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Managing Sleep Disorders Disclosures and Depression in Patients No - - PDF document

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6/25/2018 Managing Sleep Disorders Disclosures and Depression in Patients No conflicts of interest to report with Liver Disease ECHO Program Presentation, June 25, 2018 Richard Yanofsky, MD, FRCPC Lecturer, University of Toronto

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6/25/2018 1

Managing Sleep Disorders and Depression in Patients with Liver Disease

ECHO Program Presentation, June 25, 2018 Richard Yanofsky, MD, FRCPC Lecturer, University of Toronto University Health Network, Centre for Metal Health Psychiatrist, Francis Family Liver Clinic richard.yanofsky@uhn.ca

Disclosures

  • No conflicts of interest to report

Why have this talk?

  • High comorbidity of depression in patients with chronic liver disease
  • Linked prognostically with severity of liver disease
  • Vulnerable population for medication induced adverse reactions
  • Concerns related to drug induced liver injury for certain psychotropic

medications

  • Liver disease interferes with drug metabolism at multiple

pharmacokinetic stages

Why have this talk?

  • Prevalence rates of Sleep-Wake disturbances are amongst highest of

chronic medical conditions

  • Early indicator of covert hepatic encephalopathy
  • Associated with critical comorbidities
  • Under-diagnoses and poorly managed
  • Contributes greatly to risk, morbidity and QOL

Learning Objectives

  • Review major considerations for treatment of depression in patients

with liver disease

  • Develop a better understanding of the nature of Sleep-Wake

disturbances in Cirrhotic Patients

  • Increase comfort with the diagnosis and management of these

common complaints

Two topics

  • Depression
  • Pharmacokinetics
  • Drug-induced liver injury
  • Monitoring
  • Sleep-wake disturbances
  • Insomnia
  • Hypersomnolence
  • Sleep associated disturbed behaviours
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Depression in CLD

  • Comorbidity is higher than expected, even compared to other

chronic medical conditions (40%)

  • Severity of depression is correlated to severity of liver disease
  • Depression severity impacts CLD outcomes
  • Antidepressants are effective treatments for depression in CLD

patients

Depression in CLD – Pharmacokinetics

Distribution

  • Intra and extra (and therapeutic) shunts and decreased first-pass

metabolism

  • Less drug passes through the liver before systemic distribution
  • Elevation in drug concentrations in the blood
  • His effect is particularly important for drugs with extensive first-pass

metabolism

Depression in CLD – Pharmacokinetics

(Telles-Correia et al, 2017)

Depression in CLD – Pharmacokinetics

Protein Binding

  • Most psychotropic medications are highly protein bound
  • Higher concentration of free, active drug when liver is cirrhotic
  • Particularly important for highly protein-bound drugs, such as

benzodiazepines

  • Venlafaxine, lithium, topiramate, gabapentin, pregabalin,

methylphenidate are minimally protein bound

Depression in CLD – Pharmacokinetics

Metabolism

  • Lithium, gabapentin and topiramate are the only psychotropic medications

that are excreted in the urine unchanged

  • Phase I cytochrome P-450 enzymes can be significantly impaired in cirrhosis

and required for conversion of most psychotropics into inactive form

  • Phase I enzymes are occasionally required to convert prodrug to active

metabolite (certain TCAs, and notably risperidone)

  • Phase II conjugation with glucuronic acid is normally preserved even in

severe cirrhosis

  • Temazepam, oxazepam, or lorazepam do not undergo phase I metabolism

and are preferred to diazepam and other benzodiazepines for this reason

Depression in CLD – DILI

  • 0.5%-3% of patients treated with antidepressants may develop

asymptomatic mild elevation of serum aminotransferase levels

  • All antidepressants may be hepatotoxicit, and liver damage in most

cases is unpredictable and unrelated to drug dosage

  • The interval between treatment initiation and onset of liver injury is

generally between several days and 6 months

  • Life-threatening antidepressant-induced liver injury has been

described involving fulminant liver failure or death

  • Hepatocellular type hepatoxicity is more common than cholestatic

and mixed types

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Depression in CLD – DILI

  • Greater risks of hepatotoxicity are iproniazid, nefazodone,

phenelzine, imipramine, amitriptyline, duloxetine, bupropion, trazodone, tianeptine, and agomelatine

  • Lower potential for hepatotoxicity are citalopram, escitalopram,

paroxetine, and fluvoxamine

  • Cross-toxicity has been described, mainly for tricyclic and tetracyclic

antidepressants

(Voican et al 2014)

Depression in CLD – Monitoring

  • Baseline history and physical, plus LFTs before starting any psychotropic

medication in a patient with CLD

  • Non-pharmacological treatment options (which can be highly effective but
  • ften challenging to access and complete in patients with CLD)
  • There is no unanimous agreement regarding the frequency of analysis re-

assessment

  • Laboratory tests with ALT > 3ULN or ALP > 2ULN are considered sensitive

markers for liver damage, and in these cases, the psychotropic agent should be stopped

  • Patients should be counselled to report signs and symptoms of liver

dysfunction

Physiological Sleep Regulation

Sleep

  • nset

Awakening

Homeostatic ‘Sleep Pressure’

Time Awake

Physiological Sleep Regulation

Circadian Rhythm

Time of Day 7 7

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Physiological Sleep Regulation

Melatonin Pleiotropism

Sex hormone regulation (Inhibits Prolactin, LH, FSH) Mediates blood pressure through vasoconstriction and dilation Inhibits pancreatic B-cell insulin secretion Anti-inflammatory and antioxidant effects Regulates skin pigmentation in response to sunlight Mitochondrial ETC effects Phasing of circadian pacemaker Poorly understood immune modulating role

Physiological Sleep Regulation Disturbance of Sleep Regulation

‘Melatonin Model’

Disturbance of Sleep Regulation

‘Melatonin Model’

Disturbance of Sleep Regulation

‘Melatonin Model’

Disturbance of Sleep Regulation

‘Pressure Deficit Model’

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Pathophysiology of Disturbance

Cirrhosis Decompensate d Cirrhosis Cirrhosis + HE

Sleep architecture

Sleep architecture disruption in cirrhosis

Sleep attributes of cirrhotic patients Sleep attributes of cirrhotic patients

Approach to management

  • Sleep History
  • Comorbidity workup
  • Sleep Journal
  • Standardized rating scales
  • Behavioural treatments
  • Pharmacological management
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Approach to managment

  • Sleep History
  • Onset, frequency, duration, severity
  • Sleep patterns, environment, psychosoical stressors
  • Reports from bed partner

Approach to managment

  • Sleep History
  • Comorbidity workup
  • Rule out HE
  • Pain, pruritus, nocturia, ascites
  • Nicotine, caffeine, alcohol use disorders
  • Depression, anxiety
  • Obstructive sleep apnea (OSA)
  • Restless leg syndrome (RLS)

STOP BANG

  • Routine screening suggested for

patients with insomnia

  • 2/4 “STOP” or 3/8 “STOP BANG” =

70% specificity for OSA

  • Triage patients for

polysomnographyh

Approach to managment

  • Sleep History
  • Comorbidity workup
  • Sleep Journal
  • Total sleep duration, sleep schedule, time to sleep onset, number of

awakenings, daytime nap, medications

  • 2 week duration of recording
  • Diagnostic and therapeutic value

Approach to management

  • Sleep History
  • Comorbidity workup
  • Sleep Journal
  • Standardized rating scales
  • Pittsburgh Sleep Quality Index
  • Athens Insomnia Scale
  • Berlin Questionnaire
  • Epworth Sleepiness Scale
  • Restless Legs Sleep Questionnaire
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6/25/2018 7

Approach to managment

  • Sleep History
  • Comorbidity workup
  • Sleep Journal
  • Standardized rating scales
  • Behavioural treatments
  • Sleep hygiene
  • CBT for insomnia (CBT-i)

Sleep Hygeine

  • Sleep only when sleepy
  • If you cannot fall asleep within 20 minutes, get up

and do something boring until you feel sleepy

  • Maintain a regular sleep-wake schedule even on

weekends

  • Do regular exercise at least 4 hours before bedtime
  • Develop sleep rituals to cue your body for sleep
  • Only use your bed for sleep and intimacy

Sleep Hygiene

  • Stay away from caffeine-containing food, beverages, and

medications, nicotine and alcohol for at least 4-6 hours before bedtime

  • Nap only as recommended or necessary
  • Have a light snack and glass of milk before bed
  • Take a hot bath before bed
  • Make sure your bed and room are quiet and comfortable, a cooler

room is recommended

CBT-i CBT-i

  • Sleep Efficiency = (Total Sleep Time / Time In Bed)
  • Time In Bed (TIB) is restricted to increas Sleep Efficiency (SE)
  • Increase or decrease TIB weekly by only 20-30 min
  • Increase TIB if SE >90%
  • Decrease TIB if SE <80%
  • Other domains include relaxation training, sleep environment

improvement, stimulus control

  • Delivered weekly for 5-12 weeks
  • Online free, paid, app, 1:1, group
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CBT-i

  • Most effective evidence based treatment for insomnia (period!)
  • More effective than treatment with hypnotic alone
  • CBT-i alone = CBT-i + hypnotic
  • No trials in cirrhosis
  • Compliance, capacity, motivation issues

Progressive muscle relaxation Guided meditation Approach to management

  • Sleep History
  • Comorbidity workup
  • Sleep Journal
  • Standardized rating scales
  • Behavioural treatments
  • Pharmacological management
  • Hydroxyzine
  • Melatonin
  • Z-drugs
  • Antidepressants
  • Lactulose
  • Modafinil
  • Stimulants

Pharmacological management Z-Drugs

Ideal Hypnotic in cirrhosis:

  • Negligible hepatic metabolism
  • Short half-life
  • No active metabolites
  • Limited lipophilia
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Z-Drugs

Commonly used = commonly used

  • Trazodone
  • Priapism, anticholinergic, antihistaminergic load
  • Seroquel
  • Metabolic, Seizure, QTc prolongation, black box over 65
  • Tricyclics
  • Anticholinergic load, narrow therapeutic window
  • Antihistamines
  • Deliriogenic, conversion to HE
  • Melatonin*

Promoting wakefulness

  • OSA and RLS optimization
  • Light therapy
  • Late night snacking
  • Modafinil (Provigil, Alertec)
  • Lisdexamphetamine (Vyvanse)
  • Methylphenidate (Ritalin) &

Amphetamine salts (Adderall)

Promoting wakefulness

  • OSA and RLS optimization
  • Low threshold for polysomnography to diagnose OSA
  • RLS is an awake phenomenon
  • Intense, irresistible urge to move the legs, usually associated with sensory complaints
  • Motor restlessness
  • Worsening of symptoms at rest and relief with motor activation
  • Increased severity in the evening or at night
  • Periodic Limb Movement of Sleep (PLMS) is a sleep phenomenon seen on

polysomnography

  • 80% of patients with RLS have PLMS

Promoting wakefulness

  • OSA and RLS optimization
  • Light therapy
  • Effective in Delayed Sleep Phase Syndrome
  • Similar pathophysiology DSPS
  • 10,000 Lux at 12” from face x30min on awakening
  • Compliance challenges
  • Case reports of benefits in cirrhosis
  • RCT of 12 patients with cirrhosis showed no benefit

Promoting wakefulness

  • OSA and RLS optimization
  • Light therapy
  • Late night snacking
  • May exacerbate primary sleep disorders
  • Reduce periods of overnight starvation and sarcopenia
  • Minimal evidence to support outcome of improved daytime wakefulness
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Promoting wakefulness

  • OSA and RLS optimization
  • Light therapy
  • Late night snacking
  • Modafinil (Provigil, Alertec)
  • Weak dopamine reuptake inhibitor
  • Some sorotonergic and histaminergic activity
  • Good evidence for eugeroic effect in PBC
  • Well tolerated in cirrhosis
  • Low abuse potential

Promoting wakefulness

  • OSA and RLS optimization
  • Light therapy
  • Late night snacking
  • Modafinil (Provigil, Alertec)
  • Lisdexamphetamine (Vyvanse)
  • Converted to active dexamphetamine by first pass intestinal or hepatic

metabolism

  • Lower abuse potential, single daily dosing

Promoting wakefulness

  • OSA and RLS optimization
  • Light therapy
  • Late night snacking
  • Modafinil (Provigil, Alertec)
  • Lisdexamphetamine (Vyvanse)
  • Methylphenidate (Ritalin) &

Amphetamine salts (Adderall)

  • Use with caution in patients with substance use history
  • Rapid acting formulations available

Insomnia & overt HE

  • Caution regarding Benzodiazepines

(especially longer acting agents)

  • Hydroxyzine precipitated HE in 1/35 patients in

short study, theoretical risk of worsening HE

  • Antipsychotics may be useful in severe HE if

refractory to treatment and significant confusion

  • Utility of Melatonin is questionable given delayed

clearance and excess daytime sleepiness

  • Judicious use of shortest acting hypnotics may be

indicated

Sleep-wake disturbances in CLD - review

  • ‘Melotonin Model’ + ‘Pressure Deficit Model’
  • High prevalence of OSA, RLS and other comorbidities that deleteriously

impact sleep-wake balance

Sleep-wake disturbances in CLD - review

  • Diagnosis and management of common complaints
  • Systemic and focused sleep history
  • Rule out HE
  • Treat comorbidities
  • Consider behavioural treatments
  • Pharmacological management choices based on nature of target symptoms

in consideration of patient history

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Take away pearls

  • Sleep-wake disturbances in cirrhosis are usually long-term

disorders

  • A multi-pronged and systemic approach to diagnosis and

management will help minimize missed comorbidities and help focus treatments

  • Maintain a high index of suspicion for OSA and low

threshold for polysomnography referral

  • CBT-i is the most effective evidence based treatment for

insomnia

  • Dose escalation of hypnotics in the treatment of insomnia

beyond recommended range is rare in clinical experience

  • Withdrawal from Z-drugs is less problematic than

withdrawal from Benzodiazepines

Thank-you!!

richard.yanofsky@uhn.ca