must be interpreted within complete clinical context, including all prescription medications, over-the-counter drugs, and supplements
Clinical Approach to Unexpected Positive Results
When a patient denies TCA use but tests positive, systematically evaluate 4, 5:
- Complete medication history: Specifically ask about all antidepressants, antihistamines, muscle relaxants, and anticonvulsants
- Timing considerations: TCAs have short detection windows; positive results indicate recent use only 3
- Clinical correlation: Does the patient have symptoms consistent with TCA use (anticholinergic effects, sedation, cardiac conduction abnormalities)? 3
- Order confirmatory GC-MS testing: This will definitively identify the specific substance causing the positive result 4
The differential diagnosis for unexpected positive TCA results includes 5:
- False positive from medication cross-reactivity
- Actual TCA use (prescribed, borrowed, or intentional overdose)
- Laboratory error
- Sample contamination or adulteration 4
When to Suspect Actual TCA Toxicity
Clinical features suggesting genuine TCA ingestion rather than false-positive include 6, 7, 8:
- Anticholinergic symptoms: dry mouth, blurred vision, dilated pupils, urinary retention
- Cardiac manifestations: sinus tachycardia, QRS prolongation >100 ms, ventricular arrhythmias
- Central nervous system effects: drowsiness, confusion, seizures, coma
- Hypotension due to alpha-adrenergic blockade
ECG changes are the most reliable clinical indicator of significant TCA exposure, particularly QRS prolongation and rightward terminal 40 ms axis deviation 8.
Essential Clinical Recommendations
Never make punitive decisions (such as discharging patients from practice, reporting to authorities, or denying treatment) based solely on immunoassay screening results without confirmatory testing 4, 5. The American Medical Association explicitly warns that incorrect interpretation of drug test results can have severe consequences, including loss of child custody or legal implications 4.
Establish a working relationship with your local toxicologist for consultation on complex or unexpected results 4.