Newer Antidepressants and Serotonin Syndrome

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Newer Antidepressants and Serotonin Syndrome

• Presented by Dr. Bloxdorf
• Prepared by A. Hillier

2
General Principles

• Newer antidepressants termed atypical,
  heterocyclic or second generation
• Prescribed for depression, anxiety disorder,
  panic disorder, personality disorders, OCD and
  eating disorders
• Differentiated from TCAs and MAOIs
• ? More selective ? Less toxicity
• ? Fewer fatalities
• More likely to produce Serotonin Syndrome

3
General Principles

• No cardiotoxicity or conduction delays that are
  seen with TCAs
• No associated tyramine reactions like MAOIs
• Negligible affinity for acetylcholine, dopamine,
  GABA-A, glutamate or ß-adrenergic receptors
• Higher safety margin than MAOIs and TCAs

4
General Principles

• Poorly cleared by hemodialysis, hemofiltration,
  forced diuresis, whole bowel irrigation or
  activated charcoal
• Not detected by routine plasma/urine testing
• Primarily CYP-450 hepatic metabolization
• If taken with MAOIs may precipitate serotonin
  syndrome

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Trazodone-Overview

• Indicated for depression and insomnia
• Low fatality rate (1 in 1200 exposures)
• Unrelated to other antidepressants
• Half-life up to 13 hours with overdose
• Common side effects
• ? Priapism ? Drowsiness ? Dry mouth
• ? Nausea ? Orthostatic hypotension

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Trazodone-Acute Overdose

• No established toxic dose-no serious toxicity up
  to 2 grams
• Most common is CNS depression
• Severe Ingestion
• ? Ataxia ? Dizziness ? Seizures
• ? Coma ? Hypotension
• Treatment
• ? Supportive ? Charcoal
• ? Lavage for massive ingestion

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Bupropion-Overview

• Indicated for depression and nicotine cessation
• Half-life up to 20 hours
• Common side effects
• ? Dry mouth ? Dizziness ? Confusion
• ? Agitation ? Nausea ? Blurred vision
• ? Headache ? Constipation ? Tremor
• Rare side effects
• ? Rash ? Stevens-Johnson ? Seizure

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Bupropion-Acute Overdose

• Low-toxic-to therapeutic ratio
• Most common-sinus tachycardia
• Severe Ingestion
• ? Lethargy ? Generalized seizure
• ? Coma ? Cardiac arrest
• Treatment
• ? Gastric Lavage ? Activated charcoal
• ? Benzodiazepines ? Phenobarbital

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Nefazodone-Acute Overdose

• Relatively safe in overdose
• No fatalities with overdose up to 11 grams
• Most common symptoms
• ? Nausea ? Vomiting ? Somnolence
• Supportive Treatment
• Mirtazapine-Acute Overdose
• Limited toxicity in overdose
• Most common symptoms
• ? Sedation ? Confusion
• ? Sinus tachycardia ? Mild hypertension
• Supportive Treatment

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Selective Serotonin Receptor Inhibitors

• Inhibit presynaptic serotonin reuptake
• Most commonly prescribed class of antidepressants
• Fatalities uncommon (1 in 1000)
• Long half life (15 hours up to 14 days)

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Selective Serotonin Receptor Inhibitors

• Adverse events
• ? Nausea ? Anorexia
• ? Serotonin syndrome ? Headache
• ? Sedation ? Insomnia
• ? Dizziness ? Fatigue
• ? Tremor ? Nervousness
• ? Seizures ? Extrapyramidal symptoms
• ? SIADH

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Selective Serotonin Receptor Inhibitors

• Acute Overdose
• High therapeutic-to-toxic ratio
• Fatalities uncommon
• 50 of overdoses remain asymptomatic
• Most symptoms similar to adverse event profile
• Less frequent
• ? Agitation ? Hallucinations ?
  Seizures
• ? Hypertension ? Hypotension ? Widened
  QRS
• ? Prolonged QTc

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Selective Serotonin Receptor Inhibitors

• Treatment
• IV
• Cardiac monitor
• Activated charcoal 1 gm/kg
• Gastric lavage probably unnecessary
• Syrup of Ipecac-contraindicated
• Prolonged QRS/QTc-Sodium bicarbonate
• Seizures-Benzodiazepines
• Serotonin syndrome-Cyproheptadine

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Venlafaxine-Acute Overdose

• Half-life of 11 hours
• Most common effects
• ? Tachycardia ? Hypertension
• ? Diaphoresis ? Tremor
• ? Mydriasis ? Sedation
• More severe effects
• ? Coma ? Generalized seizures
• ? Widened QRS ? Prolonged QTc

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Venlafaxine-Acute Overdose

• Treatment
• IV
• Monitor
• Gastric lavage
• Activated charcoal
• Seizures-Benzodiazepines
• QRS widening-Sodium bicarbonate
• Hypertension-Nitroprusside/Esmolol or
  Phentolamine
• Avoid ß-blockers

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Serotonin Syndrome

• Rare idiosyncratic drug-induced reaction
• Most cases occur at therapeutic levels
• Less than 13 occur with overdose
• Characterized by alterations in
• Cognition and behavior
• Autonomic nervous system
• Neuromuscular activity
• Mortality rate of 11

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Serotonin Syndrome

• SS most often occurs after routine medication
  increase or addition of another 5-HT stimulating
  agent
• True incidence of SS is unknown
• SS is often difficult to diagnose because of
  varying symptoms
• ? Mild cases attributed to psychiatric disorders
• ? More severe cases attributed to NMS
• EPs may inadvertently precipitate SS by
  prescribing tramadol, dextromethorphan or
  meperidine

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Serotonin Signs and Symptoms
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Serotonin Syndrome

• Muscle rigidity
• Most often found in the lower extremities-may be
  valuable clinical marker
• Ataxia
• Check for lower extremity hypertonia
• Hyperthermia
• Usually mild-moderate, but reports up to 41oC
• Seizures
• Always generalized and usually short lived

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Serotonin Syndrome

• Unilateral muscle rigidity or focal neurologic
  findings have not been reported
• Hypertension reported twice as often as
  hypotension
• SS is a clinical diagnosis
• Lab testing done to rule-out other causes of
  symptoms

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Serotonin Syndrome

• Treatment
• No accepted guidelines for SS treatment
• Stop offending drugs
• Benzodiazepines for patient comfort and rigidity
• Monitor closely for rhabdomyolysis and metabolic
  acidosis
• Approximately 25 will require intubation
• Usually dramatic improvement within 24 hours

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Serotonin Syndrome Medications

• Cyproheptadine
• Initial dose 4-8 mg PO
• May repeat in 2 hours if no response
• Discontinue is no response noted after 16 mg
• Dantrolene
• 0.5-2.5 mg/kg IV every 6 hours
• Maximum 10 mg/kg in 24 hours

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Summary

• SSRI overdose pales in comparison to MAOIs and
  TCAs
• Still can have significant morbidity and
  mortality
• Most of the management is supportive after
  decontamination
• Beware of tramadol, dextromethorphan and
  meperidine in anyone taking SSRIs, TCAs or
  MAOIs

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Questions

• All of the following may precipitate serotonin
  syndrome except
• Paroxetine
• Meperidine
• Fentanyl
• Tramadol
• Dextromethorphan

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Questions

• Serotonin syndrome may present like all of the
  following except
• Sympathomimetic syndrome
• Neuroleptic malignant syndrome
• Acute psychosis
• Rhabdomyolysis
• Acute unilateral stroke

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Questions

• Basic management for any acute overdose consist
  of
• Rectal exam
• Call poison control
• HgbA1C
• VDRL/RPR
• Punitive Gastric Lavage

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Questions

• All of the following are included in the
  serotonin syndrome triad except
• Hepatic dysfunction
• Cognitive dysfunction
• Autonomic dysfunction
• Neuromuscular dysfunction

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Questions

• With the newer class of antidepressants which of
  the following are true
• There are not detected by routine lab tests
• Treatment is mostly supportive
• They are poorly cleared by hemodialysis, forced
  diuresis or activated charcoal
• Have no significant interactions with MAOIs
• All of the above are true

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Answers

• C-Fentanyl has never been reported to precipitate
  SS, however all the others can
• E-SS may present like all the other responses,
  but acute focal CVA should make you think of
  another diagnosis
• B-Even with the most mundane ingestion, you
  should make the call to Poison Control
• A-Although due to rhabdomyolysis etc. you may see
  liver dysfunction, it is not part of the
  presenting triad
• E-All of the above are true