Schizophrenia

Schizophrenia is a chronic mental health disorder characterized by the presence of psychotic symptoms such as delusions or hallucinations. The signs and symptoms of schizophrenia are traditionally separated into 2 groups: positive (delusions, hallucinations, and disorganized speech or behavior) and negative (flat affect, avolition, anhedonia, poor attention, and alogia). Schizophrenia is associated with a decline in both cognitive and social functioning that often precedes the development of florid psychosis. The exact etiology of schizophrenia is unknown, although it is thought to be linked to an increase in dopaminergic activity. Treatment includes antipsychotics in conjunction with behavioral therapy.

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Epidemiology and Etiology

Definition

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”

Epidemiology

  • 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

Etiology

  • 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 
    • Migration
    • Poverty
    • Stress and psychosocial factors 
    • Birth in late winter or early spring
    • Advanced paternal age at conception

Pathophysiology

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 pathwaysNormal functionRole in schizophreniaEffects/side effects of antipsychotics
Mesolimbic pathwayRole in motivation, emotions, rewardOveractivity results in positive symptomsImprovement of positive symptoms
Mesocortical pathwayCognition, executive function, emotions and affectUnderactivity results in negative symptomsWorsening of negative symptoms
Nigrostriatal pathwayControl of extrapyramidal system, purposeful motor planningNo direct role in the etiology of schizophreniaExtrapyramidal symptoms
Tuberoinfundibular pathwayInhibits prolactin releaseNo direct role in the etiology of schizophreniaHyperprolactinemia

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

Clinical Presentation

  • 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).
SymptomNotes
Premorbid
  • Appear before the onset of the first episode of schizophrenia
  • Include social withdrawal and paranoid thoughts
  • The first psychotic episode can occur without warning (asymptomatic premorbid period).
Positive (psychotic phase)
  • Easy to recognize
  • Delusions:
    • False, fixed beliefs maintained by the patient despite being contradicted by reality or logical arguments
    • Can include grandiosity, ideas of reference, paranoia, persecutory, erotomania, jealousy, and somatic delusions
  • Hallucinations:
    • Perceptual abnormalities in which sensory experiences occur in the absence of external stimuli
    • Can be auditory (most common), visual, somatic, gustatory, and olfactory
  • Illusions: distinguished from hallucinations by the presence of a real external stimuli that is simply misinterpreted by the patient
  • Disorganized speech and/or behavior: can include neologisms, echolalia, flight of ideas, pressured speech, loose associations, among others
Negative (residual phase)
  • Potentially difficult to recognize because of similarities to depression
  • Flat affect (diminished emotional expression)
  • Avolition (lack of initiative)
  • Alogia (poverty of speech)
  • Poor attention
  • Anhedonia
Cognitive
  • Usually nonspecific; related to the impact on patient’s quality of life
  • Poor executive functioning, represented by disorganized speech and/or thought that results in impaired communication
  • Inattention
  • Impaired memory

Mnemonic

To recall the negative symptoms of schizophrenia, remember the 5 As:

  • Anhedonia
  • Affect (flat)
  • Alogia (poverty of speech)
  • Avolition (apathy)
  • Attention (poor)

Diagnosis

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

Pharmacological

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
Table: Treatment considerations
ConditionTreatment considerations
Acute psychosis
  • Requires immediate attention
  • Use oral antipsychotic and benzodiazepine (may require intramuscular due to noncompliance or for more rapid effect).
  • Usually lasts 4–6 weeks
Maintenance phase
  • Obtain laboratory tests: CBC (including differential if clozapine used), electrolytes, fasting glucose, lipid profile, liver, renal and thyroid function tests, and a pregnancy test in females of fertile age
  • ECG if history of heart disease or if using drugs that may prolong the QT interval (clozapine, thioridazine, iloperidone, ziprasidone)
  • Monitor for the 1st few weeks and then regularly for involuntary movement disorders/EPS, since they may become irreversible.
  • Goal is to minimize symptoms, avoid relapses, and promote recovery that allows integration into society.
  • Minimize side effect profile.
  • Recommended maintenance treatment is > 5 years.
  • May use long-acting injectable antipsychotics for non-compliant patients after checking for tolerability/efficacy with oral agent
Poor responders
  • Roughly 40% of treated patients will demonstrate positive symptoms that are resistant to treatment.
  • Assess proper dosage and duration of treatment.
  • Do not use 2 antipsychotics at the same time as studies show no benefits.
  • Consider use of clozapine, which can be an effective treatment in persons with schizophrenia that is resistant to treatment with other antipsychotic drugs; also reduces suicide risk. However, clozapine is associated with a risk for agranulocytosis and requires frequent, intense blood monitoring.
Table: Side effects
Side effectDefinition/treatment
EPS
  • Movement disorders secondary to drugs that block dopamine receptors
  • Movement phenotypes include: dystonia (involuntary muscle contractions), akathisia (inner restlessness), parkinsonism
  • Treatment options include decreasing dosage, changing to a drug having a lower risk of EPS, or adding an antimuscarinic agent such as benztropine or diphenhydramine; propanolol and benzodiazepines are also used, and botulinum toxin injections are used for focal dystonia.
Tardive dyskinesia
  • A subset of EPS
  • Associated with long-term treatment with 1st-generation antipsychotics
  • Movement phenotypes include: torticollis (involuntary contraction of neck muscle, causing head tilt), dystonia of lips, tongue, oromandibular, or pharynx
  • Treatment includes drugs (valbenazine and deutetrabenazine) that block vesicular monoamine transporter 2 protein, which then prevents presynaptic dopamine release; injection of botulinum toxin is also used.
Elevated prolactin
  • Caused by almost all antipsychotics
  • Can result in irregular menses, galactorrhea, and sexual dysfunction.
  • Treatment includes dosage reduction/medication changes.
Metabolic
  • Weight gain, hyperlipidemia, hyperglycemia, and hypertension → increased cardiovascular risk
  • Treatment: Change from high-risk drug (e.g., olanzapine, quetiapine, risperidone) to an antipsychotic with lower metabolic risk (e.g., aripiprazole or ziprasidone) if possible.
  • Monitor and treat each cardiovascular risk factor appropriately.
Neuroleptic malignant syndrome
  • Idiosyncratic reaction to antipsychotics
  • This is a life-threatening emergency.
  • Symptoms include at least 2 of the following cardinal symptoms: fever, altered mental status, muscle rigidity, and autonomic dysfunction
  • Treatment includes immediate discontinuation of the antipsychotic medication and aggressive supportive care.

Nonpharmacological (adjunct)

Nonpharmacological treatments are known to be partially effective in treating the negative and cognitive symptoms of the disorder and increase patient adherence to medications.

  • Hospitalization:
    • 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

Prognostic factors

Associated with better outcomeAssociated with worse outcome
Late onsetEarly onset
Good social supportPoor social support
Positive symptomsNegative symptoms
Negative family historyPositive family history
Mood symptomsNo mood symptoms
Sudden onsetGradual onset
Female genderMale gender
Fewer relapsesMany relapses
Good premorbid condition (education, work)Poor premorbid condition (no education, no work)

Differential Diagnosis

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. Requires a 2-week period in which psychotic symptoms exist in the absence of affective symptoms, however 
  • 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.
Key differential diagnoses for schizophrenia
Differential diagnosisDurationNegative symptomsPositive symptomsMood disorder
Schizophrenia> 6 months (with at least 1 month of active phase symptoms)YesYesYes
Brief psychotic disorder1 day to 1 monthNoYesYes
Schizophreniform disorder> 1 month, < 6 monthsNoYesYes, rare
Schizoaffective disorderCurrent mood episodes with active phase of schizophrenia plus at least 2 weeks of lifetime history of delusions or hallucinations without mood symptomsYesYesYes, predominantly

References

  1. Le, T., Bhushan, V. (2020). First Aid for the USMLE Step 1 (30th-anniversary edition). New York: McGraw-Hill Medical.
  2. Semple, D., Smyth, R. (2013). Oxford Handbook of Psychiatry. Oxford: Oxford University Press.
  3. American Psychiatric Association. (2013). Diagnostic and statistical manual of mental disorders (5th ed.).
  4. 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
  5. 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

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