Narcolepsy Treatments

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There is no known single cure for narcolepsy; however, there are several different methods that treat the symptoms of narcoleptic patients. Targeted symptoms include: excessive daytime sleepiness (EDS), cataplexy, disturbed nighttime sleep, and sleep paralysis[25]. To target the more common symptoms of narcolepsy, EDS and cataplexy, stimulants and anti-depressants medication were initially used as treatments [15] Currently, modafinil and sodium oxybate are most commonly used [12-11]. There are also non-pharmacological approaches, and there exists a new treatment under consideration called pitolisant [12-5].



Amphetamines were first used to treat narcolepsy in 1935 by Prinzmetal and Bloombery. Methamphetamine, a potent derivative of amphetamine, is also used as treatment. The methyl group allows the molecule to be more lipophilic and therefore cross the blood-brain barrier more easily, increasing penetration to the central nervous system [9]. Amphetamines block reuptake of monoamines such as norepinephrine and dopamine, and prolong wakefulness and increase both cortical activation and behavioural arousal [15]. Because amphetamine-like compounds are related to dopamine release stimulation and reuptake inhibition, there are concerns with substance abuse and addiction [15]. Records of methamphetamine abuse have been present since the 1950s, especially in post-war Japan and Sweden [20-13].


Antidepressants are used mainly to relieve the symptoms of cataplexy in narcoleptic patients[24].

Tricyclic Anti-Depressants

In the 1960s, tricyclic antidepressants (TCAs) were first used to treat narcolepsy [2]. TCAs inhibit reuptake of norepinephrine, epinephrine and serotonin [16]; some examples of TCAs used for narcolepsy treatment include imipramine, protryptiline, and clomipramine [15]. TCAs have been shown to reduce sleep paralysis and hypnagogic hallucinations [24]. TCA has anticholinergic effects, causing adverse side effects such as impotence in males, as well as dry mouth and tachycardia [20-13]. Furthermore, some TCAs are not very selective, since some tricyclic compounds are weak dopamine reuptake inhibitors [3] and need to be refined to target more specific pathways. Abrupt discontinuation of TCA use also results in rebound cataplexy, which may last from a few days to several months [24].

Monoamine Oxidase Inhibitors

Other popular antidepressant medications used to treat narcolepsy are monoamine oxidase inhibitors (MAOIs), which help supress enzymatic degradation of catecholamines [15]. This means that MAOIs work to increase catecholamines concentrations extracellularly. MAO is a flavin-containing dominating enzyme located in outer membranes of neural and glial mitochondria [20]. There are two forms of MAO: MAO-A and MAO-B. MAO-A has a high affinity for noradrenaline and serotonin, and MAO-B has a high affinity for dopamine [20]. MAOIs show REM suppressant effects, but are also useful for treating cataplexy symptoms in narcoleptic patients [15]. MAOIs may exert negative effects, including adverse interactions with drugs that have sympathomimetic effects (meaning the effects mimic transmitter substances of the sympathetic nervous system), that are unpredictable and sometimes fatal [14]. Additionally, the first generation of MAOIs covalently bind to the active site of the enzyme leading to long term enzymatic inhibition (McDaniels, 1986). Therefore there have been safer MAOIs that are selective towards MAO-A or MAO-B, as well as some with reversible effects [15]. These compounds are effective in controlling abnormal REM sleep and cataplexy [15].

Selective Serotonin Reuptake Inhibitors

Selective serotonergic reuptake inhibitors (SSRIs) have also been explored as options to control cataplexy [24]. Several SSRI metabolites have noradrenergic reuptake inhibition effects [24]. SSRIs can sometimes be favored because they have a less severe rebound cataplexy associated with abrupt discontinuation than TCAs [10].


Fos-IR Expression in Rodent Slices
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A. After vehicle administration.
B. After modafinil administration: increase Fos-IR expression in PFx, TMN,
BSTLD, CeL, cortex, IC, and striatum. None observed in SCN and AHA.

Modafinil is a commonly used treatment for narcolepsy; however, its mechanism of action is not well known. Scammell and colleagues (2000) administered modafinil via chronic intraperitoneal catheters in mice, in varying doses and at varying times of the day. They used immunohistochemistry to identify Fos-immunoreactive (Fos-IR) neurons [23]. Fos is used as a neuronal activation marker because it is a transcription factor expressed in physiologically activated brain areas after a variety of stimuli [22]. Fos expression increased in the tuberomammilary nucleus (TMN) and orexin neurons of the perifornical area (PFx) [23]. TMN is the sole neuronal source of histamine in the brain, and antihistamines or inhibitors of histamine synthesis decrease wakefulness [12]. TMN and orexin neurons have ascending projections to the cortex, basal forebrain, midline thalamus and descending projections to other arousal-promoting regions such as dosal raphe nucleus, locus coeruleus, and pontine cholinergic regions [5]. Hypocretin-1 is a neuropepetide produced in the lateral hypothalamus, and it is important in wake regulation [26]. Its release is elevated late in the wake period in nocturnal and diurnal mammals [26]. Additionally, a deficiency in hypothalamic hypocretin (also known as orexin) neurotransmission is the primary cause of narcolepsy in humans and animal models [8]. It has been shown that following optogenetic stimulation of hypocretin neurons in vivo, there is an increase in wake transitions [1]. Fos immunoreactivity is observed in orexin neurons and TMN not only after modafinil administration but also during spontaneous wakefulness[23], indicating that perhaps orexin neurons and TMN are a measurement of wakefulness as opposed to a result of modafinil [26].
Therefore, modafinil appears to carry out its effects through interactions with the histaminergic neurons of the TMN and the orexin neurons of the PFx. However, it must be noted that modafinil may not directly act on the orexin neurons, and the increased activity in these neurons may be due to neurochemical changes accompanying sleep and wakefulness [26].

Qiu and colleagues (2012) performed lesions in the core and shell of the nucleus accumbens, which resulted in an increase in wakefulness. Moreover, core lesions, but not shell lesions, blocked arousal response to modafinil, which suggests that dopamine receptors expressed in the core are essential for modafinil’s arousal effects [18]. The nucleus accumbens is a region of the brain that helps regulate sleep-wake behaviour and mediates arousal effects of the midbrain dopamine system and modafinil [18]. Furthermore, Qu and colleages (2008) have found that D1 receptor and D2subscript receptor agonists block the effects of relatively low doses of modafinil; this illustrates the interactions between modafinil and the dopaminergic system.

Xyrem for Narcolepsy
An information video about the use of Xyrem, a drug containing sodium oxybate.

Gamma-Hydroxybutyrate or Sodium Oxybate

Gamma-hydroxybutyrate (GHB), also known as sodium oxybate, is an endogenous metabolite of GABA and converts into GABA via transamination [7]. Sodium oxybate works via GABAB receptors to modulate the activity of areas of the hypothalamus that promote sleep [8]. Administration of GHB promotes sleep, and this behavioural change causes cerebrospinal fluid (CSF) hypocretin-1 concentrations to decline [26]. This suggests that neurochemical concomitants of sleep and wake are capable of changing the physiological output of hypocretin-1 neurons. Sodium oxybate is known to diminish cataplexy, help consolidate nighttime sleep, and in higher doses, reduce EDS [8].

GH Levels and SWS versus Administration of Sodium Oxybate
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This graph shows the increase of GH secretion and SWS after sodium oxybate treatment.
There is an increase of the pairing of GH and SWS in both healthy controls and narcoleptic patients.

Narcoleptic patients are likely to become obese according to the BMI scale [11] which may be a result of hypocretin deficiency, since the hypocretin system plays a role in hormonal and autonomic functions [8]. Furthermore, long-term potentiation has been observed with the increase in activity of hypocretin neurons when subjects are awake for an extended time [26]. Danjacour and colleagues (2010) studied the effect of sodium oxybate on nocturnal growth hormone (GH) secretion and slow-wave sleep (SWS). There is an increase in GH secretion and SWS with the drug administration [8]. Danjacour and colleagues (2011) found that sodium oxybate leads to an increase in nocturnal GH secretion in healthy controls and hypocretin-deficient narcoleptic patients as well as a strengthening of temporal relation between GH secretion and slow-wave sleep. This provides an explanation for the obesity associated with narcolepsy patients as well as provide more evidence for the side effects that come with the use of sodium oxybate as a treatment.


Comparison of Effects After Placebo, Modafinil, and Pitolisant Administration
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Epworth sleepiness scale (ESS), a self assessment on how likely they fall asleep in different situations.
Improvement after pitolisant administration that is comparable to the results of modafinil administration.

Pitolisant is a selective histamine H3 receptor inverse agonist and Dauvilliers (2013) and colleagues have tested its effect on narcoleptic symptoms, because histamine neurons are crucial in maintaining wakefulness. Following pitolisant treatment, histaminergic and other major alerting systems, such as noradrenergic, dopaminergic, and cholinergic neurons, exhibited activity enhancement including in hypocretin-deficient mice. There was no activation of dopaminergic neurons in the nucleus accumbens, with a low addiction liability, absence of psychomotor activation, and behavioural senitisation, suggesting that it acts differently from a typical psychostimulant [6]. Comparatively, pitolisant reduced EDS better than a placebo and proved to be inferior to modafinil treatment.

Non-Pharmacological Approaches

Non-pharmacological approaches include regular napping [21] to help with EDS, but may be a hindrance to schedules that require attention for long periods of time. Maintaining a sleep-wake schedule may help to regulate sleeping patterns [15]. There have also been studies showing that consumption of certain foods has affected sleep; [4] have found that consumption of 50 g of glucose, as opposed to a placebo, in narcoleptic patients was associated with more sleepiness. Moreover, there was an increase in REM duration in naps after glucose intake, thus glucose should be avoided in narcoleptic subjects [15].

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