Eros Unleashed: A Case Series of Cariprazine-induced Hypersexuality

Cariprazine is a dopamine D2 and D3 receptor partial agonist, which has been approved by the US Food and Drug Administration (FDA) for the acute management of schizophrenia and bipolar affective disorder, both mania and depression.1-2 It has a strong affinity for D3 receptors, which is related to the beneficial effect on cognition and negative symptoms when compared to other atypical antipsychotics.3 It is also reported to have better tolerability with fewer adverse effects. Akathisia and insomnia are the most common adverse effects reported with cariprazine.4 Hypersexuality as a component of mania or hypomania caused by atypical antipsychotics is occasionally reported with olanzapine, risperidone, quetiapine, and aripiprazole.5 However, literature on drug-induced hypersexuality with cariprazine is scarce. Here, we present three cases of schizophrenia, schizoaffective, and bipolar disorder which had drug-related hypersexuality after initiation of cariprazine. The challenge in the diagnosis lies in differentiating illness-related sexual symptoms from drug-induced newly emergent hypersexual symptoms. Table 1 shows the details of these cases. Table 2 mentions rating scale scores at various time points. Figures 1–3 depict the symptom course intensity upon initiation and titration of cariprazine.

Table 1.

Comparison of the Baseline Characteristics, Previous Drug Details and Dosage of Cariprazine of the Cases.

	Case 1	Case 2	Case 3
Age/gender	31 years/male	26 years/male	20 years/female
Diagnosis	Schizophrenia	Schizoaffective disorder	Bipolar affective disorder
Duration of illness	15 years	13 years	7 years
Concurrent antipsychotics used	Clozapine 150 mg/day Amisulpiride 600 mg/day	Clozapine 150 mg/day Olanzapine 15 mg/day	Clozapine 50 mg/day
Mood stabilizer	Divalproex Sodium 1,000 mg/day	Divalproex Sodium 750 mg/day	Lithium 800 mg/day
Comorbidities	Seizure disorder	None	Hypothyroidism
Cariprazine dose at which affective switch occurred	3 mg/day	6 mg/day	4.5 mg/day
New emergent symptoms	Increased speech and activity related to hypersexuality	Hypersexuality	Hypersexuality
Previous history of hypersexuality	No	No	No

Table 2.

Scores on Various Rating Scales During the Course of Treatment.

Case	BPRS	YMRS			Naranjo Adverse Drug Reaction Scale
	Baseline	Baseline	After Starting Cariprazine	After Stopping Cariprazine
Case 1	47	3	19	8	6
Case 2	37	9	16	9	7
Case 3	37	18	26	14	6

BPRS: Brief Psychiatric Rating Scale, YMRS: Young Mania Rating Scale.

Figure 1. Schizophrenia (Case 1), graphical representation of symptom course intensity with rating scale upon the drug cariprazine introduction and titration.

BPRS: Brief Psychiatric Rating Scale, YMRS: Young Mania Rating Scale.

Figure 3. Bipolar affective disorder (Case 3), graphical representation of symptom course intensity with rating scale upon the drug cariprazine introduction and titration.

Case Series

Case 1

A 31-year-old married male, who was a known case of schizophrenia, ⁶ presented with complaints of talking and laughing to self, suspiciousness, and reduced interaction and emotional engagement with family members for 20 days. The patient previously maintained well on 150 mg/day of clozapine, 600 mg/day of amisulpride, and 1,000 mg/day of divalproex sodium. However, he had poor drug compliance, which led to the recent worsening of symptoms. On assessment, he scored 47 on the Brief Psychiatric Rating Scale (BPRS). ⁷ He was hospitalized, and 1.5 mg/day cariprazine was added to the preexisting medications. After five days, the dose of cariprazine was further increased to 3 mg/day in view of inadequate response. After about five days, the patient exhibited overfamiliar speech and promiscuous activity toward female inpatients and medical staff. He was seen singing romantic songs and writing poems for female staff. He insisted a female doctor to marry him. All his activities were pertinent to increased sexual interest. This behavior was not reported at any time during the course of the illness. His new onset symptoms were assessed using the Young Mania Rating Scale (YMRS), ⁸ which was 19. The Naranjo Adverse Drug Reaction Scale was applied to associate the onset of symptoms with the initiation of cariprazine, and the scores suggested probable association (score: 6). ⁹ Considering the temporal association between the onset of hypersexual behavior and initiation of cariprazine, cariprazine was stopped. Within 72 hours of discontinuation of the drug, there was around 50% reduction in hypersexual symptoms. On Day 6, the YMRS score decreased to 9. The psychotic symptoms were managed with electroconvulsive therapy. The BPRS score decreased to 26. The patient was psycho-educated on adequate compliance with medication.

Figure 2. Schizoaffective disorder, mixed type (Case 2), graphical representation of symptom course intensity with rating scale upon the drug cariprazine introduction and titration.

HDRS: Hamilton Depression.

Case 2

A 26-year-old male, diagnosed and treated as schizoaffective disorder (mixed type), ⁶ presented with complaints of low mood, decreased energy, suspiciousness, and reduced interaction and appetite. His current medications were clozapine of 150 mg/day, olanzapine of 15 mg/day, and divalproex sodium of 750 mg/day. His baseline BPRS and YMRS scores were 37 and 9, respectively. His depressive symptoms were evaluated on the Hamilton Depression Rating Scale (HDRS), ¹⁰ and the score was 12. He was started on cariprazine 1.5 mg/day along with the medications mentioned above, and the dose was increased to 3 mg/day after four days. The dosage was further increased to 6 mg/day after three days. Within two days of dose escalation, the patient exhibited hypersexual symptoms, such as self-stimulatory behavior, promiscuous behavior toward female inmates, and undressing in the ward. He was watching pornography excessively, unmindful of the people around him. On Day 5, the BPRS score was 52 and the YMRS score was 16. A drug-related emergence of hypersexuality was suspected. The total score on the Naranjo Adverse Drug Reaction Scale was 7, indicating a probable association with cariprazine. Hence, cariprazine was discontinued, following which the patient showed a reduction in hypersexual symptoms in about one week. The YMRS score decreased to 9 on Day 20. The dose of olanzapine was increased to 20 mg/day and quetiapine of 100 mg/day was added to treat psychosis.

Case 3

A 20-year-old unmarried female was admitted with frequent anger outbreaks, irritability, talking and laughing to herself, increased self-esteem, and reduced sleep for about 10 days. She was on psychotropics for the past seven years for bipolar affective disorder, and the current episode was diagnosed as mania with psychotic symptoms. ⁶ Her regular medications included lithium carbonate of 800 mg/day, clozapine of 50 mg/day, and thyroxine of 50 mcg/day (for hypothyroidism). The baseline scores on BPRS, YMRS, and HDRS were 37, 18, and 6, respectively. She was started on cariprazine of 1.5 mg/day, which was later raised to 4.5 mg/day after seven days. She showed no improvement in her presenting symptoms but rather had increased sexuality within one week. She was found standing in front of the nursing station most of the time trying to build a conversation with male attendees or staff who walked by the station. She was calling random phone numbers and engaged in sex talk. She was also sending messages with sexual content to random numbers. She purposefully undressed in the ward and was masturbating when people were around her. The YMRS score increased to 26. A probable drug-induced hypersexuality was suspected, which was supported by a score of 6 on the Naranjo Adverse Drug Reaction Scale (probable association). ⁹ The cariprazine was withheld, and the patient was started on olanzapine. She improved over one week.

Discussion

All the three patients described above had newly emergent hypersexual symptoms after initiation of cariprazine. There was no history of similar symptoms in the past. Sexual obsessions and other organic causes of hypersexuality were ruled out. The onset of sexual symptoms after the initiation of cariprazine and the resolution of the symptoms after the discontinuation of cariprazine strongly suggest a causal role of cariprazine. The probability of drug-induced adverse effects was confirmed by a higher score on the Naranjo Adverse Drug Reaction Scale. ⁹ There were no other symptoms of mania qualifying for a diagnosis of mania according to International Statistical Classification of Diseases and Related Health Problems 10th Revision (ICD-10), ⁶ such as irritable or elated mood, grandiosity, increased self-esteem, excessive spending or new interests, thus excluding the possibility of an affective switch. The new onset symptoms were assessed using the YMRS score. The total score predominantly reflected the scores of the sexual interest domain. In Case 3, though the patient presented with manic symptoms, he did not have sexual symptoms prior to the initiation of cariprazine. On initiation of cariprazine, the hypersexual symptoms occurred despite improvement in the other baseline symptoms of mania. Also, reversal of hypersexual symptoms on discontinuation of cariprazine points toward a specific association between cariprazine and hypersexuality. We did not attempt rechallenge with cariprazine in all the three cases in view of ethical concerns.

Cariprazine is called a “third-generation” antipsychotic due to its partial agonist action on the dopamine receptor. ¹¹ This exclusive mechanism of action defines the difference in the dosage required to treat mania and depression. In mania, it is used at higher doses (>3 mg/day), where it acts as a dopamine antagonist, and in depression, it is used at lower doses (<3 mg/day), where it functions as a dopamine agonist. ¹ Sexual arousal is mediated by dopamine, ¹² and antipsychotics can affect the sexual drive by blocking D2.^13-15 Sexual function is promoted by 5-HT1A agonism and 5-HT2A antagonism. Cariprazine, with its partial agonism on 5-HT1A and D3 and antagonism on 5-HT2A, could cause an increase in libido. Dopamine-agonistic effects at the mesolimbic circuit especially at the nucleus accumbent may be responsible for the hypersexual phenomenon. ¹⁶

Various abnormal behaviors, such as hypersexuality, compulsive eating, and pathological gambling, were described as impulse control symptoms (ICSs) caused by antipsychotics. This phenomenon is mediated by 5-HT1A agonism that inhibits the impulse control pathway. ¹³ This mechanism can explain the isolated hypersexual behavior with cariprazine, demonstrated in our patients. Also, its greater predilection for D3 accounts for the effect on emotions and impulsivity. ¹ Zazu et al. ¹⁶ reported seven cases of cariprazine-induced ICS in patients with schizophrenia, where hypersexuality was one among the ICS noted. Hence, hypersexuality can be explained as an isolated adverse event associated with cariprazine rather than a component of a symptom complex of the illness.

Prelog et al. ¹⁷ reported a case of a 67-year-old female, diagnosed with schizophrenia who developed compulsive masturbation and promiscuous behavior after starting cariprazine at a low dose of 3 mg/day. Her symptoms resolved following the withdrawal of the drug. It is noteworthy that this patient did not have any such episode of hypersexuality in the past despite being on antidepressants. This report was similar to our patient’s (Case 1). The occurrence of hypersexuality is observed at low doses of cariprazine (3 mg/day) in most of the studies, and this finding is in line with our study. Pons et al. ² and Prelog et al. ¹⁷ reported that an increase in the dose of cariprazine to a higher dosage did not reverse the affective changes that were also true in our patient (Case 2). It is noteworthy that all the patients were on clozapine along with cariprazine. Hypersexuality was reported with clozapine in literature by a few authors. ¹⁸ However, our patients did not develop sexual symptoms with clozapine, before the inclusion of cariprazine and also those symptoms reversed on withdrawal of cariprazine. This excludes clozapine as the sole cause of the hypersexuality. Yet, any possible additive effect of clozapine is to be considered.

Though cariprazine shares structural and functional similarities with aripiprazole, hypersexuality was scarcely reported with cariprazine compared to aripiprazole.^13,19 Pons et al. ² described three patients of bipolar disorder with depressive episodes, who developed manic switch with a low dose of cariprazine (1.5 mg/day), while they were on mood stabilizers. Similarly, mood stabilizers did not have any protective effect in our patients, though they had only hypersexuality.

The current case series is aimed to focus on the emergence of hypersexuality associated with cariprazine, in terms of clinical features, high-risk factors, and pathophysiology in three individual cases. The number of cases discussed is inadequate to draw a complete picture of the observed event. However, this observation paves the road for further research in this domain.

Conclusion

Cariprazine has promising effects on positive symptoms, negative symptoms, and cognitive symptoms via its effect on various neuroreceptors. Hypersexuality as a potential adverse effect may have a greater impact on the efficiency and compliance of the drug. The emergence of hypersexuality can be considered an isolated adverse event or a part of impulse control reaction. In-depth research is required to identify the high-risk groups, measure the prevalence, and establish management strategies for hypersexuality as an adverse event.