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Newer Antidepressants and Newer Antidepressants and Serotonin SyndromeSerotonin Syndrome
Presented by Dr. BloxdorfPresented by Dr. Bloxdorf
Prepared by A. HillierPrepared by A. Hillier
General PrinciplesGeneral Principles
Newer antidepressants termed atypical, Newer antidepressants termed atypical, heterocyclic or second generationheterocyclic or second generation
Prescribed for depression, anxiety Prescribed for depression, anxiety disorder, panic disorder, personality disorder, panic disorder, personality disorders, OCD and eating disordersdisorders, OCD and eating disorders
Differentiated from TCA’s and MAOI’sDifferentiated from TCA’s and MAOI’s▪ ▪ More selectiveMore selective ▪ Less toxicity▪ Less toxicity▪ ▪ Fewer fatalitiesFewer fatalities
More likely to produce Serotonin More likely to produce Serotonin SyndromeSyndrome
General PrinciplesGeneral Principles
No cardiotoxicity or conduction delays that No cardiotoxicity or conduction delays that are seen with TCA’sare seen with TCA’s
No associated tyramine reactions like No associated tyramine reactions like MAOI’sMAOI’s
Negligible affinity for acetylcholine, Negligible affinity for acetylcholine, dopamine, GABA-A, glutamate or dopamine, GABA-A, glutamate or ββ--adrenergic receptorsadrenergic receptors
Higher safety margin than MAOI’s and Higher safety margin than MAOI’s and TCA’sTCA’s
General PrinciplesGeneral Principles
Poorly cleared by hemodialysis, Poorly cleared by hemodialysis, hemofiltration, forced diuresis, whole hemofiltration, forced diuresis, whole bowel irrigation or activated charcoalbowel irrigation or activated charcoal
Not detected by routine plasma/urine Not detected by routine plasma/urine testingtesting
Primarily CYP-450 hepatic metabolizationPrimarily CYP-450 hepatic metabolization If taken with MAOI’s may precipitate If taken with MAOI’s may precipitate
serotonin syndromeserotonin syndrome
Trazodone-OverviewTrazodone-Overview
Indicated for depression and insomniaIndicated for depression and insomniaLow fatality rate (1 in 1200 exposures)Low fatality rate (1 in 1200 exposures)Unrelated to other antidepressantsUnrelated to other antidepressantsHalf-life up to 13 hours with overdoseHalf-life up to 13 hours with overdoseCommon side effectsCommon side effects
▪ ▪ PriapismPriapism ▪ Drowsiness▪ Drowsiness ▪ Dry mouth▪ Dry mouth
▪ ▪ NauseaNausea ▪ Orthostatic hypotension▪ Orthostatic hypotension
Trazodone-Acute OverdoseTrazodone-Acute Overdose
No established toxic dose-no serious No established toxic dose-no serious toxicity up to 2 gramstoxicity up to 2 grams
Most common is CNS depressionMost common is CNS depression Severe IngestionSevere Ingestion
▪ ▪ AtaxiaAtaxia ▪ Dizziness▪ Dizziness ▪ Seizures▪ Seizures
▪ ▪ ComaComa ▪ Hypotension▪ Hypotension TreatmentTreatment
▪ ▪ SupportiveSupportive ▪ Charcoal ▪ Charcoal
▪ ▪ Lavage for massive ingestionLavage for massive ingestion
Bupropion-OverviewBupropion-Overview
Indicated for depression and nicotine Indicated for depression and nicotine cessationcessation
Half-life up to 20 hoursHalf-life up to 20 hoursCommon side effectsCommon side effects
▪ ▪ Dry mouthDry mouth ▪ Dizziness ▪ Dizziness ▪ Confusion ▪ Confusion▪ ▪ AgitationAgitation ▪ Nausea ▪ Nausea ▪ Blurred vision ▪ Blurred vision▪ ▪ HeadacheHeadache ▪ Constipation ▪ Constipation ▪ Tremor ▪ Tremor
Rare side effectsRare side effects▪ ▪ RashRash ▪ Stevens-Johnson ▪ Stevens-Johnson ▪ Seizure ▪ Seizure
Bupropion-Acute OverdoseBupropion-Acute Overdose
Low-toxic-to therapeutic ratioLow-toxic-to therapeutic ratioMost common-sinus tachycardiaMost common-sinus tachycardiaSevere IngestionSevere Ingestion
▪ ▪ LethargyLethargy ▪ Generalized seizure ▪ Generalized seizure
▪ ▪ ComaComa ▪ Cardiac arrest ▪ Cardiac arrestTreatmentTreatment
▪ ▪ Gastric LavageGastric Lavage ▪ Activated charcoal ▪ Activated charcoal
▪ ▪ BenzodiazepinesBenzodiazepines ▪ Phenobarbital ▪ Phenobarbital
Nefazodone-Acute OverdoseNefazodone-Acute Overdose Relatively safe in overdoseRelatively safe in overdose No fatalities with overdose up to 11 gramsNo fatalities with overdose up to 11 grams Most common symptomsMost common symptoms
▪ ▪ NauseaNausea ▪ Vomiting ▪ Vomiting ▪ Somnolence ▪ Somnolence
Supportive TreatmentSupportive Treatment
Mirtazapine-Acute OverdoseMirtazapine-Acute Overdose Limited toxicity in overdoseLimited toxicity in overdose Most common symptomsMost common symptoms
▪ ▪ SedationSedation ▪ Confusion▪ Confusion
▪ ▪ Sinus tachycardiaSinus tachycardia ▪ Mild hypertension▪ Mild hypertension
Supportive TreatmentSupportive Treatment
Selective Serotonin Receptor Selective Serotonin Receptor InhibitorsInhibitors
Inhibit presynaptic serotonin reuptakeInhibit presynaptic serotonin reuptakeMost commonly prescribed class of Most commonly prescribed class of
antidepressantsantidepressantsFatalities uncommon (1 in 1000)Fatalities uncommon (1 in 1000)Long half life (15 hours up to 14 days)Long half life (15 hours up to 14 days)
Selective Serotonin Receptor Selective Serotonin Receptor InhibitorsInhibitors
Adverse eventsAdverse events▪ ▪ NauseaNausea ▪ Anorexia ▪ Anorexia
▪ ▪ Serotonin syndromeSerotonin syndrome ▪ Headache ▪ Headache
▪ ▪ SedationSedation ▪ Insomnia ▪ Insomnia
▪ ▪ DizzinessDizziness ▪ Fatigue ▪ Fatigue
▪ ▪ TremorTremor ▪ Nervousness ▪ Nervousness
▪ ▪ SeizuresSeizures ▪ Extrapyramidal symptoms ▪ Extrapyramidal symptoms
▪ ▪ SIADHSIADH
Selective Serotonin Receptor Selective Serotonin Receptor InhibitorsInhibitors
Acute OverdoseAcute OverdoseHigh therapeutic-to-toxic ratioHigh therapeutic-to-toxic ratioFatalities uncommonFatalities uncommon50% of overdoses remain asymptomatic50% of overdoses remain asymptomaticMost symptoms similar to adverse event Most symptoms similar to adverse event
profileprofileLess frequentLess frequent
▪ ▪ AgitationAgitation ▪ Hallucinations ▪ Hallucinations ▪ Seizures ▪ Seizures
▪ ▪ HypertensionHypertension ▪ Hypotension ▪ Hypotension ▪ Widened QRS ▪ Widened QRS
▪ ▪ Prolonged QTcProlonged QTc
Selective Serotonin Receptor Selective Serotonin Receptor InhibitorsInhibitors
TreatmentTreatment IVIVCardiac monitorCardiac monitorActivated charcoal 1 gm/kgActivated charcoal 1 gm/kgGastric lavage probably unnecessaryGastric lavage probably unnecessarySyrup of Ipecac-contraindicatedSyrup of Ipecac-contraindicatedProlonged QRS/QTc-Sodium bicarbonateProlonged QRS/QTc-Sodium bicarbonateSeizures-BenzodiazepinesSeizures-BenzodiazepinesSerotonin syndrome-CyproheptadineSerotonin syndrome-Cyproheptadine
Venlafaxine-Acute OverdoseVenlafaxine-Acute Overdose
Half-life of 11 hoursHalf-life of 11 hoursMost common effectsMost common effects
▪ ▪ TachycardiaTachycardia ▪ Hypertension▪ Hypertension
▪ ▪ DiaphoresisDiaphoresis ▪ Tremor▪ Tremor
▪ ▪ MydriasisMydriasis ▪ Sedation▪ SedationMore severe effectsMore severe effects
▪ ▪ ComaComa ▪ Generalized seizures ▪ Generalized seizures
▪ ▪ Widened QRSWidened QRS ▪ Prolonged QTc ▪ Prolonged QTc
Venlafaxine-Acute OverdoseVenlafaxine-Acute Overdose
TreatmentTreatment IVIV MonitorMonitor Gastric lavageGastric lavage Activated charcoalActivated charcoal Seizures-BenzodiazepinesSeizures-Benzodiazepines QRS widening-Sodium bicarbonateQRS widening-Sodium bicarbonate Hypertension-Nitroprusside/Esmolol or PhentolamineHypertension-Nitroprusside/Esmolol or Phentolamine
Avoid Avoid ββ-blockers-blockers
Serotonin SyndromeSerotonin Syndrome
Rare idiosyncratic drug-induced reactionRare idiosyncratic drug-induced reactionMost cases occur at therapeutic levelsMost cases occur at therapeutic levelsLess than 13% occur with overdoseLess than 13% occur with overdoseCharacterized by alterations inCharacterized by alterations in
Cognition and behaviorCognition and behaviorAutonomic nervous systemAutonomic nervous systemNeuromuscular activityNeuromuscular activity
Mortality rate of 11%Mortality rate of 11%
Serotonin SyndromeSerotonin Syndrome
SS most often occurs after routine medication SS most often occurs after routine medication increase or addition of another 5-HT stimulating increase or addition of another 5-HT stimulating agent agent
True incidence of SS is unknownTrue incidence of SS is unknown SS is often difficult to diagnose because of SS is often difficult to diagnose because of
varying symptomsvarying symptoms▪ ▪ Mild cases attributed to psychiatric disordersMild cases attributed to psychiatric disorders▪ ▪ More severe cases attributed to NMSMore severe cases attributed to NMS
EP’s may inadvertently precipitate SS by EP’s may inadvertently precipitate SS by prescribing prescribing tramadol, dextromethorphan or tramadol, dextromethorphan or meperidinemeperidine
Serotonin Signs and SymptomsSerotonin Signs and SymptomsCognitive-BehavioralCognitive-Behavioral Autonomic DysfunctionAutonomic Dysfunction Neuromuscular DysfunctionNeuromuscular Dysfunction
Confusion-54%Confusion-54% Hyperthermia-46%Hyperthermia-46% Myoclonus-57%Myoclonus-57%
Agitation-35%Agitation-35% Diaphoresis-46%Diaphoresis-46% Hyperreflexia-55%Hyperreflexia-55%
Coma-28%Coma-28% S. Tachycardia-41%S. Tachycardia-41% Muscle rigidity-49%Muscle rigidity-49%
Anxiety-16%Anxiety-16% Hypertension-33%Hypertension-33% Tremor-49%Tremor-49%
Hypomania-15%Hypomania-15% Tachypnea-28%Tachypnea-28% Hyperactivity-43%Hyperactivity-43%
Lethargy-15%Lethargy-15% Mydriasis-26%Mydriasis-26% Ataxia-38%Ataxia-38%
Seizures14%Seizures14% Unreactive pupils-18%Unreactive pupils-18% Shivering-25%Shivering-25%
Serotonin SyndromeSerotonin SyndromeMuscle rigidityMuscle rigidity
Most often found in the lower extremities-may Most often found in the lower extremities-may be valuable clinical markerbe valuable clinical marker
AtaxiaAtaxiaCheck for lower extremity hypertoniaCheck for lower extremity hypertonia
HyperthermiaHyperthermiaUsually mild-moderate, but reports up to 41Usually mild-moderate, but reports up to 41ooCC
SeizuresSeizuresAlways generalized and usually short livedAlways generalized and usually short lived
Serotonin SyndromeSerotonin SyndromeUnilateral muscle rigidity or focal neurologic Unilateral muscle rigidity or focal neurologic
findings have not been reportedfindings have not been reported
Hypertension reported twice as often as Hypertension reported twice as often as hypotensionhypotension
SS is a clinical diagnosisSS is a clinical diagnosis
Lab testing done to rule-out other causes of Lab testing done to rule-out other causes of symptomssymptoms
Serotonin SyndromeSerotonin Syndrome
TreatmentTreatmentNo accepted guidelines for SS treatmentNo accepted guidelines for SS treatment
Stop offending drugsStop offending drugsBenzodiazepines for patient comfort and Benzodiazepines for patient comfort and
rigidityrigidityMonitor closely for rhabdomyolysis and Monitor closely for rhabdomyolysis and
metabolic acidosismetabolic acidosisApproximately 25% will require intubationApproximately 25% will require intubationUsually dramatic improvement within 24 hoursUsually dramatic improvement within 24 hours
Serotonin Syndrome MedicationsSerotonin Syndrome Medications
CyproheptadineCyproheptadine Initial dose: 4-8 mg POInitial dose: 4-8 mg POMay repeat in 2 hours if no responseMay repeat in 2 hours if no responseDiscontinue is no response noted after 16 mgDiscontinue is no response noted after 16 mg
DantroleneDantrolene0.5-2.5 mg/kg IV every 6 hours0.5-2.5 mg/kg IV every 6 hoursMaximum 10 mg/kg in 24 hoursMaximum 10 mg/kg in 24 hours
SummarySummary
SSRI overdose pales in comparison to SSRI overdose pales in comparison to MAOI’s and TCA’sMAOI’s and TCA’s
Still can have significant morbidity and Still can have significant morbidity and mortalitymortality
Most of the management is supportive Most of the management is supportive after decontaminationafter decontamination
Beware of Beware of tramadol, dextromethorphan tramadol, dextromethorphan and meperidineand meperidine in anyone taking SSRI’s, in anyone taking SSRI’s, TCA’s or MAOI’sTCA’s or MAOI’s
QuestionsQuestions
1.1. All of the following may precipitate All of the following may precipitate serotonin syndrome except:serotonin syndrome except:
a.a. ParoxetineParoxetine
b.b. MeperidineMeperidine
c.c. FentanylFentanyl
d.d. TramadolTramadol
e.e. DextromethorphanDextromethorphan
QuestionsQuestions
2.2. Serotonin syndrome may present like all Serotonin syndrome may present like all of the following except:of the following except:
a.a. Sympathomimetic syndromeSympathomimetic syndrome
b.b. Neuroleptic malignant syndromeNeuroleptic malignant syndrome
c.c. Acute psychosisAcute psychosis
d.d. RhabdomyolysisRhabdomyolysis
e.e. Acute unilateral strokeAcute unilateral stroke
QuestionsQuestions
3.3. Basic management for any acute Basic management for any acute overdose consist of:overdose consist of:
a.a. Rectal examRectal exam
b.b. Call poison controlCall poison control
c.c. HgbA1CHgbA1C
d.d. VDRL/RPRVDRL/RPR
e.e. Punitive Gastric LavagePunitive Gastric Lavage
QuestionsQuestions
4.4. All of the following are included in the All of the following are included in the serotonin syndrome triad except:serotonin syndrome triad except:
a.a. Hepatic dysfunctionHepatic dysfunction
b.b. Cognitive dysfunctionCognitive dysfunction
c.c. Autonomic dysfunctionAutonomic dysfunction
d.d. Neuromuscular dysfunctionNeuromuscular dysfunction
QuestionsQuestions
5.5. With the newer class of antidepressants With the newer class of antidepressants which of the following are true:which of the following are true:
a.a. There are not detected by routine lab testsThere are not detected by routine lab tests
b.b. Treatment is mostly supportiveTreatment is mostly supportive
c.c. They are poorly cleared by hemodialysis, They are poorly cleared by hemodialysis, forced diuresis or activated charcoalforced diuresis or activated charcoal
d.d. Have no significant interactions with MAOI’sHave no significant interactions with MAOI’s
e.e. All of the above are trueAll of the above are true
AnswersAnswers
1.1. C-Fentanyl has never been reported to C-Fentanyl has never been reported to precipitate SS, however all the others canprecipitate SS, however all the others can
2.2. E-SS may present like all the other responses, E-SS may present like all the other responses, but acute focal CVA should make you think of but acute focal CVA should make you think of another diagnosisanother diagnosis
3.3. B-Even with the most mundane ingestion, you B-Even with the most mundane ingestion, you should make the call to Poison Controlshould make the call to Poison Control
4.4. A-Although due to rhabdomyolysis etc. you A-Although due to rhabdomyolysis etc. you may see liver dysfunction, it is not part of the may see liver dysfunction, it is not part of the presenting triadpresenting triad
5.5. E-All of the above are trueE-All of the above are true