Anti-depressants

Question 1

What is important to remember about Lithium

Answer 1

Strictly, it is not an anti-depressant

It is a mood stabilising drug.

Question 2

Summarise ECT

Answer 2

Used in cases of ‘black depression’- where the patient is not responding to talking therapies or drugs
Current across temporal lobe
Give a shot of suxamethonium short-acting NMJ blocker- to prevent any damage to the limbs from convulsions.

Question 3

Describe the different classification of psychoses

Answer 3

Split into:
Schizophrenia (thought disorders)
Affective disorders (mood-related)- which consist of mania (less common) and depression.

Question 4

Describe the emotional (psychological) symptoms of depression

Answer 4

Misery, apathy, pessimism

Low self-esteem

Loss of motivation

Anhedonia (inability to enjoy life)

Question 5

Describe the biological (somatic) symptoms of depression

Answer 5

Slowing of thought & action (psychomotor retardation)

Loss of libido

Loss of appetite, sleep disturbance

Question 6

What are the two different types of depression

Answer 6

Unipolar depression/ depressive disorder

Bipolar depression/ Manic Depression

Question 7

Describe unipolar depression / depressive disorder

Answer 7

Mood swings in same direction

Relatively late onset

Reactive depression (75%) - stressful life events (disproportionate response)

	- non-familial

Endogenous depression (25%) 	- unrelated to external
			stresses

	- familial pattern

Question 8

What is important to remember about the drug treatment for unipolar depression

Answer 8

Same for both reactive and endogenous depression.

Question 9

Describe bipolar depression

Answer 9

Oscillating depression/mania

Less common; Early adult onset

Strong hereditary tendency

Drug treatment (Lithium- oral lithium carbonate- effects I.C secondary messenger symtpoms (reduces cAMP and IP3)

Symptoms of mania- opposite to that of depression (increased exuberance, aggression etc).

Question 10

What is the key difference between bipolar depression and unipolar depression

Answer 10

Bipolar depression- symptoms in common with schizophrenia

Unipolar depression- symptoms associated with fear and aggression.

Question 11

Define what is meant by ‘psychoses’

Answer 11

Severe mental disorders, with or without, organic damage, characterised by derangement of personality and loss of contact with reality, and causing deterioration of normal social functioning.

Question 12

Describe the monamine theory of depression

Answer 12

§ Monoamine theory of depression – depression is a functional deficit of central MA transmission; Mania is a functional excess of MA transmission.
o Related to NA and 5-HT (serotonin) deficits/excesses.

Question 13

Summarise the pharmacological evidence that supports the monamine theory of depression

Answer 13

TCAs- block NA and 5-HT reuptake- Increase MOOD
MA oxidase inhibitors – Increase stores of NA and 5-HT – increase MOOD
Reserpine (MA deplete) - inhibits NA and 5-HT storage - decreases mood
a-methyltyrosine and methyldopa- inhibit NA synthesis- decreasing mood (and calming of manic patients)
ECT- increases CNS response to NA and 5-HT- increases mood.

Question 14

Describe the pharmacological evidence that disagrees with the monoamine theory of depression.

Answer 14

Amphetamine- releases NA and blocks re-uptake- no effect on mood (but causes euphoria in normal subjects).
Cocaine- inhibits NA reuptake- no effect on mood (but causes euphoria in normal subjects)
Tryptophan -increases 5-HT synthesis- mood may increase in some subjects but not all
Alpha and beta adrenoreceptor antagonists - block NA action- mood slightly reduced, but no effect on manic patients
Methysegide- 5-HT antagonist- no effect
L-dopa - increases NA synthesis - no effect
Iprindole- no effect on monamine metabolism- increases mood.

Question 15

Describe the inconsistency of the biochemical evidence of the monamine theory

Answer 15

Although a reduction of NA metabolites are seen in patients with clinical depression, there is no correlation i.e not necessarily an even greater reduction in NA metabolites for a patient with severe depression as opposed to mild depression.
There is a delayed onset of the clinical effects of drugs, when the reduction in monamines would take place acutely. This may be due to adaptive changes of the neurones of depressed patients (i.e down regulation of a2, beta and 5-HT receptors) which are only targeted by anti-depressants after a couple of weeks.

However the general conclusions remain firm- and many of the anti-depressants target monamine metabolism to have their effect

Question 16

Describe some other theories for depression

Answer 16

HPA axis (↑ CRH levels)?- 
Hippocampal neurodegeneration? - anti-depressant drugs have been shown to reverse this. 

The plasma cortisol concentration is usually high in depressed patients. Other hormones in plasma are also affected, for example, growth hormone concentration is reduced and prolactin is increased. While these changes are consistent with deficiencies in monoamine transmission, they are not specific to depressive syndromes.
But CRF1 receptor antagonists have not been effective.

Question 17

Why may cocaine not be effective in treating depression

Answer 17

Adaptive changes of neurones in depressed patients- may not express cocaine receptors.

Question 18

Describe Reserpine

Answer 18

Originally licenced as an anti-hypertensive- no longer used due to its association with depression.
Monamine depletor- that is it inhibits the synaptic proteins that package and store NA in vesicles- depleting its storage- less released.

Question 19

Give an example of a TCA

Answer 19

amitriptyline

Question 20

Summarise the chemical structures of TCAs

Answer 20

All have a tri-cyclic structure
Fall into two types:
Dibenzazepines
Dibenzcycloheptenes (amitriptyline).

Question 21

Describe the mechanism of action of TCAs

Answer 21

Neural monamine reuptake inhibitors- effect NA and 5-HT roughly equally- but different TCAs have variable selectivity- inhibiting reuptake will acutely facilitate the transmission of monamines
Also acts on other receptors:
. § a2 – block pre-synaptic inhibition of NA release and 5-HT release). - this would contribute to anti-depressant actions
§ mAChR.
§ H2 (histamine) receptors.
§ 5-HT receptors

Question 22

Explain the delayed effects of TCAs

Answer 22

Delayed down-regulation of β-adrenoceptors & 5-HT2 receptors, also A2 receptors.
Dysregulated, down-regulated to normal levels which allows them to function normally.

Question 23

Describe the pharmacokinetics of TCAs

Answer 23

o Oral administration (rapid oral absorption)
o Highly PPB – 90-95%.
o Hepatic metabolism (liver microsomal enzymes) – to ACTIVE metabolites (with weak TCA like activity) à excreted in the urine (glucuronide conjugates).
o Plasma T1/2 = 10-20 hours – dose once daily.

Question 24

Describe the unwanted effects of TCAs at a therapeutic dose

Answer 24

Atropine - like effects (amitriptyline)- muscarinic receptor block (Sedation
Anticholinergic effects (dry mouth, constipation, blurred vision, urinary retention, etc)

Postural hypotension (vasomotor centre)- blocks a2 receptors

Sedation (H1 antagonism) - may be useful if taken late at night- depression can hinder sleep quality and pattern.

Question 25

Describe the acute toxic effects of TCAs due to overdose

Answer 25

CNS: excitement, delirium, seizures  coma, respiratory depression CVS: cardiac dysrhythmias  ventricular fibrillation/sudden death (anti-muscarinic effects and increased NA effects on heart). Care - attempted suicide

Question 26

Describe the drug interactions of TCAs

Answer 26

PPB:  TCA effects (aspirin, phenytoin) - aspirin-50% PPB- compete for same binding site- increasing conc of TCAs- toxic effects Hepatic microsomal enzymes:  TCA effects (neuroleptics; oral contraceptives)- compete for metabolism- TCA broken down more slowly- increasing toxicity Potentiation of CNS depressants (alcohol)- additive effect with alcohol Antihypertensive drugs (monitor closely) - sometimes BP goes up, sometimes it goes down- just monitor it initially.

Question 27

Give an example of a monamine oxidase inhibitor

Answer 27

Phenelzine

Question 28

Describe the mechanism of action of MAOIs

Answer 28

§ Mechanism of action: o MAO enzymes: § MAO-A breaks down NA & 5-HT – key MoA! § MAO-B: breaks down DA – e.g. Selegiline. o Most are non-selective MAOIs. o Irreversible inhibition leads to a long duration of action. We are trying to develop drugs which selectively target the MAO-A, MAO-B inhibitors are important in Parkinson's.

Question 29

What is the main function of MAO

Answer 29

1. Within nerve terminals, MAO regulates the free intraneuronal concentration of noradrenaline or 5-HT. It is not involved in the inactivation of released transmitter. 2. MAO in the gut wall is important in the inactivation of endogenous and ingested amines such as tyramine that would otherwise produce unwanted effects.

Question 30

Describe the effects of MAOIs

Answer 30

§ Rapid effects – increase cytoplasmic (not enhanced release but more leakage) NA, 5-HT. § Delayed effects – delayed clinical response due to down-regulation of b-adrenoceptors and 5-HT2 receptors – again, fits with delayed clinical effect. o Inhibits other enzymes – leads to side effects. Slow the breakdown of monamines. MAOI crosses BBB, reaches noradrenaline and serotinergic pre-synaptic terminals- inhibit MAO- increasing cytoplasmic conc of NA and 5-HT- thus increasing its release (mostly leakage) and transmission.

Question 31

Summarise the structure of TCAs

Answer 31

Single ring- with reactive side chain: Hydrazines (Phenelzine) Cyclopropylamines Proprygylamines Clorygyline is MOA-A specific and used to treat depression.

Question 32

Describe the pharmacokinetics of MOAIs

Answer 32

Rapid oral absorption Short plasma t1/2 (few hrs) but longer d.o.a.- they irreversibly bind (covalently with reactive side chain) to (and thus inactivate) monamine oxidase. Metabolised in liver; excreted in urine

Question 33

Describe the unwanted effects of MOAIs

Answer 33

Atropine - like effects (< TCAs) Postural hypotension (common)- effects on vasomotor centre. One possible explanation for this effect – the opposite of what might have been expected – is that amines such as dopamine or octopamine accumulate within peripheral sympathetic nerve terminals and displace noradrenaline from the storage vesicles, thus reducing noradrenaline release associated with sympathetic activity. Sedation (Seizures in o.d.) Weight gain (possibly excessive)- due to increase appetite. Hepatotoxicity (hydrazines; rare) - due to reactive side chains- don't prescribe to patients with liver problems

Question 34

Describe the drug interactions associated with MAOIs

Answer 34

‘Cheese reaction’: Tyramine-containing foods + MAOI  hypertensive crisis (throbbing headache,  b.p., intracranial haemorrhage) MAOIs + TCAs  hypertensive episodes (avoid) MAOIs + pethidine  hyperpyrexia, restlessness, coma & hypotension- pethidine is a opioid analgesic- maybe that they are metabolised by the same enzyme- forcing pethidine into methabolism by a different enzyme- which results in the production of toxic metabolites.

Question 35

Describe the 'cheese' reaction

Answer 35

Tyramine found in foods such as marmite, game, red wine and cheese. Tyramine is normally digested by MOA-B in the gut wall However if we inhibit MOA-B, we get a build up of tyramine Tyramine, like amphetamine, is a sympathomimetic. That is, it increases the release of NA from post-ganglionic pre-synaptic nerve terminals (binds to the vesicles containing NA- facilitating their release) -hence we get hypertension seen.

Question 36

Describe the reversible MAOI inhibitors

Answer 36

Moclobemide: reversible MAO-A inhibitor (RIMA). ↓ Drug interactions ↓ doa. The irreversible MAOIs have been shown to be more efficacious.

Question 37

Give an example of an SSRI

Answer 37

Fluoxetine

Question 38

Describe the structure of Fluoxetine

Answer 38

2 cyclical rings with an aliphatic chain.

Question 39

Describe the pros and cons of SSRIS

Answer 39

Less troublesome side-effects; safer in o.d.- no cheese reaction But less effective vs severe depression - so still need other drugs

Question 40

Describe the pharmacokinetics of SSRIs

Answer 40

p.o. administration Plasma t1/2 (18-24 hrs) Delayed onset of action (2-4 weeks) Fluoxetine competes with TCAs for hepatic enzymes (avoid co-administration) - otherwise the two will potentiate and you will see toxic effects.

Question 41

Describe the unwanted effects of SSRIs

Answer 41

Fewer than TCAs/MAOIs Nausea, diarrhoea, insomnia & loss of libido Interact with MAOIs (avoid co-administration

Question 42

What is important to remember about SSRIs

Answer 42

Fluoxetine (‘Prozac’): currently most prescribed antidepressant drug No effective in all patients- so need to use other anti-depressants.

Question 43

Describe Venlafaxine

Answer 43

Venlafaxine: Dose-dependent Reuptake inhibitor 5HT > NA >> DA (SNRI)- serotonin,noradrenaline reuptake inhibitor 2nd Line treatment for severe depression

Question 44

Describe Mirtazapine

Answer 44

Mirtazapine: α2 Receptor antagonist ↑ NA & 5HT release- inhibit negative feedback. Other R interactions (sedative)- Histamine receptors Useful in SSRI-intolerant patients

Question 45

What can lithium be used to treat

Answer 45

Inorganic ion taken orally as lithium carbonate- used to control mania as well as depression- mainly used prophylactically in bipolar depression. Long plasma half-life and narrow therapeutic window, hence side effects common and monitoring of plasma concentration is essential. Unwanted effects: nausea, thirst and polyuria, hypothyroidism, tremor, weakness, mental confusion, teratogenesis. Acute overdose causes confusion, convulsions and cardiac dysrrythmias. Action enhanced by diuiretic drugs. Alternative mood-stabilisers include carbamazepine, valproate.