A 9-year-old female with iron deficiency has severe periodic limb movements while taking mirtazapine for insomnia

Abstract

Mirtazapine is a Food and Drug Administration–approved atypical antidepressant used off-label for insomnia. Mirtazapine has been associated with movement disorders in adults. A 9-year-old female was seen in the sleep clinic for symptoms of insomnia, nocturnal awakenings, restless sleep, and growing pains. Mirtazapine was started prior to presentation for severe insomnia. A sleep study showed frequent repetitive leg movements prior to sleep onset as well as significant periodic limb movement disorder with a periodic limb movement index of 25.1/hour. The child was found to have a ferritin level of 23 ng/mL and an iron saturation of 10%. There were concerns that the presence of iron deficiency along with the use of mirtazapine may have contributed to the elevated periodic limb movement index. After starting iron therapy to treat the child’s iron deficiency, mirtazapine was weaned off, with further clinical improvements in sleep quality reported. A follow-up sleep study showed a resolution of her periodic limb movement disorder with a periodic limb movement index of 1.4/hour. This is the first pediatric case to describe a sleep-related movement disorder associated with the use of mirtazapine and polysomnographic data to support resolution after discontinuation of mirtazapine along with iron therapy.

Citation:

Hawkins M. A 9-year-old female with iron deficiency has severe periodic limb movements while taking mirtazapine for insomnia. J Clin Sleep Med. 2023;19(7):1369–1373.

INTRODUCTION

Mirtazapine is a Food and Drug Administration–approved atypical antidepressant.¹ The mechanism of action is antagonism of alpha-2, H1, 5-HT2A, 5-HT2C, and 5-HT3 receptors.¹ This pharmacological profile is unique compared with other antidepressants.² Mirtazapine was first approved for the treatment of major depression in the Netherlands in 1994 and in the United States in June 1996.² There are described side effects of sedation, drowsiness, and weight gain, likely due to the relatively high affinity for H1 receptors.^2–4 Mirtazapine is prescribed off-label for insomnia symptoms in children.³ Described sleep-related effects are a decreased sleep-onset latency, reduced wake after sleep onset, increased sleep duration, and limited effect on rapid eye movement (REM) sleep compared with other commonly used sleep medications.³

REPORT OF CASE

A 9-year-old female with a past medical history of attention-deficit/hyperactivity disorder (ADHD) and anxiety presented to the sleep clinic with a history of moderate to severe sleep-onset insomnia and severe sleep maintenance insomnia for the past 2 years. Her mother reported restless sleep, frequent reports of growing pains, nocturnal awakenings, severe insomnia without the use of sleep medications, headaches, and behavior concerns. The child denied symptoms suggestive of restless legs syndrome (RLS) and her mother denied a family history of RLS. The child was treated by a psychiatrist who started mirtazapine 15 mg daily for insomnia several weeks prior to presentation. She previously tried immediate-release trazadone 25 mg for insomnia; however, it caused gastrointestinal difficulties and next-day sleepiness. Concurrent medications included guanfacine 4 mg for ADHD, sertraline 150 mg for anxiety, and supplemental magnesium for constipation. Her mother reported a consistent bedtime routine and daytime activities. An in-laboratory polysomnography was recommended to evaluate for abnormal movements during sleep that could be responsive to iron therapy. Her polysomnography showed periodic limb movement disorder (PLMD) with a periodic limb movement index (PLMI) of 25.1/hour (PLMI ≥5/hour is considered abnormal in the pediatric population) and mild sleep-disordered breathing not meeting criteria for obstructive sleep apnea. Her apnea-hypopnea index (AHI) was 1.3 events/hour and obstructive AHI (OAHI) was 0.5 events/hour; criteria for pediatric obstructive sleep apnea require an OAHI ≥1 events/hour. She had frequent repetitive leg movements prior to sleep onset. Her periodic limb movements occurred primarily during non–REM sleep and were infrequently associated with arousals, with a PLM arousal index of 1.6/hour.

Laboratory work revealed a ferritin level of 23 ng/mL and an iron saturation of 10%. The patient was started on iron therapy for severe PLMD, with improvements noted within 2 weeks of starting iron therapy. Her mother described sleeping through the night 3 weeks after starting on supplemental iron; she previously had multiple awakenings nightly. Due to a suspected association between PLMD and mirtazapine, recommendations were provided to discontinue her mirtazapine and obtain a follow-up sleep study to see if her PLMD had resolved. Approximately 2 weeks after starting on supplemental iron, mirtazapine was discontinued over a 2-week period. Her mother described further improvements in her insomnia symptoms and daytime behavior along with less-frequent movements during sleep.

The patient’s follow-up polysomnogram, obtained 3.5 months after the initial study, showed a dramatic improvement in her PLMI from 25.1/hour to 1.4/hour after starting iron therapy and discontinuing mirtazapine (see Table 1 for a comparison of her baseline and follow-up polysomnography data; see also Figure 1 and Figure 2, respectively). After 3.5 months on iron therapy (1 tablet of Vitron-C (Prestige Consumer Healthcare Inc.; Lynchburg, Virginia) twice daily), her follow-up ferritin level was 67 ng/mL and iron saturation improved to 26%. Iron therapy was continued with plans for follow-up lab monitoring.

Table 1.

Polysomnography parameters.

	Baseline Study	Follow-up Study (3.5 Months Later)
Medications	Sertraline 150 mg Mirtazapine 15 mg Guanfacine 4 mg Oral magnesium 100–200 mg	Sertraline 150 mg Guanfacine 4 mg Elemental iron 65 mg Vitamin C 125 mg
BMI, kg/m2	17.5	17.2
Sleep efficiency, %	97.2	83.5
Total sleep time, min	549	464
Sleep latency, min	9.5	35
REM percentage sleep time, %	12.1	16.4
REM sleep onset latency, min	175	291
Slow-wave sleep, %	28.1	19.4
Arousal index, events/h	7.8	10.5
Spontaneous arousal index, events/h	3.8	7.4
Respiratory event arousal index, events/h	1.0	2.8
Periodic limb movement arousal index, events/h	1.6	0.3
Periodic limb movement index, events/h	25.1	1.4
Total number of leg movements, events/h	35.3	4.1
AHI, events/h	1.3	3.0
OAHI, events/h	0.5	2.3
Snoring	None	Rare mild
Mean oxygen saturation, %	98	97
Oxygen saturation nadir, %	94	94
Oxygen desaturation index, /h	0.5	0.1
Mean EtCO2 level, mm Hg	43	40.50
EtCO2 >45 mm Hg, % of sleep time	2.9	0.0
Lowest heart rate, beats/min	48	52
Highest heart rate, beats/min	81	83
Evening blood pressure, mm Hg	108/75	114/64
Morning blood pressure, mm Hg	104/58	128/77
Parent questionnaire: Did your child sleep the same, better, or worse than usual?	Slept about the same as usual	Slept worse than usual
Parent questionnaire: Did your child breath the same, better, or worse than usual?	Breathed about the same as usual	Breathed about the same than usual

Baseline study compared with follow-up study after discontinuation of mirtazapine and initiation of iron therapy. AHI = apnea-hypopnea index, BMI = body mass index, EtCO₂ = end-tidal carbon dioxide, OAHI = obstructive apnea-hypopnea index, REM = rapid eye movement.

Figure 1. The baseline polysomnography shows frequent limb movements, particularly during the first half of the study.

Figure 2. The follow-up polysomnography shows significant improvement in the frequency of limb movements.

DISCUSSION

A review of the literature reveals an association with mirtazapine and movement disorders.¹ Mirtazapine was associated with movement disorders in 179 cases in a review article from 2020.¹ There were 69 cases of RLS and 9 cases of PLMD; all cases were in adult patients.¹ One intervention study with polysomnographic data obtained before and after the intervention showed significant periodic limb movements in 8 of 12 healthy young males after taking 30 mg of mirtazapine daily for 7 days.⁴ A case report described witnessed involuntary nocturnal limb movements in a young man treated with mirtazapine for opioid dependence.⁵ The movements were painful and caused sleep disturbance. The movements resolved when mirtazapine was discontinued and did not recur.⁵ A 2017 systematic review of antidepressant influence on RLS and periodic limb movements reported that mirtazapine may be associated with higher rates of RLS and periodic limb movements than other antidepressants.⁶ Venlafaxine was associated with an increase in RLS symptoms and periodic limb movements in one small study, while bupropion may reduce RLS symptoms in the short term in some patients.⁶ In children and adolescents, fluoxetine was associated with an elevation in the PLMI without significant effects on other sleep parameters.⁶ The risk of RLS symptoms and periodic limb movements while taking selective serotonin reuptake inhibitors and serotonin–norepinephrine reuptake inhibitors is thought to be low.⁶ Trazadone and doxepin are often used in insomnia for their sedating properties; these medications have not been found to increase the PLMI and therefore could be used in patients with risk factors for PLMD if clinically indicated.⁶

A review of the literature of mirtazapine and pediatric usage showed a retrospective review of mirtazapine used for sleep disturbances in 8 pediatric patients with Angelman syndrome.⁷ Mirtazapine 3.75 to 30 mg was provided nightly for 36 weeks. From a group of 8 patients, 7 patients had improvements in sleep onset and nocturnal awakenings. Two patients had improvements in daytime behavior.⁷ Another pediatric study of mirtazapine in autistic and other developmental disorders involved 26 patients who were provided 7.5 to 45 mg of mirtazapine daily for 4 weeks.⁸ Of the 26 patients, 9 patients showed improvement in daytime behaviors and insomnia. The conclusions of this study stated that mirtazapine was well tolerated but only had modest effectiveness.⁸ Weight gain was observed in both pediatric studies.^7,8 Abnormal sleep-related movements were not described in these reviews.^7,8 Mirtazapine is available in an oral dissolving tablet, which can be helpful for pediatric usage. Weaning is required when discontinued.⁷

There are no described pediatric cases of mirtazapine causing sleep-related movement disorders. This is the first known case describing this side effect in a child. The objective polysomnographic data further strengthen the association between the use of mirtazapine and periodic limb movements. One significant confounding factor in this case is the introduction of iron therapy in addition to discontinuation of mirtazapine. Iron therapy is the primary treatment of PLMD in children.⁹ Multiple pediatric case series have suggested that ferritin levels on the lower end of the normal range (defined as ferritin <50 ng/mL) are present in 70–75% of children with RLS.⁹ A threshold of ferritin <50 ng/mL is often used to recommend treatment with iron therapy in children.⁹ Low iron levels can exacerbate RLS symptoms despite normal hemoglobin and hematocrit levels.⁹ RLS can be a difficult diagnosis to make in younger children. Although this child denied clear symptoms of RLS, the presence of frequent repetitive leg movements prior to sleep onset suggests the possibility of having RLS along with PLMD. Some children may describe pain or run around their rooms without indicating the need to move their legs; this child did frequently complain of growing pains and had bedtime resistance. The presence of growing pains should prompt consideration of an RLS diagnosis, particularly if there is a family history of RLS or growing pains.⁹ This child also has ADHD, which is associated with an increased risk of having RLS.⁹ Genetic and physiologic research indicate that iron deficiency and dopamine dysfunction can be found in both of these conditions.⁹

The significant reduction in PLMI from 25.1/hour to 1.4/hour suggests that both discontinuation of mirtazapine and initiation of iron therapy contributed to the patient’s improvement. Clinical improvements in sleep quality and severity of insomnia were described after initiation of iron therapy, with further improvements described after discontinuation of mirtazapine. However, it is difficult to determine the exact influence of these two interventions on her clinical improvement as they were done in quick succession in attempts to improve sleep quality expediently. Our patient was also taking guanfacine and sertraline. It seems less likely that these medications were associated with her movement disorder on the initial study as she remained on stable doses during both polysomnographic studies. However, there can be night-to-night variability in the presence of periodic leg movements on polysomnography.

Mirtazapine-induced leg movements peaked after the first drug night but rapidly decreased over the course of the 7-day intervention study in the healthy adult males described above.⁴ Our patient had been taking mirtazapine for several weeks when her polysomnography showed a PLMI of 25.1/hour. It is possible that genetic factors, age, or other medications the patient was currently taking could predispose to her lack of tolerance.

Another pediatric sleep-related movement disorder, restless sleep disorder (RSD), is characterized by frequent large movements during sleep along with daytime impairment.¹⁰ RSD criteria are more than 5 large movements per hour observed by polysomnography.¹⁰ RSD is also associated with decreased ferritin levels and treated with iron supplementation.¹⁰ RSD was considered in the differential diagnosis for our patient due to the report of restless sleep and daytime impairment; however, polysomnographic criteria for RSD were not met.

Sleep-related movement disorders are uncommonly associated with the use of mirtazapine.¹ In this case, the use of a prescription sleep aid in the setting of iron deficiency seemed to be associated with clinical worsening of sleep quality and likely contributed to causing PLMD. Polysomnograms are often not available to be performed in a timely manner but provided useful objective information in this case. In a similar case, the author would recommend iron therapy if clinically indicated as the standard treatment for pediatric PLMD. Clinical screening for sleep-related movements is recommended after initiation of mirtazapine. Alternate treatment options could be considered if there are concerns for increased restlessness or sleep disruption persisting after the first month of therapy.

DISCLOSURE STATEMENT

Dr. Hawkins is the clinical provider for the described patient and reviewed and interpreted both described polysomnography studies. Dr. Hawkins continues to care for the described patient and obtained consent to describe this case for educational purposes. Dr. Hawkins performed a review of the literature, drafted the initial manuscript, reviewed and revised the manuscript, and approved the final manuscript as submitted. Dr. Hawkins agrees to be accountable for all aspects of this manuscript. Work for this report was performed at the Pediatric and Adolescent Sleep Center. The author reports no conflicts of interest.

ABBREVIATIONS

PLMD

periodic limb movement disorder

PLMI

periodic limb movement index

RLS

restless legs syndrome

RSD

restless sleep disorder