eMedicine Specialties > Psychiatry > Adult

Schizophrenia: Differential Diagnoses & Workup

Author: Frances R Frankenburg, MD, Associate Professor, Department of Psychiatry, Boston University School of Medicine; Chief of Inpatient Psychiatry and Consulting Psychiatrist, Edith Nourse Rogers Memorial Veterans Administration Medical Center; Associate Psychiatrist, McLean Hospital
Contributor Information and Disclosures

Updated: Sep 10, 2009

Differential Diagnoses

Other Problems to Be Considered

Other psychiatric illnesses

• Bipolar disorder: Schizophrenia and bipolar affective disorder (manic-depressive illness) may be difficult to distinguish from each other. Patients with manic-depressive illness predominantly have disturbances in their affect or mood. Psychotic symptoms may be prominent during a mania or depression. In classic manic-depressive illness, the psychotic symptoms are congruent with mania or depression, and the person has periods of euthymia (normal mood) with no psychotic symptoms between the episodes. However, some patients have, in the absence of depression or mania, periods of psychotic symptoms. The diagnosis of schizoaffective disorder is used in these cases.
• Delusional disorder: In this disorder, the person has a variety of paranoid beliefs, but these beliefs are not bizarre and are not accompanied by any other symptoms of schizophrenia. For example, a person who is functioning well at work but becomes unreasonably convinced that his or her spouse is having an affair has a delusional disorder rather than schizophrenia.
• Schizotypal personality disorder: In this personality disorder, a pervasive pattern of discomfort in close relationships with others exists, and odd thoughts and behaviors occur. The oddness in this disorder is not as extreme as that observed in schizophrenia.
• Schizoid personality disorder: In this personality disorder, the person has difficulty and lack of interest in forming close relationships with others and prefers solitary activities. No other symptoms of schizophrenia are present.
• Paranoid personality disorder: In this personality disorder, the person is distrustful and suspicious of others. No actual delusions or other symptoms of schizophrenia are present.

Medical illnesses

• Anatomic lesions
  • Brain tumors: Patients with these conditions rarely initially present with psychosis. But brain tumors have no predictable set of symptoms. Because brain tumors can be treated and can be lethal, it is important to consider brain imaging studies for every person with a new onset of a psychotic illness or, perhaps, a marked change in symptomatology.
  • Idiopathic calcification of the basal ganglia: This is a rare disorder in which patients may present early in adulthood with psychosis.¹⁴
  • Intracranial bleeds: Patients who report head trauma or who, for whatever reason, are not able to provide a clear history, probably should have brain imaging performed to rule out subdural hematomas, which can manifest as changes in mental status.

• Wilson disease: This illness, also known as hepatolenticular degeneration, is a disorder of the metabolism of copper. It is an autosomal recessive illness, the gene for which has been located on chromosome 13. The first symptoms are often vague changes in behavior during adolescence, followed by the appearance of odd movements. The diagnosis can be indicated by the laboratory findings of increased urinary copper levels and low levels of serum copper and ceruloplasmin or the detection of Kayser-Fleischer rings (copper deposits around the cornea) with or without a slit-lamp examination. The diagnosis is usually confirmed by finding increased hepatic copper at biopsy.
  
  The diagnosis can be quite difficult to make because not all patients with Wilson disease have low serum ceruloplasmin or Kayser-Fleischer rings, the 2 findings most commonly associated with this disorder. Because the treatment of this disease is also difficult, some experts recommend liver biopsy so that a tissue diagnosis may be made before chelating therapy is started. This is an important diagnosis to make because of the existence of a very specific treatment.
• Porphyria: Patients with this disorder of heme biosynthesis can present with psychiatric symptoms. There may be a family history of psychosis. The psychiatric symptoms may be associated with electrolyte changes, peripheral neuropathy, and episodic severe abdominal pain. Abnormally high levels of porphyrins in 24-hour urine collections confirm the diagnosis.
• Other metabolic disturbances: Patients with hypoxemia or electrolyte disturbances may present with confusion and psychotic symptoms. A hypoglycemic person is particularly likely to be confused, irritable, and mistaken for a person who is psychotic.
• Delirium: Delirium, from whatever cause (eg, metabolic or endocrine disorders), is an important condition to consider, especially in the elderly or hospitalized person.

Endocrine disorders

• Thyroid dysfunction: Severe hypothyroidism or hyperthyroidism can be associated with psychotic symptoms. Hypothyroidism is usually associated with depression. If the depression is severe, associated psychotic symptoms may exist. A hyperthyroid person is typically depressed, anxious and irritable. In infrequent cases, the presentation may be confused with schizophrenia.
• Adrenal dysfunction: Mental status changes may occur in hypoadrenalism (Addison disease) and hyperadrenalism (Cushing disease). Artificially induced hyperadrenalism, as when patients are treated with high doses of steroids for medical illnesses, is associated with changes in mental status.
• Parathyroid dysfunction: Hypoparathyroidism or hyperparathyroidism with changes in calcium can on occasion be associated with vague mental status changes.

• Neurosyphilis: This can be divided into meningovascular syphilis, tabes dorsalis, or general paresis. Patients with general paresis may present with behavioral changes, psychosis or dementia. The diagnosis can be suggested by a history of exposure, personality changes, and pupillary changes such as the Argyll Robertson pupil. The Venereal Disease Research Laboratory (VDRL) and rapid plasma reagin (RPR) tests are nontreponemal tests that use antigens to detect antibodies to Treponema pallidum. Antibodies decline during the disease, so these tests have a high false-negative rate. If neurosyphilis is strongly suspected, the more specific treponemal tests, such as the fluorescent-treponemal antibody absorption test (FTA-ABS) can be useful.
• HIV: HIV penetrates the blood-brain barrier early in the course of HIV infection, so HIV infection is associated with a number of mental status changes, particularly dementia or other neuropsychological impairment. Patients with HIV are at risk for opportunistic infections, such as neurosyphilis, toxoplasmosis, cryptococcal meningitis, progressive multifocal leukoencephalopathy, cytomegalovirus encephalopathy, and tuberculous meningitis, all of which can lead to altered mentation. Persons infected with HIV are also at risk for primary central nervous system lymphoma and may present with vague symptoms such as confusion and memory loss. Many drugs used to treat HIV may cause mental status changes. Finally, persons infected with HIV are at risk for nutritional deficiencies that also contribute to mental status changes.
• Cerebral abscess: Patients with cerebral abscesses rarely initially present with psychosis, but brain imaging should be considered to rule out this treatable possibility. Immunosuppressed or persons living in or traveling in underdeveloped countries are particularly at risk.
• Creutzfeldt-Jakob disease: Prions cause the rare Creutzfeldt-Jakob disease (CJD), one of the transmissible spongiform encephalopathies. The disease usually occurs in people older than 50 years and is marked by rapid deterioration, dementia, abnormal EEG complexes, and myoclonic jerks. A variant of this illness, vCJD, is the human form of mad cow disease, bovine spongiform encephalopathy. Fewer than 200 cases of vCJD have occurred worldwide, and only 2 cases have occurred in the United States (as of 2003). Unlike CJD, this disease seems to affect people aged 20-40 years. The illness is much longer lasting than CJD and begins with behavioral changes. In several cases, the person was diagnosed with schizophrenia before the diagnosis of vCJD was made.

• Multiple sclerosis: This illness is notoriously difficult to diagnose in its early stages. The physical symptoms can be overlooked, and psychological symptoms may occasionally be the presenting feature.
• Huntington disease: In this neurodegenerative disorder, neuronal loss throughout the brain occurs, especially in the striatum. This is an autosomal dominant disorder, the gene for which has been located on chromosome 4. Family history is essential to making the diagnosis, but it can be misleading. The occurrence of choreoathetoid movements well before exposure to antipsychotic agents is suggestive of Huntington disease. About three fourths of patients with Huntington disease initially present with psychiatric symptoms, and most need inpatient psychiatric care at some point in their illness.
• Dementia with Lewy bodies: Patients with the second most common type of dementia (after Alzheimer disease) present with fluctuating mental status and prominent psychiatric symptoms, including depression and visual hallucinations. This is an important disorder to diagnose because these patients are reported to do poorly when treated with antipsychotic drugs.
• Lipid storage disorders: These disorders include metachromatic leukodystrophy, adrenoleukodystrophy, GM2 gangliosidosis, and ceroid lipofuscinosis. These illnesses usually occur in childhood but may occasionally come to medical attention during adolescence. Patients may present with psychiatric symptoms such as cognitive deterioration and changes in personality. Patients may be diagnosed with schizophrenia until the neurologic symptoms of these illnesses become more prominent.¹⁵
• Paraneoplastic neurologic syndromes: Malignancies can occasionally lead to dramatic mental status changes early in their course and before they have been diagnosed or metastasized to the brain. The etiology is not clear. Various syndromes have been described, including subacute cerebellar degeneration, encephalopathy with brainstem involvement, diffuse encephalopathies with mental symptoms, and limbic encephalopathy. The carcinoma is typically a bronchial oat-cell carcinoma.
• Seizure disorder: Occasionally, patients with a seizure disorder, especially temporal lobe epilepsy, may display odd behavior before, during, or after a seizure. Aura and ictal symptoms can include hallucinations, disturbances of memory, or affective and cognitive changes. Ictal and postictal phenomena can include motor abnormalities, which can be quite complex.
• Systemic lupus erythematosus: Patients with this connective tissue disease, typically young women, present with unexplained fever and/or joint pain in association with psychiatric symptoms, such as psychosis or cognitive deficit. The diagnosis can be suggested by the physical findings of malar flush and the laboratory findings of anemia, renal dysfunction, and elevated erythrocyte sedimentation rate (ESR) and, most specifically, antinuclear antibody (ANA) levels.
• Vasculitis: In cases of systemic vasculitides, such as polyarteritis nodosa, Churg-Strauss syndrome, Wegener granulomatosis, or Behcet disease, patients may present with personality changes. Other symptoms such as weight loss and fever usually occur. MRI scans show characteristic lesions of vasculitis.

• Heavy metal toxicity: People exposed to heavy metals, usually in the course of their work, may develop changes in their personality, cognitions, or mood. Heavy metals sometimes contaminate herbal medications.
• Medication: Many medications have been associated with mental status changes. The more commonly implicated ones are corticosteroids (psychosis or mania); levodopa (hallucinations or insomnia); antidepressants (mania); interferon-alpha (depression); and beta-blockers, including beta-blockers in eye drops (depression).
• Substance abuse (eg, alcohol, cocaine, opiates, psychostimulants, hallucinogens): Disturbed perceptions, thought, mood, and behavior associated with substance abuse are not uncommon. Anabolic steroids used by body builders can lead to psychotic symptoms.¹⁶
• Anticholinergic medications can lead to delirium and can be abused.

• Thiamine deficiency: People who rely on alcohol for calories or patients with advanced malignancies or malabsorption syndromes may become deficient in this vitamin. Acute and severe depletion of this vitamin can lead to Wernicke encephalopathy, marked by oculomotor disturbances, ataxia, and confabulation. If untreated, Korsakoff psychosis may develop. Wernicke encephalopathy is a common cause of chronic cognitive impairment in people with alcoholism, and it is underdiagnosed.¹⁷
• Vitamin B-12 and/or folate deficiency: Patients with either deficiency may present with depression or dementia or, very rarely, delusional thinking.

Workup

Laboratory Studies

No characteristic laboratory results are found in schizophrenia. The following blood work should be performed on all patients, at the beginning of the illness and periodically afterwards:

• Complete blood count
• Liver, thyroid, and renal function tests
• Electrolyte, glucose, B12, folate, and calcium level
• If the patient's history provides any reason for suspicion, check HIV; RPR; ceruloplasmin; ANA; urine for culture and sensitivity and/or drugs of abuse; a.m. cortisol, and 24-hour urine collections for porphyrins, copper, or heavy metals.
• If the patient is a woman of childbearing age, a pregnancy test is important.
• If a strong suspicion of neurosyphilis exists, specific treponemal tests may be helpful.

Imaging Studies

• Brain imaging is indicated to rule out subdural hematomas, vasculitis, cerebral abscesses, and tumors.
• A chest x-ray should be done if pulmonary illness or occult malignancy is suspected.

Other Tests

• Neuropsychological testing in patients with schizophrenia often shows poor information processing, impaired memory, difficulty in abstraction and recognizing social cues, and easy distractibility. Determination of the patient's cognitive weaknesses and strengths can be helpful in treatment planning.
• If indicated, an electroencephalogram can be useful.
• Dexamethasone suppression test and adrenocorticotropic hormone (ACTH) stimulation tests are used to establish the diagnosis of hypercortisolism and hypocortisolism, respectively.

Procedures

• If a strong suspicion of Wilson disease exists, consider a liver biopsy (or multiple biopsies) to confirm the diagnosis.

• Search for CME/CE on This Topic »

• Schizophrenia (Emergency Medicine)
• Schizophrenia and Other Psychoses (Pediatrics: Developmental and Behavioral)
• Schizophreniform Disorder (Psychiatry)
• Borderline Personality Disorder (Psychiatry)

• Mental Health and Behavior Center
• Schizophrenia Overview
• Schizophrenia Causes
• Schizophrenia Symptoms
• Schizophrenia Treatment

• Violence in Schizophrenia Rare in the Absence of Substance Abuse
• Schizophrenia Plus Diabetes Linked With Higher CAD Yet Lower Revascularization Rates
• Patients with Schizophrenia May Have Flawed Antioxidant Defense System

• Psychiatric Comorbidities and Schizophrenia
• Prenatal Nutritional Deficiency and Risk of Adult Schizophrenia
• Association Between Paternal Schizophrenia and Low Birthweight: A Nationwide Population-Based Study

• Schizophrenia Resource Center