Sleep Disorders

What are the Benefits of Sleep?

Describe the function of this as it relates to sleep:

• Suprachiasmatic nucleus –

• Brainstem (pons and medulla)

• Thalamus 

• Pineal gland 

• Basal forebrain 

• Amygdala:

Sleep Functions

• Suprachiasmatic nucleus –

  • receives information about light exposure  -> Controls sleep rhythms

• Brainstem (pons and medulla)

  • controls transition btw sleep/wakefulness;

  • Relaxes muscles during REM 

• Thalamus 

  • relays information from senses -> cortex;

  • active during REM sleep

    • (quiet during other phases)

• Pineal gland 

  • Produces melatonin

• Basal forebrain 

  • releases adenosine,

    • supports sleep drive

    • Caffeine blocks this

• Amygdala:

  • Active during dreaming

Differentiate between the Role of Adenosine and Orexin in Sleep/Wake Regulation

Role of Adenosine and Orexin in Sleep/Wake Regulation

• Adenosin:

  • Buildups during wakefulness -> sleepiness

    • Cleared by sleep

• Orexin:

  • In hypothalamus

  • Promotes wakefulness

    • Highest activity during wake, lowest during sleep

  • Loss of signaling =

    •  fragmented sleep/wake

      • (normal total amount of sleep over 24 hours)

Describe the The Ebb and Flow of Sleep Deprivation

Describe what happens in

• NREM (stages 1-4)

• REM

NREM  (1-4)

• Stage 1 

  • Lightly asleep.

• Stage 2 

  • Onset of sleep; 

  • detached with environment, 

  • normal breathing + HR 

  • body temperature decreases.

• Stage 3 and 4:

  • Deepest and most restorative  sleep

  • BP + RR Decreases, 

  • release hormones for growth and development

• REM (25% of night):

  • Brain = Active; Dreams

  • Muscles shut down -> body is immobile + relaxed. 

  • HR + RR = Irregular

Describe Dreams

• What are they?

• Relationship to memory:

• When do they occur?

• Brain Areas Associated:

  • Active during

  • Nonactive

• Dreamwork

Dreams

• What are they?

  • Sleep-dependent thoughts

    • Vivid images and increased emotions

    • Visual sense predominates

• Relationship to memory:

  • During: hypermnesia

    • Increased memory access 

  • Awakening: Decreased memory of dream

• When do they occur:

  • REM; but can also during NREM

    • Less aggressive; More Social

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Brain Areas Associated:

• Active:

  • visuospatial regions, 

  • motor cortex,

  • hippocampus, 

  • amygdala, 

  • cingulate cortex

• Nonactive:

  •  Left and right prefrontal cortex

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Dreamwork:

• Condensation 

  • two figures combined in one

• Displacement 

  • characteristics of one figure are put on another

• Symbolization

• Dyssomnias = affect the amount, quality, or timing of sleep.

• Parasomnias= unwanted physical events, movements, or unusual experiences that intrude into the sleep cycle

Describe  Adjustment Insomnia (transient or short-term)

• Duration:

• Resolves:

Describe Chronic insomnia (long-term)

• Duration:

• Characteristics:

 Adjustment Insomnia (transient or short-term)

• Duration:

  • 1 night -> few weeks

• Resolves:

  • removal of stressor 

  • or adaptation

---

Chronic insomnia (long-term)

• Duration:

  • 1 month -> years

• Characteristics:

  • waxes and wanes

  • exist as an isolated disorder (primary) or Comorbid

What is the relationship between Insomnia and obesity

List the Impacts of Insomnia

Describe Insomnia Disorder

• Essential Feature: 

• Consequence:

• Does not occur exclusively during

• Pharmacologic Agents 

Insomnia Disorder

• Essential Feature: 

  • difficulty initiating or maintaining sleep or nonrestorative sleep 

    • > 3 nights per week for at least 3 months 

  • NOT DUE to direct physiologic effects of a substance or general medical condition

• Consequence:

  •  distress 

  • impairment in 

    • Social, occupational, or other important areas 

• Does not occur exclusively during

  • Course of another sleep disorder

  • Course of another mental disorder

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Pharmacologic Agents 

• Nonprescription

  • Sedating antihistamines, melatonin, herbal therapies

• Low-Dose Sedating Antidepressants

  • trazadone, amitriptyline, doxepin, mirtazapine

• Low-Dose Antipsychotic Medications

  • quetiapine, olanzapine, risperidone

• Benzodiazepines

  • temazepam, triazolam, flurazepam, quazepam, estazolam, other

• Nonbenzodiazepines

  • Zolpidem, eszopiclone, zaleplon

• Melatonin Receptor Agonist

  • Ramelteon

• Orexin Receptor Antagonist

  • Suvorexant, daridorexant, lemborexant, seltorexant

List the Good Sleep Practices

Good Sleep Practices:

• Standardize wake time

• Limit amount of time in bed

• Limit napping 

• Avoid exercise immediately before bedtime

• Avoid looking at clock after going to bed

• Avoid blue light 

• Reduce or eliminate nicotine, caffeine, and alcohol

Describe the dx criteria for Hypersomnolence Disorder

Hypersomnolence Disorder

Diagnosis Criteria:

• >7 hours w/ one of the following:

  • Recurrent periods of sleep or lapses into sleep w/in same day

  • prolonged main sleep episode of > 9 hours that is nonrestorative

  • Difficulty being fully awake after abrupt awakening

• >3 times a week for at least 3 months

Describe Primary Hypersomnia

• Characteristics

• Polysomnographic findings

• Tx

Primary Hypersomnia

• Characteristics:

  • Prolonged nocturnal sleep + continued daytime sleepiness

  • Grogginess on awakening

    • Lasts several hours

  • Pts take long naps (>1 hour)

• Polysomnographic findings

  • Diminished delta sleep

  • Increased number of awakenings

  • Reduced REM latency

• Treatment

  • Sleep hygiene

  • Scheduled Naps

  • Medications

    • Stimulants (methylphenidate and dextroamphetamine)

    • Modafanil/Armodafanil

    • Protryptyline

Describe Narcolepsy

• dx criteria

• Describe:

  • Sleep attacks

  • Sleep Paralysis

  • Hypnogognic and Hypnopompic Hallucinations

• Tx

Dx criteria:

•  Irresistible need to sleep, lapsing into sleep, or napping 

  • 3x a week over at least 3 month\

• One of more of following:

  • Cataplexy 

    • (brief episodes of sudden bilateral loss of muscle tone, 

    • most often in association with intense emotion)

  • Hypocretin deficiency 

    • measured by CSF 

  • Nocturnal polysomnography Showing 

    • REM latency of less than 15 minutes, Or

    • MSLT of less than 8 minutes and 2 or more sleep-onset REM periods

---

• Sleep Attacks

  • Last from seconds to 30 minutes

  • Can occur in any situation

  • Cataplexy occurs in 60 – 90%

    • Collapse may occur without loss of consciousness

• Sleep Paralysis

  • Temporary loss of muscle tone with resulting inability to move

  • falling asleep or awakening

  • several seconds -> several minutes

• Hypnogognic and Hypnopompic Hallucinations

  •  Occur as falling asleep or on awakening

  • Vivid hallucinations 

  • Narcoleptics can have several times per week

  • Generally occur several years after onset of sleep attacks

---

Treatment

• Brief naps

• Pharmacologic

  • Stimulants

  • Modafanil

  • TCA’s may help catalepsy or sleep paralysis

  • Sodium oxybate for cataplexy

Describe Sleep Apnea

• What is it?

• Types?

• Definitions:

  • Apnea:

  • Hypopnea: 

  • Apnea hypopnea index: 

• Clinical History with OSA

• Tx

Sleep Apnea

• What is it?

  • episodes of breathing cessation for 10 sec or more 

    • frequency of 15 events per hour

• Types:

  • Central, obstructive or mixed

• Definitions:

  • Apnea:

    •  cessation of airflow for at least 10 seconds

  • Hypopnea: 

    • reduction of airflow with resultant oxygen desaturation of at least 4%

  • Apnea hypopnea index: 

    • average frequency of apnea and hypopnea events per hour

---

Clinical History with OSA

• Disruptive snoring

• Witnessed apnea or snort arousals

• Gasping/choking sensations

• Excessive daytime sleepiness

• Difficulty concentrating

• Excessive nocturia

• Difficulty maintaining sleep

• Restless or unrefreshing sleep

• Morning headaches

• Irritability

• Daytime fatigue

---

OSA: Tx

• Lifestyle: 

  • Weight loss, exercise, lateral sleep position

• Continuous positive airway pressure (CPAP)

• Oral appliance

• •Uvulopalatopharygoplasty

What is Nightmare Disorder?

Nightmare Disorder

What is it?

• Repeated extended, extremely dysphoric, and well-remembered Nightmares 

• generally occur during second half of sleep episode

Describe Non-Rapid Eye Movement Sleep Arousal Disorders

• What is it?

• Symptoms?

Non-Rapid Eye Movement Sleep Arousal Disorders

• What is it?

  • Recurrent episodes or incomplete awakening from sleep

  • occurring in first third of sleep, 

• Symptoms:

  • Sleepwalking: 

  • Sleep terrors:

    • (Relative unresponsiveness to comfort from others)

  • Dream imagery not recalled.

  • Amnesia for episodes

Describe REM Eye Movement Sleep Behavior Disorder

• What is it?

• dx Criteria?

REM Eye Movement Sleep Behavior Disorder

• What is it?

  • Repeated episodes of arousal during sleep associated with vocalization and/or complex motor behaviors

  • Individual completely awake and alert upon awakening

• Dx criteria:

  • Either of the following:

  • REM sleep without hypotonia on polysomnography

  • History of REM sleep behavior disorder + established synucleinopathy diagnosis 

    • (Parkinson’s, multiple system atrophy)

Describe Restless Legs Syndrome

• What is it?

• Characteristics

Restless Legs Syndrome

• What is it?

  • urge to move legs +  Unpleasant sensation in the legs

• Characteristics:

  • Urge worsens during period of inactivity

  • Urges relieved by movement

  • Worst at night

Describe Hypnotics

• Clinical Usage

• Synergy

• AE

List the Class and Members

List the Benzodiazepine and Nonbenzodiazepine AE

Nonbenzodiazepines vs BZD’s

Hypnotics

• Clinical Usage:

  •  temporary relief for insomnia

• Synergy:

  • In combo w/ sleep hygene

• AE:

  • Habit-forming

    • Schedule IV

      • EXCEPT ramelteon and doxepin

  • Increased mortality and cancer incidence

    • (Highest cause of mortality is infection)

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Class/Members:

• Benzodiazepines

  • Estazolam (Prosom)

  • Flurazepam (Dalmane)

  • Quazepam (Doral)

  • Temazepam (Restoril)

  • Triazolam (Halcion)

• Nonbenzodiazepine

  • Zolpidem (Ambien, Ambien CR)

  • Zaleplon (Sonata)

  • Eszoplicone (Lunesta)

• Orexin receptor antagonists

  • Suvorexant (Belsomra)

  • Lemborexant (Dayvigo)

  • Daridorexant (Qyviviq)

• Other

  • Ramelteon (Rozerem)

  • Doxepin (Silenor)

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Benzodiazepine and Nonbenzodiazepine AE

• Ataxia

  • Increased risk of head injury 1.67x 

• Daytime sedation

• Cognitive effects

• Anterograde amnesia

• Respiratory depression

• Rebound insomnia

---

Nonbenzodiazepines vs BZD’s

• Less abuse potential than BZD’s

• Little tolerance

• Tend not to cause daytime sleepiness

Describe Ramelteon (RozeremTM)

• MOA

• Overall Safety findings

MOA:

• Potent, selective MT1/MT2 receptor agonist

  • 17 times as potent as melatonin

• NEGATIVE affinity for:

  • MT3

  • GABAA 

    • (dopamine, serotonin, ACh, glutamate, noradrenaline, or opiate receptors

---

Overall Safety Findings

• No clinically meaningful effects with respect to:

  • Respiratory function: mild-to-moderate COPD or sleep apnea

    • Not recommended 

  • Next-day residual effects

  • Rebound or withdrawal effects

  • Abuse liability

  • Tolerance

  • Lab results and QTc interval

Describe Suvorexant, Lemborexant, Daridorexant

• MOA

• AE

Suvorexant, Lemborexant, Daridorexant

• MOA:

  • Dual orexin receptor (Ox1R and Ox2R) antagonist (DORA)

    • Decreased sleep latency

    • Increased sleep efficiency, total sleep time

• AE:

  • Schedule IV

  • (Little evidence of tolerance, rebound insomnia)

Describe Modafanil and Armodafanil

• Clinical usage

• MOA

• Cog Effects

• AE

Modafanil and Armodafanil

• Clinical Usage:

  • Wakefulness-promoting agent

    • Indications: Narcolepsy, Obstructive Sleep Apnea and Shift Work Sleep Disorder

    • Other off-label uses:

      • Depression, Medication- induced sleepiness or cognitive problems (pain, schizophrenia, chemotherapy), Multiple sclerosis, Fibromyalgia, Parkinson’ disease, ADHD

• MOA: (speculation)

  • inhibition of GABA release via a serotonergic mechanism 

  • Inhibition of dopamine transporter

• Cog. Effects:

  • Improves working memory

• AE:

  • Anxiety

  • Irritability

  • Sleep disturbances

  • Potential for Stevens-Johnson Syndrome, Toxic Epidermal Necrolysis

Describe Solriamfetol

• Clinical Usage

• MOA

• AE

Solriamfetol

• Clinical USage:

  • Wakefulness-promoting agent

    • narcolepsy or obstructive sleep apnea

• MOA: 

  • blockade of dopamine and NE transporter

• AE:

  • Increased BP + HR

  • Anxiety, insomnia and irritability