Epidemiology and Etiology
Schizophrenia is a chronic serious mental disorder characterized by loss of contact with reality and manifested by two main symptoms: hallucinations and delusions.
- Should be distinguished from neuroses: less serious mental disorders that cause a sense of distress and deficit in functioning, and are characterized by anxiety, depression, or other feelings of distress that are out of proportion to the circumstances of a person’s life
- Also commonly confused with dissociative identity disorder (DID), previously known as multiple personality disorder (MPD), or commonly called “split personality”
- Affects 20 million people worldwide
- Lifetime prevalence of approximately 0.50% in the United States and globally
- Men and women are equally affected, but with a slight difference in the age of onset
- Men: average age of onset = 23 years
- Women: average age of onset = 26 years
- No single etiological factor is responsible for schizophrenia, a syndrome comprising multiple diseases that present with similar signs and symptoms.
- The disorder manifests when a person with genetic predisposition is exposed to one of many environmental stressors.
- Genetic predisposition:
- Affected first-degree relative = 10% risk
- Affected monozygotic twin = 48% risk
- Affected dizygotic twin = 14% risk
- Offspring with 2 affected parents = 40% risk
- Environmental stressors are believed to be triggers of schizophrenia rather than true causes of the disorder.
- Childhood trauma
- Residence in an urban area
- Social isolation
- Frequent cannabis use in early adolescence
- Stress and psychosocial factors
- Birth in late winter or early spring
- Advanced paternal age at conception
Genetic and environmental risk factors appear to act via a common pathway of disrupting the function of 1 or more neurotransmitter components.
- Dopaminergic theory:
- Almost all drugs with antipsychotic properties block the dopaminergic D2 receptor.
- However, antipsychotics are only 70% effective and clozapine, the most effective antipsychotic for treating schizophrenia, is a weak D2 antagonist.
- Hyperactivity of dopamine D2 receptor neurotransmission in subcortical, and limbic brain regions contribute to the positive symptoms of schizophrenia.
- Hypofunctionality of dopamine D1 receptor neurotransmission in the prefrontal cortex contributes to both negative and cognitive symptoms.
- Other theories:
- Hypofunction of the N-methyl-D-aspartate (NMDA) glutamate receptor
- Dysfunctional gamma-amino-butyric acid (GABA) interneurons
- Dysfunctional nicotinic acetylcholine receptors
|Dopamine pathways||Normal function||Role in schizophrenia||Effects/side effects of antipsychotics|
|Mesolimbic pathway||Role in motivation, emotions, reward||Overactivity results in positive symptoms||Improvement of positive symptoms|
|Mesocortical pathway||Cognition, executive function, emotions and affect||Underactivity results in negative symptoms||Worsening of negative symptoms|
|Nigrostriatal pathway||Control of extrapyramidal system, purposeful motor planning||No direct role in the etiology of schizophrenia||Extrapyramidal symptoms|
|Tuberoinfundibular pathway||Inhibits prolactin release||No direct role in the etiology of schizophrenia||Hyperprolactinemia|
Patients with schizophrenia also have physical abnormalities of the brain tissue, which can be seen in neuroimaging studies.
- Loss of cortical tissue volume, including the limbic system, prefrontal cortex, thalamus, hippocampus, and amygdala
- Ventricular enlargement (third and lateral)
- Decreased symmetry
- Hypoactivity of the frontal lobes and hyperactivity of the basal ganglia
- Impairment of thoughts and affect, characterized by a distorted perception of reality
- The impairments are severe enough to affect the patient’s ability to participate in social events or to form relationships.
- Patients with schizophrenia often lack awareness about their illness (insight).
- Co-existing substance abuse and dependence is common (“dual diagnosis”).
- Symptoms can be classified into premorbid, positive, negative, and cognitive (see table below).
|Positive (psychotic phase)|
|Negative (residual phase)|
To recall the negative symptoms of schizophrenia, remember the 5 As:
- Affect (flat)
- Alogia (poverty of speech)
- Avolition (apathy)
- Attention (poor)
Diagnosis is made by clinical observations based on the type of symptoms presented, their severity and duration, and how the patient’s life is affected by their presence.
- A total duration of symptoms of at least 6 months, including a period of positive symptoms lasting at least 1 month
- The presence of a mix of positive and/or negative symptoms, especially delusions, hallucinations, disorganized speech, or grossly disorganized or catatonic behavior
- The presence of these symptoms must disturb the patient’s daily functioning, including the social, personal, and professional areas of life.
- Other conditions must be ruled out to make a definitive diagnosis:
- Schizoaffective, brief psychotic, and schizoaffective disorders
- Mood disorders (e.g., major depressive disorder, bipolar disorder)
- Substance abuse (requiring urine and blood toxicology tests)
Management and Prognosis
Antipsychotic medications form the centerpiece of treatment for schizophrenia, especially the positive symptoms. Only caroprazine has been shown to have significant effects on negative symptoms. The choice of a specific agent is mostly based on the adverse effect profile, required route of administration, and the patient’s previous response to the drug. Patients who respond usually show the most rapid improvement in the 1st 2 weeks and will often continue to improve during the following weeks. While there is a wide variety of mechanisms of action, most antipsychotics block postsynaptic dopamine receptors.
1st-generation antipsychotics (FGAs):
- Older medications (before 1989)
- Dopamine receptor antagonist
- Common side effects: EPS (which may become irreversible), hyperprolactinemia, neuroleptic malignant syndrome, QT prolongation, sudden death, and an increased risk of mortality in older adult patients with dementia
- Examples: haloperidol, fluphenazine, chlorpromazine
2nd-generation (atypical) antipsychotics (SGAs):
- Newer medications, starting with clozapine (approved in 1989)
- Associated with a lower risk for EPS compared with FGAs and therefore the 1st-line drugs to use (although the risk of metabolic syndrome is increased with SGAs)
- The decreased risk for EPS is the most important distinction from FGAs, as the pharmacologic properties, therapeutic effects, and adverse effects are not distinct between the 2 groups.
- Serotonin and dopamine antagonists
- Common side effects: metabolic syndrome, hypotension, sedation, anticholinergic symptoms, hyperprolactinemia, EPS, cardiac effects, cardiomyopathies, cataracts, and sexual dysfunction
- Examples: risperidone, aripiprazole, quetiapine, olanzapine, ziprasidone, clozapine
|Neuroleptic malignant syndrome|
Nonpharmacological treatments are known to be partially effective in treating the negative and cognitive symptoms of the disorder and increase patient adherence to medications.
- May be required to ensure safety of patients
- In certain cases, isolation may be required for a short period of time.
- Psychosocial therapy:
- Cognitive-behavioral therapy
- Compliance therapy
- Individual psychotherapy
- Group therapy
- Electroconvulsive therapy (ECT): mostly treatment-resistant cases for augmentation to pharmacotherapy
|Associated with better outcome||Associated with worse outcome|
|Late onset||Early onset|
|Good social support||Poor social support|
|Positive symptoms||Negative symptoms|
|Negative family history||Positive family history|
|Mood symptoms||No mood symptoms|
|Sudden onset||Gradual onset|
|Female gender||Male gender|
|Fewer relapses||Many relapses|
|Good premorbid condition (education, work)||Poor premorbid condition (no education, no work)|
The following conditions are differential diagnoses for schizophrenia:
- Brief psychotic disorder: defined as the presence of one or more psychotic symptoms lasting > 1 day and < 1 month. Characterized by a sudden onset, often with a specific trigger, and associated with a return to full function. The main distinguishing factor is the duration of symptoms.
- Schizophreniform disorder: a disorder in which the patient meets the criteria of schizophrenia, with symptoms lasting 1–6 months. The disorder has a much better prognosis than schizophrenia. The main distinguishing factor is the duration of symptoms.
- Schizoaffective disorder: a disorder with features of both affective disorders and schizophrenia. Symptoms of depression or mania should be concurrent with features from the criterion of schizophrenia. Schizoaffective disorder excludes patients with separate episodes of schizophrenia and affective disorders. It does, however, require a 2-week period whereby psychotic symptoms exist in the absence of affective symptoms.
- Delusional disorder: a disorder in which patients suffer from 1 or more delusions for at least 1 month without any other psychotic symptoms or behavioral changes and no decline in functioning abilities.
- Substance-induced psychotic disorder: Alcohol, stimulants, hallucinogens, and steroids can all prompt psychotic episodes. A detailed history relating to onset, duration, and cessation of symptoms in relation to drug or alcohol use must be taken.
- Psychotic disorder due to a general medical condition: Organic disorders of the brain (variant Creutzfeldt-Jakob disease, head injury, encephalitis, meningitis, central nervous system tumors), as well as metabolic and endocrine disorders (Cushing’s syndrome, hyperthyroidism, hypernatremia), can mimic symptoms of schizophrenia.
- Mood disorders with psychotic features: Psychotic features are mood-congruent and preceded by a clinical picture dominated by symptoms of a mood disorder, including major depressive disorder and bipolar disorder.
|Differential diagnosis||Duration||Negative symptoms||Positive symptoms||Mood disorder|
|Schizophrenia||> 6 months (with at least 1 month of active phase symptoms)||Yes||Yes||Yes|
|Brief psychotic disorder||1 day to 1 month||No||Yes||Yes|
|Schizophreniform disorder||> 1 month, < 6 months||No||Yes||Yes, rare|
|Schizoaffective disorder||Current mood episodes with active phase of schizophrenia plus at least 2 weeks of lifetime history of delusions or hallucinations without mood symptoms||Yes||Yes||Yes, predominantly|
- Le, T., Bhushan, V. (2020). First Aid for the USMLE Step 1 (30th-anniversary edition). New York: McGraw-Hill Medical.
- Semple, D., Smyth, R. (2013). Oxford Handbook of Psychiatry. Oxford: Oxford University Press.
- American Psychiatric Association. (2013). Diagnostic and statistical manual of mental disorders (5th ed.).
- Fischer BA, Buchanan RS. (Literature review current through July 2020; last updated: June 3, 2020). Schizophrenia in adults: Clinical manifestations, course, assessment, and diagnosis. UpToDate Evidence-Based Medicine. https://www.uptodate.com/contents/schizophrenia-in-adults-clinical-manifestations-course-assessment-and-diagnosis?search=schizophrenia&source=search_result&selectedTitle=1~150&usage_type=default&display_rank=1
- Stroup TS, Marder S. Pharmacotherapy for schizophrenia: Acute and maintenance phase treatment. (Literature review current through July 2020; last updated: April 21, 2020). UpToDate Evidence-Based Medicine. https://www.uptodate.com/contents/pharmacotherapy-for-schizophrenia-acute-and-maintenance-phase-treatment?search=schizophrenia&source=search_result&selectedTitle=2~150&usage_type=default&display_rank=2