Mania Precipitated by Oral Clomiphene in an Adult Male: A Case Report

To the editor,

Clomiphene is a selective estrogen receptor modulator used to treat infertility in women. It is also used off-label to treat hypogonadism and infertility in men. Its estrogen antagonizing action on the hypothalamus increases the secretion of luteinizing hormone, thereby leading to an increase in testosterone levels and improvement in fertility. ¹ Serious psychiatric adverse events are considered rare with clomiphene; nonetheless, reports link it to exacerbations of prior psychiatric illness.^2,3,4 We report the case of an adult male who developed a manic episode de novo following six months of therapy with clomiphene citrate.

Case Report

Mr A, a 36-year-old male with mild intellectual developmental disorder, presented to the emergency room with a two-month history of persistent irritable mood, increased energy levels, increased goal-directed activity, and being assaultive/abusive, unlike his usual self. On examination, he was restless and distractible, with inappropriately cheerful affect. He was admitted for management of excitement. On further probing, it emerged that from age 18, he was under regular psychiatric treatment with low dose risperidone (1-2mg) and divalproex sodium (250mg) for behavioural changes that included intermittent anger spells and being adamant. However, these behaviors were neither persistent nor pervasive before the current episode.

His treatment history further revealed that he was taking Tab. clomiphene citrate 25 mg daily for treatment of infertility and hypogonadism and that symptoms of irritability and increased speech had first emerged six months after initiating therapy with clomiphene. The treating physician then discontinued the drug. But affective symptoms continued to worsen, and the criteria for a manic episode were met one month after cessation of clomiphene. He was diagnosed with first-episode mania, and at admission, he scored 26 on the Young Mania Rating Scale (YMRS). After admission, risperidone was increased to 4 mg/day and divalproex was increased to 500 mg/day at 10 mg/kg body weight. Tab. quetiapine 75 mg per day was added to control excitement. A week later, there was a significant reduction in the intensity of aggression and irritable mood. He scored 8 on YMRS and was discharged at the request of his family. Informed consent was obtained from the patient and family for publishing the report.

Discussion

Because our patient had no prior syndromal manic episode and the current episode occurred after the initiation of clomiphene therapy, it is possible that the drug precipitated the episode. A score of 6 in the Naranjo Adverse Drug Reaction Probability Scale suggests “probable” causality.

Serious psychiatric adverse events are unusual with clomiphene. Most such cases reported are of women who had onset of symptoms within the first two weeks of treatment; these attenuated significantly after stopping the drug. Those with a past psychiatric history appear more vulnerable.^2,3,4 To our knowledge, only one prior report of a male patient exists; this was a middle-aged adult with known bipolar disorder in remission who developed a manic episode within a week of initiating clomiphene therapy. ⁵ Our patient was unique in that there was no predisposing history of an affective illness, though the presence of intellectual developmental disorder is a risk factor. Further, the onset of mania was delayed by several months after initiation of clomiphene; in contrast, all prior incriminating reports recorded the emergence of affective symptoms within days to weeks of initiation of the agent. Thus, the index case adds to the body of evidence on psychiatric adverse effects on clomiphene.

Clomiphene increases the amount of testosterone secreted from Leydig cells, which in turn increases the amount of estrogen produced through aromatisation. ¹ In a placebo-controlled double-blind trial, exogenously administered testosterone led to a significant increase in several measures of manic and aggressive symptoms. ⁶ Testosterone and its associated metabolites can stimulate extracellular signal-related kinase pathways in key brain areas regulating mood and emotional responses; this may potentially trigger mood episodes and influence their course. ⁷ The persistence of mood symptoms after cessation of clomiphene in an individual with no prior affective episodes may point to the unmasking of bipolar diathesis. We recommend that clinicians exercise prudence when prescribing clomiphene to male patients with prior psychiatric illness and educate patients and caregivers about possible psychological adverse effects of the medication. Additionally, close monitoring for treatment-emergent mood symptoms is warranted.