Cariprazine- induced mania: A case series report

Bipolar depression is the most prevalent phase of bipolar disorder (BD). There is a risk of inducing treatment-emergent affective switches (TEAS) with antidepressants (ADs). Hence, clinical guidelines do not recommend their use in monotherapy. Cariprazine is a dopamine-serotonin partial agonist, with a recent FDA approval as a monotherapy for BD type 1 (BD-I) depression. To our knowledge, there is no significant evidence of cariprazine-induced TEAS in bipolar depression. We describe three clinical cases of patients admitted to our acute psychiatric ward who developed manic episodes after the introduction of low doses of cariprazine. Two of the patients met the DSM-5 criteria for BD-I,and one for schizoaffective disorder, bipolar type. All patients were initially treated with low doses of cariprazine (1.5 mg) during a depressive phase. All 3 cases were simultaneously treated with mood stabilizers, regardless of which they switched to a manic episode when cariprazine was initiated. In our review of previous studies assessing the efficacy and side effects profile of cariprazine in BD-I, TEAS have not been found to be significant. However, according to our experience, cariprazine may induce affective switches in BD-I patients. Patients and psychiatrists should receive information regarding early warning symptoms and monitor possible cariprazine-induced mood switching.


| BACKG ROU N D
Bipolar depression is the most prevalent phase of bipolar disorder (BD). The depressive bipolar phase is also the most challenging, considering the efficacy and safety of currently available treatment options, and that it is associated with a worse course of the illness both in terms of morbidity and mortality. 1 The management of bipolar depression is especially difficult because of the risk of inducing treatment-emergent affective switches (TEAS) with antidepressants (ADs), mostly in monotherapy.
Clinical guidelines do not recommend the use of ADs as a first-line treatment for bipolar depression, and if they are used, it is recommended to introduce them while the patient is treated with effective doses of

Key message
Cariprazine has proved its efficacy in randomized clinical trials for the treatment of depressive and manic episodes in BD-I. However, three BD-I patients in a depressive phase presented a manic switch in the context of lowdose cariprazine treatment. Cariprazine may induce TEAS but this hypothesis needs confirmation within further research. Moreover, it should be explored if a dose increase of cariprazine could address the manic emerging symptoms associated with a low dose. mood stabilizers (MS). 2 Current evidence focuses on the short-term efficacy of several second-generation antipsychotics (SGAs) for bipolar depression, including cariprazine, a dopamine-serotonin partial agonist.
Cariprazine was initially approved by the Food and Drug Administration (FDA) for the acute treatment of schizophrenia (1.5-6 mg/day) and acute mania/mixed mania in BD type 1 (BD-I) disorder (3-6 mg/day).
Recently, cariprazine has also received FDA approval as a monotherapy for BD-I depression (1.5-3.0 mg/day). 3 Although TEAS induced by SGAs are not frequent, several cases have been reported. In reviewing the literature, we found TEAS with the use of olanzapine, risperidone, ziprasidone, aripiprazole, quetiapine, and other SGAs. To our knowledge, cariprazine-induced TEAS in bipolar depression have not been described to date. 4 To our knowledge, there is no evidence of cariprazine-induced TEAS in bipolar depression.
We describe below three clinical cases of BD patients admitted at the psychiatric ward of the Bipolar and Depressive Disorders Unit at the Hospital Clinic of Barcelona. All of them developed a manic episode presumably induced by the introduction of low doses of cariprazine.

| C A S E 1
A 56-year-old man with BD-I disorder and Asperger Syndrome was hospitalized due to the onset of a depressive episode for 2 months.
His first mood episode was at the age of 26, with a depressive predominant polarity. His home medication was divalproex sodium 500 mg twice a day and immediate release quetiapine 50 mg as supportive medication for insomnia.
The main symptoms were low mood, anhedonia, apathy and avolition, anxiety, suicidal thoughts with neglect of hygiene and social activities, and complete isolation at home. He had a previous history of AD-induced TEAS.
During the hospitalization, cariprazine 1.5 mg once a day was initiated as an add-on treatment for depressive symptoms to avoid the use of ADs. After an initial and sudden improvement of depressive symptoms and suicidal thoughts (within 4 days), the patient developed elevated energy, dysphoric mood, anxiety, irritability, distractibility, suspiciousness, racing thoughts, pressured speech with loose associations and psychomotor agitation, and decreased need for sleep. Therefore, cariprazine was discontinued and lurasidone 37 mg a day was started. A progressive improvement of the symptomatology was observed within 10 days, with reduced anxiety, irritability, and returning to a euthymic state. Finally, the patient was discharged to a therapeutic community to continue his recovery.
The main clinical features of the three cases are shown in Table 1.

| C A S E 2
A 24-year-old female college student, with severe type I Diabetes Mellitus and diagnosed with bipolar type schizoaffective disorder and severe obsessive-compulsive disorder (OCD), was admitted to the psychiatry ward due to a depressive episode with suicidal thoughts. She also presented with psychotic symptoms and exacerbation of the OCD symptomatology, mainly contamination phobia and compulsive handwashing leading to severe contact dermatitis that needed specialized dermatologic care. In this episode, as well as in the previous one, she discontinued her treatment including insulin therapy.
Previous to the mentioned depressive episode which required hospitalization, treatment with low doses of cariprazine was initiated in combination with 800 mg of lithium carbonate a day, because of resistant depression symptoms and considering the favorable metabolic profile. 5 Following the introduction of cariprazine 1.5 mg a day in an out-patient setting, she started with racing thoughts, expansive mood, inflated self-esteem, distractibility, impulsivity (as she reported: "I started to make improvised and imprudent decisions"), as well as irritability and grandiose and mystic-religious delusions. The patient herself decided, against psychiatric advice, to discontinue treatment with cariprazine. She eventually developed a depressive recurrence which precipitated hospitalization.

| C A S E 3
A 29-year-old woman, diagnosed with BD-I disorder in 2011, was hospitalized due to a manic episode. Her illness followed a seasonal pattern, with depressive episodes in winter and manic symptoms in summer. The patient had maintained stability for the last 4 months. In the last appointment with her psychiatrist due to the presence of subthreshold depressive symptoms, cariprazine 1.5 mg a day was added to her maintenance treatment with lithium carbonate 1200 mg/day as a mood stabilizer and immediate-release quetiapine 50 mg/day as supportive medication for insomnia.
Four weeks later, in October, and opposite to her usual seasonal pattern, she presented with expansiveness and mood lability, elated mood, delusions with mystic and magical content, decreased need for sleep, behavioral disorganization, and aggressiveness. Once admitted to the hospital, cariprazine was progressively increased to

LEARNING POINTS
• Cariprazine is a dopamine D 2 and D 3 receptor partial agonist, approved by the Food and Drug Administration (FDA) for the acute treatment of schizophrenia (1.5-6 mg/day), acute mania/mixed mania in BD type 1 (BD-I) disorder (3-6 mg/day), and for BD-I depression (1.5-3.0 mg/day). 3 • In previous studies, cariprazine has not significantly arisen alerts for treatment-emergent affective switches.
According to our experience, cariprazine may induce affective switches in BD-I patients. Information regarding early warning symptoms must be delivered. 6 mg. The symptoms remitted after 15 days of hospitalization with the mentioned treatment.

| DISCUSS ION
Cariprazine is a dopamine D 2 and D 3 receptor partial agonist with preferential binding to D 3 receptors. Cariprazine would be preferable at higher doses (3.0-6.0 mg/day) for mania to enhance its dopamine-antagonistic actions and at low doses (1.5-3 mg/day) for depression, to emphasize its agonistic actions and potentially its unique D 3 -preferred properties whose receptor is expressed in brain regions controlling reward, emotions, and motivation. 3 In our series, two of the patients met the DSM-5 criteria for BD-I, depressive episode, and one of them met DSM-5 criteria for schizoaffective disorder, bipolar type. A summary of the patient's clinical characteristics is shown in Table 1. All patients were initially treated with low doses of cariprazine (1.5 mg) during a depressive phase of BD-I or schizoaffective disorder. All three cases were simultaneously treated with mood stabilizers, lithium in two of the patients, and valproate in one. In these cases, despite the ongoing MS treatment, all three patients switched to a manic episode when cariprazine was initiated.
Adherence to the MS was confirmed in all cases by blood levels. In patient 3, once the dose was titrated to 6 mg, an improvement of manic symptoms was observed. As above-mentioned, cariprazine, at a high dose could be used to treat manic or mixed episodes associated with BD-I, as it emphasizes its D 2 antagonistic properties. 3 Thus, as a potential strategy in cases of TEAS induced by cariprazine a dose increase might be effective. However, based on our findings, patients and psychiatrists should receive information regarding early warning symptoms and monitor possible cariprazineinduced mood switching.

ACK N OWLED G M ENTS
We are extremely grateful to all the participants. The authors would like to thank the support of the Spanish Ministry of Science and Innovation; the CIBER of Mental Health (CIBERSAM). This work has been also supported by the Spanish Ministry of Science, Innovation and Universities integrated into the Plan Nacional de I+D+I y cofinanciado por el ISCIII-Subdirección General de Evaluación y el Fondo Europeo de Desarrollo Regional (FED) and the FIS grants (PI15/00283 and PI18/00805 to EV and PI18/01001 to IP). Dr Anmella's research is supported by a Pons Bartran 2020 (PI046549).

CO N FLI C T O F I NTE R E S T
EV has received grants and served as a consultant, an advisor, or a CME speaker for the following entities (unrelated to the present work): AB-Biotics, Abbott, Allergan, Angelini, Dainippon Sumitomo Pharma, Ferrer, Gedeon Richter, Janssen, Lundbeck, Otsuka, Sage, Sanofi-Aventis, and Takeda. IP has received CME-related honoraria or consulting fees from ADAMED, Janssen-Cilag, and Lundbeck. GA has received CME-related honoraria or consulting fees from Janssen-Cilag, Lundbeck, and Angelini with no financial or other relationship relevant to the subject of this article. The rest of authors report no biomedical financial interests or potential conflicts of interest related to the present article.

DATA AVA I L A B I L I T Y S TAT E M E N T
The data that support the findings of this study are available on request from the corresponding authors.