Cariprazine-Induced Extrapyramidal Symptoms and a Rare Downward Eye Deviation in Oculogyric Crisis: A Case Series

Abstract

Cariprazine is one of the newer generation antipsychotics with dopamine receptor partial agonist activity which has been approved for management of schizophrenia and bipolar affective disorder. It is known to have lesser propensity to cause extrapyramidal adverse effects due to D2 and D3 partial agonism. We intend to disseminate our newly acquired experience regarding tolerability and the adverse effect profile of cariprazine. In this case series, we describe three cases with different symptom profiles who had experienced significant adverse drug reaction with cariprazine. We also describe a unique presentation of oculogyric crisis in the form of downward fixation of eyes as well the use of amantadine as an alternative option for the management of extrapyramidal adverse effects.

Cariprazine belongs to a group of drugs known as dopamine receptor partial agonist (DRPA), which got approval for the treatment of schizophrenia in adult patients in Germany in 2017. The pharmacological class of DRPAs currently comprises three drugs (aripiprazole, brexipiprazole, and cariprazine). These molecules are also called “third-generation antipsychotics.” ¹ Cariprazine prefers D3 partial agonism, with additional agonistic effects on D2 and 5-HT_1A receptors, while antagonizing 5-HT_2B receptors. In addition, it also has a moderate affinity for adrenergic, histaminergic, and cholinergic receptors. ² It has been approved for the management of schizophrenia (USA and Europe: 1.5–6 mg/d), mixed and manic episodes of bipolar I disorder (USA: 3–6 mg/d), and bipolar depression (USA: 1.5 and 3 mg/d) in adults. ¹ Cariprazine has proven its efficacy, especially in the treatment of negative symptoms of schizophrenia in terms of self-care, interpersonal relationships, social interaction, and professional activities. ³ Cariprazine has two active metabolites of cariprazine, desmethyl cariprazine (DCAR), and di-desmethyl cariprazine (DDCAR), which substantially contribute to the drug’s antipsychotic activity. Cariprazine has a half-life of 2–4 days, and its major metabolite, DDCAR, displays a half-life of up to 3 weeks, the longest of any atypical antipsychotic. The extended half-life could work as a double-edged sword, delaying the recurrence of symptoms after missed dosing while prolonging the adverse drug reactions (ADRs) that could persist for weeks after discontinuation. Extrapyramidal side effects (EPS) are attributed to D2 antagonism and include acute manifestations such as dystonia, akathisia, and parkinsonism, whereas chronic manifestations include tardive dystonia, tardive akathisia, and tardive dyskinesia. ⁴ So far, cariprazine is a partial agonist at D2 and D3, and only akathisia has been described as the clinically most relevant ADR. In contrast, other less-intolerable ADRs of DRPAs described include sedation, blurred vision, and arterial hypertension. ⁵ We encountered a lesser well-known ADR of cariprazine in three cases. This case series aimed to disseminate existing and newly acquired knowledge about the ADR of cariprazine to other healthcare professionals to facilitate early recognition and management and improve patient safety in the future.

Highlights of Case Series

• Cariprazine in doses of three mg or more can cause severe EPS in young/vulnerable individuals.

• Amantadine can be used successfully to treat drug-induced EPS.

• Oculogyric crisis (OGC) can present as sustained downward fixation of eye gaze (usual presentation is upward deviation).

Case Details

Case 1

A 21-year-old girl presented with an illness of 3 year duration, acute onset, characterized by the delusion of persecution, auditory hallucinations, disorganized behaviour, alogia, anhedonia, and asociality. She was started on tablet olanzapine 20 mg divided doses on an outpatient basis, on which she had significant improvement in positive symptoms, but minimal improvement in other symptoms was reported. The Positive and Negative Syndrome Scale ⁶ rating was P₁₅N₃₁G₃₅. Response and tolerability were monitored at every follow-up, and no ADRs were reported with this treatment. Because of persistent disabling negative symptoms such as social and emotional withdrawal, anhedonia, and avolition, she was started on tablet cariprazine 1.5 mg, which was increased to 3 mg at the end of 1 week, while olanzapine was tapered and stopped. After 5 days of increasing cariprazine to 3 mg, the patient started to have bilateral cog-wheel rigidity, tremors of hands, mask-like facies, and akathisia. Her EPS score was rated as 26 on the Simpson Angus Scale ⁷ , suggestive of severe EPS, and score of 4 on the Barnes Akathisia Rating Scale (BARS), ⁸ suggestive of marked akathisia. There was no history of any other concomitant medications. At the first follow-up in outpatient department (OPD), tablet cariprazine was stopped immediately as other causes of EPS were ruled out, and the patient was started on tablet aripiprazole 10 mg/day. The EPS symptoms were treated by trihexyphenidyl (THP) 4 mg/day and propranolol 40 mg/day. On this regimen, while attaining some clinical response (P₁₅N₂₅G₃₀), it took around 20 days for the EPS to resolve completely, which is a significantly longer period as compared to shorter exposure to any other antipsychotics. We also applied the Naranjo ADR probability scale. ⁹ It scored 6 out of 10, which suggests “probable cause” of the given ADR as the offending agent.

Case 2

A 19-year-old girl presented in OPD with symptoms of low mood, anhedonia, marked fatigability, ideas of hopelessness, and death wishes. She was admitted to the psychiatry ward for further management and monitoring. Detailed history taking revealed that around 2 months ago, she had an episode characterized by a euphoric mood, increased energy, over-talkativeness, and grandiose ideas. During the first episode, she was treated with tablet olanzapine 20 mg and benzodiazepines, on which she achieved remission in a month, followed by discontinuation of treatment by the patient. The diagnosis was confirmed as bipolar affective disorder, a current episode of severe depression without psychotic symptoms. She was started on a tablet cariprazine 1.5 mg per day which was increased to 3 mg after 1 week, along with tablet lithium 600 mg per day. After 1 week of these medications, she developed significant dystonia, tremors, rigidity, and slowness of movement with akathisia.

Along with these symptoms, the patient also developed dry mouth and constipation. Her EPS score on the Simpson Angus Scale ⁷ was 21 (Significant EPS, which warrants a change in antipsychotic agent). On the BARS ⁸ , the score was 3 (Suggestive of moderate Akathisia). Because of the young age and severe EPS in a relatively shorter duration of treatment, a detailed assessment of other contributing causes of EPS was performed. Complete blood counts, renal function tests, liver function tests, and serum electrolytes were within normal limits. Neurology opinion was sought for any possible neurological factors causing the current presentation. The magnetic resonance imaging (MRI) of the brain showed hyperintensity in the posterior limb of the internal capsule relative to basal ganglia and thalamus, suggestive of post-natal hypoxic changes, which could be a factor for increased vulnerability to side effects. For management of her EPS, she was treated with amantadine 100 mg immediate-release capsules and, in 3 days, increased to 200 mg in divided doses, and cariprazine was cross-tapered with tablet quetiapine 300 mg. Her EPS was resolved over a month on this regimen. Amantadine was eventually tapered off and stopped. There was no relapse of manic symptoms and EPS. The patient had a 6/10 score on the Naranjo ADR probability scale, ⁹ suggestive of—the “probable cause” of the given ADR being the offending agent.

Case 3

A 19-year-old male with a known case of type 1 diabetes mellitus (DM 1) presented with the first episode of severe manic episode with psychotic symptoms. Initially, his symptoms were managed with tablet olanzapine 20 mg, but later on, due to inadequate response Tablet. Lithium up to 900 mg was added. He had remission within a month of treatment on this regimen. In the maintenance phase, he developed weight gain and EPS on olanzapine. Hence, he was started on tablet cariprazine from 1.5 mg and increased to 3 mg in 10 days and further increased to 4.5 mg in the next 10 days. After a week of reaching the 4.5 mg, he developed episodes of sustained downward deviation of eyes, which were distressing to the patient and associated with restricted upward movement. These episodes would last 30 minutes to 1 hour, with a frequency of two to three episodes per day. No features suggestive of tonic-clonic movement of the body, loss of consciousness, confusion, or bowel-bladder incontinence were reported during these episodes. Blood sugar levels were also regularly monitored and were within normal limits. On further evaluation and detailed neurological examination, he was found to have had bilateral rigidity and postural tremors in his hands. Considering the temporal association of titrating cariprazine and the occurrence of EPS, cariprazine was decreased to 3 mg, but no improvement was reported. The differential diagnosis considered were dissociative motor disorder or ocular pathology. During these episodes, the patient was fully conscious, aware, and distressed about abnormal eye deviation.

No associated gains could be elicited; hence, dissociative disorder was ruled out. Detailed ophthalmological examination revealed no significant pathology. The literature review suggested a few case reports with oculogyric crises involving downward or lateral deviation of eyeballs ¹⁰ . We conceptualized this as an Oculogyric crisis (OGC) secondary to cariprazine-induced dopaminergic blockade, and cariprazine was further reduced to 1.5 mg. Subsequently, both sets of symptoms, characterized by downward fixation of the eyes and rigidity and tremors, were resolved without any other intervention or relapse of affective symptoms. The patient had a 5/10 score on the Naranjo ADR probability scale, suggestive of—the “probable cause” of the given ADR is the offending agent ⁹ .

Discussion

It is noteworthy to report a range of extrapyramidal symptoms caused by cariprazine after a week of escalating the dosage from 1.5 mg to 3 mg per day in all cases. All described cases are young patients in their early twenties, the usual age of starting schizophrenia or bipolar disorder. Usually, cariprazine has been reported to have minimal EPS except a higher propensity to cause akathisia.^11,12 Very few reports have mentioned such significant EPS due to cariprazine in the literature. Similar to our findings, the case series by Heck et al. also reported the vulnerability of young patients to develop severe EPS on cariprazine 3mg/d or more. ¹³ This case series supports these findings and adds knowledge to the tolerability concerns of cariprazine.

Case 2 shows that amantadine can be an effective alternative agent to treat drug (cariprazine)-induced EPS symptoms. In this case, amantadine was chosen due to the existing anticholinergic side effects of antipsychotics, such as dry mouth and constipation, which could get worse with the use of THP. The other reason was to use established molecules other than THP to treat severe EPS to build confidence and new learning for the treating team for its future use. It can be a very important molecule, particularly in cases where anticholinergics like THP are not tolerated well, such as acute glaucoma, urinary retention, etc. Amantadine is a weak N-methyl-D-aspartate (NMDA) receptor antagonist, which increases dopamine release in nigrostriatal tracts. Many small clinical trials have found it effective in the usual doses of 200–300 mg (in divided doses) orally. ¹⁴ In Case 3, we report a unique presentation of severe EPS and its successful management. It demonstrates the OGC presented as sustained fixed downward deviation of the eye. This is an extremely rare variant of OGC; to our knowledge, it has been described in a case report. ¹⁵ It is therefore important to familiarize psychiatrists with atypical variants of OGC for timely management.

Only one patient had MRI findings of hyperintensity in the posterior limb of the internal capsule relative to basal ganglia and thalamus, suggestive of possibly post-natal hypoxic changes that could be another risk factor in our patient for developing severe rigidity, tremors, and dyskinesias.

The important limitation of our case series is complexity in definite attribution of severe EPS solely to the administration of cariprazine as all patients also have received other second-generation antipsychotics. In one patient, there was a preexisting brain insult. We have applied the Naranjo ADR probability scale, which determines the probability of adverse reactions attributed to a given drug.

Conclusion

From a pharmacovigilance perspective, reporting cases in which an ADR can be ascribed to a single agent/event with full certainty is neither necessary nor reasonable. Rather, this case series is a part of post-marketing surveillance studies on this novel molecule. Interestingly, it also opens the window for neurobiological research on possible newer pathways of the mechanism of action of cariprazine, which is responsible for causing severe EPS.