Schizophrenia Flashcards
Mesostriatal DA
Substantia nigra to Dorsal Striatum
Mesocortical DA
VTA to neocortex
Mesoaccumbens DA
VTA to Nacc (ventral striatum
Kindling metaphor of mental illness
Graham Goddard, observed full tonic clonic seizures after many low intensity stimulations. In some brain regions, where you stuck an electrode and applied low intensity stimulation, the first time you do something nothing happens. After a few stimulations, you see full blown seizures.
Typical Antipsychotics
Haloperidol is absorbed better; remains the gold standard for antipsychotic effectiveness
Metabolized very slowly; half-life of 48-96 hours w/ oral administration, weeks w/ IM administration;
stored in other tissues (lots of depot binding) such as liver, lungs, and spleen
ED50 = 2mg; LD50 = unknown; TI = estimated to be 100-500
Metabolized in liver by CYP, excreted in urine
DA Hypothesis Problems
Dopamine levels not elevated in schizophrenics
What results in hypofrontality?
Loss of DA release from VTA neurons projecting to prefrontal cortex (mesocortical pathway)
What happens after hypofrontality?
Hypofrontality results in less glutamate stimulation from PFC back to VTA
Glutamate-dopamine model
Impaired NMDA function makes this GLU stimulation of VTA even less effective… further reducing DA release in PFC -> leads to excessive DA release in limbic regions
Major depression
recurring episodes of dysphoria and negative thinking
Reactive depression
state of sadness in response to situations like loss of a loved one.
Pathological depression
resembles an emotional state we have all experienced but differs significantly in intensity and duration
Biological Bases for affective illness:
affective illnesses are due at least in part to an impairment in the function of two different monoamine neurotransmitters, norepinephrine and serotonin.
Resperine
blocks vesicular transporter, can lead to depression… or can be used to treat mania.
What do antidepressant drugs do?
Antidepressant drugs alter NE and 5-HT synapses in the nervous system… acute effects not clinically relevant, chronic effects are.
Lithium
may be effective in manic-depressives, as it stabilizes 5HT synthesis
5HT in bipolar disorder
; low 5HT levels may lead to NE levels determining mood. HI NE = mania; LO NE = depression.
MAOIs
acutely block MAO and elevate levels of 5HT and NE, and ultimately produce long-term changes in the postsynaptic cell
Lots of side effects;
MAOIs in use
currently 3 in regular use; best known is tranylcypromine (parnate), which irreversibly inhibits MAO; start-up; 5-10 TI
Tricyclics
Replaced MAOis
May block 5HT reuptake, or NE reuptake, or both… and DA reuptake; D-2 antagonist; 5-HT2 antagonist; block Na+ and Ca2+ channels (dirty drugs)
SSRI’s:
2nd golden age of psychopharm –
Prozac, 2nd generation of antidepressants; favored due to fewer side effects and higher TI, though therapeutic effects often no better.
Specifically block 5 HT reuptake carrier; a modified tricyclic
BAR 5HT receptors in depressed individuals
BAR 5HT receptors – primary norepinephrine receptor…. Decrease in receptor number if patient is on antidepressants
Why is lithium effective in treating bipolar disease?
Unknown mechanism of action – may stabilize proteins in neural membrane; reduced Ca2+ dependent release of catecholamines (but not 5-HT!); stabilize synthesis of 5-HT; alters many different aspects of 2nd messenger function.
Dangers of lithium
Very low TI (~3); can kill if patient has heart of kidney problems; long half life, so several small doses taken each day; eliminated by kidneys without being metabolized (at Li+)
NaCl and Lithium levels
Must watch NaCl intake as increased Na+ levels reduce amount of Li+ that can be excreted, NaCl levels too low cause toxic levels of Li+ to be retained.
Drugs other than lithium for bipolar disease
Carbamazepine/oxacarbazapine and valproate also used as adjuncts or primary treatment; mechanism of action unclear; GABA indirect agonists; decrease neural excitability.
