52 - Pathophysiology of schizophrenia/psychotic disorders (Watts) Flashcards
General Considerations of Schizophrenia
antipsychotiic = neuroleptic = anti-schizophrenic
- severe illness, most ___ of psychotic disorders
- affects ___ of population
- onset age ___ - ___ years old
- no split personality
- debilitating
- 1%
- 15-20
etiology
neurodevelopmental and anatomical
- in utero/adolescence increased ___ size and changes in ___ and ___ matter
genetics-neuronal growth, migration of neurons
- ___ studies
- families-multiple genes
environmental
- ___ complications, infections
Gene-Environment Interaction
- COMT - ___
Neurodevelopment-Environment Interaction
- ventricle, gray, white
- twin
- birth
- marijuana
symptoms
___ Symptoms - respond well to drug therapy
examples:
- hallucinations
- delusions
- bizarre behavior
- thought disorders
positive
symptoms
___ Symptoms: little response to drug therapy, newer agents are better
examples:
- blunted emotion
- poor self care
- social withdrawal
- poverty in speech
negative
symptoms
cognitive symptoms: decrease in cognitive function
- involves ___ and ___ receptos
D1, glutamate
neurotransmitter hypothesis
___ : first to be developed, but incomplete
___ : based on mechanism of LSD and mescaline
___ : based on phencyclidine and ketamine
dopamine
serotonin
glutamate
serotonin hypothesis of schizophrenia
- ___ and ___ were identified as 5HT agonist, inspired search for endogenous hallucinogens
- pharmacological studies with 5HT receptors identified 5HT ___ receptor as mediator of hallucinations
- antagonism and inverse agonism linked to ___ activity
- 5HT2A receptors modulate ___ release in cortex, limbic regions, and striatum
- 5HT2A receptors modulate ___ release and NMDA receptors
- 5HT ___ agonist may be beneficial in schizoprenia
- LSD, mescaline
- 2A
- anti-psychotic
- dopamine
- glutamate
- 2C
Glutamate Hypothesis of Schizophrenia
- glutamate is major ___ neurotransmitter
- ___ and ___ , noncompetitive inhibitors of NMDA receptors exacerbate psychosis and cognition deficits
- LY2140023-mGLuR2/3 ___ effective in schizophrenia
- ampakines (AMPA receptors) - effective in animal models
- GlyT inhibitors (under development as adjuncts)
- excitatory
- phencyclidine, ketamine
- agonist
Dopamine Hypothesis of Schizophrenia
- D2 receptor ___ - binding and therapeutics; strong correlations receptor biding affinity vs. clinical effectiveness
- dopaminergic agents (L-DOPA, amphetamine, bromocriptine) ___ symptoms of schizophrenia
- ___ D2 receptor density in treated and untreated patients of schizophrenia
- imaging studies increased ___ release and receptor ___ in patients
- dopamine metabolites in CSF - D2 receptor and antagonists initially ___ metabolites in the CNS and later ___ metabolites in CNS
- antagonists
- exacerbate
- increased
- DA, occupancy
- increase, decrease
Determining Binding Affinity
binding affinity: ___ force between ligand and receptor
Kd/Ki: estimated concentration at which ___ of the recptors are occupied
- intermolecular
- 1/2
Receptors Antagonized by Antipsychotics
Major: ___
- D1 like (D1, D5)
- D2 like (D2, D3, D4)
Newer agents: ___
- 5HT2A receptor antagonist: (3)
- older agents: (3)
dopamine
serotonin
- clozapine, olanzapine, and risperidone
- chlorpromazine, haldol, thioridazine
Receptors Antagonized by Antipsychotics (minor)
norepinephrine (NE)
- a1 receptor blockade SE: hypotension, ___
- a2 receptor blockade SE: may be helpful in therapy
acetylcholine (ACh)
- muscarinic receptors: anticholinergic effects (2)
histamine
- H1 receptor antagonists: sedation, ___
- sedation
- clozapine, thioridazine
- weight gain
which receptor is key for therapeutic effectiveness?
there is no clear ___
- ___ receptors; individualize therapy based on patient response
- unable to predict ___ of each therapy for individual patient
multiple receptors = many ___ = poor adherence
pattern
- multiple
- effectiveness
SE
Bindinf Affinicty Vs. Clinical Dose
correlation between binding potency and clinical effectiveness for ___ receptors, therefore more effective drug target
most antipsychoic drugs are receptor ___
D2
antagonists
Actions of D2 Antagonists in CNS
basal ganglia (nigrostriatal pathway) - motor effects, ___ symptoms
mesolimbic: primary ___ effects
mesocortical: ___ function in schizophrenia, antagonists may exacerbate ___ deficits
hypothalamus and endocrine systems: D2 receptor blockade in endocrine system - increased release of ___ after blocking
medulla: chemoreceptor trigger zone; D2 antagonists are ___
- EPS
- therapeutic
- decreased, cognitive
- prolactin
- anti-emetics
