PSYCHIATRIC DISTURBANCES ASSOCIATED WITH GANCICLOvrn. THERAPY Julie L. Chen, Joseph M. Brocavich, and Anne Y.F. Lin
To report a case of possible ganciclovir-induced psychiatric disturbances.
A patient with AIDS who had no known psychiatric history and mild renal dysfunction experienced exacerbation of cytomegalovirus retinitis and was treated with ganciclovir 5 mg/kg iv q 12h. The patient complained of nightmares and developed visual hallucinations and severe agitation on day 15 of ganciclovir therapy. The problems resolved after haloperidol administration and ganciclovir withdrawal and reappeared when the same regimen was reinstituted. However, the patient was able to tolerate the maintenance dose of ganciclovir at 5 mg/kg/d along with haloperidol later without further episodes of visual hallucinations. CASE SUMMARY:
DISCUSSION: Case reports in the literature on ganciclovir- or its analog, acyclovir-, induced psychiatric disturbances were reviewed and compared. The potential relationship between ganciclovir accumulation in patients with renal insufficiency and the observed central nervous system problems in our patient was postulated.
It is likely that ganciclovir accumulation contributed to the acute psychotic episodes observed in our patient. Adjusting ganciclovir dosage based on the patient's renal function is probably the only approach required to prevent or reduce the incidence of these episodes. CONCLUSIONS:
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an acyclic deoxyguanosine analog structurally similar to acyclovir, possesses in vitro antiviral activity against human herpes viruses, including cytomegalovirus (CMV), herpes simplex virus types I and 2 (HSV1, HSV-2), Epstein-Barr virus (EBV), and varicella zoster virus (VZV).I.S Ganciclovir is indicated for the treatment of CMV retinitis in immunocompromised individuals, including patients with AIDS.4.'O Induction therapy in patients with normal renal function consists of ganciclovir 5 mg/kg every 12 hours for 14-21 days. Following induction treatment, the recommended maintenance regimen is 5-6 mg/kg/d for 5-7 days each week indefinitely. The dosage should be adjusted in patients with renal impairment.' In clinical trials to date, the development of psychiatric abnormalities with ganciclovir has been rare.S,8.11 The manufacturer states that the incidence of abnormal thoughts, nightmares, or psychosis associated with ganciclovir therapy is less than one percent.' However, psychiatric abnormalities such as agitation, visual hallucinations, delusions, GANCICLOVIR SODIUM,
JULIE L. CHEN, Phann.D., is an Assistant Professor, Long Island University, Arnold and Marie Schwartz College of Phannacy and Health Sciences. Brooklyn. and the Clinical Coordinator, Department of Phannacy Services, Montefiore Medical Center. Bronx; JOSEPH M. BROCAVICH, Phann.D., is an Associate Professor and the Director, Phann.D. Program; and ANNE V.F. LIN, Phann.D., is an Assistant Professor and the Director of Drug Information, College of Pharmacy and Allied Health Professions, St. John's University, Jamaica, NY. Reprints: Julie L. Chen, Phann.D.• Pharmacy Department, Montefiore Medical Center. III E. 210 St., Bronx, NY 10467.
disorientation, and depression have been occasionally reported with acyclovir use,12·17 Because of ganciclovir's structural similarity to acyclovir, it can be postulated that similar disturbances may occur with ganciclovir. We report a case of reversible psychiatric disturbances in a patient with AIDS who received intravenous ganciclovir induction therapy for CMV retinitis. CASE REPORT A 45-year-old black woman (168 em, 59.5 kg) was admitted with fever, supraorbital headache, and progressive vision loss in her right eye. The patient had lost vision in her left eye secondary to CMV retinitis that had been diagnosed one year prior to admission. She had refused ganciclovir therapy previously. Her past medical history was also significant for human immunodeficiency virus (HIV) infection that had progressed into AIDS. She had experienced multiple episodes of Pneunwcystis carinii pneumonia and had developed oral candidiasis and left-sided weakness. This patient did not have a personal or family history of any psychiatric disorders, although on admission she did express feelings of intermittent depression and irritability secondary to the progression of her disease. Medications on admission included zidovudine 200 mg q4h, ketoconazole 200 mg/d, and hydroxyzine 10 mg tid. Both zidovudine and hydroxyzine were discontinued on admission. Her temperature was 38.3 DC; blood chemistries were: blood urea nitrogen 3.93 mmol/L of urea (normal 3.57-7.14), serum creatinine 114.92 fJ.111oVL (70.72-106.08) with an estimated creatinine clearance of 0.86 mL/s (Cockcroft-Gault method"), sodium 137 mmoVL (135-145), potassium 4.0 mmoVL (3.5-5.0), and albumin 23 gIL (33-55). Complete blood count showed: hemoglobin 106 gIL (120-160), hematocrit 0.32 (0.37-0.47), platelet count 266 x 109!L (150-350), and white blood cell count 2.8 x H)9!L (5.0-10). Samples of both her blood and urine were positive for CMV antibodies. A diagnosis of CMV retinitis in both eyes was made based on ophthalmologic examinations and positive CMV fluorescent antibody tests of both blood and urine. Ganciclovir 300 mg (approximately 5 mg/kg) infused intravenously over 1 hour q 12h was initiated on day 2. Other concurrent medications included ketoconazole 200 mg/d po, folate I mg/d po, docusate sodium 100 mg po bid, multivitamin one tablet po daily, and clotrimazole troche 10 mg five times a day. The patient responded well both subjectively and objectively to ganciclovir induction therapy with improvement observed on funduscopic examination. On day 15 of ganciclovir therapy, the patient awoke secondary to the development of vivid nightmares. She was terrified by the dreams and experienced continuous visual hallucinations while awake. She became severely agitated and could not be reasoned with. Haloperidol 2 mg im was administered. The patient was alert and oriented approximately 1 hour after the event. In addition to visual hallucinations, the patient claimed that she had begun to experience occasional nightmares since the initiation of ganciclovir therapy. A possible ganciclovir-induced psychosis was then suspected. Ganciclovir was stopped and haloperidol 2 mg im pm for agitation was prescribed. To rule out other possible causes of psychosis, appropriate laboratory tests were ordered on day 15. Except for hyperkalemia (potassium 5.8 mmol), other
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findings were either normal or within the patient's baseline values. Head computed tomography (IT) results were insignificant. A lumbar puncture that had been performed four days prior to these events revealed negative fmdings with a glucose concentration of 2.89 mrnol/L (concurrent serum glucose concentration 4.11 mmol/L), protein 0.26 gIL (0.15-0.45), 0 white blood cells, and 6 x 10"/L red blood cells (" As acyclovir and ganciclovir are structurally similar, the possibility of drug accumulation in the CNS in conjunction with other unidentified predisposing factors cannot be overlooked in our patient. Davis et al. reported the only other published case of ganciclovir-induced CNS disturbances in a postrenal transplant patient. Similar to our patient, their patient developed symptoms of agitation, delirium, and mild confusion after receiving ganciclovir 5 mg/kg iv q 12h for eight days (Table I). Other concurrent medications included ranitidine, prednisone, and azathioprine. Unlike our patient, however, Davis et al. 's patient did not respond to haloperidol, nor did the patient respond to the withdrawal of ranitidine or to a reduction in the prednisone dose. 20 This fact is important because both agents have been reported to cause CNS dis-
Table 1. Cases Associated with Ganciclovir-Induced Central Nervous System Disturbances" AGE/GENDER
renal transplant, CMV hepatitis and duodenitis
agitation, delirium, confusion
AIDS, renal insufficiency, CMV retinitis
nightmares, agitation, confusion, visual hallucinations
symptoms did not respond to haloperidol but resolved after a ganciclovir dose reduction to 2.5 mg/kg q 12h symptoms resolved after haloperidol and drug discontinuation, but reappeared after resuming the dose; no symptoms were observed with the 5-mg/kg/d maintenance dose
"Ganciclovir doses 5 mg/kg ql2h. CMV =cytomegalovirus; CNS =central nervous system; F =female; M =male; NA =not available.
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turbances.P-" However, their patient's symptoms improved with a 50 percent dose reduction of ganciclovir," This is similar to our case, although other possible causes cannot be ruled out completely in either case. We present a case of possible ganciclovir-induced psychosis. Although haloperidol may be helpful in the management of acute CNS toxicity associated with ganciclovir therapy, withholding the dose of ganciclovir for one or two days is probably the only approach necessary for patients with less severe symptoms. Dosage reduction of ganciclovir in patients with impaired renal function may reduce or prevent the development of eNS toxicity. The overall incidence of ganciclovir-induced CNS toxicity to date is low. However, with the increasing use of ganciclovir in AIDS patients with CMV retinitis and concurrent renal insufficiency, additional cases of ganciclovir-induced psychosis may be reported. ~ References I. Cheng Y ·C, Huang E·S, Lin J·C, et al, Uniquespectrumof activity of 9-[1,3-dihydroxy-2-propoxymethyl]-guanine against herpes viruses in vitro and its mode of action againsl herpes simplex virus type I. Proc NatlAcad Sci USA 1983;80:2767-70. 2. Field AK, Davis ME, DeWitt C, et al. 9- ([2-hydroxy-I-(hydroxymethyl) ethoxy[methyl] guanine: a selective inhibitorof herpes group virusreplication. Proc Natl Acad Sci USA 1983;80:4139-43. 3. Russler SK, Tapper MA, Carrigan DR. Susceptibilityof human herpes virus6 to acyclovirand ganciclovir (letter). Lancet 1989;2:382. 4. Matthews T, Boehme R. AntiviralactiviIy and mechanism of action of ganciclovir. Rev InfectDis 1988; 100suppi 3):S490-4. 5. Buhles WC, Mastre BJ, Tinker AJ, Strand V, Korez SH, The Synlex Collaborative Ganciclovir Treatment Study Group. Ganciclovir treatmentof life- or sight-threatening cytomegalovirus infection: experience in 314 immunocompromised patients. Rev Infect Dis 1988; IO(suppI3):S495-504. 6. Package insert. Ganciclovir (Cytovene). Palo Alto: Syntex Laboratories,1989. 7. Jabs DA, Enger C, Bartelett JG. Cytomegalovirus retinitis and acquired immunodeficiency syndrome. Arch OphthalmoI1989;107:7580. 8. Koretz SH, Buhles WC, Brewin A, et al. Treatment of serious cytomegalovirusinfectionswith 9-(1,3-dihydroxy-2-propoxymethyl) guanine in patients with AIDS and other immunodeficiencies. N Engl J Med 1986;314:801-5. 9. Laskin OL, Cederberg DM, Mills J, et al, Ganciclovir for the treatment and suppression of seriousinfections caused by cytomegalovirus. Am J Med 1987;83:201-7. 10. Jacobson MA, Mills J. Seriouscytomegalovirus disease in the acquired immunodeficiency syndrome (AIDS):clinical fmdings,diagnosis,and treatment. Ann InternMed 1988; 108:585-94. II. Chachoua A, Dieterich D, Krasinski K, et aI. 9-(1,3-dihydroxy-2-propoxymethyl)guanine (ganciclovir) in the treatmentof cytomegalovirus gastrointestinal diseasewith the acquiredimmunodeficiency syndrome. Ann InternMed 1987;107:133-7. 12. Cohen SMZ, Minkove JA, Zebley JW, Mulholland JH. Severe but reversibleneurotoxiciIy from acyclovir (letter).Ann Intern Med 1984; 100:920. 13. Tomson CR, Goodship THJ, Rodger RSC. Psychiatricside effect of acyclovir in patients with chronic renal failure (letter).Lancet 1985;I: 385-6. 14. Bataille P, Devos P, Noel JL, Dautrevaux C. Psychiatric side effects with acyclovir(letter). Lancet 1985; I:724. 15. Jones PG, Beier-Hanratty SA. Acyclovir: neurologic and renal toxicity (letter). Ann InternMed 1986; 104:892.
16. Feldman S, Rodman J, Gregory B. Excessive serum concentrations of acyclovirand neurotoxicity. J InfectDis 1988; 157:385-8. 17. Sirota P, Stoler M, Meshulam B. Majordepression with psychotic features associated with acyclovirtherapy.Drug Intell Clin Pharm 1988; 22:306-8. 18. Cockcroft DW, Gault MH. Prediction of creatinine clearance from serumcreatinine. Nephron 1976;16:31-41. 19. Wade JC, Meyers JD. Neurologic symptomsassociated withparenteral acyclovir treatment after marrow transplantation. Ann Intern Med 1983;98:921-5. 20. Davis CL, Springmeyer S, Gmerek BJ. Central nervous system side effectsof ganciclovir (letter). N Engl J Med 1990;322:933-4. 21. Blazer DG n, Petrie WM, Wilson WP. Affective psychoses following renal transplant. Dis Nerv Syst 1976;37:663-7. 22. Lewis DA, Smith RE. Steroid-induced psychiatric syndromes. J Affective Disord 1983;5:319-22. 23. Perry PJ, Tsuang MT, Hwang MH. Prednisolonepsychosis:clinical observations. Drug IntellClin Pharm 1984; 18:603-9. 24. Price W, Coli L, Brandstetter RD, Gotz VP. Ranitidine-associated hallucinations. Eur J Clin PharmacoI1985;29:375-6. 25. Patterson JF. Mania associatedwith intravenous ranitidine therapy(letter).South Med J 1987;80:1467.
La psicosis es un efecto adverso que ocurre en menos de uno por ciento de los pacientes que reciben ganciclovir. Este articulo describe el caso de un paciente que desarroll6 psicosis asociada con pesadillas y alucinaciones visuales despues de 15 mas de tratamiento de inducci6n de ganciclovir por via intravenosa. Este paciente estaba siendo tratado para una retinitis causada por Cytomegalovirus. Tenia ademas el sfndrome de inmunodeficiencia adquirida e insuficiencia renal. Los sfntomas desaparecieron cuando el tratamiento fue interrumpido 0 cuando se administr6 haloperidol. Mas adelante, a este paciente se Ie administr6 una dosis mas baja de ganciclovir junto con haloperidol oral. Este se mantuvo asintomatico en este regimen por cuatro semanas. Aunque no se ha establecido una relaci6n entre el desarrollo de sfntomas neurol6gicos y niveles plasmaticos de aciclovir (un analogo estructuralmente similar a ganciclovir), la mayoria de los pacientes que desarrollan toxicidad neurol6gica con este medicamento han recibido altas dosis y/o han tenido disfunci6n renal concurrente. Debido a esta similaridad estructural entre ambos medicamentos, la posibilidad de que haya ocurrido acumulaci6n de ganciclovir en el sistema nervioso central aI igual que otros factors de predisposici6n de este paciente deben considerarse. LYDIAGONzALEZ RESUME
La psychose est un effet indesirable potentiel du ganciclovir, etant rapportee chez moins d'un pourcent des patients. Ce rappor decrit un cas de psychose associee 11 des cauchemars et des hallucinations visuelles qui s'est produit suite 11 l'utilisation intraveineuse d'une dose d'induction de ganciclovir chez une patiente sidatique et insuffisante renale, souffrant d'une retinite 11 cytomegalovirus. Les symptoms de psychose se dissipaient lorsqu'on interrompait la therapie ou lorsqu'on administrait de l'haloperidol. Une dose de maintenance plus faible de gancyclovir associee 11 de l'haloperidol a ete recommencee par la suite. La patiente est demeuree asymptomatique durant un suivi de quatre semaines. La dose ou la concentration sanguine du medicament pourrait jouer un role imporrtant dans cette reaction.
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