Quetiapine-Induced Sleep-Related Eating Disorder-Like Behavior
Quetiapine-Induced Sleep-Related Eating Disorder-Like Behavior
SRED is characterized by recurrent episodes of partial arousals with involuntary eating during the main sleeping period, usually within the first three hours of sleep. A strong association between somnambulism and SRED has been reported. Somnambulism has been primarily linked to NREM sleep instability, particularly an abnormality in regulation of slow wave sleep (SWS). It is commonly precipitated by other factors including sleep deprivation, presence of other primary sleep disorders (sleep apnea, periodic limb movement disorder) as well as medications that raise the threshold for arousals.
Our patients had a few important predisposing factors for parasomnia including increased work-related stress, depression and severe sleep apnea with high arousal index. If a patient with parasomnia has any other concomitant primary sleep disorder, the treatment is initially directed towards that aspect which often resolves the parasomnia. Our first patient had severe sleep apnea that was treated adequately, but he continued to have sleepwalking and SRED despite good compliance with treatment probably because his SWS had increased after using BiPAP. Our second patient was not able to be compliant with the CPAP initially until she stopped taking quetiapine.
Sleepwalking and SRED have been commonly reported after taking zolpidem as well as sodium oxybate. However, one case report has proposed quetiapine as a potential treatment of somnambulism because it decreases brain delta activity. The somnambulism phenomenon from quetiapine may be explained by the serotonin hypothesis of parasomnia. Quetiapine is found to block 5-hydroxytryptamine-2A (5HT-2A) and dopamine receptors subtype 2 (D2) increasing cortical dopamine release by 5HT-1A agonism. The serotonergic neurons of the dorsal raphe nucleus (DRN) in the brain stem constitute an integral component for generation of SWS. Among a variety of subtypes of serotonergic receptors, 5HT-2A receptors in the DRN are known to regulate frequency and amplitude of SWS. These neurons projecting into the ventrolateral preoptic area help maintain and increase the SWS. These serotonergic neurons are also thought to modulate the motor system by dampening the sensory input and attenuating cortical activation, which helps maintain the hypotonia of the antigravity muscles during SWS. Normally, maintenance of SWS is well coordinated with motor inhibition so that motor activity does not happen without an arousal. A blockade of serotonergic input can withdraw this motor inhibition, enabling the person to walk and perform other motor activities. Quetiapine has been known to alter central serotonin activity by blocking the 5-HT serotonergic receptor which may, in turn, dissociate these two components (state of sleep and muscle hypotonia), leading to sleepwalking without a complete arousal.
From the literature support described above, we propose a potential mechanism of quetiapine-induced SRED and somnambulism phenomenon explained in Figure 1. Sleepwalking aggravated by quetiapine may be explained by the above hypothesis; however, how it may also lead to eating during sleep is unclear. This may be again related to its effect on another serotonin receptor: 5HT-2C. The serotonin receptor 5HT-2C in the hypothalamus regulates mood, anxiety, feeding, and reproductive behavior. Antagonism of the serotonin receptor 5HT-2C by antipsychotic drugs, including quetiapine, olanzapine and clozapine, increases appetite leading to increased food intake and weight gain. Patients who are on these antipsychotic medications and gaining weight were also found to have elevated leptin levels. Because quetiapine blocks 5HT-2C, it may cause leptin resistance at the level of the hypothalamus, contributing to increased food intake and obesity (Figure 1). Often, an obese body shape is not even perceived to be a problem or stressful, as assessed by the perceived stress scale.
(Enlarge Image)
Figure 1.
Potential mechanism of quetiapine-induced SRED and somnambulism. SRED: sleep-related eating disorder; SWS: slow wave sleep; VLPO: ventrolateral preoptic nucleus.
Discussion
SRED is characterized by recurrent episodes of partial arousals with involuntary eating during the main sleeping period, usually within the first three hours of sleep. A strong association between somnambulism and SRED has been reported. Somnambulism has been primarily linked to NREM sleep instability, particularly an abnormality in regulation of slow wave sleep (SWS). It is commonly precipitated by other factors including sleep deprivation, presence of other primary sleep disorders (sleep apnea, periodic limb movement disorder) as well as medications that raise the threshold for arousals.
Our patients had a few important predisposing factors for parasomnia including increased work-related stress, depression and severe sleep apnea with high arousal index. If a patient with parasomnia has any other concomitant primary sleep disorder, the treatment is initially directed towards that aspect which often resolves the parasomnia. Our first patient had severe sleep apnea that was treated adequately, but he continued to have sleepwalking and SRED despite good compliance with treatment probably because his SWS had increased after using BiPAP. Our second patient was not able to be compliant with the CPAP initially until she stopped taking quetiapine.
Sleepwalking and SRED have been commonly reported after taking zolpidem as well as sodium oxybate. However, one case report has proposed quetiapine as a potential treatment of somnambulism because it decreases brain delta activity. The somnambulism phenomenon from quetiapine may be explained by the serotonin hypothesis of parasomnia. Quetiapine is found to block 5-hydroxytryptamine-2A (5HT-2A) and dopamine receptors subtype 2 (D2) increasing cortical dopamine release by 5HT-1A agonism. The serotonergic neurons of the dorsal raphe nucleus (DRN) in the brain stem constitute an integral component for generation of SWS. Among a variety of subtypes of serotonergic receptors, 5HT-2A receptors in the DRN are known to regulate frequency and amplitude of SWS. These neurons projecting into the ventrolateral preoptic area help maintain and increase the SWS. These serotonergic neurons are also thought to modulate the motor system by dampening the sensory input and attenuating cortical activation, which helps maintain the hypotonia of the antigravity muscles during SWS. Normally, maintenance of SWS is well coordinated with motor inhibition so that motor activity does not happen without an arousal. A blockade of serotonergic input can withdraw this motor inhibition, enabling the person to walk and perform other motor activities. Quetiapine has been known to alter central serotonin activity by blocking the 5-HT serotonergic receptor which may, in turn, dissociate these two components (state of sleep and muscle hypotonia), leading to sleepwalking without a complete arousal.
From the literature support described above, we propose a potential mechanism of quetiapine-induced SRED and somnambulism phenomenon explained in Figure 1. Sleepwalking aggravated by quetiapine may be explained by the above hypothesis; however, how it may also lead to eating during sleep is unclear. This may be again related to its effect on another serotonin receptor: 5HT-2C. The serotonin receptor 5HT-2C in the hypothalamus regulates mood, anxiety, feeding, and reproductive behavior. Antagonism of the serotonin receptor 5HT-2C by antipsychotic drugs, including quetiapine, olanzapine and clozapine, increases appetite leading to increased food intake and weight gain. Patients who are on these antipsychotic medications and gaining weight were also found to have elevated leptin levels. Because quetiapine blocks 5HT-2C, it may cause leptin resistance at the level of the hypothalamus, contributing to increased food intake and obesity (Figure 1). Often, an obese body shape is not even perceived to be a problem or stressful, as assessed by the perceived stress scale.
(Enlarge Image)
Figure 1.
Potential mechanism of quetiapine-induced SRED and somnambulism. SRED: sleep-related eating disorder; SWS: slow wave sleep; VLPO: ventrolateral preoptic nucleus.
