Key Facts

Schizophrenia is a severe, chronic mental illness characterised by psychotic symptoms, negative symptoms, and cognitive dysfunction. It typically presents in late adolescence or early adulthood and requires lifelong treatment.

Epidemiology

Lifetime prevalence is approximately 1% worldwide. Annual incidence is ~15-20 per 100,000. Males have earlier onset (18-25) than females (25-35). Schizophrenia reduces life expectancy by 15-20 years primarily due to cardiovascular disease, suicide, and metabolic syndrome.

Aetiology

• Genetic: Heritability ~80%; monozygotic twin concordance ~48%; polygenic — >100 associated loci
• Neurodevelopmental: Obstetric complications, prenatal infection, childhood adversity
• Neurochemical: Dopamine dysregulation, glutamate (NMDA receptor hypofunction), serotonergic involvement
• Environmental: Cannabis (especially adolescent use of high-potency), urban upbringing, migration, social adversity
• Neurodevelopmental hypothesis: Schizophrenia as a disorder of abnormal brain development, with genetic and environmental risk factors converging

Pathophysiology

• Dopamine hypothesis: Mesolimbic pathway overactivity → positive symptoms; mesocortical pathway underactivity → negative and cognitive symptoms
• Glutamate hypothesis: NMDA receptor hypofunction → downstream dopamine dysregulation (supported by PCP/ketamine models)
• Structural changes: Enlarged lateral ventricles, reduced cortical grey matter, reduced hippocampal volume
• Synaptic pruning: Excessive synaptic pruning in adolescence (complement C4 gene association) may contribute to symptom onset

Positive Symptoms

• Delusions: Persecutory, grandiose, referential, nihilistic, erotomanic, somatic; bizarre delusions (culturally implausible)
• Hallucinations: Auditory most common (voices — third person, running commentary, thought echo); visual, olfactory, tactile possible
• Thought disorder: Tangentiality, circumstantiality, loosening of associations, word salad, neologisms, thought blocking
• Passivity phenomena: Thought insertion, withdrawal, broadcast; made actions/feelings/impulses

Negative Symptoms

• Flat or blunted affect
• Alogia (poverty of speech)
• Avolition (loss of motivation)
• Anhedonia (loss of pleasure)
• Social withdrawal

Cognitive Symptoms

• Impaired working memory, attention, processing speed
• Executive dysfunction
• Often present before psychotic symptoms and persist after positive symptoms treated

Red Flags

• First-episode psychosis in young person — urgent assessment (early intervention in psychosis team)
• Command hallucinations to harm self/others — immediate risk assessment
• Catatonia — medical emergency; consider benzodiazepines, ECT
• Neuroleptic malignant syndrome on antipsychotics — pyrexia, rigidity, altered consciousness, raised CK

Bedside

• Mental state examination (MSE): Comprehensive assessment of appearance, behaviour, speech, mood, thought form/content, perception, cognition, insight
• Risk assessment: Suicide (5-10% lifetime risk), violence, self-neglect, vulnerability
• Cognitive assessment: Brief cognitive screen (MoCA, MMSE)
• Collateral history: Essential — from family, friends, GP

Bloods

• FBC: Baseline for antipsychotic monitoring; WCC for clozapine
• U&Es, LFTs: Baseline renal and liver function
• TFTs: Exclude thyroid dysfunction
• Fasting glucose, HbA1c, lipid profile: Metabolic syndrome baseline (antipsychotics cause weight gain and metabolic disturbance)
• Prolactin: Baseline and if symptoms suggest hyperprolactinaemia (antipsychotic side effect)
• Urine drug screen: Exclude substance-induced psychosis

Imaging

• MRI brain: Consider in first episode to exclude organic cause (tumour, demyelination)
• CT head: If MRI unavailable or acutely indicated

Special Tests

• ECG: QTc baseline before antipsychotics (many prolong QT)
• EEG: If seizures or encephalitis suspected
• NMDA receptor antibody testing: If suspected autoimmune encephalitis (especially young women with psychosis + movement disorder)

Non-pharmacological

• Early Intervention in Psychosis (EIP) team: All first-episode psychosis — NICE mandated within 2 weeks
• CBT for psychosis (CBTp): At least 16 sessions for all patients
• Family intervention: Reduces relapse rate by ~50%; 10+ sessions over 3-12 months
• Supported employment: Individual Placement and Support (IPS) model
• Arts therapies: Particularly for negative symptoms

Pharmacological (NICE CG178)

First-episode psychosis:

• Oral atypical antipsychotic: Risperidone 2-6mg OD, olanzapine 10-20mg OD, aripiprazole 10-30mg OD, or quetiapine 300-750mg/day
• Discuss efficacy, side effect profile with patient — shared decision-making
• Trial for 4-6 weeks at therapeutic dose before switching

Treatment-resistant schizophrenia (failed ≥2 antipsychotics):

• Clozapine: Start 12.5mg OD, titrate slowly to 300-450mg/day (max 900mg)
• Mandatory CPMS (Clozapine Patient Monitoring Service): Weekly FBC for 18 weeks → fortnightly for 1 year → monthly thereafter
• Side effects: Agranulocytosis (~1%), metabolic syndrome, sedation, constipation (can be fatal), myocarditis (~1-3%), seizures

Long-acting injectable antipsychotics (LAI):

• Paliperidone palmitate, aripiprazole lauroxil, flupentixol decanoate — if oral adherence poor

Referral Criteria

• Suspected first-episode psychosis — urgent EIP team referral (within 2 weeks)
• Treatment-resistant schizophrenia — clozapine initiation (specialist)
• Forensic risk — forensic psychiatry
• Catatonia — emergency psychiatric assessment

• Rule of thirds: ~1/3 good outcome, ~1/3 intermediate, ~1/3 chronic/severe course (simplified)
• Life expectancy: Reduced by 15-20 years vs general population
• Suicide: Lifetime risk 5-10%; highest risk in first 5 years and following discharge
• Relapse: ~80% relapse within 5 years if antipsychotic discontinued; ~20% on medication
• Clozapine: Response rate 30-60% in treatment-resistant cases; also reduces suicidality
• Good prognostic factors: Late onset, female sex, acute onset, good premorbid function, affective symptoms, family history of mood disorder, adherence to treatment
• Poor prognostic factors: Early onset, male sex, insidious onset, social isolation, prominent negative symptoms, substance misuse, family history of schizophrenia

Antipsychotic Side Effect Comparison

Dopamine Pathways