4) Schizophrenia I Flashcards
Schizophrenia (definition)
= a serious debilitating mental disorder (‘psychosis’) that manifests itself during early adulthood
- frequency (~1%), core symptoms and course are quite uniform across all cultures (= physiological basis)
- life expectancy 12-15 yrs <. average
- high rates of suicide
- high co-morbidity
- high health costs
History of Schizophrenia
Emil Kraeplin - 1887
- realised that there was a different group of patients in psychiatric care with psychosis
- named it ‘dementia praecox’ –> premature aging or dementia
- characterised by rapid cognitive decline in the late teens to early adulthood
- Kraeplinian dichotomy = separation between manic-depressive psychosis (bipolar disorder) and dementia praecox (Schizophrenia)
- core feature: cognitive decline –> dire diagnosis
Eugen Bleuler - 1908
- introduced term ‘Schizophrenia’: split personality –> disorder of dissociation
- not as dire as Kraeplin’s description
- Schizophrenia as a biological process, dementia was a secondary symptom
- separation among personality, cognition, memory and perception
- core feature: negative symptoms
Kurt Schneider -1920s
- criteria for schizophrenia–> groundwork for DSM and ICD diagnosis
First ranked symptoms:
- auditory hallucinations
- passivity experiences (external forces controlling the body)
- thought withdrawal
- thought insertion
- thought broadcasting
- delusional percpetion
Core feature: psychosis
Diagnosis of Schizophrenia (DSM-5)
- at least 2 symptoms (one at least from category 1-3) for at least 1 month
- attenuated symptoms at least 6 months
> otherwise could be drug-induced psychosis/other mental disorder
> sometimes even healthy population shows sign of psychosis (only shortly)
Positive symptoms
1) delusions
2) hallucinations
Cognitive symptoms
3) disorganised speech (eg frequent derailment/incoherence)
4) disorganised behaviour (eg Catatonia)
5) negative symptoms
- flat affect (not or inappropriate emotions)
- alogia (poverty of speech)
- avolition (little interest or drive)
Positive symptoms = something new which should not be there
Cognitive symptoms = ineffective encoding, retrieval or processing
Negative symptoms = something is missing which should be there
natural course of schizophrenia
- often starts in childhood with soft cognitive signs
- stabilises by 70 years old
> patients die early
> dopermingeric/glutaminergic systems ‘die’ with age
Heterogeneous spectrum
- encompasses a varitey of disorders in the psychotic spectrum (psychotic disorder, schizophreniform disorder, delusional disorder, schizoaffective disorder)
- symptomatic (and genetic) overlap to the affective psychoses –> bipolar disorder (mania and depression), major depressive disorder
- symptomatic (and genetic) overlap to neurocognitive or affective disorders (autism spectrum disorder)
- direct brain alteration may mimic any mental disoders including schizophrenia
> drugs (amphetamines/cocaine, Phencyclidine (PCP), ketamine)
> head trauma or emotional trauma - trend to dimensional rather than categorical approaches
Epidemiology and risk factors: Lifetime prevalence around 1% (world-wide)
- prevalence (current cases) < 0.5%, incidence (new cases) 1/10,000/year
> ~1 Mio Germans currently have schizophrenia
> three medical students from each cohort/semester will develop schizophrenia
> ~50 Chartié employees already have schizophrenia, at least 1 new case every year
Epidemiology and risk factors: Sex differences
- lifetime prevalence equal in men and women –> men often more severe (greater negative symptoms and longer duration)
- age of onset (psychosis) in women ~5 years later and second spike ~45/50 years
> menopause, hormonal influence cause bimodal distribution in women
Epidemiology and risk factors
- general lifetime prevalence (~1%)
- sex differences (bimodal distribution in women, severity in men)
- perinatal and early childhood risk factors (pregnancy and birth complications, age of father)
- environmental factors (infections, high expressed emotion families, cities, migration status)
- genetics and influences on the neurotransmitter systems
- histological, structural and functional brain abnormalities
Two (or multiple) hits hypothesis
- likely a combination of environmental and genetic factors
Epidemiology and risk factors: Perinatal and early childhood risk factors
- obstretric complications, low birth weight, in-utero infection
- maternal infections during pregnancy (eg influenza)
- increasing age of father (genetic mutations in sperm occur more often)
Epidemiology and risk factors: Environmental factors
- infections (T. gondii)
- high expressed emotion families
- growing up in large cities (odds ratio ~2)
- immigration status
–> stress
Toxoplasma gondii
= single cell parasite found in cats
- life cycle depends on cats and mice, humans only secondary
- in mice, change in behaviour/brain –> stop being afraid of cats
- some sort of plasticity/re-wiring in mice –> what effect on human brain/what kind of immune response?
- infection (humans) increases risk of schizophrenia by 2-8 fold
- travels via nervous system to the brain and may influence behaviour
- associated with psychomotor dysfunction, depression, bipolar disorder, addiction and suicide
Treatment of positive symptoms
- antipsychotic medication
- electroconvulsive therapy (ECT) (?)
- repetitive transcranial magentic stimulation (rTMS) (?)
- cognitive behavioural therpay (?)
Epidemiology and risk factors: Biologcial risk factors
Genetics is the major risk factor
- schizophrenia is a complex genetic disorder with high heritability (~80%)
> likely many genetic variants contributing to the diagnosis
> genetic underpinnings of schizophrenia are still poorly understood
Neurotransmitter systems
- dopamine-agonists induce positive symptoms
- glutamate-antagonists may induce all core symptons (PCP=
- dyfunction of GABAergic (inhibitory) neurtransmission (alcohol)
–> all anti-psychotics block D2-receptor (dopamine)
Histological, structural and functional brain abnormalities
- hippocampus, PFC, medial temporal cortex, white matter connectivity
Treatment of schizophrenia: negative symptoms
- clozapine
- psychosocial interaction
Treatment of schizophrenia: neurocognitive symptoms
- cognitive remediation therapy
- rTMS (?)
- vocational training
Electroconvulsive therapy (ECT)
- treatment resistant schizophrenia (failed at least two treatment trials)
- used to treat catatonic symptoms
- effective at treating positive symptoms (paranoid delusions)
- some effectiveness at treating negative symptoms
- may improve responsiveness to medication (eg clozapine)
- causes retrograde amnesia
- need for more specific treatment
Psychosocial interventions
- cognitive behavioural therpay
- social skills training
- family therpay
- vocational rehabilitation and supported employment
Pro
- may be the only effective treatment for negative symptoms
- overall increase in quality of life
Con
- none really
- time, effort, ressources –> depending on insurance
Antipsychotics (overview)
- used for treatment of schizophrenia, schizoaffective disoder, affective disorder, dementia, delusional disorder, substance-induced psychosis and others
- heterogeneous class of medication
- first discovered in 1950s (chlorpromazine) –> sedating effect, by accident discovered that it actually helps with symptoms
1st generation (typical)
- butyrophenones (haloperidol)
- phenothiazines (chlorpromazine)
- thioxanthenes (zuclopenthixol)
> efficacy against positive symptoms (delusions, hallucinations)
2nd generation (atypical)
- clozapine (!)
- olanzapine
- risperidone
- ziprasidone
- quetiapine
- aripiprazole (sometimes 3rd gen)
Antipsychotics: side effects
1st generation
- extrapyramidal symptoms (EPS): parkinsonism, dystonia, akathisia, tardive dyskinesia
2nd generation
- agranulocytosis/neuropenia (= deficiency of granulocytes in blood, clozapine)
- weight gain, diabetes, hyperlimpidemia
- BUT lower risk for EPS
all antipsychotics:
- sedation
- hyperprolactinemia (= abnromally high prolactin in blood)
- neuroleptic malignant syndrome
- fatty liver
- sexual dysfunction
- QT elongation and others
Clozapine
- first synthesised in 1958
- high affinity for 5HT receptors (serotonin) and low affinity for D2 receptors (dopamine)
Advantages
- only antipsychotic treatment that is effective in treatment resistant patients
- may also be efficacious in the treatment of negative symptoms
Disadvanates
- originally taken off the market bc it causes agranulocytosis (low white blood cell count)
–> with active monitoring the risk can drop to <1%
- worst antipsychotic for treatment emergent weight gain
Repetitive transcranial magentic stimulation
- treatment resistant schizophrenia (failed at least two treatment trials)
- some effectiveness at treating negative symptoms and cognitive symptoms
- no retograde amnesia
- better evidence for treatment of depression
- not as effective as ECT treatment for schizophrenia
Heritablity and genetics
- adoption studies demonstrate genetic influence
> heritability 80-85% (hip arthritis 60%, hypertension 30-50%, height 80%) - BUT genetic variation associated with schizophrenia does NOT explain high level of heritability
Gene by envrionment interaction
- multiple hits leading to the neurodevelopment of schizophrenia
- explains only 10-15% of heritability
- high degree of variability
- common variants –> overlap of bipolar disorder, depression (mayn small changes can lead to mental disorders)
- Autism –> very different type of genetic variation, large change but rare
Is schizophrenia an immunological disease?
- most genes involved in autoimmune regulation
- HLA - human leukocyte antigen complex
–> does not prove that schizophrenia is an immune related disease
C4 (picture) complement was first discovered as a marker for lysed cells
- critical to synaptic pruning (brain development and plasticity)
- Schizophrenia evidence:
> genetic findings
> abnormal dendritic spines in patients
> excessive cortical thinning in patients
> age at onset
