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Evidence-Based Reviews

Psychosis: 6 steps rule out medical causes in kids

Time-saving algorithm combines efficiency with a thorough evaluation.

Vol. 5, No. 2 / February 2006

John, age 16, is admitted to our inpatient psychiatric unit, complaining of “a 2-week constant headache” caused by “voices arguing in my head.” He has lived in Mexico with an uncle for 6 months but returned home last week for medical evaluation of his headaches.

His parents report that John developed normally until 3 years ago, when he gradually lost interest in his favorite activities and became socially withdrawn. He has not attended school in 2 years. He has no history of illicit drug use and is not taking prescription or over the-counter medications.

Complete physical examination, neurologic exam, and routine screening lab test results are normal. Thinking that a high lead content of cookware used in Mexico might be causing John’s symptoms, we order a lead level: result-0.2 mg/dL (<10 mg/dL is normal for adolescents). We do no additional diagnostic tests—such as an EEG, CT, or MRI—because John’s clinical presentation does not suggest a specific medical condition that could be causing or exacerbating his psychotic symptoms.

We diagnose schizophreniform disorder, but John’s parents refuse to accept this diagnosis. They repeatedly ask if we can do more to identify a medical cause of their son’s psychiatric symptoms.

As in John’s case, young patients or their parents may resist the diagnosis of a chronic mental illness such as schizophrenia. Understandably, they may be invested in trying to identify “medically treatable” causes. You can address their anxieties by showing them that you have systematically evaluated medical causes of psychosis.

We offer such a tool: an algorithm and tables to help you identify common and rare medical conditions that may cause or exacerbate psychotic symptoms in patients ages 3 to 18.

An evidence-based algorithm

Multiple factors—developmental, psychological, family, environmental, or medical—typically cause psychotic symptoms in a child or adolescent. Evaluating all possibilities is essential, but guidelines tend to minimize medical causes. American Academy of Child and Adolescent Psychiatry guidelines, for example, recommend that “all medical disorders (including general medical conditions and substance-induced disorders) are ruled out,”1 but they do not specify which medical conditions to consider.

To supplement existing guidelines, we searched the literature and developed an evidence-based algorithm to help you systematically consider medical causes of pediatric psychotic symptoms. We excluded children age <3 because determining conclusively that a 2-year-old is experiencing “psychotic symptoms” is very difficult.2

How to use it. The algorithm walks you through a medical systems review. You begin with a complete history, then address six causes of psychotic symptoms: substance abuse, medication reactions, general medical conditions, unexplained somatic symptoms (such as from toxic environmental exposures), developmental and learning disabilities, and atypical presentations.

Don’t stop if you find one possible cause of psychotic symptoms; continue to the end of the algorithm. The more factors you identify, the greater your chance of finding a treatable cause that may ameliorate your patient’s symptoms.

To make the algorithm clinically useful, we listed conditions in order of decreasing probability of causing psychotic symptoms. For example, the first cause listed is substance-induced disorders,3 which are most common among adolescent patients. We also “triaged” medical conditions from common to rare (based on estimated prevalence of association with psychotic symptoms), listing rare causes only in cases of atypical presentation or treatment resistance.

Supporting tables. The following discussion summarizes data that support the algorithm and its tables:

  • medications reported to cause psychosis (Table 1)
  • medical conditions most likely to cause psychosis (Table 2)
  • medical conditions that rarely cause psychosis (Table 3).

Table 1

Drugs that may cause psychotic symptoms

Drug class

Psychotic symptoms

Bizarre behavior/delusions

Auditory or visual hallucinations

Amphetamine-like drugs



Anabolic steroids



Angiotensin-converting enzyme (ACE) inhibitors



Anticholinergics and atropine



Antidepressants, tricyclic












Beta-adrenergic blockers



Calcium channel blockers









Dopamine receptor agonists



Fluoroquinolone antibiotics



Histamine H1 receptor blockers



Histamine H2 receptor blockers



HMG-CoA reductase inhibitors



Nonsteroidal anti-inflammatory drugs






Procaine derivatives (procainamide, procaine penicillin G)






Selective serotonin reuptake inhibitors






Source: Adapted from reference 10.

Table 2

Common medical conditions that may cause pediatric psychosis symptoms*


Conditions not to forget

Common symptoms/comments


Lupus erythematosus

Joint pain, fever, facial butterfly rash, prolonged fatigue


Viral encephalitis

Fever, headache, mental status change; may occur in perinatal period


Multiple sclerosis

Varied neurologic deficits, especially ophthalmologic changes and weakness



Personality change, ataxia, stroke, ophthalmic symptoms


Seizure (temporal lobe epilepsy, interictal psychosis)

Paroxysmal periods of sudden change in mood, behavior, or motor activity with or without loss of consciousness


Carbon monoxide poisoning

Shortness of breath, mild nausea, headache, dizziness

* Clinically significant symptoms that meet DSM-IV-TR criteria for a primary psychiatric disorder.

Click here to view citations supporting statements in this table

Table 3

Medical conditions that rarely cause pediatric psychosis symptoms*





Tachycardia, weight loss, excessive sweating, tiredness, inability to sleep, diarrhea, shakiness, muscle weakness

Thymoma/myasthenia gravis

Shortness of breath, swelling of face, muscle weakness (especially around eyes)


Porphyria (acute intermittent porphyria, porphyria variegate)

Intermittent abdominal pain (severe) accompanied by dark urine


Fabry’s disease

Burning sensations in hands and feet that worsen with exercise and hot weather

Niemann-Pick disease, type C

Vertical gaze palsy, hepatosplenomegaly, jaundice, ataxia

Prader-Willi syndrome

Obesity, hyperphagia, mild to moderate mental retardation, hypogonadism, tantrums, obsessive-compulsive disorder


Epstein-Barr virus

Fever, sore throat, adenopathy, fatigue, poor concentration

Lyme disease

Target lesion, fever; high-risk geographic area

Malaria/typhoid fever

Fever, mental status change; endemic area

Mycoplasma pneumonia

Fever, mental status change; may occur in absence of pneumonia


History of exposure



Mental status change, high plasma citrulline and ammonia

Tay-Sachs disease

Unsteadiness of gait and progressive neurologic deterioration


Dislocated lenses, blood clots, tall stature, some mental retardation

Juvenile metachromatic leukodystrophy

Cognitive decline, ataxia, pyramidal signs, peripheral neuropathy, dystonia; 60% of cases present before age 3


Central pontine myelinolysis

Suspect in patient with pathogenic polydipsia

Huntington’s disease

Chorea, myoclonic seizures, poor coordination, emotional lability

Moyamoya disease

Paresis, syncopal episodes


Excessive daytime sleepiness, cataplexy

Subacute sclerosing panencephalitis

Visual hallucinations, loss of developmental milestones

Traumatic brain injury

Occurring 4 to 5 years after a loss of consciousness >30 minutes

Wilson’s disease

Tremors, muscle spasticity, possible liver inflammation


Pellagra (vitamin B6 deficiency)

Redness, swelling of mouth and tongue, diarrhea, rash, abnormal mental functioning; seen with isoniazid treatment for tuberculosis


Cancers (pancreatic, CNS papilloma, germinoma)

Postural headache, neurologic signs, increased intracranial pressure, early morning nausea, vomiting


Lead intoxication

Headache, fatigue, mental status change

Mercury poisoning

Abdominal pain, bleeding gums, metallic taste; history of exposure

* Clinically significant symptoms that meet DSM-IV-TR criteria for a primary psychiatric disorder.

Click here to view citations supporting statements in this table

Substance abuse

Substance abuse is common among adolescents and adults with psychotic illnesses.4 Drug-induced states can cause delusions, hallucinations, paranoia, and disorganized behavior,5 which are reported most commonly during intoxication and withdrawal.6 Diagnosis is often straightforward because of the temporal association between the substance abuse and onset of psychotic symptoms.

Little evidence supports a causal relationship between drug use and the development of chronic psychotic symptoms, however. Case reports link use of 3,4-methylenedioxymethamphetamine (“Ecstasy”), lysergic acid diethylamide (LSD), and marijuana to chronic schizophrenia-like symptoms.7 The strongest evidence links long-term methamphetamine and cocaine use to chronic psychotic symptoms.8,9


Side effects of at least 25 drug classes have been reported to mimic psychosis (Table 1),10 but little is known about the incidence and prevalence of this problem. Case reports and chart reviews provide the only data that associate most medications with psychotic symptoms. These disagree on what defines a “psychotic symptom,” and most fail to rule out delirium as a possible cause.

The relationship between glucocorticosteroids and psychotic symptoms has been studied extensively. A clear link has been found between corticosteroids at dosages >40 mg/d and a markedly elevated risk for transient psychotic symptoms.11

Medical conditions

We identified 27 medical conditions that may cause or worsen clinical symptoms of psychosis (Tables 2 and 3) by searching PubMed, psychiatric journals, and neuropsychiatry and consult-liaison textbooks. We included only conditions:

  • shown to cause significant morbidity in pediatric populations
  • shown to have a statistically significant association with psychotic symptoms, or patients’ symptoms consistently resolved when the condition was treated.

Neurologic conditions. Many neurologic conditions had been reported to cause psychotic symptoms,12 but only four met at least one of our inclusion criteria. Psychotic symptoms are statistically associated with epilepsy,13 Huntington’s disease,14 and Wilson’s disease;15 psychotic symptoms associated with multiple sclerosis resolve when the underlying medical condition is treated.16

Endocrine disorders. Behavioral disturbances (including psychosis) may be the earliest manifestation of an endocrine disorder.17 Cushing’s syndrome,18 hyperthyroidism,19 and hypothyroidism20—met our inclusion criteria.

Cushing’s syndrome—caused by long-term systemic glucocorticoids and thyroid disorders—is not uncommon in children and adolescents but rarely presents with psychotic behaviors. For each endocrine disorder we included, however, at least one case report described delayed diagnosis because of prominent psychosis. Treating the endocrinopathies resolved the psychotic symptoms.

Genetic disorders. Genetically determined neurodevelopmental disorders usually present in very young children, but some may appear later. Genetic conditions that co-occur with psychotic symptoms at rates significantly greater than the population prevalence include Prader-Willi syndrome,21 metachromatic leukodystrophy,22 Turner’s syndrome,21 velocardiofacial syndrome,23 and Wilson’s disease.15

Acute intermittent porphyria, GM2 gangliosidosis (Tay-Sachs disease), and homocystinuria are rare conditions with unknown prevalence in patients with psychotic disorders. Still, they are important to consider when evaluating youths with psychosis because case reports link their treatment with psychotic symptom resolution.24-26

Infectious disease. An infectious CNS disease does not usually present with psychotic symptoms only. When this does happen, making the correct diagnosis as soon as possible is critical because early treatment is associated with better outcomes.27 Misdiagnosis as a primary psychotic disorder may expose a patient to psychotropics that may adversely affect clinical outcome.

Viruses that affect the CNS (viral encephalopathies) are the infections most likely to cause psychotic symptoms. By decreasing frequency, they are human simian virus, HIV, influenza, measles, Epstein-Barr virus, mumps, and rabies.27,28 Bacterial infections that cause psychosis include mycoplasma pneumonia,29 syphilis,30 typhoid fever,31 and Lyme disease.32

Brain tumor. Childhood brain tumors often present with behavioral symptoms associated with headache, vomiting, visual changes, and motor and cognitive symptoms. A CNS tumor rarely presents with isolated neuropsychiatric symptoms.33 A few case reports describe intracranial tumors initially misdiagnosed as primary psychotic illness because of prominent psychotic symptoms.34,35 In each case, these symptoms resolved with tumor resection.

A temporal relationship does not necessarily equate to a “causal” relationship, however. Tatter et al36 describe a case of “reoccurrence” of manic symptoms initially thought to be caused by an arteriovenous malformation (AVM) 10 years after the AVM was successfully removed. The important point is that, although rarely, pediatric brain tumor can present with prominent psychotic symptoms.

Environmental toxin exposure may cause well-defined psychiatric syndromes,37 although frank psychosis is uncommon at presentation. Most often, environmental toxins produce an encephalopathic process of which psychosis may be one symptom. A few toxic exposures—such as lead,38 carbon monoxide,39 and elemental mercury40 —have presented with prominent psychotic symptoms without other encephalopathic symptoms.

Collagen vascular disease is associated with significantly elevated rates of psychiatric illness, especially depression, but only systemic lupus erythematosus (SLE) is known to be associated with prominent psychosis. Case series report delayed SLE diagnosis in patients with this presentation.41

High-dose pulse corticosteroids have been reported to effectively treat SLE-related psychotic symptoms,42 although high-dose corticosteroids can also cause psychotic symptoms. The timing and character of the symptoms can help you determine whether using corticosteroids is helping or making the patient worse.

Using the algorithm

John’s mother and father fear that the inpatient team’s diagnosis of a primary psychotic disorder means that a medical cause has been permanently “ruled out.” To reassure them, we use the algorithm to explain in concrete terms the thought process that led us to John’s psychiatric diagnosis. We walk them through the algorithm and its tables, explaining how we used evidence to rationally rule out all known medical causes of psychotic symptoms in pediatric patients.

John’s parents are relieved to know that the case is not closed, even though we found no medical cause for their son’s condition. If more clinical data become available, we remain open to considering the possibility that medical conditions could be causing or worsening their son’s symptoms.

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