Manic and nonadherent, with a diagnosis of breast cancer
Ms. A, age 58, is admitted with new-onset agitation and auditory hallucinations. She has a history of bipolar disorder and recently had a diagnosis of breast cancer. How would you care for her?
Treating breast cancer
The mainstays of breast cancer treatment are surgery, radiation therapy, chemotherapy, hormone therapy, and targeted monoclonal antibody therapy. The protocol of choice depends on the stage of cancer, estrogen receptor status, expression of human epidermal growth factor receptor 2 (HER-2), treatment history, and the patient’s menopausal status. Overexpression of HER-2 oncoprotein, found in 25% to 30% of breast cancers, has been shown to promote cell transformation. HER-2 overexpression is associated with aggressive tumor phenotypes, lymph node involvement, and resistance to chemotherapy and endocrine therapy. Therefore, the HER-2 oncoprotein is a key target for treatment. Often, several therapies are combined to prevent recurrence of disease.
Breast cancer treatment often can cause demoralization, menopausal symptoms, sleep disturbance, impaired sexual function, infertility, and disturbed body image. It also can trigger psychiatric symptoms in patients with, or without, a history of mental illness.
Trastuzumab is a recombinant humanized monoclonal antibody against HER-2, and is approved for treating HER-2 positive breast cancer. However, approximately 50% of patients with HER-2 overexpression do not respond to trastuzumab alone or combined with chemotherapy, and nearly all patients develop resistance to trastuzumab, leading to recurrence.12 This medication is still used in practice, and research regarding antiepileptic drugs working in synergy with this monoclonal antibody is underway.
OUTCOME Stability achieved
Quetiapine and valproic acid are first-line choices for Ms. A because (1) she would be on long-term tamoxifen to maintain cancer remission maintenance and (2) she is in a manic phase of bipolar disorder. Tamoxifen also could improve her manic symptoms. This medication regimen might enhance the action of cancer treatments and also could reduce adverse effects of cancer treatment, such as insomnia associated with tamoxifen.
After the team educates Ms. A about how her psychiatric medications could benefit her cancer treatment, she becomes more motivated to stay on her regimen. Ms. A does well on these medications and after 18 months has not experienced exacerbation of psychiatric symptoms or recurrence of cancer.
The authors’ observations
There are 3 major classes of mood stabilizers for treating bipolar disorder: lithium, antiepileptic drugs, and atypical antipsychotics.13 In a setting of cancer, mood stabilizers are prescribed for managing mania or drug-induced agitation or anxiety associated with steroid use, brain metastases, and other medical conditions. They also can be used to treat neuropathic pain and hot flashes and seizure prophylaxis.13
Valproic acid
Valproic acid can help treat mood lability, impulsivity, and disinhibition, whether these symptoms are due to primary psychiatric illness or secondary to cancer metastasis. It is a first-line agent for manic and mixed bipolar states, and can be titrated quickly to achieve optimal benefit. Valproic acid also has been described as a histone deacetylase (HDAC) inhibitor, known to attenuate apoptotic activity, making it of interest as a treatment for cancer.14 HDAC inhibitors have been shown to:
- induce differentiation and cell cycle arrest
- activate the extrinsic or intrinsic pathways of apoptosis
- inhibit invasion, migration, and angiogenesis in different cancer cell lines.15
In regard to breast cancer, valproic acid inhibits growth of cell lines independent of estrogen receptors, increases the action of such breast cancer treatments as tamoxifen, raloxifene, fulvestrant, and letrozole, and induces solid tumor regression.14 Valproic acid also reduces cancer cell viability and could act as a powerful antiproliferative agent in estrogen-sensitive breast cancer cells.16
Valproic acid reduces cell growth-inducing apoptosis and cell cycle arrest in ERα-positive breast cancer cells, although it has no significant apoptotic effect in ERα-negative cells.16 However, evidence does support the ability of valproic acid to restore an estrogen-sensitive phenotype in ERα-negative breast cancer cells, allowing successful treatment with the anti-estrogen tamoxifen in vitro.10
Antipsychotics
Antipsychotics act as dopamine D2 receptor antagonists within the hypothalamic-pituitary-adrenal axis, thus increasing the serum prolactin level. Among atypicals, risperidone and its active metabolite, paliperidone, produce the greatest increase in the prolactin level, whereas quetiapine, clozapine, and aripiprazole minimally elevate the prolactin level.
Hyperprolactinemia correlates with rapid breast cancer progression and inferior prognosis, regardless of breast cancer receptor typing. Therefore, prolactin-sparing antipsychotics are preferred when treating a patient with comorbid bipolar disorder and breast cancer. Checking the serum prolactin level might help guide treatment. The literature is mixed regarding antipsychotic use and new mammary tumorigenesis; current research does not support antipsychotic choice based on future risk of breast cancer.6
Other adverse effects from antipsychotic use for bipolar disorder could have an impact on patients with breast cancer. Several of these medications could ameliorate side effects of advanced cancer and chemotherapy. Quetiapine, for example, might improve tamoxifen-induced insomnia in women with breast cancer because of its high affinity for serotonergic receptors, thus enhancing central serotonergic neurotransmitters and decreasing excitatory glutamatergic transmission.17
