Schizophrenia And Related Disorders

• Prevalence of all psychotic disorders: approximately 2–3% ^[1]
• Lifetime risk of developing schizophrenia: ~1% ^[1]
• Median incidence rate of schizophrenia: 15.2 per 100,000 per year ^[1]
• Lifetime prevalence of psychotic disorders in Hong Kong: 2.5% (Chang et al. 2017) ^[1]
• Schizophrenia is traditionally described as a high-prevalence, low-incidence disease — meaning it is relatively common in the population at any given time (because it is chronic), but new cases per year are not that many ^[2]

Why the gender difference in onset? Oestrogen is thought to have a neuroprotective/antidopaminergic effect — it raises the threshold for psychosis. This is why women develop schizophrenia later (while oestrogen is high) and have a second peak at perimenopause (when oestrogen drops).

Incidence rates varied widely across regions (7.7–43 per 100,000 per year) ^[1], with elevated incidence being associated with:

• Migrants of ethnic minority (from developing countries to western developed countries, e.g. UK, Netherlands) (vs locally-born Caucasians) ^[1]
• Individuals being brought up in urban (vs rural) areas (urbanicity) ^[1]

These observations support the social defeat hypothesis / stress-dopamine sensitisation — chronic social stress (discrimination, social exclusion, isolation) sensitises the mesolimbic dopamine system, lowering the threshold for psychosis ^[1].

• Suicide is the single largest cause of premature death in schizophrenia ^[2]
  • 5.6% lifetime suicide risk (highest in the first year of illness) ^[2]
  • 12× general population suicide risk ^[2]
• Reduced lifespan by 10–15 years on average ^[2]
• 2.6× all-cause mortality, the majority being non-suicidal causes ^[2]
  • Reasons: (1) Sedentary lifestyle, poor nutrition; (2) High rates of smoking, substance/alcohol abuse; (3) Metabolic syndrome from 2nd-generation antipsychotics; (4) Possibly inherent disease process accelerating aging and medical morbidity ^[2]
• No. 12 leading disability worldwide, accounting for substantial direct and indirect costs ^[2]

This is the anatomical backbone of the dopamine hypothesis and explains both the symptoms and the side effects of treatment.

Why does dopamine blockade in the nigrostriatal pathway cause EPS? Dopamine in the basal ganglia normally facilitates smooth, coordinated movement by modulating the direct and indirect pathways of motor control. When antipsychotics block D2 receptors here, the result is an imbalance favouring the indirect (inhibitory) pathway — clinically manifesting as parkinsonian features (rigidity, bradykinesia, tremor), akathisia, and dystonia.

Structural / neuroanatomical abnormalities in schizophrenia (by sMRI) ^[1]:

• Reduced whole brain volume / grey matter (GM) volume ^[1]
• Reduced GM volumes in temporal lobe (hippocampus, amygdala, superior temporal gyri [STG]), prefrontal cortex, thalamus, anterior cingulate ^[1]
• Increased ventricular volume ^[1]
• Reduced cortical thickness (cortical thinning) ^[1]
• Reduced cortical surface area ^[1]

Structural & functional connectivity alterations ^[1]:

• Altered integrity of white matter tracts (via DTI — diffusion tensor imaging) ^[1]
• Altered resting-state functional connectivity (via fMRI) ^[1]

Why does disconnectivity matter? Schizophrenia is increasingly understood as a disconnection syndrome — the problem isn't just in individual brain regions, but in how they communicate with each other. This explains the bizarre juxtaposition of symptoms: a patient can have intact memory for facts but completely disordered thinking — the "wires" between brain areas are disrupted.

Evidence indicates progressive structural brain changes (volume reduction) across the course of illness, at least in a subgroup of patients ^[1].

High degree of heritability (estimated as 80% contributed by genetic cause) ^[1]

The MZ concordance of ~50% (not 100%) is critical — it proves that genetics alone is NOT sufficient. Environmental factors must also be involved ^[2].

Polygenic (multiple genes with small effects contributed by each gene) ^[1]:

• Many identified candidate genes are related to dopamine, glutamate, synaptic functions, and immune mechanisms ^[1]
• Single nucleotide polymorphisms (SNPs): common variants conferring small individual risks; 108+ genomic loci identified, including the MHC locus on chromosome 6 (immune function) ^[2]

Rare copy number variants (CNVs) with larger effect ^[1]:

• e.g. Chromosome 22q11.2 deletion syndrome (DiGeorge Syndrome or Velo-cardio-facial syndrome, VCFS) ^[1]
• Associated with 20–30-fold increase in risk of schizophrenia ^[1]

Why Ch22q11.2 deletion? This deletion encompasses genes involved in neuronal migration, synaptic signalling, and catecholamine metabolism (including COMT — catechol-O-methyltransferase, which degrades dopamine). Loss of COMT may lead to dopamine dysregulation. Additionally, the resulting congenital anomalies (cardiac defects, palatal abnormalities, thymic hypoplasia) reflect the broader neurodevelopmental disruption.

Schizophrenia shares genetic risk with other schizophrenia-spectrum disorders: schizoaffective disorder, schizotypal personality disorder, paranoid personality disorder, and even bipolar disorder and autism ^[2][3].

The old subtypes (paranoid, hebephrenic/disorganised, catatonic, simple, undifferentiated, residual) were removed from DSM-5 due to poor reliability, low diagnostic stability, and limited clinical utility. However, they may still appear in ICD-10 and are worth knowing:

Previously known as paranoid psychoses/paranoia ^[2]:

• Epidemiology: Uncommon; lifetime risk 0.05–0.1%; median age of onset 46 years ^[2]
• Clinical features:
  • Delusion that is non-bizarre (could theoretically happen in real life), systematised (well-organised, coherent), and single-themed (cf. fragmented, multiple, bizarre in schizophrenia) ^[2]
  • Themes: Persecutory (commonest), erotomania, jealous, somatic, grandiose, mixed, unspecified ^[2]
  • Encapsulated: behaviour unrelated to the delusion is often normal ^[2]
  • No/minimal hallucinations — if present, tend to be fleeting and related to the delusional theme ^[2]
  • No/minimal negative symptoms and impact on functioning ^[2]
• Course: Acute onset with generally stable trajectory (a proportion goes on to develop full-blown schizophrenia) ^[2]

DSM-5 Diagnostic Criteria for Delusional Disorder ^[2]:

• A. ≥1 delusion lasting ≥1 month
• B. Criterion A of schizophrenia has never been met (hallucinations, if present, are not prominent and are related to delusional theme)
• C. Functioning and behaviour are relatively normal apart from the delusion
• D. If mood episodes have occurred, they are brief relative to the delusional periods
• E. Not attributable to substance or medical condition

These represent a diminution or loss of normal functions. They are linked to hypodopaminergic transmission in the mesocortical pathway ^[1] and correlate with prefrontal cortex atrophy.

Negative symptoms are often more disabling than positive symptoms and are harder to treat.

The "5 A's" of negative symptoms:

Catatonia ("kata" = down, "tonos" = tension) — a syndrome of psychomotor disturbance that can occur in schizophrenia, mood disorders, or medical conditions.

Pathophysiology of catatonia: Hypothesised to involve GABAergic dysfunction (hence response to benzodiazepines, which enhance GABA), with additional involvement of dopaminergic, glutamatergic, and potentially autoimmune mechanisms. Always consider anti-NMDA receptor encephalitis as a differential for catatonia in young patients.

• Working memory deficits (PFC dysfunction)
• Attention and concentration impairment
• Processing speed reduced
• Executive function impairment (planning, abstract thinking, cognitive flexibility)
• Verbal learning and memory deficits

These are present before the onset of frank psychosis (in the prodromal period) and are relatively stable over time — they do not fluctuate with positive symptoms. They are the strongest predictor of functional outcome — more so than positive or negative symptoms. Unfortunately, they are also the hardest to treat with current medications.

• Depression — extremely common in schizophrenia (up to 80% experience depressive symptoms at some point); contributes significantly to suicide risk
• Anxiety — often present, especially in paranoid presentations
• Dysphoria / irritability

Brief psychotic disorder / acute & transient psychotic disorders (ATPD) ^[1]:

• Acute onset / complete remission / brief period (1–3 months, depends on criteria) ^[1]
• Polymorphic features (~cycloid psychosis): rapidly changing clinical pictures, prominent fluctuated mood state, perplexity ^[1]
• Duration: 1 day – 1 month (DSM-5 brief psychotic disorder); onset ≤2 weeks for ATPD (ICD-10) ^[2]
• May be precipitated by acute stress (intense stressor or traumatic event) ^[2]
• Rapid recovery is typical

Why distinguish this from schizophrenia? Prognosis is vastly different. Brief psychotic disorder has excellent prognosis with full return to premorbid functioning. Mislabelling it as schizophrenia carries enormous stigma and may lead to unnecessary long-term antipsychotic treatment.

Schizoaffective: concurrent schizophrenic and mood symptoms are equally prominent (fulfilling a major mood episode e.g. manic or depressive episode) ^[1]

• Diagnosed when a major mood episode (depressive or manic) occurs concurrently with psychotic symptoms meeting Criterion A of schizophrenia ^[2]
• The critical DSM-5 requirement: psychosis must exist for ≥2 weeks in the ABSENCE of a major mood episode during the total illness duration ^[2]
  • This is what separates it from a mood disorder with psychotic features (where psychosis occurs ONLY during mood episodes)
• Prognosis is intermediate between schizophrenia (worse) and mood disorders (better)

Why is this distinction so important clinically? Treatment differs. Schizoaffective disorder typically requires BOTH an antipsychotic AND a mood stabiliser (or antidepressant, depending on subtype), whereas a mood disorder with psychotic features may respond to mood treatment plus short-term antipsychotic.

Delusional disorder ^[1]:

• Systematized, likely single-theme delusion, non-bizarre in nature (classic definition) ^[1]
• No or non-prominent hallucination ^[1]
• Minimal negative symptoms, reported of having better functioning ^[1]
• Over-represented by women and adult-onset ^[1]
• Relatively rare ^[1]
• Lifetime risk 0.05–0.1%, median onset 46 years ^[2]
• Delusion themes: persecutory (commonest), erotomania, jealous, somatic, grandiose ^[2]
• Behaviour unrelated to the delusion is often normal (encapsulated) ^[2]

• Prevalence: 0.6–4.6%, familially aggregates with schizophrenia ^[2]
• A pervasive, enduring pattern (trait-like, > 2 years) of social/interpersonal deficits with attenuated psychotic-like features ^[2]:
  • Cognitive distortions ("attenuated delusions"): odd beliefs, ideas of reference, magical thinking, paranoid ideation ^[2]
  • Perceptual distortions ("attenuated hallucinations"): illusions, "sixth sense" ^[2]
  • Odd behaviour ("attenuated disorganisation"): vague/circumstantial speech, eccentric appearance ^[2]
  • Social isolation ("attenuated negative symptoms") ^[2]
• Never met full criteria for schizophrenia throughout entire life ^[2]
• Considered personality disorder in DSM-5 but schizophrenia-like disorder in ICD-10; part of the schizophrenia-spectrum ^[2]

Schizotypal vs Schizoid personality disorder: Schizoid PD has similar social isolation and emotional detachment but NO cognitive/perceptual distortions (no attenuated positive symptoms). Schizotypal has the "quasi-psychotic" features; schizoid is just detached and cold ^[2].

Manic episode with psychotic symptoms misdiagnosed as schizophrenia ^[3] — this is a classic pitfall.

Misdiagnosis is especially common — among 600 patients with bipolar disorder, 69% were initially misdiagnosed and most frequently as major depression, followed by anxiety disorders, substance/alcohol use disorder ^[3]. Correct diagnosis and treatment was delayed by 5–7 years on average ^[3].

Key distinguishing features between mania with psychosis and schizophrenia ^[2]:

Why is this misdiagnosis so consequential? Because treatment with antipsychotics alone (appropriate for schizophrenia) is insufficient for bipolar disorder — the patient needs a mood stabiliser (lithium, valproate). Conversely, treating bipolar depression with antidepressants alone (if misdiagnosed as MDD) can trigger a manic switch and accelerate cycling ^[3].

• Mood disturbance (depression) dominates the clinical picture ^[2]
• Psychotic content is often mood-congruent: nihilistic delusions ("I am already dead," "my organs are rotting"), delusions of guilt/worthlessness, persecutory delusions (believe punishment is deserved), auditory hallucinations with derogatory content ^[2]
• Psychotic symptoms occur only during depressive episodes and resolve when depression remits
• Unlike schizophrenia: no prominent formal thought disorder, no bizarre delusions, no negative symptoms outside of depression

• Some obsessions may resemble delusions due to the oddity of beliefs or intensity of conviction (poor-insight OCD) ^[2]
• Compulsive behaviours and weak resistance may look like disorganised or bizarre behaviour
• Key distinction: OCD symptoms are ego-dystonic (the patient recognises them as unwanted, intrusive, and distressing) whereas delusions in schizophrenia are ego-syntonic (the patient believes them to be true)
• NB: OC symptoms are also common within schizophrenia — always elicit other psychotic features actively ^[2]

• Borderline personality disorder (BPD): Can present with transient, stress-related paranoid ideation or dissociative symptoms that resemble psychosis. However, these are brief, occur in the context of interpersonal stress, and the patient has an enduring pattern of affective instability, identity disturbance, and impulsive behaviour ^[2]
• Paranoid personality disorder: Pervasive distrust and suspiciousness, but beliefs are overvalued ideas rather than fixed delusions. Maintains reality testing.
• Personality disorder with prominent irritability can mimic manic psychosis ^[3]
• Key: personality disorders are trait-like (enduring, pervasive, stable over years), NOT episodic ^[2]

Attention deficit and hyperactivity disorder ^[3]:

• Similarities with mania: decreased attention, difficulty with task completion, increased energy, disinhibited behaviour ^[2]
• Differences: ADHD should NOT have increased self-esteem, grandiosity, flight of ideas, decreased need for sleep ^[2]
• Course: ADHD is chronic (trait-like) rather than episodic ^[2]
• ADHD-like symptoms can also overlap with the cognitive and negative symptom dimensions of schizophrenia (poor concentration, reduced motivation), but ADHD lacks psychotic features

• Flashbacks can be misinterpreted as hallucinations
• Hypervigilance and paranoia may resemble persecutory delusions
• Key distinction: PTSD symptoms are clearly linked to a specific traumatic event, and the "hallucinations" are actually re-experiencing phenomena (vivid reliving of the trauma), not true perceptions without external stimuli in the schizophrenia sense

• Can present with social withdrawal, restricted interests, unusual behaviour, and communication difficulties that superficially resemble negative symptoms and disorganisation
• However: no delusions, no hallucinations; the social difficulties stem from impaired social cognition and restricted interests, not from paranoia or avolition
• DSM-5 allows comorbid diagnosis: if a person with ASD develops prominent delusions or hallucinations for ≥1 month, an additional diagnosis of schizophrenia can be made ^[2]

• The great mimicker — delirium can present with vivid hallucinations (typically visual), delusions, disorganised speech, agitation or stupor ^[2]
• Key distinctions from schizophrenia:
  • Fluctuating consciousness and attention (cardinal feature)
  • Disorientation (to time first, then place, then person)
  • Rapid diurnal changes (sundowning)
  • Acute onset with identifiable precipitant
  • Usually in elderly or medically unwell patients
• Always rule out delirium before diagnosing a primary psychotic disorder, especially in first presentations, older patients, or medically unwell patients ^[2]

• Especially Lewy body dementia — characterised by vivid visual hallucinations (often well-formed, detailed images of people or animals), fluctuating cognition, and parkinsonism ^[2]
• Also: Alzheimer's disease (delusions common in moderate–severe stages), frontotemporal dementia (behavioural variant can mimic negative symptoms and disorganisation)
• Key distinction: Progressive cognitive decline is the primary feature; psychosis is secondary

• Anti-NMDA receptor encephalitis — especially important in young women; presents with psychiatric symptoms (psychosis, agitation, catatonia) followed by seizures, movement disorders, autonomic instability. This is treatable with immunotherapy and is a critical "don't miss" diagnosis
• Temporal lobe epilepsy — can cause ictal and post-ictal psychosis, déjà vu, olfactory/gustatory hallucinations
• Autoimmune/infectious encephalitis, MS, leukodystrophies, cerebral lupus (SLE), head trauma, space-occupying lesions (SOL), stroke, neurodegenerative disorders ^[2]

• Thyroid disorders (both hyper- and hypothyroidism — "myxoedema madness")
• Parathyroid disorders (hypercalcaemia → psychosis)
• Adrenal disorders (Cushing's disease — cortisol excess; Addisonian crisis)
• Vitamin deficiency: B12 (subacute combined degeneration → psychiatric symptoms), B1 (Wernicke's — but this more commonly causes delirium), B3 (pellagra — the classic "3 D's": dermatitis, diarrhoea, dementia/psychosis)
• Hepatic/uraemic encephalopathy
• Acute intermittent porphyria (classically presents with abdominal pain, neuropsychiatric symptoms, and autonomic dysfunction in young women)
• Wilson's disease (copper accumulation — psychiatric symptoms can precede neurological signs; look for Kayser-Fleischer rings) ^[2]
• Infections: HIV (direct CNS involvement), neurosyphilis (general paresis of the insane — grandiose delusions classically), Lyme disease ^[2]

• Key distinction: Substance-induced psychosis should remit after the substance clears (typically days to weeks). If it persists beyond this, consider a primary psychotic disorder that was "unmasked" by the substance ^[2]
• Always perform urine toxicology screen in first-episode psychosis ^[2]

• Neurological drugs: Barbiturates, benzodiazepines (especially during withdrawal), anticholinergics, antidepressants (serotonin syndrome), antiepileptics, antiparkinsonian agents (L-DOPA, dopamine agonists) ^[2]
• Other medications: Corticosteroids (steroid psychosis — dose-related), antimalarials (mefloquine), digoxin, dextromethorphan ^[2]
• Toxins: Carbon monoxide, organophosphates, heavy metal poisoning (arsenic, manganese, mercury, thallium) ^[2]

This is essentially a "provisional schizophrenia" — if symptoms persist beyond 6 months, the diagnosis is upgraded to schizophrenia ^[2].

Cognitive impairment is a core feature in schizophrenia ^[1]:

• Key determinant of functional outcome ^[1]
• Unmet therapeutic need, not responsive to antipsychotic treatment ^[1]
• Generalised cognitive impairment encompassing multiple cognitive domains: sustained attention, executive functions (planning, set-shifting, inhibition control), working memory, verbal and visual memory (immediate registration and recall), processing speed ^[1]
• In general, 1–2 standard deviations below normal healthy controls ^[1]
• Healthy first-degree relatives of patients also demonstrate deficits (albeit less severe) in cognition ^[1]
• Impairment in social cognition observed including deficits in Theory of Mind (ToM), emotion recognition etc. ^[1]

Formal neuropsychological testing (e.g. MATRICS Consensus Cognitive Battery) can be used to quantify deficits and guide cognitive remediation therapy, though this is typically done after acute stabilisation rather than during the acute diagnostic work-up.

This is critically important given the metabolic morbidity associated with schizophrenia and its treatment:

Antipsychotic medication as the mainstay treatment ^[1]

Effective in treating positive psychotic symptoms ^[1]

> 80% of patients with first-episode psychosis respond to antipsychotic treatment in first psychotic episode ^[1]

Mechanism of action: D2 receptor antagonist (striatum) ^[1]

Why D2 blockade works: In schizophrenia, the mesolimbic pathway is hyperdopaminergic. D2 receptor antagonism in the mesolimbic system reduces this excess dopaminergic signalling, thereby reducing the aberrant salience that drives delusions and hallucinations. The drug only needs to occupy 70–80% of striatal D2 receptors to be clinically effective ^[2].

Excessive D2 blockade (> 70–80% of striatal D2 receptors) → motor side-effects ^[1]

Why does excessive blockade cause EPS? Beyond the 70–80% threshold needed for therapeutic effect, additional D2 blockade in the nigrostriatal pathway tips the balance of the direct/indirect motor pathways, causing parkinsonism, dystonia, and akathisia. This is the therapeutic window concept — enough blockade to treat psychosis, not so much as to cause EPS.

The traditional classification divides antipsychotics into first-generation (FGA, "typical") and second-generation (SGA, "atypical"), though newer evidence suggests this classification has limited clinical significance — drugs should be considered individually based on their side effect profiles ^[2].

Why do SGAs cause less EPS? The 5-HT2A antagonism of SGAs disinhibits dopamine release specifically in the nigrostriatal pathway, partially counteracting the D2 blockade there. This "restores" some dopaminergic tone in the motor pathway, reducing EPS risk. However, this comes at the cost of metabolic effects from histamine H1, muscarinic, and serotonin receptor interactions.

Side effects of antipsychotics are explained by their receptor binding profiles beyond D2:

"Anti-HAM" = anti-Histaminergic + anti-Adrenergic (α1) + anti-Muscarinic effects. This framework lets you predict side effects from receptor profiles ^[2].

Why use depot injections? Non-adherence is the major risk factor for relapse — up to 52% of patients are non-adherent ^[2]. Depot formulations guarantee medication delivery and remove the daily decision to take or skip a pill. Studies show depots reduce relapse and rehospitalisation rates.

High risk of relapse ^[1]

Major risk factor of relapse: non-adherence to medication ^[1]

At least 1–2 year maintenance antipsychotic treatment following positive symptom remission is recommended for first-episode psychosis (also depends on individual case) ^[1]

Why such long maintenance? The neurobiology doesn't "reset" after a psychotic episode. The underlying dopamine dysregulation persists. Antipsychotics suppress psychosis but don't cure the underlying vulnerability. Stopping medication removes the suppressive effect, and the mesolimbic hyperdopaminergia re-emerges → relapse. Additionally, each relapse may cause further neurotoxic damage and progressive structural brain changes.

Treatment-resistant schizophrenia ^[1]:

• Persistent, prominent positive psychotic symptoms despite at least 2 trials of different types of antipsychotic medications with adequate dose and adequate duration (6–8 weeks) ^[1]
• Indication for clozapine initiation ^[1]

Clozapine is the gold standard for TRS — it is the only drug proven to be superior in treatment-resistant patients ^[2].

Clozapine Side Effects — The Trade-off:

Clozapine Monitoring:

Clozapine Contraindications ^[2]:

• Neutropenia (absolute)
• Cardiac disease (myocarditis, cardiomyopathy)
• Uncontrolled seizure disorder (relative)
• Severe hepatic impairment (relative)
• Paralytic ileus (relative)

If Clozapine Fails — little consensus on best treatment ^[2]:

• Add another antipsychotic to clozapine (e.g. amisulpride, aripiprazole)
• ECT augmentation
• Lamotrigine augmentation (evidence for reducing positive symptoms when added to clozapine)

• Benzodiazepines: For acute behavioural disturbances, aggression, agitation, insomnia. Used as short-term adjunct, NOT as standalone treatment for psychosis ^[2]
• Antidepressants/lithium: For augmentation in treatment-resistant cases (evidence limited), especially when there are significant affective symptoms (e.g. schizoaffective disorder, post-schizophrenia depression) ^[2]

Cognitive-behavioural therapy (CBT) ^[1]:

• Residual positive psychotic symptoms (e.g. residual AH) ^[1]
• Comorbid depressive and anxiety symptoms ^[1]

This is a major focus for mental health service development in the past 20 years ^[2]:

Why is early intervention so important? The "critical period" hypothesis proposes that the first few years after psychosis onset represent a window of neuroplasticity where treatment has maximal impact. Longer DUP is associated with reduced grey matter volume, worse cognitive function, and poorer treatment response. Early detection and intensive treatment during this window can alter the long-term trajectory of illness.

ECT for catatonia / treatment-resistant schizophrenia ^[1]

Suicide is the single largest cause of premature death in schizophrenia ^[1]

Why is the first year after FEP the highest risk period? Several factors converge: (1) the patient is often an intelligent young person who develops insight into the devastating nature of their diagnosis — this "insight–despair paradox" is a powerful driver of hopelessness; (2) depressive symptoms are extremely common in early psychosis; (3) command auditory hallucinations may instruct self-harm; (4) the transition from acute treatment to community care is a vulnerable period with potential loss of support ^[2].

Additional suicide risk factors specific to schizophrenia:

• Young age, male sex
• Good premorbid functioning (more to lose → greater perceived loss)
• High education level
• Early illness course (especially first 1–5 years)
• Comorbid depression (present in ~25% — post-schizophrenia depression ^[2])
• Comorbid substance abuse
• Command hallucinations
• Previous suicide attempts
• Recent hospital discharge
• Social isolation, loss of role/employment
• Poor adherence → relapse → crisis

Excess mortality in schizophrenia patients ^[1]:

• Schizophrenia reduces an affected individual's lifespan by on average 10–15 years ^[1]
• All-cause standardised mortality ratio (SMR): 2 to 3 ^[1]
• SMR of schizophrenia: 2.5, shortened life expectancy: 8–10 years in Hong Kong (Yung et al. 2021) ^[1]
• Elevated both in suicide and natural deaths ^[1]
• Increased risk of premature deaths related to a wide range of physical illnesses ^[1]

Possible reasons for elevated rate of natural deaths ^[1]:

Why is cardiovascular disease the biggest killer in schizophrenia? It is the perfect storm: intrinsic metabolic dysregulation + antipsychotic-induced metabolic syndrome + cigarette smoking + sedentary lifestyle + poor nutrition + substance abuse + poor access to healthcare (patients may not report symptoms, may not be taken seriously in medical settings ["diagnostic overshadowing"], and may struggle to navigate healthcare systems). Each factor alone increases cardiovascular risk; together, they are devastating.

The conditions cause profound disruptions in individuals' personality development, social relationships, scholastic and vocational trajectories ^[1]

Potentially chronic, remitting-relapse course, with significant functional impairment ^[1]

Cognitive impairment is a core feature in schizophrenia, a key determinant of functional outcome, and represents an unmet therapeutic need, not responsive to antipsychotic treatment ^[1]. This means that even when positive symptoms are well-controlled, patients may remain functionally disabled due to persistent cognitive deficits. This is why cognitive remediation and psychosocial rehabilitation are critical complements to medication.

• Patients with schizophrenia have a modestly increased risk of violence compared to the general population, but this is largely mediated by comorbid substance abuse — patients without substance abuse have only marginally elevated risk
• Risk factors: active positive symptoms (persecutory delusions, command hallucinations), substance abuse, non-adherence, history of violence
• Important context: Patients with schizophrenia are far more likely to be victims of violence and exploitation than perpetrators. Stigma from exaggerated media portrayal of violence in schizophrenia is one of the most damaging barriers to care

Catatonia can occur as a complication of schizophrenia itself (discussed in the clinical features section). Malignant catatonia — characterised by fever, autonomic instability, rigidity, and delirium — is a medical emergency with significant mortality if untreated. Treatment is with benzodiazepines (first-line) and/or ECT ^[2].

• Cognitive: Acute post-ictal confusion; anterograde and retrograde amnesia (generally short-lived, days to weeks; bilateral > unilateral placement)
• Medical: Headache, nausea, muscle pain; rare cardiac arrhythmias; extremely rare aspiration
• Mortality: 2–4 per 100,000 (comparable to minor surgery under GA)

• Schizophrenia and related psychoses account for substantial direct and indirect costs to the society ^[1]:
  • Direct costs: hospitalisation, medication costs etc. ^[1]
  • Indirect costs: loss of productivity in patients and their caregivers, disability allowance etc. ^[1]
• The name "schizophrenia" itself carries immense stigma — many Asian countries (including Japan, South Korea, and Hong Kong) have renamed or discussed renaming the disorder (Japan changed to "integration disorder" in 2002)
• Stigma leads to: delayed help-seeking, social exclusion, housing discrimination, employment discrimination, "diagnostic overshadowing" (physical symptoms dismissed as psychiatric), and internalised shame

High risk of relapse ^[1]. Major risk factor of relapse: non-adherence to medication ^[1].

Non-adherence (up to 52% ^[2]) creates a vicious cycle:

Non-adherence → relapse → hospitalisation → medication restarted → side effects → poor adherence → relapse...

Each relapse carries risk of:

• Incomplete recovery (the "scar" effect — each episode may leave behind increasing residual deficit)
• Progressive functional decline
• Progressive structural brain changes (grey matter loss) — it is postulated that active psychosis is neurotoxic and delayed treatment leads to irreversible neurological deterioration ^[2]
• Increased suicide risk during acute relapse
• Social consequences (loss of employment, relationships, housing)

• Patients with chronic schizophrenia are overrepresented in homeless populations and the criminal justice system
• This reflects the combination of functional impairment, substance abuse, medication non-adherence, inadequate community mental health services, and stigma

• Expressed emotion (EE) — critical, hostile, or emotionally over-involved attitudes from family — is both a complication (resulting from caregiver burnout) and a perpetuating factor (increasing relapse risk if EE exposure > 35h/week) ^[2]
• Caregivers experience increased rates of depression, anxiety, social isolation, financial hardship, and physical health problems
• Family intervention (psychoeducation, support groups, EE reduction) directly addresses this