- Email: [email protected]
Potential Vascular and Bleeding Complications of Treatment With Selective Serotonin Reuptake Inhibitors
Rogers et al.
heterogeneity of Briquet's syndrome (and hence of somatization disorder).28 Researchers working in the field need to refine their definitions of many of the somatoform syndromes by using more rigorous and conservative criteria such as the abridged Escobar criteria for "somatization syndrome.,,29 The associations or lack thereof between specific anxiety and somatoform disorders may actually reflect definitional problems as much as small sample size or possible rater bias. Researchers need to continue to focus on the prevalence of somatoform disorders by using more rigorous criteria and revised definitions. This will allow for an increasingly valid and sophisticated understanding of the important field of somatoform disorders and its overlap with anxiety disorders.
This work was supported by the Upjohn Company. the Harvard/Brown Anxiety Disorders Research program is conducted with the participation of the following investigators: M.B. Keller. M.D. (chairperson); P.M. Lavori. Ph.D. (co-chairperson); H. Samuelson. M. Warshaw. M.S.S .. M.A. (Brown University); E. Fierman. M.D .. F. Rodriguez-Villa. M.D.(Beth Israel Hospital. Harvard Medical Schoo/); M. Rogers. M.D. (Brigham and Women' s Hospital. Harvard Medical School); R. Goisman. M.D.
(formerly Brighton-Allston Mental Health Clinic. presently Massachusetts Mental Health Center. Harvard Medical School); P. Alexander. M.D .. A. Gordon. M.D. (Butler Hospital. Brown Medical Schoo/); J. Ellison. M.D .. J.C. Perry. M.D. (Cambridge Hospital. Harvard Medical School); R. Vasile. M.D. (New England Deaconess Hospital. Harvard Medical Schoo/); J. Reich. M.D. (Massachusetts Mental Health Center. Harvard Medical Schoo/); A. Vukovic. M.D .. K. Yonkers. M.D. (McLean Hospital. Harvard Medical Schoo/); J. Rice. Ph.D. (Renard Hospital. Washington University School of Medicine. St. Louis); K. White. M.D. (Rhode Island Hospital. Brown Medial School); A.a. Massion. M.D .. L. Peterson. M.D. (University 0/ Massachusetts Medical School); J. Curran. M.D. (Veterans Administration Hospital. Providence. Brown Medical Schoo/); Addition contributions from R. M. A. Hirschfeld. M.D. (University o/Texas. Galveston); J. Hooley. D. Phil. (Harvard University); G. Steketee. Ph.D. (Boston University School ofSocial Work); and M. Weissman. Ph.D. (Columbia University). The Quintiles Corporation provided valuable consultation services to this project. This publication was reviewed by the HARP Publication Committee.
References I. Kaplan C. Lipkin M. Jr., Gordon GH: Somatization in primary care: patients with unexplained and vexing medical complaints. J Gen Intern Med 1988; 3:177-190 2. Swartz M, Landerman R, George LK, et al: Somatization disorder, in Psychiatric Disorders in America, edited by Robins LN, Regier D. New York, Free Press, 1990 3. Kirmayer U. Robbins JM: Three fonns of somatization in primary care: prevalence, co-occurrence. and sociodemographic characteristics. J Nerv Ment Dis 1991; 179:647-655 4. Barsky AJ, Wyshak G. Klerman GL, el al: The prevalence of hypochondriasis in medical outpatients. Soc Psychiatry Psychiatr Epidemiol 1990; 25:89-94 5. Stefansson JG, Messina JA, Meyerowitz S: Hysterical neurosis, conversion type: clinical and epidemiological considerations. Acta Psychiatr Scand 1976; 53: 119-139 6. Ford CV: The Somatizing Disorders: Illness as a Way of Life. New York, Elsevier Biomedical, 1984 7. Simon GE. Von Korff M: Somatization and psychiatric
VOLUME 37. NUMBER I. JANUARY - FEBRUARY 1996
disorder in the NIMH Epidemiologic Catchment Area Study. Am J Psychiatry 1991; 148: 1494-1500 8. Lepine JP. Pariente P, Boulenger JP. et al: Anxiety disorders in a French general psychiatric outpatient sample: comparison between DSM-II and DSM-III-R criteria. Soc Psychiatry Psychiatr Epidemiol 1989; 124:301-308
9. Noyes R. Reich J. Clancy J. et al: Reduction in hypochondriasis with treatment of panic disorder. Br J Psychiatry 1986; 149:6631-6635 10. Barsky AJ. Wyshak G. Klerman GL: Psychiatric comorbidity in DSM-III-R hypochondriasis. Arch Gen Psychiatry 1992; 49: 101-108 II. Tomasson K, Kent D. Coryell W: Somatization and conversion disorders: comorbidity and demographics at presentation. Acta Psychiatr Scand 1991; 84:288-293 12. Orenstein H: Briquet's syndrome in association with depression and panic: a reconceptualization of Briquet's syndrome. Am J Psychiatry 1989; 146:334-338
21
Prevalence of Somatofonn Disorders
13. Torgensen S: Genetics of somatoform disorders. Arch Gen Psychiatry 1986; 43:502-505 14. Rief W. Schaefer S. Hiller W. et al: Lifetime diagnoses in patients with somatoform disorders: which came first? European Archives of Psychiatry and Clinical Neuroscience 1992; 241 :236-240 15. Swanz M. Blazer D. George L. et al: Somatization disorder in a community population. Am J Psychiatry 1986; 143: 1403-1408 16. Hogarty G (original developer). Larkin BH. Hirschfeld RMA (added later revisions) (1980): Personal History of Depressive Disorders (PHDD). Available from Dr. Hirschfeld at Univesity of Texas Medical Branch. Department of Psychiatry. Galveston. TX 77550 17. Myers JK. Yale Greater New Haven Health Survey (modified for use in HARP): Available from Dr. Myers at Yale University. New Haven. CT 06509-1905 18. Spitzer RL. Williams JBW. Gibbon M. et al: Structured Clinical Interview for DSM-III-R Patient Version (SCID-P). New York. New York State Psychiatric Institute. Biometrics Research Department. 1988 19. Endicott J. Spitzer RKL: A diagnostic interview: the schedule for affective disorders and schizophrenia (SADS-L). Arch Gen Psychiatry 1978; 35:837-844 20. Keller MB. Lavori PW. Nielsen E: SCALUP Diagnostic Interview 1990. Available from Dr. Keller at Butler Hospital. 345 Blackstone Boulevard. Providence. RI. 02906 21. Schefmer W. Endicott J: (1984) Medical History Form II. Revised from Scheftner W. Endicotl J. Clayton P. et al. Medical History Form. 1979. Available from Dr.
22
Scheftner at Rush Medical Center. 1753 West Congress Parkway. Chicago. IL 60612 22. Keller MB. Lavori PW. Friedman B. et al: The longitudinal interval follow-up evaluation: a comprehensive method for assessing outcome in prospective longitudinal studies. Arch Gen Psychiatry 1987; 44:5~548 23. Endicott J. Spitzer RL. Fleiss JL. et al: The Global Assessment Scale: a procedure for measuring overall severity of psychiatric disturbances. Arch Gen Psychiatry 1976; 33:766-771 24. Simon GE. VonKorff M: Letter to the editor-reply. Am J Psychiatry 1992; 149:1282 25. Fierman EJ. Hunt MF. Pratt LA. et al: Trauma and posttraumatic stress disorder in subjects with anxiety disorders. Am J Psychiatry 1993; 150: 1972-1974 26. Davidson JRT. Hughes D. Blazer DO. et al: Posttraumatic stress disorder in the community: an epidemiological study. Psychol Med 1991; 21:713-717 27. Warshaw MG. Fierman EJ. Pratt LA. et al: Quality of life and dissociation in anxiety disorder patients with histories of trauma or PTSD. Am J Psychiatry 1993; 150:1512-1516 28. Liskow B. Othmer E. Penick EC. et al: Is Briquet's syndrome a heterogeneous disorder? Am J Psychiatry 1986; 143:626-629 29. Escobar 11. Rubio-Stipec M. Canino G. et al: Somatic Symptom Index (SSI). a new and abridged somatization construct: prevalence and epidemiological correlates in two large community samples. J Nerv Ment Dis 1989; 177:140--146
PSYCHOSOMATICS
Fluoxetine and Cyclosporine in Organ Transplantation Failure to Detect Significant Drug Interactions or Adverse Clinical Events in Depressed Organ Recipients THOMAS
B.
CHRISTINE
STROUSE, M.D., LYNN
E.
A.
FAIRBANKS, PH.D.
SKOTZKO, M.D., FAWZY
I. FAWZY,
M.D.
Depression and anxiety disorders are common clinical problems in organ transplant recipients. but there is a paucity of clinical data to inform the selection of psychopharmacologic treatment. The authors retrospectively compared 13 depressed organ transplant recipients treated with j7uoxetine with 13 nondepressed matched control recipients and II transplant recipients treated with tricyclic antidepressants (nortriptyline or desipramine). Blood level:dose ratios and dose-response relationships for cyclosporine were virtually identical in all three groups before and during treatment. No increase in adverse clinical events was detected in either active treatment group compared with the control subjects. Fluoxetine appeared to be well tolerated by this population oftransplant patients, and the authors failed to detect significant alterations in cyclosporine levels or graft function. (Psychosomatics 1996; 37:23-30)
T
he arrival of cyclosporine in the late 1970s heralded a new era in organ transplantation. With extended patient survival, however, the high incidence of new and recurrent mood and anxiety disorders in transplant recipients was recognized. '-3 Although organ transplantation psychiatry has evolved at a rapid pace,4 the field has produced little data to inform such basic clinical decisions as the psychopharmacologic approach to the treatment of major depression in transplant recipients. s Instead, clinical decision making has been driven primarily by considerations of the pharmacokinetics and side-effect profiles of the standard pharmacopeia in persons with end-organ failure or recently grafted transplants. (HI Fluoxetine, and more recently sertraline and paroxetine, offer appealing alternatives to VOLUME 37. NUMBER I • JANUARY - FEBRUARY \996
conventional antidepressant agents in the treatment of depression in transplant patients. FIuoxetine's minimal affinity for muscarinic, dopaminergic, histaminergic, and alpha-adrenergic receptors 9•IO is associated with few anticholinergic, sedative, and autonomic side effects. The activation experienced by many who take fluoxetine can be helpful to anergic, withdrawn medical patients. Recognition of fluoxetine's potent proteinReceived October 7. 1993; revised December 14. 1993; accepted February 9. 1994. From the University of California at Los Angeles (UCLA). Depanment of Psychiatry and Biobehavioral Sciences. UCLA School of Medicine. Address reprint requests to Dr. Strouse. Chief. ConsultationLiaison Psychiatry Service. UCLA Neuropsychiatric Institute. 7W Westwood Plaza. Los Angeles. CA 90024. Copyright © 1996 The Academy of Psychosomatic Medicine.
23
Fluoxetine and Cyclosporine in Organ Transplantation
binding and hepatic microsomal enzyme-inhibiting effects, however, has prompted concern about drug interactions ' 1.l 2 and wariness about fluoxetine's safety in patients with complex medical regimens. In particular, fluoxetine's capacity to alter serum levels of cyclosporine has been proposed; potential effects on immune suppression and graft function are hypothesized. 6.s Nonetheless, no case reports or formal studies appear in the literature to describe these effects. At our large-volume, multi-organ transplant center, we frequently encounter organ recipients who require antidepressant pharmacotherapy and who do not tolerate trials of conventional antidepressants. We often choose fluoxetine, and our failure to observe the theoretical problems proposed earlier led to this retrospective review of our experience over 20 years (1990--1993). We compared blood cyclosporine levels, medical courses, and various measures of organ function in fluoxetine-treated, tricyclic-treated, and nondepressed control transplant recipients. METHODS Sampling Procedures With authorization from the University of California at Los Angeles (UCLA) Human Subjects Protection Committee, computer reviews of pharmacy records were done for all patients treated at UCLA Medical Center between January 1990 and January 1993. A linked search identified the medical record numbers of inpatients and outpatients who were simultaneously treated with fluoxetine and cyclosporine during this 3-year period. A control group of nondepressed, nonfl uoxetine-treated patients was matched to the index group by age, organ type, and month of transplant. A comparison group of tricyclic antidepressant-treated (either nortriptyline or desipramine) transplant patients was selected by the same computer method. For each patient, the start date of antidepressant pharmacotherapy (D = 0) was identified. (For matched control patients, D 0 equaled D =0 for the fluoxetine index patients.)
=
24
The following data were then compiled for each patient 30, 15, and 7 days before D = 0 and 7, 15, 30, 45, 60, 75, and 90 days after D = 0: I) cyclosporine high-performance liquid chromatography (HPLC) and radioimmunoassay (RIA) blood levels (reviews of these techniques and their uses are available in references 13-16); 2)y20cyclosporine dosing (total daily dose in mgs and route); 3) blood urea nitrogen/creatinine; 4) bilirubin total and direct; 5) albumin; 6) serum glutamate oxaloacetate transaminase (SGOT) and serum glutamate pyruvate transaminase (SGPT); 7) a complete list of other medications being taken at each date; and 8) a complete listing of medical events and diagnoses, such as hospital admissions, suspected or confirmed episodes of rejection, graft or organ dysfunction, new- onset syndromes or illnesses, and antidepressant medication side effects. Many transplant centers record both HPLC and RIA cyclosporine levels. HPLC levels are more reliable than RIA because the HPLC technique provides a highly accurate measure ofthe cyclosporine parent compound in blood. Particularly in the setting of acute organ dysfunction, where cyclosporine metabolites are likely present, the anti-serum in the RIA cross-reacts with these metabolites and can produce RIA: HPLC ratios of up to 15: 1. 13- 16 The immunosuppressive activity of cyclosporine metabolites is poorly understood. We expected that a better correlation would be found between dose and HPLC values (compared with dose and RIA values) for all patient groups at all phases ofthe study. The I-month period before initiation of antidepressant therapy was chosen to provide adequate numbers of data points for calculation of "baseline" dose-response relationships to cyc1osporine and to evaluate pretreatment trends in organ functioning. The 90-day follow-up period was chosen because of the extended elimination half-life in normals of fluoxetine and norfluoxetine (4 and 7-9 days, respectively);I? some hepatic dysfunction was expected in the liver recipients posttransplant, and fluoxetine/norfluoxetine half-lives are increased twoto threefold in patients with liver disease. IS PSYCHOSOMATICS
Strouse et al.
Subjects The initial computer review supplied 15 f1uoxetine-/cyclosporine-treated patients, and II tricyclic-/cyclosporine-treated patients. One of the f1uoxetine-treated patients had not received an organ transplant and was eliminated from the analysis. A second f1uoxetine-treated patient was eliminated because of noncompliance with medical follow-up. Final data analysis was done on 13 f1uoxetine-treated, II tricyclic-treated, and 13 matched-to-f1uoxetine control subjects. The f1uoxetine-treated group was composed of 9 liver recipients and 4 heart recipients. Their posttransplant mean status was 10.8 months, range I-50 months, and median 24 months; by study design, this group composition was replicated in the matched control subjects. The tricyclic group contained only liver recipients; our transplant cardiologists avoid treating heart recipients with tricyclic antidepressants. 6 The liver recipients' mean posttransplant status was 6 months, range 2 weeks to 24 months, and median 12 months. The fluoxetine-treated patients took 5-20 mgs daily; of the 13 in the group, 10 took 20 mgs daily, 2 took 10 mgs daily, and I took 5 mgs daily. The lower doses reflect careful use of f1uoxetine in patients with hepatic dysfunction at baseline. F1uoxetine and norfluoxetine blood levels were not collected. The tricyclic-treated patients took daily doses of 50--100 mgs of nortriptyline or 100--200 mgs of desipramine. All patients reported regular compliance with the daily dosing regimens of their antidepressants. Serum tricyclic levels were obtained in some but not all patients and are not reported. RESULTS Cyclosporine-HPLC Levels by Treatment Group If fluoxetine affects cyclosporine levels, we would expect cyclosporine levels to change after the start of f1uoxetine treatment. Figure I shows the individual cyclosporine HPLC blood VOLUME 37. NUMBER I • JANUARY - FEBRUARY 1996
FIGURE t.
Individual cyclosporine:highperformance liquid chromatography (HPLC) dose ratios for nuoxetine, tricyclic, and matched control patients at each study date before and during treatment
8q1e....
3.0,.-----'---~-----------,
•
2.'
• FI"oxetine Trtcyclic
o
o
2.0
•
~30
-15
Con~
0
-7
level:dose ratios by treatment day in the fluoxetine, tricyclic, and matched control patients. Before the start of antidepressant therapy, the mean ± SD blood level:dose ratios were virtually identical between the three groups (fluoxetine: 0.44 ± 0.08, tricyclic: 0.40 ± 0.06, control: 0.44 ± 0.06), but there was more variability in the individual values of the f1uoxetine-treated patients. In Figure I, there are five outlying points in the fluoxetine pretreatment phase, representing HPLC:dose ratios for three patients, all of whom were liver recipients and whose notable clinical characteristics included pretreatment elevations in bilirubin and transaminases, and serum albumins of less than 3. Because of their baseline hepatic dysfunction, fluoxetine dosing was reduced in these patients: one received 5 mgs daily, and the other two 10 mgs daily. In the first treatment month, one of these three fluoxetine-treated patients (who had received 5 mgs daily) was discontinued on cyc1osporine because of reactivation of a previous hepatitis B condition and chronic renal failure, thus making additional HPLC:dose ratio data unavailable. The other two, represented by three data points, in addition to one tricyclic-treated patient (who had moderate baseline ratio elevation), showed HPLC:dose ratios above 1.0. With no change in fluoxetine or tricyclic dosing, cyclosporine HPLC:dose ratios for these pa25
heterogeneity of Briquet's syndrome (and hence of somatization disorder).28 Researchers working in the field need to refine their definitions of many of the somatoform syndromes by using more rigorous and conservative criteria such as the abridged Escobar criteria for "somatization syndrome.,,29 The associations or lack thereof between specific anxiety and somatoform disorders may actually reflect definitional problems as much as small sample size or possible rater bias. Researchers need to continue to focus on the prevalence of somatoform disorders by using more rigorous criteria and revised definitions. This will allow for an increasingly valid and sophisticated understanding of the important field of somatoform disorders and its overlap with anxiety disorders.
This work was supported by the Upjohn Company. the Harvard/Brown Anxiety Disorders Research program is conducted with the participation of the following investigators: M.B. Keller. M.D. (chairperson); P.M. Lavori. Ph.D. (co-chairperson); H. Samuelson. M. Warshaw. M.S.S .. M.A. (Brown University); E. Fierman. M.D .. F. Rodriguez-Villa. M.D.(Beth Israel Hospital. Harvard Medical Schoo/); M. Rogers. M.D. (Brigham and Women' s Hospital. Harvard Medical School); R. Goisman. M.D.
(formerly Brighton-Allston Mental Health Clinic. presently Massachusetts Mental Health Center. Harvard Medical School); P. Alexander. M.D .. A. Gordon. M.D. (Butler Hospital. Brown Medical Schoo/); J. Ellison. M.D .. J.C. Perry. M.D. (Cambridge Hospital. Harvard Medical School); R. Vasile. M.D. (New England Deaconess Hospital. Harvard Medical Schoo/); J. Reich. M.D. (Massachusetts Mental Health Center. Harvard Medical Schoo/); A. Vukovic. M.D .. K. Yonkers. M.D. (McLean Hospital. Harvard Medical Schoo/); J. Rice. Ph.D. (Renard Hospital. Washington University School of Medicine. St. Louis); K. White. M.D. (Rhode Island Hospital. Brown Medial School); A.a. Massion. M.D .. L. Peterson. M.D. (University 0/ Massachusetts Medical School); J. Curran. M.D. (Veterans Administration Hospital. Providence. Brown Medical Schoo/); Addition contributions from R. M. A. Hirschfeld. M.D. (University o/Texas. Galveston); J. Hooley. D. Phil. (Harvard University); G. Steketee. Ph.D. (Boston University School ofSocial Work); and M. Weissman. Ph.D. (Columbia University). The Quintiles Corporation provided valuable consultation services to this project. This publication was reviewed by the HARP Publication Committee.
References I. Kaplan C. Lipkin M. Jr., Gordon GH: Somatization in primary care: patients with unexplained and vexing medical complaints. J Gen Intern Med 1988; 3:177-190 2. Swartz M, Landerman R, George LK, et al: Somatization disorder, in Psychiatric Disorders in America, edited by Robins LN, Regier D. New York, Free Press, 1990 3. Kirmayer U. Robbins JM: Three fonns of somatization in primary care: prevalence, co-occurrence. and sociodemographic characteristics. J Nerv Ment Dis 1991; 179:647-655 4. Barsky AJ, Wyshak G. Klerman GL, el al: The prevalence of hypochondriasis in medical outpatients. Soc Psychiatry Psychiatr Epidemiol 1990; 25:89-94 5. Stefansson JG, Messina JA, Meyerowitz S: Hysterical neurosis, conversion type: clinical and epidemiological considerations. Acta Psychiatr Scand 1976; 53: 119-139 6. Ford CV: The Somatizing Disorders: Illness as a Way of Life. New York, Elsevier Biomedical, 1984 7. Simon GE. Von Korff M: Somatization and psychiatric
VOLUME 37. NUMBER I. JANUARY - FEBRUARY 1996
disorder in the NIMH Epidemiologic Catchment Area Study. Am J Psychiatry 1991; 148: 1494-1500 8. Lepine JP. Pariente P, Boulenger JP. et al: Anxiety disorders in a French general psychiatric outpatient sample: comparison between DSM-II and DSM-III-R criteria. Soc Psychiatry Psychiatr Epidemiol 1989; 124:301-308
9. Noyes R. Reich J. Clancy J. et al: Reduction in hypochondriasis with treatment of panic disorder. Br J Psychiatry 1986; 149:6631-6635 10. Barsky AJ. Wyshak G. Klerman GL: Psychiatric comorbidity in DSM-III-R hypochondriasis. Arch Gen Psychiatry 1992; 49: 101-108 II. Tomasson K, Kent D. Coryell W: Somatization and conversion disorders: comorbidity and demographics at presentation. Acta Psychiatr Scand 1991; 84:288-293 12. Orenstein H: Briquet's syndrome in association with depression and panic: a reconceptualization of Briquet's syndrome. Am J Psychiatry 1989; 146:334-338
21
Prevalence of Somatofonn Disorders
13. Torgensen S: Genetics of somatoform disorders. Arch Gen Psychiatry 1986; 43:502-505 14. Rief W. Schaefer S. Hiller W. et al: Lifetime diagnoses in patients with somatoform disorders: which came first? European Archives of Psychiatry and Clinical Neuroscience 1992; 241 :236-240 15. Swanz M. Blazer D. George L. et al: Somatization disorder in a community population. Am J Psychiatry 1986; 143: 1403-1408 16. Hogarty G (original developer). Larkin BH. Hirschfeld RMA (added later revisions) (1980): Personal History of Depressive Disorders (PHDD). Available from Dr. Hirschfeld at Univesity of Texas Medical Branch. Department of Psychiatry. Galveston. TX 77550 17. Myers JK. Yale Greater New Haven Health Survey (modified for use in HARP): Available from Dr. Myers at Yale University. New Haven. CT 06509-1905 18. Spitzer RL. Williams JBW. Gibbon M. et al: Structured Clinical Interview for DSM-III-R Patient Version (SCID-P). New York. New York State Psychiatric Institute. Biometrics Research Department. 1988 19. Endicott J. Spitzer RKL: A diagnostic interview: the schedule for affective disorders and schizophrenia (SADS-L). Arch Gen Psychiatry 1978; 35:837-844 20. Keller MB. Lavori PW. Nielsen E: SCALUP Diagnostic Interview 1990. Available from Dr. Keller at Butler Hospital. 345 Blackstone Boulevard. Providence. RI. 02906 21. Schefmer W. Endicott J: (1984) Medical History Form II. Revised from Scheftner W. Endicotl J. Clayton P. et al. Medical History Form. 1979. Available from Dr.
22
Scheftner at Rush Medical Center. 1753 West Congress Parkway. Chicago. IL 60612 22. Keller MB. Lavori PW. Friedman B. et al: The longitudinal interval follow-up evaluation: a comprehensive method for assessing outcome in prospective longitudinal studies. Arch Gen Psychiatry 1987; 44:5~548 23. Endicott J. Spitzer RL. Fleiss JL. et al: The Global Assessment Scale: a procedure for measuring overall severity of psychiatric disturbances. Arch Gen Psychiatry 1976; 33:766-771 24. Simon GE. VonKorff M: Letter to the editor-reply. Am J Psychiatry 1992; 149:1282 25. Fierman EJ. Hunt MF. Pratt LA. et al: Trauma and posttraumatic stress disorder in subjects with anxiety disorders. Am J Psychiatry 1993; 150: 1972-1974 26. Davidson JRT. Hughes D. Blazer DO. et al: Posttraumatic stress disorder in the community: an epidemiological study. Psychol Med 1991; 21:713-717 27. Warshaw MG. Fierman EJ. Pratt LA. et al: Quality of life and dissociation in anxiety disorder patients with histories of trauma or PTSD. Am J Psychiatry 1993; 150:1512-1516 28. Liskow B. Othmer E. Penick EC. et al: Is Briquet's syndrome a heterogeneous disorder? Am J Psychiatry 1986; 143:626-629 29. Escobar 11. Rubio-Stipec M. Canino G. et al: Somatic Symptom Index (SSI). a new and abridged somatization construct: prevalence and epidemiological correlates in two large community samples. J Nerv Ment Dis 1989; 177:140--146
PSYCHOSOMATICS
Fluoxetine and Cyclosporine in Organ Transplantation Failure to Detect Significant Drug Interactions or Adverse Clinical Events in Depressed Organ Recipients THOMAS
B.
CHRISTINE
STROUSE, M.D., LYNN
E.
A.
FAIRBANKS, PH.D.
SKOTZKO, M.D., FAWZY
I. FAWZY,
M.D.
Depression and anxiety disorders are common clinical problems in organ transplant recipients. but there is a paucity of clinical data to inform the selection of psychopharmacologic treatment. The authors retrospectively compared 13 depressed organ transplant recipients treated with j7uoxetine with 13 nondepressed matched control recipients and II transplant recipients treated with tricyclic antidepressants (nortriptyline or desipramine). Blood level:dose ratios and dose-response relationships for cyclosporine were virtually identical in all three groups before and during treatment. No increase in adverse clinical events was detected in either active treatment group compared with the control subjects. Fluoxetine appeared to be well tolerated by this population oftransplant patients, and the authors failed to detect significant alterations in cyclosporine levels or graft function. (Psychosomatics 1996; 37:23-30)
T
he arrival of cyclosporine in the late 1970s heralded a new era in organ transplantation. With extended patient survival, however, the high incidence of new and recurrent mood and anxiety disorders in transplant recipients was recognized. '-3 Although organ transplantation psychiatry has evolved at a rapid pace,4 the field has produced little data to inform such basic clinical decisions as the psychopharmacologic approach to the treatment of major depression in transplant recipients. s Instead, clinical decision making has been driven primarily by considerations of the pharmacokinetics and side-effect profiles of the standard pharmacopeia in persons with end-organ failure or recently grafted transplants. (HI Fluoxetine, and more recently sertraline and paroxetine, offer appealing alternatives to VOLUME 37. NUMBER I • JANUARY - FEBRUARY \996
conventional antidepressant agents in the treatment of depression in transplant patients. FIuoxetine's minimal affinity for muscarinic, dopaminergic, histaminergic, and alpha-adrenergic receptors 9•IO is associated with few anticholinergic, sedative, and autonomic side effects. The activation experienced by many who take fluoxetine can be helpful to anergic, withdrawn medical patients. Recognition of fluoxetine's potent proteinReceived October 7. 1993; revised December 14. 1993; accepted February 9. 1994. From the University of California at Los Angeles (UCLA). Depanment of Psychiatry and Biobehavioral Sciences. UCLA School of Medicine. Address reprint requests to Dr. Strouse. Chief. ConsultationLiaison Psychiatry Service. UCLA Neuropsychiatric Institute. 7W Westwood Plaza. Los Angeles. CA 90024. Copyright © 1996 The Academy of Psychosomatic Medicine.
23
Fluoxetine and Cyclosporine in Organ Transplantation
binding and hepatic microsomal enzyme-inhibiting effects, however, has prompted concern about drug interactions ' 1.l 2 and wariness about fluoxetine's safety in patients with complex medical regimens. In particular, fluoxetine's capacity to alter serum levels of cyclosporine has been proposed; potential effects on immune suppression and graft function are hypothesized. 6.s Nonetheless, no case reports or formal studies appear in the literature to describe these effects. At our large-volume, multi-organ transplant center, we frequently encounter organ recipients who require antidepressant pharmacotherapy and who do not tolerate trials of conventional antidepressants. We often choose fluoxetine, and our failure to observe the theoretical problems proposed earlier led to this retrospective review of our experience over 20 years (1990--1993). We compared blood cyclosporine levels, medical courses, and various measures of organ function in fluoxetine-treated, tricyclic-treated, and nondepressed control transplant recipients. METHODS Sampling Procedures With authorization from the University of California at Los Angeles (UCLA) Human Subjects Protection Committee, computer reviews of pharmacy records were done for all patients treated at UCLA Medical Center between January 1990 and January 1993. A linked search identified the medical record numbers of inpatients and outpatients who were simultaneously treated with fluoxetine and cyclosporine during this 3-year period. A control group of nondepressed, nonfl uoxetine-treated patients was matched to the index group by age, organ type, and month of transplant. A comparison group of tricyclic antidepressant-treated (either nortriptyline or desipramine) transplant patients was selected by the same computer method. For each patient, the start date of antidepressant pharmacotherapy (D = 0) was identified. (For matched control patients, D 0 equaled D =0 for the fluoxetine index patients.)
=
24
The following data were then compiled for each patient 30, 15, and 7 days before D = 0 and 7, 15, 30, 45, 60, 75, and 90 days after D = 0: I) cyclosporine high-performance liquid chromatography (HPLC) and radioimmunoassay (RIA) blood levels (reviews of these techniques and their uses are available in references 13-16); 2)y20cyclosporine dosing (total daily dose in mgs and route); 3) blood urea nitrogen/creatinine; 4) bilirubin total and direct; 5) albumin; 6) serum glutamate oxaloacetate transaminase (SGOT) and serum glutamate pyruvate transaminase (SGPT); 7) a complete list of other medications being taken at each date; and 8) a complete listing of medical events and diagnoses, such as hospital admissions, suspected or confirmed episodes of rejection, graft or organ dysfunction, new- onset syndromes or illnesses, and antidepressant medication side effects. Many transplant centers record both HPLC and RIA cyclosporine levels. HPLC levels are more reliable than RIA because the HPLC technique provides a highly accurate measure ofthe cyclosporine parent compound in blood. Particularly in the setting of acute organ dysfunction, where cyclosporine metabolites are likely present, the anti-serum in the RIA cross-reacts with these metabolites and can produce RIA: HPLC ratios of up to 15: 1. 13- 16 The immunosuppressive activity of cyclosporine metabolites is poorly understood. We expected that a better correlation would be found between dose and HPLC values (compared with dose and RIA values) for all patient groups at all phases ofthe study. The I-month period before initiation of antidepressant therapy was chosen to provide adequate numbers of data points for calculation of "baseline" dose-response relationships to cyc1osporine and to evaluate pretreatment trends in organ functioning. The 90-day follow-up period was chosen because of the extended elimination half-life in normals of fluoxetine and norfluoxetine (4 and 7-9 days, respectively);I? some hepatic dysfunction was expected in the liver recipients posttransplant, and fluoxetine/norfluoxetine half-lives are increased twoto threefold in patients with liver disease. IS PSYCHOSOMATICS
Strouse et al.
Subjects The initial computer review supplied 15 f1uoxetine-/cyclosporine-treated patients, and II tricyclic-/cyclosporine-treated patients. One of the f1uoxetine-treated patients had not received an organ transplant and was eliminated from the analysis. A second f1uoxetine-treated patient was eliminated because of noncompliance with medical follow-up. Final data analysis was done on 13 f1uoxetine-treated, II tricyclic-treated, and 13 matched-to-f1uoxetine control subjects. The f1uoxetine-treated group was composed of 9 liver recipients and 4 heart recipients. Their posttransplant mean status was 10.8 months, range I-50 months, and median 24 months; by study design, this group composition was replicated in the matched control subjects. The tricyclic group contained only liver recipients; our transplant cardiologists avoid treating heart recipients with tricyclic antidepressants. 6 The liver recipients' mean posttransplant status was 6 months, range 2 weeks to 24 months, and median 12 months. The fluoxetine-treated patients took 5-20 mgs daily; of the 13 in the group, 10 took 20 mgs daily, 2 took 10 mgs daily, and I took 5 mgs daily. The lower doses reflect careful use of f1uoxetine in patients with hepatic dysfunction at baseline. F1uoxetine and norfluoxetine blood levels were not collected. The tricyclic-treated patients took daily doses of 50--100 mgs of nortriptyline or 100--200 mgs of desipramine. All patients reported regular compliance with the daily dosing regimens of their antidepressants. Serum tricyclic levels were obtained in some but not all patients and are not reported. RESULTS Cyclosporine-HPLC Levels by Treatment Group If fluoxetine affects cyclosporine levels, we would expect cyclosporine levels to change after the start of f1uoxetine treatment. Figure I shows the individual cyclosporine HPLC blood VOLUME 37. NUMBER I • JANUARY - FEBRUARY 1996
FIGURE t.
Individual cyclosporine:highperformance liquid chromatography (HPLC) dose ratios for nuoxetine, tricyclic, and matched control patients at each study date before and during treatment
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3.0,.-----'---~-----------,
•
2.'
• FI"oxetine Trtcyclic
o
o
2.0
•
~30
-15
Con~
0
-7
level:dose ratios by treatment day in the fluoxetine, tricyclic, and matched control patients. Before the start of antidepressant therapy, the mean ± SD blood level:dose ratios were virtually identical between the three groups (fluoxetine: 0.44 ± 0.08, tricyclic: 0.40 ± 0.06, control: 0.44 ± 0.06), but there was more variability in the individual values of the f1uoxetine-treated patients. In Figure I, there are five outlying points in the fluoxetine pretreatment phase, representing HPLC:dose ratios for three patients, all of whom were liver recipients and whose notable clinical characteristics included pretreatment elevations in bilirubin and transaminases, and serum albumins of less than 3. Because of their baseline hepatic dysfunction, fluoxetine dosing was reduced in these patients: one received 5 mgs daily, and the other two 10 mgs daily. In the first treatment month, one of these three fluoxetine-treated patients (who had received 5 mgs daily) was discontinued on cyc1osporine because of reactivation of a previous hepatitis B condition and chronic renal failure, thus making additional HPLC:dose ratio data unavailable. The other two, represented by three data points, in addition to one tricyclic-treated patient (who had moderate baseline ratio elevation), showed HPLC:dose ratios above 1.0. With no change in fluoxetine or tricyclic dosing, cyclosporine HPLC:dose ratios for these pa25