Lecture 15: Schizophrenia Flashcards
What are the three major symptoms of schozphrenia?
Positive or psychotic symptoms: hallucinations, delusions
Negative symptoms: Blunted emotional responses, withdrawal from social interactions, a lack of motivation
Cognitive symptoms: disorganized life leads to long tern disability, working memory, executive functions
There is no treatment, can be found to some degree before the positive symptoms appeared
What are positive symptoms?
Hallucinations:
- percepts that occur in the absence of appropriate sensory stimuli
- Audity hallucinatins; voices - a diaglog, commands; noises or music
Delusions: firm beliefs that are not realstic and not explained by the patients culture
What are the early symptoms of schoziphrenia?
Negative symptoms:
- 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 markedly disordered thinking and abnormalties in the regulation of emotion, interspersed with periods of residual symptoms
After the first few episodes; the patient rarely returns to full normal functioning
What are the treatment options for schoziphrenia?
Antipsychotic drugs: most effective at diminishing the positive symptoms
No medications reliability benefits the cognitive symptoms
What is the etiology of schizophrenia?
It runs in families - genetic factors. It is genetically heterogeneous - many genes are associated with schizophrenia >100. There are two forms of genetic variation; variations in single nucleotide bases, large chromosomal deletions, duplications or translocation. Many genes associated with schizophrenia are expressed during neurodevelopment.
Disc-1 is one of many genes associated with schizophrenia. Disc1 is important for brain development. Chromosomal translocation - chromosomes 1 and 11. Inactivates a gene, called Disrupted in Schizophrenia-1 (DISC-1). Some family members exhibit serious mental illness, but not necessarily SZ - bipolar disorder, major depression. Disc-1 must interact with other genes and non-genetic factors to determine the final phenotype
Other risk factors:
- New mutations (de novo mutation: mutations not from parents)
- Epigenetic modification of DNA
- Environmental factors
- Stochastic factors
What are the anatomical divisions of the CNS and brain?
- Spinal cord
- Brain stem; Medulla, Pons, Midbrain
- Cerebellum
- Diencephalon; Thalamus, Basal ganglia, Hypothalamus
- Cerebral Cortex; Frontal, Parietal, Temporal, Occipital lobes
What is an MRI?
This technology allows us to investigate the SZ living brain non-invasively.
What is the Anatomy of Neuron?
Cell body
Dendrite
Axon
Synapse
(Spine)
What are the neurotransmitters?
Amino acids - glutamate, gaba
Biogenic amines - histamine, seratonin, catecholamine (noradrenaline, adrenaline, dopamine)
Acetylcholine
Neuropeptide (e.g., orexin, oxytocin)
What are the structural abnormalities seen in schizophrenia?
Thinning of specific areas of the prefrontal, temporal and parietal cerebral cortex.
Prefrontal cortex - the most pronounced area, dorsolateral prefrontal cortex - working memory, cognitive functions
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 schizophrenia at Cellular & Synaptic level
Loss of gray matter in the cerebral cortex - not due to cell death, due to, a reduction in dendritic, axonal and synaptic processes.
Smaller thalamus - may be loss of cell bodies in the mediodorsal nucleus of the thalamus, loss of axonal terminals in the DLPFC, contributes to the reduction of cortical dendrites and the dendritic spines
When are the abnormalities observed?
Schizophrenia is diagnosed in late teenage years or in early twenties.
Early adulthood is an important period of brain development
Cortical abnormalities and ventricular enlargement are generally observed at the time of first diagnosis
Genetic studies also have implicated genes involved in development
What drugs are used in schizophrenia?
Antipsychotic drugs - 1st generation
- Act on the dopaminergic pathways
- Chlorpromazine - originally developed for anti histamic and sedating effects, not for its psychiatric effects
- Produced Parkinson-like side effects
Antipsychotic drugs - 2nd generation:
- Inspiration of clozapine - less likliehood of causing parkinsons 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
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
Fist-line treatments in Scotland
Atypical drugs
Amisulpride
Olanzapine
Quentiapine
Risperidone
Zotepine
What are the 2 families of dopamine receptors?
D1 (D1 and D5) - coupled to stimulatory G proteins that activate adenylyl cyclase. Striatum, cerebral cortex and hippocampus
D2 (D2, D3 and D4)
- Coupled to inhibitory G protein that inhibits A, Striatum, cerebral cortex, amygdala and hippocampus, The main target of antipsychotic drugs on positive symptoms.
What are the Theories of Schizophrenia?
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 schizophrenia
- 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 lead 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
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 dopamine
Other mechanisms;
- GABAergic neurons - Fewer parvalbumin-positive neurons in the PFC
- Microglia - Abnormalities in synaptic pruning
