Week 10: Drugs and Psychiatric Illness - Schizophrenia Flashcards
Schizophrenia: prevalence + what is it not?
-Debilitating disease that impacts 1% of the population worldwide
No difference across gender, culture, race, social circumstances, or nationality
Is not multiple personality disorder
Symptoms of schizophrenia
Positive – not present in general population. Prototypical psychotic symptoms. Hallucinations, delusions, paranoia, disordered thought and speech
Negative – absence of “normal” behaviour. Flat affect, alogia (lack of speech), lack of motivation, social isolation
Cognitive - Deficits in attention, memory, decision processes, “executive function”
Onset of schizophrenia
-Symptoms appear gradually, beginning in late childhood and adolescence
Much interest in the “prodrome” of schizophrenia (lead-up + how we can prevent onset)
-Full blown psychotic episode triggers chronic disease state i.e. cognitive impairments (want to prevent ever getting to this stage)
Natural history of schizophrenia onset
-Premorbid = have risk factors sitting dormant
-Prodromal = build up some tendencies
-Onset = full blown psychiatric attack
-Deterioration= Cycle between episodes and manage functional impairments may be chronic (negative, chronic)
-Chronic/ residual = can usually manage the psychotic symptoms but the cognitive/ negative symptoms often remain chronically.
Schizophrenic symptoms that may occur in prodrome period?
-Extremely active imagination
-Imaginary friends
(in childhood)
Genetic component to schizophrenia
-Schizophrenia is not a purely genetic disease: No one gene causes it like in Cystic fibrosis, Huntington’s disease,
Sickle cell anemia
-Instead many different genes have been identified that contribute. At least 128, in 108 distinct locations in the human genome
Genome wide association studies (GWAS)
-Identify single nucleotide polymorphisms (SNPs) between patients and controls
AAGCCTA vs AAGCTTA
-WHich SNIPs are more likely to be associated with schizophrenia
-Plot on Manhattan plots -> further away the line from the bottom the greater probability of being linked to schizophrenia.
-Note: difficult to isolate the roles of genes and how they link to schizophrenia symptoms due to vast functions/ process that each are implicated in.
Relation to others with schizophrenia and risk? what does this show?
-Having a close relative with schizophrenia or similar disease (schizotypy) increases risk by up to 10x
-Identical twins have only around 50% concordance: indiciates cannot all be genetic
Schizophrenia is a developmental disease
-Produced by a genetic predisposition interacting with environmental factors
-Environmental factors could be prenatal or post natal and enough of these ‘hits’ in combination with genetic predisposition is likely to cause illness
-If however you only have the hits OR only have the disposition schizophrenia is unlikely to occur.
Dopamine hypothesis of schizophrenia + support
-Dominant theory of schizophrenia since the 1960s
-Main idea is that schizophrenia and other psychoses result from abnormal dopamine activity in the brain
-Two main sources of support:
-> Stimulant psychosis – high enough doses or chronic administration produces a psychosis which is indistinguishable from schizophrenia
-> All effective antipsychotics are dopamine antagonists
D2 receptors and schizophrenia
-With the advent of haloperidol in the late 1960s, it became clear that D2 receptors were critical
-The more a drug for schizophrenia interacts with D2 receptors the better the drug will be at managing clinical symptoms
-Excess transmission at these receptors is implicated in the disease: i.e.
->Increased binding of D2 receptors in schizophrenia
-> Also increased dopamine release in striatum in schizophrenia
Striatal D2 binding and schizophrenia
-Striatum has the highest concentration of D2 receptors in the brain
-Increase dopamine release in the striatum is seen in schizophrenia
Where do we start to see clear dopaminergic abnormalities in schizophrenia+ what happens following this?
-Early stages of dopamine dysfunction seen in childhood and combine with genetic/ environmental factors.
-Start to see clear dopaminergic abnormalities in adolescence (prodrome)
-After have dopaminergic flux associated with acute psychosis
-Treatment sees altered dopamine development in glutamate and GABA and stabilises dopamine-based psychotic symptoms. In this stage the negative systems persist and there is huge symptom heterogeneity in terms of severity.
How are both the positive and negative symptoms caused by altered dopamine activity in schizophrenia?
Overactivity of dopamine in the striatum = positive symptoms
Reduced cortical dopamine activity =cognitive/ negative functions
Glutamate hypothesis of schizophrenia
-Dissociative drugs (PCP, ketamine) produce psychosis and other schizophrenia-like symptoms
-These drugs bind to glutamate NMDA receptors and antagonize glutamate action
-Suggested that genetic predisposition to NMDA hypofunction cascades into full-blown schizophrenia
