Pharm of Mood Disorders Flashcards
positive sx (schiz)
overactivity of DA neurons in mesolimbic pathway
Psychotic sx:
-delusions (false belief)
-hallucinations (false perception, usually voices)
Disorganized sx:
-thought disorders->wild trains of though, w/ irrational conclusions
Primary feature of acute episodes
Negative sx (schiz)
- hypoactivity of DA neurons in the PFC (mesocortical pathway)
- withdrawal from social contact
- flattening of emotional responses
- decreased motivation
- poverty of speech
Cognitive sx:
decreased attn span, exec function
poor working memory
Predominant component of chronic schizophrenia
Dopamine hypothesis of schizophrenia
Abnormality of brain function in schiz is due to overactivity in brain DA pathways, especially in the mesolimbic pathway
Pros:
almost all antipsychotics block dopamine D2 receptors
-drugs that increase dopaminergic activity produce or aggravate psychosis
Cons:
-block of D2 receptors immediate: onset of psychoses, improvement 3-6 weeks
-Clozapine=weak D2 blocker but extremely effective antipsychotic
Evidence for role of glut, serotonin, and acetylcholine systems
Mesolimbic pathway
- brain DA pathway
- subserve the integration of sensory input and motor responses with affective or emotional data
Mesocortical pathway
- brain DA pathway
- involved in communication and social abilities
- -hypoactivity due to cell loss in PFC contributes to negative sx
- ->respond well to atypical antipsychotics (clozapine, olanzapine) via additional block of 5HT2A receptors
Nigrostriatal pathway
- Part of basal ganglia (aka extrapyramidal tract) plays a central role in planned, coordinated movement
- loss of DA in this region –>Park
Tuberoinfundibular pathway
brain DA pathway
- hypothalamic neurons release DA in pituitary to inhibit prolactin release
- Antipsychotic drug use (D2 block) can cause hyperprolactinemia and interference with body temp (poikilothermia) and alteration of eating behavior (weight gain)
Serotonin Hypothesis
- evolved from discovery that indoleamine hallucinogens (mescaline–LSD) act in CNS as serotonin agonists.
- ->activation of 5HT2A receptors was the basis for hallucinatory effects
Activation of 5HT2A receptors on DA neurons in PFC (striatal and cortical pathways)
decrease DA release
-negative sx
(use 5HT2a receptor blockers here to alleviate negative sx)
Activation of 5HT2A receptors on glutamate pyramidal cells in PFC
-result in stim of DA neurons in VTA–> increase in DA release in the mesolimbic pathway–>positive sx
Glutamate hypothesis
-Hypothesis states hypofunction of NMDA receptors located on GABAergic interneurons
in the PFC leads to diminished inhibitory influences that affect both mesolimbic and
mesocortical dopamine pathways giving rise to both positive and negative symptoms
Cortical Glu neurons activate cortical GABA neurons to produce a tonic inhibition of cortical Glu excitation of mesolimbic DA neurons
Hypofunction in cortical NMDA-Glu neurons–>remove GABA inhibiton–>activate DA neurons–>positive sx in schiz
Mesolimbic pathway and glutamate hypofunction
cortical Glu neurons activate GABA to inhibit cortical Glu to inhibit VTA GABA to produce tonic excitation of mesocortical DA neurons
Cortical Glu–>GABA–>Glut–>GABA–>mesocortical DA
Hypofunction in cortical NMDA-Glu neurons–>remove inhibition of VTA GABA–>inhibit mesocortical DA–>negative sx in schiz
Typical antipsychotic agents
HIGH D2/5HT2a blocking ratio
- good D2 block (good for pos sx, but high incidence of extrapyramidal toxicity)
- High potency: increased D2 side effects (EPSE), but less ADRs via M-H1-alpha1 block (Haloperidol)
- low potency: low EPSE, but increased ADRS from M-H1 alpha1 block (chlorpromazine)
M-H1: sedative action
Alpha1: hypotensive actions
Atypical antipsychotic agents
low D2/5HT2A blocking ratio
Poor D2 block: yet good antipsychotic efficacy
Good 5HT2A block: good for negative sx
Poor D2 block + good 5HT2A block: reduced incidence of EPSE
Clozapine, Quetiapine
Muscarinic block
ADR thats increased with typical-low potency dry mouth blurred vision urination diff constipation tachycard sedation
