• Childhood period before any psychiatric symptoms emerge.
• Some patients show subtle abnormalities: motor deficits, neurological soft signs, lower IQ, poor social functioning.
• These premorbid features support the neurodevelopmental hypothesis — the idea that schizophrenia is not purely degenerative but involves abnormal brain development from early life.

• Attenuated (sub-threshold) psychotic symptoms: vague suspiciousness, perceptual disturbances, social withdrawal, functional decline.
• Most people meeting an at-risk definition do not transition during short-term follow-up; risk varies by sample, criteria and follow-up duration, so the lecture's “~30%” is not an individual prognosis.
• Offer specialist assessment, CBT with or without family intervention, treatment for depression/anxiety/substance use and structured follow-up. Do not prescribe antipsychotics solely to prevent psychosis in an at-risk state. ^[12]

• Full-blown psychotic symptoms meeting diagnostic criteria.
• Critical period = first 3–5 years after onset — outcomes during this window strongly predict long-term trajectory.

• Variable: some fully recover, some have relapsing-remitting course, some develop chronic residual deficits (predominantly negative symptoms and cognitive impairment).

Reading the course diagram: the vertical axis represents illness/function burden and the horizontal axis time. The prodromal trajectory branches before FEP because some at-risk patients improve without ever crossing a psychosis threshold. After FEP, the several arrows deliberately show heterogeneity—recovery, relapsing residual symptoms or persistent/progressive disability—not an inevitable downhill path. The diagram is conceptual and cannot predict one patient's outcome.

The most common positive symptoms include delusion of reference and persecution, and auditory verbal hallucination (AVH). ^[1]

Delusions:

• Fixed, false beliefs held with unshakeable conviction despite contradictory evidence, not accounted for by cultural/religious background.
• Un-understandable (Jaspers, 1913) / Bizarreness — a key characteristic. ^[1]
• Types: persecutory (most common), referential (most common alongside persecutory), grandiose, nihilistic, somatic, erotomanic, jealous.

A belief that is firmly held (unshakeable) on inadequate ground. — This exact definition appeared in the 2023 Fourth Summative MCQ Q23. ^[5]

Hallucinations:

• False perceptions in the absence of a sensory stimulus, not controlled by will.
• Auditory hallucinations are the commonest modality in schizophrenia. ^[2]
• Prominent visual or multimodal hallucinations—especially with fluctuating attention, cognitive change, focal neurological findings or a substance/medicine time-link—should widen the differential, but visual hallucinations can still occur in schizophrenia.

Kurt Schneider (1959): symptoms of "first rank of importance" — specific to schizophrenia and facilitating diagnostic assignment. ^[1]

Mnemonic (from Ryan Ho): SPECTRA — Somatic hallucination, Passivity, Echo of thoughts, Commentary, Thought alienation, Running commentary, Alien (delusional) perception. ^[4]

Literature showed that FRS are not specific to schizophrenia & with minimal prognostic predictive value. Nonetheless, FRS are still widely applied & emphasized in current classifications. ^[1]

How should FRS be used now? They are precise psychopathology descriptions and remain heavily tested, but neither DSM-5-TR nor ICD-11 treats them as pathognomonic. They can occur in mood, substance-induced and medical psychoses, so diagnosis depends on the full syndrome, duration, functional impact and exclusions—not a single FRS.

Lecture wording: a core feature of schizophrenia, a key determinant of functional outcome and an unmet therapeutic need—“not responsive to antipsychotic treatment.” ^[1]

Mnemonic: The 5 A's of negative symptoms.

Why are negative symptoms so important? Because:

1. They are the strongest predictor of long-term functional outcome (more than positive symptoms).
2. Primary, persistent negative symptoms respond poorly to available antipsychotics, although secondary negative symptoms may improve when positive symptoms, depression, EPS, sedation, substance use or social deprivation are treated.
3. They are often confused with depression or medication side effects (secondary negative symptoms from EPS, sedation, or depression must be excluded).

• Abnormality in the form (not content) of thinking.
• Loosening of association (derailment, tangentiality, circumstantiality) is characteristic of schizophrenia. ^[2]
• Other features: word salad, neologism, over-inclusion, concrete thinking, knight's move thinking.
• Disorganized behaviour: unpredictable, bizarre, inappropriate actions.

• Depression and mania can co-occur with schizophrenia.
• Depressed mood is one of the strongest predictors of suicide in early-stage psychotic disorders. ^[1]

• Posturing, waxy flexibility, mutism, stupor, negativism, echolalia, echopraxia.
• Remember: catatonia is not specific to schizophrenia — it can occur in mood disorders, medical conditions (encephalitis, metabolic), and is a DSM-5 specifier.

Lecture wording: a core feature in schizophrenia, a key determinant of functional outcome and an unmet therapeutic need—“not responsive to antipsychotic treatment.” ^[1]

In general, 1-2 standard deviations below normal healthy controls. Healthy first-degree relatives also demonstrate deficits (albeit less severe). Impairment in social cognition is observed including deficits in Theory of Mind (ToM) and emotion recognition. ^[1]

Why do relatives show deficits? This supports the genetic basis — cognitive impairment is an endophenotype (an intermediate trait between genotype and clinical phenotype) that is heritable and present even in unaffected relatives.

The group average of 1-2 standard deviations does not mean every patient is impaired in every domain. Assess cognition and functioning directly; antipsychotics are not established cognitive enhancers, while cognitive remediation and supported education/employment may improve real-world function.

Suicide is the single largest cause of premature death in schizophrenia. Lifetime risk: ~5.6% (from FEP cohorts). Risk is highest in the early stage, especially the first year after FEP. Suicide risk is 12× that of the general population. ^[1]

The percentages are historical cohort/meta-analysis estimates, not a score for an individual. Risk is dynamic and must be reassessed at first presentation, relapse, discharge/transition, treatment changes and new psychosocial stress.

Depressed mood is one of the strongest predictors of suicide, and is frequently observed in the early stage of illness. ^[1]

Other risk factors for suicide in schizophrenia:

• Male sex, young age, early stage of illness
• Higher premorbid functioning (more insight into lost potential → hopelessness)
• Command hallucinations
• Previous suicide attempts
• Comorbid substance abuse
• Social isolation

Schizophrenia reduces lifespan by 10-15 years on average. All-cause SMR: 2-3. In HK: SMR 2.5, shortened life expectancy 8-10 years. ^[1]

Possible reasons for elevated natural deaths: (1) Sedentary lifestyle, lack of exercise, poor nutrition; (2) Cigarette smoking, substance/alcohol abuse; (3) Metabolic syndrome (obesity, DM, hyperlipidaemia) — partly from second-generation antipsychotics; (4) ?Inherent disease process involving accelerated aging. ^[1]

Clinical implication: physical-health prevention applies to every patient, not only those taking a “second-generation” drug. Before antipsychotic treatment record weight, waist circumference, pulse/BP, fasting glucose or HbA1c, lipids, prolactin, movement disorders, nutrition and activity; obtain an ECG when the product information or cardiac/inpatient context indicates it. During treatment monitor response and adverse effects, weight weekly for 6 weeks then at 12 weeks, 1 year and annually, and repeat BP, glycaemia and lipids at 12 weeks, 1 year and annually. Use local protocols where they differ. ^[12]

High degree of heritability: ~80% contributed by genetic cause. Polygenic: multiple genes with small effects. Many candidate genes related to dopamine, glutamate, synaptic functions, and immune mechanisms. ^[1]

Interpret heritability correctly: approximately 80% is a population-level estimate of variation under particular environmental conditions; it does not mean that 80% of one person's illness is “genetic,” nor does family history make illness inevitable.

Rare copy number variants (CNV) with larger effect: e.g. Chromosome 22q11.2 deletion syndrome (DiGeorge / VCFS) — associated with 20-30 fold increase in risk. ^[1]

Why only 50% concordance in MZ twins? Because genetics confers vulnerability, not certainty. Environmental factors must interact with genetic predisposition (gene × environment interaction).

Distal (prenatal/perinatal): obstetric complications, winter birth, maternal infections (influenza, toxoplasmosis), advanced paternal age at conception. ^[1]

Proximal social risk factors: substance abuse (cannabis), migration (ethnic minority), urbanicity (urban upbringing). ^[1]

Why cannabis? Cannabis (especially high-potency THC) acts on the endocannabinoid system which modulates dopamine release. Adolescent cannabis use during the critical period of brain maturation increases risk of psychosis in genetically vulnerable individuals.

Why advanced paternal age? Spermatogonia accumulate de novo mutations with each cell division over a man's lifetime. Older fathers have more mutations, including in genes relevant to neurodevelopment.

Gene × environment interactions. ^[1]

The stress-vulnerability model: A person's genetic loading determines their threshold for psychosis; environmental stressors push them over that threshold. Some people have very low thresholds (high genetic risk) and need minimal stress; others have high thresholds and may never develop psychosis even with significant adversity.

Increased pre-synaptic dopamine synthesis in the striatum → hyperdopaminergic transmission → manifestations of psychosis. ^[1]

The four dopamine pathways — absolutely essential for exams:

Reading the pathway image: the mesolimbic and mesocortical tracts arise mainly from the ventral tegmental area and project to limbic/striatal reward regions and cortex respectively; the nigrostriatal tract runs from substantia nigra to dorsal striatum/basal ganglia; and the tuberoinfundibular tract runs from hypothalamic arcuate neurons to the median eminence/pituitary portal system. The diagram links where D2 modulation occurs to desired and adverse effects, rather than showing four separate diseases.

The “mesolimbic excess/mesocortical deficit” account is an exam model, not a complete regional map. D2 antagonism or partial agonism mainly improves positive symptoms; claims that antipsychotics invariably worsen primary negative/cognitive symptoms are too absolute because drug, dose, EPS, sedation and relief of secondary symptoms all matter.

Other neurotransmitters: glutamate (NMDA hypofunction), GABA. Excess glutamate neurotransmission → neurotoxicity / may lead to hyperdopaminergia. ^[1]

The glutamate-NMDA hypothesis: NMDA receptor hypofunction (e.g. from PCP or ketamine, which are NMDA antagonists) produces psychosis-like symptoms including both positive AND negative symptoms — better mimicking schizophrenia than pure dopaminergic agents. This suggests glutamate dysfunction is upstream of dopamine abnormalities.

The slide juxtaposes NMDA hypofunction with “excess glutamate/neurotoxicity”; these are related research models, not a single proven linear mechanism. Neither is a clinical biomarker or a basis for routine glutamatergic prescribing.

Absence of gliosis + lack of evidence of neuronal loss + reduction in synapse-rich neuropil → argues AGAINST a neurodegeneration hypothesis. ^[1]

Translation: If schizophrenia were a neurodegenerative disease (like Alzheimer's), you'd expect to see gliosis (scarring from dead neurons) and neuronal loss. The absence of these, combined with reduced synaptic density (neuropil), supports the neurodevelopmental hypothesis — the problem is aberrant brain development (abnormal synaptic pruning, connectivity), not progressive neuronal death.

Reduced whole brain volume / gray matter (GM) volume — especially temporal lobe (hippocampus, amygdala, STG), prefrontal cortex, thalamus, anterior cingulate. Increased ventricular volume. Reduced cortical thickness. Altered white matter integrity (DTI). Altered functional connectivity (fMRI). Evidence of progressive structural brain changes across illness course in a subgroup. ^[1]

Motor function deficits occur before onset. Neurological soft signs. Poor premorbid adjustment. Low IQ / mental retardation associated with higher risk. Cognitive deficits emerge in the prodromal period. ^[1]

“Mental retardation” is obsolete terminology; use intellectual disability. These features are non-specific risk associations and should not be used to screen or label an individual as destined to develop schizophrenia.

Stress-vulnerability model for psychosis development. ^[1]

Reading the neurodevelopmental model: genetic liability and prenatal stressors feed into early vulnerabilities such as altered white matter, synaptic plasticity and hippocampal development. Adolescent pruning/disconnectivity interacts with psychosocial stressors or substance exposure, leading to brain dysfunction. The lower branch shows neurocognitive deficits feeding into social-cognitive and role-function impairment, while both symptoms and functioning shape later outcome. The arrows represent a probabilistic, interacting pathway—not proof that a scan can diagnose schizophrenia or that brain change inevitably progresses.

Structural MRI findings are group-level associations with large overlap with healthy populations. Routine neuroimaging is therefore not diagnostic of schizophrenia; image when the history/examination suggests neurological or other organic pathology.

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

Current DSM-5-TR distinction: there must be a major mood episode concurrent with schizophrenia Criterion A, at least 2 weeks of delusions or hallucinations without a major mood episode, and mood episodes must occupy the majority of the total active and residual illness duration. “Equally prominent” at one cross-section is not enough; diagnosis is longitudinal.

Acute onset / complete remission / brief period (1-3 months, depends on criteria). Polymorphic features (~cycloid psychosis): rapidly changing clinical pictures, prominent fluctuating mood state, perplexity. ^[1]

Do not merge classification systems: DSM-5-TR brief psychotic disorder lasts at least 1 day but less than 1 month, with eventual full return to premorbid functioning; schizophreniform disorder lasts 1-6 months. ICD acute and transient psychotic disorder uses different symptom and duration rules. A brief label is provisional until longitudinal recovery is observed, and acute psychosis still requires urgent risk, substance and medical assessment.

Systematized, likely single-theme delusion, non-bizarre in nature (classic definition). No or non-prominent hallucination. Minimal negative symptoms, reported of having better functioning. Over-represented by women and adult-onset. Relatively rare. ^[1]

Delusional disorder themes (from Ryan Ho notes): Persecutory (commonest), erotomania, jealous, somatic, grandiose. ^[4]

• Drug-related questions commonly tested and commonly failed ^[10]
• Know: antipsychotics (typical vs atypical, side effects, clozapine monitoring), antidepressants, mood stabilizers, benzodiazepines
• For involuntary assessment/treatment, use the current Hong Kong Mental Health Ordinance and local operational policy; do not treat abbreviated form-number mnemonics from senior notes as legal instructions.