Non-24-hour sleep-wake disorder, also known as free running disorder, is a circadian rhythm sleep disorder when a patient's endogenous circadian rhythm cycles fail to synchronize to a 24-hour day. It was first found in, and is common in, blind individuals without light perception and it is relatively rare in sighted individuals [5]. In mammals, the circadian rhythm is regulated by the suprachiasmatic nucleus ((SCN)) of the hypothalamus. It receives direct input from the retina, which detect and signal light to the central nervous system [6].

The rods and cones that function as photoreceptors in the eyes relay light to our central neural system, by which they play a role in circadian photoentrainment. Also, there is a group of photosensitive, specialized retinal ganglion cells distributed throughout the retina with similar function, projecting to the SCN, and contain melanopsin as their photopigment [7][8]. The light regulates our sleep-wake cycle via sequential nerve conduction to the central circadian pacemaker, and in blind patients, whose light reception is disrupted, the prevalence of N24SWD is much higher.

In a case series published by Emens et al., an intact internal central circadian pacemaker and circadian photoreception (proved by a positive melatonin suppression test) was observed in a sighted patient with N24SWD. And it indicates that the behavioral and environmental factors, such as daily light exposure pattern and sleep-wake timing, might contribute to the dysynchrony between a normal central circadian pacemaker with a non-24-hour sleep-wake pattern, leading to the phenotype of N24SWD in those sighted patients [24].

It is not uncommon to see altered circadian rhythms in patients with psychiatric disorders, although the mechanism between circadian rhythm disruption and psychopathology remains unclear. Rodent studies have shown that the disruption of circadian rhythms can cause affective changes [9]. There were also studies showing abnormal melatonin production/ levels in patients with schizophrenia, major depressive disorder and bipolar disease [10].

In our case, patient has concurrent bipolar disorder, which is well controlled with lamotrigine, bupropion and psychiatric counselling. It's noted that circadian rhythm dysfunction may be a trait marker of bipolar disease in mood disorders [15,16].

Studies have also has shown that irregularity of the social zeitgeber (an external or environmental cue that entrains or synchronizes an organism's biological rhythms with the natural environmental light/dark cycles) can trigger the first onset of mood episode [17]. And interestingly, the wake therapy which involves sleep deprivation was found to be antidepressant [18]. And exogenous melatonin has been shown to have antidepressant effects proved in many studies [19]. Although the causal effects remain unclear, the interaction between circadian rhythm disorder and psychiatric diseases are likely bidirectional.

Medications such as fluvoxamine, flupentixol, and haloperidol were also found to have a potential role in causing iatrogenic circadian rhythm sleep disorders [20-22], although our patient is on none of these medications. It is important to be cautious with the use of these medications if possible while evaluating and treating circadian rhythm sleep disorders. Our patient is started on a trial of Tasimelteon, which has some evidence of entraining totally blind people with N24SWD, and the clinical response is to be followed [23].

Patients with a suspected circadian rhythm sleep disorder should be advised to use of a sleep log or diary-the diagnosis requires at least 14 days of documentation of progressively shifting sleep-wake times with sleep diaries and/or actigraphy. Actigraphy is also indicated for evaluation. Meanwhile, polysomnography is indicated to rule out other potential sleep disorders. It is noted that circadian phase markers such as melatonin can be a useful tool when determining the circadian phase and also confirm the diagnosis. The evidence behind the Morningness-Eveningness Questionnaire (MEQ) [11] is insufficient.

According to 2015 American Academy of Sleep Medicine (AASM) guidelines, timed oral melatonin agonists have a weak recommendation in blind adults but no recommendation in sighted patients. There is no recommendation for other treatment including prescribed sleep-wake scheduling, light therapy, sleep-promoting medications and wakefulness-promoting medications [12].

Yet, timed light exposure, exogenous melatonin or the combination of both are suggested to be probably useful in sighted patients [13]. There are also cases in which patients achieved successful phase advancement with the use of timed melatonin (the most commonly used dose was 3 mg) [14]. Notably in patients with circadian rhythm disorder who have concurrent bipolar disorder, social rhythm therapy such as interpersonal and social rhythm therapy (IPSRT) which aims to address medication noncompliance, social rhythm dysfunction, and stressful experiences, has been shown to improve stabilizing social rhythms and daily routines, as well as occupational functioning [25].