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
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