Delirium arises through the interaction of a number of predisposing and precipitating factors. A predisposing factor might be any biological, psychological or social factor that increases an individual’s susceptibility to delirium. An individual with multiple predisposing factors is said to have "high baseline vulnerability". A precipitating factor is any biological, psychological or social factor that can trigger delirium. The division of causes into "predisposing" and "precipitating" is useful in order to assess an individual’s risk of suffering from delirium, and in guiding the management of delirium – however there may be a significant degree of overlap between the two categories.

Delirium most commonly affects the old age and those of ill health. Health results from physical and socioeconomic assets, and opposing factors come from physical and socioeconomic deficits. Individuals with significant predisposing factors don't compensate for physical or social stressors ("precipitating factors"). In such an individual, a single or mild precipitating factor could be sufficient to trigger an episode of delirium. Conversely, delirium may only result in a healthy individual if they suffer serious or multiple precipitating factors. It is important to note that the factors affecting those of an individual can change over time, thus an individual’s risk of delirium is in a state of flux.

The most important predisposing factors are listed below:

- Older age

- Cognitive impairment / dementia

- Physical comorbidity (biventricular failure, cancer, cerebrovascular disease)

- Psychiatric comorbidity (e.g., depression)

- Sensory impairment (vision, hearing)

- Functional dependence (e.g., requiring assistance for self-care and/or mobility)

- Dehydration / malnutrition

- Drugs and drug-dependence.

- Alcohol dependence

Excited delirium occurs most commonly in males with a history of serious mental illness or acute or chronic drug abuse, particularly stimulant drugs such as cocaine and MDPV. Alcohol withdrawal or head trauma may also contribute to the condition.

A majority of fatal case involved men.

People with excited delirium commonly have acute drug intoxication, generally involving PCP, methylenedioxypyrovalerone (MDPV), cocaine, or methamphetamine. Other drugs that may contribute to death are antipsychotics.

The pathophysiology of excited delirium has been unclear, but likely involves multiple factors. These may include positional asphyxia, hyperthermia, drug toxicity, and/or catecholamine-induced fatal cardiac arrhythmias.

There is limited evidence that caffeine, in high doses or when chronically abused, may induce psychosis in normal individuals and worsen pre-existing psychosis in those diagnosed with schizophrenia.

Delirium tremens is mainly caused by a long period of drinking being stopped abruptly. Withdrawal leads to a biochemical regulation cascade. It may also be triggered by head injury, infection, or illness in people with a history of heavy use of alcohol.

Another cause of delirium tremens is abrupt stopping of tranquilizer drugs of the barbiturate or benzodiazepine classes in a person with a relatively strong addiction to them. Because these tranquilizers' primary pharmacological and physiological effects stem from their manipulation of the GABA chemical and transmitter somatic system, the same neurotransmitter system affected by alcohol, delirium tremens can occur upon abrupt decrease of dosage in those who are heavily dependent. These DTs are much the same as those caused by alcohol and so is the attendant withdrawal syndrome of which they are a manifestation. That is the primary reason benzodiazepines are such an effective treatment for DTs, despite also being the cause of them in many cases. Because ethanol and tranquilizers such as barbiturates and benzodiazepines function as positive allosteric modulators at GABA receptors, the brain, in its desire to equalize an unbalanced chemical system, triggers the abrupt stopping of the production of endogenous GABA. This decrease becomes more and more marked as the addiction becomes stronger and as higher doses are needed to cause intoxication. In addition to having sedative properties, GABA is an immensely important regulatory neurotransmitter that controls the heart rate, blood pressure, and seizure threshold among myriad other important autonomic nervous subsystems.

Delirium tremens is most common in people who have a history of alcohol withdrawal, especially in those who drink the equivalent of of beer or of distilled beverage daily. Delirium tremens also commonly affects those with a history of habitual alcohol use or alcoholism that has existed for more than 10 years.

Approximately three percent of people who are suffering from alcoholism experience psychosis during acute intoxication or withdrawal. Alcohol related psychosis may manifest itself through a kindling mechanism. The mechanism of alcohol-related psychosis is due to the long-term effects of alcohol resulting in distortions to neuronal membranes, gene expression, as well as thiamin deficiency. It is possible in some cases that alcohol abuse via a kindling mechanism can cause the development of a chronic substance induced psychotic disorder, i.e. schizophrenia. The effects of an alcohol-related psychosis include an increased risk of depression and suicide as well as causing psychosocial impairments.

Various psychoactive substances (both legal and illegal) have been implicated in causing, exacerbating, or precipitating psychotic states or disorders in users, with varying levels of evidence. This may be upon intoxication, for a more prolonged period after use, or upon withdrawal. Individuals who have a substance induced psychosis tend to have a greater awareness of their psychosis and tend to have higher levels of suicidal thinking compared to individuals who have a primary psychotic illness. Drugs commonly alleged to induce psychotic symptoms include alcohol, cannabis, cocaine, amphetamines, cathinones, psychedelic drugs (such as LSD and psilocybin), κ-opioid receptor agonists (such as enadoline and salvinorin A) and NMDA receptor antagonists (such as phencyclidine and ketamine).

Stimulant psychosis is a psychosis symptom which involves hallucinations, paranoia, and/or delusions and typically occurs following an overdose on psychostimulants; however, it has also been reported to occur in approximately 0.1% of individuals, or 1 out of every 1,000 people, within the first several weeks after starting amphetamine or methylphenidate therapy.

The most common causative agents are substituted amphetamines and dopamine reuptake inhibitors such as cocaine and methylphenidate.

Delirium tremens (DTs) is a rapid onset of confusion usually caused by withdrawal from alcohol. When it occurs, it is often three days into the withdrawal symptoms and lasts for two to three days. Physical effects may include shaking, shivering, irregular heart rate, and sweating. People may also see or hear things other people do not. Occasionally, a very high body temperature or seizures may result in death. Alcohol is one of the most dangerous drugs from which to withdraw.

Delirium tremens typically only occurs in people with a high intake of alcohol for more than a month. A similar syndrome may occur with benzodiazepine and barbiturate withdrawal. Withdrawal from stimulants such as cocaine does not have major medical complications. In a person with delirium tremens it is important to rule out other associated problems such as electrolyte abnormalities, pancreatitis, and alcoholic hepatitis.

Prevention is by treating withdrawal symptoms. If delirium tremens occurs, aggressive treatment improves outcomes. Treatment in a quiet intensive care unit with sufficient light is often recommended. Benzodiazepines are the medication of choice with diazepam, lorazepam, chlordiazepoxide, and oxazepam all commonly used. They should be given until a person is lightly sleeping. The antipsychotic haloperidol may also be used. The vitamin thiamine is recommended. Mortality without treatment is between 15% and 40%. Currently death occurs in about 1% to 4% of cases.

About half of people with alcoholism will develop withdrawal symptoms upon reducing their use. Of these, three to five percent develop DTs or have seizures. The name delirium tremens was first used in 1813; however, the symptoms were well described since the 1700s. The word "delirium" is Latin for "going off the furrow," a plowing metaphor. It is also called shaking frenzy and Saunders-Sutton syndrome. Nicknames include the shakes, barrel-fever, blue horrors, bottleache, bats, drunken horrors, elephants, gallon distemper, quart mania, and pink spiders, among others.

The symptoms of sedative/hypnotic toxidrome include ataxia, blurred vision, coma, confusion, delirium, deterioration of central nervous system functions, diplopia, dysesthesias, hallucinations, nystagmus, paresthesias, sedation, slurred speech, and stupor. Apnea is a potential complication. Substances that may cause this toxidrome include anticonvulsants, barbiturates, benzodiazepines, gamma-Hydroxybutyric acid, Methaqualone, and ethanol. While most sedative-hypnotics are anticonvulsant, some such as GHB and methaqualone instead lower the seizure threshold, and so can cause paradoxical seizures in overdose.

In general, alcohol abusers with withdrawal symptoms, such as alcoholic hallucinosis, have a deficiency of several vitamins and minerals and their bodies could cope with the withdrawal easier by taking nutritional supplements. Alcohol abuse can create a deficiency of thiamine, magnesium, zinc, folate and phosphate as well as cause low blood sugar. However, several tested drugs have shown the disappearance of hallucinations. Neuroleptics and benzodiazepines showed normalization. Common benzodiazepines are chlordiazepoxide and lorazepam. It has been shown that management has been effective with a combination of abstinence from alcohol and the use of neuroleptics. It is also possible to treat withdrawal before major symptoms start to happen in the body. Diazepam and chlordiazepoxide have proven to be effective in treating alcohol withdrawal symptoms such as alcoholic halluciniosis. With the help of these specific medications, the process of withdrawal is easier to go through, making alcoholic hallucinosis less likely to occur.

The cause of alcoholic hallucinosis is unclear. It seems to be highly related to the presence of dopamine in the limbic system with the possibility of other systems. There are many symptoms that could possibly occur before the hallucinations begin. Symptoms include headache, dizziness, irritability, insomnia, and indisposition. Typically, alcoholic hallucinosis has a sudden onset.

The symptoms of an opiate toxidrome include the classic triad of coma, pinpoint pupils, and respiratory depression as well as altered mental states, shock, pulmonary edema and unresponsiveness. Complications include bradycardia, hypotension, and hypothermia. Substances that may cause this toxidrome are opioids.

Pooled data suggest the incidence of NMS is between 0.2%–3.23%. However, more physician awareness coupled with increased use of atypical anti-psychotics have likely reduced the prevalence of NMS. Additionally, young males are particularly susceptible and the male:female ratio has been reported to be as high as 2:1.

One of the clearest risk factors in the development of NMS is the course of drug therapy chosen to treat a condition. Use of high-potency neuroleptics, a rapid increase in the dosage of neuroleptics, and use of long-acting forms of neuroleptics are all known to increase the risk of developing NMS.

It has been purported that there is a genetic risk factor for NMS, since identical twins have both presented with NMS in one case, and a mother and two of her daughters have presented with NMS in another case.

Demographically, it appears that males, especially those under forty, are at greatest risk for developing NMS, although it is unclear if the increased incidence is a result of greater neuroleptic use in men under forty. It has also been suggested that postpartum women may be at a greater risk for NMS.

An important risk factor for this condition is Lewy body dementia. These patients are extremely sensitive to neuroleptics. As a result, neuroleptics should be used cautiously in all cases of dementia.

One study from as early as 1895 reported that approximately 10% of the population experiences hallucinations. A 1996-1999 survey of over 13,000 people reported a much higher figure, with almost 39% of people reporting hallucinatory experiences, 27% of which daytime hallucinations, mostly outside the context of illness or drug use. From this survey, olfactory (smell) and gustatory (taste) hallucinations seem the most common in the general population.

The underlying neurophysiology and psychopathology of Cotard syndrome might be related to problems of delusional misidentification. Neurologically, the Cotard delusion (negation of the Self) is thought to be related to the Capgras delusion (people replaced by impostors); each type of delusion is thought to result from neural misfiring in the fusiform face area of the brain (which recognizes faces) and in the amygdalae (which associate emotions to a recognized face).

The neural disconnection creates in the patient a sense that the face they are observing is not the face of the person to whom it belongs; therefore, that face lacks the familiarity (recognition) normally associated with it. This results in derealization, or a disconnection from the environment. If the observed face is that of a person known to the patient, they experience that face as the face of an impostor (the Capgras delusion). If the patient sees their own face, they might perceive no association between the face and their own sense of Self—which results in the patient believing that they do not exist (the Cotard delusion).

Cotard's syndrome is usually encountered in people afflicted with a psychosis (e.g., schizophrenia ), neurological illness, mental illness, clinical depression, derealization, brain tumor, and with migraine headache. The medical literature indicate that the occurrence of Cotard's delusion is associated with lesions in the parietal lobe. As such, the Cotard-delusion patient presents a greater incidence of brain atrophy—especially of the median frontal lobe—than do the people in the control groups.

The Cotard delusion also has resulted from a patient's adverse physiological response to a drug (e.g., aciclovir) and to its prodrug precursor (e.g., valaciclovir). The occurrence of Cotard delusion symptoms was associated with a high serum-concentration of 9-Carboxymethoxymethylguanine (CMMG), the principal metabolite of the drug aciclovir. As such, the patient with weak kidneys (impaired renal function) continued risking the occurrence of delusional symptoms, despite the reduction of the dose of aciclovir. Hemodialysis resolved the patient's delusions (of negating the Self) within hours of treatment, which suggests that the occurrence of Cotard-delusion symptoms might not always be cause for psychiatric hospitalization of the patient.

Cocaine can be snorted, swallowed, injected, or smoked. Most deaths due to cocaine are accidental but may also be the result of body packing or stuffing with rupture in the gastrointestinal tract. Use of cocaine causes tachyarrhythmias and a marked elevation of blood pressure (hypertension), which can be life-threatening. This can lead to death from acute myocardial infarction, respiratory failure, stroke, cerebral hemorrhage, or heart failure. Cocaine overdose may result in hyperthermia as stimulation and increased muscular activity cause greater heat production. Heat loss is also inhibited by the cocaine-induced vasoconstriction. Cocaine and/or associated hyperthermia may cause muscle cell destruction (rhabdomyolysis) and myoglobinuria resulting in renal failure. Individuals with cocaine overdose should be transported immediately to the nearest emergency department, preferably by ambulance in case cardiac arrest occurs en route. According to the National Institute on Drug Abuse, approximately 5000 deaths occur annually in the US due to cocaine overdose.

Disorders that cause injury or damage to the brain and contribute to OBS include, but are not limited to:

- Alcoholism

- Alzheimer's Disease

- Attention deficit/hyperactivity disorder

- Autism

- Concussion

- Encephalitis

- Epilepsy

- Fetal alcohol syndrome

- Hypoxia

- Parkinson's disease

- Intoxication/overdose caused by drug abuse including alcoholism

- Sedative hypnotic dependence and drug abuse

- Intracranial hemorrhage/trauma

- Korsakoff Syndrome

- Mastocytosis

- Meningitis

- Psychoorganic syndrome

- Stroke/transient ischemic attack (TIA)

- Withdrawal from drugs, especially sedative hypnotics, e.g. alcohol or benzodiazepines

Other conditions that may be related to organic brain syndrome include: clinical depression, neuroses, and psychoses, which may occur simultaneously with the OBS.

Only 25% of people who experience seizures or status epilepticus have epilepsy. The following is a list of possible causes:

- Stroke

- Hemorrhage

- Intoxicants or adverse reactions to drugs

- Insufficient dosage or sudden withdrawal of a medication (especially anticonvulsants)

- Consumption of alcoholic beverages while on an anticonvulsant, or alcohol withdrawal

- Dieting or fasting while on an anticonvulsant

- Starting on a new medication that reduces the effectiveness of the anticonvulsant or changes drug metabolism, decreasing its half-life, leading to decreased blood concentrations

- Developing a resistance to an anticonvulsant already being used

- Gastroenteritis while on an anticonvulsant, where lower levels of anticonvulsant may exist in the bloodstream due to vomiting of gastric contents or reduced absorption due to mucosal edema

- Developing a new, unrelated condition in which seizures are coincidentally also a symptom, but are not controlled by an anticonvulsant already used

- Metabolic disturbances—such as affected kidney and liver

- Sleep deprivation of more than a short duration is often the cause of a (usually, but not always, temporary) loss of seizure control.

The article "Cotard's syndrome: A Review" (2010) reports successful pharmacological treatments (mono-therapeutic and multi-therapeutic) using antidepressant, antipsychotic, and mood stabilizing drugs; likewise, with the depressed patient, electroconvulsive therapy (ECT) is more effective than pharmacotherapy. Cotard syndrome resulting from an adverse drug reaction to valacyclovir is attributed to elevated serum concentration of one of valacyclovir's metabolites, 9-carboxymethoxymethylguanine (CMMG). Successful treatment warrants cessation of the drug, valacyclovir. Hemodialysis was associated with timely clearance of CMMG and resolution of symptoms.

There are symptoms that are mechanism-based that are associated with hallucinations. These include superficial pressure and stabbing pain. Others include a burning-like sensation or electric shock feeling. Human studies of these symptoms remain mostly unclear unlike similar studies in animals.

Tardive dysphrenia, was proposed by the American neurologist Stanley Fahn, the head of the Division of Movements Disorders of the Neurological Institute of New York, in collaboration with the psychiatrist David V Forrest in the 1970s.

It originally was linked to a unique, rare, behavioral/mental neuroleptic drug-induced tardive syndrome observed in psychiatric patients (schizophrenia in particular) treated with the typical antipsychotic drugs or neuroleptics. Tardive dysphrenia is one of many neuroleptic-induced tardive syndromes, including tardive dyskinesia and the other already-recognized tardive dystonia, and tardive akathisia.

More recently, the Brazilian psychiatrist Leopoldo Hugo Frota, Adjunct Professor of Psychiatry at Federal University of Rio de Janeiro, extended the original Fahn's construct to enclose the — independently described but etiologically related concepts of — rebound psychosis, supersensitivity psychosis (Guy Chouinard) and schizophrenia pseudo-refractoriness (Heinz Lehmann & Thomas Ban) or secondary acquired refractoriness.

There is some disagreement in the psychiatric community regarding the diagnosis of tardive dysphrenia. Therefore, the following description should be considered general and tentative.

The cause of all these syndromes was ascribed by Frota to an adaptative, but extreme and long-lasting up-regulation of the dopaminergic mesolimbic pathway D2-like receptor. He also emphasized the outstanding role of modern second-generation atypical antipsychotic drugs with predominant actions on the dopaminergic mesolimbic pathway differently from the typical ones, which act chiefly on the nigrostriatal pathway .