Schizophrenia

Summary

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.

Epidemiology

 Prevalence: < 1% [1]

 Sex: ♂ = ♀  [2]

 Age of onset: late teens to mid-30s [3]

 Men: typically early 20s

 Women: typically late 20s

References:[4][5][3]

Epidemiological data refers to the US, unless otherwise specified.

Etiology

Risk factors

 Genetic factors: risk significantly increased if relatives are also affected

 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

 Urban environment

 Birth in late winter or early spring

  Advanced paternal age at conception

References:[3][6][7]

Pathophysiology

Dysregulation of neurotransmitters [8]

 ↓ Dopamine in prefrontal cortical pathway may cause negative symptoms of psychosis.

 ↑ Dopamine in mesolimbic pathway may lead to positive symptoms of psychosis.

 ↑ Serotonergic activity and ↓ dendritic branching

 ↓ Glutamatergic neurotransmission may lead to psychosis.

 ↓ GABA leads to ↑ dopamine activity.

Structural and functional changes to the brain [9][10]

 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

Diagnostics

 Schizophrenia is a clinical diagnosis. Diagnostic criteria include (according to DSM-5):

 At least two of the following symptoms, at least one of which is from the top three:

1. Delusions

1. Hallucinations
 1. Disorganized speech

1. Grossly disorganized or catatonic behavior

1. Negative symptoms
 The above symptoms persist for ≥ 1 month over a period of ≥ 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

Negative symptoms of schizophrenia include the 5A’s: Affect (flat), Avolition, Asociality, Anhedonia,

and Apathy.

Personality disorders

 Schizotypal personality disorder

  Odd and eccentric behavior

 Magical thinking (inventing causal relationships between behaviors and events with

no evidence) that is inconsistent with the patient's cultural norms

 Discomfort in close relationships

 Schizoid personality disorder

 Having no interest in social relationships

 Restricted emotional expression and anhedonia

 Paranoid personality disorder

 Distrustful of others

 Suspicious of friends and family

 Superficial relationships

Other causes of psychosis

 PTSD

 Organic causes of psychosis

 Delirium

 Dementia

 Cushing syndrome

 Substance use disorder (e.g., hallucinogens)

 Thyroid disorder (e.g., thyrotoxicosis)

 Vitamin B12 deficiency

 Systemic lupus erythematosus

 Neoplasm (e.g., brain tumor)

 Epilepsy (e.g., temporal lobe epilepsy)

 Wilson disease

 Porphyria

Mood-congruent delusions are usually seen in severe depression/mania, whereas schizoaffective

disorder manifests with delusions that are not congruent with the mood!
References:[4][5][3][12]

The differential diagnoses listed here are not exhaustive.

Treatment

 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 [13]

 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 in depot form for those at risk

of poor adherence (e.g., fluphenazine, haloperidol, chlorpromazine)

 Treatment-resistant schizophrenia: clozapine for persistent positive symptoms

(i.e., delusions, hallucinations, and/or disorganized speech) despite trials of ≥ 6
weeks of 2 different antipsychotics at their maximum doses 

 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 for more details.

  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!

References:[4][11]

Prognosis

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

 Predictive factors for an unfavorable course of illness

 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).