Schizophrenia

Schizophrenia is a severe psychiatric disorder characterized by chronic or recurrent psychosis. The majority of individuals with schizophrenia initially experience symptoms in their 20s. The exact mechanism is unknown but is thought to relate to increased dopaminergic activity in the mesolimbic neuronal pathway and decreased dopaminergic activity in the prefrontal cortical pathway. Clinical features include positive psychotic symptoms, negative psychotic symptoms, cognitive impairment, abnormal motor behavior (e.g., catatonia), and mood symptoms. The mainstay of treatment is psychoeducation and antipsychotic therapy with dopamine antagonists.

• Prevalence: < 1% ^[1]
• Sex: ♂ > ♀ (∼1.4:1) ^[2]
• Age of onset: late teens to mid-30s ^[3]
  • Men: typically early 20s
  • Women: typically late 20s

Epidemiological data refers to the US, unless otherwise specified.

Risk factors

• Genetic factors: risk significantly increased if relatives are also affected ^[4]
  • One schizophrenic parent: ∼ 10%
  • Two schizophrenic parents: ∼ 40%
  • Concordance rate in monozygotic twins: 30–40%
  • Concordance rate in dizygotic twins: 10–15%
• Environmental factors
  • Stress and psychosocial factors
  • Frequent use of cannabis during early teens (associated with increased incidence and worse course of positive symptoms) ^[5][6]
  • Urban environment
  • Advanced paternal age at conception

Dysregulation of neurotransmitters ^[7]

• ↓ Dopamine in prefrontal cortical pathway may cause negative symptoms of psychosis.
• ↑ Dopamine in mesolimbic pathway may lead to positive symptoms of psychosis.
• ↑ Serotonergic activity
• ↓ Dendritic branching
• ↓ Glutamatergic neurotransmission may lead to psychosis.
• ↓ GABA leads to ↑ dopamine activity.

Structural and functional changes to the brain ^[8][9]

• Enlarged lateral and third ventricles
• Decreased symmetry
• Decreased volume of the limbic system, prefrontal cortex, and thalamus
• ↓ Volume of the hippocampus and amygdala
• Hypoactivity of the frontal lobes and hyperactivity of the basal ganglia

Schizophrenia typically manifests with a prodrome of negative symptoms and psychosis (e.g., social withdrawal) that precedes the positive psychotic symptoms (e.g., hallucinations and bizarre delusions). ^[3]

Positive symptoms of schizophrenia

Psychosis

• Hallucinations and/or illusions (auditory hallucinations are most common)
• Delusions, e.g., grandiosity, ideas of reference, paranoia, persecutory delusions
• Disorganized thought or disorganized speech: e.g., loose associations, word salad, tangential speech

Abnormal motor behavior

• Grossly disorganized behavior: an abnormal behavior characterized by inadequate goal-directed activity (e.g., purposeless movements) and bizarre emotional responses (e.g., smiling or laughing when inappropriate)
• Catatonia (See “Subtypes and variants” below.)

Negative symptoms of schizophrenia

• Flat affect: reduced or absent emotional expression
• Avolition: reduced or absent ability to initiate purposeful activities
• Alogia: impaired thinking that manifests with reduced speech output or poverty of speech (e.g., always replying to questions with one-word answers)
• Anhedonia: inability to feel pleasure from activities that were formerly pleasurable or from any new positive stimuli
• Apathy: lack of emotion or concern, especially with regard to matters that are normally considered important
• Emotional and social withdrawal

Other features

• Cognitive symptoms
  • Inattention
  • Impaired memory
  • Poor executive functioning
• Mood symptoms and anxiety
  • Mostly depression
  • Social or specific phobia
  • Post-traumatic stress disorder
  • Obsessive-compulsive disorder
  • Panic disorder
• Neurological abnormalities: sensory disturbances and impaired coordination
• Metabolic abnormalities: hypertension, diabetes, hyperlipidemia

DSM-V omits subtypes of schizophrenia previously included in DSM-IV (disorganized, paranoid, catatonic, undifferentiated, residual) because they are no longer thought to reflect the heterogeneity of schizophrenia.

Catatonia

• Definition: a behavioral syndrome characterized by abnormal movements and reactivity to the environment
• Classification
  • Catatonia associated with mental disorders
    • Psychotic disorders
    • Bipolar disorder
    • Depressive disorders
    • Neurodevelopmental disorders
  • Catatonia associated with medical disorders
    • Hepatic encephalopathy
    • Drug adverse effects (e.g., antipsychotics)
• Clinical features
  • Retarded catatonia: immobility, posturing, negativism (resisting external commands), staring, mutism
  • Excited catatonia: excessive, purposeless movement in both the upper and lower limbs, restlessness, and impulsivity
  • Malignant catatonia: fever, autonomic instability (e.g., tachycardia, tachypnea, abnormal BP, and sweating), rigidity, and delirium (resembles neuroleptic malignant syndrome)
• Treatment ^[10]
  • Benzodiazepines (Intravenous or sublingual lorazepam): first-line for all forms of catatonia
  • Electroconvulsive therapy
    • First-line for malignant catatonia and nonmalignant catatonia due to a mood disorder with psychotic features
    • Second-line in case of inadequate response to benzodiazepine therapy
  • Discontinue dopamine blocking drugs (e.g., antipsychotics); only reinitiate after catatonia resolves
  • Treat the underlying psychiatric condition with appropriate pharmacotherapy
  • Supportive measures
    • DVT prophylaxis
    • Pressure ulcer prevention
    • Adequate hydration and specialized nutritive support

• Schizophrenia is a clinical diagnosis. Diagnostic criteria include (according to DSM-V): ^[3][11]
  • At least two of the following symptoms, at least one of which is from the top three:
    • Delusions
    • Hallucinations
    • Disorganized speech
    • Grossly disorganized or catatonic behavior
    • Negative symptoms
  • The above symptoms persist for ≥ 1 month over a period of continuous disturbance for ≥ 6 months.
  • Symptoms must cause social, occupational, or personal functional impairment lasting ≥ 6 months.
  • Schizoaffective disorder and mood disorder with psychotic features have been ruled out.
  • Medical or substance use disorder has been ruled out.
• Brain imaging of patients with schizophrenia often shows cortical atrophy, decreased hippocampal and temporal mass, and enlargement of the cerebral ventricles.
• Rule out medical or substance use disorder by performing the following tests:
  • Urine toxicology
  • Blood tests, e.g., CBC, BMP, LFT, TSH, and fasting glucose
  • ECG to assess
    • Presence or absence of metabolic syndrome
    • Baseline QTc interval before starting antipsychotic

See “Psychotic disorders” for details.

• Schizophrenia spectrum disorders
  • Schizophreniform disorder
  • Brief psychotic disorder
  • Schizoaffective disorder
  • Delusional disorder
  • Shared psychotic disorder
  • Schizotypal personality disorder
• Other psychiatric conditions
  • Mood disorders with psychotic features
  • Anxiety disorders with psychotic features
• Psychotic disorder due to another medical condition: e.g., delirium, dementia, SLE, thyrotoxicosis, TBI, brain tumors, Wilson disease, porphyria
• Substance-induced psychotic disorder: due to e.g., alcohol, cannabis, sympathomimetic drugs, hallucinogens

The differential diagnoses listed here are not exhaustive.

• General considerations
  • Establish a therapeutic alliance when taking care of patients with delusions.
  • Acknowledge the patient's emotional state.
  • Avoid validation of delusions or confronting patients about the delusional nature of their symptoms.
  • Initial response to treatment during the first 2–4 weeks is associated with a better long-term response.
  • Hospitalization if acutely psychotic
• Pharmacotherapy ^[12]
  • Acute psychotic episode: short-acting antipsychotics
  • Acute manic episode: mood stabilizers (e.g., lithium, valproate, carbamazepine)
  • First-line treatment: second-generation antipsychotics (e.g., risperidone, quetiapine), which are especially effective at treating positive psychotic symptoms
  • Alternative treatment: first-generation antipsychotics
  • Treatment nonadherence: Use long-acting injectable formulations.
    • First generation antipsychotics: fluphenazine, haloperidol
    • Second generation antipsychotics: risperidone, aripiprazole, olanzapine, paliperidone
  • Treatment-resistant schizophrenia: persistent positive symptoms (i.e., delusions, hallucinations, and/or disorganized speech) despite trials of ≥ 6 weeks of 2 different antipsychotics at their maximum doses
    • Drug of choice: clozapine
    • Clozapine therapy requires regular blood counts because of the risk of agranulocytosis.
  • Treatment during pregnancy: first-generation antipsychotics (e.g., haloperidol) as a first-line treatment
  • Treatment of depression: SSRIs or tricyclic antidepressants (e.g., sertraline, imipramine)
  • Treatment of anxiety: SSRIs
  • See “Antipsychotics.”
• Psychoeducation (used as an adjunct to avoid relapse)
  • Patient, family, and group psychosocial therapy and education
  • Cognitive-behavioral therapy
  • Supportive social measures

Long-acting injectable antipsychotics should be considered for patients struggling with compliance and frequent relapses.

Negative symptoms are more difficult to treat and often persist even after the resolution of positive symptoms.

Because both generations of antipsychotics have similar efficacy, the choice of the agent is based on its side-effect profile.

Clozapine and olanzapine should not be used as first-line agents for first-episode patients because of their adverse effects, such as agranulocytosis (clozapine only), weight gain, hyperglycemia, and hyperlipidemia.

Schizophrenia is a progressive disorder that causes significant impairment, with many patients presenting with psychosocial dysfunction.

• Predictive factors for an unfavorable course of illness ^[13]
  • Family history
  • Earlier onset of disease
  • Poor network of social support
  • Male sex
  • Slower onset of illness
  • More negative symptoms
  • Depression
  • Concomitant substance use disorder
  • Suicidal ideation/suicide attempt

Patients with schizophrenia are at an increased risk for alcohol use disorder, depression, violence, and suicide (∼ 5% complete suicide).