How psychiatric drugs are discovered and tested, part 2

March 6, 2016

This will continue our look at Iversen and Iversen's look at neuropharmacology. The best scenario of psychiatric drug testing involves evaluating a drug by testing it on humans, patients and animals while they perform relevant tasks. One use of this approach is the Cambridge Neuropsychological Test Automated Battery (CANTAB). This involves using animal parallels to describe and characterize different forms of cognitive dysfunction in neurological diseases such as Alzheimer's disease and Parkinson's disease as well as psychiatric disorders. It can also be used to characterize and distinguish working memory and planning, attention, visual memory, cognitive flexibility, response control, decision making and risk taking. Tests have been adapted for use in various animals such as rhesus monkeys and squirrels.

Empirical or predictive validity of the drug must be established. This involves establishing pharmacological validity. The scientist determines whether or not laboratory response mirrors the clinical drug response. The following criteria must be fulfilled in this respect:

"(1) The same range of drugs produce the clinical and experimental responses;

(2) the potencies of different drugs should match on clinical and experimental responses;

(3) the onset time and the degree of tolerance to the drug should be the same on both responses; and

(4) clinical and experimental responses should be antagonized or augmented by the same compounds."

Desired clinical response must be differentiated from side effects, since drugs have multiple responses. Type 1 drugs reduce symptoms with undesirable secondary effects. Type 2 drugs have only side effects. Type 3 drugs are chemically inert and produce neither. The best laboratory model involves responses to type 1 drugs rather than other classes. Some drugs, however, can imitate secondary effects of drugs that have proven effective, without actually being effective.

"Antidepressants are excellent examples of type 1 drugs, having secondary anticholinergic effects similar to those of atropine or scopolamine. Antidepressant activity might be ascribed to this secondary effect, but if so, atropine and scopolamine should be clinically effective antidepressants, which they are not. The anticholinergics are therefore type 2 drugs that do not reduce the symptoms of depression and do not show a positive response in validated laboratory models for antidepressants."

Next, laboratory and clinical potencies should be isomorphic with one another. It involves undertaking a wide dose-response stud in both humans and animals. In one excellent study, the potency of several antipsychotic drugs, whose purpose is to control schizophrenia symptoms, is highly correlated with the ability of these drugs to bind to dopamine D2 receptors in an in vitro binding study. This is how we determine whether or not drugs work, and also the neurochemical mechanisms by which they work.

Interestingly enough, laboratory response is immediate whereas clinical responses take several weeks to emerge in the cases of antidepressants and antipsychotic medications. This effect is relevant to the aforementioned third criterion. This determines "both models the temporal onset of the responses should be of the same order and that the development of tolerance to the response (if it occurs with repeated doses) should follow the same pattern."

So how are new psychotropic drugs evaluated? Originally, potentially useful drugs were tested through an extremely basic set of tests in animals. Then they were quickly tested on psychiatric programs. Nowadays, "evaluations of lead compounds proceed within the framework of existing knowledge of the standard classes of drugs in widespread clinical use." Suppose there is a chemical of a certain class. We can observe a straightforward "me-too" effect in this drug insofar as it is part of a drug class that tends to affect a certain neurotransmitter. However, newer challenges emerge if a psychotropic drug is novel and the target does not respond in a way that is easily conformable to a certain disease phenotype. Interestingly enough, antidepressants were previously not investigated for their anxiolytic effects, although some of these drugs have been found, ironically, to be more anxiolytic than antidepressant.

So how does behavioral screening process work? A set of physiological and behavioral responses are recorded at specific times after the drug is administered. A simple brain screen is used to determine effects on the different nervous systems, such autonomic and skeletal.

"One can easily obtain dose–response data, get a good indication of possible side effects, and study time of onset of drug action and its duration. Measures include tremors, ptosis (eyelid droop), temperature, salivation, defecation, hypo- and hyperreflexes, response to pain (tail pinch), motor coordination (rotarod or inclined grid), and catalepsy (abnormal maintenance of distorted posture). These simple screens are also useful for studying drug interactions. Sometimes, drugs have no effect on their own but modify the effect of another drug. For example, antidepressants potentiate the rise in temperature induced by amphetamine, and although they do not increase locomotor activity per se, they reverse the sedation induced by reserpine."

Genetic manipulation can also be used. This involves using knock-outs and trans-genic knock-ins for mice. It involves removing genes in some mice and placing them in some mice. This helps to determine how drugs affect neurotransmitters and alter behavior. This means it is important to develop and validate tests which were originally designed for larger animals in the smaller mouse strains. Next, it is important to study simple unconditioned behaviors which involve automated means of measurement:

"For example, locomotor activity and exploration in different environments are easily quantified with well-located photocells or computer-assisted video recordings. The “open field” is commonly used to measure exploratory locomotor activity. Animals are placed in an unfamiliar walled space and exploration of the corners or the center of the field, rearing on the walls, and responses to novel or familiar objects placed in the field or to conspecifics can be recorded easily (see Chapter 3). A wide range of other naturalistic behaviors fall into this category of screening."

Next, there is the third stage of screening for complex conditioned behaviors and studying response to both reinforcement or punishment, as well as the ability to learn and remember or manipulate and attend to information in more complicated procedures.

"As we have seen, schedules of reinforcement or punishment play a dominant role in the first of these enabling measurements of the stable performance of acquired responses over repeated testing sessions. In the latter areas, in addition to discrete trial procedures (mazes and shock-avoidance boxes), computer-controlled cognitive tasks (of which the CANTAB is an example) are increasingly playing an important role and are of particular value in developing equivalent tasks for rats, monkeys, and humans. In the final screening stage, the aim is to move beyond empirical validity based on the pharmacological criteria discussed previously to the use of models with face and construct validity."

Indeed, "These are the behavioral tasks in animals and humans targeted specifically at the neuropsychiatric disorder or disorders for which the drug is being developed. Most recent developments rely on mimicking only specific signs or symptoms associated with the psychopathological conditions, rather than attempting to model the entire syndrome." An example of this can be seen in attempting to treat memory impairment in those with Alzheimer's disease. The presence or absence of this disorder can be helpfully evaluated with the use o the Morris water maze. However,the most useful tasks are those which put pressure on the individual's ability to retain and use information in recent memory. This involves testing both episodic and working memory and it is the most relevant way of determining the presence of Alzheimer's disease. Likewise, hindrance to discriminated active shock avoidance has typically been used as a means of evaluating the usefulness of antipyschotic drugs, whereas nowadays, it is the antagonism of dopamine-related, amphetamine-induced locomotor activity or motor stereotypy that is the most useful in testing the efficacy of this type of drug.

http://www.examiner.com/article/how-psychiatric-drugs-are-discovered-and-tested-part-2