A Look at Reversible Clomiphene-Associated Manic Episodes

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ACADEMY OF CONSULTATION-LIAISON PSYCHIATRY

We recently managed a case of clomiphene-induced acute mania that resolved after discontinuation of clomiphene and empiric treatment with olanzapine. Physicians are advised to consider clomiphene-associated phenomena with acute psychiatric presentations following recent use of this medication. Discontinuation of clomiphene, close serial clinical observation of mental status, empirical treatment of psychiatric symptoms, subsequent avoidance of clomiphene, and clinical follow-up are indicated.

Case Report

The patient was a 37-year-old male with no prior medical history who presented with acute onset of psychomotor agitation, pressured speech, and psychosis. On day 1, the patient started using Clomid (clomiphene) as a supplement, which he had ordered from an overseas website after a friend recommended it as a pre-workout supplement that could “increase testosterone levels.”

The patient reported feeling “energetic” shortly after starting the drug; however, by day 3 of taking it, the patient felt that the sensation of increased energy was becoming “too much.” Notably, on that same date, the patient uncharacteristically drank 8 beers while attending a basketball game and consumed multiple shots of hard alcohol later that evening.

Per collateral history from the patient’s wife, he took his last dose of Clomid/clomiphene on day 7, at which time he appeared “elevated” and “hyperverbal.” On that date, he began to workout at 3:00 AM. His affect had become labile, and he was not hungry, with decreased PO intake and loss of weight. As this had never happened before, the patient’s wife made him an appointment with a community psychiatry clinic. On the evening of day 9, the patient was sent to the emergency department (ED) from the clinic and placed on a psychiatric commitment order. 

He was initially seen in the ED on day 9 for acute onset of irritability, grandiosity, excess/nonsensical goal-directed behaviors, disorganized thinking, and decreased need for sleep. Family members who reported that the patient had been having acute onset delusional thoughts and exhibiting signs of excess energy. The patient had never had similar symptoms before, and there was no family history of psychosis or mania.

Physical examination was notable for psychomotor agitation, flight of ideas, and tangential speech. Abnormal lab values included serum creatinine 1.19 mg/dL, aspartate 46 U/L, ketones 20 mg/dL, and thyroxine 1.73 ng/dL. To treat the patient’s acute agitation, the emergency physician administered 4 mg IV midazolam and 5 mg IV droperidol; after these medications, the patient improved and was subsequently discharged home on day 10 with a referral for outpatient psychiatric follow-up.

The patient’s wife stated that when she went to see her husband in the ED prior to discharge, he was still experiencing racing thoughts and had not fully returned to baseline.

Once the patient returned home, his wife noticed some improvement, but noted that the patient was still reporting racing thoughts, whereupon he quickly decompensated. He became perseverative and exhibited nonsensical behaviors, dropping to his knees while crying and calling his wife “mommy.”

He was observed cleaning the house excessively and was overheard saying to himself, “You can’t go too fast,” which he claimed was to slow his thoughts down. He was noted to be “saying things in a loop,” exclaiming that “no one wants to connect,” with pressured speech.

Furthermore, he was also observed pacing back-and-forth in the backyard, ripping a crucifix off the wall and breaking it in 2, and referring to members of the family as religious figures. Throughout this episode, the patient reported feeling increasingly “ramped up.”

The patient’s relatives attempted to stay with the patient overnight to help calm him down and assist with sleep, but he did not sleep at all. His wife called her brother-in-law for help, whereupon the patient ran outside and began to pull the grass out from their lawn.

The patient’s wife, her brother-in-law, and additional family called a non-emergency police line because they were concerned with the patient’s behavior. Law enforcement came and transported the patient back to the ED on a second psychiatric commitment order. The patient stated that, “It had to happen that way, because at that time I felt like no one could hurt me, not even getting shot by the police.”

On day 11, the patient was again seen in the ED for worsening symptoms, at which point he was given olanzapine, lorazepam, droperidol 5 mg, and midazolam 6 mg, and was kept on the psychiatric observation unit attached to the ED. Upon psychiatric evaluation on day 12, the patient stated that he felt the best that he had felt in the past few days. He attributed this improvement to the fact that he was “finally able to get sleep.” He reported feeling “really anxious” due to the demands of running a small business on top of caring for his 5 children. 

The patient recounted the events prior to this hospitalization, stating that he remembered feeling agitated while restrained in the ED. He reported feeling like he “could not turn off” his brain during the time he had severe symptoms. He readily agreed to abstain from using supplements like Clomid/clomiphene, binge drinking, and all illicit substance use in the future. He was given a nighttime dose of olanzapine 5 mg and kept under observation.

Upon reevaluation on day 13, the patient said he was feeling “well” overall, that he was greatly improved compared to prior days, and that he was close to his baseline. On MSE, patient appeared of stated age with well-groomed black/grey hair and beard. He was cooperative, provided appropriate eye contact, and was able to recall events that led to his hospitalization with accurate dates. He did not exhibit any psychomotor agitation or psychomotor retardation. His speech was fluent with normal rate and rhythm. When asked about his mood, the patient stated that he was “mentally feeling good.”

His affect was congruent and stable, and his thought process was now linear. He had no suicidal or homicidal ideation. He was able to recall some of his thoughts from when he was in the manic episode (eg, “I feared my wife was going to leave me” and “I did not want to cooperate because I did not understand that they had my best interest in mind”). The patient now demonstrated good insight and judgement.

After visiting with his wife on the psychiatry observation unit, the patient was discharged in stable condition, s/p manic episode, resolved, on maintenance olanzapine 5 mg bedtime with instructions to obtain psychiatric follow-up within 1 week.

Discussion

Clomiphene (Clomid) is a selective estrogen receptor modulator that is clinically used to stimulate ovulation; however, it has also been utilized for the treatment of central hypogonadism. Studies have established that it exerts its effects by blocking beta estrogen receptors (ER-beta) and activates or partially blocksalpha estrogen receptors (ER-alpha).¹ By ultimately acting as a partial estrogen agonist in the hypothalamus, clomiphene results in estrogenic negative feedback inhibition that increases gonadotropins and stimulates ovulation.

Clinical application of low-dose clomiphene citrate in studies has shown to improve the testosterone/estradiol ratio and stimulate the endogenous androgen pathway, thereby potentially benefiting male patients with hypogonadism by improving libido, sexual function, bone density, and mood, among other factors.^2,3 Nevertheless, these reports have also highlighted the drug’s undesirable and deleterious effects including, but not limited to, gynecomastia, testicular atrophy, declined sperm counts, and skin irritation.

Clomiphene has been associated with psychiatric adverse effects including psychosis,⁴ with prior case reports describing adverse psychiatric symptoms such as severe depressive episodes with suicide attempts, anxiety, insomnia, thought disorganization, delusions of reference, manic delirium, irritability, and mood swings.^5-7 Among these reports, there was variability in whether the patients had known prior psychiatric histories.

On day 1, the patient from our case report began to take Clomid 25 mg daily. Within several days of starting Clomid, he experienced an acute onset of mania, leading to social/occupational dysfunction and ultimately 2 ED presentations.

His subjective description of symptoms and emergency presentation were classic for a manic episode, including sleep disturbance with decreased need for sleep, psychomotor agitation, excessive energy, pressured speech, paranoia, flight of ideas, grandiosity, racing thoughts, increased goal-directed activities, impulsivity, and delusions.

The patient also reported a single day of heavy alcohol consumption at that time. Alcohol was likely contributory to his presentation; however, the patient was not a regular user of alcohol or other substances. It is plausible that disinhibition attributable to clomiphene contributed to his out-of-character use of alcohol.

Additionally, clomiphene is hepatically metabolized, and the patient first reported onset of manic symptoms the day of the binge-drinking event. This raises the possibility that his hepatic metabolism of clomiphene was impacted by this extensive consumption of alcohol, considering the fact that liver metabolism of alcohol is a process largely facilitated by zero-order kinetics,⁸ which may have contributed to symptom onset.

The patient discontinued clomiphene after 7 daily doses, which he had been taking prior to exercise. His initial ED presentation was 10 days after starting clomiphene and 3 days after his last dose. Notably, this was the patient’s first manic episode at the age of 37 years. He did not have a history of major depressive disorder, and there was no family history of bipolar disorder.

The timeline of patient’s clomiphene initiation and emergence of manic symptoms appeared temporally correlated, and his timeline of clomiphene use and subsequent symptoms was confirmed by his wife.

This case illustrates that a manic episode can be induced by systemic medications. Several cases of corticosteroid-induced mania have been cited in the literature, including reports of patients who, despite never having experienced neuropsychiatric symptoms while using corticosteroids routinely, exhibited manic symptoms after dose increases.

Other cases have found that patients exhibit manic symptoms when reinitiating corticosteroid therapy. Cumulatively, the findings of such reports have led to a concerted effort to encourage physicians to monitor patients for manic symptoms on initiation, reintroduction, and dose modulation of corticosteroid therapy.^9,10

The patient from our case report had discontinued the clomiphene by the time he was held for a brief 48-hour observation in the ED. Daily monitoring of MSE and administration of 2 nighttime doses of olanzapine 5 mg resulted in recovery of baseline mental status within 48 hours.

Physicians are reminded that clomiphene and similarly acting agents may carry a risk of inducing manic episodes. If an isolated manic episode can be attributed to medication and/or substances of abuse, this does not support a diagnosis of bipolar disorder (hence the DSM-5-TR diagnosis of substance/medication induced bipolar and related disorder).

Thorough workup including complete blood count, comprehensive metabolic panel, neuroimaging, infectious disease workup, urine studies, and thyroid levels should be ordered, and empirical treatment of manic symptoms with olanzapine (or similarly acting agents) may lead to symptom resolution.

Our case highlights the importance of discussing the potential impacts of initiating over-the-counter (OTC) supplements with physicians prior to initiation, as OTC supplements are not regulated by the US Food and Drug Administration (FDA) and may contain variable concentrations of the medication despite being purportedly labeled as containing a specific dose.

Additionally, it is possible that the supplement our patient took contained other drugs that could have caused these symptoms, as one can never be sure of the ingredients of supplements purchased on the internet.

The findings in this case report as well as the cited literature further highlight the need for more thorough research studies to be conducted with larger sample sizes in order to better understand the risk that clomiphene use presents to patients, and whether the risk varies greatly depending upon age, body mass index, lifestyle factors, interactions with illicit substances, and numerous other contributory variables.

Dr Tongpalad is a resident in psychiatry, Mr Gaeta and Mr Martin are medical students, Dr Santos is a clinical pharmacist, and Dr Bourgeois is vice chair of hospital psychiatry services. All authors are at the University of California Davis Medical Center in Sacramento, California.

References

1. Trost LW, Khera M. Alternative treatment modalities for the hypogonadal patient. Curr Urol Rep. 2014;15(7):417.

2. Liao Y, Chang YK, Wang SM, Chang HC. Ceiling effect of clomiphene citrate on the testosterone to estradiol ratio in eugonadal infertile men. PLoS One. 2022;17(1):e0262924.

3. Shabsigh A, Kang Y, Shabsign R, et al. Clomiphene citrate effects on testosterone/estrogen ratio in male hypogonadism. J Sex Med. 2005;2(5):716-721.

4. Mbi Feh MK, Wadhwa R. Clomiphene. National Library of Medicine. Last updated June 27, 2022. Accessed May 15, 2023. https://www.ncbi.nlm.nih.gov/books/NBK559292/

5. Knight JC, Pandit AS, Rich AM, et al. Clomiphene-associated suicide behavior in a man treated for hypogonadism: case report and review of the literature. Psychosomatics. 2015;56(5):598-602.

6. Sinha P, Garg A. Could clomiphene kindle acute manic episode in a male patient? a case report. Gen Hosp Psychiatry. 2014;36(5).

7. Parikh AR, Liskow BI. Manic delirium associated with clomiphene-induced ovulation. Psychosomatics. 2007;48(1):65-66.

8. Cederbaum AI. Alcohol metabolism. Clin Liver Dis. 2012;16(4):667-685.

9. Jasani R, Deacon JW, Sertich A. Corticosteroid-induced mania after previous tolerance of higher doses. Cureus. 2021;13(9):e17719.

10. Kazi SE, Hoque S. Acute psychosis following corticosteroid administration. Cureus. 2021;13(9):e18093.