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Successful Use of Clozapine With Immunosuppressive Therapy in a Renal-Transplant Patient

TO THE EDITOR:  Nearly 500,000 patients carry a diagnosis of end-stage renal disease (ESRD) in the United States, and the incidence rate is steadily increasing.¹ Although dialysis is the mainstay of treatment for ESRD, access to renal transplantation is on the rise. Government funding provides for universal treatment of ESRD; thus, a large population of patients has access to both dialysis and renal transplantation.¹ Among this population are patients with mental illness.

It is increasingly common to encounter hospitalized patients with ESRD who carry chronic and active psychiatric diagnoses.¹ In addition to primary causes of ESRD, use of antipsychotic medications that are associated with metabolic complications of weight gain, diabetes mellitus, and hyperlipidemia may contribute to the development or exacerbation of renal disease in these patients. Medical noncompliance, common in the psychiatric population, may put these patients at even greater risk for the development of progressive renal failure.

Clozapine is the only FDA-approved therapy for treatment-resistant schizophrenia.² Its use in treatment-resistant and refractory schizoaffective and bipolar disorder patients has also been well-documented.³ Clozapine is associated with numerous side effects, including weight gain, tachycardia, lowering of the seizure threshold, sialorrhea, sedation, and, most notably, idiosyncratic agranulocytosis. Agranulocytosis is estimated to occur in 1% to 2% of clozapine-treated patients; it is most likely to occur in the first 6 months of treatment, and it is more common in women and in elderly patients.⁴ The standard clozapine treatment protocol requires regular evaluation of the white blood cell (WBC) count and mandates discontinuation of the drug for neutropenia, per published guidelines.⁵

Immunosuppressive therapy is a standard part of renal-transplant treatment.⁶ The use of other agents with immunomodulating potential, such as clozapine, in conjunction with renal-transplant immunosuppressive treatment, must be carefully considered. No formal guidelines exist regarding the use of clozapine in renal-transplant patients or in other patients requiring long-term immunosuppressive therapy. Cases of clozapine use together with other drugs having myelosuppressive potential have been described in the context of cancer-related chemotherapy treatments. In each of six cases, clozapine was used successfully alongside cancer chemotherapy agents without additional or problematic immunosuppression.^7–12

We report here a case of continued clozapine treatment in a patient receiving immunosuppressive therapy as part of a renal-transplant protocol.

Case Report
A 50-year-old white man with a past medical history of ESRD, hypertension, pancreatitis, and hypothyroidism presented for cadaveric renal transplantation. His psychiatric history was notable for diagnoses of schizoaffective disorder bipolar-type, posttraumatic stress disorder, and polysubstance abuse. Psychiatric medications on admission included clozapine 350 mg bid, clonazepam 0.5 mg tid, citalopram 40 mg qd, and benztropine 1.0 mg qhs. Previous treatment trials had included lithium, valproic acid, and risperidone. The patient had suffered from persistent auditory hallucinations, paranoid delusions, and related agitation until he was placed on clozapine. Mood and psychotic symptoms had improved significantly, and WBC counts had been within normal limits during a 6-year course of clozapine therapy. End-stage renal disease (treated with hemodialysis 3 times weekly) was diagnosed 2 years before his admission for renal transplantation.

The patient underwent uncomplicated cadaveric renal transplantation. The medical-psychiatry service was consulted regarding concerns about an increased risk of agranulocytosis caused by potential synergistic effects of transplant immunosuppressant agents and clozapine. Evaluation of the patient’s past medical and psychiatric histories suggested that the benefits of restarting clozapine outweighed any known risks of combined therapy. The patient’s clozapine was restarted, and transplant immunosuppressive medications, including tacrolimus (Prograff), mycophenolate mofetil (Cellcept), and prednisone were initiated. Follow-up has noted excellent compliance, remitted psychiatric symptoms, stable renal function, and normal WBC counts.

Discussion
This case describes the safe use of clozapine, an antipsychotic drug with a documented risk of agranulocytosis, in combination with other agents having immunosuppressive potential. As in the findings of earlier cases reporting the use of clozapine with cancer chemotherapy agents, we found no evidence of additive or unexpected immunosuppression when clozapine was used in conjunction with a transplant-medication regimen. In contrast to those patients with clozapine use during a discrete and time-limited period of cancer-chemotherapy treatment, this patient must remain on life-long immunosuppressive therapy. The immunosuppressive risk associated with clozapine is granulocyte-based, whereas transplant-related immunosuppression is T-cell/lymphocyte-based, which likely explains the safe use of these agents in combination.

Given the growing number of psychiatric patients with renal failure and the increasing availability of renal transplantation as a treatment for ESRD, guidelines directing the use of clozapine in combination with other immunosuppressive therapies are needed.

REFERENCES

1. Kimmel PL, Thamer M, Richard CM, et al: Psychiatric illness in patients with end-stage renal disease. Am J Med 1998; 105:214–221[CrossRef][Medline]
2. Wahlbeck K, Cheine M, Essali A, et al: Evidence of clozapine’s effectiveness in schizophrenia: a systematic review and metaanalysis of randomized trials. Am J Psychiatry 1999; 156:990–999[Abstract/Free Full Text]
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8. McKenna RC, Bailey L, Haake J, et al: Clozapine and chemotherapy (letter). Hosp Community Psychiatry 1994; 45:831[Free Full Text]
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