L7 Psych Med Schizophrenia

Overview

This lecture covers psychosis as a syndrome and schizophrenia as its prototypical disorder: the positive and negative symptom clusters and their relative prevalence, diagnostic criteria, cognitive impairment, the history of the “dementia praecox” concept, epidemiology (global and NZ-specific), the genetic and structural-brain-network aetiology, clinical course and outcome predictors, the social, health, mortality and economic burden of the illness, and antipsychotic drug treatment (history, D2 occupancy/efficacy relationship, duration of treatment, and oral vs depot formulations).

Psychosis and its symptoms

• Psychosis is a syndrome (mixture of symptoms), not a single disorder: delusions, hallucinations, distorted reality testing, abnormal speech and behaviour, motor disturbances; presentations may be paranoid, excited/disorganised, or depressive.
• It is the defining feature of schizophrenia, schizoaffective disorder and drug-induced psychotic disorder, but can also occur in mania, depression, dementias (Alzheimer’s, Parkinson’s), medical illness, delirium, or be drug-induced.
• Positive symptoms (excess/distortion of normal function): hallucinations (perception), delusions (reality testing), disorganised speech or behaviour.
  • Specific positive symptoms: delusions (fixed false beliefs), ideas/delusions of self-reference, hallucinations (perceptions without external stimuli), loss of thought boundaries, passivity, disorganised behaviour/movements, formal thought disorder.
• Negative symptoms (diminution/loss of normal function): affective blunting, poverty of thought/speech, avolition/apathy, anhedonia, impaired attention, and other cognitive impairments (working memory, processing speed, problem solving deficits).

Diagnosis and symptom factor structure

• Schizophrenia diagnosis: 2 or more of delusions, hallucinations, disorganised speech, disorganised or catatonic behaviour, negative symptoms; at least 1 month of active symptoms; overall duration of 6+ months.
• Factor analysis groups schizophrenia symptoms into three factors:
  • Reality distortion: hallucinations (auditory 19-51%, somatic/tactile 20-30%, olfactory 1-5%, visual 15%) and delusions (persecutory up to 47%, of being controlled up to 25%, of reference up to 21%, of mind reading up to 19%).
  • Disorganisation: formal thought disorder (~30%), disorganised behaviour including difficulty completing goal-directed tasks and catatonia.
  • Negative symptoms: affective blunting (32-54%), alogia (20-30%), avolition (33-41%), anhedonia (38-41%), impaired attention (25-30%).

Cognitive impairment

• Lifelong IQ disadvantage of 7-8 points versus peers.
• Deficits across multiple neuropsychological domains, ranked by effect size (largest to smallest): attention, general intellectual ability, declarative memory, processing speed, executive functions, working memory maintenance and manipulation, motor speed, working memory maintenance, language, perception.

History

• 1896: Kraepelin divided “insanity” into dementia praecox and manic depression, emphasising chronicity and delusions/hallucinations in dementia praecox; onset typically in young adulthood, rare in children.

Epidemiology

• Lifetime prevalence approximately 1%; incidence about 15 new cases per 100,000 population per annum; M:F incidence ratio 1.7:1.
• 5-fold variation in incidence internationally, with higher rates associated with increased immigration and urban living; core symptoms are the same across groups.
• 2015 NZ data (Stats NZ analysis, 2017): prevalence 6.7/1000 (aged 18-64). By gender: M 8.9/1000, F 4.7/1000 (OR 0.52). By ethnicity: European 6.3/1000, Māori 16.7/1000 (OR 3.36), Pacifika 10.9/1000 (OR 1.70), Asian 3.0/1000. Highest prevalence in the 35-54 age groups.
• Age of onset: males peak in early 20s; females show no clear peak. Around 70% of cases are preceded by a prodrome (gradual deterioration over 3-24 months), with symptoms of mild/moderate disturbance in perception, cognition, language, motor function, will, initiative, energy level and stress tolerance.
• Developmental progression model: social adversity and genetic/developmental risk factors feed into a sequence through childhood/adolescence/early adulthood: cognitive, motor and social impairment -> anxiety and depressive symptoms -> social withdrawal and subjective cognitive changes -> prodromal symptoms -> psychosis.

Risk factors and aetiology

• Risk factor model: genetic vulnerability (identified genes include neuregulin 1, dysbindin, possibly COMT) interacts with prenatal environment (obstetric complications, viral exposure, maternal stress and malnutrition), childhood environment (child-rearing, abuse, head injury) and later-life environment (drug abuse, migration/ethnicity, urbanicity, social adversity/life events) to produce onset.
• Also more common in: unmarried people, low socioeconomic status (downward drift), and immigrants (with immigrants’ children having risk roughly halfway between immigrants and locals).
• Genetic epidemiology (family/twin/adoption studies): risk of developing schizophrenia rises with percentage of genes shared, from general population 1% up to identical twins 48% (Gottesman 1991); intermediate points include first cousins/uncles-aunts 2% (12.5% genes shared), nephews/nieces 4%, grandchildren 5%, half-siblings 6% (25% shared), parents 6%, siblings 9%, children 13%, fraternal twins 17% (50% shared).
  • Family studies (11 studies): 10/11 show familiality of schizophrenia.
  • Adoption studies (5 studies): adoptees with schizophrenia have OR=5 for risk in biological vs adoptive parents; parents with schizophrenia have OR=3.5 for risk in biological vs control children.
  • Twin studies (12 studies, MZ vs DZ): heritability in liability to schizophrenia = 81%, environmental effects = 11%.
• Genetic architecture — three converging lines of genetic evidence linked to brain network abnormalities:
  1. SNP studies: polygenic, >140 risk alleles of small effect, each with low odds ratios (1.1-1.5) and low positive predictive value/clinical utility; considerable genetic overlap with bipolar disorder (rg=0.7), major depression (0.32) and autism spectrum disorder (0.26).
  2. Copy number variants (CNVs): deletions/duplications of DNA from a few hundred bp to several million bp; important cause of genetic/phenotypic variability; CNVs cover more of the genome than SNPs (12% vs 0.3%), evaluated using GWAS.
  3. Rare gene mutations: ultra-rare protein-truncating variants in 10 genes that dramatically increase risk (prevent production of full-length functional protein). Example: GRIA3 (present in 0.0009% of population, 48.2% odds of developing schizophrenia, component of the AMPA glutamate receptor); GRIN2A (present in 0.0021%, 18.1% odds, component of the NMDA glutamate receptor). Genes affected by CNVs and mutations are consistently involved in signalling and/or neuronal function.
  • Across these mechanisms there is an inverse relationship between variant frequency and effect size: rare mutations (e.g. GRIA3, GRIN2A) have the highest effect sizes at the lowest frequencies; CNVs are intermediate; common SNPs have effect sizes near 1 across much higher frequencies.
• Schizophrenia can be conceptualised as a disorder of brain connectivity/network dysfunction: distinct neural networks are defined by correlated regional activity during tasks or at rest, studied with MRI, EEG, MEG and statistical models; altered network activity/coherence may contribute to onset and symptoms. Friston and Frith (1995): profound disruption of large-scale prefronto-temporal interactions, relevant because many positive symptoms reflect failure to integrate intrinsically generated behaviour with concurrent perception.
• Structural brain changes: loss of brain volume, particularly grey matter, evident early in the disease (even in antipsychotic-naive patients) with further progression over time; effect sizes for grey matter volume loss are around -0.5 in medicated and -0.3 in antipsychotic-naive patients (all measured brain volume domains show negative/loss effect sizes except CSF, which increases).

Clinical course and outcome

• Course: prodrome in 73% of patients; full recovery (mild symptoms, good social functioning for >2 years) in 14%; improved/good outcomes in 40-42%; poor outcome in 20-30%. Relapse rates are influenced by medication compliance, substance use, service availability and social challenges.
• Predictors of good outcome: acute onset, a stressful life event at onset, family history of depressive illness, no family history of schizophrenia, confusion or perplexity, prominent affective symptoms, being married, higher IQ.
• Predictors of poor outcome: younger age at onset, insidious onset, unmarried, emotional blunting, lower IQ, poor work record, prominent premorbid schizoid traits, male.

Social, health, mortality and economic impacts

• Social/health impacts: high unemployment, poverty, smaller/absent social network and isolation, poor nutrition, high smoking rates, high rates of obesity, high rates of rehospitalisation, reduced life expectancy (>15 years), high rates of drug abuse and suicide (~10%).

• Suicide rate is approximately 20x higher (adjusted) than the general population (Denmark data, BMJ 2004). Overall mortality is 1.6-2.2x higher (UK 1999-2006 data, BMJ 2011).

• Suicide risk factors: younger age, male, unmarried, living alone, unemployed, being intelligent and well-educated, having high personal expectations and hopes, good premorbid adjustment/functioning, awareness that life’s expectations will not be met, recent (within 3 months) life events, poor work functioning, access to lethal means (e.g. firearms). Risk is higher during the first psychotic break and the first decade of illness.
• Suicide prevention: strategies to improve medication compliance (clozapine has demonstrated antisuicidal activity; depot antipsychotics reduce relapses), identifying and treating comorbid depression, and supportive interventions (CBT, rehabilitation, social skills training, supported employment, family education/support).
• Economic burden (2024 US data): direct costs 20% of total (yearly cost US$103,880/patient); indirect costs 80%, comprising productivity losses (15%), shortened life expectancy (13%), reduced quality of life (11%) and uncompensated caregiver losses (29%). Domain-level societal costs are dominated by caregiver unpaid wages and other caregiver impacts, employment losses and reduced lifespan, offset partly by cost-of-living and justice-system savings.

Drug treatment

• History: chlorpromazine (1952) was the first antipsychotic; first-generation drugs (1950s-60s, e.g. haloperidol) share similar antipsychotic efficacy but differ in potency and side-effect profile (movement disorder liability/EPSE, sedation). Clozapine (late 1960s, atypical) has greater antipsychotic efficacy with no EPSE or hyperprolactinaemia, but risk of agranulocytosis. In the 1970s the relationship between D2 affinity and average daily dose was described. Second-generation drugs (1990s: risperidone, olanzapine, quetiapine, ziprasidone, aripiprazole, amisulpride) have efficacy equal to haloperidol but are better tolerated with reduced motor side effects.
• D2 occupancy, efficacy and side effects: all antipsychotics show some degree of D2 antagonism; D2 antagonist potency predicts efficacy, daily dose and liability for EPSE and hyperprolactinaemia. Roughly 65% D2 occupancy is needed for antipsychotic efficacy, while occupancy above 80% produces EPSE.
• Treatment duration: antipsychotics should be given for 1-2 years after a first psychotic episode; without treatment, ~70% relapse within 1 year; more than 50% of patients may require long-term treatment. Key issues are poor compliance/insight; the Mental Health Act may be used to support compliance. Oral quetiapine XR maintains a much higher survival (relapse-free) rate than placebo over 6 months.
• Oral vs depot medication: depots are given every 2-4 weeks by a community nurse and carry a lower risk of relapse due to regular appointments and verified dosing/improved compliance (illustrated by paliperidone oral vs depot pharmacokinetic profiles).

Summary

• Key symptoms of psychosis are delusions, hallucinations, disorganisation and negative symptoms; schizophrenia is one type of psychosis and may reflect impaired integration in brain networks.
• Schizophrenia affects social functioning and physical wellbeing: many people with schizophrenia are socially disabled, suicide rate is increased ~20x, and overall mortality is increased ~2x.
• Antipsychotic medication together with psychosocial support and rehabilitation can support community living.

Self-test

1. Distinguish positive from negative symptoms of psychosis, giving three examples of each.
2. What are the diagnostic criteria for schizophrenia in terms of symptom count, minimum duration of active symptoms, and total illness duration?
3. List the three symptom factors identified by factor analysis in schizophrenia, with one example symptom from each.
4. Describe the pattern of cognitive impairment seen in schizophrenia, including the domain most affected.
5. What did Kraepelin propose in 1896, and what features did he emphasise in dementia praecox?
6. Describe how schizophrenia prevalence in the 2015 NZ data varied by gender and by ethnicity.
7. Describe the typical age-of-onset pattern for men versus women, and the prodrome that precedes onset in most cases.
8. List the three tiers of environmental risk factors for schizophrenia (prenatal, childhood, later life), giving one example of each.
9. Using the relative-risk data from family studies, explain how risk of schizophrenia changes with degree of genetic relatedness, from general population to identical twins.
10. Summarise the findings of family, adoption and twin genetic epidemiology studies for schizophrenia, including the heritability estimate.
11. Describe the three types of genetic contribution to schizophrenia (SNPs, CNVs, rare mutations) and how their frequency and effect size relate to each other.
12. Explain the “disorder of brain connectivity” model of schizophrenia and what Friston and Frith (1995) proposed.
13. What predicts a good outcome in schizophrenia, and what predicts a poor outcome? Give at least four factors each.
14. What are the suicide and overall mortality risks in schizophrenia relative to the general population, and what factors increase suicide risk?
15. Describe the strategies used for suicide prevention in schizophrenia.
16. Outline the historical development of antipsychotic drugs from chlorpromazine to second-generation agents, noting one key advantage of each generation.
17. Explain the relationship between D2 receptor occupancy and antipsychotic efficacy versus extrapyramidal side effects.
18. A patient has just had a first psychotic episode. What does the transcript say about recommended treatment duration and relapse risk if untreated?
19. Compare oral and depot antipsychotic formulations in terms of relapse risk and why.

Answers

Reveal answers

1. Positive symptoms reflect an excess/distortion of normal function, e.g. hallucinations, delusions, disorganised speech or behaviour. Negative symptoms reflect a diminution or loss of function, e.g. affective blunting, avolition/apathy, anhedonia.
2. Two or more of delusions, hallucinations, disorganised speech, disorganised or catatonic behaviour, or negative symptoms; active symptoms for at least 1 month; overall illness duration of 6 months or more.
3. Reality distortion (e.g. hallucinations or delusions), disorganisation (e.g. formal thought disorder or catatonia), negative symptoms (e.g. affective blunting or avolition).
4. A lifelong IQ disadvantage of 7-8 points versus peers, with deficits across multiple neuropsychological domains; attention shows the largest effect size, followed by general intellectual ability and declarative memory, down to perception with the smallest effect size.
5. Kraepelin divided “insanity” into dementia praecox and manic depression; he emphasised chronicity and the presence of delusions and hallucinations in dementia praecox, with onset typically in young adulthood and rare in children.
6. Prevalence was higher in males (8.9/1000) than females (4.7/1000, OR 0.52). By ethnicity, prevalence was highest in Māori (16.7/1000, OR 3.36), followed by Pacifika (10.9/1000, OR 1.70), European (6.3/1000), and lowest in Asian (3.0/1000).
7. Males peak in incidence in their early 20s; females show no clear peak. Around 70% of cases are preceded by a prodrome, a gradual deterioration over 3-24 months with mild/moderate disturbances in perception, cognition, language, motor function, will, initiative, energy and stress tolerance.
8. Prenatal environment (e.g. obstetric complications, viral exposure, maternal stress/malnutrition), childhood environment (e.g. child abuse, head injury), later-life environment (e.g. drug abuse, migration, urbanicity, social adversity/life events).
9. Risk rises steadily with shared genetic material: general population 1%, third-degree relatives (12.5% shared) ~2%, second-degree relatives (25% shared) 4-6%, first-degree relatives (50% shared) 6-17% (parents 6%, siblings 9%, children 13%, fraternal twins 17%), rising to 48% in identical twins (100% shared).
10. Family studies: 10 of 11 studies showed familiality. Adoption studies: adoptees with schizophrenia have OR=5 for risk via biological vs adoptive parents, and children of parents with schizophrenia have OR=3.5 for risk via biological vs control children. Twin studies: heritability in liability to schizophrenia is 81%, with environmental effects of 11%.
11. SNPs are common but individually low-effect (>140 risk alleles, ORs 1.1-1.5, polygenic). CNVs are intermediate in frequency and effect size, covering more of the genome than SNPs. Rare gene mutations (e.g. GRIA3, GRIN2A) are extremely rare in the population but confer very high individual odds of schizophrenia (up to ~48%). Overall, effect size increases as variant frequency decreases.
12. Schizophrenia is proposed to arise from disrupted large-scale brain network connectivity rather than a single lesion; Friston and Frith (1995) proposed profound disruption of large-scale prefronto-temporal interactions, relevant because many positive symptoms reflect a failure to integrate self-generated behaviour with concurrent perception.
13. Good outcome: acute onset, stressful life event at onset, family history of depressive illness, no family history of schizophrenia, confusion/perplexity, prominent affective symptoms, married, higher IQ. Poor outcome: younger age at onset, insidious onset, unmarried, emotional blunting, lower IQ, poor work record, premorbid schizoid traits, male.
14. Suicide rate is roughly 20x higher (adjusted) than the general population; overall mortality is 1.6-2.2x higher. Suicide risk is increased by younger age, male sex, being unmarried or living alone, unemployment, high intelligence/education and high expectations, good premorbid functioning, recent life events, poor work functioning, and access to lethal means; risk is highest in the first psychotic break and first decade of illness.
15. Improving medication compliance (clozapine has antisuicidal activity; depot antipsychotics reduce relapse), identifying and treating comorbid depression, and supportive interventions such as CBT, rehabilitation, social skills training, supported employment and family education/support.
16. Chlorpromazine (1952) was the first antipsychotic. First-generation drugs (1950s-60s, e.g. haloperidol) had similar efficacy to each other but varied in potency and side effects (EPSE, sedation). Clozapine (late 1960s) offered greater efficacy with no EPSE/hyperprolactinaemia, but risked agranulocytosis. Second-generation drugs (1990s) matched haloperidol’s efficacy with better tolerability and fewer motor side effects.
17. D2 antagonist potency predicts both antipsychotic efficacy and side-effect liability. Roughly 65% D2 receptor occupancy is needed for antipsychotic efficacy, while occupancy above ~80% produces extrapyramidal side effects.
18. Antipsychotics should be continued for 1-2 years after a first psychotic episode; if untreated, about 70% relapse within 1 year, and more than 50% of patients may need long-term treatment.
19. Depot formulations (given every 2-4 weeks by a community nurse) carry a lower relapse risk than oral medication because they ensure regular appointments and verified dosing, improving compliance compared with oral dosing which relies on patient adherence.