Antidepressants Flashcards
What are the two types of psychoses?
Schizophrenia: Disorder of thought processes.
Affective disorders: Disorder of mood.
What are affective disorders further split into?
Which one is more common?
Depression (more common)
Mania
What are some signs and symptoms of depression?
Emotional/psychological - Misery, apathy, pessimism - Low self-esteem - Loss of motivation - Anhedonia: Inability to enjoy every day activity Biological (somatic) - Slowing of thought & action (Psychomotor retardation) - Loss of libido - Loss of appetite, sleep disturbance
What are the two types of depression?
Unipolar depression/depressive disorder
Bipolar depression/manic depression
What are some features of unipolar depression?
Mood swings occur in same direction. There is a relatively late onset.
What are the two subtypes of unipolar depression?
Reactive depression: This is an inappropriate reaction to stress component. There is no genetic component to this type of depression. Reactive depression is also extremely common, accounting for 75% of all cases of unipolar depression.
Endogenous depression: This is unrelated to stress and there is an inheritance pattern.
The same classes of drug are used for reactive and endogenous depression.
What are some features of bipolar depression?
This is oscillating depression and mania. This type of depression is far less common and has an early adult onset. There is a strong hereditary tendency.
What is given to treat bipolar depression?
LITHIUM is given to treat this type of depression. Lithium is a mood stabiliser and restricts the swings between the two polar ends of the condition. The mechanism of action is complex and involves intracellular messengers e.g. the amount of IP3 is reduced. This isn’t well understood.
There is also a very narrow therapeutic reload which means that it is easy to overdose on lithium because too much builds up in the plasma (similar to DIGOXIN).
Who proposed the monoamine theory of depression?
Schildkraut
What is the monoamine theory of depression?
The theory states that there is a functional deficit of central monoamine transmission in depression and a functional excess in mania. Initially, the study was based around noradrenaline, but Schildkraut noticed that the levels of noradrenaline were also mirrored by the levels of 5-HT, so the studies were then expanded to include 5-HT as well.
There is also a lot of pharmacological evidence which supports this theory.
What was reserpine initially used for and what is it used for now?
Reserpine was used as a regional hypertensive drug, but because of its effects (inhibiting NA & 5-HT storage), it is now used in models to test effects of new antidepressants. Mice developed depression after being given reserpine due to inhibition of NA and 5-HT and so the effects of the antidepressants can be seen clearly.
What is a piece of biochemical evidence that does not support the monoamine theory?
In clinical studies, if you look at the concentration of monoamine metabolites in the urine in the chronically depressed, the level of metabolites is often lower than normal suggesting that there is less metabolism of the monoamines. So with an increase in severity, you might expect to see decreased concentration metabolites in the urine, however this is not the case.
What could the delay in the clinical effects of antidepressant be due to?
The neurological change occurs relatively rapidly in response to the drugs. However, the clinical responses are not often seen until a few weeks after taking the antidepressants. Time-wise, this seems to correlate with the downregulation of α2, β, and 5HT receptors. So the response to antidepressants may occur with the knock on effects of these receptors rather than the original changes to NA and 5-HT.
What are some other theories about depression?
New research ongoing suggests that the HPA axis may also be involved in clinical depression. There is an increase in corticotropin levels in severe depression which supports this. Another theory suggests that there may be some degree of hippocampal neurodegeneration during chronic depression and some drugs have been shown to to slow down this neurodegeneration or even reverse it.
What are the types of antidepressant drugs?
- Tricyclic antidepressants (TCAs)
- Monoamine oxidase inhibitors (MAOIs)
- Selective 5-HT reuptake inhibitors (SSRIs)
- Lithium
- Other
ECT (Electroconvulsive therapy) is also used. Suxamethonium is given beforehand in order to help prevent violent convulsions (ECT). ECT is very effective for severe depression.
Name an example of a tricyclic antidepressant
Amitriptyline
What are the pharmacodynamics of TCAs?
TCAs are neuronal monoamine reuptake inhibitors. TCAs inhibit central noradrenaline reuptake, and also an equivalent amount of central 5-HT reuptake. They achieve this by binding to the reuptake protein carriers. In this way, they enhance the levels of NA and 5-HT.
NOTE: They do not bind to receptors. They bind to protein carriers.
What are the pharmacokinetics of TCAs?
Rapid oral absorption
Highly plasma protein bound (90-95%)
It is metabolised by the liver which often generates active metabolites. It is then excreted renally via the glucuronide conjugates.
The plasma half life is 10-20 hrs (so only need to take once a day)
What are the side effects of TCAs?
- Atropine-like effects: This is due to the muscarinic antagonist effects of the TCAs e.g. blurred vision, dry mouth, constipation.
- Postural hypotension: TCAs affect the vasomotor centre in the brain centre.
- Sedation (H1 antagonism): Patients feel drowsy during the day. Because of this side effect, amitriptyline can be used to treat insomnia. However, sedation may carry over to the next day.
What are the signs and symptoms of acute toxicity of TCAs?
CNS: Excitement, delirium, SEIZURES which eventually leads to coma and respiratory depression.
CVS: Cardiac dysrhythmias, ventricular fibrillation/sudden death.
TCAs are often used in attempted suicide by overdosing. Last year, there were 400 successful suicides with TCAs.
What are some examples of drug interaction with TCAs?
Because TCAs are highly plasma protein bound, the TCA effect will be increased if there are other drugs also competing for the same binding sites e.g. aspirin, phenytoin, warfarin. All of these examples will displace TCAs and therefore may push the plasma TCA level up to toxic levels.
TCAs will also compete with other drugs for hepatic microsomal enzymes potentially up to toxic levels e.g. neuroleptics, oral contraceptives.
There may also be potentiation of CNS depressants for example with alcohol. People who attempt suicide, will often take alcohol before they overdose on TCAs.
TCAs can affect the blood pressure of people on antihypertensive drugs. This is unpredictable so needs to be monitored closely.
Name an example of a MAOi.
Phenelzine
What are the pharmacodynamics of MAOis?
There are two main types of MAO:
MAO-A: NA & 5-HT
MAO-B: DA
They preferentially metabolise the listed molecule, but they will also metabolise others.
The MAOIs used as drugs are non-selective.
This is an irreversible inhibition so this leads to a long duration of action. This is because the hydrazine group on the end of the aliphatic group forms a covalent bond with the MAO enzymes which can not be broken.
The immediate effects are an increase in cytoplasmic NA and 5-HT. This increase in intracellular levels allows leakage of NA and 5-HT back into the synapse.
The clinical effects are delayed by 2-3 weeks before optimal antidepressant activity. This seems to correlate with down-regulation of β-adrenoceptors and 5-HT2 receptors.
These drugs aren’t totally selective for MAO and so may inhibit other enzymes as well.
What are the pharmacokinetics of MAOis?
Rapid oral absorption
Short plasma half life (few hours) but longer duration of action (because they are irreversible). They can be given once a day or even once every other day.
They are metabolised in the liver and excreted in the urine.
