Psychosomatics 39:118-123, April 1998
© 1998 The Academy of Psychosomatic Medine
Methylphenidate in Post Liver Transplant Patients
Lori Plutchik, M.D.,
Stephen Snyder, M.D.,
Martin Drooker, M.D.,
Lawrence Chodoff, Pharm.D., and
Patricia Sheiner, M.D.
Received March 20, 1997; revised July 22, 1997; accepted August 6, 1997. From the Beth Israel Medical Center and the Mount Sinai Medical Center, New York. Address reprint requests to Dr. Plutchik, Beth Israel Medical Center, Suite 509, Fierman, 317 East 17th Street, New York, NY 10003.
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ABSTRACT
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Methylphenidate (Ritalin, manufacturer: Ciba/Geigy) has been shown effective for the treatment of depression in various medically ill populations, but to our knowledge its use in organ transplant patients has not been described. The authors retrospectively reviewed clinical records of the first eight inpatients who received methylphenidate for treatment of depressive and/or cognitive symptoms in the post liver transplant period at Mount Sinai Medical Center. Target symptoms included psychomotor and cognitive slowing as well as lack of motivation for recovery, poor rehabilitation effort, social withdrawal, and apathy. A positive response was noted in seven patients, and in one patient the response was equivocal. Side effects noted were increased blood pressure (N=2) and subjective restlessness/agitation (N=3). Methylphenidate appears to be an effective, rapidly acting agent in this setting at dosages of 10–20 mg/day, with minimal side effects. Methylphenidate may have a significant role in the care of an ever-increasing population of organ transplant recipients with multiple medical problems and associated disabilities.
Key Words: Methylphenidate • Transplants • Transplantation • Organ Donation • Liver Transplants
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INTRODUCTION
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Methylphenidate (Ritalin, manufacturer: Ciba/Geigy) has been found to be a useful treatment for depression in medically ill patients because of its rapid action and favorable side-effect profile.1–9 It has been shown to improve certain medical patients' motivation and ability to comply with physical rehabilitation regimens.2,3,8 Depression, psychomotor and cognitive slowing, social withdrawal, apathy, and poor effort in physical rehabilitation are all common problems post liver transplantation. It seemed that methylphenidate might have a valuable niche in this setting. Trzepacz et al., in a recent review of psychopharmacology in organ transplantation, suggest a potential role for methylphenidate in improving depressive symptoms in transplant patients.10 However, to our knowledge there have been no prior published reports of methylphenidate's use in the transplant setting. We report the results of the first eight postliver transplant inpatients whom we treated with methylphenidate at Mount Sinai Medical Center in New York City.
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Case Reports
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Patient No. 1. A 61-year-old man had alcoholic cirrhosis after long-term alcohol abstinence. Mild cognitive deficits and psychomotor slowing had been noted pretransplant in the setting of hepatic encephalopathy. Post liver transplant, he had persistent cognitive impairment, with lethargy, verbal perseveration, and disorganization of speech, as well as depressed mood with expression of a passive wish to die. Mental symptoms were initially attributed to azotemia but persisted despite improvement in renal function. Methylphenidate was started 27 days posttransplant. The patient had a rapid increase in alertness within 24 hours but remained cognitively impaired with verbal perseveration and was disoriented to time. The dosage was increased to 20 mg/day after 5 days. Mild restlessness was described, but no specific treatment was required, and he remained on methylphenidate (20 mg/day). Mood and cognition improved slowly. Four weeks after treatment with methylphenidate was begun, the patient was in good spirits and could read and do crossword puzzles. Methylphenidate was discontinued after 6 weeks of treatment. Four days later, at hospital discharge, there was no observable worsening of his mental state.
Patient No. 2. A 54-year-old woman received a transplant for hepatitis C cirrhosis. Nine days posttransplant she remained agitated, with periods of confusion and persecutory thinking, and was quite withdrawn. Haloperidol (0.5 mg po qhs) was begun. The acute agitation resolved, and haloperidol was discontinued after 10 days. Three days later (22 days posttransplant), she appeared indifferent and apathetic but denied feeling depressed. Mild cognitive deficits ("WORLD" backwards was given as "DLOW"), psychomotor slowing, periods of amnesia, and severe impoverishment of thought and speech were noted. Methylphenidate was started 27 days posttransplant at 5 mg bid. Within hours of the first methylphenidate dose, the patient was noted to be more verbal. Methylphenidate was increased to 15 mg/day 2 days later, and by the next day she was dramatically improved, much more verbal and affable, and doing the New York Times crossword. Methylphenidate was decreased to 10 mg/day after she complained of restlessness. She was discharged home on methylphenidate (10 mg/day). On a subsequent admission 1 month later, the patient was still taking methylphenidate (10 mg/day) and appeared cognitively intact and minimally depressed. Methylphenidate was decreased to 5 mg qam. Two months later, she had discontinued methylphenidate and appeared in reasonable spirits and cognitively intact.
Of note, she had had episodes of mild depression for several months following the birth of each of her first 3 children, and then at age 32 she had a severe depressive episode after the birth of her fourth child. She had made a suicide attempt, had been successfully treated with electroconvulsive therapy, and then had taken lithium carbonate for 1 year only. She had remained without any recurrence of depression in the subsequent 22 years up until the time of transplant. On questioning, she stated that her posttransplant symptoms were qualitatively different from those experienced 22 years earlier during her previous severe depressive episode, but the patient did not provide specific details.
Patient No. 3. A 67-year-old woman had cirrhosis attributed to hepatitis C. On examination 10 days posttransplant, she was lethargic, uncooperative, and had disorientation, visual hallucinations, and poor sustained attention. By 60 days posttransplant, she was somewhat improved, although still quite slowed and often disoriented. Methylphenidate was started 60 days posttransplant at 5 mg po qam, and the patient showed some increase in psychomotor speed within 24 hours. Blood pressure, which had ranged from 120–200 systolic and 70–100 diastolic, reached 220/100 on 1 occasion 4 days after methylphenidate was begun. Nifedipine was begun 10 mg sublingual tid (NOTE: the sublingual route is no longer generally recommended11), and methylphenidate was stopped for 1 day, then restarted. Methylphenidate was gradually increased to 20 mg/day, and gradual improvement in cognition and in animation was noted. After 51 days of treatment with methylphenidate (111 days posttransplant), the patient's affect was much brighter, and she was able to spell "WORLD" backwards and recall 1/3 objects at 5 minutes. No further unusual elevations were noted in blood pressure, which ranged from 120–180 systolic and 70–110 diastolic through the remainder of the hospital stay.
Patient No. 4. A 39-year-old woman was readmitted with respiratory depression attributed to oral methadone use for pain 17 months after liver transplantation for cryptogenic cirrhosis. She described depressed mood, poor appetite, and sleep-wake cycle reversal. She was withdrawn, spoke minimally, and had a bland affect. During this hospitalization, she remained on about 15–20 mg/day of methadone for pain management. Methylphenidate was initiated at 5 mg/day. Within 2 days, the patient had a brighter affect and improved appetite, and was more talkative. By the next day, her daytime sleepiness had resolved. Methylphenidate was increased to 5 mg bid on Day 4 of treatment. (The patient had initially felt "jittery" on Day 1, but this side effect had resolved spontaneously by Day 2). By Day 4, she was more hopeful and engaged readily in conversation. Methylphenidate was decreased to 5 mg/day on Day 5 because of a single episode of elevated blood pressure (of 170/100). The patient was discharged that same day on methylphenidate (5 mg/day), with repeat blood pressure within normal limits, and methadone (20 mg/day) to outpatient psychiatric follow-up.
Patient No. 5. A 31-year-old man with cirrhosis attributed to hepatitis C and alcohol had mild cognitive impairment pretransplant, thought to be secondary to hepatic encephalopathy. The patient had been abstinent from alcohol for 4 years. The surgical intensive care unit (SICU) course following liver transplant was complicated by disseminated intravascular coagulation, renal failure, cachexia requiring feeding through a gastrostomy tube, and tracheostomy.
He was often noted to be confused, with periods of acute agitation, disorientation, suspiciousness, and physical combativeness toward staff. After discharge from the SICU, the patient's agitation gradually improved, although he still required occasional doses of haloperidol (0.5 mg po). He intermittently expressed feelings of depressed mood, hopelessness, and a passive wish to die. He remained irritable and short-tempered, affect was constricted, and he was poorly compliant with physical therapy. He refused to cooperate with cognitive examination. Methylphenidate was initiated 98 days posttransplant at 5 mg/day and was gradually increased to 15 mg/day, whereupon he was noted to have improved motivation and to be more conversant. On 20 mg/day, the patient had continued improvement in motivation, with better mood and good rehabilitation effort. The patient was transferred to an inpatient physical rehabilitation center on 20 mg/day of methylphenidate.
Patient No. 6. A 66-year-old man had cryptogenic cirrhosis and a history of hypothyroidism, which was treated with supplemental thyroxine. Mild cognitive slowing was noted pretransplant and was thought to be caused by hepatic encephalopathy. He had a complicated posttransplant SICU course, with chronic rejection, bilateral pneumonia, adult respiratory distress syndrome, and numerous other infections. He required a tracheostomy after a prolonged intubation and remained ventilator dependent. In his fourth SICU month posttransplant, he was noted to be confused and agitated on a chronic fentanyl drip. Fentanyl was changed to haloperidol, and buspirone was begun for ventilator anxiety. Buspirone was increased to 20 mg/day, and the haloperidol was discontinued. The patient remained negativistic, apathetic, and made limited effort in physical therapy. Methylphenidate was initiated 122 days posttransplant at 5 mg/day and was gradually increased to 10 mg bid over the next 5 days. By Day 7 of methylphenidate, the patient was noted to be much more alert; buspirone was tapered and discontinued. The patient showed continued improvement in mood and appetite. By Day 15 of methylphenidate, the patient was much more engagable and responsive. He remained on methylphenidate (20 mg/day), and by 3 weeks of treatment he was described as upbeat, vigorous, and eating well, as well as had improved sleep and was able to respond to supportive psychotherapy. He was discharged home on methylphenidate (20 mg/day).
Patient No. 7. A 60-year-old woman had cryptogenic cirrhosis and mild pretransplant cognitive slowing, which was thought to be caused by hepatic encephalopathy. She received a first liver transplant, then a second liver transplant 13 days later for acute rejection. For 1 month after the second transplant, the patient was noted to be lethargic and cognitively impaired. She had periods of agitation and expressed a wish to die. The cognitive symptoms and agitation failed to improve with reduction of cyclosporine dose. Methylphenidate was started at 10 mg/day 30 days after the second transplant. The patient reported feeling more alert within 24 hours, and she had some improvement in orientation, yet remained cognitively impaired. Methylphenidate was gradually increased to 20 mg/day, at which point she showed improved rehabilitation effort and less disorganization. Although she remained at times emotionally labile with episodes of crying and irritability, she reported a much brighter mood, was more congenial, joked at times with staff, and had improved energy. She was transferred to a nursing home on methylphenidate (20 mg/day).
Patient No. 8. A 63-year-old woman with alcoholic cirrhosis received a liver transplant and had a prolonged SICU course complicated by a cardiopulmonary arrest. Persistent cognitive impairment was noted posttransplant and post arrest. Multiple medical problems posttransplant included pneumonia followed by ventilator dependence, tracheostomy, renal failure requiring dialysis, and severe deconditioning. On examination 4.5 months posttransplant, she was disheveled, poorly cooperative, depressed, and angry, with poor sustained attention. Decreased appetite and noncompliance with physical therapy were noted. Methylphenidate was initiated on postoperative day 174 at 5 mg/day, and the dosage was gradually increased to 15 mg/day. Some increase in alertness, talking, smiling, and attention to tasks was noted, but she still appeared confused and had perseverative speech. Methylphenidate was increased to 20 mg/day, at which point the patient appeared more alert and responsive, with decreased agitation and better sleep and appetite. However, she remained cognitively impaired and occasionally disoriented. Methylphenidate was discontinued after re-admission to the SICU for respiratory support. The effect on her mental state of stopping methylphenidate was difficult to assess, because of her severe physical illness. She remained with persistent severe cognitive impairment and expired 345 days after the liver transplant.
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DISCUSSION
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Results of this uncontrolled, open-label series suggest that methylphenidate is well tolerated in this group and may treat cognitive as well as depressive symptoms. Four patients (Case Reports 2, 4, 5, and 6) showed dramatic overall improvement in function; in two cases (Cases 2 and 4) this occurred within 4 days after methylphenidate was begun. In the other 4 patients (Cases 1, 3, 7, and 8), improved alertness was observed quite early in the course of methylphenidate treatment (within 24 hours for the patients in Cases 1, 3, and 7), but significant cognitive impairment remained despite continued treatment. The apparent usefulness of methylphenidate in our series is consistent with previous clinical work that used stimulants post cardiac surgery3 and in other situations requiring mobilization for physical rehabilitation after serious medical illness.2,8
Side effects, which included increase in blood pressure (n=2) and mild subjective restlessness or agitation (n=3), were manageable in our series and did not require discontinuation of methylphenidate. Since immunosuppressants may also cause hypertension, combined treatment with immunosuppressants and methylphenidate should include careful monitoring of blood pressure. There was initial concern that methylphenidate would cause anorexia and weight loss in transplant patients, especially since immunosuppressant medications have been associated with anorexia and weight loss.12 However, at least 3 of our patients (Cases 4, 6, and 8) showed improved appetite after methylphenidate was begun. This finding is consistent with another recent study that noted improved appetite in many stimulant-treated cancer patients.7 No systematic attempt in the current study was made to describe the patients' comorbid medical conditions, concurrent medications, or laboratory values because of the extraordinary number and complexity of such variables.
Methylphenidate, a piperidine-derivative stimulant, is a Federal Drug Administration-approved first-line treatment for attention-deficit hyperactivity disorder in children and for narcolepsy, but has found extensive "off-label" use in the treatment of medically ill depressed adults.1,9 Its mechanism of action in the central nervous system appears to be its ability to induce the release of intraneural dopamine.9
The patients were a heterogeneous group with regard to psychiatric syndromes. Seven were treated during the initial transplantation admission, and 1 patient (Case 4) was treated much later on re-admission. Only 1 patient (Case 2) was noted to have a history of primary mental disorder, although at least 4 patients (Cases 1, 5, 6, and 7) had pretransplant cognitive disorders presumed to be caused by hepatic encephalopathy.
Formal diagnostic classification was not attempted. It is likely, though, that many of the patients would have met DSM-IV criteria for delirium posttransplant, since DSM-IV uses less restrictive criteria for delirium, and that some of them might still have qualified as having delirium at the time methylphenidate was initiated. At least 6 of the 8 patients had cognitive symptoms at the time methylphenidate was begun (Table 1). Although the psychiatric literature has mainly discussed methylphenidate as a treatment for depression in the medically ill,1 it seems possible that many if not most of the patients in this series had primarily cognitive disorders with associated mood symptoms, rather than mood disorders per se. Satel and Nelson1 have suggested that the controversy in psychiatry surrounding methylphenidate treatment of depression may reflect underlying uncertainties as to diagnosis. It is possible that methylphenidate may have also served to treat undiagnosed sleep disorders in some of these patients. Further resolution of the uncertainty of psychiatric diagnosis in posttransplant stimulant candidates will require studies that use objective ratings of depression, cognition, and delirium, and perhaps sleep measurement as well.
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CONCLUSION
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Methylphenidate appears to be useful in the rehabilitation of post liver transplant patients with cognitive and/or depressive symptoms. Additional clinical series may be expected to further define the role of stimulants in the treatment of the postoperative liver transplant patient with neuropsychiatric morbidity.
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ACKNOWLEDGMENTS
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An earlier version of this work was presented at the Academy of Psychosomatic Medicine 43rd Annual Meeting, San Antonio, Texas, November 15, 1996.
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REFERENCES
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Satel SL, Nelson JC: Stimulants in the treatment of depression: a critical overview. J Clin Psychiatry 1989; 50:2491–2492
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Kaplitz SE: Withdrawn, apathetic geriatric patients responsive to methylphenidate. J Am Geriatr Soc 1975; 23:271–276[Medline]
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Kaufmann MW, Cassem N, Murray G, et al: The use of methylphenidate in depressed patients after cardiac surgery. J Clin Psychiatry 1984; 45:82–84[Medline]
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Fernandez F, Adams F, Holmes VF, et al: Methylphenidate for depressive disorders in cancer patients. Psychosomatics 1987; 28:455–461[Abstract/Free Full Text]
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Lazarus LW, Moberg PJ, Langsley PR, et al: Methylphenidate and nortriptyline in the treatment of poststroke depression: a retrospective comparison. Arch Phys Med Rehabil 1994; 75:403–406[Medline]
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Woods SW, Tesar GE, Murray GB, et al: Psychostimulant treatment of depressive disorders secondary to medical illness. J Clin Psychiatry 1986; 47:12–15
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Olin J, Masand P: Psychostimulants for depression in hospitalized cancer patients. Psychosomatics 1996; 37:57–62[Abstract/Free Full Text]
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Clark ANG, Mankikar GD: d-Amphetamine in elderly patients refractory to rehabilitation procedures. J Am Geriatr Soc 1979; 27:174–177[Medline]
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Masand PS, Tesar GE: Use of stimulants in the medically ill. Psychiatr Clin North Am 1996; 19:515–547[Medline]
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Trzepacz PT, DiMartini A, Tringali RD: Psychopharmacologic issues in organ transplantation, part 2: psychopharmacologic medications. Psychosomatics 1993; 34:290–298[Abstract/Free Full Text]
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Grossman E, Messerli FH, Grodzicki T, et al: Should a moratorium be placed on sublingual nifedipine capsules given for hypertensive emergencies and pseudoemergencies? JAMA 1996; 276:1328–1331[Abstract/Free Full Text]
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Mor E, Sheiner PA, Schwartz ME, et al: Reversal of severe FK506 side effects by conversion to cyclosporine-based immunosuppression. Transplantation 1994; 58:380–382[Medline]
This article has been cited by other articles:
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H. W. Goforth and K. G. Shiry
Electroconvulsive Therapy for Severe Major Depressive Disorder After Orthotopic Liver Transplantation * Case Report
Psychosomatics,
May 1, 2008;
49(3):
271 - 272.
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ABSTRACT
INTRODUCTION
