Rhabdomyolysis during adjunctive treatment with cariprazine in a clozapine-resistant schizophrenia patient

Abstract

We report the case of a 49-year-old male treatment-resistant schizophrenia patient, whose treatment with clozapine and sertraline was supplemented with cariprazine 1.5 mg/day while regularly presenting for electroconvulsive therapy. After 3 weeks of adjunctive treatment with cariprazine, blood tests revealed pronounced signs of rhabdomyolysis, including a creatine kinase serum level of 20 386 U/L and an AST serum level of 696 U/L. Clinically, the patient did not report somatic symptoms other than mild back pain. After discontinuation of cariprazine and normal saline infusion, the above-mentioned findings resolved rapidly. Although very rare, rhabdomyolysis can be a potentially dangerous side effect of cariprazine and clinicians should be aware of its possible occurrence.

Introduction

Persistent negative symptoms frequently make up for a large part of the impairment in everyday functioning of people living with schizophrenia (Galderisi et al., 2018). Thus, addressing this aspect of psychopathology is a focus in the development of new antipsychotics such as cariprazine, which has been approved for clinical use relatively recently. Next to its efficacy in the treatment of positive, negative, and cognitive symptoms of schizophrenia (Laszlovszky et al., 2021), cariprazine is generally considered to be a relatively well-tolerated substance. Moreover, combined treatment with clozapine and cariprazine appears to be an effective therapeutic approach for schizophrenia patients who insufficiently respond to clozapine monotherapy or other combination and augmentation strategies (Oloyede et al., 2022; Pappa et al., 2022). Initially reported common side effects of cariprazine included extrapyramidal symptoms, headache, akathisia, insomnia, constipation and nausea, as well as a modest dose-related increase in creatine kinase (CK) levels (Earley et al., 2017). CK levels >1000 U/L have been reported in a number of patients receiving placebo, cariprazine, or other antipsychotic agents (Herbert Y. Meltzer, 1996; Earley et al., 2017). The European Medicines Agency (EMA) considers rhabdomyolysis “an important potential risk for cariprazine” (European Medicines Agency, 2017) and lists rhabdomyolysis as a rare side effect with a frequency of ≥1/10 000 to <1/1000 cases (European Medicines Agency, 2022). The presented report provides an account of complications during the utilization of cariprazine, aiming to further the understanding of cariprazine-associated rhabdomyolysis.

Case presentation

We report the case of a 49-year-old male patient suffering from chronic schizophrenia including mild to moderate positive and moderate negative symptoms, as assessed by clinical judgment. The patient had been in treatment in our clinic beginning in January 2022, after moving in from another city. The pharmacological daily treatment regimen initially consisted of the oral administration of clozapine 350 mg/day, sertraline 100 mg/day, trazodone 150 mg/day and lorazepam 2 mg/day, as well as propranolol 15 mg/day. According to the records of the physicians who had previously treated the patient, sertraline was initiated for concomitant depressive symptoms and propranolol for persistent tachycardia. A previous attempt of combining clozapine with aripiprazole, in a daily dose of up to 20 mg, had to be discontinued due to the development of extrapyramidal symptoms.

During several previous inpatient treatments and outpatient appointments between January and September 2022, the patient had shown chronic formal thought disorder, acoustic hallucinations, and anxiety. The daily clozapine dose had been increased to 450 mg and combined with amisulpride 400 mg/day. However, the patient’s condition deteriorated (worsening of formal thought disorder and acoustic hallucinations, delusional thinking, suicidal ideation), and he was referred to our clinic for a series of electroconvulsive therapy (ECT) treatment by his treating psychiatrist. An ECT treatment series was performed in September and October 2022 and led to a significant amelioration of residual symptoms. During said series, a total number of 14 ECT sessions were administered in a frequency of two to three sessions per week. Subsequently, treatment with propranolol and lorazepam could be discontinued. In parallel, 50 mg of pirenzepine were prescribed for the treatment of clozapine-induced hypersalivation.

The patient then presented fortnightly for scheduled readmissions for single maintenance ECT sessions. In early November 2022, oral lorazepam was re-initiated due to a worsening of thought blockades and was later increased to 2 mg daily. In late December 2022, the patient’s psychopathological condition worsened again and he showed symptoms of akathisia. Therapeutic drug monitoring revealed an amisulpride plasma level above the therapeutic reference range (494 ng/ml; range 100–320 ng/ml), resulting in a reduction of the daily dose to 200 mg. Clozapine plasma levels at the time were below the reference range (306 ng/ml; range 350–600 ng/ml), but as they had before been recorded within the therapeutic reference under the same daily dose, the administration was not immediately modified. Therapeutic drug monitoring under reduced amisulpride and maintained clozapine doses later revealed plasma levels within the therapeutic reference range of both drugs. This regimen resulted in no significant change of symptoms within 4 months and during an acute readmission, amisulpride was subsequently substituted by cariprazine 1.5 mg daily in late April 2023. At a planned readmission for an ECT several days after, the change in medication appeared to be well-tolerated by the patient, even though no palpable improvement in psychopathology could be noted at that point. However, during an inpatient readmission scheduled for a maintenance ECT treatment session three weeks later (25 days after cariprazine initiation), blood tests revealed pronounced signs of rhabdomyolysis for the first time, including a CK serum level of 20 386 U/L [>100 × above the upper limit of normal (ULN)], a lactate dehydrogenase (LDH) serum level of 1244 U/L (almost 5 × above the ULN) and an aspartate aminotransferase (AST) serum level of 696 U/L (>10 × above the ULN). With an estimated glomerular filtration rate of >60 ml/min/1.73 m² renal function was not impaired. Clinically, the patient did not report somatic symptoms other than mild back pain. Most importantly, he did not show signs of malignant neuroleptic syndrome, in particular no fever, tachycardia, tachypnea, rigor, or altered state of consciousness. The planned ECT treatment was postponed to the following readmission.

After immediate discontinuation of cariprazine and intravenous administration of saline fluids, the above-mentioned laboratory findings improved rapidly. CK decreased to 630 U/L, LDH to 592 U/L, and AST to 55 U/L within five days and a further analysis carried out during the next readmission a week later revealed that values had normalized.

The patient provided written consent to the publication of the presented case report.

The related observations were reported as per our clinic’s internal pharmacovigilance guidelines and forwarded by our institution’s pharmacological department to the Austrian Federal Office of Safety in Health Care [Bundesamt für Sicherheit im Gesundheitswesen (BASG)].

Discussion

We regard it highly unlikely that the observed adverse event has been caused by suxamethonium, which had been administered regularly during ECT treatment sessions and for which rhabdomyolysis has been described as a potential side effect (Orebaugh, 1999). It has been used repeatedly during ECT treatment sessions both before and after the described event and observed CK levels have at all times been within physiological limits or merely slightly elevated. The observed maximum CK level outside the reported period of interest was a magnitude lower at 1140 U/L. This was recorded in January 2023 at an admission before the administration of a maintenance ECT session, during which the patient presented with relatively pronounced psychopathology including inner unrest and psychomotoric tension, which we considered causal for said relatively mild elevation. The discontinuation of amisulpride prior to the reported event could also be an, albeit improbable, causal factor, as similar conditions have been described after the discontinuation of other antipsychotic drugs (Kurien and Vattakatuchery, 2013). However, as a conclusion, we consider the observed signs of rhabdomyolysis to have been caused by cariprazine, as this appears to be the most plausible causative agent, taking into account our patient’s clinical course and reports of similar cases.

Rhabdomyolysis and CK elevation has been described as a potential side effect of a number of antipsychotic drugs (Laoutidis and Kioulos, 2014; Packard et al., 2014). The pathophysiological mechanism underlying antipsychotic-induced rhabdomyolysis and CK elevation is not exactly known, however, an increased cell membrane permeability in skeletal muscles has previously been suggested to be a potential mechanism (Herbert Y. Meltzer, 1996). Particularly, 5-HT2A receptor have been suggested as central in a causative pathway (Meltzer, 2000), which appears conclusive with the current case report, as cariprazine has been described as a 5-HT2A receptor antagonist (Herman et al., 2018). Other explanatory models have been suggested, implying a more central mechanism in form of the blockade of dopaminergic nigrostriatal pathways and resulting disruption of motor function (Devarajan and Dursun, 2000) or an increase of CK synthesis elicited by atypical antipsychotic agents (Melkersson, 2006).

In reference to the suggested classification of rhabdomyolysis and isolated CK elevation under antipsychotics as distinct clinical and etiological entities (Laoutidis and Kioulos, 2014; Masi et al., 2014), the diagnostic classification of the reported event should be discussed. Massive Asymptomatic Creatine Kinase Elevation (MACKE) is defined as a syndrome of isolated CK elevation with no or only modest elevations of AST and LDH and the absence of myoglobinuria, while rhabdomyolysis has been described as presenting with a trias of myalgia, weakness and dark urine (Masi et al., 2014). Unfortunately, the patient’s urine has not been examined for myoglobine at the time. Considering the patient’s mild myalgia, the degree of CK and AST/LDH elevation and the negative symptoms present while lacking reported darkened urine and generalized weakness, a clear classification of the reported case as either rhabdomyolysis or MACKE appears difficult, but the latter has to be considered a potential differential diagnosis. However, even if the presented event was indeed a case of MACKE instead of rhabdomyolysis, our discontinuation of the presumably causative drug is in line with the recommendations of Masi et al. for CK elevation beyond 5000 U/L (Masi et al., 2014).

Even though cariprazine has been shown to be a generally well-tolerated compound, the presented case points towards potentially severe complications associated with its use. The risk of such side effects in individuals suffering from schizophrenia is complicated by the reported relative pain insensitivity in said population, both in experimental and in everyday settings (Engels et al., 2014; Stubbs et al., 2015). Next to the residual symptoms of the disorder, this may impede detecting side effects and complications of treatment with psychotropic medication including rhabdomyolysis. In spite of a substantial elevation of CK levels to a degree that bears the risk of renal dysfunction (Holt and Moore, 2001) the patient presented in this report only described mild back pain. By itself, this would hardly have been considered a warning sign of a severe side effect of pharmacological treatment and did not motivate the patient himself to seek medical attention. Similar mechanisms of reduced pain sensitivity leading to an increased risk of severe complications have been discussed, for example, in the context of constipation resulting in ileus during treatment with clozapine (Levin, 2002).

The reported case underlines the importance of continuously screening for the emergence of side effects and complications when initiating cariprazine and other antipsychotic drugs, even when patients present with non-specific or mild symptoms. Moreover, in the case of CK elevation, further diagnostic steps to distinguish between rhabdomyolysis and a more benign isolated CK elevation should be considered, as e.g. outlined by Laoutidis and Kioulos (Laoutidis and Kioulos, 2014).

Acknowledgements

Conflicts of interest

There are no conflicts of interest.