Medications Causing False-Positive TCA Results
The most clinically important medications that cause false-positive tricyclic antidepressant (TCA) results on immunoassay screening are carbamazepine, cyclobenzaprine, diphenhydramine, certain antipsychotic medications, and other antihistamines—all of which require confirmatory testing with gas chromatography-mass spectrometry (GC-MS) before making any clinical decisions. 1
Primary Offending Medications
Anticonvulsants
- Carbamazepine is the most well-documented cause of false-positive TCA screens, with dose-dependent interference particularly at therapeutic levels of 8.0-11.6 mg/L (12 of 13 patients showed positive results at these levels) 2
- The cross-reactivity occurs because carbamazepine shares a three-ringed chemical structure similar to TCAs 1
- Oxcarbazepine shows minimal cross-reactivity (0.7 µg/L TCA detected per mg/L oxcarbazepine) compared to carbamazepine (4.2 µg/L TCA detected per µg/L carbamazepine) and rarely causes false positives 2
Antihistamines
- Diphenhydramine causes false-positive TCA results on urine immunoassays, which is particularly problematic because diphenhydramine intoxication mimics TCA toxicity clinically (altered mental status, tachycardia, mydriasis) 3
- Other antihistamines with similar structures can also cross-react 1
Muscle Relaxants
- Cyclobenzaprine commonly triggers false positives, with the Biosite Triage assay being particularly susceptible to this interference 1, 4
Antipsychotic Medications
- Certain antipsychotic medications cause false-positive results, though specific agents are not detailed in the highest-quality evidence 1
Critical Clinical Approach
When You Encounter a Positive TCA Screen:
Obtain complete medication history including all prescription medications, over-the-counter drugs (especially cold medications and sleep aids), and supplements before interpreting results 5
Order confirmatory GC-MS testing immediately before making any clinical decisions—immunoassay screening tests are presumptive only and have known specificity limitations due to cross-reactivity 5, 6
Never make punitive decisions (discharging patients from practice, reporting to authorities) based solely on immunoassay results without confirmation 6, 7
Assay-Specific Limitations:
- Serum fluorescence-polarized immunoassay shows linear dose-dependent interference with carbamazepine levels 2
- Urine enzyme-linked immunoassay has minimal interference from carbamazepine or oxcarbazepine 2
- Neither the Syva Rapid Test nor Biosite Triage reliably detects clomipramine, even at supratherapeutic levels 4
Key Clinical Pitfalls to Avoid
- Do not assume positive TCA screens represent actual TCA use or overdose without confirmatory testing, especially in patients taking the medications listed above 1
- Recognize that urine immunoassays cannot distinguish between subtherapeutic, therapeutic, or toxic serum concentrations—positive urine results must be interpreted with clinical findings and quantitative serum levels 4
- Be aware that false positives are more likely when screening tests are used in patients without clinical findings suggesting TCA toxicity 6
- Understand your specific laboratory's testing methodology, as different immunoassay platforms have varying susceptibilities to cross-reactivity 2, 4
When to Suspect True TCA Toxicity vs. False Positive
Suspect false positive when:
- Patient is taking carbamazepine (especially at levels >8 mg/L), cyclobenzaprine, diphenhydramine, or certain antipsychotics 1, 2
- Clinical presentation does not match TCA toxicity (QRS widening, anticholinergic syndrome, seizures, cardiac arrhythmias) 3
- Patient denies TCA use and has plausible alternative medication explanation 6