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Organic Anxiety Disorder with Symptoms of Akathisia in a Patient Treated with the Immunosuppressant FK506 Lawson Bernstein, M.D. and Steven R. Daviss, M.D.
FK506 is a novel immunosuppressant currently used after organ transplantation, which has a superior toxicity and side effect profile when compared with cyclosporine [1,2]. FK506 works by blocking the production of interleukin-2 by lymphocytes [3], resulting in a decreased cellular rejection response to transplanted tissues. Literature on the neuropsychiatric sequelae of FK506 is scant, and Medline literature search beginning with 1980 revealed no reported cases of FK506-associated movement disorders other than tremor and akinetic mutism [4-61. We present the case of a 39year-old man admitted for renal transplantation who developed new-onset anxiety with restlessness in the setting of FK506 immunotherapy.
Case Report Mr. A, a 39-year-old single insurance executive, presented with polycystic kidney disease, hypertension, and a history of partial parathyroidectomy; 4 weeks prior to psychiatric consultation, he had undergone renal transplant. The patient was begun on FK506,lO mg p-0. b.i.d., posttransplant, but 10 days after surgery his creatinine level had risen to 8 mg/ml, and a renal biopsy showed cellular rejection. After initiation of treatment with prednisone 20 mg p.o. q.d., OKT3 5 mg p.o. q.d., and an increase of FK506 to 14 mg p.o. b.i.d., the patient developed a transient clinical syndrome of cognitive slowing, vivid nocturnal visual hallucinations, and electroencephalic (EEG) slowing consistent with delirium, which cleared with cessation of OKT3. When, on postoperative day 30, in the setting of a rising serum FK level (3.0 @ml), the patient was noted to be “depressed and anxious“ with
210 ISSN 0163-8343/92/$5.00
the persistent thought that “I’m going to die,” a psychiatric consultation was requested. Examination revealed a pale, unshaven man, who cooperated with the interviewer, but spoke slowly and hesitantly. Although he was depressed, he was able to joke appropriately. He complained of insomnia and poor concentration, which he related to intense “jitteriness” and concerns that he was “going crazy.” He described feeling an intense and constant urge to get up and move around and admitted to feeling a sense of “impending doom,” but denied suicidal ideation. There was no evidence of psychosis except for the morbid preoccupation noted above; his Mini-Mental state exam score was 22 out of 30. Physical exam was notable for moderate motor restlessness without evidence of tremor, fasciculations, choreoathetoid movement, or focal neurologic deficit. No history was elicited of past personal or familial psychiatric, neurologic or movement disorders, nor did the medical record contain evidence of recent neuroleptic or antiemetic exposure. Current medications included prednisone 15 mg p.o. q.d. nifedipine 30 mg p.o. q.d., acyclovir 800 mg p.o. b.i.d., trimethoprim/sulfa 55 mg p.o. q.d., aspirin 80 mg p.o. q.d., B6 50 mg p.o. q-d., isoniazid 300 mg p-o. q.d., omeprazole 20 mg p.o. b.i.d., furosemide 80 mg p.o. q.d., and famotidine 20 mg p.o. q.d. There had been no recent medication changes except as noted above. Serum chemistries including complete blood count with differential, electrolytes, liver function tests, and calciumlphosphorus/magnesium levels were all unremarkable, except for a blood urea nitrogen of 58, a creatinine of 3.6, and a white blood count/ platelet count of 3,400/88,000. Previous FK506 level 4 days prior to consultation was 2.6 ng/dl (suggested therapeutic level l-3 ng/dl). An EEG done 2 weeks prior to consultation demonstrated diffuse bilateral General Hospital Psychiatry 14, 210-211, 1992 Q 1992 Elsevier Science Publishing Co., Inc. 655 Avenue of the Americas, New York, NY 10010
Letters to the Editor
slowing with a background rhythm of 7 hertz and no focal dysrhythmia. Given the temporal association between the onset of the patient’s symptoms and a rising FK506 serum level, a presumptive diagnosis of organic anxiety disorder with akathisia was made. He was begun on propranolol 10 mg p.o. t.i.d. for his akathisia, and haloperidol 0.5 mg p.o. q.h.s. for his morbid ruminations. The following morning, after receiving one dose of haloperidol and two of propranolol, the patient reported 80% resolution of his restlessness and anxiety and a return “to my old self.” The following day the patient reported complete cessation of his psychiatric and motor symptoms. Haloperidol was stopped 3 days after initiation without recurrence of anxiety and restlessness. At follow-up 2 weeks after discharge, the patient continued to be cognitively clear and symptom free on propranolol 10 mg t.i.d. This case report is the first to document an organic anxiety disorder presenting with symptoms of akathisia in association with FK506 immunotherapy. This has significant clinical implications given the growing popularity of FK506 as an immunosuppressant. Organic anxiety disorder is defined as an increased level of anxiety in the setting of a specific organic factor not occurring exclusively in the setting of delirium. Akathisia, a syndrome characterized by varying degrees of motor and psychic agitation [7J, has been described as a sequela of neuroleptic treatment and other organic etiologies. The onset of restlessness and anxiety in the setting of rising FK506 levels, and the cessation of symptoms with low-dose beta-blocker therapy (a recognized effective treatment for akathisia [S]) suggest the presence of both these syndromes in our patient. It should be noted that the cessation of akathisia coincided with a falling FK506 level (1.8 ng/ dl 5 days after consultation and dose reduction to 6 mg p.o. b.i.d.). This change cannot be ruled out as the sole cause of his improvement. It is unlikely that haloperidol ameliorated this patient’s restlessness and anxiety as this agent tends to cause akathisia. In addition, the fact that haloperidol was stopped 3 days after initiation without recrudescence of the patient’s psychic or motor symptoms
argues against haloperidol as the effective agent in this case. Physicians treating patients on FK506 should inquire about anxiety and akathisia symptoms and consider low-dose propranolol to treat them. More formal inquiry into this question is currently under way at this institution. Lawson Bernstein, M.D. Steven R. Daviss, M.D., Psychiatric Consultation Service University of Pittsburgh Medical Center and Department of Psychiatry, Western Psychiatric lnstitute & Clinic Pittsburgh, Pennsylvania
References 1. Venkataramanan
2.
3. 4.
5.
6.
7.
8.
R, Jain A, Cadoff R, Warty V, et al: Pharmacokinetics of FK506: preclinical and clinical studies. Transplant Proc 22:52-56, 1990 Morris R, Wu J, Shorthouse R: Comparative immunopharmacologic effects of FK506 and CyA in in vivo models of organ transplantation. Transplant Proc 22:110-112, 1990 Kay JE, Moore AL, Doe S, et al: The mechanism of action of FK506. Transplant Proc 22~96-99, 1990 Shapiro D, Fung J, Jain AB, Parks P, Todo S, Starzl TE: The side effects of FK506 in humans. Transplant Proc 22:35-36, 1990 Trzepacz PJ, Levenson J, Tringali R: Psychopharmacology and neuropsychiatric syndromes in organ transplantation. Gen Hosp Psychiatry 13:233-245, 1991 Eidelman B, Abu Elmgad K, Wilson J, et al: Neurotoxicity of FK506 in liver and thoracic organ transplant recipients (Abstracts) 1st Int Conf on FK506, 74, September, 1991 Kaplan H, Sadock 8: Biological Therapies. In Fisher MG (ed), Synopsis of Psychiatry. Baltimore, Williams & Wilkins, 1988 Kramer MS, Gorkin RA, DiJohnson C, Sheves P: Propranolol in the treatment of neuroleptic-induced akathisia in schizophrenics: a double-blind, placebocontrolled study. Biol Psychiatry 24:823-827, 1988
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Organic Anxiety Disorder with Symptoms of Akathisia in a Patient Treated with the Immunosuppressant FK506 Lawson Bernstein, M.D. and Steven R. Daviss, M.D.
FK506 is a novel immunosuppressant currently used after organ transplantation, which has a superior toxicity and side effect profile when compared with cyclosporine [1,2]. FK506 works by blocking the production of interleukin-2 by lymphocytes [3], resulting in a decreased cellular rejection response to transplanted tissues. Literature on the neuropsychiatric sequelae of FK506 is scant, and Medline literature search beginning with 1980 revealed no reported cases of FK506-associated movement disorders other than tremor and akinetic mutism [4-61. We present the case of a 39year-old man admitted for renal transplantation who developed new-onset anxiety with restlessness in the setting of FK506 immunotherapy.
Case Report Mr. A, a 39-year-old single insurance executive, presented with polycystic kidney disease, hypertension, and a history of partial parathyroidectomy; 4 weeks prior to psychiatric consultation, he had undergone renal transplant. The patient was begun on FK506,lO mg p-0. b.i.d., posttransplant, but 10 days after surgery his creatinine level had risen to 8 mg/ml, and a renal biopsy showed cellular rejection. After initiation of treatment with prednisone 20 mg p.o. q.d., OKT3 5 mg p.o. q.d., and an increase of FK506 to 14 mg p.o. b.i.d., the patient developed a transient clinical syndrome of cognitive slowing, vivid nocturnal visual hallucinations, and electroencephalic (EEG) slowing consistent with delirium, which cleared with cessation of OKT3. When, on postoperative day 30, in the setting of a rising serum FK level (3.0 @ml), the patient was noted to be “depressed and anxious“ with
210 ISSN 0163-8343/92/$5.00
the persistent thought that “I’m going to die,” a psychiatric consultation was requested. Examination revealed a pale, unshaven man, who cooperated with the interviewer, but spoke slowly and hesitantly. Although he was depressed, he was able to joke appropriately. He complained of insomnia and poor concentration, which he related to intense “jitteriness” and concerns that he was “going crazy.” He described feeling an intense and constant urge to get up and move around and admitted to feeling a sense of “impending doom,” but denied suicidal ideation. There was no evidence of psychosis except for the morbid preoccupation noted above; his Mini-Mental state exam score was 22 out of 30. Physical exam was notable for moderate motor restlessness without evidence of tremor, fasciculations, choreoathetoid movement, or focal neurologic deficit. No history was elicited of past personal or familial psychiatric, neurologic or movement disorders, nor did the medical record contain evidence of recent neuroleptic or antiemetic exposure. Current medications included prednisone 15 mg p.o. q.d. nifedipine 30 mg p.o. q.d., acyclovir 800 mg p.o. b.i.d., trimethoprim/sulfa 55 mg p.o. q.d., aspirin 80 mg p.o. q.d., B6 50 mg p.o. q-d., isoniazid 300 mg p-o. q.d., omeprazole 20 mg p.o. b.i.d., furosemide 80 mg p.o. q.d., and famotidine 20 mg p.o. q.d. There had been no recent medication changes except as noted above. Serum chemistries including complete blood count with differential, electrolytes, liver function tests, and calciumlphosphorus/magnesium levels were all unremarkable, except for a blood urea nitrogen of 58, a creatinine of 3.6, and a white blood count/ platelet count of 3,400/88,000. Previous FK506 level 4 days prior to consultation was 2.6 ng/dl (suggested therapeutic level l-3 ng/dl). An EEG done 2 weeks prior to consultation demonstrated diffuse bilateral General Hospital Psychiatry 14, 210-211, 1992 Q 1992 Elsevier Science Publishing Co., Inc. 655 Avenue of the Americas, New York, NY 10010
Letters to the Editor
slowing with a background rhythm of 7 hertz and no focal dysrhythmia. Given the temporal association between the onset of the patient’s symptoms and a rising FK506 serum level, a presumptive diagnosis of organic anxiety disorder with akathisia was made. He was begun on propranolol 10 mg p.o. t.i.d. for his akathisia, and haloperidol 0.5 mg p.o. q.h.s. for his morbid ruminations. The following morning, after receiving one dose of haloperidol and two of propranolol, the patient reported 80% resolution of his restlessness and anxiety and a return “to my old self.” The following day the patient reported complete cessation of his psychiatric and motor symptoms. Haloperidol was stopped 3 days after initiation without recurrence of anxiety and restlessness. At follow-up 2 weeks after discharge, the patient continued to be cognitively clear and symptom free on propranolol 10 mg t.i.d. This case report is the first to document an organic anxiety disorder presenting with symptoms of akathisia in association with FK506 immunotherapy. This has significant clinical implications given the growing popularity of FK506 as an immunosuppressant. Organic anxiety disorder is defined as an increased level of anxiety in the setting of a specific organic factor not occurring exclusively in the setting of delirium. Akathisia, a syndrome characterized by varying degrees of motor and psychic agitation [7J, has been described as a sequela of neuroleptic treatment and other organic etiologies. The onset of restlessness and anxiety in the setting of rising FK506 levels, and the cessation of symptoms with low-dose beta-blocker therapy (a recognized effective treatment for akathisia [S]) suggest the presence of both these syndromes in our patient. It should be noted that the cessation of akathisia coincided with a falling FK506 level (1.8 ng/ dl 5 days after consultation and dose reduction to 6 mg p.o. b.i.d.). This change cannot be ruled out as the sole cause of his improvement. It is unlikely that haloperidol ameliorated this patient’s restlessness and anxiety as this agent tends to cause akathisia. In addition, the fact that haloperidol was stopped 3 days after initiation without recrudescence of the patient’s psychic or motor symptoms
argues against haloperidol as the effective agent in this case. Physicians treating patients on FK506 should inquire about anxiety and akathisia symptoms and consider low-dose propranolol to treat them. More formal inquiry into this question is currently under way at this institution. Lawson Bernstein, M.D. Steven R. Daviss, M.D., Psychiatric Consultation Service University of Pittsburgh Medical Center and Department of Psychiatry, Western Psychiatric lnstitute & Clinic Pittsburgh, Pennsylvania
References 1. Venkataramanan
2.
3. 4.
5.
6.
7.
8.
R, Jain A, Cadoff R, Warty V, et al: Pharmacokinetics of FK506: preclinical and clinical studies. Transplant Proc 22:52-56, 1990 Morris R, Wu J, Shorthouse R: Comparative immunopharmacologic effects of FK506 and CyA in in vivo models of organ transplantation. Transplant Proc 22:110-112, 1990 Kay JE, Moore AL, Doe S, et al: The mechanism of action of FK506. Transplant Proc 22~96-99, 1990 Shapiro D, Fung J, Jain AB, Parks P, Todo S, Starzl TE: The side effects of FK506 in humans. Transplant Proc 22:35-36, 1990 Trzepacz PJ, Levenson J, Tringali R: Psychopharmacology and neuropsychiatric syndromes in organ transplantation. Gen Hosp Psychiatry 13:233-245, 1991 Eidelman B, Abu Elmgad K, Wilson J, et al: Neurotoxicity of FK506 in liver and thoracic organ transplant recipients (Abstracts) 1st Int Conf on FK506, 74, September, 1991 Kaplan H, Sadock 8: Biological Therapies. In Fisher MG (ed), Synopsis of Psychiatry. Baltimore, Williams & Wilkins, 1988 Kramer MS, Gorkin RA, DiJohnson C, Sheves P: Propranolol in the treatment of neuroleptic-induced akathisia in schizophrenics: a double-blind, placebocontrolled study. Biol Psychiatry 24:823-827, 1988
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