methods of research in psychopharmacology

cross tolerance

• diminished effect of second drug

metabolic/pharmacokinetic tolerance

• enzymatic induction

pharmacodynamic tolerance

• down regulation

behavioral tolerance

• context-specific

• state-dependent

what are some simple observations?

• reflexes

• eating/drinking

• tremors

• immobility

latency

• time it takes to return

what are measures of motor activity?

• open field

• photobeams

  • imp for measuring anxiety-like behaviors

types of operant conditioning?

• self-administration

• drug discrimination

• delay discounting

• conditioned place preference

• mazes

describe self administration

• schedules of reinforcement

• breaking points

FR, FI, VR, VI, breakpoint — definitions

• FR — reward after a fixed set of bar presses

• FI — reward after a fixed amount of time

• VR — reward after an unknown amount of bar presses

• VI — reward after an unknown amount of time

• breakpoint — when the effort exceeds the value

drug discrimination

• the rat is able to tell the difference between saline and drug.

• it presses a dif lever based on which drug or saline it is administered in order to get a reward

delay discounting

• rewards lose their value over time

• the ability to WAIT for a reward = measure of impulsivity

• ppl tend to choose smaller, immediate rewards over larger, delayed ones.

delay discounting in rats

• they will continue to press the lever that is riskier if they are on amphetamine

conditioned place preference

• CPP — preference

• vs

• CPA — aversion

CPP — forced vs unforced

• biased based on initial chamber

• they are forced to choose between two sides, no neutral site — forced

• they can choose neutral site — unforced

CPP — biased vs unbiased

• animals may prefer one chamber

• biased — you put the drug on the side that they did not prefer to see drugs effect on preference

• unbiased — you don’t pay attention to initial preference

types of mazes

• morris water maze

• elevated plus maze

• radial arm maze

morris water maze

• tests spatial memory

• they put rat in murky water, place visual signs on the walls outside container, see how long it takes rat to stand on submerged escape platform

• they then bring rat back in at a diff time and do it again to see if the rats latency decreases and to test its spatial memory

elevated plus maze

• it is used to test anxiety

• they will put rat in exposed area and see how it behaves and if it rushes to hidden place

• they may give it a drug and see if it makes the rat less anxious or more anxious and test it by seeing if the rat stays in open or hides

radial arm maze

• short term vs long term memory

• you may put food at the end of one of the arms and see how long the rat takes to get the food. if he goes back down an arm he previously went down, then might not have good STM.

• they place rat back in maze again at another day and see if he remembers which arm the food is down, if he does = good LTM

what must drugs do?

• must be safe and effective to be sold in US

• only 20% of drugs make it to FDA approval

FDA approval steps

• preclinical research (5 yrs)

  • investigational new drug application sent to FDA

• clinical studies (7 yrs)

  • new drug application sent to FDA

• review by FDA (1.5 years)

  • approval by fda

• postmarketing surveillance (ongoing)

preclinical research

• discovery and early in vitro screening of compound

• large-scale synthesis

• animal testing

CS — phase I

• goal is safety and dosage

• 20-100 humans

• 70% make it through

CS — phase II

• goal is effectiveness

• (efficacy and side effects)

• up to 300 humans

• 33% make it through

CS — phase III

• studies different populations, doses and combos

• up to 3000 people

• 30% make it through

postmarketing surveillance

• monitor adverse reactions, product defects, long-term side effects, drug interactions

generic drugs requirements

• must have same active components (dosage, safety, strength, ROA, intended use, performance)

  • must work the same and provide same benefit

• cannot look or be exactly the same

  • trademark laws prevent this

  • qualities that do not affect performance can differ

• good manufacturing practices

  • to ensure quality and consistency

what must generic drugs prove?

• bioequivalence — generic delivers same active ingredients into bloodstream at same rate and extent as name brand

why do generic cost less?

• bc they don’t have to go through FDA process

name brand patent protection =

10-20 yrs

when and why was the FDA accelerated approval put in place?

• in 1992

• to treat serious, life threatening diseases

what must FDA AA prove?

• must show that it is reasonable likely to be clinically beneficial

  • i.e. caner drug that shrinks tumors

  • Drug approval typically requires clinical trials with endpoints that demonstrate a clinical benefit, such as increased survival for cancer patients. Drugs with accelerated approval can initially be tested in clinical trials that use a surrogate endpoint

surrogate endpoint

• predicts clinical benefit

• require less time

• much faster to measure reduction in tumor size, than overall patient survival

FDA AA graph

.

what are examples of other expedited processes?

• overall, they encourage treatments for conditions without one

1. fast track approval

2. breakthrough therapy

3. priority review

fast track approval

• designed to facilitate development and review of unmet medical need

• more frequent FDA meetings

  • rolling review: submit when ready

• HIV drugs in the 1990s used this pathway

breakthrough therapy

• based on early promising clinical data

  • must show substantial improvement over current treatments

• some cancer therapies receive this designation

priority review

• directs the attention towards a drug

  • shortens the review clock by several months