Etiology
Psychosis can occur in any individual, but the risk is increased in individuals with an underlying genetic predisposition and in those with damage to brain structures (e.g., through trauma, disease, or chemical or drug exposure). In some people, more than one risk factor may be present. For example, psychosis induced by use of illicit substances may occur in a patient with concurrent chronic schizophrenia. It is therefore important to consider the full range of possible etiologies.
Primary psychotic disorders
Primary psychotic disorders are common and include:
Schizophrenia
Schizoaffective disorder
Brief psychotic disorder
Schizophreniform disorder
Depression with psychotic features
Bipolar disorder
Delusional disorder.
These conditions are distinguished based on the presence of key positive or negative symptoms, the duration of symptoms, and the presence or absence of mood disturbances. Secondary causes must be excluded before psychosis can be attributed to a primary psychotic disorder.
Drug or toxin exposure
Over-the-counter drugs and supplements, prescription drugs, and recreational drugs may cause psychosis and other psychiatric symptoms.
Over-the-counter drugs
Examples of over-the-counter drugs that may cause psychosis include:
Antihistamines
St. John's wort
Dextromethorphan (cough suppressant)
Phenylpropanolamine (decongestant).
Psychosis usually occurs with chronic use of these drugs, or very high doses. Ephedra-containing herbal supplements, such as ma huang, can also trigger psychosis.
Prescription drugs
Prescription drugs that can trigger psychosis include:
Adrenergics (stimulants, propranolol, and clonidine)
Anticholinergics
Corticosteroids
Dopamine agonists
Thyroid hormones.
Psychosis is a rare and relatively idiosyncratic adverse effect of many other medications. These include isotretinoin, indomethacin, several antibiotics, and antiviral drugs.
Recreational drugs
Psychosis may be induced by intoxication with recreational drugs, such as:
Alcohol[12]
Amphetamines
Cannabis
Cocaine
Inhalants (solvents, aerosols, gases, nitrites)
Phencyclidine.
Cannabis use is a risk factor for development of a persistent psychotic disorder.[13] This occurs in a dose-related fashion, increasing the risk by two to six times for patients without other risk factors.[14] Cannabis use by age 15 years has been shown to increase the risk of developing schizophreniform disorder.[15] Cannabis use can also cause a psychosis of short duration. Paradoxically, patients with psychotic disorders may use cannabis as a way to temporarily relieve anxiety and distress associated with their symptoms. However, there is a clear relationship between cannabis use and psychotic relapse.[16][17][18] Withdrawal syndromes, such as from benzodiazepines, barbiturates, and alcohol, may also include psychosis.
Heavy metal exposure
Heavy metal exposure causes a wide range of psychiatric and physical (cardiovascular, renal, reproductive, gastrointestinal, neurologic) sequelae. The most common heavy metals responsible for toxic exposures in the US are arsenic, mercury, and lead. Any of these can cause psychosis as a rare symptom.
Ingestion of arsenic-containing ant killer, and industrial (glass and semiconductors production, wood preservation) and agricultural contamination, are important sources of arsenic exposure in the US. Arsenic found in seafood (organic) has low toxicity to humans and is rapidly excreted in urine. Wine made from grapes sprayed with arsenic-containing pesticides may have appreciable levels of toxic inorganic arsenic. Arsenic poisoning through contaminated well-water is common in Bangladesh and contiguous areas of the Indian subcontinent.[19]
Occupational lead exposure may occur in welders, glassmakers, and scrap-metal workers. Parents employed in these occupations may bring lead dust home on their clothes, thereby exposing family members as well. Hobbies associated with possible lead exposure include bullet-making, indoor firearm shooting, fishing-weight manufacture, soldering (stained glass), and remodeling of older homes.
All forms of mercury are toxic, but organic forms are more toxic to the central nervous system than inorganic forms. Exposure occurs through eating contaminated fish and is a risk in a wide range of industries (e.g., automotive industry, paper mills, battery manufacture, farming, and jewelry making).
Organophosphate exposure
Organophosphates are a large group of chemicals used in both household and industrial settings that sometimes induce psychosis. These chemicals are used in insecticides, herbicides, and ophthalmic agents. The precise symptoms of toxicity depend on the specific chemical.
Neurologic disorders
Insults to the central nervous system can lead to a range of psychiatric symptoms, including psychosis. Causes include:
Epilepsy
Traumatic brain injury
Multiple sclerosis
Brain tumors
Dementia
Stroke.
Patients with epilepsy have an almost eight-fold risk of psychosis.[20] Epilepsy-associated psychosis is classified according to the time of onset in relation to seizures. Symptoms are classified as:
Ictal (occurring during seizure activity)
Postictal (occurring within 7 days of a seizure)
Interictal (occurring independently of seizures).
Interictal psychosis is associated with small gangliogliomas and hamartomas. 'Alternative psychosis' refers to a situation in which psychotic symptoms occur following suppression of seizure activity, due to antiepileptic drug treatment or after epilepsy surgery. In these patients (generally people with long-standing epilepsy), psychotic symptoms are inversely related to the occurrence of seizures.[21]
Psychosis secondary to traumatic brain injury is usually associated with a moderate to severe brain injury or multiple mild brain injuries. The onset of psychosis may be acute (e.g., secondary to a subdural hematoma) or may occur years after the head trauma.[4]
Multiple sclerosis is a common neurologic condition affecting 1 in 700 people in the US. It usually begins in adults in their 30s but can present at any time from childhood to the age of 50 to 60 years. Psychosis occurs in around 5% of patients with multiple sclerosis, possibly due to temporal lobe lesions.[22]
Dementias (Alzheimer, Parkinson, Huntington, vascular dementia, Lewy body dementia) should be considered when new-onset psychosis occurs in older people and/or those with cognitive impairment. It is often associated with classic symptoms specific to the disorder, such as memory loss, tremor, or chorea.
Intracranial tumors are rare causes of psychosis, however, they should be included in the differential diagnosis as they may be treatable if identified early. An intracranial tumor should be considered when other neurologic features such as seizures, headaches, and focal neurologic deficits (e.g., arm or leg weakness, or vision loss) are present. Patients often have subtle symptoms for a long period before the tumor is diagnosed. Cases of persistent psychosis as a delayed result of childhood intracranial tumors have also been reported.[23]
Approximately 7% of patients develop new onset psychotic symptoms following a stroke.[24][25] There may be a delayed onset of psychotic symptoms and patients are most likely to develop a delusional disorder. Psychosis may occur more often in people with right frontoparietal lesions and subcortical atrophy and may be associated with seizures.[26]
Infection
Psychosis can be a manifestation of encephalitis. Encephalitis can be broadly grouped into autoimmune encephalitis and infectious encephalitis.
Infectious encephalitis is typically caused by viral infection (particularly herpes simplex virus [HSV]-1). Causes include:
Herpes viruses (e.g., HSV-1, HSV-2, varicella zoster virus, cytomegalovirus, Epstein-Barr virus)
HIV
Measles
Mumps
Rabies.
Other causes of infectious encephalitis include:
Bacteria (e.g., the spirochete Treponema pallidum, causing neurosyphilis, Neisseria meningitidis, and Mycoplasma)
Parasites (e.g., malaria, the tapeworm Taenia solium [neurocysticercosis])
Prion diseases (e.g., Creutzfeldt-Jakob disease)
Fungi (e.g., cryptococcosis).
Autoimmune encephalitis may be antibody-mediated, paraneoplastic or associated with another autoimmune disease (e.g., systemic lupus erythematosus).[27] See section on “Autoimmune disorders” below.
Delirium
Delirium (also called 'acute confusional state’) is a common syndrome characterized by disturbed consciousness, impaired cognitive function and perception, including auditory and visual hallucinations, and a fluctuating course. Psychosis is a common feature. Delirium is often reversible but carries a high morbidity and mortality. Delirium most often occurs in older patients and those with pre-existing medical disorders. The range of causes is wide and includes hypoxia, hypoglycemia, hyperthermia, anticholinergic toxicity, alcohol withdrawal, sepsis, metabolic disorders, neurologic disorders, adverse drug reactions, and postoperative states. See Evaluation of Delirium.
Vitamin deficiency
Vitamin deficiencies that may be associated with psychosis include:[28][29][30][31]
Folate (vitamin B9) deficiency
Cobalamin (vitamin B12) deficiency
Niacin (vitamin B3) deficiency
Thiamine (vitamin B1) deficiency.
Folate deficiency is the most common vitamin deficiency in North America and Western Europe, and most frequently results from alcohol misuse. Folate deficiency may cause psychosis but is more often associated with depression. People with an inborn error of folate metabolism (hyperhomocysteinemia) may also present with psychotic symptoms, accompanied by neurologic signs.
Vitamin B12 deficiency can cause psychosis as well as a number of psychiatric symptoms. Associated features of B12 deficiency include anemia (pernicious anemia), peripheral neuropathy, weakness, and decreased positional and vibration sense. Severe and long-standing deficiency will lead to degeneration of spinal cord and brain white matter (subacute combined degeneration). The psychiatric symptoms may include both acute and chronic psychosis, along with delirium, cognitive impairment, and mood or personality changes. Vitamin B12 deficiency usually occurs due to inadequate absorption, but deficiency can develop in people adhering to a vegan diet who do not take vitamin supplements.
Niacin deficiency may cause psychosis, accompanied by memory impairment, disorientation, confusion and confabulation, depression, mania, or delirium. This deficiency may be due to malnutrition, cirrhosis, chronic diarrhea, or pyridoxine-inactivating drugs (e.g., anticonvulsants, isoniazid, cycloserine, corticosteroids, or penicillamine). Skin, mucous membrane, and gastrointestinal effects are common.
Chronic thiamine deficiency, a result of chronic high alcohol intake, may cause Korsakoff psychosis. Symptoms include memory loss, confusion, amnesia, personality change, and confabulation and may accompany Wernicke encephalopathy, which is characterized by confusion, ataxia, and oculomotor dysfunction (nystagmus and ophthalmoplegia). Diagnosis is based on a history of chronic alcohol misuse and favorable response to treatment with thiamine.
Endocrine disorders
Endocrine causes of psychosis include:[32][33][34][35][36][37]
Cushing syndrome
Hyperparathyroidism
Thymoma
Thyroid dysfunction.
Hypercortisolism, which is due to various causes, including Cushing syndrome disease and exogenous corticosteroids, can also cause psychosis.
Hyperparathyroidism, caused by tumors of the parathyroid glands, is another rare cause of psychosis. Symptoms of weakness and depression are also present and are usually long-standing.
Thymoma, a tumor of the thymus gland, is frequently associated with paraneoplastic diseases. It rarely causes hallucinations, deja vu, altered consciousness, and changes in taste and smell.
Hyperthyroidism may rarely cause an affective psychosis, with either depressive or manic components. Appropriate medical or surgical treatment of the hyperthyroid state will usually lead to resolution of the psychosis.
Hypothyroidism may cause a range of psychiatric symptoms. The most common symptom is depression but memory impairment, decreased attentiveness, apathy, and psychosis can occur. Hypothyroidism is rare in adolescents, but when it occurs it is more frequently associated with hallucinations, seizures, and confusion.
Autoimmune disorders
People with certain autoimmune diseases, including thyrotoxicosis, celiac disease, intestinal malabsorption, acquired hemolytic anemia, chronic active hepatitis, interstitial cystitis, alopecia areata, myositis, polymyalgia rheumatica, and Sjogren syndrome, are at an approximately 45% increased risk of developing a chronic psychotic disorder compared with the general population. It is unclear whether there is a shared underlying biologic vulnerability or whether psychosis is a symptom of the autoimmune disorder.[38]
Autoantibodies directed against neuronal surface and synaptic proteins can result in autoimmune encephalitis.[39] Although potentially fatal, patients often respond to immunotherapy if treated early.[40] Autoimmune encephalitis is most commonly caused by antibodies to the N-methyl-D-aspartate receptor (NMDAR).[41] It predominantly affects young female adults, and around 20% of cases are associated with ovarian teratomas.[40] The clinical syndrome is multi-stage, with prominent psychiatric symptoms early on and cognitive impairment, seizures, abnormal movements and reduced levels of consciousness emerging later. Psychosis is the most common psychiatric symptom and patients often present to mental health services initially. Autoantibodies against LGI1, CASPR2, and AMPAR antigens can also cause autoimmune encephalitis associated with psychotic symptoms, amongst others. Over 25 different autoantibodies have been identified which can cause autoimmune encephalitis, and autoantibodies continue to be discovered.[42] International consensus guidelines for the diagnosis of autoimmune encephalitis, and the diagnosis and management of autoimmune psychosis, have been published.[43][44]
Lupus cerebritis causes inflammation of the brain, leading to headache, seizure, stroke, and, rarely, psychosis. Psychosis occurs in <3% of people with systemic lupus erythematosus (SLE), and tends to present early in the course of the disease. Additionally, corticosteroids used to treat SLE may cause psychosis.[45]
Metabolic disorders
Psychosis is associated with:
Wilson disease
Lysosome storage diseases
Homocystinuria
Acute hepatic porphyria
Metachromatic leukodystrophy.
Wilson disease is an inherited disorder in which excessive amounts of copper accumulate in the body. Although the accumulation of copper begins at birth, symptoms appear later in life, between the ages of 6 and 40 years. Although the primary symptom for about 40% of patients is liver disease, many patients initially develop either neurologic or psychiatric symptoms, or both. Psychiatric symptoms may resemble the onset of psychosis, alongside personality change, inappropriate behavior, and deterioration of school/work performance.
Niemann-Pick diseases, one of a group of lysosome storage diseases affecting metabolism, are caused by autosomal recessive mutations. Niemann-Pick disease type C (NPC) is an extremely rare disorder (affecting 1:150,000 people), for which there are a few published cases of psychosis. Niemann-Pick disease may only be recognized with emerging features of dementia, ataxia, dysarthria, and vertical supranuclear ophthalmoplegia.
Tay-Sachs disease (TSD) is another lysosome storage disorder, with an autosomal recessive inheritance pattern. The late-onset form is rare, occurring at the age of 20 to 40 years, with symptoms of speech and swallowing difficulties, unsteadiness of gait, spasticity, cognitive decline, and psychiatric illness. Psychosis is present in 30% to 50% of adult-onset cases. In populations of Ashkenazi Jewish, French Canadian, and Cajun descent, the carrier rate for TSD may be as high as 1 in 30, as opposed to 1 in 300 in the general population.[46]
Fabry disease is an X-linked recessive lysosomal storage disease, caused by a deficiency of the enzyme needed to metabolize lipids. The deficiency leads to a harmful buildup of lipids in skin, eyes, kidney, and heart. Depression is common and psychosis is rare. If there is high suspicion of this disorder due to family history, confirmation by assay for the alpha-galactosidase enzyme in plasma or serum is possible.
Homocystinuria may be caused by a rare autosomal recessive disorder of methionine metabolism (affecting 1 in 200,000 people). Typical symptoms are developmental delay, dislocation of the lens and/or severe myopia, skeletal abnormalities, and thromboembolism. About half of affected patients have psychiatric illness with psychosis as a common feature. Quantitative tests for homocysteine in urine and blood are available commercially. Molecular genetic testing is clinically available.[47]
Acute hepatic porphyria (1 in 100,000 adults) is characterized by psychosis, seizures, extreme back and abdominal pain, and acute polyneuropathy.
Metachromatic leukodystrophy is a rare autosomal recessive disorder (1 in 40,000) causing demyelination of the central and peripheral nervous systems. When symptoms begin in late adolescence or adulthood they are predominantly psychiatric, including auditory hallucinations and bizarre delusions in 50% of patients. Other symptoms include gait disturbance and peripheral neuropathy. The diagnosis may be made if arylsulfatase A enzyme activity is decreased in WBCs or cultured skin fibroblasts.[48]
There are a variety of case reports associating other rare genetic/metabolic disorders with psychosis. These disorders include glucose-6-phosphate dehydrogenase deficiency, Kartagener syndrome, and albinism. However, there is no good evidence of a causal relationship, and psychosis is not a common symptom. Thus, a workup for these disorders for a new presentation of psychosis is not warranted without other reasons to suspect the disorder.
Chromosomal disorders
Chromosomal disorders associated with psychosis include:
Klinefelter syndrome
22q11.2 deletion syndrome (velocardiofacial syndrome, DiGeorge syndrome)
Prader-Willi syndrome.
Klinefelter syndrome (XXY) occurs in up to 1 in 400 men and has some evidence for increased risk of psychosis, although a population study disputes this.[49][50] It is unclear whether XO (Turner syndrome) has increased risk of psychosis.
22q11.2 deletion syndrome (DiGeorge syndrome) affects an estimated 1 in 4000 births. The condition may be more common, because some people with the deletion have few signs and symptoms and may be undiagnosed. Almost all cases (between 78% and 93% of cases) have a de novo deletion of 22q11.2; others inherit the 22q11.2 deletion from a parent in an autosomal dominant manner. Psychosis is common, occurring in 10% to 30% of people, and accompanies a range of symptoms, including congenital heart disease (74%), palatal abnormalities (69%), learning difficulties (70% to 90%), hearing loss, seizures, skeletal abnormalities, and renal abnormalities. A molecular cytogenetic test confirms the diagnosis.
Prader-Willi syndrome (1 in 10,000 to 20,000 children) is caused by missing or inactive genes on chromosome 15. Psychotic symptoms are strongly associated with a subtype in which there are two maternal copies of chromosome 15. Prader-Willi syndrome is often diagnosed in infancy or early childhood because of hypotonicity, delayed developmental milestones, and insatiable appetite, leading to obesity.
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