L19: Affective Disorders - Antidepressant Drugs Flashcards
What is the classification of affective disorders? What are their characteristics?
-
unipolar depressive disorder:
i) depression without associated mania;
ii) more common in older patients;
iii) can be associated with anxiety and agitation -
bipolar depressive disorder:
i) oscillation between depression and mania;
ii) strong evidence for a hereditary link (not completely);
iii) biochemical imbalance
What are the symptoms for major depressive episode?
- depressed or irritable mood (necessary)
- decreased interest in, or unable to experience, pleasurable activities (necessary)
- low self-esteem: guilt, inadequacy, ugliness
- sleep disturbance - insomnia / hypersomnia
- fatigue / loss of energy
- indecisiveness and loss of motivation
- retardation of thought / concentration
- loss of appetite
- suicidality / thoughts of death
at least five of these symptoms necessary to characterize as depression
What are the symptoms of mania?
- Excessive exuberance (quality of being full of energy)
- Excessive self-confidence
- Excessive enthusiasm
- Excessive physical activity
- Irritability, impatience and anger.
What are the brain regions involved in mood? What are they responsible for?
- frontal cortex and hippocampus: memory impairment, worthlessness, hopelesness, guilt, doom, suicidality
- hypothalamus: sleep, appetite, energy impairment, reduced interest in pleasurable activities
- Nucleus accumbens and amygdala: anhedonia (behaviour that keeps repeating pleasurable activities, but not feeling the reward), anxiety, reduced motivation
What are the main classes of drugs used for treating affective disorders?
Most widely used drugs for treating depression have known actions on the levels of monamines in the brain (monoamines system)
First generation antidepressants:
- tricyclic antidepressants (TCAs) (imipramine, amitriptyline)
- monoamine oxidase inhibitors (MAOI) (phenelzine, tranylcypromine, moclobemide)
Second generation antidepressants (knowledge from 1st generation, but upgraded to be more specific)
- selective serotonin (5-HT) re-uptake inhibitors (SSRI) (fluoxetine, fluvoxamine)
- noradrenaline and serotonin specific antidepressants NaSSA (venlafaxine)
- receptor-targeted actions (mirtazapine, nefazodone)
What are the first generation anti-depressants? What are their examples?
First generation antidepressants:
- tricyclic antidepressants (TCAs) (imipramine, amitriptyline)
- monoamine oxidase inhibitors (MAOI) (phenelzine, tranylcypromine, moclobemide)
What are the second generation anti-depressants? What are their examples?
Second generation antidepressants (knowledge from 1st generation, but upgraded to be more specific)
- selective serotonin (5-HT) re-uptake inhibitors (SSRI) (fluoxetine, fluvoxamine)
- noradrenaline and serotonin specific antidepressants NaSSA (venlafaxine)
- receptor-targeted actions (mirtazapine, nefazodone)
What is the main reason for depression? What is monoamine theory? How is it related?
Depression is due to a functional deficit of monoamine neurotransmission. Main evidence for monoamine theory of depression is: drugs that increase or alleviate the symptoms of affective disorders have known effects on the 5-HT and NA systems
What is the main reason for mania?
Mania is regarded as being due to the opposite mechanism to depression, i.e. functional excess of these neurotransmitters.
What are the main monoamine neurotransmitters?
- noradrenaline
- dopamine
- serotonin (5-HT, not monoamine, but functions in the same way)
Where does the main 5-HT production take place?
In the brain stem
What is the evidence supporting the monoamine theory of depression?
- Drugs that increase monoamine levels alleviate depression.
i) Inhibiting re-uptake of NA and 5-HT; tricyclic antidepressants and SSRIs
ii) preventing breakdown of NA and 5-HT, e.g. monoamine oxidase inhibitors - Drugs that decrease monoamine levels increase depressive symptoms.
i) inhibition of NA and 5-HT synthesis, e.g. alpha-methyltyrosine
ii) depleting vesicular stores, e.g. reserpine
What are the inconsistent evidence with the monoamine theory of depression?
- Amphetamine releases NA and blocks NA re-uptake but has no effect on depression
- Cocaine blocks NA re-uptake but has no effect on depression
- Tryptophan increases 5-HT synthesis but has inconsistent effects on mood.
- alpha- and beta-adrenoceptor antagonists have no effect on manic patients and only decrease mood slightly in other subjects.
- Methysergide, a 5-HT receptor antagonist, has no effect on mood.
- L-dopa increases NA synthesis but has no effect on mood.
- The antidepressant iprindole has weak effects on monoamine systems.
What are the two main problems with the monoamine theory of depression?
- the biochemical actions of drugs are very rapid, but antidepressant effects usually take days or weeks to develop
- current antidepressant DO NOT improve symptoms in ALL patients
How are the stress hormones disturbed in depression? What is the effect?
CRF and cortisol are elevated in many depressed patients. Promotes cognitive symptoms of depression (e.g. worthlesness, guilt, doom, suicidality). Associated symptoms with anxiety
What is the effect of CRF in amygdala and other brain areas?
May promote insomnia, anxiety, and depress appetite for food and sex
What is the effect of cortisol to hippocampal neurones?
May damage hippocampal neurones, reducing inhibitory feedback on cortisol production.
How does hippocampal volume change in depressed humans?
Hippocampal volume is reduced
How do antidepressants acting through monoamine pathways can reduce CRF and cortisol levels?
High monoamine levels may reverse cortisol-induced damage by increasing growth factor production (e.g. brain derived neurotrophic factor (BDNF)) through genomic mechanisms.
In cases of depression there is reduced capacity and connections, however antidepressant drugs can promote spine growth and connections of a neurone. That’s why it takes long for drugs to start acting, as new development takes time.
What are the examples of tricyclic anti-depressants?
Imipramine, amitriptyline
How do tricyclic antidepressants act? What is their effect? Is it used in any other diseases treatment?
- They’re non-selective inhibitors of 5-HT and NA reuptake; block the transporters that reuptake 5-HT and NA.
- Acute sedative effects of some TCAs useful for agitated or anxious patients, that’s why it’s also used depression, panic attacks, phobic and obsessional states.
Why are effects of tricyclic antidepressants so different in each individual?
Hydroxylation is carried out by CYP2D6, which has many different allelic variants (polymorphisms) with variable activity. Some variants hyperactive, some inactive. If hyperactive - might not feel the drug at all, as it’s metabolised very quickly.
What are the additional and unwanted effects of tricyclic antidepressants?
- acute effects include sedation (H1 receptor block), confusion and motor in-coordination
- atropine-like autonomic side effects related to mAChR block
- postural hypotension (alpha-adrenoreceptor block in the vasomotor centre located in the brainstem)
- overdose acute toxicity!
What are the important interactions of tricyclic antidepressants with other drugs?
- microsomal metabolism in the liver may be inhibited by competing drugs such as antipsychotics and steroids
- CYP enzymes are inhibited by competing drugs leading to increased TCA plasma levels
- TCAs potentiate the effects of alcohol (more active) (respiratory depression)
- TCAs can interact with some anti-hypertensive drugs (ACE inhibitors) causing large and potentially hazardous swings in blood pressure
