Risk factors

Rapid increases and high doses of antipsychotic medication

IM antipsychotic use Dehydration/poor nutrition, comorbid medical illness

Young age

Male

Presence of mood disorder

Previous episode of NMS

Elderly

Concurrent use of ≥ 2 serotonergic agents (e.g., selective serotonin reuptake inhibitors [SSRIs], monoamine oxidase inhibitors [MAOIs], L-tryptophan, meperidine, lithium)

High doses (dose-related)

Young adults (mean age = 33 years)

Women

Schizophrenia, manic or depressed mood states

Comorbid infection, metabolic, other medical conditions

Genetic predisposition

Neuromuscular disorder (e.g., myopathy)

Typical symptoms

Altered mental status

Lead-pipe rigidity

Autonomic instability

Hyperthermia

Decreased:

Salivation/sight/sweat

Lacrimation

Urination

Bowel movements

Gastrointestinal symptoms (diarrhea, nausea/emesis)

Extreme hyperactivity (“catatonic excitement”) and progressive hyperthermia before onset of stupor

Hyperthermia with muscular rigidity s/p recent administration of an anesthetic agent

Clinical features

Altered mental status

Hyperthermia

Confusion/agitation

Rigidity/tremor

Autonomic instability (hypoor hypertension, tachycardia, high fever, diaphoresis

Extrapyramidal symptoms (dystonia, akinesia, tremor, cogwheeling, lead-pipe rigidity)

Altered mental status

Fever

Dilated, sluggish pupils/blurred

Change in mental status/delirium

Flushed skin

Dry skin and mucous membranes

Dry mouth

Urinary retention

Constipation/absent bowel sounds

Hallucinations

Tachycardia

Altered mental status

Diaphoresis

Flushing/sweating

Shivering/restlessness

Tremor

Akathisia

Myoclonus

High fever

Elevated blood pressure

Hyperreflexia

Ataxia

Rhabdomyolysis

Altered mental status

Fever

Confusion

Violent and self-destructive behavior (e.g., no p.o. intake)

Mood lability

Rigidity/waxy flexibility

Psychotic symptoms

Autonomic instability: tachycardia, diaphoresis, elevated or labile blood pressure

Hyperthermia

Muscular rigidity

Arrhythmias

Ischemia

Diaphoresis

Hot skin

Mottled cyanosis

Hypotension

Rhabdomyolysis

Mechanism

Sudden decrease in central dopaminergic function after blockade of dopamine receptors at multiple sites (e.g., basal ganglia, hypothalamus)

Excessive blockade of acetylcholine receptors

Overactivation of central 5-HT receptors

Reduced dopaminergic functioning within the basal ganglia-thalamocortical circuits

Inherited disorder triggered by a halogenated inhaled anesthetic (e.g.,

Halothane) and/or depolarizing muscle relaxant (e.g., succinylcholine), causing increased calcium levels in skeletal muscle.

Lab findings

Elevated creatine phosphokinase (CPK) (> 300 U/mL)

Elevated white blood cell count (>10 K/mm³)

Increased aldolase, alkaline phosphatase, AST, ALT

Low serum Fe, Ca, and Mg

Hypo/hypernatremia

Myoglobinuria

No specific lab findings

Acute renal failure

Elevated CPK

Leukocytosis

Transaminitis

Decreased serum

Fe

Elevated CPK

Acute renal failure

Disseminated intravascular coagulation

Respiratory/metabolic acidosis

Hyperkalemia

Hypermagnesemia

Management

Thorough medical/neurological and mental status evaluation and exam

Discontinue all medications

Supportive measures (cooling, hydration, nutrition, aspiration precautions, anticoagulation)

Consider dopaminergic agonist (bromocriptine 5 mg BID-TID), dantrolene and/or electroconvulsive therapy (ECT) may help

While restarting the neuroleptic:

Consider reintroduction of antipsychotic no earlier than 2 weeks after resolution of NMS

Use lowest effective dosage of antipsychotic agent, but monitor closely for relapse

Discontinue suspected agent

Acute reversal may entail IV physostigmine 1-2 mg (1 mg/min) but do not use for maintenance treatment (risk of bradycardia, nausea/emesis, seizures)

Supportive measures (cooling, hydration)

Discontinue suspected agent(s)

Supportive measures (e.g., cooling, hydration, respiratory, pain management, nutrition)

Additional agents-dantrolene, bromocriptine, propanolol, methysergide, and cyproheptadine (serotonin antagonist) may be helpful

Mechanical ventilation

Hold antipsychotic drugs

Rule out comorbid medical illness

Watch for medical complications

Supportive measures (e.g., hydration, maintenance of nutritional status)

Benzodiazepines (e.g., lorazepam 1-2 mg p.o./IM BID-TID)

ECT if above ineffective

Dantrolene 100% O₂ Supportive measures (e.g., cooling, NaHCO₃, hydration)

Mortality

Mortality ˜20%

Mortality ˜9%

Mortality rare (most commonly with medication combinations containing MAOIs)