PYB260 Psychopharmacology of Addictive Behaviour Week 3 Research Methods PDF

PYB260 PSYCHOPHARMACOLOGY OF ADDICTIVE BEHAVIOUR Week 3: Research methods in behavioural pharmacology Melanie White 1  ACKNOWLEDGEMENT OF TRADITIONAL OWNERS QUT acknowledges the Tur...

PYB260 PSYCHOPHARMACOLOGY OF ADDICTIVE BEHAVIOUR Week 3: Research methods in behavioural pharmacology Melanie White 1  ACKNOWLEDGEMENT OF TRADITIONAL OWNERS QUT acknowledges the Turrbal and Yugara, as the First Nations owners of the lands where QUT now stands. We pay respect to their Elders, lores, customs and creation spirits. We recognise that these lands have always been places of teaching, research and learning. ​ QUT acknowledges the important role Aboriginal and Torres Strait Islander people play within the QUT community.​ CRICOS No.00213J Faculty of Health  Lecture Outline Research design Within vs. between subjects design Placebos & nocebos Research methods Measuring drug effects on arousal, performance & behaviour Identifying good research design Drug licensing Animal studies in drug development 3  Reflection Questions (egs, not exhaustive) Next week’s tute (& lab report): applying this knowledge to a real-world example: designing a study to investigate the effects of caffeine on human behaviour What kind of design could we run for an in-class experiment? What would we be interested in looking at the effects of caffeine on? And how would we measure these outcomes? Pros & cons of each type/choice? How could we ensure our experiment is as controlled as possible? Think of an example from your own experience/ observations that is explained by a) the placebo effect & b) the nocebo effect. What characteristics define these experiences? Explain the hypothesized mechanisms by which these effects arise Compare the benefits of a 3-group design vs. 4-group balanced placebo design  Research designs in psychopharmacology  Experimental research design Independent variables (IV) Variable that is manipulated in a study E.g., amount of drug administered/ type of drug administered Dependent variables (DV) Variable that is measured in a study (to observe effect of IV) E.g., behaviour/mood/cognition/motor performance Experimental control  Experimental research design Between-subject designs (independent groups) Experiments are conducted with 2 (or more) different groups (IV is operationalised as different groups) E.g., Group A given a new drug; Group B given CBT Usually interested in the difference between the means of these groups.  Research design: Between groups cont. Advantages: Easier & more time efficient to run Allows observation of variables that are not stable (i.e., habituation, practice effects, etc.) Disadvantages: Many variables are unable to be controlled (e.g., systematic differences between the groups) need more participants so these effects average out Results are presented in terms of group differences; masks changes within the individual Method of allocating to groups (randomised controlled trial; consecutive case design?)  Experimental research design Within-subject designs (repeated measures) Same participants involved in every level of the experiment IV is operationalised as different levels/testing occasions that all participant receive E.g., same participants are tested for attention span before & after taking a drug Usually interested in difference in the mean of the 2(+) testing occasions  Research design: repeated measures cont. Advantages: Requires fewer participants Each participant acts as their own control Disadvantages: Not amenable to measurement of unstable variables Time & money May need alternate forms to assess DV to counteract practice effects May need to counteract cross-over effects (Landauer, 1975)  Experimental research design Control groups/conditions Used to ensure the effect observed is due to the variable we manipulated & not some other variable Especially important in between-subject designs A control group will be identical to the groups being tested, except for the manipulation E.g.: Group A: has depression & given new antidepressant (exp. group) Group B: has depression but receives no treatment (control group) - participants with same symptoms/severity, demographics etc. as experimental group If no difference is observed between the 2 groups, then it appears the new antidepressant did not work.  Experimental research design Placebo controls sometimes in drug research a placebo condition will be used A placebo control condition will be similar to the experimental condition, except rather than receiving the drug (or no drug) they receive a substance containing no active ingredients (a placebo) E.g., Group A: has depression, receives new antidepressant Group B: has depression, & receives sugar pill Placebo controls are extremely useful for investigating whether any benefits derived from a drug are due to placebo effects  Video clip to view about here: “THE POWER OF THE PLACEBO EFFECT” (4.5mins long) https://www.youtube.com/watch?v=z03FQGlGgo0 13  Expectancy & context 1. Not given drug, not told they’re given the drug 2. Given the drug, not told they’re given the drug 3. Not given the drug, told they’re given the drug 4. Given the drug, told they’re given the drug McKim & Hancock, 2013, p 54.  Experimental research design Three-groups designs 3 groups may be used 1. Given a new drug 2. Given a proven drug 3. Given a placebo - Allows comparison between new drug & placebo - Allows comparison between new & established drugs - Allows experimenter to see if measures are sensitive enough to detect change (i.e., compare proven drug & placebo)  Experimental research design Alternate combinations of groups used to answer Qs of: effectiveness of drugs vs. non-pharmacological interventions e.g., CBT group vs. drug-treated & placebo-groups specificity of drug effects: e.g., include groups comprising people with different mental illnesses → does the drug work in depression exclusively? Effects may also be assessed over time (multiple measurements (longitudinal design) or once-off (cross-sectional design)  Experimental research design Sources of bias Bias results in systematic errors in measurement or prediction Bias can enter an experiment from many different sources Experimenter & participant expectations/bias (double blind studies) Selection bias: experimental controls Demographic differences (age/gender) Cultural differences Personality differences Education etc. etc. etc……  Research methods Low Introspection Naturalistic observation Case history Survey Test Correlation Experiment High Ethical & legal constraints on drug research In most drug studies there are severe ethical & legal constraints E.g., alcohol studies: legal constraints are relatively few (except min. age), but there are still ethical problems (e.g., how do people get home after experiment?) administering alcohol (& other legal drugs) to participants to participants can be costly (time & money) retrospective consumption questionnaires are often used (or daily consumption questions (diaries)) Outcome measures: what do we measure & how?  Potential variables Depending on the drug & its action, some of the domains in which we may look for effects are: Arousal Cognition Perception Motor function Mood We might also want to measure side effects / biochemical or physiological drug effects.  Measuring performance The more measures we use: the more comprehensive our assessment the more costly our experiment (financial & time) the greater the need to consider experimental controls & logistics (e.g., order we administer measures). Assessing change/differences in performance across performance domains (e.g., arousal, cognition, perception, motor function) tells us something about how the drug works, & the effects it produces (primary & side effects) Some examples….  Measuring arousal Arousal level changes naturally throughout the day, but can also be affected by a number of things – including drug use Most drugs are thought of as either ‘ stimulants’ or ‘depressants’, when given in large doses (at low doses this categorization does not hold) ‘uppers’ & ‘downers’ imply a relationship between arousal & mood – not necessarily that clear High arousal  high activity  Measuring arousal Since various drugs have an effect on arousal how we measure arousal is important Electroencephalograph (EEG): a measure of arousal/ detects potential differences between points on the scalp & neutral points on the body Other ways to measure arousal: Introspection? Unstructured Introspection Systematic Introspection – e.g., self-report scales (e.g., VAS) Ask an observer?  Measuring arousal Levels of Arousal Death Coma Sleep Drowsy Normal Normal range of arousal Aroused Highly excited Mania Convulsions Death  Measuring mood Drugs can impact significantly on mood Can be studied experimentally (e.g., we can test drug effects by inducing mood states) or using a between-groups design (e.g., depressed vs. non- depressed patients) Measurements could be by self-report, doctor’s assessment, informant report, questionnaire, tests of biological markers of depression etc. Consider the advantages & disadvantages of these ways of assessing drug effects on mood.  Measuring perception Refers to the detection & integration of external stimuli Visual & auditory perception are most often studied Perception research often investigates the changes in the sensitivity of a person’s perception brought about by changes in the internal or external environment (e.g., drug use) These changes in sensitivity = thresholds (two types) Absolute Threshold Lowest value of stimulus detectable by an organ (e.g., eyes) Difference Thresholds Organ detects a change in level of stimulation  Measuring perception Absolute thresholds – lowest value of a stimulus that can be accurately detected 50% of the time. E.g., Vision: candle flame on a dark, straight road, at 60km Smell: 1 drop of perfume in a 6-room apartment Hearing: watch tick 6 m away Taste: 1 tsp sugar in 8 L water Touch: wing of a fly falling on your cheek from 1cm  Measuring perception Difference thresholds – measure the ability of an individual to detect a change in a stimulus E.g., when can you tell the light is brighter than it was before? Critical frequency at fusion (CFF) – sensitive to drug effects  Measuring cognitive performance Ability to process, store & retrieve information (e.g., attention, memory, learning, etc.); can also include higher-level processes such as planning, set-shifting & response inhibition Often manipulated experimentally Effect of drug at different stages of cognitive process can be assessed (e.g., may affect storage of information, or earlier attention processes) See text & caffeine readings for examples of specific tests (e.g., N-back or digit span for working memory; GoNogo tasks for inhibition; continuous performance task or clock test for vigilance/sustained attention, etc.)  Measuring motor performance Drugs can have a significant impact on motor tasks like coordination (e.g., alcohol) How might we measure these? ? simple or choice reaction time, tapping, pursuit rotor, etc. Measuring side effects/physiological effects Some methods of assessing side effects: Questionnaire (e.g., yes/no questions; rating scale etc.) Biochemical assay Doctor's check-up/ physical examination Informant report Strengths & weaknesses of these methods Some methods of assessing physiological effects: biochemical assays, MRI scans, PET scans Identifying good research design  Identifying good research design Some general issues: What is the research question: does the chosen design allow that question to be answered? What are the strengths & limitations of the measures used to assess effects? How sensitive/ appropriate are the measures? How precisely can measurements be made? What experimental controls have been put in place? Effect size: how meaningful is the change observed in terms of everyday functioning?  Identifying good research design (2) Some special factors to consider with drug studies Washout effects (esp. in w/g designs) Deprivation study designs (withdrawal) Level of drug administered Dose of drug used (e.g., compliance with instructions) Inclusion of biochemical assays Controls for routine / habitual or other drug use Non-specific treatment effects Special group selection factors (mild, moderate, & severe depression?) Timeframe for assessing effect Reporting of adverse events/non-compliance / attrition  Identifying good research design (3) Special factors to consider with drug studies (cont.) If in-vitro cellular trials are used: how generalizable are results to intact living systems? If animal trials are used: how similar is the species, apparatus, domain of function being tested? Further reading – see Sections 2.3-2.6 of textbook (latest version; or pp. 30-35 of previous edition) for some common animal behaviour paradigms used in behavioural pharmacology (e.g., spontaneous motor activity; stereotyped behaviour; anxiety/fear responses; paw lick test of analgesia; conditioned behaviour). “This drug was tested on 2000 white mice, and they had a ball.” David W. Harbaugh.  Research Ethics APS Code of Ethics (SB.14 Research): https://www.psychology.org.au/About-Us/What-we-do/ethics-and-practice- standards/APS-Code-of-Ethics NHMRC guidelines: https://www.nhmrc.gov.au/research-policy/ethics/animal-ethics National Statement on Ethical Conduct in Human Research: https://www.nhmrc.gov.au/guidelines-publications/e72 https://www.psychology.org.au/getmedia/d873e0db-7490-46de-bb57-c31bb1553025/18APS-Code-of-Ethics.pdf Approving drugs: licensing  Drug development The development, testing, manufacturing, & eventual marketing of any drug is time-consuming & expensive: 10-15 years & US$1.8 billion (Paul et al., 2010). www.nature.com/nrd/journal/v9/n3/pdf/nrd3078.pdf US$161m-4.54billion (Schlander et al., 2021, systematic review) https://doi.org/10.1007/s40273-021-01065-y A drug company may evaluate 1000s of different chemicals before finding one that moves successfully through all phases of testing & is finally approved by the FDA/equiv. for release & marketing Major considerations in drug development: 1. Medical need 2. Commercial potential 3. Feasibility for mass production “Orphan drugs” StagesFDA approval processes: 4 stages 1. Preclinical investigation (basic science; tests on cells & animals; effects of drugs noted for side effects, toxic effects, addictions, cancerous tumors, fetal deformities, pharmacodynamics) 2. Clinical investigation (human testing, 4 phases, incl. 3 phases of clinical trials) 3. Review of NDA (New Drug Application) 4. Postmarketing studies Source: Holland and Adams (2011), Pearson Education.  Drug development & animal testing (Stage 1) How applicable are the results from animal drug studies? Specific limitations of animal studies, e.g., Cats: markedly different sleep-wake cycles (e.g., sleep 65-80% of the time) Monkeys: develop obvious behavioural abnormalities from confinement Rabbits: different enzymes from humans (e.g., can eat some plants that would be poisonous to humans) Despite limitations, animals studies generally provide a valid indication of the likely drug effect in humans (Palfai & Jankiewicz 1997) -some notable exceptions…  Drug development & animal testing (Stage 1) Step 1. Determining toxicity Acute toxicity (for single doses) Subacute toxicity (short term use of drug) Chronic toxicity (longer-term drug use) Special toxicity (carcinogenic? teratogenic?) Step 2 next slide…  (Stage 1) Step 2. Pharmacological studies (direct & indirect) Direct: – to locate direct measures of changes induced by drugs via tools such as: rating scales, objective measures (e.g., “jiggle-cage”/ “tail suspension test”), conditioning studies (see next slides), sites-of-action studies Indirect: - to identify markers or signs of effects rather than evidence of the effect itself or - to observe effects on behaviours that are induced in animals  (Stage 1) Direct pharmacological studies - conditioning: General principles Stimulant substances: rapid learning/acquisition of conditioned response, poor discrimination / ready generalisation, slow termination/ extinction Depressant substance: slow acquisition/learning, poor generalisation/easy discrimination, rapid extinction A Skinner Box for a Rat McKim & Hancock, 2013, p.31 A Skinner Box for a Rat Hancock & McKim, 2018 Measuring conditioned behavior in nonhumans Schedules of Reinforcement: pattern that determines when reinforcements are to be given Ratio Schedules Fixed ratio (FR) Variable ratio (VR) Interval Schedules Fixed Interval (FI) Variable Interval (VI) Avoidance-Escape Task Punishment Stimulus Properties of Drugs stimulus properties ability to act as a discriminative stimulus in a discrimination learning task.  Reinforcing properties of drugs Rate of Responding Progressive Ratio Breaking point (organism will stop responding) Choice 2 levers; one has consequences. Exposure to 2 drugs over separate sessions; then observe animal’s choice of drug A or B. Conditioned Place Preference Animal will spend time in area of reinforcement  FDA approval processes Stage 1 Pre-clinical (animal studies to determine suitability as therapeutic agent; measurement of ED50 , LD50 & therapeutic index) – i.e., toxicity & pharmacological studies Stage 2 Clinical investigation (human volunteers): Phase 1: Pharmacokinetic & Safety Testing - human testing to determine toxicity & side effects in healthy human (paid) volunteers Phase 2: Small-scale Effectiveness Testing - human testing in clinical samples (i.e., patient groups) to assess potential therapeutic effects (+adverse) Phase 3: Large-scale Effectiveness Testing - expanded clinical trials using basic 3-group design approval or rejection of new drug for licensing & marketing Phase 4: accumulation of data on drug effects  Phases of human testing (clinical trials) Phase 1 20-100 healthy volunteers Informed consent mandatory evaluate side effects establish final, correct dosage pharmacokinetics studied generally takes 2 years Phase 2 100-300 patients who have disease drug intended to treat drug given on experimental basis determines therapeutic effect usually takes 2 years  Phases of human testing (clinical trials) Phase 3 1000-3000 ill patient volunteers administered same way that it will be used on the market performance vs. other drugs currently on the market (3-group design with placebo; single or double-blind) usually lasts 2-4 years Completion of Phase 3 drug company submits all documentation to FDA in a New Drug Application (NDA) waits for final FDA decision → approval or denial only 20% NDAs receive final FDA approval for marketing  Postmarketing studies (Phase 4) After NDA review completed & approved Lasts on average, 15 years New drug placed on the market Surveillance: check for new harmful effects in larger group of humans Drug removed from market if serious problems occur  Conclusion At the end of this lecture you should: Be familiar with research designs & related concepts that may be used in psychopharmacology (e.g., within vs. between subjects design, placebos, etc.) Be able to utilizing understanding of these concepts to identify & critique design elements of research in this area Be familiar with the types of outcome variables & some ways of measuring these (e.g., measuring arousal, & cognitive, motor, perceptual performance, side effects etc.) Understand the steps taken to license drugs, and the types of research methods used to study animal responses to drugs in pharmacological studies  Reflection Questions (egs, not exhaustive) Next week’s tute (& lab report): applying this knowledge to a real-world example: designing a study to investigate the effects of caffeine on human behaviour What kind of design could we run for an in-class experiment? What would we be interested in looking at the effects of caffeine on? And how would we measure these outcomes? Pros & cons of each type/choice? How could we ensure our experiment is as controlled as possible? Think of an example from your own experience/ observations that is explained by a) the placebo effect & b) the nocebo effect. What characteristics define these experiences? Explain the hypothesized mechanisms by which these effects arise Compare the benefits of a 3-group design vs. 4-group balanced placebo design  Reminder & further information Tutorials: This week (Tute 2, Week 3): read Tute 2 handout & the 6 tutorial caffeine readings on QUT Readings (if you have not already finished these): read & bring them to your second tute. Next week (Tute 3, Week 4): read Tute 3 handout (designing a caffeine experiment) Additional references/ Further info Textbook (7th or 8th editions) (Chapter 2)