pharmacology of psychosis Flashcards
Explain the dopamine theory of schizophrenia and its limitations.
Abnormality of brain function in schizophrenics is due to overactivity in brain dopaminergic pathways, especially in the mesolimbic pathway.
mesolimbic pathway normal function
integration of sensory input and motor responses with affective or emotional data.
mesocortical pathway normal function
communication and social abilities.
factors supporting and against dopamine theory of schizophrenia
supporting: Virtually all antipsychotic drugs block dopamine D2 receptors. Drugs that increase dopaminergic activity produce or aggravate psychosis. Against: Block of D2 is immediate but onset of psychosis improvement takes 3-6 weeks.
supporting: Virtually all antipsychotic drugs block dopamine D2 receptors. Drugs that increase dopaminergic activity produce or aggravate psychosis. Against: Block of D2 is immediate but onset of psychosis improvement takes 3-6 weeks.
Describe the mechanism of antipsychotic drug action, including a description of brain dopamine systems affected.
Antipsychotics block dopamine D2 receptors. The main dopamine system affected is the mesolimbic pathway (hyperactivity leads to positive symptoms). Antipsychotics block these positive symptoms. Hypoactivity of the mesocortical pathway leads to negative symptoms of schizophrenia, but D2 blockers are less efficent at reducing these symptoms
How do antipsychotics cause extrapyramidal side effects
antipsychotics block of D2 receptors affeccts the nigrostriatal pathway which plays a role in planned, coordinated movement.
Side effects of antipsychotics on hypothalamus
Block of D2 receptors in hypothalamus interferes with the tuberoinfindibular pathway (in which dopamine normally inhibits pituitary release of prolactin). This leads to hyperprolactinemia as well as poikilothermia (altered thermoregulation) and weight gain
acute vs chronic schizophrenia
acute: features positive symptoms (hallucinations and delusions) and thought disorders. Chronic: features negative symptoms (withdrawal, flattened affect, cognitive problems).
Effects of glutamate excess excitation and excitotoxicity
excess excitation causes seizures and insomnia. Excitotoxicity causes damage to neurons, neurodegeneration and cell death
Role of glutamate in mesolimbic pathway and how it is altered in schizophrenia
Normally, neurons from cortex release glutamate at brainstem to activate GABAergic neurons. This produces tonic inhibition of mesolimbic dopamine neurons. Hypofunction of cortical NMDA-glutamate neurons will cause positive symptoms of schizophrenia
Role of glutamate in mesocortical pathway and how it is altered in schizophrenia
Normally, cortical glutamatergic neurons activate brainstem dopaminergic neurons (VTA) to produce tonic excitation of mesocortical dopaminergic neurons. Hypofunction of cortical NMDA-glutamate neurons will cause negative symptoms of schizophrenia
Describe the relationship between receptor blocking potency-selectivity (esp. 5HT vs DA), efficacy in schizophrenia, and side effect profile for typical and atypical antipsychotic agents.
5HT2 receptors on DA neurons in prefrontal cortex decrease dopamine release. Block of these receptors with atypical agents increases DA release and alleviates the negative symtpoms of schizophrenia. Block of D2 receptors will alleviate the positive symptoms of schizophrenia
List the typical/first generation antipsychotics
haloperidol and chlorpromazine
List the atypical/ second generation antipsychotics
Aripiprazole, risperidone, olanzapine, clozapine
compare the D2/5HT blocking ratio for typical vs atypical antipsychotics
Typical: high D2 / 5HT2A blocking ratio. Atypical: low D2/5HT2A blocking ratio
