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To The Editor: Tamoxifen, an antiestrogen agent used in breast cancer treatment, inhibits protein kinase C and may have antimanic properties (1–3). We present the case of a patient with bipolar disorder who became depressed while receiving tamoxifen.
A 55-year-old Caucasian woman with bipolar disorder presented in December 2006 for evaluation of depression after starting tamoxifen for the treatment of breast cancer. While she was in her 20s, the patient’s bipolar disorder was characterized primarily by hypomania. Beginning in her 30s, depressive episodes predominated. She was subjectively euthymic but at times hypomanic, and she was medication free for 3 years before starting tamoxifen. In December 2004, at age 53, she was diagnosed with stage I breast cancer and treated with lumpectomy and radiation, followed by 18 months of tamoxifen. The patient had no other conditions that present with depression. Two antidepressant trials plus stimulants had little effect until tamoxifen was discontinued by her oncologist in June 2006 when a mixed state ensued. Subsequently, lithium was started, which precipitated worsening mood. We feel that tamoxifen, then lithium, “stabilized” her mood in the depressed phase of the illness. We recommended increased dosing of lithium, antidepressant taper, avoidance of stimulants, and the addition of lamotrigine.
Mood stabilizers have been anecdotally associated with stabilization in the depressed phase of bipolar disorder. There is only indirect evidence for this phenomenon in that anticonvulsants, including valproate, are associated with risk of depression (4). Evidence for an association between tamoxifen and depression is conflicting (3, 5, 6).
One possible explanation for these clinical observations is that the pathophysiology of bipolar disorder may involve protein kinase C. Chronic administration of lithium and valproate has been shown to reduce protein kinase C isoenzymes in the frontal cortex and hippocampus in rats, and increased protein kinase C activity has been observed in postmortem brain tissue in bipolar disorder patients (7). Tamoxifen was antimanic in three small clinical studies (1–3), supporting evidence for a possible role of protein kinase C in bipolar disorder. Our case supports the need for larger studies of protein kinase C-inhibiting agents in hypomania. Because tamoxifen is widely used in the treatment of breast cancer, understanding its potential effect on mood regulation is also clinically important.
Limitations of this report include the episodic nature of bipolar disorder and unavailable follow-up data, making the association between tamoxifen use and depression tentative. We therefore advise careful consideration of risks and benefits before discontinuing tamoxifen for symptoms of depression.
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