How psychiatric drugs are discovered and tested, part 1

March 6, 2016

This will continue are look at Iversen & Iversen's neuropharmacology book. The advent of antidepressants, anxiolytics and antipsychotics are one of the great advancements of modern medicine. However, few people are aware of how these drugs are discovered, developed or approved for consumption. The aim is to first test the drug on animal models with the hope of anticipating its effects on a human subject. Partially due to the difficulty of discovering drugs which act with genuinely novel molecular mechanisms, many companies develop compound which closely mimic the mechanism of other compounds. Similarly though they may be to their archetypes, they may offer improvements in oral absorption, reduced side effects or duration of action.

Increasingly, psychiatrists have become interested in determining genetic risk factors for neuropsychatric problems. In the case of Alzheimer's disease, it was determined on a molecular level that unusually high levels of beta-amyloid accumulated in the brain. This was found through postmortem examination of the brain on a microscopic level. Using genetic engineering to produce mice with certain abnormalities which mimic or induce the symptoms of diseases. Once a molecular target has been identified, chemicals can be tested to see if they manipulate the relevant neurotransmitters, ion channels, enzymes, cell membrane component, or neuropeptide receptors responsible for the disease.

 But how is this done?

"Screening takes many different forms; for example, it may monitor the binding of compounds to the target through displacement of radiolabeled or fluorescent tracers, the activity of enzymes, or the electrical signals generated on occupation of the target by an appropriate ligand. High-throughput screening methods, using laboratory robots, may permit screening of very large numbers of chemicals—as many as 1 million or more is not uncommon. These large numbers of chemicals are generated by combinatorial chemistry, a method that automatically synthesizes a wide range of variants on a particular chemical scaffold, again using robotic techniques."

Pharmaceutical companies typically have chemical libraries containing millions andmillionsof compounds. These libraries contain drug-like molecules using what are known as "Lipinski rules." This means that they are naed after the chemist who identified them and examined the molecular features of drugs on the market. "These rules restrict molecular weight, chemical reactivity, and lipophiliity."

Suppose that a promising chemical lead has been found. This chemical can be refined further in a process known as "lead optimization." This process produces compounds with more and more affinity for the target, as well as improved water solubility and greater selectivity. It may also have longer action duration or be better absorbed orally. This is a valuable trait since most medications are given by mouth. Next, the medicine undergoes preclinical evaluations before human subjects are tested.

But what do these preclinical development trials consist of? We first examine what sorts of behavioral effects the drugs have on animals. This helps establish its chemical stability, shelf life, metabolic stability and bioavailability. This helps establish a "pharmacokinetic profile," according to which it is determined whether or not this compound endures in the body long enough, as well as to identify major metabolites to see if they have their own pharmacological effects.

Unsurprisingly, medications which act on the brain must prove capable o passing the blood-brain barrier to enter the central nervous system. This can be measured simply by measuring drug levels in the brain as opposed to plasma.Imaging methods can help determine its ability to displace radiolabeled ligand from the relevant binding sites. This determines whether or not the drug penetrates the blood-brain barrier. Furthermore, the safety of these drugs must be established through animal testing before human testing can begin.

"Such safety assessment takes a number of different forms. General safety is established by treating two separate mammalian species with doses up to the maximum safely tolerated dose every day for 6 to 12 months. Biochemical and hematological parameters are monitored in regular blood samples, and at the end of the test period animals are culled and each organ is examined histologically to determine if any damage has occurred. Other in vitro and in vivo tests will search for genotoxicity, assessing the likelihood that the drug induces chromosomal DNA breaks or damage. Other tests in both male and female animals will search for reproductive toxicity, changes in fertility or potential damage to the fetus."

When a drug is to be used for chronic human usage, possible carcinogenic effects is tested. This involves administering a very high dosage of the drug to two mammal species every day for two years. Next, possible signs of tumors of malignancy are sought out. In vivo pharmacology tests determine whether the relevant drug has dangerous effects on peripheral functions such as gastrointestinal systems, airways, cardiovascular or renal systems. Lately, this involves eliminating effects on conduction impulses in the heart. This is because some drugs can prolong "QT intervals" which is correlated with risk of dangerous cardiac arrhythmias.

Behavioral studies have helped scientists classify and differentiatemajor classes of drugs. This was limited, for a long time, to behavioral paradigms of rodents. It was how new drugs were tested in the treatment of psychiatric disorders. While useful, the greater challenge is to understand the neurobiological processes that are changed in human mental illnesses in order to devise animal models which "place specific demands on the aspects of the brain function deemed to be dysfunctional in that disorder."

In the early days o such testing, "animal model" was used to refer to any attempt to reproduce the symptoms of a psychiatric disorder in an animal. What was sought out was a behavioral response that could evaluate the effectiveness of drugs in treating the symptoms of mental illness. This is known as "pharmacological isomorphism." This method is still useful, but it does not determine the mechanisms of action of the drug. The purpose of the model is to produce an experimental preparation in order to study distinct conditions in the same or different species. This typically involves the use of an independent variable, which involves inducing manipulation, as well as a dependent variable, which involves measuring in order to examine the effects of the manipulation.

How is the manipulation determined? Hypotheses about the origins of the disease determine what is manipulated and how. Choice of measures are determined on the basis of behavioral abnormalities which are believed to be the core features of a psychiatric problem. This has proved particularly successful in the development of antipsychotics. Aversive stimuli and stress are very helpful in testing antidepressants and anxiolytic drugs. It is also possible to produce lesions in the brains of mice or subject them to genetic manipulation and social isolation.

Cognitive neuroscience has become increasingly important in singling out neural circuits which mediate components of complex behaviors. Animal models can be particularly helpful in this case. Psychopharmacology, more and more, has begun to use human volunteers where measurement of behavioral responses can be used alongside brain imaging in order to correlate certain behaviors and thoughts patterns with the relevant brain activity. This helps to associate certain disorders with abnormalities in specific neurotransmitters and neural circuits as well as the genes relevant for maintaining these things.

The human behavioral paradigm has revolutionized drug discovery. Previously, new drugs were given to psychiatric patients and clinical trials were undertaken. Nowadays, they are given to normal, healthy subjects as they perform very specific tasks relevant to the psychiatric disorder being studied. New drugs are then moved into clinical trials in patients who actually have the relevant disorder. These studies, unfortunately, are very complicated and expensive. This is one of the reasons animal models prove valuable.

http://www.examiner.com/article/how-psychiatric-drugs-are-discovered-and-tested-part-1