Psychiatric disorders are common in patients with end-stage kidney disease (ESKD) and especially in patients on maintenance dialysis where their prevalence is as high as 71% [1,2]. ESKD is defined as a glomerular filtration rate (GFR) of < 15 ml/min [3] and is the most severe stage of chronic kidney disease (CKD) which is classified into five stages (Table 1) [4,5].

The development of CKD and its progression to ESKD is a significant cause of reduced quality of life and premature mortality [6]. In ESKD, the presence of psychiatric disorders can lead to poor adherence with dialysis and disruptions on dialysis units [7-9] and is also associated with significant morbidity, greater mortality and a risk of suicide [7]. Although less common than other psychiatric disorders, psychotic disorders have been reported in about 10% of patients receiving dialysis [10], with their hospitalization reaching 1% [11]. A possible explanation for the link between dialysis and psychosis may be the role of phenolic acids, which accumulate in CKD, and which inhibit dopa decarboxylase, the enzyme that converts dopa to dopamine. This leads to large amounts of dopa being removed during dialysis, creating a dopamine deficiency in the peripheral circulation and relatively higher concentrations of dopamine in the central nervous system [12].

Using drugs in CKD needs careful consideration because of the alteration of the pharmacokinetics of drugs in renal impairment and because some drugs are nephro-toxic. In particular, there is a reduction in the capacity to excrete drugs and their metabolites [13]. Most antipsychotics are safe in mild to moderate renal dysfunction but may require dose adjustment in severe to ESKD. The kidney excretes few first generation antipsychotics (FGAs) as inactive metabolites, and hence most FGAs are safe in CKD and do not require dose adjustment. Similarly, most second generation antipsychotics are also considered safe in renal disease as most of them are metabolized in the liver, although the metabolites of olanzapine, risperidone, quetiapine, clozapine and iloperidone are excreted by the kidney [14]. Paliperidone is excreted by the kidney in an unchanged form, and amisulpride and sulpiride both having renal eliminations and should best be avoided in renal failure and ESKD [12,14]. Long acting (depot) preparations of all typical and atypical antipsychotic medications are best avoided in CKD as their dose and frequency cannot be easily adjusted should renal function change [13]. Data on the use of antipsychotics in hemodialysis (HD) is limited with no available randomized controlled trials (RCTs) and available studies consisting entirely of case reports and case series [12].

There are no reported cases of psychosis in HD patients with nephrectomy and only one previous report on the use of long-acting aripiprazole in HD. Nephrectomies involve the surgical removal of a kidney when there is irreversible kidney damage. When both kidneys are removed, dialysis is required unless a kidney transplant is received. We report a case of bilateral nephrectomy who developed psychosis with life-threatening refusal of HD and the reasoning for selecting long-acting aripiprazole, leading to remission and resumption of HD.

The case is summarized in Table 2. Written informed consent was obtained from the patient. Ethical approval was granted by the Tawam Human Research Ethics Com-mittee (approval number: MF2058-2024-1029).

This case highlights the rationale for choosing an antipsychotic (aripiprazole) in HD, and the challenge of managing non-compliance given the impact of psychosis on insight, leading to refusal of treatment, including dialysis, necessitating a long-acting antipsychotic.

Choice of Antipsychotic in HD

The use of antipsychotics in HD poses a significant clinical challenge, as to date there are no RCTs on their use in HD and the data available on patients with renal failure who are not dialysis-dependent is not entirely applicable in HD [12].

Because the evidence-base for selecting antipsychotics in HD is limited, choice should be guided by the individual characteristics of the drug, especially the extent to which it is dialyzable or not. In general, the extent to which a drug is affected by dialysis is determined by several characteristics including its molecular size, protein binding, volume of distribution, water solubility and plasma clearance (the sum of renal and nonrenal clearance), in addition to technical aspects of the dialysis procedure (such as the characteristics of the dialysis membrane and blood and dialysate flow rates) (Table 3) [15]. These factors will be of importance in selecting an antipsychotic during HD and determine its safety, tolerability and need for dose adjustments. Patients on HD often have an altered volume of distribution and plasma albumin/globulin ratio, change in body weight and possible fluctuating levels of peripheral dopa-decarboxylase, which may lead to increased bioavailability of the drug, increased washout or increased permeability in the central nervous system [12]. Therefore, when evaluating medications in ESKD or in dialysis, the general pharmacokinetic principles to consider when dosing psychotropics should include: (i) What is the contribution of renal clearance to total clearance of the drug? If renal clearance represents < 30% of total clearance, then ESKD will unlikely affect drug pharmacokinetics and no dosage adjustment is required. (ii) Is the drug metabolized to active or toxic metabolites that are renally cleared? For drugs that undergo extensive liver metabolism, if active or toxic metabolites are formed and renal elimination of these compounds is substantial, dose decrease or drug avoidance should be considered. (iii) Is the parent compound and/or metabolites cleared by dialysis? In general, psychotropics have large volumes of distribution and extensive plasma protein binding and therefore substantial removal by dialysis is highly unlikely. If dialysis does not result in appreciable drug clearance (i.e., dialysis clearance is < 30% of total clearance), it is important to consider whether drug accumulation is likely. If accumulation occurs, dose decrease or drug avoidance may be necessary [7]. The half-life of an antipsychotic with significant renal clearance increases during HD, prolonging the time to reach the steady-state plasma concentration (which is dependent on the half-life of the active metabolite) and which could lead to the accumulation of metabolites and an increase in side effects or toxicity. The free fraction of most antipsychotics gets reduced during HD and this could create lesser bioavailability potentiated by the high protein binding nature of antipsychotics, most of which are > 90% protein-bound. Because of the state of relative hypoalbuminemia in patients on HD, alterations in the dose of antipsychotics need to be considered [12].

Choice of Aripiprazole in HD

Aripiprazole is a partial D2 and 5HT1A agonist and a full 5HT2A antagonist [16]. The choice of aripiprazole in our case was partly guided by its pharmacokinetic properties which, based on its renal clearance, protein binding, molecular size, lipid-solubility and volume of distribution (Table 3), suggests that aripiprazole removal is unlikely to be significant during dialysis [12,13,15,17-22].

In addition, our choice of aripiprazole was guided by its lower propensity to cause extrapyramidal and metabolic side effects compared to most other antipsychotics [13] and (because of issues with medication compliance) its availability as a LAI, which would not be an issue when prescribing it in a patient with nephrectomy as the removal of both kidneys means there is no GFR, so there would be no risk of further kidney function deterioration, hence no requirement for dose adjustments once the patient is established on it. Recent studies have also demonstrated that a number of LAIs, including long-acting aripiprazole are associated with improvements in symptom severity and social functioning in schizophrenia [23,24]. Furthermore, a review of literature found a number of case reports on the successful use of aripiprazole in patients receiving dialysis. Carpiniello et al. [25] reported on a 72-year-old male with delusional infestation associated with severe renal failure and dialysis who achieved remission on oral aripiprazole 15 mg. Similarly, Tzeng and Chiang [26] reported the case of an 83-year-old male receiving HD who developed delusional parasitosis and achieved remission on 5 mg of oral aripiprazole. Duarte et al. [27] reported on a 75-year-old lady with delusional parasitosis and visual hallucinations four months after starting peritoneal dialysis and responded to oral aripiprazole 15 mg, although not fully achieving remission. De Donatis et al. [16] reported on the use of monthly aripiprazole 400 mg depot in a 64-year-old male with chronic schizophrenia on HD who achieved a good response without relapse or clinically significant side effects. His serum aripiprazole levels were closely monitored for 22 months and remained within therapeutic range (100−350 ng/ml) with very limited variations between pre- and post-dialysis values.

Conclusions

In this case we demonstrated the challenges of managing a case of psychosis with bilateral nephrectomy on HD and its successful treatment with long-acting aripiprazole guided by a knowledge of its pharmacological and pharmacokinetic properties in CKD and ESKD. This case suggests that aripiprazole may be a reasonable choice of antipsychotic in patients on HD who develop psychosis and adds to the currently small, but hopefully growing literature in this field.

We wish to thank the patient and her family for supporting this project.

No potential conflict of interest relevant to this article was reported.

Conceptualization: All authors. Data acquisition: Omar Bin Abdul Aziz, Khalid Jawabri, Hind Mohd Ahmed, Alyazia Alkaabi. Formal analysis: Karim Abdel Aziz, Emmanuel Stip, Aysha Alhashmi. Supervision: Karim Abdel Aziz, Emmanuel Stip, Aysha Alhashmi. Writing—original draft: Karim Abdel Aziz. Writing—review & editing: Omar Bin Abdul Aziz, Khalid Jawabri, Hind Mohd Ahmed, Alyazia Alkaabi, Aysha Alhashmi, Emmanuel Stip.