Psychiatry - Antidepressants

Question 1

What is depression?

Answer 1

Depression is an affective (or mood) disorder
It is much more common than mania/ bipolar
Characterised by core features of persistent low mood, anhedonia and fatiguability

Question 2

What are the different types of antidepressants? What are atypical antidepressants?

Answer 2

1. ) Tricyclics - older drugs that are often sedative and have autonomic side effects which limits use
   - Most dangerous in overdose because of cardiotoxicity

2.) SSRIs - newer drugs with a wide margin of safety and different side effects (mostly GI)

3. ) MAOIs - used less often cf. other antidepressants because of their interaction with some foods and drugs
   - Introductions of RIMA’s (reversible inhibitors of monoamine oxidase type A) has led to increase in the use of this drug

4.) Atypical antidepressants - these are not MAOIs and do not affect amine uptake

Question 3

Are antidepressants safe in epilepsy?

Answer 3

All antidepressants may provoke seizures and no particular drug is safe for the depressed epileptic patient.

TCAs are particularly prone to causing seizures in overdose

Question 4

Do antidepressants have an immediate effect?

Answer 4

No. Beneficial effects of antidepressants are not apparent for about 2-3 weeks.

Reason for this is unknown but may be related to gradual changes in the sensitivity of central 5-HT and/ or adrenoceptors.

Question 5

What is the prognosis of patients on antidepressants?

Answer 5

About 70% of patients respond satisfactorily to treatment.

Severe or refractive cases may require ECT in addition to medication.

Antidepressants should be continued for 4-6 months because this reduces the risk of relapse. Abrupt withdrawal of antidepressants (especially MAOIs) causes nausea, vomiting, panic, anxiety and akathisia (motor restlessness)

Question 6

What is the monoamine theory of depression?

Answer 6

The monoamine theory is based on the fact that certain drugs can affect brain norepinephrine/ serotonin function, which may be associated with depression.

E.g.

• Reserpine depletes the brain of noradrenaline and serotonin and often causes depression.
• But tricyclics and related compounds block noradrenaline and serotonin reuptake. MAOIs increase their concentration in the brain - both of these actions increase synaptic NAd and serotonin

Question 7

What are the problems with the monoamine theory of depression?

Answer 7

It has been difficult to find the expected defects in cerebral noradrenaline/ serotonin function that the monoamine theory would predict.

• TCAs rapidly block noradrenaline/ serotonin reuptake but require weeks of administration to achieve an antidepressant effect
• Some drugs are antidepressant but do not affect amine levels (e.g. trazodone), while cocaine blocks uptake but is not antidepressant

Question 8

What is the mechanism of action of SSRIs?

Answer 8

MoA of antidepressants is poorly understood in general.

SSRIs cause an increase in extracellular 5-HT that initially activates auto receptors, an action that inhibits 5-HT release and reduces extracellular 5-HT to its previous level.

With chronic treatment, inhibitory auto receptors desensitise and there is then a maintained increase in forebrain 5-HT that causes the therapeutic effect.

Question 9

Mechanism of action of antidepressants inhibiting noradrenaline re-uptake

Answer 9

These drugs probably act indirectly, either by stimulating serotonergic neurones (that have excitatory noradrenergic input) or by desensitising inhibitory pre synaptic alpha 2 receptors in the forebrain.

Question 10

What TCAs have sedative action?

Answer 10

Amitriptyline
Dosulepin

These drugs are more suitable for agitated and anxious patients and if given at bedtime will also act as a hypnotic

NB - no TCA has superior antidepressant activity and the choice of drug is determined by side effect profile

Question 11

What are the side effects of TCAs?

Answer 11

TCAs have a similar structure to phenothiazines and have blocking action at:

• cholinergic muscarinic receptors
• alpha 1 adrenoceptors
• histamine receptors

Blocking muscarinic receptors has an atropine like effect causing blurred vision, dry mouth, urinary retention and constipation

Blocking alpha adrenoceptors (located on vascular smooth muscle) causes postural hypotension and tachycardia

Question 12

Why are TCAs dangerous is overdose?

Answer 12

The anticholinergic activity and quinidine like action of the tricyclics on the heart may cause arrhythmias and sudden death.

They are contraindicated in heart disease

Question 13

Which TCAs produce the most receptor blockade and therefore worse side effects?

Answer 13

Amitriptyline and imipramine have a greater receptor blockade than dosulepin and lofepramine so produce more anti-muscarinic and alpha 1 adrenoceptor side effects

NB - remember that amitriptyline and dosulepin have sedative action

Question 14

What are the side effects of SSRIs?

Answer 14

SSRIs (e.g. fluoxetine, citalopram) do not have the autonomic side effects of the TCAs but have different ones - mostly gastrointestinal - e.g. nausea, vomiting, constipation, diarrhoea

They may also cause sexual dysfunction

Question 15

How do venlafaxine and nefazodone work?

Answer 15

These are new drugs that inhibit the reuptake of both 5-HT and noradrenaline but lack the receptor blocking side effects of the TCAs.

Their adverse effects are generally similar to the SSRIs but nefazodone rarely causes sexual dysfunction.

Question 16

What are the atypical antidepressants?

Answer 16

These are drugs that have little or no activity on amine uptake. They cause fewer autonomic side effects and because they are far less cardiotoxic they are much less dangerous in overdose.

Examples include mirtazapine and trazodone (both of these are sedative antidepressants)

Question 17

How does mirtazapine work?

Answer 17

Mirtazapine is an atypical antidepressant.

It has alpha 2 adrenoceptor blocking activity and by blocking inhibitory alpha 2 auto receptors on central noradrenergic neurones it may increase the amount of noradrenaline in the synaptic cleft.

Question 18

What are the older MAOIs?

Answer 18

These drugs (e.g. phenelzine) are irreversible non selective inhibitors of monoamine oxidase.

They are most useful in atypical depression and phobic anxiety states (a type of neurotic disorder).

Question 19

What are the adverse side effects of the older MAOIs?

Answer 19

The older MAOIs block muscarinic and alpha 2 adrenoceptors and cause anticholinergic effects plus postural hypotension, dizziness, and liver damage).

They can also interact with sympathomimetic agents particularly ephedrine (found in cough mixtures) or foods containing tyramine which can cause severe hypertension.

Question 20

What is the “cheese or tyramine reaction”?

Answer 20

Older MAOIs interact with tyramine that is often found in cheese, game and alcoholic drinks.

Ingested tyramine is normally metabolised by monoamine oxidase in the gut wall and liver, but when the enzyme is inhibited tyramine reaches the circulation and causes the release of noradrenaline from sympathetic terminals (via indirect sympathomimetic action) causing hypertension.

Question 21

What drugs do MAOIs affect?

Answer 21

MAOIs affect the metabolism of opioid analgesics, barbiturates, and alcohol

Question 22

What drug is especially dangerous when given with MAOIs?

Answer 22

Pethidine.
It causes (by an unknown mechanism) hyperpyrexia, hypotension and coma

Question 23

What is moclobemide?

Answer 23

Moclobemide is a reversible monoamine oxidase inhibitor (cf. older MAOIs which are irreversible)

It selectively affects MAOI-A

It is well tolerated and the main side effects are dizziness, insomnia and nausea.

Moclobemide interacts with the same drugs as other MAOIs but because it is reversible its effects rapidly diminish when the drug is discontinued

Question 24

What is Lithium used for?

Answer 24

Lithium is used for prophylaxis in manic/ depressive illness.

It is also used in the treatment of acute mania but because it takes several days for Lithium to take effect an antipsychotic drug is usually preferred for acutely ill patients.

It is also used as an antidepressant in combination with tricyclics in refractory patients.

Question 25

What is the therapeutic range for Lithium?

Answer 25

Lithium is rapidly absorbed from the gut.
Therapeutic and toxic doses are similar - so it is important to measure serum Lithium concentrations regularly.

Range = 0.4-1.0mM

Question 26

Adverse effects of Lithium

Answer 26

• Nausea
• Vomiting
• Anorexia
• Diarrhoea
• Tremor in the hands
• Polydipsia and polyuria (a few patients develop nephorogenic diabetes insipidus)
• Hypothyroidism
• Weight gain

Question 27

What are the signs of Lithium toxicity?

Answer 27

Drowsiness, ataxia, confusion, and at serum levels above 2-3mM life threatening seizures and coma

Question 28

What is the mechanism of action of Lithium?

Answer 28

Lithium is a mood stabiliser but its exact mechanism is unknown.

Lithium at concentrations of