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
  • Birth in late winter or early spring
  • 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 psychosis

Hallucinations

• Definition
  • Hallucinations: perceptual abnormalities in which sensory experiences occur in the absence of external stimuli
  • Illusions: a perceptual abnormality, in which real external stimuli are misinterpreted
• Types
  • Auditory (most common)
  • Visual
  • Somatic (tactile)
  • Gustatory
  • Olfactory

Delusions

• Definition: fixed, false beliefs that are maintained despite being contradicted by reality or rational arguments and are not related to one's religious beliefs or culture
• Types
  • Bizarre delusions: delusions that cannot be true or are inconsistent with the patient's social and cultural norms (e.g., a patient insisting that they can fly)
  • Nonbizarre delusions: delusions that can be true or are consistent with the patient's social and cultural norms (e.g., a patient insisting that they have won the lottery when this is not the case)
• Subtypes
  • Grandiosity: The patient insists that they have special powers or importance.
  • Ideas of reference: The patient believes that normal events are of special importance to him or to her (e.g., an individual might feel that a television reporter is talking about them).
  • Paranoia: The patient has an exaggerated distrust of others and is suspicious of their motives.
  • Persecutory: The patient insists that they are being cheated on, conspired against, or harassed.
  • Erotomania: The patient believes that other individuals are in love with them.
  • Jealousy: The patient believes their partner is unfaithful without justification.
  • Somatic delusion: The patient believes they are experiencing a bodily function or sensation when there is none present.
  • Mixed delusions: two or more delusions occurring simultaneously; No delusion is predominant over the other.
  • Unspecified delusions: a delusion that does not fit the criteria of other types or cannot be clearly defined

Disorganized thought and speech processes

• Loose associations: incoherent thinking expressed as illogical, sudden, and frequent changes of topic
• Word salad: incoherent thinking expressed as a sequence of words without a logical connection
• Tangential speech: nonlinear thought expressed as a gradual deviation from a focused idea or question
• Neologisms: the creation of new words with idiosyncratic meanings
• Echolalia: involuntary repetition of other's words or sentences
• Flight of ideas: quick succession of thoughts usually demonstrated in a continuous flow of rapid speech and abrupt changes in topic
• Clang association: use of words based on rhyme patterns rather than meaning
• Circumstantial speech: non-linear thought expressed as a long-winded manner of explanation, with multiple deviations from the central topic, before finally expressing the central idea
• Thought-blocking: an objective observation of an abrupt ending in a thought process, expressed as a sudden interruption in speech
• Pressured speech: accelerated thoughts that are expressed as rapid, loud, and voluminous speech; often in the absence of social stimulation

Negative symptoms of psychosis

• 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

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.)

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

• Schizophrenia is a clinical diagnosis. Diagnostic criteria include (according to DSM-V): ^[11][3]
  • 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

Psychotic disorders [3]
	Duration of symptoms	Clinical features		Function
Schizophrenia	≥ 6 months	≥ 2 of the following symptoms Delusions Hallucinations Disorganized speech Grossly disorganized or catatonic behavior Negative symptoms The majority of patients with schizophreniform disorder subsequently develop schizophrenia or schizoaffective disorder, while one-third experience no further disturbance.		Impaired
Schizophreniform disorder	1–6 months
Brief psychotic disorder	> 1 day but ≤ 1 month	≥ 1 of the following symptoms Delusions Hallucinations Disorganized speech Grossly disorganized or catatonic behavior Brief psychotic disorder usually develops after stressful life-events.
Schizoaffective disorder	≥ 2 weeks of psychosis without manic/depressive symptoms	Psychotic symptoms with or without mood symptoms Mood symptoms should present for the majority of the illness as a prominent feature. However, when mood symptoms are present, psychotic symptoms are more dominant.		Impaired
Mood disorder with psychotic features	Major depressive episode for at least 2 weeks Manic episode lasting ≥ 1 week	Mood symptoms with or without psychotic symptoms Psychotic symptoms appear exclusively during manic or depressive episodes.		Impaired
Delusional disorder	≥ 1 month	At least one type of delusion without any other psychotic symptoms (e.g., hallucinations, disorganized speech, negative symptoms) Hallucinations only occur during delusional episodes.		Not markedly impaired
Delusional symptoms in partner of individual with delusional disorder	Not determined	Formerly known as shared psychotic disorder or folie à deux Occurs in the context of a relationship Delusional themes from an individual with delusional disorder are mirrored in the delusional beliefs of their partner.		Normal

Personality disorders

• Schizotypal personality disorder
  • Odd and eccentric behavior
  • Magical thinking
  • Discomfort in close relationships
  • Short psychotic episodes may occur with less frequency and severity than in schizophrenia.
• 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)
  • Substance/medication-induced psychotic disorder
  • 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.

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 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.”
• 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).