Manic episode occurring during investigational treatment with pan‐class I phosphoinositide 3‐kinase inhibitor in a patient with breast cancer

Breast cancer as a life‐threatening illness can be related to anxiety, demoralization, or depression, which can occur at any moment of the clinical‐diagnostic pathway. Despite the fact that brain metastases, paraneoplastic syndromes, or pharmacotherapy might induce mood alterations, spontaneous hypomanic and manic episodes usually do not occur in patients with breast cancer. Concerning mood alterations associated with the administration of antitumor drugs, orally available, pan‐class I phosphoinositide 3‐ kinase (PI3K) inhibitors, which exert their activity on breast cancer cells positive for estrogen receptor (ER), particularly in some sub‐populations (for instance, some PI3K mutations), can induce anxiety, euphoria, anhedonia, or depression. We report a case of a patient with breast cancer and without a familial and personal history of mood or anxiety disorders, who experienced a manic episode at the age of 54 during the treatment with an investigational pan‐class I PI3K inhibitor. A written informed consent was obtained from the patient for the publication of this case report. The local Ethical Committee (Comitato Etico per Parma) approved the double‐blind placebo controlled clinical trial in which the patient was enrolled (reference number for the approval, 3553; date of approval, 29/01/2013).


| INTRODUCTION
Breast cancer as a life-threatening illness can be related to anxiety, demoralization, or depression, 1,2 which can occur at any moment of the clinical-diagnostic pathway.
Despite the fact that brain metastases, paraneoplastic syndromes, or pharmacotherapy might induce mood alterations, spontaneous hypomanic and manic episodes usually do not occur in patients with breast cancer.
Concerning mood alterations associated with the administration of antitumor drugs, orally available, pan-class I phosphoinositide 3kinase (PI3K) inhibitors, which exert their activity on breast cancer cells positive for estrogen receptor (ER), particularly in some sub-populations (for instance, some PI3K mutations), 3 can induce anxiety, euphoria, anhedonia, or depression. 4 We report a case of a patient with breast cancer and without a familial and personal history of mood or anxiety disorders, who experienced a manic episode at the age of 54 during the treatment with an investigational pan-class I PI3K inhibitor.
A written informed consent was obtained from the patient for the publication of this case report. The local Ethical Committee (Comitato Etico per Parma) approved the double-blind placebo controlled clinical trial in which the patient was enrolled (reference number for the approval, 3553; date of approval, 29/01/2013). She was married, and she lived with her husband and with their 31-year-old daughter (with motor disability secondary to a pertussisassociated encephalitis when she was 2 years old). The global functioning was satisfying, and overall the patient adopted good coping strategies for her daughter disability.

| CASE REPORT
She entered the trial on February 28, 2014. No major psychopathological concerns emerged during the first 2 months of treatment, while at the beginning of May she complained tiredness, avolition, and demoralization; therefore, the oncologist suggested to take some days off. When on holidays in Paris, on May 9, she became irritable and verbally aggressive. Few days later, when back home, she was hyperactive, easily distractive, talkative, and agitated. Later on, she became insomniac and developed grandiose self-esteem, satisfying the criteria for a full-blown manic episode.
On May 22, the oncologist referred her to the psychiatry consultation-liaison service, where a diagnosis of a manic episode was made.
The patient refused any treatment, and she was sectioned and taken into the acute psychiatric ward. At the first evaluation, she was extremely talkative, with flight of ideas, grandiosity, and high irritability.
The patient was put on Olanzapine 10 mg b.i.d. and Lorazepam 2 mg in the evening both intra-muscular. The blood tests showed a mild elevation in levels of the liver enzymes transaminases (AST 55 U/L; ALT 61 U/L) and lactate dehydrogenase (LDH 710 U/L) and low iron levels (30 μg/dL). The neurological examination was unremarkable, and the brain computerized axial tomography (CAT) scan did not show any metastases or acute vascular damage. occurred in 17% to 45% of patients treated with this class of drugs.
To explain this effect, it has been hypothesized that the dysregulation of the PI3K pathway can be associated with changes in serotonin levels, and, therefore, with mental disturbances such as anxiety and depression. 9 Summarizing, even though we cannot exclude other possible causes, the timing of symptom development, the negativity of personal and familial psychiatric history, and the absence of clinical neurological findings or CT scan alterations suggest a treatment-related manic episode.
To our knowledge, this is the first report that describes the onset of a manic episode during treatment with a pan-class I PI3K inhibitor, showing that also a severe mood disorder can be induced by this class of drugs. Our observation, along with previous findings of depression and anxiety related to this treatment, 9 suggest that mental health should be carefully monitored in patients treated with PI3K inhibitors and mild mood alterations should be also recognized and properly treated to prevent the development of severe mood episode.
Isoform-specific PI3K inhibitors are becoming more and more popular, because their specificity offers considerable advantages in terms of both efficacy and safety. Specifically, p110α-specific PI3K inhibitors may have the advantage of a neuron-specific regulation of class I PI3K catalytic subunits that would make these compounds associated with a lower risk of induced-mood disorders, especially when compared with pan-PI3K inhibitors. 10 The authors declare that they have no competing interests. • PI3K inhibitors can be associated with changes in brain serotonin levels and mental disturbances.
• In this case report, pan-class I PI3K inhibitor administration was associated with the development of a manic episode