Special Article

The following article was written in the winter of 2025-2026. I tried several times to get it published in various journals, but apparently there is something about it that editors don't like. My assumption is that since the article suggests, in a vague and rather general way, that clinicians make mistakes, it is considered outside the pale of what can be published. 

I just don't have it in me anymore to fight this fight. I believe that what is written here is important. Therefore, I have decided that I simply don't want to waste any more time getting this information in front of the eyes of people with narcolepsy, their caregivers, families, friends, employers and significant others.

The article explains why so many people with narcolepsy are diagnosed with depression, and why in all likelihood a great many of those diagnoses are erroneous.  The science is not hard to read; make yourself move through it. 

Failed Motivational Activation

and

Emotional Mimicry

in Narcolepsy

a draft article by

Moshe Turner

mturner@niceer.ngo

Abstract

People with narcolepsy are often diagnosed with depression before their narcolepsy is recognized. In this article, we present our understanding of how the depressive behaviors expressed in narcolepsy can easily be misattributed to the symptoms of depression. We argue that this emotional mimicry does not arise from a primary mood disorder, but instead reflects a downstream consequence of the destruction of orexin neurons, which is the root cause of narcolepsy itself.

We explain how the loss of these neurons and the peptides and proteins they express, i.e., orexin, dynorphin and NARP, results in impaired orexin-dependent motivational activation within mesolimbic dopamine pathways. In turn, brain regions responsible for translating desire into action, e.g., the ventral tegmental area (VTA) and the locus coeruleus (LC), are no longer effectively spurred into action by intact reward valuation signals. Even though emotional valence and the ability to recognize the value of a reward are preserved, the neural processes required to act on that valuation are compromised.

We conclude that impaired orexin-dependent motivational signaling gives rise to the expressed depressive behaviors of narcolepsy that can easily be mistaken for depression. Finally, we suggest directions for future research and encourage clinicians to consider emotional mimicry when evaluating patients whose persistent sleepiness plays a central role in their presentation.

Introduction

People with narcolepsy generally experience lengthy diagnostic journeys, with a median time to diagnosis of approximately ten years [1]; along the way many are diagnosed with depression. One study found that 50% of people with narcolepsy were diagnosed with depression prior to receiving a narcolepsy diagnosis [2]. A recent meta-analysis of pooled data put the prevalence of depressive symptoms in narcolepsy at 32% [3], bringing it into line with what is seen in other, similarly burdensome diseases: 35% in Parkinson's Disease [4], 31% in Multiple Sclerosis [5], and 23% in Epilepsy [6].

The International Classification of Sleep Disorders (ICSD-3-TR, 2023) defines narcolepsy as a hypersomnia of central origin having two phenotypes: Type 1 (NT1) and Type 2 (NT2), with and without cataplexy, respectively [7]. In both phenotypes excessive daytime sleepiness (EDS) is universally present, with NT1 accounting for more than half of patients [8,9]. While the etiology of the disorder is not certain, some studies have shown that when most (NT1) or some (NT2) of the small population of orexin (also known as hypocretin [10] neurons clustered in the lateral hypothalamus are destroyed, the resulting loss of orexinergic signaling leads to the development of narcolepsy [11-13]. Initially understood to be regulators of feeding behavior and energy storage and expenditure [14,15], it soon became clear that the orexins also play a substantial role in the regulation of sleep/wake states [16] and that the loss of orexinergic signaling causes narcolepsy [17,18]. Of particular relevance to the present work, recent research has shown that the orexin system is one of the primary drivers of the neurological process that enables desire to be transformed into action through recruiting the mesolimbic dopamine pathways, which assign incentive salience [19,20].

Throughout this article we use the term “expressed depressive behaviors” to describe outward behaviors that mimic the symptoms of depression. We contend that these behaviors do not arise from a primary mood disorder, but are best understood as consequences of underlying neurological signaling failures.

The Diagnostic Challenge: Symptom Overlap

As there is no definitive physical test for depression, clinicians need to rely on their training, experience, and established diagnostic criteria when evaluating depressive disorders. They are guided in their assessment by the diagnostic guidelines listed in the Diagnostic and Statistical Manual of Mental Disorders, 5th ed, Text Revision (DSM-5-TR) [21].

Initially, the clinician will likely have the patient complete a self-reporting screening questionnaire such as the PHQ-9 or the Beck Depression Inventory [22]. To screen positive for depression, a patient must experience five or more of nine specific symptoms nearly every day during a 2-week period. Of importance for the present work, one of those symptoms must be loss of interest in doing things that generate pleasure or are otherwise rewarding. Since the symptoms of narcolepsy map almost completely onto the symptoms of depression, a person with narcolepsy will screen strongly for depression, leading the clinician down the wrong diagnostic path from the very outset [table 1].

The hinge on which the diagnostic process turns is the clinical interview [23]. Querying the patient about their experiences and feelings, the clinician skillfully elicits responses that are sufficiently informative to help them make an at least conditional diagnosis. If the patient’s narrative reiterates many positive answers to the nine screening questions, that will work to reinforce the clinician’s perception of depression.

Of course, various forms of depression can certainly occur in narcolepsy patients. We suggest that in many cases the presentation of depressive behaviors in narcolepsy maps most closely onto the symptoms of Major Depressive Disorder with Atypical Features [24]. While the inability to experience pleasure or reward is symptomatic of melancholic depression, positive mood reactivity remains intact in atypical depression. Because this ability for ‘emotional brightening’ when presented with an appealing idea or object is also present in narcolepsy, when considered along with the narcoleptic expression of depressive symptoms it can lead clinicians to diagnose atypical depression. What is important here is to distinguish between symptoms of a real primary mood disorder and depressive behaviors that are only expressed.

Compounding the diagnostic challenge are symptoms that narcolepsy shares with certain psychiatric disorders. One example is sleep paralysis, which occurs when the inability to move that is characteristic of REM sleep persists while transitioning from sleep to wakefulness [25]. The dreams of sleep paralysis are often terrifying, and accompanied by a feeling of dread and of the presence of a threatening other person in the room [26]. The occurrence of sleep paralysis can be misattributed to a panic or trauma-related disorder. Another example is the intrusion of some features of REM sleep into full wakefulness, which can happen to people with narcolepsy at any moment during the day, presenting as waking hallucinations that can be misdiagnosed as symptomatic of psychosis [27,28 ]. The overlap of the symptoms and manifestations of narcolepsy onto other disorders creates the potential for misinterpretation that extends beyond just depressive symptoms [29].

Given all of the foregoing, a clinician not familiar with narcolepsy to begin with, and even more so unaware of its ability to impersonate depression, could quite reasonably find compelling evidence for a diagnosis of some form of depression.

Emotional Mimicry: Anhedonia vs. Avolition

To gain further insight into why the expressed depressive behaviors of narcolepsy can be misunderstood as symptoms of depression, it is necessary to distinguish between the avolition of the former and the anhedonia of the latter. Anhedonia is when the desire to do pleasurable or otherwise rewarding things is not present. In avolition, however, the desire and interest in those activities is present but the person finds it difficult or is unable to initiate and/or persist in doing them [21]. We will now examine how the anhedonia of depression can develop due to interoceptive dysfunction and how the avolition of narcolepsy arises from a neurological signaling failure.

Interoception is a process in which the anterior insular cortex (insula) integrates the internal and external somatosensory inputs it receives from the autonomic nervous system [30,31]. The orexin system, together with dopaminergic signals from the ventral tegmental area (VTA) balance or ‘tune’ those inputs [32], helping the insula to create a ‘data set’ that holistically describes how the organism is doing. The insula wants to know, “Am I hungry? Am I happy? Do I have a full bladder? Does anything hurt?” It then uses this information to create a ‘feeling map’ which describes the organism’s current physical and emotional state. This ‘map’ is then transmitted to the dorsal anterior cingulate cortex (ACC) which evaluates it [33,34], asking, "Is everything okay? Is there anything that requires action?” If the ACC identifies an action item, it notifies the medial prefrontal cortex (PFC) which then orders the appropriate metabolic and/or behavioral responses [35,36].

Some forms of depression develop when the insula begins to misread these inputs [37,38]. It starts to misinterpret or exaggerate negative signals or may even generate them on its own. It might, for example, interpret normal fatigue as profound exhaustion or amplify minor aches into significant pain. It may also generate a persistent feeling of "wrongness," dread, or malaise [39,40]. This malfunction on the part of the insula may bring it to create an incorrect ‘feeling map’ depicting illness, injury or other trouble that doesn’t actually exist. When the ACC evaluates that map, it transmits a ‘trouble code’ to the PFC. A potential response by the PFC is to initiate a state of energy conservation, which can produce these classical symptoms of depression [41,42]:

• Anhedonia: The brain determines that since the body is unwell, conservation of energy is necessary. Pursuit of rewarding or pleasurable activities is curtailed.

• Social withdrawal: Energy is required to deal with others; the brain concludes that it is best to be alone.

• Rumination:  A person becomes preoccupied with thinking negative thoughts, leading to a further descent into depression.

While it is certainly true that other models exist for explaining the etiology of depression [40-42], the distorted interoceptive processing that we have described above provides a coherent neurological explanation of how the symptoms of depression can develop in an intact brain [37,39].

In contrast to the dysfunction that leads to the development of depression, the depressive behaviors expressed in narcolepsy arise as a result of a physical lesion in the brain, i.e., the destruction of the orexin neurons [43,44]. While the narcoleptic patient’s interoceptive map remains accurate, this lesion in physical brain tissue causes a signaling failure that largely prevents the motor and arousal centers from being spurred into action to attain a desirable reward or goal [45,46].

All For One and One For All; the Three Musketeers of Motivation

In the neurotypical brain, the insula correctly processes interoceptive inputs and generates an accurate feeling map [31]. When a person has an idea to engage in some pleasurable or otherwise rewarding activity, that idea is processed in the PFC against the ever-changing interoceptive map created by the insula, checking to see if current conditions will allow it to proceed [47]. If the PFC assesses that conditions are right to go ahead with the activity it issues a ‘go’ signal to all the brain regions that will generate the physical energy and motivational drive needed to proceed, primarily the VTA, the locus coeruleus (LC), and the amygdala [48,49]. As we will now see, a key player in that creation is the orexin system.

The neurotransmitters dopamine, serotonin, norepinephrine, acetylcholine, histamine and epinephrine are directly regulated or modulated by orexin neurons [50,51]. Intimately involved in directing homeostasis, metabolism, mood and the maintenance of arousal through signaling with the peptide orexin [52-54], the orexin system is also the primary source of the neurological ‘push’ that gets other brain regions busy doing their respective jobs of initiating and maintaining motivated behaviors [55,56]. Orexin neurons have been called the “conductors of an orchestra of neurotransmitters” [57,58]; without orexinergic signaling to tell each member of the ‘orchestra’ what to play and when, the neurological ‘music’ will become discordant, resulting in considerable downstream autonomic dysregulation [59,60].

Colocalized on orexin neurons is the precursor protein prodynorphin, which is cleaved into the inhibitory neuropeptide dynorphin [61]. Dynorphin plays a critical role in the LC, which provides the tonic arousal and noradrenergic signaling required for vigilance, attention, and, in conjunction with the amygdala, mood and emotional processing [62]. The inhibitory action of dynorphin acts in opposition to the excitatory effect of orexin in a push-pull manner as they work together to fine tune the LC’s role in the genesis and maintenance of motivation [63].

Also colocalized on orexin neurons is NARP (neuronal activity-regulated pentraxin) [64]. NARP is a structural protein essential for clustering excitatory AMPA receptors at the synapse [65]. This clustering of the AMPA receptors sensitizes the receiving synapse to better ‘hear’ incoming glutamatergic signals, thereby maintaining the cell’s intrinsic excitability. Without NARP the VTA would go functionally ‘deaf’ to the instructions it is receiving from the PFC [66]. Similarly, NARP sensitization of the LC helps to maintain the stability of LC-generated tonic arousal [67].

Ordinarily, when the ‘go’ signal is broadcast by the PFC, the orexin neurons dispatch orexin, dynorphin, and NARP in response [68]. However in narcolepsy, with all or most of the orexin neurons having been destroyed, these Three Musketeers of neurochemical signaling are lost as well. Without NARP, the VTA and the LC are effectively deaf to the ‘go’ signal from the PFC. The lost orexin is not there to ‘push’ the system into action, and the missing dynorphin is not present to tune the state of the system. Without them, the narcoleptic brain is left motivationally hobbled [69].

The Amygdala: The Evidence for Behavioral Differentiation

In the context of motivated behaviors, the function of the amygdala is to recognize each external stimulus and assign it a specific emotional value based on the internal maps created by the insula [61,62]. Identifying something as desirable or rewarding, or dangerous or abhorrent is a cognitive and emotional process that assigns valence [63] to the stimulus and does not, by itself, require physical action.

Recognition, however, is not the same as pursuit. In order to transform a properly valued ‘reward’, be it a pleasing experience or an escape from danger, into an actionable desire, the brain must undergo motivational activation [64], i.e., there needs to be an initiating ‘push’ that changes thinking into doing. It is the orexin system that provides that activating push. When the amygdala determines that some outcome is desirable, it enlists the orexin neurons to begin working towards that goal. They attach an “I want this” tag to that goal, and then, through their dense projections to the VTA pass it along to the brain’s execution centers [65]. In this manner they provide the necessary push that causes the brain to assign incentive salience to a goal that is perceived as rewarding. It is this chemical ‘tagging’ that turns a passive appreciation of a reward into an active wanting that can overcome the discounting of the effort required to get it [66].

In the narcoleptic brain the amygdala’s ability to assign positive emotional valence to stimuli remains fully functional. The individual can perceive a potential reward, appreciate its value, and desire the outcome. This is confirmed by the presence of positive mood reactivity; the person’s "brightening", or experiencing delight in response to good news or humor is the visible proof that the amygdala has successfully recognized and valued the reward [67,68].

However, although the reward is still recognized and appreciated in the amygdala, the orexin neurons are not present to communicate the “I want this” tag to the VTA, preventing the assignment of positive incentive salience to the reward. This results in a state of total effort discounting: the amygdala correctly identifies the reward’s value, but without the orexinergic push and the resulting dopamine-induced wanting, the brain cannot execute on that reward because the perceived metabolic price of the effort required to do so remains too high [69,70].

The result is a neurological stalemate. The narcoleptic individual is not suffering the inability to feel pleasure, i.e anhedonia, but rather from avolition, the inability to want that pleasure enough to actively pursue it [21]. This explains why narcoleptics can appreciate a goal but not chase after it, and why they in many cases fail to perceive the dopaminergic reward of drugs of addiction; the brain sees the value, but ability to want it is essentially offline [71].

This ‘wall’ that stands between desire and action argues forcefully against a diagnosis of depression [72,73]. The amygdala identifies high incentive value and issues a strong command for action, but the command cannot get through [74,75 ]. What an observer misinterprets as the apathy of anhedonia is actually a system that is unaware of an order to act [76]. It is avolition, a failure of execution and arousal in the presence of a fully functional will.

Diagnostic Refuge

In narcolepsy, difficulty with initiating motivated behaviors is often misattributed to character flaws such as laziness, apathy or oppositional behavior. While this stigma hurts at any age, affecting employment, marriages and social interactions, in younger narcoleptics these accusations are particularly devastating for their developing psyches [77,78]. In the context of this stigmatization, a diagnosis of depression, even if incorrect, offers profound relief.

As Jutel notes in her landmark essay [79], “Being diagnosed gives permission to be ill. What was previously a complaint is now a disease. Light duty, rest, sick leave, and disability payments are authorised as the individual becomes patient and (in some cases) pampered.” Patients may unwittingly embrace this "diagnostic refuge," as it provides a socially acceptable explanation for their suffering. Unfortunately, taking refuge in an incorrect diagnosis can pause the search for the true neurological condition underlying these expressed depressive behaviors, potentially delaying a proper diagnosis of narcolepsy, perhaps by many years [80].

There has been discussion in the psychiatric community for quite some time about the utility of labeling a patient with a diagnosis, suggesting that a misdiagnosis is worse than no diagnosis at all [81]. We take no position in that debate, but we do implore psychiatrists to learn more about the emotional mimicry which is an intrinsic, albeit under-recognized and under-documented part of narcolepsy.

Conclusion

We have explained our hypothesis that the misdiagnosis of narcolepsy as depression is often the result of the misattribution of the depressive behaviors expressed by narcoleptics to the symptoms of depression due to significant symptom overlap. We have also elucidated the neurological mechanisms that give rise to these behaviors, i.e. the signaling failures of orexin, dynorphin and NARP in the mesolimbic dopaminergic reward pathway.

Although our hypothesis as presented here is supported by the existing literature, we recognize that there has been no rigorous scientific work to determine, in a suitably large cohort of narcolepsy patients, the incidence of actual versus apparent depression or the degree to which avolition blocks action. Also, it is clear that people with narcolepsy are indeed capable of acting on their desires, some of them more of the time than others. How the neural circuitry we described does not fail entirely or transiently fails is beyond our understanding and would be an interesting area for further research.

By learning about the neurological basis of this emotional mimicry and how to recognize it, clinicians can potentially help to reduce the misdiagnosis of depression in narcolepsy, and by doing so, also help to reduce the long diagnostic journeys experienced by people with narcolepsy.

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