THE TRICYCLIC SCREEN

TCA Tests and Indications for Use
To assist in the management of patients with TCA overdoses, the Toxicology Section of the YNHH Clinical Chemistry Laboratory offers a serum "Tricyclic Screen", which is also performed as part of the "Serum Overdose Panel" (both available STAT). If an intentional TCA overdose is suspected, the Serum Overdose Panel (which tests for alcohols, acetaminophen, barbiturates and salicylates, as well as TCAs) is recommended since multiple drug ingestion is common.

The Tricyclic Screen is a semi-quantitative immunoassay which yields a result which roughly corresponds to the total amount of TCAs present. Because the results are semi-quantitative, drug levels are reported as ranges. The Tricyclic Screen lacks adequate precision and specificity for therapeutic drug monitoring. For therapeutic monitoring, or when it is important to identify specific TCA components, one should order the "Tricyclic Antidepressants" test, done weekly by HPLC (cut off time Tuesday 1 PM). Because specific identification is not needed for overdose management, this test is not available on a stat basis. However, toxic levels measured by the Tricyclic Screen will be automatically confirmed with this test on the next scheduled run.

Interpreting the Results of the Tricyclic Screen
Results of the Tricyclic Screen are reported as the following ranges:

<25         ng/mL         
0-300       ng/mL         
300-500     ng/mL         
500-1000    ng/mL         
>1000       ng/mL         

Results of "<25 ng/mL" are below the detection limits of the assay; in most cases, no drug whatsoever is present. Generally, a level less than 300 ng/mL is considered therapeutic, 300-500 ng/mL is considered supratherapeutic, and a level greater than 500 ng/mL may be toxic, but there are many important exceptions. When interpreting these ranges it is useful to remember two points:

1. Drug levels correlate poorly with toxicity and recovery.
TCAs have a relatively prolonged absorption phase; it takes approximately 2-6 hours to reach peak serum levels. The TCAs also have a very large volume of distribution, so it takes several more hours for them to equilibrate with the tissues (i.e. they have very long distribution half-lives). Thus, drug levels measured shortly after an overdose may be higher or lower than the final equilibrated level, which will determine whether toxicity occurs. Furthermore, patients on TCAs may develop tolerance (tachyphylaxis) to both the desired effects and side effects of the drug. For example, a patient who has been taking imipramine for two months may have a peak serum level of 500-1000 ng/mL two hours after his normal 300 mg dose and show no signs of toxicity; a repeat measurement several hours later would indicate that he had reached his usual steady-state level of 300-500 ng/mL. Conversely, a person who has never taken imipramine may show signs of toxicity at that same 300-500 ng/mL level.

Different TCAs also react differently with the antibody used in the Tricyclic Screen (see Table). For imipramine, desipramine, amitriptyline, and nortriptyline, antibody recognition approximates 100%. But trimipramine, clomipramine, and protriptyline cross-react at approximately 50%; therefore levels of these drugs will be underestimated by two-fold. Similarly, doxepin levels will be underestimated by approximately three-fold, and maprotiline by five- to ten-fold.

Given these four features of the TCAs: prolonged absorption phase, long distribution half-life, development of tolerance, and varying cross-reactivities among the TCAs in the Tricyclic Screen, management of the patient should not be based on levels. Instead, the patient's clinical course and EKG findings should dictate management. Repeat levels are indicated to ascertain whether absorption or distribution has been completed, and to document a level less than 300 ng/mL prior to discharge (given a normal EKG for 24 hours and resolution of other symptoms). But using the Tricyclic Screen to "follow the level down" is strongly discouraged. Clinical responses, particularly the EKG findings, have much better prognostic significance.

2. Several non-TCA drugs may be detected by the Tricyclic Screen if present at high levels.
Other tricyclic drugs, including carbamazepine, cyclobenzaprine, cyproheptadine, diphenhydramine, chlorpromazine, and perphenazine, as well as other antihistamines and phenothiazines (see Table), have a low level of cross-reactivity with the antibody used in the Tricyclic Screen. Consequently, if one of these drugs is present at high enough levels, a range of 0-300 ng/mL may be reported. Therefore, one might consider toxicity from one of these other tricyclic drugs if a level of 0-300 ng/mL is reported and the patient is exhibiting signs of toxicity. Conversely, the antidepressants amoxapine, buproprion, fluoxetine, paroxetine, sertraline, and trazadone show little to no cross-reactivity in the Tricyclic Screen; therefore, even toxic levels of these drugs will be missed by this test.

Please contact the Lab Medicine Resident at 785-2444 if you have any questions regarding test selection, cross-reactivity, or the interpretation of the Tricyclic Screen as it pertains to your particular patient.

References

1. Frommer, D. A., Kulig, K.W., Marx, J.A., Rumack, B.H. (1987). Tricyclic antidepressant overdose - A review. JAMA 257, 521-526.
2. Goldfrank, L. R., Flomenbaum, N.E., Lewin, N.E., Weisman, R.S., Howland, M.A. (1990). Goldfrank's Toxicologic Emergencies. Prentice Hall, Englewood Cliffs, N.J.

Mark Velleca, M.D., Ph.D. Pete Rainey, M.D., Ph.D.