PSYCHOPHARMACOLOGY AND THE DRUG INDUSTRY Drug Development, Drug Licensing FEDERAL REGULATIONS: HISTORY OF REGULATION 1906: The Pure Food and Drug Act required labels to indicate the amounts of alcohol, opiates, cocaine and marijuana in medicines 1914: Harrison Narcotics Act: makes opiates and cocaine available only by prescription, and then only in certain circumstances 1938: Federal Food, Drug and Cosmetics Act Passed in consequence of over 100 deaths caused by a drug company's use of antifreeze as a sulpha solvent Prior to this bill, only "narcotics" required an MDs prescription Defined a DRUG as any chemical affecting bodily structure or function Required drug companies to file applications for approval of ALL new drugs, showing that they were SAFE (not necessarily effective!) Required better drug labeling Allowed every drug company to determine whether a particular product was OTC or prescription 1951: Durham-Humphrey Amendment: drugs falling into any of 3 categories were made prescription drugs: 1. Drug is habit-forming 2. Drug potentially toxic, not safe for unlimited supply and self-medication 3. New compound, safety uncertain 1962: Kefauver and Harris amendments: A result of the thalidomide disaster Required demonstration of efficacy and safety of new drugs Allowed FDA to set standards for drug testing and manufacture REGULATORY STEPS FOR NEW DRUGS: Step 1: Preclinical research and development This step typically uses animals Tests must be conducted on 3 species PK characterization is required As are toxicity studies of side effects, teratogenesis, mutagenesis and carcinogenesis Based on the above, company must then obtain an Investigational New Drug license from the FDA Step 2: Clinical Research and Development - this involves three discrete phases: Phase 1 - Initial Clinical Stage - drug is tested on between 20 and 100 "volunteers" Phase 2 - Clinical Pharmacological Evaluation Stage - usually the double-blind, placebo- controlled crossover study; number of patients still small, usually 300 or so Phase 3 - Extended Clinical Evaluation - drug is given to selected physicians to prescribe to thousands of patients Step 3: Permission to Market At this point, box loads of data are submitted to the FDA for approval Generally after jerking the company around for several years, the FDA then approves Step 4: Post-marketing Surveillance. All prescribing physicians are to report any problems to the Drug Company, which compiles and passes on these reports to the FDA DESPITE all the above, it is still common to find substantial health risks only at this stage This entire process takes 12 years or more, and from $ 200 to $ 500 million or more There are "fast track" provisions which allow short-cuts for lethal diseases such as AIDs DRUG DEVELOPMENT AND ANIMAL MODELS ANIMAL RESEARCH PLAYS A CRITICAL ROLE IN NEW DRUG DEVELOPMENT AND APPROVAL Drug safety evaluations AND drug discovery! DRUG DISCOVERY: Involves two rather different processes: Variations on existing medications: For example, serotonin reuptake blockers are known to have antidepressive effects Allowing rapid testing of tens of thousands of chemical variants of existing SSRIs to discover molecules which are more potent, more efficacious, or just more patentable than known compounds Increasingly, these sorts of tests can be conducted in vitro Discovery of NEW treatments These are more demanding, but potentially more beneficial as well Such discoveries often grow out of advances in basic science, and especially in improved knowledge of a disease state, immune system function, or cell biology And in such research, animal models are still essential The two types of animal model: Animal Assay Models: So long as an animal reacts in any measurable way to some chemical, this reaction can be used as a BIOASSAY Spurious example: if rats got runny noses when exposed to SSRIs, one could develop a runny-nose assay for detection of new SSRIs Homologous Animal Models: An animal model of a human disease state Example: chemical induction of specific cancers in mice HOPEFULLY HOMOLOGOUS ANIMAL MODELS OF PSYCHIATRIC DISORDERS: THE PROBLEM: We don't KNOW what causes psychiatric disorders. Consequently, current models are based on: Similar Behavioral Syndromes Similar Response to Known Pharmaceuticals Sometimes, similarities in eliciting stimuli, such as doing things to an animal to make it sad, then testing antidepressants DEPRESSION: The Porsolt Swim Test - "depressed" animals float, don't struggle Maternal Separation: Daily 6 hr-separation in neonatal rats leads to: + increased anxiety + Abnormalities in the HPA axis, centrally and peripherally In monkeys, after 24 hrs separation the babies become inactive, huddle, self-clasp, and appear sad and dejected + They respond positively to chronic not acute imipramine + And have low brain norepi levels Separation of Siberian Hamsters These little guys mate for life When couples are isolated, the male shows reduced activity, social interaction and brain serotonin turnover Chronic imipramine is protective Chronic Mild Stress: Over a period of 3 weeks, rats are exposed to a variety of "mild" stressors, including footshock, cold swim, changed housing, reversed light cycles, food and water deprivation, culminating in one hr exposure to bright lights and noise, then open field Not surprisingly the animals freeze up in the open field But they also lose interest in sweet solutions, and are hyporesponsive to stimulation of the dopamine system, which is itself hyporesponsive Syndrome responds to ECT, tricyclics, MAOIs, SSRIs and bupropion, but not neuroleptics or anxiolytics Learned Helplessness: Current most popular model Rats are given uncontrollable tail shock Controls are given no shock, or learn to avoid shock In time this produces a depressive syndrome including: + Lowered food, water intake, weight loss + Inactivity, reduced personal grooming + Reduced social interaction + Sleep disturbances + Reduced self-stimulation of brain + Abnormalities in brain norepi and serotonin Syndrome responds to tricylics, ECT, MAOIs, SSRIs, but not stimulants or antipsychotics SCHIZOPHRENIA: Here models are less successful; as yet none is very compelling, or much used Drug-Induced Syndromes: Chronic amphetamine causes schiziform reductions in social interaction and apparent hallucinatory behavior + AND of course neuroleptics block the effects of amphetamine, hence the syndrome PCP has similar effects, and this can be blocked by chronic clozapine Neonatal hippocampal damage in rats: Recall that human schizophrenics have medial temporal lobe damage In rats, such damage causes: + Increased mesolimbic, reduced prefrontal dopamine + Hyperresponsivity to amphetamine + Deficits on pre-pulse inhibition of the startle response + As in humans, rats only show these deficits when they reach adolescence Most of these effects respond to neuroleptics Isolation Rearing Makes monkeys crazy, hyperdopaminergic Rats show schizoid pre-pulse inhibition deficits Acute isolation in humans can trigger hallucinations Animal rights movement has prevented further research on this paradigm in monkeys High Atmospheric Pressure: Causes neuroleptic-reversible schiziform disorders in divers In rats, high atmospheric pressure causes hyperactivity and increased brain dopamine MODELS OF ANXIETY DISORDERS: Most simply measure the ability of drugs to reduce behavioral manifestations of fear, hence detect anxiolytics Conflict Tests: These train a hungry/thirsty rat to do something to get food or water, then occasionally shock them for performing this response Geller-Seifter test: hungry rats are trained to bar-press for food reward, then intermittently shocked when they press the bar Vogel conflict test: Thirsty rats lick a metal tube to get water; occasionally they also get shocked Elevated Plus Maze: Two arms are dark, two light: rodents prefer the dark, especially after being frightened somehow Defensive Burying Rats and mice bury objects they don't like An electrified prod place in the home cage is quickly buried in bedding Mice do the same thing to unfamiliar marbles Social Interaction Test Works only in male rats Simply measures amount of time spent by two strangers in social interactions Sensitivity and Validity of these tests: All are sensitive to human anxiolytics, including alcohol, barbiturates None are sensitive to neuroleptics or anti- depressants All are also sensitive to anxiogenics, including ethanol withdrawal, benzodiazepine antagonists, yohimbine and amphetamines Yet factor analyses suggest subtle differences between these tests, suggesting that they tap into different aspects of rodent fear/anxiety CONCLUSION: THE FUTURE OF ANIMAL MODELS IN PSYCHOPHARMACOLOGY RECENT EFFORTS ARE COMBINING THESE BEHAVIORAL TASKS WITH ANIMALS GENETICALLY TAILORED TO BE SUSCEPTIBLE OR RESISTANT SUCH IMPROVED MODELS WILL BE IMPORTANT IN NEW DRUG DEVELOPMENT FOR THE FORSEEABLE FUTURE AND of course animal use in toxicity testing remains essential SO THE NEXT TIME SOME ONE TALKS TO YOU ABOUT THE EVILS OF ANIMAL RESEARCH, TELL THEM: To avoid hypocrisy, you are sure they will never use the new anti-cancer and anti-obesity drugs being developed from animal models, on themselves or their children AND that you expect them to volunteer for toxicity testing of new compounds!