Newer Antidepressants and Serotonin Syndrome Presented by Dr. Bloxdorf Prepared by A. Hillier

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


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


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)


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


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


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%


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


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

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Newer Antidepressants and Serotonin Syndrome Presented by Dr. Bloxdorf Prepared by A. Hillier