Newer Antidepressants and Serotonin Syndrome

1. 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 TCA’s and MAOI’s ▪ More selective ▪ Less toxicity ▪ Fewer fatalities • More likely to produce Serotonin Syndrome

3. 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 β-adrenergic receptors • Higher safety margin than MAOI’s and TCA’s

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 MAOI’s may precipitate serotonin syndrome

5. 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

6. 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

7. 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

8. 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

9. 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

10. 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)

11. Selective Serotonin Receptor Inhibitors • Adverse events ▪ Nausea ▪ Anorexia ▪ Serotonin syndrome ▪ Headache ▪ Sedation ▪ Insomnia ▪ Dizziness ▪ Fatigue ▪ Tremor ▪ Nervousness ▪ Seizures ▪ Extrapyramidal symptoms ▪ SIADH

12. 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

13. 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

14. 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

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

16. 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%

17. 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 • EP’s may inadvertently precipitate SS by prescribing tramadol, dextromethorphan or meperidine

18. Serotonin Signs and Symptoms

19. 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

20. 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

21. 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

22. 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

23. 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

24. Questions • All of the following may precipitate serotonin syndrome except: • Paroxetine • Meperidine • Fentanyl • Tramadol • Dextromethorphan

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

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

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

28. 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 MAOI’s • All of the above are true

29. 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