TCA and Serotonin Re-Uptake Inhibitors Rama B. Rao, MD Bellevue/New York University Medical Center

Tricyclic Antidepressants  A patient takes 30 tablets of nortriptylline in a suicide attempt, she calls her family member who summons an ambulance.  On arrival, the paramedics note she is unresponsive, tachycardic, and hypotensive.  She seizes.

TCA Toxicity  Anticholinergic/Antihistaminergic –Somnolence, Tachycardia   Adrenergic blockade –Hypotension  GABA Cl - Channel Antagonist –Seizures  Sodium Channel Blockade –Myocardial Depression, dysrhythmias

Myocardial Cell: Depolarization Ca 2+ SR Na

TCA Ca 2+ SR Na + pH TCA

Ca 2+ SR Na + pH TCA

Wide QRS  > 100 msec predictive of seizures  > 160 msec predictive of dysrythmias Boehnert M, Lovejoy FH Jr. New Engl J Med 1985;313:

I L aV R Myocardium

I L aV R With TCA: QRS widening from sodium channel blockade

I L aV R R in aV R S in I,L QRS > 100 msec TCA: Terminal Rightward Axis

TCA Toxicity  S in I, L  R in aV R  QRS >100 msec  Drowsy/obtunded patient   HR,  BP Boehnert M, Lovejoy FH Jr. New Engl J Med 1985;313: aV R

Sodium bicarbonate*  Place patient on monitor  Run strip  Administer bolus of 1 mEq/kg  Observe for QRS narrowing  Keep pH  Intubate/hyperventilate if sodium contraindicated NaHCO 3 * Useful for TCA, Cocaine, Type Ia antidysrhythmics

After NaHCO 3

TCA Toxicity: General Management  2 Large bore intravenous lines  Continuous ECG monitoring  Assessment for QRS widening, terminal RAD, and response to sodium bicarbonate  Aggressive decontamination  Benzodiazepines for seizure management* *Fingerstick blood glucose

St John’s Wort

Pre-synaptic Post-synaptic DA NE Neuronal Tissue MECHANISM OF ACTION: TCA, SSRI, MAO-I

Pre-synaptic Post-synaptic DA NE 5HT Neuronal Tissue

Pre-synaptic Post-synaptic DA NE 5HT Propagation Neuronal Tissue

Pre-synaptic Post-synaptic DA NE 5HT Propagation C-O-MT MAO

Pre-synaptic Post-synaptic DA NE 5HT Propagation TCA, SSRI

Pre-synaptic Post-synaptic DA NE 5HT Propagation MAO-I

Pre-synaptic Post-synaptic DA NE 5HT Propagation TCA, SSRI MAO-I

Serotonin Syndrome  Excessive serotonergic tone 5HT 1A, 5HT 2  Continuum of neuropsychiatric manifestations Serotonin

Serotonin Syndrome: Major Criteria*  Confusion  Elevated mood  Coma  Fever  Diaphoresis  Chills  Rigidity  Hyperreflexia  Myclonus  Tremor 4 major, or 3 major and 2 minor Birmes P CMAJ 2003;168:

Minor Criteria: Serotonin Syndrome  Agitation  Nervousness  Insomnia  Tachypnea  Dyspnea  Tachycardia  High or low BP  Akathisia  Incoordination  Mydriasis  Diarrhea 4 major, or 3 major and 2 minor Birmes P CMAJ 2003;168:

Fatal Serotonin Syndrome  Abrupt onset  Autonomic instability  Hyperthermia, diaphoresis  Neuromuscular rigidity, movement disorder  Altered mental status  Absence of a neuroleptic or other cause

Serotonin Syndrome  Most often iatrogenic  Resolution in hours  Death from uncontrolled hyperthermia

Serotonin Syndrome: Therapeutic Goals  Rapid identification of Hyperthermia  Continuous core temperature monitoring, aggressive cooling, benzodiazepines for sedation  Rule out other potential etiologies

Serotonin Syndrome  Identification of serotonergic factors, particularly the presence of monoamine oxidase inhibitors  ?Role of serotonin antagonists

Drugs Implicated in Serotonin Syndrome  MAO-Inhibitors  SSRIs  Clomipramine  Venlafaxine  Lithium  MDMA*  L-Tryptophan*  Meperidine*  Dextromethorphan*  Cocaine*

Citalopram  SSRI with toxic metabolite  In overdose can prolong QRS, QT c,  Seizures  Delay in onset Catalano G. Clin Neuropharmacol 2001;24:158-62

Citalopram Overdose  Immediate cardiac monitoring for QT c, IV lines  Assess and correct electrolytes, especially K +, Ca 2+, Mg 2+  Decontamination  Use of Mg 2+ for torsade  Admission of minimum 24 hours of cardiac monitoring

Myocardial Cell  G AC ATP cAMP Ca 2+ 4 SR 5