1. Drugs are not disease specific, treat symptoms
2. some patients don't respond to drugs (1/3)
3. all patients at risk for side effects
4. can't predict specific effect a drug will have for a patient (can use family history)
5. don't know how effects of drugs related to their physiological effects (have some theories)

At least 6 months in which:

• prominent psychotic symptoms present for at least 1 week
• psychosocial functioning is poor
• if present, mood disturbance is brief vs psychotic symptoms (not main problem)

1. Content of though- delusions (false beliefs, not amenable to change by reason or experience)
2. form of thought- thought disorder (word salad, loosening of associations among thoughts)
3. perceptual disturbances- hallucinations- perception occurs in absense of a stimulus usually auditory
4. negative symptoms
5. mood or affect- flat or abnormal emotions

1. Positive symptoms (delusions, hallucinations, thought disorder)-treated by drugs
2. Negative symptoms (anhedonia, withdrawn, affective blunting)-no drug effect
3. Cognitive impairment- no drug effect

1st antipsychotic

-how it started

Chlorpromazine

-1856, WWI developemnt of popular purple dye used in genes, variation = methylene blue

Chlorpromazine

WWI discovered methylene blue could tx symptoms of malaria

WWII- allies with same problem synthesized methylene blue analogues including phenothiazine

-discovered in WWII to treat malaria

-french scientists interested in phenothiazine because of antihistamine action

-dose-response effect of antihistamines: low doses caused tired, large doses caused arousal

-suggested drugs could be more specific than previously though

-led to synthesis of chlorpromazine

-French Navy anesthesiologists

-thought antihistamine could be useful in preventing fatal effects of shock in vietnam

-Histamine decreased blood pressure (factor in shock), thought chlorpromazine could stop this

-didn't decrease blodo rpessure but observed patients were more mellow after chlorpromazine

-refers to effect of chlorpromazine

-coined from greek "lepto" to make fine or delicate (makes neurons work fine or better)

News from 50 year search for more drugs to relieve psychotic symptoms

Good

-lots of drugs like chlorpromazine that can reduce some positive symptoms of schizophrenia

-antipsychotics now used for bipolar too

Bad

-can't help everyone

-not all symptoms improved

-bad side effects (2nd generation better)

- first dose makes patient sleepy (antihistamines are 1st generation), this wears off in a few week due to tolerance, not the reason they work

-symptoms improve in a few weeks (sto hearing voices, paranoia and suspiciousness less, speech connected/coherent, more self-care, more emotionally responsive)

NIH Definitive Collaborative Study

-set up

-groups

-conclusions (4)

crucial historical results for antipsychotics-showed APs the right med for psychosis

-9 hospitals, DSMII diagnosis, 344 subjects

-4 groups (3 different APs-chlorpromazine and 2 others, and placebo)

Conclusions:

-8% no response, 22% a little better=30% neuroleptic resistant

-higher doses didn't increase response, worsened side effects

-switching APs, usually no better, could help side effects

-negative core symptoms NOT reduced

1. drugs activating DA by blocking DA reuptake(amphetamine/cocaine) produce symptoms looking like schizophrenia e.g. stimulants cause paranoia
2. shizophrenics symptoms got worse when given stimulant (not w/ other diagnosis for if symptoms in remission)
3. AP could block or reduce psychosis produced by stimulants
4. L-dopa, DA precursor, worsens schizophrenia
5. AP side effects look like Parkinsons (due to loss of DA in brain)

-found ppl overdosing with stimulants showed symptoms a lot like schizophrenia

-supported the DA hypothesis

1. too much DA produces postivie psychotic symptoms

2. antagonism or reduction of DA decreases behaviors

3. antipsychotics must work because they decrease DA

-if blockade is imp for therapeutic effect then drugs that are more porent in people (clincially work better) should be better at blocking DA receptors, drugs less potent should be weaker

-drugs that block more DA should work better if this is why APs work and not simply an explanation for AP side effects

Clinical evidence for DA hypothesis

-better a drug binds to D2 receptor and blocks effect of DA there, better AP it is

-Y axis (how much is needed to know off 1/2 of the DA molecules- compared to haloperidol: DA antag)

-X axis (average clinical dose needed for effects)

-explains why AP block D2 receptors right away but clinical effects take longer

-APs block postsynaptic and presynaptic receptors

-presynaptic (autoreceptors) normally tell neuron to stop sending NT, when blocked it doesn't get this signal so the neuron produces even more of NT, presynaptic block causes an increased release

-neuron eventually burns out and it stops firing DA at high rates, DA is built up in cell so DA firing, and synthesis decrease

1. time course
2. depolarization block seen in animal studies w/ brain imaging
3. DA metabolites in the urine first go up, then down

1. nothing wrong with BL DA metabolities in urine
2. -Post-morten binding assays- showed supersensitivity of D2 receptors (critics say this coudl be due to neuroleptic tx, upregulation of DA receptors due to blocking receptors for a long time) -Pet scans in living brains conflicting

• somethings wrong w/ DA function in schizophrenia (more functional analysis then past static view)
  • greater reuptake of L-Dopa in putamen of schizos
  • schizos might synthesize more DA in frontal cortex & striatum
• DA transmission greater in schizophrenia
  • patients injected w/ amphetamine (DA reuptake blocker) had more DA released than ctrls
  • some had increase in positive symptoms, seen in neuroleptic exposed and naive patients, no increase in stable remitted patients

-compared schizophrenic patients to ctrl

-same amount of D2 receptors, same amount of DA in blood

-more amphetamine induced release of DA in schizophrenic patients then in ctrls

1. No best AP, choice made on side effects
2. most imp differences in AP was potencies (divided into 2 grps: low, medium, and high potencies) all are equally effective
3. AP are physicall safe, overdose death unlikely
4. AP are not reinforcing, no high, not abused
5. tolerance may develop to side effects, but there is no/little tolerance to clinical improvements

Neurological side effects of 1st generation AP

(5)

1. Dystonia
2. Pseudoparkinsonism
3. Tardive dyskinesia (TD)
4. Akathisia
5. Neuroleptic Malignant syndrome

-not that common

-occurs earliest

-abrupt spasms of tongue/face

-frightening; requires immediate attention (lower dose)

-evidence of increaed DA in system

-Akinesia- proverth of movement

-looks like a "mental patient"

-looks like negative symptoms (no facial emotions)

-major class of side effects

Tardive dyskinesia (TD)

-cause

-late neurological symptoms, 6 months-several years

-most feared, could be irreversable, LT outcome variable

-no best tx (increase AP & symptoms could get worse, decrease AP & psychosis could reoccur)

-abnormal motor function, usually face/upper body

Cause:

-supersensitivity (upregulation from LT use of meds)

-arguments agiainst supersensitivity, not sure of cause

-one of main reasons ppl stop taking AP

-most distressing side effect

-restlessness feeling- internal feeling

-can't sit still, often causes pacing to relieve restlesness

-most dangerous side effect

-can occur soon after taking drug

-fever, delirium, death

-very rare

1. sedation- some tolerance (antihistamine effect)
2. postural (orthostatic) hypotension-lowered blodo pressure from standing errect- tolerance (standing too quickly and getting dizzy, due to block of adrenergic receptors)
3. lowered seizure threshold- carebul w/ drug combos
4. photosensitivity- blue skin
5. anticholinergic side effects

Anticholinergic side effects

-receptor

-side effects due to blocking AcH

-constipation, dry mouth, blurry vision, memory problems

-common side effect for many drugs (ADs)

-anticholinergic is blocking muscarinic

____ block = efficacy

______ block = adverse side effects

D2 block = efficacy

histamine & adrenergic block = adverse side effects

1. about 30% of patients don't respond (others only partially respond)
2. serious, maybe intolerable side effects
3. negative symptoms not improved

Clozapine

First atypical antipsychotic

1. reduces symptoms in about 30% of nonresponders to 1st generation
2. practically produces no Parkinsonian side effects or tardive dyskinesia- could help patients who couldn't tolerate side effects
3. reduced negative symptoms (controversial, might not help, just looks like it from helping parkinsonia side effects)

Clozapine's receptor profile

-Histamine antagonism: drowsiness, weight gain

-alpha adrenergic antagonism- dizziness, decreased blood pressure

-anticholinergic (muscarinic) blockade- drowsiness, dry mouth, blurred vision, constipation, cognitive impairment

-DA blockade- antipsychotic actions

• Tuberoinfundibular (least sig, small pathway)
  • hypothalamus to anterior pituitary
  • release of hormone prolactin, DA inhibits prolactin (blocking DA=inc prolactin=inc milk)
• Nigrostriatal pathway
  • substantia nigra to basal ganglia
  • movement control, parkinsons
• Mesolimbic pathway (AP work here)
  • midbrain VTA (A 10) to nucleus accumbens
  • mediates reward and reinforcement
  • mediates positive symptoms
• Mesocortical pathway
  • midbrain VTA (A 10) to frontal & cingulate cortex
  • involved in cog impairments & neg symptoms

Why are there no Parkinsonian symptoms for 2nd generation antipsychotics (atypicals)?

(3)

• Weak DA blockade-striatum/basal gangla (where parkinsons happens) has a lot more DA then the limbic system (where schizophrenia happens)
  • lower potency and can get kicked off of receptors easier
  • gets kicked off in striatum (no side effects) stays on limbic (helps schizophrenia)
• 5HT_2a blockade - 5HT reduces DA release in striatum (PD)
  •  activates a heteroceptor on DA neuron in basal ganglia (nigrostriatal pathway) blocking 5HT lets the DA get here
• Strong anticholinergic blockade- clozapine blocks muscarinic
  • counteracts effects of DA block, DA & AcH act in opposite direction (inc DA= dec AcH, vv)
  • drugs blocking DA inc AcH, blocking AcH balances effect
  • PD patients have drugs that block AcH receptors

•  primary negative symptoms (part of disorder)
  • NOT helped by clozapine
• secondary negative smptoms- side effects
  • Due to EPS, side effect of pos symptoms and meds, depression, no enjoyment
  • Clozapine helps, reducing pos effects and EPS

*Clozapine doens't really reduce neg symptoms, just looks like it cause it helps other symptoms

Other Atypical Antipsychotics

AKA

- risperidone, risperdal

-olanzapine, zyprexa

-quetiapine, seroquel

-ziprasidone, geodon

-aripiprazole, abilify

(all attempts to match clozapine)

-AKA D2/5HT2 blockers

Abilify (general description)

-AKA Aripiperazole

-First 3rd generation antipsychotic

-incorporates concept of DA modulation or balance rather than blockade

1. presynaptic DA agonist (partial agonist, reduces DA)
2. postsynaptically a partial DA agonist-produces DA activation to a certain level, w/ lots of DA around you are tuning down full effect
3. Partial 5HT_1a agonist (antidepressant effects)
4. 5HT₂ antagonist

**agonst for DA when concentrations are low, antagonist when DA is high**

Good:

-all are effective for pos symptoms

-all produce less neurological sde effects (block 5HT2a)

Bad:

-different serious side effects (metabolic syndrome: weight gain, diabetes, blood lipid increase)

-abilify could be better

1. look like EPS
2. look like effects of frontal lobotomy (too little DA to frontal lobe)
3. DA agonist might improve them? difficult cause you'd have to inc DA in frontal while dec in limbic for pos symptoms

• emotional dullness
• impaired judgment
• poor initiative motivation and drive
• lack of insight
• difficulty in planning
• impaired problem-solving and abstract reasoning
• decreased concern for personal hygiene
• social withdrawal

Other transmitter that might be responsible for schizophrenia abnormalities

-Glutamate

-NMDA blockade w/ PCP (blocks glutamate to reduce pain and make strong) looks like psychosis

-Glutamate interacts w/ DA neurons problem w/ testing cause too much glutamate kills neurons

-used normal Drs, more realistic

-3 main phases

1st phase showed new meds better then old

-revisions of DSM

-2 new antipsychotics approved (Fanapt/Iloperidone, Saphris/Asenapine)

-published recommendations for pharmac and psychosocial treatments from the Schizophrenia Patient Outcomes Research Team (PORT), use related txs: smoking cessation, drug abuse, weight loss

-more LT studies in relapse in better quality of life

-cog and social txs get more attention

-more prescriptions in children

-more reports identifying genetic and neuroanatomical abnormalities

-malicious use of pharmaceuticals: under-recognized form of child abuse

-abusing drugs to keep kids under control

-study, results showed haloperidol had highest drop outs but no drug showed diff on PANNS scores

-should you use primary or secondary measures??

1. check for compliance
2. wait for delayed response
3. increase dose
4. decrease dose (reduce side effects)
5. switch drug (same or diff class)
6. switch to clozapine
7. augment w/ agents of diff class or other AP
8. settle for suboptimal level