PS
Psychiatry

PSYCHOPHARMACOLOGIC MANAGEMENT OF SLEEP DISORDERS

August 07, 2014.
Karl Doghramji, MD,

Educational Objectives

The goal of this program is to improve the diagnosis and management of sleep disorders in psychiatric patients. After hearing and assimilating this program, the clinician will be better able to:

1. Describe the neurophysiology and neurochemistry of brain systems that promote wakefulness and sleep.

2. Compare the efficacy and side effects of common nonprescription agents used for sleep disorders.

3. Maximize safety and efficacy when using hypnotic agents to treat insomnia.

4. Recognize and treat excessive daytime sleepiness associated with narcolepsy.

5. Manage the symptoms of restless legs syndrome.

Summary

Sleep-related symptoms in psychiatry: primarily insomnia and daytime sleepiness (seen in 80% of patients with depression); insomnia — reduced quality and quantity of sleep, inability to sleep, or repeated awakenings; hypersomnia — excessive sleeping and fatigue; predominantly seen in younger patients with depression and in bipolar depression, but may also occur in older patients with unipolar depression; patients presenting with complaints of sleep disturbances often have underlying depressive disorder

Persistence of sleep-related symptoms: sleeplessness and hypersomnia often remain after treatment of depressive episode; effects on depression — significant increases in short-term and long-term recurrence rates; vulnerability to suicidal thinking and suicide attempts; vulnerability to metabolic, cardiometabolic, and cardiac conditions

Relationship between depression and sleep-related symptoms: complex; probably circular or bidirectional in nature, implying that psychiatrists must address depression and sleep-related symptoms simultaneously

Revised definition of insomnia in Diagnostic and Statistical Manual of Mental Disorders (Fifth Edition): includes early morning awakening; specifies number of nights per week insomnia must occur (≥3); required duration increased from >1 mo to >3 mo; individuals must have adequate opportunity to sleep; reclassified as “insomnia disorder” (allows coding of, eg, depression or anxiety disorders as comorbidities instead of primary vs secondary phenomenon, and thereby avoids implying direction of causality)

Neurophysiology of sleep: pathways controlling arousal — controlled primarily by serotonin, norepinephrine (in locus coeruleus), acetylcholine (in peduncular pontine tegmentum), and histamine (in tuberomammillary nucleus); ascending pathways; pathways controlling sleep — eg, ventrolateral preoptic nucleus (critical for sleep production; controlled by inhibitory neurotransmitters γ-aminobutyric acid [GABA; primarily] and galanine); “flip-flop switch” — balance between GABA-galanine and excitatory neurotransmitters controls whether individuals sleep or remain awake; activating one of these systems enhances its own activity and inhibits opposing system

Nonprescription Sleep Agents

Antihistamines: primarily diphenhydramine and doxylamine (antiemetic); have some sedative potential; side effects include paradoxical excitation, next-day sedation, cough, and thickening of bronchial mucosa; potential for medication interaction via inhibition of cytochrome P450 2D6

Diphenhydramine: most frequently used antihistamine; not indicated for insomnia; peak concentration (and thus maximum sedative potential) occurs 8 hr after administration, leading to sedation after waking; study (Agostini et al, 2001) — patients receiving diphenhydramine had higher rates of cognitive symptoms

Nutraceuticals and dietary supplements: unregulated; effects have not been well established in controlled studies; purity and active ingredients have been questioned; providing agents with questionable efficacy could delay other treatment for insomnia and other conditions

Valerian: supplements typically recommend dose of 400 to 450 mg; possible anxiolytic, muscle relaxant, and sleep-promoting effects; data on side effects remain scant, but include suggested risk for gastrointestinal irritation and reports of hepatotoxicity

Melatonin: most commonly used “natural agent” for sleep; ubiquitous rhythm-setting and sleep-promoting hormone; release from pineal gland controlled by suprachiasmatic nucleus; meta-analysis (Buscemi et al, 2006) — suggested melatonin lacks efficacy with typical insomnia but may have role in treating delayed sleep phase syndrome and circadian rhythm abnormalities

Off-Label Prescription Medications

Sedating antidepressants: low potential for abuse; available as low-cost generics; disadvantages include long-acting tendencies plus antihistaminergic and anticholinergic next-day side effects

Doxepin: typically dosed at 25 to 50 mg: based on study data, doxepin may be best for insomnia characterized by middle-of-night awakenings and late-morning insomnia

Trazodone: commonly used; study (Walsh et al, 1998) — tolerance occurred within 2 wk, and data on adjusting dosage limited; pharmacokinetics — long half-life; complex set of actions at serotonin (5-HT) 1a and 2c receptors (including postsynaptic receptor blocking) and antihistaminic potential may cause multidirectional side effects; combination with other serotonergic agents may cause serotonin syndrome; may produce next-day impairments in memory and coordination

Quetiapine: short half-life and peak time (1 hr) provide rapid benefits for insomnia with comorbid psychotic disturbances

Antipsychotics: not recommended for primary insomnia due to risks for, eg, extrapyramidal symptoms; used to control psychosis and promote sleep in patients with psychotic disturbances

Hypnotic Agents Approved by Food and
Drug Administration (FDA)

γ-Aminobutyric acid: among most common neurotransmitters in central nervous system; inhibitory neurotransmitter; produces sleep, anticonvulsant activity, anxiolysis, and motor inhibition (contributes to side effects); GABA-ergic agents may produce incoordination and memory disturbances; physicians must manipulate GABA to maximize sleep potential and minimize side effects

Benzodiazepines (BZDs): eg, estazolam, flurazepam, quazepam; most have long half-lives; BZDs with shorter half-lives (eg, triazolam) produce less daytime somnolence

Selective benzodiazepine receptor agonists (BZRAs): eg, zaleplon, zolpidem (Ambien), zolpidem extended-release (Ambien CR), eszopiclone (Lunesta); all have equal efficacy in helping patients fall asleep; however, zolpidem extended-release and eszopiclone have superior efficacy with middle-of-night or terminal insomnia; zolpidem variants — eg, sublingual (Intermezzo), low-dose sublingual (1.75 mg in women, 3.5 mg in men), and oral spray (Zolpimist) formulations; sublingual used for awakening during middle of night (patients must remain in bed for 4 hr after use); oral spray has rapid effects (peak concentration after 0.9 hr)

Proposed FDA changes in dosing of zolpidem: ≈20% of patients (predominantly women) who take zolpidem at beginning of night cannot metabolize it before morning, and thus have next-day impairments; FDA recommends using half-doses of zolpidem preparations in women (eg, 5 mg zolpidem, 5 mg zolpidem oral spray, 6.25 mg zolpidem extended-release); higher doses permitted in men, but FDA recommends starting at lower doses

Issues with BZRAs: daytime sedation; rebound insomnia (uncommon); transient insomnia lasting 24 hr after rapid discontinuation (slow discontinuation recommended); respiratory depression in patients with chronic obstructive pulmonary disorder (COPD) or sleep apnea (contraindicated in severe to moderate cases unless apnea has been effectively treated [confirmed by home oximetry or evaluation at sleep center]); schedule IV agents with potential for abuse or misuse (more common; eg, dosing slightly above recommendation or at inappropriate times); however, in data gathered over 1 yr, dose escalation and excessive dosing uncommon

Parasomnias: reported in lay literature; involve actions during sleep without patient’s awareness; association with, eg, automobile accidents and deaths has caused legal issues; data inadequate to indicate whether zolpidem has unique effects or simply causes more reports due to greater use; effects could probably occur with any BZRA, so physicians must ensure lack of risk factors for parasomnia behavior (eg, use of alcohol or other sedatives with BZRAs, history of parasomnias [ask about patient and family history of sleepwalking], taking BZRAs at wrong time [instruct patients to take medication at bedtime and immediately go to bed])

Long-term study (Krystal et al, 2008): patients using intermittent doses (3-4 per week) of zolpidem extended-release for 24 wk showed no evidence of tolerance; study of eszopiclone had similar outcomes

Ramelteon: agonist of melatonin-1 and -2 receptors in suprachiasmatic nucleus; nonscheduled agent; short-acting (1-2.5 hr half-life); headaches reported as primary adverse event (relatively low incidence); study (Kryger et al, 2007) — ramelteon did not affect respiration in vulnerable individuals with mild to moderate COPD and obstructive sleep apnea; study (Mayer et al, 2009) — long-term usage did not produce tolerance

Low-dose doxepin (3.5-6 mg; Silenor): indicated for insomnia characterized by middle-of-night awakenings or terminal insomnia (rather than sleep latency insomnia); nonscheduled; contraindicated in patients taking monoamine oxidase inhibitors or with narrow-angle glaucoma

Ramelteon vs doxepin: doxepin works best with middle-of-night or terminal insomnia, whereas ramelteon indicated in patients with difficulty falling asleep

Excessive Daytime Sleepiness (EDS)

Background: common in patients with depression or psychotic disturbances

Narcolepsy: always involves EDS; hallmark symptoms — cataplexy (emotionally produced muscle paralysis or paresis with sudden onset; seen in 60%-80% of narcoleptic patients); hypnagogic imagery (vivid, typically dreamlike visuals with hallucinatory nature); sleep paralysis; fragmented sleep

Confusion with other disturbances: common; cataplexy can mimic transient ischemic attack (TIA; but shorter in duration) or syncope (but with only partial loss of consciousness); hypnogogic hallucinations may be mistaken for nightmares or schizophrenic nightmares; sleep paralysis mimics TIA and nocturnal panic; sleep disruptions misdiagnosed as primary insomnia; frequent coexistence with other psychiatric disturbances exacerbates confusion

Diagnosis: primarily relies on multiple sleep latency test; in test of daytime napping, ≥2 sleep-onset rapid eye movement (REM) episodes plus sleep latency <8 min strongly indicates narcolepsy (in absence of other sleep pathology)

Treatment: indicated for sleepiness of narcolepsy — dextroamphetamine (Dexedrine); mixed amphetamine salts (Adderall); other amphetamines; sodium oxybate (Xyrem); modafinil or armodafinil (schedule IV agents with [probably] preferable safety profile and prescribing convenience); pharmacokinetics — although many treatments have long half-life, methylphenidate has half-life of ≈3.5 hr (allows quick-acting benefits and safe to use as needed); sodium oxybate — only treatment indicated for cataplexy; given in 2 doses (at beginning of sleep and during middle of night); can significantly intensify slow-wave sleep; shows potential neuroprotective effects which may last throughout next day; anti-REM agents — effective for cataplexy (ie, REM sleep occurring at wrong time); eg, antidepressants (excluding bupropion and nefazodone); warnings — sodium oxybate may cause EDS, parasomnia behaviors, and urinary incontinence; in rare cases, modafinil and armodafinil cause Stevens-Johnson syndrome (warn patients to stop medication and contact physician if serious rash occurs)

Restless Legs Syndrome (RLS)

Background: characterized by urge to move (pathognomonic symptom); typically occurs at bedtime, but may occur during inactive sitting; sometimes associated with unpleasant sensations or pain in legs; symptoms induced by rest and immobility (activity decreases some symptoms); shows high comorbidity with other psychiatric disorders; anecdotal studies suggest bupropion may have protective effect; checking ferritin levels recommended (if serum ferritin <50 ng/mL, consider supplementation via ferrous sulfate [check for toxicity every 6 mo])

Treatments: indicated — pramipexole (0.125 mg) and ropinirole (0.25 mg); treated patients require monitoring for fatigue, orthostatic hypotension, morning rebound, and augmentation (rare phenomenon with intensification of RLS symptoms during day); rotigotine — transdermal patch with benefits lasting throughout day; side effects similar to indicated treatments; gabapentin enacarbil — salt of gabapentin specifically indicated for RLS

Questions and Answers

Pediatric patients: no sleep medications indicated for children; different cognitive behavioral therapies (CBT) have been used; sleep studies before treatment strongly recommended (particularly with obesity or craniofacial deformities), due to high rates of apnea; speaker uses melatonin, but has concerns over lack of data on long-term use and its effects on, eg, gonadal function

Correctional settings: unscheduled agents preferred (eg, trazodone, low-dose doxepin, ramelteon) due to lack of addictive qualities, respiratory suppression, and medication interactions

Patients with history of substance abuse: similar to correctional setting (eg, ramelteon, low-dose doxepin, low-dose antidepressants); speaker occasionally uses schedule IV agents, but only for patients currently clean and monitored by coordinated care plan

Cannabis: not linked with insomnia; more likely to cause hypersomnia, daytime impairment, and fatigue (may last long after stopping use)

Nightmares: prazosin — α-adrenergic antagonist; showed strong efficacy against nightmares among veterans in 2 small controlled studies; not FDA-indicated; monitor patients for hypotension (uncommon); other agents — sedating antidepressants (eg, paroxetine) or antipsychotics

Using short-acting agents twice nightly: speaker prefers switching to long-acting agent

Tolerance: commonly misidentified in psychiatric patients whose high levels of distress or anxiety render medications ineffective; for genuine tolerance, switch to long-acting agents instead of escalating dosage

Discontinuation of BZDs and BZRAs: taper dosage slowly (eg, decrease zolpidem by 2.5 mg per month) while increasing CBT; add new agents only after ≈2 mo of tapering

Dementia: all sleep medications may cause daytime impairment in cognitive function; may be greater in patients with dementia

L-tryptophan: recently reintroduced; appears safe, but efficacy remains unsubstantiated

Mirtazapine: low doses seem to show efficacy with insomnia (unproven); may cause weight gain; useful for patients who cannot receive scheduled agents; not FDA-indicated

Inhibition of REM with antidepressants: occurs regardless of dosing schedule; ramifications unknown; speaker focuses on patient’s symptomatic description

Acknowledgments

Dr. Doghramji spoke at the 19th Annual Psychopharmacology Update, held February 12-16, 2014, in Las Vegas, NV, and sponsored by the Nevada Psychiatric Association, the American Psychiatric Association, and the University of Nevada School of Medicine. To learn about future meetings presented by the Nevada Psychiatric Association, please go to nvpsychiatry.org. The Audio-Digest Foundation thanks the speakers and the sponsors for their cooperation in the production of this program.

Readings

Disclosures

In adherence to ACCME Standards for Commercial Support, Audio-Digest requires all faculty and members of the planning committee to disclose relevant financial relationships within the past 12 months that might create any personal conflicts of interest. Any identified conflicts were resolved to ensure that this educational activity promotes quality in health care and not a proprietary business or commercial interest. For this program, the following has been disclosed: Dr. Doghramji is a consultant for Aptalis, Jazz Pharmaceuticals, and Vanda Pharmaceuticals, and owns stock in Merck & Co. The planning committee reported nothing to disclose. In his lecture, Dr. Doghramji presents information related to the off-label or investigational use of a therapy, product, or device.