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What is Excited Delirium (ED)?

Excited delirium is a brain disorder. 

This disorder is usually drug-related (cocaine or "crack", PCP or "angel dust", methamphetamine, amphetamine), but can occur in non-drug users as well. 

The presentation of excited delirium occurs with a sudden onset, with symptoms of bizarre and/or aggressive behavior, shouting, paranoia, panic, violence toward others, unexpected physical strength, and hyperthermia. Hyperthermia is a harbinger of death in these cases.

Neurochemical systems in the brain are abnormal in this disorder. At the molecular level, excited delirium is characterized by dysregulated dopamine transporters (hyperdopaminergic state), elevated heat shock proteins (hyperthermia), and immediate early gene activation as a marker of paranoid aggression (c-fos protein). These molecular changes serve as biomarkers of the disorder.

While many factors are associated with sudden death in individuals requiring restraint for excited delirium, these individuals develop a disturbance in thought, behavior and mood, and become agitated and violent. This abnormal behavioral state is due to CNS mechanisms which are the cause of lethality. The brain controls the heart and respiration. Abnormal brain activity leads to the psychosis and sudden death.

History of Excited Delirium

While excited delirium is best characterized in cocaine users, medical examiners and forensic scientists have noted a similarity in psychiatric presentation between sudden unexplained deaths in custody and psychiatric states associated with or without drug abuse.  This seminal work was first described by Dr. Charles Wetli and his collaborator David Fishbain in the mid 1980s, when the "crack" cocaine epidemic first hit the streets of Miami, Florida (Wetli and Fishbain, 1985). But this disorder was known more than a decade earlier.

In 1849, Dr. Luther Bell first described a "disease" resembling some advanced stage of mania and fever, distinguished as an overlooked and often unrecorded malady (Bell, 1849). This “exhaustive mania” was described in 40 cases by Dr. Bell where “exhaustion due to mental excitement” caused three quarters of these patients to die. lutherbell

Similarly, a condition called neuroleptic malignant syndrome (NMS) was described in the 1960s as a potentially fatal complication of antipsychotic drugs. This highly lethal disorder is seen in patients taking dopamine (DA) antagonists or following abrupt withdrawal from DAergic agonists (Caroff et al., 2007; Friedman et al., 1985; Kosten and Kleber, 1988; Levenson, 1985; Strawn et al., 2007). 

In their seminal 1985 paper, Wetli and Fishbain reported excited delirium in a cocaine body packer, and within the next few years, the syndrome was recognized in cocaine abusers as well.  NMS is usually associated with muscle rigidity, while the cocaine variant of the syndrome presents with brief onset of rigidity immediately prior to respiratory collapse (Kosten and Kleber, 1988).  In 1988, Kosten and Kleber proposed that cocaine-induced excited delirium was a variant of NMS. Alternatively, NMS may be an attenuated version of acute exhaustive mania/excited delirium. There is no doubt that these three disorders represent a common brain disease that likely has a genetic risk for certain individuals.

Neurochemical Biomarkes of Excited Delirium

Recent studies by our group supporting the hypothesis that NMS and cocaine-induced excited delirium are related and due to a brain disorder, involves dysregulated dopamine transport (Staley et al., 1994, 1995b; Wetli et al., 1996; Mash et al., 2002; Mash et al, 2008). 

Cocaine blocks the dopamine transporter (DAT,red plugs in the presynaptic membrane) which leads to an elevation of the neurotransmitter in the synaptic cleft (shown above). An elevation of DA activates postsynaptic receptors (blue plugs in the synaptic membrane) on receiving cells. Pathologic levels of DA in the synapse causes the paranoia, delusions and psychosis. Too much DA in the synapse causes a dysregulation in the centers of the brain that controls temperature. DA is known to be linked to the central command centers in brain that controls the heart. Chaotic DA signaling in the brain underlies the emergence of paranoia and psychosis.

Cocaine-related excited delirium is always seen in chronic abusers. The brain on cocaine is "not the same" and has adapted to a new state. Many neurochemical systems are dysregulated, but the final common pathway is most likely linked to DA. Excited Delirum is characterized as a hyperdopaminergic state.

What is Excited Delirium ?

Wetli suggests that there are three related syndromes: (1) acute exhaustive mania, as described by Bell in psychiatric patients, (2) excited delirium, due to psychostimulants (cocaine, methamphetamine, MDMA) and psychiatric illness; and (3) the attenuated variant - NMS (Wetli, 2005; Wetli and Natarjajan, 2005).

With advances in molecular genetics, the gene or genes and environment interactions that cause Excited Delirium will be identified. This will only be possible if the biospecimens are made available to fully characterize excited delirium as a brain disease.

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