|Year : 2021 | Volume
| Issue : 3 | Page : 272-274
Organ transplantation, immunosuppressant therapy, and management dilemma in drug-induced psychiatric manifestations: Lessons learned from a case report
Shivani Dua1, Jayaprakash Russell Ravan1, Vijay Raj Pratheek1, J Ipsita Pattnaik2, Sai P Sahoo3
1 Department of Psychiatry, Kalinga Institute of Medical Sciences, Bangaluru, India
2 Department of Psychiatry, St Johns Medical College, Bangaluru, India
3 Department of Nephrology, Kalinga Hospital, Bhubaneswar, Odisha, India
|Date of Submission||31-Aug-2020|
|Date of Decision||13-Dec-2020|
|Date of Acceptance||14-Jan-2021|
|Date of Web Publication||30-Sep-2021|
Dr. Jayaprakash Russell Ravan
Co founder, Biipbsar, Bhubaneswar, Odisha; Department of Psychiatry and Behavioral Sciences, Kalinga Institute of Medical Sciences, KIIT University, Bhubaneswar 751024, Odisha
Source of Support: None, Conflict of Interest: None
Solid organ transplantation is the intervention of choice for end-stage renal disease burdening the patient and care givers. Posttransplant patients receive immunosuppression therapy to prevent graft rejection which might lead to psychiatric side effects induced by the drugs, which require psychotropics for symptomatic relief. We present the case of a young man who developed tacrolimus-induced psychosis and management dilemma due to the drug interactions. Risperidone or haloperidol, which is usually given for acute management of psychotic symptoms, is contraindicated due to the interactions with immunosuppressant therapy. In consultation–liaison psychiatry, it is imperative to know the interactions between psychotropics and transplant medications. We also discuss in detail the posttransplant psychiatric conditions and safer alternative psychotropics for different psychiatric conditions in view of potential drug–drug interaction of other medications with that of immunosuppressants.
Keywords: Case report, drug interactions, immunosuppressants, psychotropics
|How to cite this article:|
Dua S, Ravan JR, Pratheek VR, Pattnaik J I, Sahoo SP. Organ transplantation, immunosuppressant therapy, and management dilemma in drug-induced psychiatric manifestations: Lessons learned from a case report. Indian J Transplant 2021;15:272-4
|How to cite this URL:|
Dua S, Ravan JR, Pratheek VR, Pattnaik J I, Sahoo SP. Organ transplantation, immunosuppressant therapy, and management dilemma in drug-induced psychiatric manifestations: Lessons learned from a case report. Indian J Transplant [serial online] 2021 [cited 2021 Nov 29];15:272-4. Available from: https://www.ijtonline.in/text.asp?2021/15/3/272/327383
| Introduction|| |
Solid organ transplantation is the most effective treatment for end-stage organ failure. Patients who undergo transplantation are subjected to immunosuppressant therapy, multiple investigations, and adverse drug reactions and suffer a significant impairment in functioning.
Neuropsychiatric side effects of immunosuppressants following solid organ transplantation include seizures, encephalopathy, and delirium. Calcineurin inhibitors (CiNs) like tacrolimus are commonly used immunosuppressant in solid organ transplant patients. CiNs cause downregulation of dopamine and N-methyl-d-aspartate receptors possibly resulting in psychosis and delirium.
The medical comorbid state mandates careful monitoring and management with psychotropics to minimize side effects and adverse drug–drug interaction and better clinical outcomes.
We present a case of renal transplantation who developed psychotic behavior following the use of immunosuppressants in order to highlight the potent drug–drug interaction of tacrolimus with psychotropics.
| Case Report|| |
A 38-year-old male who had undergone renal transplant for chronic kidney disease started showing early signs of graft rejection such as decreased urine output (oliguria), pain/tenderness over graft area, and increased temperature. Hence, he was started on intravenous (IV) steroids (Wysolone 10 mg once daily) and tacrolimus 1.5 mg twice a day. On the 5th day, following commencement of immunosuppressant medication and steroid, the patient developed sleep disturbances, mood swings, psychotic symptoms in the form of hallucinatory behavior, perplexity and agitation with no evidence of disorientation, confusion, and other features of delirium. There was no clinical evidence to support seizures, cerebrovascular accidents, head injury, thyroid dysfunction, or other metabolic conditions leading to acute psychosis.
Hence, a diagnosis of drug induced psychosis was made, where IV steroid and tacrolimus both could be contributory. The Immunosuppressants and steroids could not be tapered or reduced because of risk of graft rejection and no toxicity signs of tacrolimus were seen, hence it was not substituted with cyclosporine. Other indications for tacrolimus substitution with cyclosporine such as signs of new onset diabetes, malignancies, and thrombotic microangiopathy were not present, hence a cross tapering dose of tacrolimus was not considered on the decision of transplant team, and also, the facility to measure trough levels of tacrolimus was not available at our hospital.
Hence, for drug-induced psychosis, antipsychotic medication was considered. The commonly used antipsychotics such as haloperidol and risperidone were not considered due to potential drug–drug interactions causing alteration in metabolism of tacrolimus. Due to its safer pharmacokinetic and pharmacodynamic profile, Chlorpromazine 100 mg was prescribed to the patient along with short acting benzodiazepine lorazepam (1 mg/day). The patient improved over the course of time and was discharged. After 6 months, the patient was followed up with no signs of relapse of psychotic symptoms.
| Discussion|| |
In this 21st century with the rise of organ transplantation due to end-stage diseases and immunosuppressant therapy, it is always a challenge to manage psychiatric emergencies in posttransplant patient. Hence, we discuss the issues and lessons learned from the case to enhance the area of knowledge regarding management of these conditions.
Knowledge of drug interactions between antipsychotics, mood stabilizers, or antidepressants with tacrolimus and steroids is important to ensure that the medications remain in their narrow therapeutic window, as they may lead to clinically significant under- or overexposure to tacrolimus, with acute rejection episodes or serious nephrotoxicity.
Transplantation and psychiatric challenges
End-stage disease and transplantation make patients susceptible to emotional disturbances, aggression, and hostility which might warrant a psychiatric liaison. Following transplantation, patients may develop delirium, depression, anxiety, or psychosis. Postoperatively, psychiatric manifestations are seen in up to 80% of the intensive care unit (ICU) patients. Management includes evaluation of risk factors, infections, metabolic disturbances with symptomatic treatment, and reduction in dose of medications, if possible.
Neuropsychiatric manifestations of immunosuppressants
Immunosuppressants commonly used are CiNs (tacrolimus and cyclosporine), antiproliferative agents (mycophenolate and azathioprine), mechanistic target of rapamycin inhibitor (sirolimus), and steroids (prednisone). Immunosuppressants predominantly utilize the CYP450 3A4 for hepatic metabolism. Tacrolimus and cyclosporine have a similar neurotoxic profile. These can cause mild symptoms such as tremulousness, headache, restlessness, insomnia, vivid dreams, photophobia, anxiety, agitation, and moderate-to-severe symptoms such as cognitive impairment, coma, seizures, focal neurological deficits, dysarthria, cortical blindness, psychosis, and delirium. Corticosteroids can cause mild symptoms including agitation, anxiety, distractibility, insomnia, lethargy, labile mood, and restlessness and severe symptoms such as affective symptoms, psychosis, and cognitive impairment. Azathioprine has been reported to cause depressive symptoms in combination, with cyclosporine and prednisone. Mycophenolate has central nervous system adverse effects such as anxiety, depression, delirium, seizures, psychosis, and somnolence. Treatment generally includes dose reduction or discontinuation of the drug. If dose reduction is not feasible, symptomatic treatment is recommended.
Psychotropics and interaction with immunosuppressants
The possible clinical drug interactions coupled with a narrow therapeutic index make monitoring drug levels essential whenever medications are adjusted. Medications should be prescribed in the start low and go slow method, with a clear awareness of the signs and symptoms of toxicity.
Specific CYP450 3A4 inhibitors in decreasing order are as follows: fluvoxamine, nefazodone > fluoxetine > tricyclic antidepressant, paroxetine > venlafaxine. Mirtazapine, which does not act on cytochrome system, may be used to promote weight gain or sleep in patients awaiting transplant or in the postoperative period. Escitalopram is safer alternative with fewer drug interactions.
Benzodiazepines can be considered for short-term use in posttransplant patients with anxiety and insomnia. CYP3A4 inhibitors can also modestly affect plasma concentrations of oral alprazolam, diazepam, and midazolam. Lorazepam is only mildly affected by liver or renal dysfunction, so is preferable.
Cyclosporine increases lithium resorption by proximal tubule. Lithium can cause leukocytosis, which may confuse the picture in transplant patients with corticosteroid boluses, yeast infection, and tuberculosis infection.
Carbamazepine is a potent CYP3A4 inducer and can decrease the serum levels of immunosuppressive drugs, causing failure of immunosuppression. Leukopenia may be caused by carbamazepine, which can be associated with cytomegalovirus infection in transplant recipients. Less potent CYP3A4 inducers include oxcarbazepine and topiramate.
In recipients who were receiving mycophenolate, valproate decreased the bioavailability of the immunosuppressant drug, and when valproate was discontinued, the bioavailability is increased 1.8- to 2.2-fold.
Haloperidol and risperidone which are commonly used antipsychotics are generally to be avoided in patients on immunosuppressant therapy. Like tacrolimus, haloperidol is also metabolized by cytochrome CYP3A4, hence there is a chance of elevated tacrolimus levels leading to toxicity. Furthermore, co-administration of haloperidol and tacrolimus can lead to prolonged cardiac depolarization leading to prolonged cardiac repolarization and torsade de pointes. Risperidone is found to inhibit p-glycoprotein of the small intestine and thus can increase the absorption of tacrolimus causing toxic effects.
Many newer antipsychotics are also metabolized through CYP3A4 including aripiprazole, quetiapine, sertindole, and ziprasidone. Quetiapine in low dose is often used for delirium in ICU settings after transplant and is not thought to be a substrate for P-glycoprotein, so can be preferred. Clozapine is contraindicated with mycophenolate because of increased potential for agranulocytosis. Chlorpromazine is relatively safe that can be given in psychosis secondary to the use of high-dose prednisolone and tacrolimus. The relative safety was in view of its metabolism through CYP2D6 enzyme and not by CYP3A4 enzyme. Fluphenazine is also metabolized by CYP2D6 and is the better alternative to Chlorpromazine.
Knowledge of drug interactions between antipsychotics, mood stabilizers or antidepressants with tacrolimus and steroids is important to ensure that the medications remain in their narrow therapeutic window, as they may lead to clinically significant under or overexposure to tacrolimus, with acute rejection episodes or serious nephrotoxicity.
| Conclusion|| |
Knowledge about the immunosuppressant-related neuropsychiatric side effects and drug–drug interactions with psychotropics is imperative while dealing with posttransplant patients.
Transplantation is a challenging process for patients, caregivers, and medical professionals with significant psychosocial impact. Psychotropic agents have a significant interaction with immunosuppressants. Commonly used antipsychotics risperidone and haloperidol should be avoided in posttransplant patients with psychosis.
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Dhar R. Neurologic complications of transplantation. Handb Clin Neurol 2017;141:545-72.
Rushlow WJ, Seah C, Sutton LP, Bjelica A, Rajakumar N. Antipsychotics affect multiple calcium calmodulin dependent proteins. Neuroscience 2009;161:877-86.
Warrington TP, Bostwick JM. Psychiatric adverse effects of corticosteroids. Mayo Clin Proc 2006;81:1361-7.
DiMartini AF, Dew MA, Trzepacz PT. Organ transplantation. In: Levenson JL, editor. Textbook of Psychosomatic Medicine. Washington, DC: American Psychiatric Press; 2005. p. 675-700.
Armstrong SC, Cozza KL, Benedek DM. Med-psych drug-drug interactions update. Psychosomatics 2002;43:245-7.
DiMartini A, Crone C, Fireman M, Dew MA. Psychiatric aspects of organ transplantation in critical care. Crit Care Clin 2008;24:949-81, x.
Anil Kumar BN, Mattoo SK. Organ transplant & the psychiatrist: An overview. Indian J Med Res 2015;141:408-16.
Iwasaki K. Metabolism of tacrolimus (FK506) and recent topics in clinical pharmacokinetics. Drug Metab Pharmacokinet 2007;22:328-35.
Akers WS, Flynn JD, Davis GA, Green AE, Winstead PS, Strobel G. Prolonged cardiac repolarization after tacrolimus and haloperidol administration in the critically ill patient. Pharmacotherapy 2004;24:404-8.
Watanabe N, Higashi H, Nakamura S, Nomura K, Adachi Y, Taguchi M. The possible clinical impact of risperidone on P-glycoprotein-mediated transport of tacrolimus: A case report and in vitro
study. Biopharm Drug Dispos 2018;39:30-7.