LETTERS Spurious tricyclic levels To the Editor: I wish to draw the attention of your readers to a serious problem in the use of tricyclic antidepressant (TCA) assays: the fact that collection ofspecimens in Vacutainer tubes produces a spurious drop in plasma TCA levels due to the tris phosphate plasticizer in their stoppers. Although this problem has been clearly documented,I.) it still is not widely appreciated by practitioners and clinical laboratories. .In a telephone survey of 15 general hospitals in the San Francisco area (including ten teaching centers, seven of them university affiliated), I found that 13 of these facilities were employing Vacutainers instead of Venojects (which are accurate). Of the five commercial laboratories that perform the TCA assays for these hospitals, two requested specimens in Vacutainers, one suggested but did not require Venojects, while the remaining two required the latter. Despite the fact that five hospitals used the laboratories that suggest or require Venoject tubes, three of these still used Vacutainers. Thus only two of the 15 hospitals queried were correctly handling their specimens. In view of the significant variability in plasma levels obtained with Vacutainers, it is likely that several hundred patients in this geographic area have unjustifiably been given excessive tricyclic doses, resulting in an unknown but probably significant number of toxic reactions. I assume that this problem is not confined to San Francisco.
A second implication of this situation is that the currently suggested therapeutic ranges for plasma TCA levels may be inaccurate. These are acknowledged to be approximate at best and the studies generating them inconsistent. The reason may well include erroneous collection procedures. Many of the relevant studies were carried out before this source of variability was reported in 1977, and many of the subsequent studies may have failed to take it into account. In randomly reviewing 20 studies of TCA levels and clinical response, I found that all 20 failed to specify what type of specimen tubes were employed. Therefore it would seem that the entire body of research on this important subject falls under a thick cloud of suspicion, and that many if not all of the therapeutic ranges so generated may be unreliable. If the above information fails to convince your readers of the magnitude of this problem, I would suggest that they submit split samples on a few of their patients on TCAs. I suspect that they will find the result of this experiment as persuasive as I did. Robert S. Hoffman, M.D. St. Mary's Medical Center San Francisco REFERENCES 1 Brunswick OJ. Mendels J: Reduced levels ot tricyClic antidepressants In plasma with Vacuo tainers Commun Psychopharm 1 131· t 34. 1977. 2 Borga O. Piafsky KM. Nilsen OG Plasma pro· tein binding of basic drugs: I. selective dis· placement from alpha·acid glycoprotein by Ins (2-butoxyethyl) phosphate. Clin Pharmacol Ther 22:539·544. 1977 3. Veith RC. Raisys VA. Perera C: The clinical impact of blood collection methods on tricyclic antidepressants as measured by GC/MS-SIM Commun Psychopharmaco/2:491·494. 1978
Dr. Hoffman is quite correct that there is a significant difference in the tricyclic antidepressant values obtained on blood samples collected in Vacutainer versus Venoject tubes. I also share his concern about the less-than-rigorous approach that many commercial and hospital laboratories utilize regarding this problem and the possible consequences thereof. Finally, it is also true that the vast majority of articles published in this field do not clearly specify the method of sample collection, thereby making firm interpretation of the data difficult at best. Most researchers have been aware of this problem since 1977 and, to the best of my knowledge, have taken the appropriate corrective measures in sample handling. Therefore, the growing body of information of this type will determine to what degree previously collected data are valid. I believe the more important concerns at this time are first, that clinical samples will not be collected properly as mentioned by Dr. Hoffman, and second, that the commercial and hospital laboratories that are offering these assays for clinical use hilVe not always adequately validated their techniques and may be reporting erroneous data. Consequently, it is up to the practicing physician to ensure that sample collection is handled properly and also that the validity and reliability of the assay procedures utilized are acceptable. Robert O. Friedel, M.D. Medical College of Virginia PSYCHOSOMATICS