Transcript Newer Antidepressants and Serotonin Syndrome

Newer Antidepressants and
Serotonin Syndrome
Presented by Dr. Bloxdorf
Prepared by A. Hillier
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 TCA’s and MAOI’s

▪ More selective
▪ Fewer fatalities

▪ Less toxicity
More likely to produce Serotonin
Syndrome
General Principles
No cardiotoxicity or conduction delays that
are seen with TCA’s
 No associated tyramine reactions like
MAOI’s
 Negligible affinity for acetylcholine,
dopamine, GABA-A, glutamate or βadrenergic receptors
 Higher safety margin than MAOI’s and
TCA’s

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 MAOI’s may precipitate
serotonin syndrome

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
Trazodone-Acute Overdose
No established toxic dose-no serious
toxicity up to 2 grams
 Most common is CNS depression
 Severe Ingestion

▪ Ataxia
▪ Coma

▪ Dizziness
▪ Hypotension
Treatment
▪ Supportive
▪ Charcoal
▪ Lavage for massive ingestion
▪ Seizures
Bupropion-Overview
Indicated for depression and nicotine
cessation
 Half-life up to 20 hours
 Common side effects

▪ Dry mouth
▪ Agitation
▪ Headache

▪ Dizziness
▪ Confusion
▪ Nausea
▪ Blurred vision
▪ Constipation ▪ Tremor
Rare side effects
▪ Rash
▪ Stevens-Johnson
▪ Seizure
Bupropion-Acute Overdose
Low-toxic-to therapeutic ratio
 Most common-sinus tachycardia
 Severe Ingestion

▪ Lethargy
▪ Coma

▪ Generalized seizure
▪ Cardiac arrest
Treatment
▪ Gastric Lavage
▪ Benzodiazepines
▪ Activated charcoal
▪ Phenobarbital
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
▪ Sinus tachycardia

▪ Confusion
▪ Mild hypertension
Supportive Treatment
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)

Selective Serotonin Receptor
Inhibitors

Adverse events
▪ Nausea
▪ Serotonin syndrome
▪ Sedation
▪ Dizziness
▪ Tremor
▪ Seizures
▪ SIADH
▪ Anorexia
▪ Headache
▪ Insomnia
▪ Fatigue
▪ Nervousness
▪ Extrapyramidal symptoms
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
▪ Hypertension
▪ Prolonged QTc
▪ Hallucinations
▪ Hypotension
▪ Seizures
▪ Widened QRS
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

Venlafaxine-Acute Overdose
Half-life of 11 hours
 Most common effects

▪ Tachycardia
▪ Diaphoresis
▪ Mydriasis

▪ Hypertension
▪ Tremor
▪ Sedation
More severe effects
▪ Coma
▪ Widened QRS
▪ Generalized seizures
▪ Prolonged QTc
Venlafaxine-Acute Overdose
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Treatment
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

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


IV
Monitor
Gastric lavage
Activated charcoal
Seizures-Benzodiazepines
QRS widening-Sodium bicarbonate
Hypertension-Nitroprusside/Esmolol or Phentolamine

Avoid β-blockers
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%
Serotonin Syndrome

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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

EP’s may inadvertently precipitate SS by
prescribing tramadol, dextromethorphan or
meperidine
Serotonin Signs and Symptoms
Cognitive-Behavioral Autonomic Dysfunction Neuromuscular Dysfunction
Confusion-54%
Hyperthermia-46%
Myoclonus-57%
Agitation-35%
Diaphoresis-46%
Hyperreflexia-55%
Coma-28%
S. Tachycardia-41%
Muscle rigidity-49%
Anxiety-16%
Hypertension-33%
Tremor-49%
Hypomania-15%
Tachypnea-28%
Hyperactivity-43%
Lethargy-15%
Mydriasis-26%
Ataxia-38%
Seizures14%
Unreactive pupils-18%
Shivering-25%
Serotonin Syndrome

Muscle rigidity


Ataxia

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Check for lower extremity hypertonia
Hyperthermia

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Most often found in the lower extremities-may
be valuable clinical marker
Usually mild-moderate, but reports up to 41oC
Seizures

Always generalized and usually short lived
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
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

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

Summary
SSRI overdose pales in comparison to
MAOI’s and TCA’s
 Still can have significant morbidity and
mortality
 Most of the management is supportive
after decontamination


Beware of tramadol, dextromethorphan
and meperidine in anyone taking SSRI’s,
TCA’s or MAOI’s
Questions
1.
All of the following may precipitate
serotonin syndrome except:
a.
b.
c.
d.
e.
Paroxetine
Meperidine
Fentanyl
Tramadol
Dextromethorphan
Questions
2.
Serotonin syndrome may present like all
of the following except:
a.
b.
c.
d.
e.
Sympathomimetic syndrome
Neuroleptic malignant syndrome
Acute psychosis
Rhabdomyolysis
Acute unilateral stroke
Questions
3.
Basic management for any acute
overdose consist of:
a.
b.
c.
d.
e.
Rectal exam
Call poison control
HgbA1C
VDRL/RPR
Punitive Gastric Lavage
Questions
4.
All of the following are included in the
serotonin syndrome triad except:
a.
b.
c.
d.
Hepatic dysfunction
Cognitive dysfunction
Autonomic dysfunction
Neuromuscular dysfunction
Questions
5.
With the newer class of antidepressants
which of the following are true:
a.
b.
c.
d.
e.
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 MAOI’s
All of the above are true
Answers
1.
2.
3.
4.
5.
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