Psychosomatics 48:65-66, February 2007
doi: 10.1176/appi.psy.48.1.65
© 2007 Academy of Psychosomatic Medicine
Manic Delirium Associated With Clomiphene-Induced Ovulation
Aashish R. Parikh, M.D., and
Barry I. Liskow, M.D.
Received October 25, 2005; revised March 19, 2006; accepted March 31, 2006. From the University of Kansas Medical Center, Department of Psychiatry and Behavioral Sciences, Kansas City, KS. e-mail: aparikh{at}kumc.edu
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INTRODUCTION
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Clomiphene citrate is the most commonly used medication for inducing ovulation. It binds to hypothalamic estrogen receptors for weeks and decreases the negative feedback mechanism of endogenous estrogens. Psychiatric complications of clomiphene are rare but include sleeplessness, anxiety, irritability, mood changes, and psychosis.1,2 To our knowledge, this is the first report of clomiphene-associated manic delirium. Initially described by Bell3 in 1849, manic delirium is a life-threatening psychiatric condition. Fink4 described a syndrome of excitement, grandiosity, affect instability, delusions, and insomnia characteristic of mania and confusion, disorientation, and altered consciousness typical of delirium. The current case describes a close temporal relationship between clomiphene use and manic delirium.
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Case Reports
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"Ms. A" is a 35-year-old, Caucasian woman, with a history of bipolar disorder successfully treated with lithium in the past. She is married with no children and is a teacher with a master’s degree. In 2003, she consulted her community psychiatrist when contemplating pregnancy. Because of concern about a link between prenatal exposure and congenital malformations, lithium was discontinued, and lamotrigine was started. After 1 year of unsuccessful attempts to conceive, she consulted a fertility specialist, and treatment with clomiphene was initiated. The patient did undergo an infertility work-up before starting clomiphene, but the results are not known to the authors. During this year, Ms. A had no symptoms of depression or mania with lamotrigine. Other outpatient medications included clonazepam and bupropion. The patient did report taking medications as prescribed before this episode. Clomiphene was prescribed for 20 days before artificial insemination. Six days after starting clomiphene, she met with her outpatient psychiatrist and complained about feeling "a little revved up."
Nine days after completing clomiphene use, she suddenly began exhibiting mood swings, increased energy levels, rapid thinking, crying spells, sleeplessness, and episodes of persecutory delusions. Two days later, she became enraged at her husband and cautioned him about floods, funerals, death, and heaven. Ms. A was taken to a regional hospital emergency room after making multiple self-inflicted lacerations to both wrists. Later that day, she was transferred to the University of Kansas Medical Center Psychiatric Unit.
On admission, Ms. A appeared disheveled and confused. Her eyes were closed through much of the interview. She was evasive and unable to answer many questions coherently. Her speech ranged from soft and mumbled to pressured, loud outbursts filled with foul language. At times she stuttered and had difficulty finding words. She was not oriented to time or place. Ms. A was easily distracted and showed diminished concentration. She acknowledged that her thoughts were extremely rapid. Her thought process was illogical and filled with loose associations. She denied any suicidal or homicidal thoughts. No signs of perceptual disturbance were noticed. Ms. A did have multiple persecutory-type delusions centered on mystic and religious themes.
Upon physical exam, she was afebrile, with stable vital signs. Three 3-cm lacerations were present on her left wrist and one 3-cm laceration on her right wrist. Approximately 40 sutures were in place. The rest of the exam was unremarkable. Blood alcohol and urine toxicology tests were negative. CBC, thyroid, and liver-function tests were within normal limits. Chemistry profile showed a potassium level of 3.1 mEq/liter. Serum human chorionic gonadotropin (hCG) was 25 IU/liter (normal: <0.8), although urine hCG was negative.
A history revealed symptoms of depression and mania starting at age 20 with a diagnosis of bipolar disorder type 1. Previous episodes of mania included delusional thinking and insomnia, but no disorientation. Ms. A had three previous psychiatric hospital admissions, and her last manic episode had been 2 years earlier. She had no previous suicide attempts or gestures. Ms. A had no significant history of illicit drug or alcohol use. Her mother suffered from multiple untreated periods of depression. Her sister suffered from one episode of major depression, successfully treated with citalopram. The family also recalled having a relative in an "asylum" many years ago.
Hospital course. Ms. A was hospitalized for 26 days. Initially, all outpatient medications were stopped, and lorazepam, haloperidol, and diphenhydramine were given as needed. During the first 7 days, she became increasingly delusional, remaining focused on religious themes and spending much of the day writing nonsensical statements in a journal. At times, she would shout and become combative, often requiring four-point restraints. She slept for only 1.5 to 3 hours per night.
The issue of possible pregnancy and a serum hCG value of 25 IU/liter was addressed with an obstetrics consultation. False-positive results occur in the range of 5 to 25 IU/liter. A level >25 IU/liter can be confidently stated as positive. To confirm the existence of a pregnancy, repeating the test in 2 days normally confirms a trend upward.5 Ms. A’s serum hCG level decreased, and urine hCG remained negative. The patient reported no vaginal bleeding or abdominal cramping with clomiphene use or in the days subsequent to its discontinuation. Artificial insemination had failed, and Ms. A was most likely never pregnant.
On Hospital Day 7, lithium citrate was initiated. She was observed running in hallways, and she demonstrated echolalia. Hypersexuality was noted, as she made obscene sexual statements and publicly undressed. She also maintained complex poses for long periods while in two-point restraints. During Week 3, haloperidol and diphenhydramine were discontinued because of concern that the drugs were contributing to the delirium. Ms. A still showed no signs of improvement. She was eating and drinking less, requiring intravenous fluids. Surrogate consent was obtained for electroconvulsive therapy (ECT), and all scheduled medications were discontinued.
On Day 17, Ms. A received the first of five ECT treatments. All treatments were right-sided, unilateral. By the second treatment, Ms. A was calm, more focused, and communicated thoughts well. After the fourth treatment, her condition was greatly improved, and all symptoms of mania subsided. Ms. A went home with her family and received one ECT treatment as an outpatient. Lithium was later restarted, and Ms. A returned to work 4 months after she was discharged from the hospital.
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Discussion
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The findings of this case report suggest a link between clomiphene use and affective instability with catatonia in a bipolar-disorder patient. Mania after induction of ovulation with gonadotropins has been previously reported in a patient without a history of bipolar disorder.6 Previous research suggests that significant changes in hormonal status may precipitate affective instability in women with bipolar disorder.7 Estradiol has been shown to up-regulate serotonin transporters.8 Estrogen has also shown increased 5-HT2A receptor binding in prefrontal regions.9 Further studies are needed to delineate a link between reproductive-hormone levels and bipolar mania. Clinicians should use particular care when patients with psychiatric illness consider inducing ovulation.
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REFERENCES
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- Oyffe I, Lerner A, Isaacs G, et al: Clomiphene-induced psychosis. Am J Psychiatry 1997; 154:1169–1170[Medline]
- Siedentopf F, Horstkamp B, Stief G, et al: Clomiphene citrate as a possible cause of a psychotic reaction during infertility treatment. Hum Reprod 1997; 12:706–707[Abstract/Free Full Text]
- Bell LV: On a form of disease resembling some advanced stages of mania and fever. Am J Insanity 1849; 6:97–127
- Fink M: Delirious mania. Bipolar Disord 1999; 1:54–60[CrossRef][Medline]
- Chard T: Pregnancy tests: a review. Hum Reprod 1992; 7:701[Abstract/Free Full Text]
- Persaud R, Lam R: Manic reaction after induction of ovulation with gonadotropins. Am J Psychiatry 1998; 155:447[Medline]
- Freeman MP, Smith KW, Freeman SA, et al: The impact of reproductive events on the course of bipolar disorder in women. J Clin Psychiatry 2002; 63:284–287[Medline]
- Weizman A, Morgenstern H, Rehavi M: Up-regulatory effect of triphasic oral contraceptive on platelet 3-hour imipramine-binding sites. Psychiatry Res 1988; 23:23–27[CrossRef][Medline]
- Kugaya A, Epperson CN, Zoghbi S, et al: Increase in prefrontal cortex serotonin2A receptors following estrogen treatment in postmenopausal women. Am J Psychiatry 2003; 160:1522–1524[Abstract/Free Full Text]
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INTRODUCTION
Case Reports
