Treatment in Psychiatry

Antipsychotic Treatment in Breast Cancer Patients Tahir Rahman, M.D. Charles V. Clevenger, M.D., Ph.D. Virginia Kaklamani, M.D. John Lauriello, M.D. Austin Campbell, Pharm.D.

Special consideration is required when prescribing antipsychotic drugs for patients with an existing diagnosis of breast cancer. The package inserts of all approved antipsychotics contain precautions regarding their administration in this patient group. These drugs are well known to elevate serum prolactin levels to varying degrees. Overexpression of the prolactin receptor is

seen in more than 95% of human breast cancers. Many genes that are activated by the prolactin receptor are associated with tumorigenesis and cancer cell proliferation. The authors discuss the pathophysiology, clinical implications, and pertinent preclinical data and make specific recommendations regarding the use of antipsychotics in patients with breast cancer.

Kari Malwitz, M.D. Robert S. Kirkland (Am J Psychiatry 2014; 171:616–621)

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ntipsychotic drugs approved for clinical use by the U.S. Food and Drug Administration (FDA) are packaged with precautions regarding their administration to patients with established breast cancer. Because of the potential for antipsychotics to cause complications in patients with breast cancer, careful consideration is required before prescribing these agents for women with breast cancer who have a comorbid mental illness. While no clear causal link has been established between the use of antipsychotics and the risk of breast cancer, many antipsychotics are known to elevate serum prolactin levels, and a significant body of evidence supports a role for prolactin in both the pathobiology and the progression of established breast cancer (1–3). Compared with normal mammary cells, cancerous breast cells overexpress the prolactin receptor (PRLr). Prolactin supports the proliferation, survival, motility, invasion, and anchorage-independent growth (an acquired ability to grow without attachment to a basement membrane) of both estrogen receptor (ER)-positive and ERnegative breast cancer cells (4–7). We present a review of pertinent studies of tumorigenesis carried out at the cellular level involving both human and mouse models and discuss the evidence that antipsychotic agents may adversely affect women with established breast cancer. Recommendations and a rationale for treating such patients are also discussed.

Prolactin Prolactin is a neuroendocrine hormone that is normally elevated during pregnancy and lactation. Prolactin not only is secreted by the pituitary gland, but also is produced in a variety of tissues, such as breast, lymphocytes, uterus, prostate, and placental decidua. Cells within these

tissues elaborate prolactin, which functions locally by affecting the cell of origin or neighboring cells in an autocrine/paracrine fashion (4). Medical conditions such as pituitary tumor, stress, hypothalamic disorders, liver disease, and kidney disease can also elevate prolactin levels. It is well established that prolactin levels become elevated as a response to many antipsychotic drugs, with resulting side effects that may include amenorrhea, galactorrhea, osteoporosis, and loss of libido. The secretion of prolactin by the anterior pituitary involves many feedback loops. Hypothalamic inhibition of lactotroph cells, which normally release prolactin, occurs via a dopamine-mediated portal pathway known as the tuberoinfundibular tract. Antipsychotic drugs block dopamine D2 receptors within this tract, resulting in increased serum prolactin levels.

Association of Elevated Prolactin Levels and Breast Cancer Since the available data are correlative, the question of whether or not elevated prolactin levels actually cause breast cancer is open to discussion. The National Nurse’s Health Study, a robust prospective case-control cohort study, showed that both pre- and postmenopausal women who are in the top quartile of normal serum prolactin levels have a higher risk of developing breast cancer (8, 9). In addition, breast cancer patients with elevated prolactin levels have more rapid disease progression and a lower survival rate (10, 11). Whether prolactin plays a role in new breast cancer development in patients with a genetic or other predisposition to the disease remains to be determined.

This article is featured in this month’s AJP Audio

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A woman with breast cancer seeks alternatives to an adjunctive antipsychotic she has been taking for major depression and anxiety. “Ms. A,” a 38-year-old married white woman with a history

Ms. A gradually accepted her cancer condition. She

of unipolar major depression and generalized anxiety

attended support groups and consulted a therapist. She is

disorder, was admitted as a new patient referral to

now being seen with her husband as a new patient in our

a psychiatric clinic at an academic center. She had been

clinic because she wanted another opinion regarding her

treated for several years with sertraline, 100 mg/day,

medications. With the new diagnosis of breast cancer and

augmented with aripiprazole, 10 mg/day. Her symptoms

additional health care expenses, she became concerned

were well controlled, with no apparent side effects. Ms. A

that the insurance copayment for aripiprazole plus the

was seen every 4–6 months for medication refills, and she

additional cancer expenses would be unaffordable. Ms. A

usually had no complaints. Although she presented as an

researched her insurance plan’s drug formulary and

anxious individual, she was generally high functioning

discovered that risperidone was less expensive than

and had a successful business career and a happy

aripiprazole on her plan. She also learned of the hormonal

marriage. She was intelligent, highly organized, and

effects of antipsychotic drugs by reading the drug package

detail-oriented. Her health had always been excellent;

inserts, and she now seeks information about the safety of

she exercised several times a week, had never smoked

the antipsychotic medication she was receiving.

cigarettes, had no history of substance abuse, and ate a healthy diet.

After gathering Ms. A’s records and interviewing the patient, the treating psychiatrist determined that by

Eighteen months earlier, Ms. A had found a lump on her

continuing to use antipsychotic drugs, Ms. A ran the risk

right breast during self-examination and was subsequently

of elevated prolactin levels. Ms. A’s receptor typing was not

diagnosed with breast cancer. She underwent a single

an issue, since prolactin promotes breast cancer cell growth

mastectomy for a 2-cm lesion. Her breast cancer receptor

regardless of receptor status. Her depression was found to

status was ER1, PR1, and HER21, indicating the presence

be similar to her previous depressive episodes and not just

of estrogen, progesterone, and human epidermal growth

demoralization from a cancer diagnosis. Therefore, other

factor receptor-2 receptors. She received adjuvant chemo-

treatment options were discussed, including increasing the

therapy with doxorubicin/cyclophosphamide followed by

dosage of sertraline, augmenting with another type of

paclitaxel and trastuzumab, which resulted in hair loss and

medication, replacing sertraline with another antidepres-

consequent feelings of shame and demoralization. Endo-

sant, adding psychotherapy, and trying ECT. Eventually the

crine therapy with tamoxifen was recommended for a total

patient did well on a combination of sertraline, 200 mg/day,

of 5 years.

and clonazepam, 0.5 mg b.i.d., without the need for

During the months following her chemotherapy, Ms. A

augmentation with an antipsychotic. This was a lower-cost

visited her primary care physician regularly in a distressed

regimen and helped reassure the patient. She also

state, upset and crying, and she complained of insomnia

responded well to cognitive therapy, education about her

and loss of appetite. Her primary care physician prescribed

treatment, and the development of an alternative treatment

alprazolam, 0.5 mg t.i.d., in addition to her usual regimen

plan should her condition worsen. After several months, the

of sertraline and aripiprazole.

clonazepam was successfully tapered off.

Antipsychotic drug database studies have not demonstrated a relationship between antipsychotics and any form of newly diagnosed cancer, although one study (12) reported a 16% higher risk of breast cancer in patients taking dopamine antagonists. Another study (13) suggested that an elevated risk of breast and other cancers after the first diagnosis of schizophrenia could be attributed to nongenetic factors, such as treatment with antipsychotics. Thus, to date, no clear association between chronic administration of antipsychotics and mammary tumorigenesis has been demonstrated in clinical studies.

Role of the Prolactin Receptor in Breast Cancer Prolactin action is mediated by the PRLr, which is a member of the cytokine receptor superfamily (14). Am J Psychiatry 171:6, June 2014

Overexpression of the PRLr is observed in more than 95% of human breast cancers and occurs in both ER-positive and ER-negative cancers (15). Loss of the PRLr in breast cancer cells results in a dramatic reduction in ER and progesterone receptors (PR), revealing another mechanism through which the PRLr may regulate breast cancer growth (i.e., through regulation of estrogen and progesterone action) (16). Many genes that are activated by PRLr in breast cancer cells are associated with tumorigenesis and cell proliferation (17). Lacking intrinsic kinase activity, the PRLr mediates its function through associated kinases such as Jak2, Src/Fyn, Tec, Nek3, AKT, and Raf/MAPK (1–3); all of these pathways have been implicated in the pathogenesis of breast cancer. Activation of these kinases induces the phosphorylation and activation of latent transcription factors such as Stat3 and Stat5 (18, 19). The PRLr and other receptors, ajp.psychiatryonline.org

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have been much better documented over the past two decades, given their recent approvals and their established role as first-line treatment agents. The elevations in serum prolactin levels associated with each agent can be compared from different studies to give us an estimation of the possible risks accompanying their use. Table 1, compiled from available data on FDA-approved antipsychotic drugs (26–33), presents the relative effects of commonly prescribed antipsychotics on prolactin Prolactin and Tumorigenesis in Mouse levels. Models In general, first-generation antipsychotics cause significant elevations in serum prolactin levels. Of the secondProlactin promotes mammary cancer in rodent models. generation drugs, risperidone and its separately marketed Warning labels accompanying FDA-approved antipsyactive metabolite, paliperidone, raise prolactin levels the chotic drugs caution physicians that chronic administramost. This is because these two drugs cross the bloodtion of these drugs has been associated with an increase in brain barrier poorly, and as a result, serum concentrations mammary neoplasms in rodents. This warning is based of risperidone and paliperidone must be higher than those on findings predominantly from models in which the efof other antipsychotics in order fects of prolactin are determined to achieve CNS levels sufficient to in mammary cells that are genetThe duration of antipsychotic exert their therapeutic effects. ically similar to human breast The pituitary is located outside cancer cells. Two types of transtreatment, the severity and the blood-brain barrier, and theregenic models are used to study type of mental illness, fore the effect of these drugs on the effects of prolactin in mice. potential effects on serum D2 receptors is greater (30, 33). A The “gain of function” approach forces the overexpression of a number of second-generation anprolactin levels, ethical gene during early cell develtipsychotics appear to have miniconsiderations, and breast opment in order to determine mal effects on serum prolactin whether cancer develops as a recancer staging may all require levels. Aripiprazole may even sult. The “loss of function” aplower prolactin levels because of careful consideration. proach entails the elimination its partial agonist effect on the of a gene using homologous redopamine receptor (28, 33). Therecombination; an existing gene is replaced by one that is fore, in the case of Ms. A, switching from aripiprazole to nonfunctioning. The resulting gene “knockout” method is well risperidone would not be deemed advisable. established in murine experimentation. Prolactin transgenic mice develop a mix of ER-positive and ER-negative Treatment Considerations mammary tumors that are histologically similar to human breast tumors (22, 23). When prolactin transgenic mice are Clinicians routinely administer antipsychotic drugs to crossed with established models of murine mammary patients suffering from both a mental illness and breast tumorigenesis, tumor development is accelerated (24). cancer. However, many clinicians and their patients may Conversely, loss of the PRLr-associated Jak2/Stat5 pathbe unaware of the potentially harmful effects that may way results in delayed tumorigenesis in existing mouse be associated with the use of such drugs in this patient models of mammary carcinoma (3, 25). Data from both of population. The widespread acceptance and clinical use these models thus support an important role for prolactin/ of antipsychotics to treat a diverse array of mental PRLr pathways in the pathogenesis and progression of conditions—bipolar disorder, major depression, autism mammary cancer in rodents. spectrum disorders, tic disorders, dementia, and schizophrenia, as well as various off-label uses—may pose an unforeseen risk in patients with established breast cancer. Effect of Antipsychotics on Prolactin In the absence of controlled studies, it is difficult to Levels predict how a particular antipsychotic might affect the prognosis for a woman with breast cancer. In fact, the role The potential of antipsychotic drugs to cause prolactin of serum prolactin levels is not currently an established elevation has been well documented in the literature and predictor in the management of breast cancer. However, is included on all product labeling. Although recent blocking the prolactin receptor has been identified as an controlled investigations are somewhat lacking for firstimportant area of potential treatment for breast cancer generation antipsychotics, several studies have reported (34). Considering the precautions that accompany antitwofold to tenfold increases in plasma prolactin levels in some psychotic drugs, and given the current available research patients. The effects of second-generation antipsychotics such as epidermal growth factor receptor (EGFr), ER, and integrin receptors, are known to play a role in breast cancer (20). Recent evidence also indicates that the PRLr has a direct nuclear function as a transcriptional coactivator that coordinates the actions of Stat5 and the nucleosome-binding protein HMGN2 on the prolactindriven Stat5-responsive promoter chromatin (16, 21).

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TABLE 1. Effects of Antipsychotics on Prolactin Levelsa Antipsychotic

Patients With Prolactin Levels .ULN (%)

Estimated Range of Prolactin Elevation

Recommendation in Patients With Breast Cancer

Risperidone Paliperidone Haloperidol Olanzapine Iloperidone Lurasidone Ziprasidone Asenapine Quetiapine Clozapine Aripiprazole

45–87 45–87 34–75 30–47 26 5–8 ,5 ,5 ,5 ,5 ,1

45 to .100 ng/mL 45 to .100 ng/mL 28–50 ng/mL 23–34 ng/mL 20–32 ng/mL $53ULN Minimal Minimal Minimal Minimal May lower prolactin

Avoid Avoid Avoid Caution Caution Caution Preferred Preferred Preferred Preferred Preferred

a

ULN5upper limit of normal. The ULN varied in the studies reviewed, but normal prolactin levels are typically considered to be ,20 ng/mL. Data drawn from references 26–33.

data, a prospective study to determine the potentially harmful effects of such drugs would be considered unethical by most standards. Hence, we have combined relevant preclinical research data, FDA precautions, and some epidemiological evidence from the fields of cellular pathology, pharmacology, oncology, and psychiatry to help inform the practicing physician about the possibility of harmful side effects accompanying the use of antipsychotics in patients with breast cancer. As with any case, clinicians must weigh the potential benefits and risks of treatment and nontreatment. It is advisable that the oncologist, psychiatrist, and other relevant clinicians be involved together with the patient (or possibly the family and guardian) to arrive at an informed decision. The duration of antipsychotic treatment, the severity and type of mental illness, potential effects on serum prolactin levels, ethical considerations, and breast cancer staging may all require careful consideration. Since prolactin appears to promote breast cancer development irrespective of receptor status, breast cancer receptor typing is not a factor when it comes to making the decision of whether or not to prescribe an antipsychotic. All women with intraductal breast cancers should be assumed to have an elevated risk of prolactin-related progression of the disease if they are treated with antipsychotic medication. Additionally, other risks of these drugs, such as metabolic side effects, may play a yet unknown role in breast cancer survival rates. For example, insulin resistance, genetics, parity, diet, smoking, dyslipidemia, abdominal obesity, and hypertension are all associated with a higher incidence of breast cancer (35, 36). Increased leptin and decreased adiponectin levels disrupt homeostatic signaling pathways involved in cancer cell proliferation and survival. After adjustment for body mass index, women with higher adiponectin levels were found to have a 65% lower risk for breast cancer than women in a control group (35). Clozapine and olanzapine have been reported to decrease levels of adiponectin (37). The effect, if any, of Am J Psychiatry 171:6, June 2014

these parameters on breast cancer risk or recurrence requires further investigation. Patients with severe psychotic illnesses such as schizophrenia are often treated with depot formulations to enhance treatment adherence. The risk of seriously exacerbating a psychotic condition by avoiding or discontinuing antipsychotic treatment may outweigh the risk of elevating levels of prolactin by administering an antipsychotic. Similarly, treatment of a delirious or agitated patient may require the relatively safer short-term use of an antipsychotic. It is recommended that serum prolactin levels be monitored in these patients to assess possible risk and to guide treatment. Switching drugs or adding dopamine agonists may also be options. Women being treated with a prolactin-elevating antipsychotic should be cautioned about the risk of unintentional pregnancy as a result of possible changes in libido and fertility after switching drugs and should be advised to consider using reliable contraception (38). The availability of alternative classes of drug that do not elevate prolactin levels should also be carefully considered. For example, an acutely manic patient with psychosis may initially be treated aggressively with several medications, including an antipsychotic, and then placed on a less aggressive regimen of one or two nonantipsychotic mood stabilizers (lithium, anticonvulsants). In the case of Ms. A, a completely different drug regimen, with reduced potential to elevate prolactin levels, was found to be an effective means of treating her mental condition. This case also highlights the need for the development of antipsychotic drugs that are not associated with such deleterious side effects, as well as the need for advocacy to ensure that the currently available antipsychotics that are relatively safer for breast cancer patients are covered by health insurance plans.

Received May 15, 2013; revision received Aug. 11, 2013; accepted Aug. 19, 2013 (doi: 10.1176/appi.ajp.2013.13050650). From the Department of Psychiatry, University of Missouri, Columbia; and the

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Departments of Pathology and Oncology, Northwestern University, Chicago. Address correspondence to Dr. Rahman (rahmantahi@ health.missouri.edu). Dr. Clevenger has served on an advisory panel for Bristol-Myers Squibb. Dr. Lauriello has received research support from Sunovion, served on monitoring boards for Janssen and Shire, and served on advisory panels and in CME activities for Sunovion and Otsuka. The other authors report no financial relationships with commercial interests.

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