New-Onset Sleepwalking in a Patient Treated With Buspirone

To the Editor:

Buspirone is an anxiolytic medication used primarily to treat generalized anxiety disorder (GAD) in patients who do not respond to or cannot tolerate selective serotonin reuptake inhibitors.¹ Buspirone is a popular medication for GAD, because, unlike benzodiazepines, it is not associated with physical dependence or withdrawal and has a favorable adverse effect profile.² The effects of buspirone seem to be mediated via its strong partial agonist activity on the serotonin 5HT1a receptor, although it also has weak affinity for 5HT2 and α-1 adrenergic receptors and can act as a D2 receptor antagonist.³

Buspirone is unrelated to benzodiazepines and does not have any GABAergic, anticholinergic, or antihistamine effects³; as a result, it is not considered to be sedating. Nonetheless, buspirone can affect sleep. Dream disturbances were a frequently reported adverse effect in the original trials and postmarketing reports (BuSpar package insert, Bristol Myers Squibb). Although it does not affect sleep fragmentation, buspirone does increase rapid eye movement (REM) sleep latency and total percentage of REM sleep, and shift REM sleep to later in the sleep cycle. Buspirone does not seem to have an effect on deep sleep (stages 3 and 4).⁴

Somnambulism (sleepwalking) is a parasomnia with a lifetime prevalence of 6.9% that occurs during slow-wave sleep (stage 3).⁵ Buspirone does not belong to a class of medications typically associated with sleepwalking nor was this adverse effect noted in its original trials;⁶ however, 2 recent case reports suggest a possible link. The first report of buspirone-associated sleepwalking occurred in 2018 in a 36-year-old woman with GAD and a history of dissociative episodes, insomnia, vivid dreams, and one instance of sleepwalking during adolescence.⁷ The patient was initiated on buspirone 2.5 mg, which was soon raised to 5 mg once daily (evening dosing). Within a day of the dose increase, the patient had a sleepwalking episode with no memory of the event. The patient discontinued the buspirone and reported no further instances of parasomnias. This was only a single event, and the patient had a history of sleepwalking; therefore, in this particular case, a direct causal link between buspirone initiation and sleepwalking cannot be confirmed.

In contrast, a 2019 report described a 38-year-old man with significant anxiety and life-long history of parasomnias (including sleepwalking), who experienced relief from both after buspirone induction.⁸ This patient reported an almost immediate effect of the medication on his anxiety symptoms and stated that all parasomnias had resolved within a day of medication initiation (10 mg twice a day); this report was corroborated by the patient’s wife. At 1- and 10-month follow-up visits, the patient reported sustained resolution of parasomnia symptoms. This report is unusual as effects of such medications usually require a few weeks of regular use.

Here, we present the case of a patient with GAD and major depressive disorder (MDD) and no history of parasomnias who began sleepwalking within a month of starting treatment with buspirone. The patient verbally consented to publishing this case.

CASE REPORT

The patient is a 40-year-old Middle Eastern female teacher referred to our Stress, Trauma, and Anxiety Research Clinic by her therapist due to her depression symptoms. She was diagnosed with MDD, recurrent, current episode moderate, and GAD. At that time due to chronic pain, she was prescribed duloxetine, but she did not tolerate it because of adverse effects. She was also not able to tolerate venlafaxine previously prescribed by the primary care physician. At this time, she was prescribed buspirone 5 mg twice daily because of lack of tolerance for 3 antidepressants (including one she could not recall). Three weeks later, the dose of buspirone was increased to 5 mg 3 times a day, and then after 5 more weeks increased to 15 mg twice daily, which the patient found helpful with reducing her anxious and depressed mood and improving her sleep. One month after the latest dose increase, the patient informed the psychiatrist that she has been found sleepwalking by the family. Her family found her in the middle of the night at the balcony or entrance door, trying to open the door. When awakened, she would not recall the event and looked confused. This was repeated several times a week to the point that the family would lock the doors for safety. Upon further investigation, the sleepwalking episodes seemed to overlap chronologically with buspirone initiation. Retrospectively, the patient was also able to recall increased frequency of sleepwalking by increasing the dose of the medication. The medication was discontinued, after which the patient did not report any new sleepwalking episodes.

DISCUSSION

Sleep disturbances are not known to be a common adverse effect of buspirone. To our knowledge, this is the second report of somnambulism caused by this medication, whereas a third report suggested improvement of such symptoms after buspirone induction. Medications that reduce the duration of slow-wave sleep—when sleepwalking occurs—may be effective pharmacological interventions for somnambulism. Certain sedative medications such as benzodiazepines and antipsychotics are believed to decrease slow-wave sleep. In addition, medications that reduce arousal such as benzodiazepines and certain antidepressants may reduce instances of sleepwalking by addressing abnormal levels of arousal.⁶ In contrast, a recent review of medication-associated sleepwalking found 4 primary classes of medication associated with somnambulism induction: GABA receptor agonists, antidepressants and other serotonergic agents, antipsychotics, and β-blockers. Although the mechanisms behind medication-associated somnambulism are not fully elucidated, medications that enhance GABAergic or serotonergic activity or inhibit β-receptor activity seem to have the highest risk.⁶

Buspirone’s impact on sleep may be related to its action on serotonergic receptors as serotonin plays a key role in the regulation of sleep architecture.⁹ Sleepwalking is associated with increased sleep fragmentation, reduced early sleep slow-wave intensity, and abnormal arousal responses.⁶ Furthermore, other monoamine neurotransmitters commonly altered in psychiatric disorders—norepinephrine and dopamine—also play a key role sleep architecture modulation.¹⁰ Rates of sleep disorders and parasomnias are higher in some populations with psychiatric disorders (eg, MDD certain anxiety disorders) so they may be at increased risk when starting a medication that impacts sleep architecture.¹¹

One theory that may explain the emergence of parasomnias, including sleepwalking, in populations using certain medication classes is increased arousal during slow-wave sleep.¹² Selective serotonin reuptake inhibitors are associated with delayed REM induction and increased arousals during sleep; this combination may contribute to somnambulism development.¹³ In support of the arousal hypothesis for buspirone-associated sleepwalking, animal studies have identified increased noradrenaline, which is associated with arousal, after treatment with buspirone.¹⁴ Furthermore, patients with GAD also have increased arousal and noradrenergic tone pretreatment.^15,16 Notably, there are sex differences in arousal responses; women are more likely to demonstrate symptoms of hyperarousal, and estradiol may cause higher levels of noradrenaline-induced arousal in women.^17,18 These sex differences may contribute to the differential responses to buspirone, although it is hard to make a conclusion based on 3 cases.

Because the serotonergic actions of buspirone do not seem to affect slow-wave sleep, an additional consideration is on the effects of the medication on REM sleep. Serotonergic medications have been associated with REM sleep without atonia.¹⁹ Atonia (loss of muscle tone) is vital during REM sleep as it prevents individuals from acting out dreams; if aperson experiences REM sleep without atonia, this may be misinterpreted as sleepwalking. Although the case we report seems to demonstrate signs of true sleepwalking (eg, difficulty arousing patient, confusion, no memory of the events) rather than REM sleep without atonia, it is still valuable to consider this additional potential mechanism and the role that it may play in reported parasomnia incidents linked to serotonergic medications such as buspirone.

Although the mechanisms underlying the effects of buspirone on sleep architecture and parasomnias are unclear, they seem to be related to the serotonergic system. It seems clear that there is the potential for buspirone to impact parasomnias; however, whether buspirone may serve to treat or induce parasomnias is uncertain and may depend on underlying neurobiological differences. With increasing evidence of a connection between serotonergic medications and sleep disturbances, it is important to gather a clear history of sleep and sleep-related disturbances before starting these medications and to carefully monitor any changes over the course of treatment.