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 Table of Contents  
CLINICAL CASE REPORT
Year : 2018  |  Volume : 31  |  Issue : 5  |  Page : 281-282

Tacrolimus-associated mania with psychotic symptoms in a child after renal transplant


Department of Psychiatry, All India Institute of Medical Sciences, New Delhi, India

Date of Web Publication24-Jun-2019

Correspondence Address:
Prashant Gupta
Department of Psychiatry, All India Institute of Medical Sciences, New Delhi
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0970-258X.261183

  Abstract 


Tacrolimus is one of the mainstays for post-transplant immunosuppression. A variety of neuropsychiatric adverse effects have been reported above the levels of its therapeutic use. Manic symptoms associated with its use have been rarely reported. We report possibly the first such case in a child post-renal transplantation and discuss the potential neuro-immunological basis of these symptoms.


How to cite this article:
Gupta P, Singh J, Mahapatra A, Sharan P. Tacrolimus-associated mania with psychotic symptoms in a child after renal transplant. Natl Med J India 2018;31:281-2

How to cite this URL:
Gupta P, Singh J, Mahapatra A, Sharan P. Tacrolimus-associated mania with psychotic symptoms in a child after renal transplant. Natl Med J India [serial online] 2018 [cited 2019 Jul 22];31:281-2. Available from: http://www.nmji.in/text.asp?2018/31/5/281/261183




  Introduction Top


Tacrolimus (FK-506) is one of the mainstays for post-transplant immunosuppression and finds some use in autoimmune diseases (Crohn disease, psoriasis and rheumatoid arthritis). It is a narrow therapeutic index drug.[1] A variety of neuropsychiatric adverse effects have been reported beyond the therapeutic levels.[1] We found only 2 published reports of manic symptoms associated with tacrolimus use.[2],[3] We report possibly the first such instance in a child and discuss the potential neuro-immunological basis of these symptoms.


  The Case Top


An 8-year-old boy underwent renal transplant for stage IV chronic kidney disease in 2013. Post-transplant, he was started on mycophenolate mofetil (500 mg/day), tacrolimus (6 mg/day) and prednisolone (5 mg/day); and an antihypertensive, amlodipine (5 mg/day) was administered regularly at the paediatric nephrology clinic. Serum tacrolimus concentration was regularly monitored and maintained within the normal maintenance range of 5–10 ng/ml. He also received valproate 400 mg/day, for generalized tonic–clonic seizures, which predated his renal transplant, and for which no specific cause could be detected. He was seizure-free since 2013 when valproate was started.

He was well till October 2016 when his parents noticed that he was not sleeping properly; he was more active than usual and did not seem to get tired. He would move around incessantly, frequently shifting tasks without completing them. He became irritable if someone interrupted his activities. He started ordering around his parents authoritatively, often shouting at them and threatening them with dire consequences, and sometimes hitting them, which was very unlike him. He appeared to be talking excessively, even with strangers, and interrupting him was difficult. He started telling people that he is ‘Lord Hanuman’, is very powerful and that he can do anything. While saying so, he would make gestures like Gods in Hindu mythology, as if to give a boon or a curse. This belief was held at a delusional intensity. All through this time, he did not have fever and his sensorium was clear. Within 2 weeks of onset, his condition warranted inpatient psychiatric management. Neither he nor his family had any history of psychiatric illness.

At the time of admission, he was receiving the above-mentioned drugs in usual doses. His weight was 24 kg and height 123 cm. His blood pressure was 120/70 mmHg and pulse rate 87/minute. There were no apparent signs of encephalitis. His haemoglobin, blood counts, serum electrolytes, urea and creatinine, liver functions and CT scan of the head were normal. Serum valproate levels were in the normal range for seizure control (55 μg/ml), but tacrolimus levels were elevated (17.8 ng/ml). The dose of tacrolimus was then reduced to 4 mg/day. In the next 4 days, serum tacrolimus levels decreased to 8.4 ng/ml, and some improvement in the manic symptoms was also noticed. Since the improvement was slow and the symptoms were severe, quetiapine was started. There was progressive improvement in the psychiatric condition, temporally correlated with a gradual reduction in tacrolimus levels from 8.8 ng/ml to 7.1 ng/ml and a gradual increase in the dose of quetiapine from 50 to 450 mg/day over a period of 7 weeks during the inpatient stay. Symptoms had resolved completely at the time of discharge. One week into the treatment, he also developed hyponatraemia and pancytopenia which improved on replacing valproate with levetiracetam.

Two months later, he had similar manic and psychotic symptoms despite continuing with quetiapine (450 mg/day) and reduced dose of tacrolimus (3.5 mg/day). The dose of quetiapine was further increased to 500 mg, which led to sedation but inadequate control of symptoms in the next 1 month. Tacrolimus levels were again found to be elevated (13.4 ng/ml). Vital parameters were normal. The patient was not on any drugs whose interaction with tacrolimus could explain the rise in its levels. Although, the laboratory parameters showed pancytopenia, no abnormalities were noticed in liver functions ruling out any problems in hepatic metabolism of the drug. Blood urea nitrogen was also within normal limits. However, there was vomiting and weight loss (2 kg), which may have contributed to the rise in tacrolimus levels. He was admitted under the paediatric nephrology unit. Tacrolimus was stopped and cyclosporine started. Supportive treatment was given for his medical condition. Quetiapine was continued in a reduced dose (400 mg/day). The mental and physical status improved over the next 2 weeks. The patient maintained well even after 3 months of replacing tacrolimus with cyclosporine (dose 150 mg/day, serum levels 1330 ng/ml). At the time of writing this report, it was decided to gradually reduce the dose of quetiapine during follow-up if the patient continues to remain asymptomatic.


  Discussion Top


The clear temporal association of psychiatric symptoms with elevated serum tacrolimus levels on 2 occasions, and their resolution with reduction of levels or removal of the drug on both occasions confirmed a diagnosis of ‘tacrolimus-associated mania with psychotic symptoms’ in this patient. Although he was also receiving prednisolone, it was in a low dose, and there had been no recent change in the dose. Moreover, his renal transplant was working well as was evident by laboratory parameters, and there was no evidence of recent seizures, ruling out other potential causes of psychiatric symptoms.

Bersani et al[2] reported a ‘manic-like psychosis’ associated with elevated blood concentrations (13.8 ng/ml) of tacrolimus in a 40-year-old man following renal transplant, and Jain et al.[3] reported a 68-year-old woman who received tacrolimus for acute lymphoblastic leukaemia and developed ‘mania with psychosis’ even with subtherapeutic levels of tacrolimus (1.6 ng/ml). Our patient also had both manic and psychotic symptoms. A few case reports of tacrolimus-associated psychotic symptoms (without manic symptoms) have also been published,[4],[5],[6] though in only 1 of them did the patient have a clear sensorium.[4] A retrospective study on adverse effects of tacrolimus in liver transplant recipients mentioned 2 patients developing psychosis and confusion, though the details were not provided.[7] All these reports are of adults, while ours is possibly the first such instance in a child. Previous reports have shown improvement in symptoms with antipsychotic drugs such as haloperidol[3],[6] or olanzapine,[2],[4] or with a reduction in the dose of tacrolimus,[2],[4] or its replacement with alternative immunosuppressant therapies (mostly change to cyclosporine).[3],[5],[6] Some have used a combination of these 2 approaches.

There has been limited research into the neurobiological basis of such adverse effects. Tacrolimus exerts its immunosuppressive effects by binding to a family of immunophilins called FK506- binding protein 12 (FKBP12).[8] The high molecular weight congener of this protein FK506-binding protein 51 (FKBP5) is a co- chaperon of glucocorticoid receptors (GR), and overexpression of FKBP5, as seen in some polymorphisms, has been shown to reduce binding of cortisol with GR as well as the nuclear translocation of GR.[9] Through this mechanism, FKBP5 has been thought to affect the stress response system and thus has been implicated in the pathogenesis of anxiety, depression, post-traumatic stress disorder and psychosis.[9],[10],[11],[12],[13],[14] We speculate that the interaction of tacrolimus with FKBP5 may have a role in the emergence of psychiatric symptoms, though the available literature is silent on this. A scientific enquiry may provide valuable insights into the neuro-immunological mechanisms of these psychiatric conditions. This case highlights the need to closely monitor patients receiving tacrolimus for the emergence of such psychiatric adverse effects.

Conflicts of interest. None declared



 
  References Top

1.
National Center for Biotechnology Information. PubChem Compound Database. Available at www.pubchem.ncbi.nlm.nih.gov/compound/445643. (accessed 27 Apr 2017).  Back to cited text no. 1
    
2.
Bersani G, Marino P, Valeriani G, Cuoco V, Zitelli C, Melcore C, et al. Manic-like psychosis associated with elevated trough tacrolimus blood concentrations 17 years after kidney transplant. Case Rep Psychiatry 2013;2013:926395.  Back to cited text no. 2
    
3.
Jain S, Hsuan Liao Y, Li D. Tacrolimus induced mania with psychosis: A case report. Clin Case Rep Rev 2015;1:[doi: 10.15761/CCRR.1000187].  Back to cited text no. 3
    
4.
Corruble E, Buhl C, Esposito D, Schuster JP, Chouinard VA, Hardy P, et al. Psychosis associated with elevated trough tacrolimus blood concentrations after combined kidney-pancreas transplant. Int J Neuropsychopharmacol 2006;9:493-4.  Back to cited text no. 4
    
5.
Chegounchi M, Hanna MG, Neild GH. Progressive neurological disease induced by tacrolimus in a renal transplant recipient: Case presentation. BMC Nephrol 2006;7:7.  Back to cited text no. 5
    
6.
Krishna N, Chiappelli J, Fischer BA, Knight S. Tacrolimus-induced paranoid delusions and fugue-like state. Gen Hosp Psychiatry 2013;35:327.e5-0.  Back to cited text no. 6
    
7.
Varghese J, Reddy MS, Venugopal K, Perumalla R, Narasimhan G, Arikichenin O, et al. Tacrolimus-related adverse effects in liver transplant recipients: Its association with trough concentrations. Indian J Gastroenterol 2014;33:219-25.  Back to cited text no. 7
    
8.
Galigniana NM, Ballmer LT, Toneatto J, Erlejman AG, Lagadari M, Galigniana MD, et al. Regulation of the glucocorticoid response to stress-related disorders by the Hsp90-binding immunophilin FKBP51. J Neuro chem 2012;122:4-18.  Back to cited text no. 8
    
9.
Binder EB. The role of FKBP5, a co-chaperone of the glucocorticoid receptor in the pathogenesis and therapy of affective and anxiety disorders. Psychoneuroendocrinology 2009;34 Suppl 1:S186-S195.  Back to cited text no. 9
    
10.
Minelli A, Maffioletti E, Cloninger CR, Magri C, Sartori R, Bortolomasi M, et al. Role of allelic variants of FK506-binding protein 51 (FKBP5) gene in the development of anxiety disorders. Depress Anxiety 2013;30:1170-6.  Back to cited text no. 10
    
11.
Rao S, Yao Y, Ryan J, Li T, Wang D, Zheng C, et al. Common variants in FKBP5 gene and major depressive disorder (MDD) susceptibility: A comprehensive meta-analysis. Sci Rep 2016;6:32687.  Back to cited text no. 11
    
12.
Xie P, Kranzler HR, Poling J, Stein MB, Anton RF, Farrer LA, et al. Interaction of FKBP5 with childhood adversity on risk for post-traumatic stress disorder. Neuropsychopharmacology 2010;35:1684-92.  Back to cited text no. 12
    
13.
Alemany S, Moya J, Ibáñez MI, Villa H, Mezquita L, Ortet G, et al Research letter: Childhood trauma and the rs1360780 SNP of FKBP5 gene in psychosis: A replication in two general population samples. Psychol Med 2016;46:221-3.  Back to cited text no. 13
    
14.
Mihaljevic M, Zeljic K, Soldatovic I, Andric S, Mirjanic T, Richards A, et al. The emerging role of the FKBP5 gene polymorphisms in vulnerability-stress model of schizophrenia: Further evidence from a Serbian population. Eur Arch Psychiatry Clin Neurosci 2016;267:527-39.  Back to cited text no. 14
    




 

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