lecture 15 - schizophrenia Flashcards
what are symptoms of schizophrenia?
Three major symptoms
Each may reflect different aspects of the pathophysiology (mechanisms)
Each responds differently to the medications
Positive or Psychotic symptoms
Hallucinations
Delusions
Negative symptoms
Blunted emotional responses
Withdrawal from social interactions
A lack of motivation
Cognitive symptoms
Disorganized life long-term disability
Working memory
Executive functions
No treatment
Can be found to some degree before the positive symptoms appeared
what are positive symptoms of psychotic episodes ?
Hallucinations
Percepts that occur in the absence of appropriate sensory stimuli
Auditory hallucinations: music, noice
Delusions
Firm beliefs that are not realistic and not explained by the patient’s culture
what are the negative symptoms of psychotic episodes ?
Behave eccentrically, Become socially isolated, Exhibit blunted affect, poverty of speech, a poor attention span, and lack of motivation
Periods of florid psychosis:
Accompanied by disordered thinking and abnormalities in the regulation of emotion.
After the first few episodes the patient rarely returns to full normal functioning
what are treatments for schizophrenia?
Antipsychotic drugs
Most effective at diminishing the positive symptoms
None of the medications reliably benefits the cognitive symptoms
what are genetic risk factors that can cause schizophrenia?
Huntington disease … 100%
Suggesting other risk factors
New mutations (de novo mutation: mutations not from parents)
Epigenetic modification of DNA
Environmental factors
Stochastic factors
what genetic factors cause schizophrenia in the gene mutations?
patient needs two forms of genetic variation, genetically heterozygous. Large chromosomal deletions, duplications, or translocations
what is Disc-1?
disc-1 is disrupted in schizophrenia-1. in schizophrenia, there is inactivation of gene which causes Disc-1. disc-1 is important fro brain development. disc-1 must interact with other genes and non-genetic factors to determine the final phenotype
what allows to investigate SZ in brain?
magnetic resonance imaging gives rise to structural imaging and functional imaging. there is gray matter and white matter. this technology allows us to investigate the SZ living brain non-invasely.
what are different types of neurotransmitters?
Amino acids - Glutamate, GABA
Biogenic amines- Histamine, Serotonin, Catecholamine (noradrenaline, adrenaline, dopamine)
Acetylcholine
Neuropeptide (e.g., orexin, oxytocin)
what are structural and functional abnormalities in the brain that we observe in SZ?
Thinning of specific areas of the prefrontal, temporal and parietal cerebral cortex.
Temporal lobe
Loss of gray matter in
the superior temporal gyrus
Temporal pole
Amygdala (may be limited to males)
Hippocampus
Structural abnormalities have been correlated with functional abnormalities.
SZ patients show deficit in working memory. Probably the structural abnormality is linking to this functional abnormality.
what is loss of gray matter and smaller thalamus due to?
loss of gray matter in the cerebral cortex is not due to cell death, but reduction in the dendritic, axonal and synaptic processes - network dysfunction.
smaller thalamus in SZ patients may be explained by cell death.
Neurons in the mediodorsal (MD) thalamus send their axons to the dorsolateral prefrontal cortex (DLPFC). The cell loss in the MD thalamus may partially explain the thinned PFC.
when are the abnormalities of SZ observed?
SZ is diagnosed in late teenage years or in the early twenties.
Adolescent (healthy) brains
Early adulthood is an important period of brain development
‘Synaptic pruning’ – circuit refinement
May be particularly important in the PFC
Pruning coincides with major changes in dopaminergic neurotransmission during late adolescence
Cortical abnormalities and ventricular enlargement are generally observed at the time of first diagnosis
Genetic studies also have implicated genes involved in development
Some abnormalities may emerge earlier.
what is chlorpromazine used as in SZ?
reducing the positive symptoms such as SZ such as hallucinations and delusions. less impact on the negative symptoms and little or no impact on cognitive deficits. produced Parkinson like side effect
what are the two families of dopamine receptors?
D1 (D1 and D5). coupled to stimulatory G proteins that activate adenylyl cyclase. stratum, cerebral cortex and hippocampus.
D2 (D2, D3 and D4) - COUPLED TO INHIBITORY g PROTEIN THAT INHIBITS AC.Striatum, cerebral cortex, amygdala and hippocampus. The main target of antipsychotic drugs on positive symptoms
what are 2nd generation antipsychotic drugs?
Inspiration of Clozapine … less likelihood of casing Parkinsonian side effects
Lower affinity for D2 receptors
Some also block the serotonin 5HT2A receptors
None of the newer drugs is equal to clozapine in efficacy
what are other antipsychotic drugs and their receptors?
Clozapine
Atypical drug
affinity: D1, D2, 5HTRs, others
Chlorpromazine
‘dirty’ drug
acting on many receptors
Haloperidol
Typical drug
high affinity for D2 receptors
Olanzapine
Atypical drug
affinity: 5-HT2A receptors > D2 receptors
Risperidone
Qualitatively atypical drug
More pronounced serotonin antagonism than dopamine antagonism
what are first lien atypical drugs in Scotland?
amisulpride, olanzapine, quetiapine, risperidone, zotepine
what are he theories behind schizophrenia?
dopamine and glutamate hypothesis
other mechanisms:
GABAergic
microglia
what is the dopamine hypothesis ?
Some drugs that block D2 receptors reduce psychotic symptoms
Other drugs that increase dopamine at synapses (such as amphetamine and cocaine) can produce psychotic symptoms, especially paranoid symptoms
dopaminergic systems are hyperactive in SZ. Amphetamine-produced increases in dopamine release were greater in SZ patients than in healthy subjects
Abnormalities in amphetamine-sensitive processes (such as DA storage, vesicular transport, DA release or DA reuptake by presynaptic neurons) might lelead to hyperactivity in the subcortical dopaminergic systems.
Dopamine activity might decrease in cortical regions and this might contribute to the cognitive symptoms
The number of D1 receptors in PFC is thought to be reduced in SZ
D1 receptors play a role in working memory and executive functions
what is the glutamate hypothesis?
Implicated in SZ
Phencyclidine and ketamine
Block the NMDA-type glutamate receptor
Produce psychotic symptoms (PCP can also induce negative symptoms)
In healthy subjects, ketamine also produces cognitive dysfunction
Decreased function of NMDA-type glutamate receptors might play a role in producing some of the positive and cognitive symptoms of SZ
Positive and Cognitive symptoms … probably the result of abnormalities in several transmitter systems that act either in parallel or in combination with dop
