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Manic episode with psychotic symptoms in a patient taking immunosuppressant medication following a renal transplant.


The calcineurin-inhibitor tacrolimus is considered one of the mainstays of posttransplant immunosuppression. Discovered in 1984, it is a macrolide lactone extracted from Streptomyces tsukubaensis as an alternative to cyclosporine (1).

Tacrolimus has similar immunosuppressive properties to cyclosporine, but is much more potent in its inhibitory effect (2). It is metabolized by the CYP3A4 located in the liver; hence, its blood concentrations are affected by both drugs inhibiting this enzyme (calcium channel blockers, antifungal agents, some antibiotics) and drugs inducing enzyme activity (anticonvulsants, rifampicin) (3). Its toxic potential is similar to that of cyclosporine: nephrotoxicity, neurotoxicity, gastrointestinal effects, hypertension, alterations in glucose metabolism, hiperkaliemia, and infectious complications. Because it pertains to the group of immunosuppressive drugs, it is used to control the immune response, thus allowing the body to accept the transplanted organ.

Though this treatment is imperiously necessary post renal transplant, a significant number of patients exhibited neurological adverse effects, with sever potential impact upon mental status and cognition. Numerous cases of moderate neurological adverse effects have been reported, which included tremor, paresthesia, and headaches, while severe neurological and psychiatric effects appear to be rarer. (4, 5)

Corticosteroids also have immunosuppressive effects upon cell-mediated immunity, but they are far less specific. Though they have been widely used for numerous conditions, corticosteroids have many psychiatric adverse effects, such as mood disorders (hypomania, mania, mixed states, depression), anxiety and panic disorder (6) delirium, suicidal thinking and behaviour, insomnia and agitation with clear consciousness, depersonalization, isolated cognitive impairments, reversible dementia (7).

Typically corticosteroid-induced psychiatric symptoms emerge in the first one or two weeks after ingesting high doses of corticosteroids. The most common adverse effect is hypomania or mania.

CellCept (Mycophenolate Mofetil) is the 2-morpholinoethyl ester of mycophenolic acid (MPA) and it is very effective for organ rejection prophylaxis and for refractory organ rejection treatment in patients receiving allogeneic renal transplants.


Patient aged 58, on his first psychiatric admission, addresses to the ER of the psychiatric clinic accompanied by his caregivers, for symptoms specific to mania with psychotic elements, which debuted approximately two weeks prior.

Personal history shows that the patient went through a renal transplant 10 months earlier, after eight years of dialysis.

He had no pathological episodes throughout his period of development.

Family history details are not important in this case, because the patient does not have first-degree relatives with psychiatric pathology.

The patient denies having consumed alcohol or other psychoactive substances; his caregivers attest to the truth of his statement.

Concerning socio-familial and professional insertion, the patient is married; he has an adult son; he lives with his wife in an urban flat and he has retired on medical grounds seven years prior. His statements and those of his family suggest that he has not had notable adaptive-integrative issues in his socio-familial environment.

In the triage of the "Socola" Psychiatric Institute, the patient exhibits psychomotor restlessness; he is irritable, irascible, incoherent in his speech; his language is trivial, his voice is high-pitched and intense; he makes ample gestures; he has delusions of grandeur with mystical and religious elements, as well as delirious thoughts of being followed and mistreated. His speech suggests exaggerated self-appreciation and over-optimistic ideas. The patient is easily distractible and suspicions; he features low tolerance to frustrations and tangibility. The interview becomes difficult, because the patient exhibits flight of ideas, which renders his speech incomprehensible. Furthermore, his attention and focus abilities are impaired. He is well oriented in space and time and concerning his own person.

The family declares that, during the morning, the patient has gone to the Nephrology Clinic for a routine appointment, where he has shown improper behaviour, accompanied by psychomotor restlessness, irritability, irascibility, logorrhea, and trivial language and overfamiliarity in his interaction with the medical personnel.

At home, the patient exhibits the same type of behaviour accompanied by aggressiveness toward the wife. She states that her husband sleeps 2-3 a night, that he talks "a lot and very loudly", "always using dirty words", "getting irritated suddenly and out of anything", "making inappropriate jokes". At the same time, within the past two weeks, he has made useless shopping, because of extravagant and unpractical ideas; he has also been neglecting his personal hygiene and his diet.

Following the psychiatric interview, the patient is admitted to a unit with doors locked, considering that he is a danger to himself and to others and that there is a risk for him to leave the hospital.

Clinical objective examination on devices and systems does not highlight any pathological alterations. Current tests range within normal parameters, while toxicological screen reveals no traces of psychoactive substances. Electroencephalogram and BESA show no presence of epileptic focus. The CT scan also ranges within normal values. Therefore, an organic origin of psychiatric symptomatology exhibited by the patient is ruled out.

The psychological exam highlights an emotionally unstable configuration with intermittent explosive manifestations, positive hyperthymic elements, and delirious, hallucinatory elements.

Once in the ward, the patient exhibits psychomotor anxiety; he is partially cooperative and communicative. His mimic is mobile, his facies is expressive, and his gestures are wide-ranged, in agreement with his affective tonality. He initiates intermittent eye contact with the interlocutor, his voice has average tonality and it is affectively modulated; he respects partially the mutual character of the dialogue. He exhibits voluntary and spontaneous hypoprosexia, with selective elements of hypoprosexia focusing on delirium and hypomnesia (due to his attention deficit disorder). However, his evocative memory is intact.


Following the psychiatric interview and a correct anamnesis, the diagnosis is set: Manic episode with psychotic symptoms by meeting the ICD-10 (8) criteria.

Considering that it is his first psychiatric admission, that he has functioned well pre-admission, and that there is no solid evidence to highlight the aetiology of these symptoms, the high level of tacrolimus in the blood stream raises suspicions. The diagnosis of corticosteroid-induced mania is ruled out, considering that has been taking only 5 mg/day (in such a situation, symptoms would have emerged within the first two weeks of treatment).


Considering the nephrotoxicity of lithium, on the day he is admitted, the patient is given 300 mg valproate in two doses (in the morning and in the evening), quetiapine XR 25 mg (in the evening), and one vial of diazepam (in the evening). During the evening, the patient exhibits psychomotor restlessness; he becomes recalcitrant, he uses improper language and he threats the medical personnel and the other patients.

In the following day, he is given quetiapine XR 50 mg/day, in the evening, and valproate 600 mg/day in two doses. Biological samples are also taken, in order to dose the blood concentration of tacrolimus.

Results reveal 18 ng/mL of tacrolimus in the blood: normal values range between 5 and 15 ng/mL. This aspect leads to an iatrogenic type of diagnosis.

A decision is made to contact his nephrologist, for a correct interdisciplinary therapeutic conduct. Discussions lead to the decision of maintaining adequate psychiatric treatment for mitigating the symptoms in the following two months (in order to mark one year since the renal transplant). The reduction of tacrolimus doses at this point would increase significantly the risk of renal transplant rejection.

Therefore, XR quetiapine XR doses gradually are increased to 600 mg/day administered all at once, in the evening; valproate doses are also increased to 1000 mg/day in two doses (in the morning and in the evening).

The evolution becomes increasingly favorable; the patient is discharged after three weeks of psychiatric stay; he has to follow the same treatment as during his hospitalization. Upon discharge, he is advised to avoid the intake of any kind of psychoactive substances and to benefit from a psycho-protective family environment. He is scheduled for a follow-up in two weeks. The follow-up shows a good evolution and a normal social and family functioning.

One year after the renal transplant, the tacrolimus dose is reduced, and the subsequent blood dosage shows a level of 8 ng/ mL (thus ranging within normal limits). Furthermore, the psychiatric medication is also reduced and eventually ceased. During his outpatient monitoring, the patient exhibits gradual remission of symptomatology, a euthymic mood, and socially and morally adequate behavior.


During Tacrolimus therapy, it is not uncommon to record oscillations in his blood concentration; the most frequent causes are drug interactions (macrolide antibiotics, antifungal drugs, or calcium channel blockers) (9).

Only limited reports on psychiatric symptoms induced by tacrolimus are present in the medical literature. Neurotoxicity and delirium have been reported to occur, hallucinations, anxiety, paranoid delusions and dissociative fugues (5, 10) have also been associated with elevated tacrolimus blood concentrations.

Though manic symptoms seem to be a rare adverse effect of Tacrolimus therapy, they may have a significant impact on long-term prognosis. In these cases, the proper management is closely connected to tacrolimus blood concentrations. Though psychiatric medication can suppress maniac symptomatology, the long-term solution is to reconsider the tacrolimus therapy or even to replace it with cyclosporine (11).

In this case, delirium, bipolar disorder, and schizoaffective disorder were ruled out, because diagnostic criteria were not met. The patient exhibited mania-like symptoms: irritability, irascibility, psychomotor restlessness, logorrhea, high energy levels and decrease need for sleep, high-pitched voice, flight of ideas, as well as delirium involving grandeur thoughts. Therefore, the diagnostic was the following: iatrogenic manic episode with psychotic symptoms.

Given the particularities of this case (provided by the pre-morbid functioning of the patient was good and by the apparent iatrogenic component), the prognosis is favorable if there is therapeutic compliance and if the patient respects the health and nutrition advice received upon discharge, from both the psychiatrist and the nephrologist. Outpatient care and the careful revaluation of the patient are also necessary; family psychoeducation is the first that can pinpoint alterations in the patient's behaviour.

Dania Andreea RADU--M. D., Ph. D. Student, "Socola" Institute of Psychiatry, Iasi, Romania

Ilinca UNTU--M. D., Ph. D. Student, "Socola" Institute of Psychiatry, Iasi, Romania

Vasile CHIRITA--Prof., M. D., Ph. D., "Socola" Institute of Psychiatry, Iasi, Romania

Roxana CHIRITA--Prof., M. D., Ph. D., "Socola" Institute of Psychiatry, Iasi, Romania


The authors declare that they have no potential conflicts of interest to disclose.


(1.) Ozawa, T., "Effects of FK506 on Ca2+ release channels (review)", Perspectives in Medicinal Chemistry, vol. 2008, no. 2, pp. 51-55, 2008.

(2.) McCauley, Jerry (2004-05-19). "Long-Term Graft Survival In Kidney Transplant Recipients". Slide Set Series on Analyses of Immunosuppressive Therapies. Medscape. Retrieved 2006-06-06.

(3.) Pincus, Matthew R., Abraham, Naif Z., Toxicology and Therapeutic Drug Monitoring. In Henry's Clinical Diagnosis and Management by Laboratory Methods, Saunders-Elsevier, 21st Edition, 2007, 308-320.

(4.) Wu, Q., Marescaux, C., Wolff, V. et al., "Tacrolimus-associated posterior reversible encephalopathy syndrome after solid organ transplantation", European Neurology, vol. 64, no. 3, pp. 169-177, 2010.

(5.) Corruble, E., Buhl, C., Esposito, D. et al., "Psychosis associated with elevated trough tacrolimus blood concentrations after combined kidney-pancreas transplant", International Journal of Neuropsychopharmacology, vol. 9, no. 4, pp. 493-494, 2006.

(6.) Charbonneau, Y, Ravindran, A. V., Successful treatment of steroid-induced panic disorder with fluvoxamine. J. Psychiatry Neurosci. 1997; 22: 346-347.

(7.) Sacks, O., Shulman, M., Steroid dementia: a follow-up. Neurology 2007; 68: 622.

(8.) ICD-10. Clasificarea tulburarilor mentale si de comportament. All Publishing House, Bucharest. 1998. pg.94-98, 138-145

(9.) Naik, P., Madhavarapu, M., Mayur, P., Nayak, K. S., and Sritharan, V., "Pharmacokinetics of tacrolimus in adult renal transplant recipients," Drug Metabolism and Drug Interactions, vol. 27, no. 3, pp. 151-155, 2012.

(10.) Krishna, N., Chiappelli, J., Fischer, B. A., and Knight, S., "tacrolimus-induced paranoid delusions and fugue-like state," General Hospital Psychiatry, vol. 35, no. 3, pp. 327.e5-327.e6, 2013.

(11.) Bechstein, W. O., "Neurotoxicity of calcineurin inhibitors: impact and clinical management", Transplant International, vol. 13, no. 5, pp. 313-326, 2000.


Vasile CHIRIJA "Socola" Institute of Psychiatry No. 36 Str. Bucium, Iasi, Romania


Submission: July, 1st, 2015

Admittance: August, 25th, 2015
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Article Details
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Title Annotation:Case Reports
Author:Radu, Dania-Andreea; Untu, Ilinca; Chirita, Vasile; Chirita, Roxana
Publication:Bulletin of Integrative Psychiatry
Article Type:Report
Date:Sep 1, 2015
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