Antidepressant Serotonin Syndrome (SS) and Neuroleptic Malignant Syndrome (NMS)

• Inhibit presynaptic reuptake of norepinephrine and/or serotonin
• Multiple receptor actions account for therapeutic and toxic effects
– GABA-A receptor antagonist
– Antihistaminic
– Anticholinergic effects thru antagonism of muscarinic receptors
– Alpha-adrenergic receptor blockade
– Na+ and k+ channel blockade in myocardial cells (most prominent effect of OD)

• Readily absorbed, peak levels occur within 2-8 hours post ingestion with therapeutic doses
– Toxic doses
• Delayed GI motility causing absorption to be slow due to anticholinergic effects of TCA, exhibit enterohepatic recirculation

• Highly plasma protein bound (73-97%)
• Highly lipophilic: Vd ranges 15-40 L/kg
• Readily crosses blood brain barrier
• Therapeutic doses: ↑t1/2 ranges (7 to 58 hrs)
– OD up to 72 hours or longer

• Metabolism
– Extensive first pass metabolism by liver
– Renal clearance <5%

Sodium Channel Blockade
A. Usual state
– Sodium depolarizes the cell →conduction →complete cardiac depolarization → opens voltage-
dependent Ca2+ channels → producing contraction
• B. TCA Toxicity
– Impairs sodium entry into myocardial cells
– Slows the action potential, prolongs depolarization (phase 0) → negative dromotropic and inotropic effects

Potassium Channel Blockade
• Prevents efflux during repolarization
• QT interval prolongation
• Torsades de pointes may develop, but is rare in TCA toxicity

Antihistaminic effects
• Potent inhibitors of histamine receptors
• Manifested as CNS sedation

• Therapeutic index of TCA is narrow
• < 1mg/kg non-toxic
• Acute ingestion of 10-20mg/kg potentially lethal dose (considered moderate to severe exposure)
• > 35mg/kg can be fatal if left untreated

• General presentation
• Varies from mild antimuscarinic to severe CV collapse
– Manifestation primarily in the autonomic system, CNS, CV

– Symptoms develop within the 1st few hours
• If NO symptoms observed w/in first 6 hours following ingestion; not likely to develop toxicity
• BUT serious complications usually occur w/in the first 12 hours

– Mechanisms
• Alpha adrenergic receptor blockade
• Anticholinergic activity
• Blockade of fast inward sodium channels

– Sinus tachycardia (50%)
• Due to anticholinergic effects
• May last hours to days

– Hypotension (15%) (multifactorial)
• Alpha1 blockade leads to vasodilation, slowed cardiac conduction and delayed CO with reduced contractility due to Na+/K+ channel blockade

– Arise from Na+/K+ channel blockade leading to both reduced conduction velocity and automaticity of cardiac cells
– Slowing of the influx of sodium during phase 0 of AP
• Can lead to life-threatening arrhythmias
• Prolongation of QRS complex (≥ 100 msec)
– Prolonged PR and QTc interval and AV block

• Arrhythmias
– Premature ventricular contraction, VT, VF, asystole

– Antihistaminic effects: Confusion, agitation, hallucination, coma (35%)
– Seizures (10%)
• Generalized tonic-clonic occurs early during ingestion
– Depressed mental status: Severe acidosis
– Lactic acid may build up, further exacerbating cardiotoxicity
• Myoclonic jerking
– Benign muscle contraction

• TCA intoxication should be suspected in any patient with lethargy, coma or seizures
• Accompanied with CV collapse
• Characteristic ECG findings
– Widened QRS, prolonged QTc
• Anticholinergic toxidrome

• Normal: QRS Interval
– QRS < 100 milliseconds (msec)

• QRS > 100 msec increased toxicity
– Coma
– Intubation
– Hypotension
– Seizures

• Increased risk arrhythmia
– > 160 msec

ABC, IV access, stabilize vital signs (fluid resuscitation), cardiac monitoring (evaluate QRS duration)
Contact Poison control
GI decontamination - Delayed TCA absorption in overdose
• Gastric lavage
– Life-threatening OD in a symptomatic patient
– Delayed GI motility with TCA may yield unabsorbed drug at 12 hours following ingestion, ER formulation
• Activated charcoal (within 2 hours)
– SDAC 1g/kg
– MDAC as TCA undergo enterohepatic recirculation are associated with ↓GI motility, may be of benefit to give 0.5-1g/kg q2h

• Considered first-line treatment for TCA-induced cardiac conduction defects, arrhythmias, and hypotension
– Indications
• Prolonged QRS interval
• TCA-induced ventricular dysrhythmias
• Hypotension
• Acidosis
• Mechanism: Na+ dependent effect: increase Na+ gradient across poisoned fast Na+ channel
to reverse Na+/K+ blockade
– ↑Plasma alkalinization, Na+ load,
– ↑TCA plasma protein binding
(↓free drug available)
– Correction of acidosis
– Goal plasma pH between 7.45-7.55

• Sodium bicarbonate 1 – 2 mEq/kg per dose
– Repeated every 3-5 minutes until QRS narrows and/or hypotension resolves
– Desired serum pH of 7.45 to 7.55
– Followed by continuous infusion for 12 – 24 hours
• NaCl 3% - theoretical alternative
• Intubation and hyperventilation (increases pH)
• Intravenous fat emulsion
– Enhanced elimination due to redistribution
– Lipid sink to trap lipophilic drug
– 1.5mg/kg (up to 6 doses)

• Lack of antidotes or reliable reversal agents
– Antidepressants
– Antipsychotics
– Local anesthetics

• Search for novel rescue therapy

• Intralipid ® 20% Emulsion
– Oil-in-water emulsion
– Typically used for parenteral nutrition

• MOA
– Block reuptake of serotonin (5-HT) into the nerve terminal
• Clinical features of SSRI toxicity
– N/V, lethargy, sedation, seizure (rare)
– QT prolongation associated with citalopram and escitalopram, maybe delayed up to 24 hours following ingestion

• Venlafaxine, desvenlafaxine, duloxetine
• Seizures – predominant effect during overdose
• Cardiac toxicity - Venlafaxine likely to cause QRS prolongation
• Other effects
– Nausea, vomiting, dizziness, tachycardia, CNS depression, hypotension
– Duloxetine - elevated hepatic enzyme concentrations

• SSRI, SNRI, SDRI
– Hydroxybupropion responsible for seizures
• Overdose clinical manifestations
– Tachycardia, hypertension, gastrointestinal symptoms, and agitation
– Dose dependant drug induced seizures and QRS prolongation
• Chronic doses greater than 450-500 mg/d place the patient at risk for seizures
– Benzodiazepines mainstay of treatment (seizures)
• Delayed effects
– Up to 10 hours (particularly with sustained-release)
– Symptoms can continue for up to 48 hours

• Largely supportive – rarely fatal alone
– Cardiac monitoring – citalopram and escitalopram
• GI decontamination
– Activated charcoal (1 g/kg)
– Orogastric lavage not generally indicated
• Serotonin syndrome
– Monitor for evidence of serotonin syndrome

• Serotonin syndrome (SS) is an adverse drug reaction
• Mechanism: Excessive selective stimulation of serotonin 5-HT2A receptors
– Lesser extent 5-HT1A receptors (hyperreflexia)
• Combinations of serotonergic agents (polypharmacy)
– Drug-drug interactions
– Drug-food interactions
– Switching therapies
– Single dose
– High therapeutic dosing
– Overdose

• Quantitative serum drug concentrations are not helpful
• Based on presence of clinical findings in patient at risk (several diagnostic criteria developed)
• Rule out other etiologies
– Infectious, metabolic, withdrawal and substance abuse
• Hunters criteria: 84% sensitive, 97% specific
– Presence of ONE of the five criteria is suggestive
– Spontaneous clonus, inducible clonus, ocular clonus, tremor and hyperreflexia, hypertonia (spasticity,
rigidity) and temp > 38oC with inducible or ocular clonus

• Treatment goals
– Reduce muscle rigidity and prevent hyperthermia
• Benzodiazepines
• External cooling / cool IV fluids (ex: NS 0.9% @ 4˚C)
• Neuromuscular block in severe cases
• Serotonin syndrome resolves within 24 hours in most patients
– Prolonged by active metabolites, long half-lives
• Cyproheptadine 4 mg oral or IV
– Antihistamine
– Nonspecific antagonist effects at 5-HT1A and 5-HT2A
– Use in patients with mild to moderate symptoms – not hyperthermic
• Alternative diagnosis

• High Potency
– Fluphenazine
(Prolixin)
– Haloperidol
(Haldol)
– Perphenazine
(Trilafon)
– Thiothixene
(Navane)
– Trifluoperazine
(Stelazine)
– Loxapine
(Loxitane)
– Molindone
(Moban)

• Low Potency
– Chlorpromazine
(Thorazine)
– Thioridazine
(Mellaril)
– Mesoridazine
(Serentil

– Clozapine (Clozaril)
– Olanzapine (Zyprexa)
– Quetiapine (Seroquel)
– Risperidone (Risperdal)
– Ziprasidone (Geodon)
– Aripiprazole (Abilify)
– Paliperidone (Invega)

• Similar to TCA toxicity
• QRS prolongation
– Blockade of the sodium current
• QTc prolongation
– Torsades de pointes (>500msec)
• Normal QTc 400msec + 76 msec
– Thioridazine > Ziprasidone>
Quetiapine > Risperidone > Olanzapine > Haloperidol
• Sinus tachycardia (anticholinergic)
• Reflex tachycardia (alpha-1 antagonism)

Not fully understood
Probably dopaminergic blockade or depletion in CNS
Genetics may be involved

• Life-threatening neurologic emergency
– Associated with every antipsychotic
– Incidence ranges from 0.2-1.4%, mortality
20% with prompt recognition and treatment
• Less severe episodes may go
undiagnosed
– Lower incidence with antipsychotics that antagonize 5-HT2A

• Pathophysiology/etiology
– Any agent that exerts antagonism at the dopamine D2 receptor
– Abrupt reductions in central dopaminergic neurotransmission in the hypothalamus, altering the core temperature "set point“
– Altered thermoregulation and other manifestations of autonomic dysfunction

• Based on clinical findings in a patient at risk and careful medication history
• Lab findings
– ↑ Creatine kinase (>1000 IU/L)
– ↑ LDH, ALT, AST
– Leukocytosis
– Rhabdomyolysis and myoglobinuria
• No universally accepted diagnostic criteria

• Rapid external cooling with ice bath if needed
• Reduce muscle rigidity (muscle relaxation), sedation
– Benzodiazepines
• Alternatives or adjuncts
– Bromocriptine (Parlodel)-central dopamine agonist
• 2.5 - 10 mg TID (titrate up)
– Reverses dopamine blockade
• Amantadine (prevents re-uptake of dopamine into presynaptic neurons
– Dantrolene (rarely indicated) extreme cases of NMS to ↓muscle rigidity and fever
• Oral: 50-100 mg/d
• IV infusion: 2-10 mg/kg/d divided q6h
» Reduces skeletal muscle activity by inhibiting ryanodine receptor calcium release channels

• Duration of up to 2 weeks
• Reintroduction of neuroleptics
– At least 1-2 weeks should pass after symptom resolution before restarting therapy
– Choose a different class of antipsychotic and with minimal EP effects