L19: Affective Disorders - Antidepressant Drugs

Question 1

What is the classification of affective disorders? What are their characteristics?

Answer 1

• 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

Question 2

What are the symptoms for major depressive episode?

Answer 2

• 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

Question 3

What are the symptoms of mania?

Answer 3

• Excessive exuberance (quality of being full of energy)
• Excessive self-confidence
• Excessive enthusiasm
• Excessive physical activity
• Irritability, impatience and anger.

Question 4

What are the brain regions involved in mood? What are they responsible for?

Answer 4

• 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

Question 5

What are the main classes of drugs used for treating affective disorders?

Answer 5

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)

Question 6

What are the first generation anti-depressants? What are their examples?

Answer 6

First generation antidepressants:
- tricyclic antidepressants (TCAs) (imipramine, amitriptyline)
- monoamine oxidase inhibitors (MAOI) (phenelzine, tranylcypromine, moclobemide)

Question 7

What are the second generation anti-depressants? What are their examples?

Answer 7

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)

Question 8

What is the main reason for depression? What is monoamine theory? How is it related?

Answer 8

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

Question 9

What is the main reason for mania?

Answer 9

Mania is regarded as being due to the opposite mechanism to depression, i.e. functional excess of these neurotransmitters.

Question 10

What are the main monoamine neurotransmitters?

Answer 10

• noradrenaline
• dopamine
• serotonin (5-HT, not monoamine, but functions in the same way)

Question 11

Where does the main 5-HT production take place?

Answer 11

In the brain stem

Question 12

What is the evidence supporting the monoamine theory of depression?

Answer 12

1. 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
2. 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

Question 13

What are the inconsistent evidence with the monoamine theory of depression?

Answer 13

1. Amphetamine releases NA and blocks NA re-uptake but has no effect on depression
2. Cocaine blocks NA re-uptake but has no effect on depression
3. Tryptophan increases 5-HT synthesis but has inconsistent effects on mood.
4. alpha- and beta-adrenoceptor antagonists have no effect on manic patients and only decrease mood slightly in other subjects.
5. Methysergide, a 5-HT receptor antagonist, has no effect on mood.
6. L-dopa increases NA synthesis but has no effect on mood.
7. The antidepressant iprindole has weak effects on monoamine systems.

Question 14

What are the two main problems with the monoamine theory of depression?

Answer 14

• 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

Question 15

How are the stress hormones disturbed in depression? What is the effect?

Answer 15

CRF and cortisol are elevated in many depressed patients. Promotes cognitive symptoms of depression (e.g. worthlesness, guilt, doom, suicidality). Associated symptoms with anxiety

Question 16

What is the effect of CRF in amygdala and other brain areas?

Answer 16

May promote insomnia, anxiety, and depress appetite for food and sex

Question 17

What is the effect of cortisol to hippocampal neurones?

Answer 17

May damage hippocampal neurones, reducing inhibitory feedback on cortisol production.

Question 18

How does hippocampal volume change in depressed humans?

Answer 18

Hippocampal volume is reduced

Question 19

How do antidepressants acting through monoamine pathways can reduce CRF and cortisol levels?

Answer 19

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.

Question 20

What are the examples of tricyclic anti-depressants?

Answer 20

Imipramine, amitriptyline

Question 21

How do tricyclic antidepressants act? What is their effect? Is it used in any other diseases treatment?

Answer 21

• 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.

Question 22

Why are effects of tricyclic antidepressants so different in each individual?

Answer 22

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.

Question 23

What are the additional and unwanted effects of tricyclic antidepressants?

Answer 23

• 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!

Question 24

What are the important interactions of tricyclic antidepressants with other drugs?

Answer 24

• 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

Question 25

What are the effects of monoamine oxidase inhibitors? What are their examples? Are they effective?

Answer 25

Two isoforms of MAOIs: MAO-A (5-HT selective); MAO-B (NA and DA preference)
- phenelzine, tranylcypromine - irreversible, non-selective
- clorgyline - MAO-A selective - good antidepressant
- selegiline - MAO-B selective - no antidepressant effects
- moclobemide - reversible, MAO-A selective

Question 26

What are the unwanted effects of MAOIs?

Answer 26

• hypotension
• excessive central stimulation: tremors, excitement, insomnia, and in cases of overdose convulsion
• weight gain: attributed to stimulation of appetite
• atropine-like side effects: dry mouth, but less of a problem than with TCAs
• hepatotoxicity
• taken with SSRIs they can induce the “serotonin syndrome” (tremor, hyperthermia and cardiovascular collapse)

Question 27

What is “Serotonin Syndrome”?

Answer 27

A potentially fatal drug-induced condition caused by too much serotonin in synapses in the brain.

Question 28

What are the interactions of MAOI with other drugs?

Answer 28

1. cheese-reaction - sympathomimetic actions of ingested tyramine (shouldn’t eat food with tyramine) - acute hypertension, headache (intracranial haemorrhage)
2. similar interactions with other indirectly acting sympathomimetics e.g. ephedrine, amphetamine, can also lead to hypertension

Question 29

What are the examples of Selective Serotonin Reuptake Inhibitors? What is their mechanism of action?

Answer 29

• Fluoxetine, fluvoxamine
• highly selective 5-HT reuptake inhibitor

Question 30

What are the advantages of second generation drugs over first generation drugs?

Answer 30

• no anti-cholinergic or cardiovascular side effects
• no weight gain problems
• low acute toxicity
• no food reactions

Question 31

What are the unwanted effects of SSRIs?

Answer 31

• nausea, anorexia, anxiety, sexual dysfunction, insomnia
• increase aggression(?)
• dependence(?)

Question 32

What are Noradrenaline and serotonin specific antidepressants (NaSSA)? What are their examples?

Answer 32

Venlafaxine, mirtazapine, nefadozone, they have less undesirable side effects compared with the SSRIs

Question 33

What is the mechanism of action of mirtazapine? How does it reduce unwanted effects?

Answer 33

• It is a noradrenaline and serotonin specific antidepressant (NaSSA)
• increases 5-HT and NA levels by blocking presynaptic alpha-2 adrenoreceptors
• enhances 5-HT1A receptor mediated neurotransmission
• Blocks 5-HT3 - therefore no nausea
• Blocks 5-HT2 - reduces effects on anxiety, sleep, sexual dysfunction

Question 34

What is the mechanism of action of nefadozone?

Answer 34

5-HT reuptake block (weak NA reuptake block) combined with 5-HT2 receptor block.

Question 35

What is the action of ketamine? How is considered to be an antidepressant?

Answer 35

• Ketamine is an NMDA glutamate receptor antagonist, it has shown antidepressant actions in animal models of depression and in clinical studies.
• ketamine is a general anaesthetic agent and an hallucinogen which has also been shown to induce psychosis
• antidepressant actions of ketamine are elicited by sub-anaesthetic doses, rapid in onset and sustained for up to seven days after a single dose

Key is to find a drug that doesn’t bind 5-HT2 receptor (hallucinations receptor) or a drug that could be used in combination with ketamine, to block the receptor.