Summary

Schizophrenia is a severe psychiatric disorder characterized by chronic or recurrent psychosis. The majority of patients with schizophrenia initially experience symptoms in their 20s. The exact mechanism is unknown, but it is thought to be related 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, catatonia, and mood symptoms. The mainstay of treatment is psychoeducation and antipsychotic therapy with dopamine antagonists.

Epidemiology

Prevalence
- < 1%
- Lifetime risk: ♂ = ♀
Age of onset: young adults aged 18–35
- Men: typically early 20s
- Women: typically late 20s

References:^[1]^[2]

Epidemiological data refers to the US, unless otherwise specified.

Etiology

Multiple factors
- Dysregulation of dopaminergic activity
  - ↓ Dopamine in prefrontal cortical pathway → negative symptoms of psychosis
  - ↑ Dopamine in mesolimbic pathway → positive symptoms of psychosis
- Enlarged lateral and third ventricles
- ↓ Volume of the hippocampus and amygdala
- Altered glucose metabolism → reduced glucose in the prefrontal cortex
Risk factors
- Stress and psychosocial factors
- Frequent use of cannabis
- Genetics
  - If any first-degree relative is affected: 12%
  - If monozygotic twin is affected: 50%
  - If both parents are affected: 40%

Clinical features

Schizophrenia tends to present initially with a prodrome of negative symptoms (classically social withdrawal) that precedes the positive psychotic symptoms (i.e., hallucinations and bizarre behaviors).

Features
Positive symptoms of psychosis	Hallucinations: a perceptual abnormality, in which sensory experiences occur in the absence of external stimuli (may be auditory (most common), visual, somatic, gustatory, or olfactory) Delusions: fixed, false beliefs that are not amenable to reason, despite evidence to the contrary Bizarre: impossibility of being true or not consistent with the patient's social and cultural norms Non-bizarre: possibility of being true or consistent with the patient's social and cultural norms May be grandiose , ideas of reference , paranoid, or erotomanic Illusions: a perceptual abnormality, in which real external stimuli are misinterpreted Disorganized thought and speech processes Loose associations: incoherent thinking expressed as illogical, sudden, and frequent changes of topic Word salad: incoherent thinking expressed as sequence of words without a logical connection Neologisms: the creation of new words with idiosyncratic meanings Echolalia Flight of ideas: quick succession of thoughts usually demonstrated in a continuous flow of rapid speech and abrupt changes in topic Clang associations: 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 Tangential speech: non-linear thought expressed as a gradual deviation from a focused idea or question 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 affective expression Avolition: reduced or absent ability to initiate purposeful activities Alogia: impoverished thinking that presents as 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 any new positive stimuli Apathy: lack of emotion or concern, especially with regards to matters that are normally considered important Emotional and social withdrawal
Cognitive symptoms	Inattention Impaired memory Poor executive functioning
Mood symptoms and anxiety	Depression is common.
Catatonia	A behavioral syndrome characterized by abnormal movements and reactivity to the environment 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)
Neurological abnormalities	Sensory disturbances and impaired coordination
Metabolic abnormalities	Hypertension, diabetes, hyperlipidemia

Positive symptoms are usually an exaggeration of normal thoughts, speech, and/or behavior, while negative symptoms involve a deficit or absence of these normal processes..

Subtypes and variants

Subtypes of schizophrenia according to DSM IV (no longer in use)
	Characteristics
Disorganized schizophrenia	Predominantly disorganized Onset is usually before 25 years of age.
Paranoid schizophrenia	Delusions are predominantly of the paranoid type. Older age of onset
Catatonic schizophrenia	Catatonia is a predominant symptom.
Undifferentiated schizophrenia	Usually has features of more than one subtype
Residual schizophrenia	At least one psychotic episode Followed by flat affect, odd behavior, social withdrawal

Diagnostics

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

A) ≥ 2 of the following symptoms for ≥ 1 month (at least one of the symptoms must be from the group that is bolded)
1. Delusions
2. Hallucinations
3. Disorganized speech
4. Grossly disorganized or catatonic behavior
5. Negative symptoms
B) Symptoms must cause social, occupational, or personal functional impairment.
C) Some sign of illness must persist for at least 6 months.
D) Schizoaffective disorder and mood disorder with psychotic features have been ruled out.
E) Symptoms must not be due to a medical or substance use disorder.
F) If there is a history of autism spectrum disorder or other communication disorder beginning in childhood, the additional diagnosis of schizophrenia is made only if prominent delusions or hallucinations are also present for at least a month (or less if successfully treated).

Brain imaging of schizophrenia patients often shows cortical atrophy and enlargement of the cerebral ventricles.

References:^[3]

Differential diagnoses

Psychotic disorders
Schizophrenia	Psychotic symptoms lasting > 6 months
Brief psychotic disorder	Psychotic symptoms lasting > 1 day but ≤ 1 month Triggered by stressful situations
Schizophreniform disorder	Psychotic and residual symptoms lasting 1–6 months
Schizoaffective disorder	Features of schizophrenia AND a major mood disorder (depression or bipolar disorder) Psychosis must have been present for at least 2 weeks in the absence of any mood disturbance. Mood symptoms do not appear in the absence of psychosis
Delusional disorder	≥ 1 delusion with a duration of ≥ 1 month and no other psychotic symptoms Functioning is not markedly impaired and behavior is not obviously bizarre or odd Symptoms are not better explained by substance abuse, other medical conditions, or other mental illnesses. Common central themes of the delusions are grandiosity, jealousy, and persecution
Delusional symptoms in partner of individual with delusional disorder	Formerly known as shared psychotic disorder or folie à deux One person's delusion is transferred to another person Management Assess both individuals separately to determine the degree of delusions in each First-line therapy: cognitive-behavioral therapy and atypical antipsychotics (e.g., ziprasidone, aripiprazole)
Mood disorder with psychotic features	Meets criteria for a mood disorder (e.g., depression or manic phase of bipolar mood disorder) Psychotic features appear exclusively during manic or depressive episodes. Mood symptoms may be present in the absence of psychosis.
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 patient's cultural norms Discomfort in close relationships
Schizoid personality disorder	Odd and eccentric behavior Restricted emotional expression and anhedonia Lack of close friends
Borderline personality disorder	Unstable moods Impulsive Unstable relationships Transient paranoia
Please note: Personality disorders should not be diagnosed if there is an underlying general medical condition or substance use disorder that can better explain the symptoms.

Mood-congruent delusions are usually seen in severe depression/mania, whereas schizoaffective disorder presents with delusions that are not congruent with the mood!

References:^[1]^[2]^[4]

The differential diagnoses listed here are not exhaustive.

Treatment

Hospitalization if acutely psychotic
General approach: Establish 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 complaints
Antipsychotic treatment: see antipsychotics for more details
- Acute psychotic episodes: short-acting antipsychotics (e.g., olanzapine ) +/- mood stabilizer for acute mania (e.g., lithium, valproate, carbamazepine), if present
- First-line treatment: second-generation antipsychotics (atypical antipsychotics; e.g., olanzapine, risperidone, quetiapine), which are especially effective at treating positive psychotic symptoms
- Alternatively, first-generation antipsychotics (typical antipsychotics) in depot form for those at risk of poor adherence (e.g., fluphenazine, haloperidol, chlorpromazine)
- Clozapine for 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
- Treatment during pregnancy: 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!

References:^[1]

Prognosis

Schizophrenia is a progressive disease that causes significant disability, with > 30% of patients presenting with psychosocial dysfunction.

Predictive factors for an unfavorable course of the illness
- Family history
- Earlier onset of disease
- Poor network of social support
- Being male
- Slow onset of illness
- More negative symptoms
- Concomitant substance use disorder
Predictive factors for a favorable course of the illness
- Later onset of disease
- Being female
- Mood symptoms
- Good network of social support
- Acute onset of illness
- More positive symptoms

Patients with schizophrenia are at an increased risk of alcohol abuse, depression, violence, and suicide (∼ 50% will attempt suicide)!