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Metoclopramide-Induced Akathisia During the Second Trimester of a 37-Year-Old Woman's First Pregnancy

Received December 10, 1999; revised August 7, 2000; accepted September 14, 2000. From Department of Psychiatry, Rush Medical College, Chicago, Illinois. Address correspondence and reprint requests to Dr. Poortinga, Department of Psychiatry at Good Samaritan Regional Medical Center, 925 E McDowell Road, 4th Floor, Phoenix, AZ 85006; e-mail: Ernie_poortinga{at}yahoo.com

Key Words: Pregnancy • Akathisia • Metoclopramide

Akathisia is an extrapyramidal disorder consisting of a subjective feeling of needing to move, which is often manifested in an inability to sit still.¹ It is frequently mistaken for an exacerbation of psychotic symptoms, anxiety and/or depression.

Metoclopramide (Mp) is a dopamine-2 (D₂) receptor antagonist used for various gastrointestinal disorders, the most frequent being control of emesis. Its safety in pregnancy rating of "B" indicates that its presumed safety is based on animal studies. It is used widely during pregnancy for nausea and vomiting.^2,3 Mp has a serum half-life in humans of 4–6 hours. Mp has been associated with causing or exacerbating several extrapyramidal movement disorders, including acute akathisia.^4–9 The average time period from initiation of treatment to the onset of extrapyramidal symptoms (EPS) has been reported as 72 hours.¹⁰ Miller and Jankovic¹¹ reviewed 1,031 reported cases of Mp-associated movement disorders, 10% of which had akathisia. Little incidence data were available. Ganzini et al.¹² prospectively studied 51 Mp patients matched to control subjects on age, gender, and presence or absence of diabetes mellitus. The relative risk for drug-induced movement disorders was 4.0 with a 95% confidence interval of 1.5 to 10.5. Jungmann and Schoffling¹³ studied the effect of an intravenous (IV) 10-mg bolus of Mp in healthy subjects and found that 25% "complained of akathisia," usually within 15–30 minutes and lasting for 3–4 hours. Borenstein and Bles¹⁴ administered high doses of Mp to psychiatric patients and reported movement disorders in 25%. They did not specify the rate of akathisia.

Despite the numerous reports mentioned above, akathisia is frequently unrecognized or ignored¹¹ and can frequently be misdiagnosed as other psychiatric illnesses.¹⁵ We describe a case of akathisia in a pregnant woman whose symptoms developed after the initiation of Mp therapy. This case illustrates the difficulty in making the diagnosis of a drug side effect when the symptoms are delayed by several weeks from the initiation of medication, and it also demonstrates how pregnancy can complicate a diagnosis.

Case Report

Ms. Z. was a 37-year-old primigravid white woman in her 21st week of pregnancy. She presented to a community hospital with a chief complaint of "an inner sense of restlessness for the past 6 days."

Ms. Z. had been in her usual state of good health until the second week of her pregnancy when she began to experience nausea and vomiting throughout the day. These symptoms gradually worsened over a 5-day period until she sought medical attention. Ms. Z. was admitted to the medical floor of her local hospital where she was told that she was suffering from hyperemesis gravidarum. Treatment consisted of IV fluids and IV Mp. She remained in the hospital for 2 days and was discharged with oral Mp (10 mg q 6 hrs prn) for nausea. At the time of discharge, Ms. Z. was able to eat and drink without nausea. Three days postdischarge she began to experience nausea and vomiting. She began to use the Mp two to three times a day at 10 mg po each time. This dosing schedule worked well to control her symptoms and Ms. Z. continued to take Mp in this manner until her admission to RSLPMC.

One week before admission, Ms. Z. began to experience an inner sense of restlessness. She describes the restlessness as an irresistible urge to move her limbs. This state was accompanied by mild tremulousness and anxiety about when the next episode of restlessness was going to occur. The first episode of restlessness occurred at 2 a.m. and roused Ms. Z. from sleep. The episode lasted 1 hour. Over the next 3 days, the restlessness increased in frequency and severity, impairing Ms. Z.'s ability to sleep. In the 2 days prior to admission, she had been constantly anxious about these restlessness symptoms, which had been occurring four or five times per day.

When asked about stressful events occurring in her life, Ms. Z. described the recent miscarriage experienced by a close friend as very stressful but denied worrying excessively about her own pregnancy. She denied any previous problems with anxiety, depression, mania, or psychoses. In addition to insomnia and anxiety, she admitted to a decreased appetite for the past 3 days, increased feelings of guilt for disturbing her husband over the past week, difficulty in concentration because of her constant anxiety, weight loss of 9 pounds during pregnancy, and decreased energy over the past week. Ms. Z. denied having depressed mood or any homicidal or suicidal ideation. She stated that she felt unsafe being alone at home because of the fear of having more episodes of restlessness. Twice in the past week she asked her husband to come home from work to be with her during an episode of restlessness.

Ms. Z.'s past medical history was notable for a diagnosis of irritable bowel syndrome 5 years previously. Her symptoms were controlled with diet. She took no medications besides Mp and prenatal vitamins. Her only allergy was to penicillin, which gave her a rash. Ms. Z. had never had any surgery and reported no psychiatric or medical problems in her parents but described postpartum depression and "anger control problems" in her only sibling.

Ms. Z. was employed as an actuary, but she had missed 2 months of work with hyperemesis gravidarum and the past week because of restlessness and anxiety. Before her pregnancy she consumed approximately 2 to 3 glasses of wine per week and denied any illicit drug use and does not smoke. A review of systems was unremarkable.

Ms. Z.'s mental status exam revealed a pleasant, cooperative woman who was alert and oriented to person, place, and date. Ms. Z. was sitting up in bed, wearing a hospital gown, and making excellent eye contact. Her speech was normal in volume, rate, and tone. Her mood was "worried" with a slightly anxious, appropriate, mood-congruent affect. Ms. Z.'s thought process was logical and goal directed, while her thought content was free of auditory or visual hallucinations. Cognition was intact and she had good insight into her condition as well as good judgment in general.

Ms. Z.'s physical exam and vital signs were unremarkable. Laboratory results on admission were normal, including serum TSH, T-4, and 24-hour urine catacholamines.

Our initial diagnoses included general anxiety disorder, panic disorder, anxiety disorder secondary to general medical condition (hyperthyroidism, pheochromocytoma), and akathisia secondary to metoclopramide therapy. Ms. Z. was admitted to the psychiatric floor and Mp was withheld. During her 48 hours of hospitalization, she reported only 2 episodes of agitation with an uncontrollable urge to move her limbs. Each of these episodes lasted approximately 40 min. She experienced no other symptoms and was discharged from the hospital with a prescription for phenobarbital (30 mg po tid for 2 days). Ms. Z. was advised that she was likely experiencing an adverse reaction to Mp and that she could continue to take the phenobarbital (30 mg) every 4 to 6 hours, if necessary, for any return of her symptoms.

Follow-up at 48 hours postdischarge revealed no further episodes of agitation or restlessness. She was using the phenobarbital as prescribed. Follow-up at 1 week and at 1 month postdischarge revealed no further symptoms of akathisia, anxiety, or nausea. Ms. Z. had not taken any phenobarbital since the initial 2 day dose.

Discussion

The main differential diagnoses we considered in Ms. Z. were general anxiety disorder, panic disorder, anxiety secondary to hyperthyroidism, and anxiety secondary to pheochromocytoma. Because she did not meet the DSM-IV criteria for either panic disorder or general anxiety disorder and was found to have normal serum TSH and urinary catecholamine levels, we decided on akathisia secondary to Mp therapy as our working diagnosis. The fact that Ms. Z. continued to have symptoms for up to 48 hours after cessation of her last Mp dose is consistent with the kinetics of Mp. Five half-lives for complete elimination would take at least 30 hours. The most crucial piece of evidence confirming our diagnosis was the fact that she had no further episodes of akathisia once the Mp was eliminated from her body. If this had been a form of panic disorder or general anxiety disorder, we would have expected her symptoms to continue after discharge and especially after her phenobarbital course was finished. We believe that this is one of the first reports of Mp-induced akathisia during pregnancy. There are several case reports and reviews of anxiety disorders in pregnant and postpartum women,^16,17 but we have no reports of Mp-induced akathisia during pregnancy in the MEDLINE search (1969 to 1999) we performed. The extensive biological changes associated with pregnancy have been reviewed.¹⁶ These changes occur in the central nervous system and in the periphery and may impact both the pharmacokinetics of Mp and how a woman reacts to its side effects. We will attempt to summarize some of the changes in pregnancy that may have a role in drug-induced akathisia.

Pregnancy is also a period of physiologic upheaval with marked hormonal changes. Foremost among these hormonal effects are the gonadal steroids, which undergo marked changes during pregnancy. Circulating estrogen levels may vary by 100 times during pregnancy (from 0.3 ng/ml of estradiol at conception to 30 ng/ml near term). Most of this increase occurs in the first two trimesters of gestation with estradiol levels averaging 20–30 ng/ml at Week 21 (when Ms. Z. began complaining of restlessness).¹⁸ Progesterone levels during pregnancy are biphasic. For the first 10 weeks of gestation, serum progesterone levels remain in what is referred to as a "luteal range" of 10–35 ng/ml. After Week 10, the placenta replaces the corpus luteum as the major source of serum progesterone and levels begin to rise sharply. By Week 20 these levels plateau between 100 and 300 ng/ml, with a very gradual rise until term.¹⁸ Thus, Ms. Z. began experiencing her symptoms at roughly the onset of maximum influence of both estrogen and progesterone.

The major question raised in response to these elevated hormones is what is the effect of these sex hormones on central dopamine binding and on the behavioral sensitivity to dopaminergic drugs. Several studies working with animal models point to an increased sensitivity to D₂ antagonists under the hormonal conditions of late pregnancy. Guivarch et al.¹⁹ showed under controlled culture conditions that estradiol strongly favored the production of the long isoform of D₂ receptor mRNA over the short D₂ receptor. In the presence of progesterone, estradiol effects were minimized and equal amounts of the D₂ receptor subtypes were produced. Lee and Mouradian²⁰ were able to replicate these results in cultures of human D₁ receptors.

Striatal dopamine transporters are also affected by sex hormones. Carbrera and Bregonzio²¹ found that progesterone was able to enhance dopamine release stimulated by NMDA on Days 5 and 15 of a rat pregnancy but not on Days 1, 10, and 20. Carbrera and Bregonzio hypothesized that the differences suggested that an increased synthesis and/or release of dopamine takes place on certain days of pregnancy, and simultaneously, there is a significant increase in the responsiveness of striatal dopaminergic nerve terminals to excitatory inputs. A similar fluctuation in dopamine release in humans could explain why Ms. Z. developed akathisia several weeks after the initiation of Mp therapy.

Further evidence for the influence of gonadal steroids on dopamine comes from animal studies involving dopamine transport. Ovariectomy resulted in the upregulation of striatal DA transporters in rats. This upregulation was blocked by estradiol and estradiol plus progesterone but not by progesterone alone.²² Thompson and Moss²³ found, in rats, that dopamine release was significantly potentiated during diestrus, a time of high serum estradiol. Thompson et al.²⁴ were unable to show an increased incidence of EPS during times of elevated serum estrogens in women taking dopamine antagonists.

The psychosocial factors in the evaluation of akathisia during pregnancy should not be neglected. Pregnancy is associated with major social changes that can be stressful and may contribute to the susceptibility to anxiety disorders, making the diagnosis of akathisia even more complicated. Women, such as Ms. Z., who are having their first child, face significant changes in their marital relationship and perhaps in their career. For some families the birth of a child is associated with stressful financial concerns. Attention to these psychosocial stressors must be addressed in order to effectively diagnose and treat women with akathisia during pregnancy.

In conclusion, the diagnosis of Mp-related akathisia during pregnancy can be difficult. Ms. Z.'s case illustrates the importance of recognizing drug-related akathisia as a possible cause of restlessness and anxiety during pregnancy. Early recognition may save patients additional anxiety and the health care system thousands of dollars in medication and hospitalization costs.

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				M. T. Wright Antiemetics, Akathisia, and Pregnancy Psychosomatics, December 1, 2007; 48(6): 461 - 466. [Abstract] [Full Text] [PDF]

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