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

General Principles Newer antidepressants termed atypical, heterocyclic or second generation Newer antidepressants termed atypical, heterocyclic or second generation Prescribed for depression, anxiety disorder, panic disorder, personality disorders, OCD and eating disorders Prescribed for depression, anxiety disorder, panic disorder, personality disorders, OCD and eating disorders Differentiated from TCA’s and MAOI’s Differentiated from TCA’s and MAOI’s ▪ More selective▪ Less toxicity ▪ Fewer fatalities More likely to produce Serotonin Syndrome More likely to produce Serotonin Syndrome

General Principles No cardiotoxicity or conduction delays that are seen with TCA’s No cardiotoxicity or conduction delays that are seen with TCA’s No associated tyramine reactions like MAOI’s No associated tyramine reactions like MAOI’s Negligible affinity for acetylcholine, dopamine, GABA-A, glutamate or β- adrenergic receptors Negligible affinity for acetylcholine, dopamine, GABA-A, glutamate or β- adrenergic receptors Higher safety margin than MAOI’s and TCA’s Higher safety margin than MAOI’s and TCA’s

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

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

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

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

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

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

Selective Serotonin Receptor Inhibitors Inhibit presynaptic serotonin reuptake Inhibit presynaptic serotonin reuptake Most commonly prescribed class of antidepressants Most commonly prescribed class of antidepressants Fatalities 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 Inhibitors Adverse events Adverse events ▪ Nausea ▪ Anorexia ▪ Serotonin syndrome ▪ Headache ▪ Sedation ▪ Insomnia ▪ Dizziness ▪ Fatigue ▪ Tremor ▪ Nervousness ▪ Seizures ▪ Extrapyramidal symptoms ▪ SIADH

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

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

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

Venlafaxine-Acute Overdose Treatment Treatment IV IV Monitor Monitor Gastric lavage Gastric lavage Activated charcoal Activated charcoal Seizures-Benzodiazepines Seizures-Benzodiazepines QRS widening-Sodium bicarbonate QRS widening-Sodium bicarbonate Hypertension-Nitroprusside/Esmolol or Phentolamine Hypertension-Nitroprusside/Esmolol or Phentolamine Avoid β-blockers Avoid β-blockers

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

Serotonin Syndrome SS most often occurs after routine medication increase or addition of another 5-HT stimulating agent SS most often occurs after routine medication increase or addition of another 5-HT stimulating agent True incidence of SS is unknown True incidence of SS is unknown SS is often difficult to diagnose because of varying symptoms 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 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 Muscle rigidity Most often found in the lower extremities-may be valuable clinical marker Most often found in the lower extremities-may be valuable clinical marker Ataxia Ataxia Check for lower extremity hypertonia Check for lower extremity hypertonia Hyperthermia Hyperthermia Usually mild-moderate, but reports up to 41 o C Usually mild-moderate, but reports up to 41 o C Seizures Seizures Always generalized and usually short lived Always generalized and usually short lived

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

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

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

Summary SSRI overdose pales in comparison to MAOI’s and TCA’s SSRI overdose pales in comparison to MAOI’s and TCA’s Still can have significant morbidity and mortality Still can have significant morbidity and mortality Most of the management is supportive after decontamination Most of the management is supportive after decontamination Beware of tramadol, dextromethorphan and meperidine in anyone taking SSRI’s, TCA’s or MAOI’s 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. Paroxetine b. Meperidine c. Fentanyl d. Tramadol e. Dextromethorphan

Questions 2. Serotonin syndrome may present like all of the following except: a. Sympathomimetic syndrome b. Neuroleptic malignant syndrome c. Acute psychosis d. Rhabdomyolysis e. Acute unilateral stroke

Questions 3. Basic management for any acute overdose consist of: a. Rectal exam b. Call poison control c. HgbA1C d. VDRL/RPR e. Punitive Gastric Lavage

Questions 4. All of the following are included in the serotonin syndrome triad except: a. Hepatic dysfunction b. Cognitive dysfunction c. Autonomic dysfunction d. Neuromuscular dysfunction

Questions 5. With the newer class of antidepressants which of the following are true: a. There are not detected by routine lab tests b. Treatment is mostly supportive c. They are poorly cleared by hemodialysis, forced diuresis or activated charcoal d. Have no significant interactions with MAOI’s e. All of the above are true

Answers 1. C-Fentanyl has never been reported to precipitate SS, however all the others can 2. E-SS may present like all the other responses, but acute focal CVA should make you think of another diagnosis 3. B-Even with the most mundane ingestion, you should make the call to Poison Control 4. A-Although due to rhabdomyolysis etc. you may see liver dysfunction, it is not part of the presenting triad 5. E-All of the above are true