madness and medicine psychopharmacology

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psychopharmacology overview

-aka the third biological psychiatry
-author calls it the 2nd biological psychiatry
-main treatment is giving ppl drugs

rise of psychopharmacology

-from freud to prozac
-characterized as a scientific revolution
-transition from psychoanalytic to biochemical paradigms "changed from blaming the mother to blaming the brain"

thomas kuhn

-psychoanalysis never reached paradigm status, therefore it was NOT a true revolution in a Kuhnian sense
-science alternates btw periods of normal science and revolutionary science where the paradigm shifts and the old ways of thinking are thrown out
-normal science is paradigm driven and designed to confirm the paradigm, not disprove. all other things that are found inconsistent with the paradigm are thrown out

our modern psychopharmacology paradigm in a Kuhnian sense

-operating under a biochemical paradigm that says that mental disorders have a biochemical basis
-mental disorders are organic and reducible, and can be treated by manipulation of brain chemistry

neuronal stuff

-central part of a neuron: soma (cell body), nucleus inside
2 types of neurites:
1. shorter: dendrites
2. longer: axons
-myelin makes brain tissue white
-axon terminal button makes contact w/ next neuron at a synapse
-electrical signals can't go directly from one neuron to another (pre/postsynaptic neurons)

agonists

drug that stimulates receptors

antagonist

drug that blocks receptors
-some drugs attach to receptors and do not turn them off, but block other drugs from binding

making neurotransmitters

-process can be altered by psych drugs
-L dopa effects the precursor to a NT

vesicle storage disruption

reserpine blocks the storage of neurotrans in vesicles

drug that breaks down neurotrans

MAO breaks down a type of transmitter
-used to treat depression
-Iproniazid blocks MAO

reuptake blockers

block reuptake of neurotransmitter
-ex. SSRI's, Prozac and Paxil-antidepressants

drugs that stimulate neurotrans release

Amphetamine (Aderol)
methyphenidate (ritalin)

autoreceptors

presynaptic inhibition

monoamine neurotransmitters

-Catecholamines-dopamine, norepinephrine (noradrenaline), epinephrine (adrenaline)
-Indolamine-serotonin (5HT)

serendipity

the discovery of something not sought

antipsychotics also known as

neuroleptics
major tranquilizers
ataractics

chlorpromazine

blocks receptor
clinically more useful than reserpine
from this most of modern antipsycs made

reserpine

-antipsychotic
-blocks storage in synaptic vesicles
-used for around 10 yrs in 1950s as an antipsychotic
-didnt work as well as chloropromazine

phenothiazines

-dyes made from coal tar (methylene blue)
-used as antiparasitics
-methylene blue tried in mental patients
-chloropromazine belongs in this class

methylene blue

-Ehrlich discovered new dyes selectively stain bacteria
-also found to stain the malaria parasite-antiparasitics
-lead to its use as antimalarial
-tried on mental patients b/c found when put it a test tube could stimulate O2 consumption -phenothiazine

phenothiazine amines

-made in search for antiparasitics
-routine screening reveals antihistamine activity
-histamine implicated in allergic reactions and shock
-benadryll-antihistamine and sedative

Laborit's theory of shock

-during surgery his patients went into shock-he was trying to prevent that
-autonomic NS control's body's rxn to stressful, traumatic situations
-he thought ANS was triggered, which damaged the blood vessels, which caused the release of histamine, which causes vascular hyperpermeability (blood vessels leak)
-put together a lytic cocktail to stop that effect
-used promethazine in his cocktail and it had psych effects on ppl
*linked antihistamines to psych medication

secondary qualities of promethazine (5)

hypnotic (weak and reversible)
no clouding of consciousness
indifference
analgesic
hypothermic

promethazine and surgery

Laborit used it as a preoperative sedative, replaced morphine as an analgesic
-also because of its hypothermic effects it potentiates anesthesia reducing the amount required

clinical applications of promethazine

-preop sedative
-analgesic
-psychiatric sedative?
-anesthetic potentiator (artificial hibernation)

chloropromazine history

-synthesized by Charpentier in 1950
-lab tests reveal exceptional central activity
-spring 1951 clinical trials of cpz begin
-psych application discovered in 1952 by Delay and Deniker at St. Anne's hospital in Paris

clinical applications of chloropromazine

-preanesthetic, antiparkinsonism, psychaitric
-cpz had strong effects on conditioned reflex behavior in animals (ex. rope climb test)
-in clinical trials:
1. used to potentiate barb sedation in sleep therapy and narcoanalysis

delay and deniker

credited w/ discovering pscyhiatric applications of chlorpromazine
-delay: chief of medicine at St. Anne's psychiatric center
-deniker: head, mens dept (confined, insane)

CPZ in France/US

-France: marketed as Largactile in 1952 as antiemetic and to calm agitated/excited states
-US: Thorazine 1954

1954 Steck

reports parkinsonism and tardive dyskinesia (extrapyramidal side effects)

impact of CPZ (3)

1. transformed ward environ-it was said that the effect of CPZ could be measured in psych hospital decibels
2. other somatic therapies decline
3. population of mental hospitals decline for first time in 150 yrs

neuroleptics not a panacea

-2/3rds have continuing impairment
-1/3 require chronic or frequent hospitalization
-benefits greatest in acute schizophrenia (shortens episode, lessens impact, reduces relapse)
-negative symptoms often refractory

neuroleptic (extrapyramidal side effects)

dystonia
akathesia
parkinsonism (tremor, rigidity, akinesia)
-tardive dyskinesia

Reserpine

-plant Rauwolfia serpentina
-used in India by scientists saying it has antihypertensive and antipsychotic action
-reported as psychiatric sedative in 1954
-thought to be depressogenic (Nathan Kline)
-acts like a tranquilizer
*quickly becomes obsolete

reserpines antipsychotic mechanism of action/cpz's action

depletes dopamine
-cpz on the other hand is a dopamine receptor (D2) antagonist

dopamine hypothesis of schizophrenia

-drugs that interfere w/ dopamine reduce schizophrenic symptoms
-drugs that facilitate dopamine exacerbate schizo symptoms
-schizo is caused by hyperdopaminergia
-Jacques van Rossum's theory

problems with the dopamine hypothesis (3)

1. no reliable abnormalities in dopamine or dopamine metabolites
2. there is an increase in dopamine receptors in brains of schizophrenics
3. increased dopamine receptors in schizophrenics are probably iatrogenic

typical antipsychotics (conventional antipsychotics) (7)

1. chlorpromazine (thorazine)
2. thioridazine (Mallaril)
3. trifluoperzine (stelazine)
4. thiothixene (navane)
5. haloperiodol (haldol)
6. pimozide (orap)
7. loxapine (loxitane)

atypical antipsychotics (5)

1. clozapine (clozaril)
2. risperidone (risperidol)
3. olanzapine (zyprexa)
4. quetiapine (seroquel)
5. aripiprazole (abilify)

atypicality

-reduced extrapyramidal side effects
-different mechanism of action
-increased efficacy particularly for negative symptoms (maybe)

positive symptoms of schizophrenia

psychotic behaviors not seen in healthy people
-include hallucinations, delusions, thought disorders, movement disorders

negative symptoms of schizophrenia

-absence of normal behavior
-flat affect, blunting, lack of pleasure in everyday life

joseph beiderman

-thought that treating children with resperidol (risperidal) could help bipolar disorder and ADD
-world's most prominent advocate of diagnosing bipolar disorder in even the youngest children and of using antipsychotic medicines to treat the disease

Monoamine oxidase inhibitors

-1952-tuberculosis action of isoniazid and iproniazid discovered
-ZELLER reports that iproniazide blocks MAO
-psychologic side effects lead to trial in psych patients (not developed w/ psych in mind)
-by 1958-380,000 mental patients had been treated w/ iproniazid
-1961: withdrawn b/c of hepatotoxicity

monoamine hypothesis

-iproniazid elevates monoamines (dopamines, epi/norepi, serotonin
-depressogenic action attributed to reserpine-which decrease monoamines in brain
*based on idea that brain is deficient in thse neurons

Everett and Toman monoamine hypothesis

-1958
-depression caused by deficient monoamines

tricyclic antidepressants

-discovery of cpz led drug companies to synthesize and screen similar drugs
-Roland Kuhn tries imipramine in psychiatric patients b/c of similarity in structure to cpz-1955
-patients became euphoric when on imipramine

monoamine hypothesis-norepinephrine

-imipramine blocks norepinephrine and serotonin reuptake
-1965-schildkraut proposes norepinephrine hypothesis (lack of neurotrans causes depression)
-1967 Coppen proposes serotonin hypothesis

problems with monoamine hypothesis

1. lack of reliable biochem evidence: can't check transmitter levels on a living person
2. Bupropion (an atypical antidepressant) doesn't affect NE or 5-HT
3. reserpine is not really depressogenic
4. discrepancy btw action of antidepressants and onset of clinical effects. takes time to get better but should be immediate based on drug action

tricyclics and NE and 5HT

-have different effects on neurotransmitters depending on the drug
-those that block reuptake of NE-behavioral activation (get ppl moving-psychomotor activation)
-preferential effect on 5HT-mood elevation

despramine

selectively blocks reuptake of norepinephrine

the first neuroleptics (2)

chlorpromazine
reserpine

SSRIs (5)

fluoxetine (prozac): 1st blockbuster antidepressant
sertraline (zoloft)
paroxetine (paxil)
citalopram (celexa)
escitalopram (lexapro)

first antidepressant

iproniazid

prozac panacea

Peter kramer's book: Listening to Prozac
-really talked up prozac
-said it reduced anxiety, caused happiness, increased self-confidence, emotional resilience, affective numbing, increased sociability

cosmetic psychopharmacology

taking a drug to make you "better than well"
-Peter Kramer said this of Prozac

SSRI's and suicide

link btw SSRI's and suicide suggested
-akathesia one of the main reasons for that
-main proponent: DAVID HEALY
-accused drug companies of trying to cover this up

controversy of SSRI and suicide linkage

since introduction of SSRI's suicide rates in adolescents in US and Europe DECREASED
-Healy thinks drop in suicide rates comes from ill-reported deaths

FDA and SSRI's

-made a black-box warning about increased risk of suicidal ideation in adolescents
-since then SSRI prescriptions in children have DECLINED and suicide rates have INCREASED
-dr.s began to prescribe atypical antipsychotics to depressed teens

lithium

-used at first to treat Gout
-used to treat depression and mania (1886) by Lang
-JOHN CADE: rediscovers mood stabilizing effect (1949)
-primarily used in bipolar
-problem: has a low therapeutic index

anxiolytics

-Meprobamate discovered and marketed as Miltown and Equanil-discovered by researchers trying to make gram neg resistant drug
-you can die from w/drawal and can impair function

benzodiazepines

-anti-anxiety
-pretty safe
-Klonopin=safest, valium=drug of the starts in the 60's, xanax, dalmane, restoril

stimulants

-Freud pushes cocaine (1884)
-alles discovers CNS stimulant effect of amphetamine
-Bradley uses amphetamine to treat childhood behavior disorders

Bradley home and amphetamines

-benzadrine
-used to treat ADHD
-gave students amphetamine to take away headaches after spinal tap
-found out it helped with attention
-called "math pill"?

provigil

stimulant
-treatment for narcolepsy
-keeps ppl awake in the military

ways drug companies increase drug sales

create demand where there is no need
-market drugs for specific indications
-gifts to doctors
-evergreening (repurposing and reformulating)
-marketing for off-label use

industry and research

-industry is largest funder of medical research
-spend billions on it
-effect: sets research agenda, affects way information is presented, research outcomes consistent w/ marketing goals of industry

generic vs. brand name

-FDA requires generics to have 80% to 125% bioequivalency to brand name

the first neuroleptic (antipsychotic) drugs

chlropromazine
reserpine

upjohn illness

marketing a drug for a specific illness
ex. xanax for anxiety disorder

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