L22: Schizophrenia Flashcards
What is schizophrenia? Who is mostly affected?
Dissociation of thought, emotion and mood; inability to interpret feelings and thoughts. Integration disorder. More males are affected.
What other factors is schizophrenia associated with?
- depression (>30% patients)
- substance abuse (50% patients)
- suicidal behaviours (10% individuals)
What are the positive symptoms of schizophrenia?
Generally associated with uplifting:
- Disorder of thought: incoherent thinking; dissociation of ideas
- Delusions: persecution, grandeur, referential, somatic
- Hallucinations: auditory, visual, olfactory
many positive symptoms respond to therapy
What are the negative symptoms of schizophrenia?
- Blunted emotional response: catatonia (disrupts awareness of the world around); affective flattening; reduced emotional expression
- Alogia: reduced speech
- Avolition: Intense apathy
Limited response to therapy
What are the changes in the brain causing schizophrenia?
- cortical thinning (more dense cells in the forebrain, 30% less)
- reduced synapse number (associated with thinning)
- reduced inhibitory synapses (soma targeting; that maintain excessive activity)
- reduced basal ganglia volume (dopamine - reward/movement)
- impaired blood flow (prefrontal cortex - executive function)
What are the causes of schizophrenia?
- genetic / inherited
- environmental
What are the genetic causes of schizophrenia?
- All schizophrenia patients: up to 128 single nucletoide polymorphisms (SNPs) at 108 genetic loci
- Early onset Schizophrenia (<18 years of age): 4 genetic loci
What are the key genes in schizophrenia patients?
- DISC1 (Disrupted in Schizophrenia 1): anchoring molecule in subcellular compartments (incl. synapses)
- NRG1 (Neuroregulin-ERBB4 signalling pathway): progenitor cell proliferation, neural migration, signalling axon guidance, inhibitory (GABA, to less extent glycine) interneuron maturation
- NRX1 (Neurexin 1): synaptic protein, scaffold element
- KCNH2 (hERG K+ channel): potassium channel
What are the environmental factors that cause schizophrenia?
Early life stressors:
- prenatal infection
- in utero nutrition
- maternal substance abuse
- obstetric complications
Often associated with underlying genetic predisposition
Hypothalamic-pituitary-adrenal (HPA) axis implicated in onset of symptoms (common to depression)
How is brain development in schizophrenia altered?
- deficient myelination
- reduced interneuron activity
- excessive excitatory pruning
When do patients with schizophrenia start to onset?
~20 years of age
If early life effects are additive - why do behaviours manifest so late?
- saturation of circuit ability to compensate
- specific circuits especially prone to dysfunction in late adolscence
What are the theories of schizophrenia?
- dopamine: reward/movement
- glutamate: excitatory neurotransmission
- GABA: inhibitory neurotransmission
What are the four dopamine pathways in the brain? How do they relate to schizophrenia?
- Mesolimbic (SCZ - increase in DA causes positive symptoms)
- Mesocortical (SCZ - DA hypoactivity: negative, cognitive and affective symptoms)
- Nigrostriatal (Drugs - EPS and TD drug side effects)
- Tuberohypophyseal (Drugs - hyperprolactinemia side effects)
How does L-DOPA therapy of Parkinson’s disease affect schizophrenia patients?
Increase schizophrenia-like effects (hallucinations)
How does amphetamine (dopamine releaser) affect schizophrenia patients?
Increases positive symptoms
How does D2 antagonists and reserpine affect schizophrenia patients?
Decrease positive symptoms
How does D2 receptor agonists affect schizophrenia patients?
Boost D2 dependant inhibition, increase positive symptoms
What systems are targeted by first generation medications for schizophrenia and how are they affected? What is the mechanism? What are the common side-effects?
- increase mesolimbic dopaminergic function, which results in positive symptoms
- decrease prefrontal dopaminergic, which results in negative symptoms and cognitive impairment
They usually act as dopamine antagonists
Side effects include: movement problems, extrapyrimidal symptoms; tardive dyskinesia
Example: chlorpromazine
What is the mechanism of second/third generation medications for schizophrenia? What are their side effects?
- Mechanism: antagonism of 5-HT2, D1 and D2 receptors - paliperidone, asenapine, clozapine
Alternatively:
- antagonism of D2 and D3 receptors - amisulpride
- partial agonism of D2 (third generation) - aripiprazole
They have fewer side effects compared to first generation:
- low blood pressure
- high risk of weight gain/obesity
Limited effects on negative symptoms
What is the glutamate signalling theory in schizophrenia?
In schizophrenic patients:
- 30% of excitatory synapses are lost
- NMDA receptors are reduced
Drugs like ketamine and PCP (NMDA receptor antagonists) mimic negative features. Clozapine boosts NMDAr function and signalling
Theory is that glutamatergic signalling is linked to schizophrenia
What are the candidate drugs supporting the glutamate theory regarding schizophrenia? What is their mechanism?
- increasing NMDA receptor function (clozapine)
- boosting endogenous levels of Glycine (NMDA receptor co-agonist)
What is the GABA theory regarding schizophrenia?
Multiple evidences of GABA signalling deficits in schizophrenic post mortem brains.
- reduced GABA enzymes
- decreased GABA receptor mRNA
- decreased GABA neurochemicals
- decreased GABA transporters
What is the endocannabinoids target for schizophrenia therapy?
- cannabis (THC) may increase psychotic events in susceptible individuals
- cannabis use disorder more likely schizophrenics
- CBD may improve cognition and psychosis
