Schizophrenia - pathophys and treatment Flashcards
What are the important second generation antipsychotic drugs and what how are they different than the first generation ones?
• Clozapine is the poster child of the second generation antipsychotics
○ Also risperidone
○ Olanzapine
○ Quetiapine
○ Asenapine
○ Ziprasidone
§ All try and mimic clozapine and block of 5Ht-2 receptors
• Also called an atypical neuroleptic
• Has antidopaminergic activity, but did not cause as much parkinsons symptoms as expected
• Called atypical because of reduced risk for induced parkinsonism
• Seems to be more effective than other neuroleptics for 30% of patients
• Under strict observation still for tendency to participate in agranulocytosis (white blood cell production problems)
What’s the principle advantage of the atypical neuroleptics?
• Reduced parkinsonism
• However, they do have increased weight gain, hypercholesterolemia and DM associated with them
○ Ehanced appetite in many patients
What are the most important first generation antipsychotic drugs?
• Chlorpromazine is the first one
• After that success 19 mimics were made, all dopamine blockade
• Three basic types
○ Phenothiazines
○ Thioxanthines
○ Butyrophenones
• Highly lipophilic, slowly eliminated (days 1/2 lives)
• No tolerance build to therapeutic effects
What, after a very long time with first gen neuorleptic treatment, can happen to movement systems?
- There can be restructureing of the caudate and putamen (increase DA receptors)
- Result is tardive dyskinesia
What are the important butyrophenones?
*(haloperidol)
What are the important thioxanthines?
• Thiothixine
What are the important phenothiazines?
- Chlorpormazine
* Perphenazine
What is the dopaminergic mechanism of antipsychotic drugs?
• All antipsychotics can produce parkinsonism. Thus all of them deal with DA systems
• Compete with DA for post-synaptic receptors on many neurons.
• Five DA receptors (DR1-5) are involved
• DR2 is on postsynaptic synapses on many neurons, including the DA neurons themselves where it acts as a modulator of dopamine release
• The most senstive to antipsychotics is DR2
• Full basis of therapeutic effect is unknonw, but DR2 receptor activation causes neurons to be more senstive to sensory inputs
○ Compounding patient’s problems with information process and sensory gating (more under stress)
While schizophrenia was once the ‘graveyard of neuropathologists’, there are more recent discoveries that have helped compile some better pathology-related understanding of the disease. What are these discoveries?
• Evidence for inhibitory interneuron deficits
○ Both number and expression of various peptides and proteins
○ AND their migration from cortical subplate
• Ultrastructural studies of synaptic proteins in postmortem human brains demonstrate reduced synapse number in the frontal cortex, hippocampus and basal ganglia
• Also detected altered dendritic numbers in schizophrenia, suggesting failure to develop normal synaptic connections by both pyramidal and inhibitory neurons.
• MRI shows consistent evidence of enlarged ventricles and diminished volume in several regions, including the hippocampus and the superior temporal cortex
• NEGATIVE signs of gliosis and inflammation
How is the thalamus involved in psychotic illness?
• The thalamus is the gateway to cortical processing for all incoming sensory information
○ Somatosensory
○ Auditory
○ Visual
• Two abnormalities of thalamic function have been proposed in schizophrenia
• First, a decrease in the total thalamic volume might signify a breakdown of its sensory filtering abilitites
○ Leads to increased stimulation of primary sensory cortical areas
• Second, dysfunction of the medial dorsal nucleus of the thalamus leads to impairments of cortical association areas, especially the dorsal lateral prefontal cortex
How is the medial temporal lobe involved in psychotic illness?
• Medial temporal lobe has two major functions
○ Integrate multimodal sensory information for storage and retrieval of memory
○ Attach limbic valence to sensory information
• In schizophrenia, mild cortical atrophy has been reported in the medial temporal lobe
• Focal abnormalities indicating abnormal alignment of neurons have been observed in medial temporal lobe structures such as the amygdala, entorhinal cortex and hippocampus
How is the hippocampus involved in psychotic illness?
• There is also evidence of hippocampal dysfunction in the pathogenesis of schizophrenia
○ Serial circuity of glutamatergic pyramidal and nonpyramidal neurons provides the structural basis for the formation of long term membories
○ The hippocampus is also closely connected with the limbic system
○ Hippocampal formation is recruited via these connections to regulate emotion or to modulate information with respoect to emotions
§ Most studies have found no change in the number of hippocampal pyramidal neurons
§ But nonpyramidal cells in the hippocampus seem to be reduced
§ Synaptic architecture also seems to be changed, suggesting altered plasticity
§ Blood flow and metabolism is increased at baseline
§ Noticeably increased during positive symptom of psychosis
Describe the layout of the association cortex (layers)
- 6 layer isocortex
- Layers 2 and 4 are defined by a high density of interneurons
- 3 and 5 are defined by a high density of pyramidal cells that collect input through their dendrites and project to other cortical or subcortical areas
- Interneurons are GABA
- Pyramidal cellsa re gulatmate
What is going on with the association cortex in schizophrenia?
- Volume reduction of the association cortex has been reported
- rCBF and glucose metablosim are abnormal in the frontal cortex at rest and during the performance of cognitive tasks
- Patients can exhibit hypofrontality (not even being able to activate prefrontal cortex)
- DLPFC (dorsolateral pre-frontal cortex) is actually HYPERactive, indicating inefficiency
What does the dopamine theory of psychosis say?
- Psychosis is caused by dysregulation of dopamine in the brain
- Involved mesolimbic system and mesocortical system
What does the mesocortical system have to do with psychosis?
• Mesocortical system is composed of DA neurons from VTA and the substantia nigra
• VTA neurons included in the mesocortical system release dopamine to the prefrontal cortex and regulate areas involved in cognitive processing
○ One example being dorsal lateral prefrontal cortex for executive function
• This is the system associated with negative symptoms of schizoprenia
What do the mesolimbic and mesocortical systems have to do with psychosis?
- Mesolimbic system is composed of the dopamine neurons from the ventral tegmental area (VTA)
- Release dopamine to the nucleus accumbens
- Regulates reward pathways and emotional processes and is associated with the positive symptoms of schizophrenia
What are the NT systems that play a role in the pathogenesis of schizophrenia?
- Dopamine, serotonin and glutamate
* These are the targets for the various antipsychotic drugs
The earliest, and perhaps the most pharmacologically supported, theory for schizophrenia’s major NT pathway is what?
• Dopamine theory
• First antipsychotics developed deal with DA release pathways
• (postulates) The abnormality in brain fucntin in schizophrenics is due to overactivity in brain dopaminergic pathways, especially in the mesolimbic pathway
• Support -
○ Effective antipsychotics block CNS dopamine receptors (postsynaptic D2)
○ Drugs that increase DA activity can aggravate/produce schizophrenia
○ Post-mortem studies showing increased striatal dopamine synthesis and release and receptors (indicating overactive NT system)
