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LECTURE 1: INTRODUCTION IN PSYCHOPHARMACOLOGYWHAT IS PSYCHOPHARMACOLOGY?
Pharmacology is the field that studies the influence of substances on biological processes in living
beings. Psychopharmacology focuses on the effects of substances on behaviour, cognition and affect,
incl. their mechanisms in the brain.
Why is this of interest?
1. We all use some of psychoactive substances (for example alcohol, caffeine, smoking).
2. And pychoactive drugs also have some clinical implications. It is important that as a clinician
you see all options: psychoactive drugs are also an option.
3. There are quite a bit of psychoactive drugs that are being used. But a problem: There is
always a one-third of patients who don’t benefit from pharmacological treatment. So a big
aim is to develop new treatments (what takes a lot of time).
There are two subfields:
1) Pharmacokinetics is about ‘How does a substance move through the body?’ / What does the
body to the substance? For example: how long does it stay in the body? We have the blood-
brain barrier, where not all substances get through. And for example: if you snort/smoke
something, it’s much faster as when you eat something.
2) Parmacodynamics: what does the substance do to the body?
1) To what receptors does the substance bind?
2) What effect does the substance have on the receptor?
In psychopharmacology this means: interactions with neurotransmitters
WHERE DO PSYCHOACTIVE DRUGS ACT?
Synapse
Presynaptic neuron releases the neurotransmitter to bind at the
postsynaptic neuron. Points of engagement drugs:
Amount of transmitter
1) Some drugs act at the synthesis: they can act at:
1) The presence of the precursor. For example
Parkinson is treated with L-Dopa, which is a
precursor of dopamine, so that the patients
have more dopamine available.
2) The activity of enzymes: substances that help
putting the molecules together.
2) Uptake of transmitter in and release from vesicles
(blaasjes). Some drugs facilitate of prevent to putting
the neurotransmitter in the vesicles (3) or facilitate or prevent releasing it in the synaptic
gap (4)
, Blocking or modulating receptor (5)
When a neurotransmitter binds to the postsynaptic neuron, a lot of actions happen.
Ending influence through reuptake or degradation
There are two ways in way the neurotransmitter can be deleted.
1) Reuptake (6) it is taken back in the presynaptic neuron and is broken down there.
2) Degradation (7) broken down in the synaptic gap
THE BASIS FOR OUR KNOWLEDGE ON PSYCHOPHARMACOLOGY
From serendipity to hypothesis-based research
Most of the drugs we know today are mostly found by accident / from serendipity. Later we got into
hypothesis-based research: research programs in pharmaceutical industry and universities for
targeted drug discovery. Hypotheses are based on:
1) Basic knowledge
- For example: how neurotransmitter levels are de- or increased.
‘Preclinical research’
2) Clinical knowledge
- For example: which brain functions are most impaired in this population?
‘Clinical research’
We have very little insight in what subgroups there are in populations who maybe need other
treatments. So it can be different to decide which treatment is the best for this specific patient.
Hypothesis-based research: starts with knowledge from the literature: what is known about a
(clinical) phenomenon? So an important question is: what is not known and would be important to
find out?
WHEN CAN A NEW SUBSTANCE CAN BE PRESCRIBED?
When the substance is discovered, there is a long trajectory before it is being described in practice.
There is an authority in each county who makes the decision:
NL: College ter Beoordeling van Geneesmiddelen (CBG)
Europe: Europe Medicine Agency (EMA)
US: Food & Drug Administration (FDA)
You need to have proven that the drug is effective, but also it doesn’t come with too much side
effects. You need to considerate if it is better than other drugs for this condition.
Preclinical phases. Mostly, animal research precedes first administration in humans.
You look at the:
1) Efficacy
2) Administration: Does the substance survive the gastro-intestinal system?
And the blood-brain barrier?
3) Safety: Are there serious side effects?
Clinical trials (in humans):
Phase 1: non-toxic, tolerable
Phase 2: limited efficacy studies
Phase 3: large, multi-center studies
Monitoring after introduction
,PRECLINICAL PHASE: DRUG SAFETY
The safety is being expressed in the therapeutic index= the
relation between the toxic dose in half of the cases and the
effective dose in half of the cases. So: TD50/ED50: dose at
which 50% shows dangerous side effects (TD50) versus the dose
at which 50% has the intented effect (ED50)
The closer the two lines get together, the more dangerous.
Ideally, the therapeutic index is a lot higher.
Drug interactions
There are a lot of ways where drugs can interact with other processes/substances.
Toxicity
There are some expected side effects; these are often temporary. But there also can be
unexpected side effects, for example allergies.
For safety, a lot of animal research is being done in psychopharmacology.
CLINICAL PHASE
Phase 1: Is the substance safe?
In the first phase researchers test whether human subjects (most often healthy volunteers)
tolerate the substance. If the substance is sufficiently safe, phase 2 starts. It is very rarely that
it goes wrong in this phase. How safe a compound should be depend on:
1) The severity of the disease that may be cured or alleviated by the drug.
2) Whether there is already an alternative treatment.
The cost/benetfit ratio is important with a more severe condition, more side effects are
tolerated then with a less severe condition. For example chemotherapy in cancer.
Phase 2: Does it work?
In phase 2, sick people take the place of the healthy. Aim is now to test whether the
substance really works against the disease. Most often this phase starts with a small number
of patients who take the new drug.
Phase 3: Does it work, and is it better than other existing drugs?
When the results in phase 2 are good, larger trials start with larger number of patients. In this
phase, the new drug is first tested against a placebo and then against existing treatments.
When the results are satisfactory, after phase 3 follows registration by CBG, EMA, and/or FDA
of the substance as an official medication. Physicians may now prescribe the drug to their
patients.
Phase 4: optimalisation of application
Even after a drug has been registered, research continues. This is mostly focussed on side
effects in the long term, or the optimal treatment duration. But often the medicine is tested
for its effects on other diseases as well. Phase 4 is important because major side effects
usually do not come to light until this phase (example: rimonabant)
1) For example: Optimal dose: 2 criteria
o Lowest dose with the maximal therapeutic effect
, o and/or: Highest dose with side effects at placebo level
What is in a name/formula?
Chemical name/formula
Codename
- LY110140
Generic name, easier to communicate
- For example: fluoxetine
Brand name (®)
- Patent holder: ‘Prozac’ (Eli-Lilly). After the patent expires, it is also sold under the generic
name for a lower cost. Most people still know it from the original brand name and will
pay more for it.
Difference in drug versus medicine: a medicine aims to cure, a drug does not necessarily have the
purpose. Hence: all medicines are drugs, whereas not all drugs are medicines. Another definition is
medication= the process of treating an illness with medicine.
Costly process
The clinical drug research is a long and costly process. A great disadvantage: medicines must have
enough market to be at least somewhat profitable. So for more rare disorders, people relie on
government refunding’s. This is the case in what we call ‘orphan drugs’/ ‘orphan diseases’: this are
medicines for relatively rare disorders
1) Support from governments / non-profit funds to fund medicines in this category.
2) Or: huge costs per patient
A medicine is registered for a certain indication (e.g. for a certain disease) and/or for a certain group
(e.g. for adults). But: physician is allowed to prescribe a registered medicine for another indication of
group. This is called ‘off-label’ use. Addition: there must be scientific evidence for efficacy, and it must
be used per protocol or guide line.
The golden standard in drug research is that it is 1) randomized 2) placebo-controlled and 3) double-
blind. Placebo is important because an inert substance can be quite effective: especially in disorders
in which intensity of symptoms wax and wane regularly. Therefore, when all patients receive the
active substance and they know it (what we call ‘open-label’-research, this can be worthwhile to get
a first impression, but is not real evidence for efficacy.
EVIDENCE-BASED MEDICINE
The golden standard is that we have evidence-bases medicine. Use meta-analyses rather than relying
on a single study! But there are some problems with evidence-based medicine:
Quality research is very costly – therefore, there is too little good research
Meta-analysis summarizes different (clinically distinguishable) responses
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