De novo schizophrenia after liver transplantation: A case report

Abstract

BACKGROUND

This report describes the development of schizophrenia in a 63-year-old female patient approximately six months after undergoing liver transplantation. The patient exhibited no previous indications of psychiatric conditions and did not have any familial background of schizophrenia.

CASE SUMMARY

This particular case serves as an illustration of the intricate interaction of various elements, such as the liver transplantation process, surgical trauma, intraoperative narcosis, and immunosuppression, which may potentially contribute to the onset of schizophrenia. This report examines the clinical trajectory, diagnostic assessment, and therapeutic strategies employed in this case.

CONCLUSION

This report emphasizes the significance of identifying and managing psychiatric issues during the post-transplant phase, highlighting potential underlying mechanisms that may link transplantation-related factors to the onset of schizophrenia.

Key Words: De novo schizophrenia; Post-transplant psychosis; Calcineurin inhibitor neurotoxicity; Tacrolimus; Late-onset schizophrenia; Liver transplantation; Case report

Core Tip: We present the inaugural instance of new-onset schizophrenia occurring within one year post-liver transplantation in a 63-year-old female patient. The diagnosis was determined using structured interviews, sequential Positive and Negative Syndrome Scale scores, and thorough exclusion of metabolic, viral, and toxic variables. Following the commencement of antipsychotic treatment alongside low-dose tacrolimus and mycofenolate mofetil immunosuppression, the patient showed rapid improvement of symptoms, indicating calcineurin-inhibitor neurotoxicity as a direct catalyst; and surgical stress and anesthesia likely exacerbated individual vulnerability. This instance highlights the necessity for proactive neuropsychiatric monitoring and tailored immunosuppression in liver transplant recipients.

INTRODUCTION

Schizophrenia is a highly debilitating and enduring psychiatric condition marked by the presence of hallucinations, delusions, disorganized thought processes, and poor social abilities[1]. Although the precise origins of schizophrenia are still unknown, various predisposing variables, including genetic vulnerability and environmental triggers, have been found[1]. In recent years, there has been a growing acknowledgment of a probable correlation between organ transplantation and the emergence or aggravation of psychosis[2-4].

In this report, we describe a 63-year-old female patient who developed symptoms of schizophrenia approximately six months after liver transplantation. The temporal correlation between the transplantation operation and the subsequent manifestation of psychiatric symptoms suggests the potential existence of a causal connection. Based on the available information, this is a rare case in which the onset of schizophrenia was observed subsequent to liver transplantation, potentially linked to surgical stress[5], intraoperative narcosis[6], and the administration of immunosuppressive agents[7-10]. It is imperative to comprehend the potential correlation between liver transplantation and the onset of schizophrenia in order to ensure the best patient care. Enhanced consciousness among healthcare practitioners engaged in the field of transplantation, encompassing surgeons, anesthesiologists, psychiatrists, and transplant coordinators, has the potential to expedite the prompt recognition, timely intervention, and suitable implementation of management approaches for patients encountering psychiatric complications.

CASE PRESENTATION

Chief complaints

A 63-year-old woman who underwent liver transplantation for primary biliary cirrhosis presented with persecutory delusions and auditory hallucinations six months post-operation.

History of present illness

Six months ago, the patient received an orthotopic liver transplantation due to primary biliary cirrhosis and was placed on a long-term immunosuppressive protocol with tacrolimus as the cornerstone, following an uncomplicated postoperative recovery. The commencement of significant behavioral disturbances was noted by her family. The clinical presentation encompassed persecutory delusions, disorganized speech (including inexplicable statements like, “my head is falling off”), and a state of heightened suspiciousness. Additionally, the patient reported first-hand experiences of auditory hallucinations and referential delusions.

History of past illness

The patient had no history of diabetes, hypertension, heart disease, tuberculosis, chronic hepatitis B or hepatitis C infection, cerebrovascular disease, psychiatric disorders, or any other systemic diseases.

Personal and family history

The patient did not have a history of smoking or alcohol consumption, and there was no family history of similar diseases.

Physical examination

Physical examination revealed altered mental status with restlessness and uncooperativeness. Respiration was stable. The patient presented with a sallow complexion but showed no evidence of jaundice in the skin or sclerae. The abdomen was mildly distended, with no edema in the lower extremities. No hepatomegaly, splenomegaly, or significant ascites was detected.

Laboratory examinations

The laboratory results indicated that white blood cells, red blood cells, hemoglobin, platelets, blood electrolytes, glucose, urea, creatinine, total bilirubin, alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, albumin, blood ammonia, C-reactive protein, toxoplasmosis and other infections including syphilis, human immunodeficiency virus, hepatitis viruses, varicella virus and parvovirus B19, rubella, cytomegalovirus, herpes simplex virus, and Epstein-Barr virus were all within normal limits.

Imaging examinations

Brain magnetic resonance imaging revealed no acute pathology.

FINAL DIAGNOSIS

The Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) criteria were confirmed using the structured clinical interview for DSM-5-revised version, conducted independently by two psychiatrists; criteria A-D and F were met. Initial Positive and Negative Syndrome Scale scores were as follows: Positive sub-score 32, negative sub-score 24, general psychopathology 46, total 102 (severe range). Plus, Clinical Global Impression-Severity Scale 6 (critically sick). No fundamental characteristics of delirium, such as variable attention and sleep-wake reversal, were detected in the patient[11]. Based on the DSM-5 criteria, a diagnosis of schizophrenia was established. The patient met the criteria for hallucinations, delusions, disorganized speech, and negative symptoms. Prior to the initiation of antipsychotic therapy, the subsequent assessments were conducted: The laboratory results indicated that white blood cells, red blood cells, hemoglobin, platelets, blood electrolytes, glucose, urea, creatinine, total bilirubin, aminotransferase, aspartate aminotransferase, alkaline phosphatase, albumin, blood ammonia, C-reactive protein, toxoplasmosis and other infections including syphilis, human immunodeficiency virus, hepatitis viruses, varicella virus and parvovirus B19, rubella, cytomegalovirus, herpes simplex virus, and Epstein-Barr virus were all within normal limits, and brain magnetic resonance imaging revealed no acute pathology. The patient had no prior history of psychotropic drug use. The tacrolimus level was sustained within the range of 3-8 ng/mL during this period (Figure 1), and no potent cytochrome P450 3A4 inhibitors or inducers were concurrently supplied, suggesting that a straightforward ‘over-dosage’ neurotoxic mechanism was unlikely. A DSM-5 diagnosis of schizophrenia was made after excluding metabolic, viral, toxic, and structural causes.

Figure 1  Trend graph of serum tacrolimus C0 levels after liver transplantation.

TREATMENT

Treatment for schizophrenia was promptly initiated. The patient was prescribed an antipsychotic medication (olanzapine and quetiapine fumarate) at a low dose, which was gradually increased to achieve symptom alleviation [olanzapine was started at 5 mg quaque nocte (qn) and increased by 5 mg every 3 days to 15 mg qn; quetiapine was started at 50 mg qn, and titrated to 200 mg qn]. Since neither olanzapine nor quetiapine exhibit cytochrome P450 inhibitory or inducing properties, their administration is not expected to have an impact on the blood concentration of tacrolimus[12-14]. Regular psychiatric follow-up visits were scheduled to monitor treatment response and manage potential side effects. Aripiprazole was not administered after consultation by psychiatrists because the patient partially responded to low-dose olanzapine. Psychoeducation and supportive therapy were provided to the patient and her family to enhance understanding of the diagnosis and improve adherence to the treatment plan.

OUTCOME AND FOLLOW-UP

The patient had partial improvement in psychotic symptoms following the initiation of antipsychotic treatment. Auditory hallucinations decreased in frequency and intensity, and paranoid ideation became less pronounced. Disorganized speech and negative symptoms showed limited response to treatment. The patient is currently undergoing psychiatric care and will continue to be monitored for any changes in symptomatology or adverse medication effects. Throughout the entire psychiatric treatment duration, the patient’s liver function was consistently monitored and maintained within normal parameters.

DISCUSSION

Liver transplantation is a multifaceted medical operation that entails surgical intervention, potentially leading to both physical and psychological strain for the recipient. Neuropsychiatric symptoms have been linked to surgical trauma, including those related to disease process, fear of surgery, anesthetic drugs, drug interactions, tissue damage, and body responses to postoperative medications[6,15,16]. The following immunological response and inflammation may potentially contribute to modifications in neurotransmitter systems, hence potentially initiating or intensifying psychiatric diseases such as schizophrenia.

Immunosuppressive drugs, such as tacrolimus and mycofenolate mofetil (MMF), are employed in the context of organ transplantation to mitigate the risk of graft vs host disease. However, it has been found that there is an association between certain pharmaceutical substances and adverse psychological effects. The calcineurin inhibitors (CNIs) encompass tacrolimus and cyclosporine, which are immunosuppressive drugs that effectively impede the proliferation and differentiation of T-cells[17]. CNIs have been linked to neurotoxicity and neuropsychiatric issues, including disruptions in the sleep/wake cycle and affective abnormalities. In rare instances, CNIs have also been connected with memory deficiencies and a condition known as akinetic mutism[18,19]. The incidence of neurotoxicity related to the utilization of CNIs is higher in liver transplant recipients compared to individuals who have undergone other types of solid organ transplantation. The presence of hyponatremia and pre-transplant hepatic encephalopathy has been observed as potential risk factors associated with the occurrence of drug-induced neurotoxicity following transplantation[20]. The potential neurotoxicity of CNIs may be associated with the activation of endothelin receptors, impairment of the blood-brain barrier, and modulation of neuromodulator systems, including inhibition of the gamma-amino butyric acid system and depletion of neuronal serotonin[21]. The potential neuropsychiatric symptoms associated with severe tacrolimus neurotoxicity, such as delusional ideas, hallucinations, disturbed speech, altered mood, and others, may be attributed to the direct impact of calcineurin. Calcineurin is a widely distributed protein found in both the central and peripheral nervous systems. It has a significant role in regulating the dopaminergic, glutamatergic, and gamma-amino butyric acidergic systems, all of which have been implicated in the underlying mechanisms of psychiatric disorders characterized by psychotic symptoms, such as schizophrenia or bipolar disorder[22,23]. There is possibility for mood disorders and psychotic symptoms to be influenced by the antimetabolite MMF. The prescribing instructions for MMF include depression as a documented side effect. However, there have been limited accounts that have provided descriptions of the phenomenon of depression. According to the prescribing instructions of MMF, depression is documented as an adverse event with a prevalence ranging from more than 3% to less than 20% among patients who were assessed in clinical trials[24].

When assessing the incidence of schizophrenia after liver transplantation, it is imperative to consider individual predisposing variables. The potential impact of inherited predisposition and pharmacogenetic variations on an individual's vulnerability to the psychological effects of surgical trauma, anesthesia, and immunosuppression has been suggested. The possible impact of polymorphisms in genes related to drug metabolism, neurotransmitter receptors, or immune system regulation on the susceptibility to schizophrenia development is worth considering. The potential involvement of the calcineurin gene in the manifestation of symptoms associated with schizophrenia has been observed, as alterations in this gene and its messenger RNA have been detected in certain individuals with schizophrenia, both in vivo and through post-mortem investigations[25].

This particular case underscores the necessity of employing a multidisciplinary methodology when addressing individuals who experience psychological issues subsequent to undergoing liver transplantation. The recognition and addressing of potential contributory factors necessitate a close coordination among transplant surgeons, hepatologists, anesthesiologists, and psychiatrists. The timely recognition and intervention of a condition are of utmost importance in order to maximize results and customize treatment strategies according to the unique requirements of each individual.

A systematic search of PubMed utilizing the terms (“liver transplantation” OR “hepatic transplant”) AND (“schizophrenia” OR “schizophreniform disorder”) AND (“new-onset” OR “de-novo”) resulted in the identification of a singular previously documented case of psychosis subsequent to liver transplantation, involving a female who experienced an episode of schizophrenia 20 years post-transplantation[26]. This case report is the first instance of new schizophrenia in a patient subsequent to liver transplantation within a brief timeframe worldwide. It offers valuable insights into the potential correlation between liver transplantation, surgical trauma, intraoperative narcosis, immunosuppressive medications, and the onset of schizophrenia. However, it is crucial to recognize the inherent limitations of a solitary case study. Additional study is necessary, particularly in the form of larger-scale studies and prospective investigations, in order to gain a more comprehensive understanding of the underlying mechanisms involved, determine the prevalence of these events, and develop evidence-based strategies for managing them.

CONCLUSION

In summary, this case report underscores the probable correlation between liver transplantation and the eventual onset of schizophrenia. Potential risk factors that necessitate careful evaluation include surgical trauma, intraoperative narcosis, and the use of immunosuppressive drugs. Gaining a thorough comprehension of these intricate relationships would enhance the ability to promptly identify, implement specific interventions, and enhance the outcomes for individuals who encounter neuropsychiatric issues after liver transplantation. Further investigation is warranted to broaden our understanding in this domain, ultimately augmenting the quality of care delivered to this distinct cohort of patients.