Antidepressants ADR

Question 1

MAOI ADR

Answer 1

 Postural hyoptension

• Probably due to sympathetic block produced by accumulation of dopamine in the cervical (neck) ganglia, where is acts as an inhibitory transmitter

 Restlessness and insomnia due to central nervous system (CNS) stimulation

Question 2

MAOI DDI FDI

Answer 2

1) pethidine
2) cheese
3) concentrated yeast product (eg marmite)
4) tyramine (amines in food)

 Should not be combined with or other drugs enhancing serotoninergic function (e.g. pethidine)
cause–> • Hyperexcitability, increased muscular tone, myoclonus (jerking, involuntary movements), loss of consciousness

The cheese reaction

• Major limitation on the use of MAOIs.
• Acute hypertension, giving severe throbbing headache, and occasionally intracranial haemorrhage.

Less likely to occur with MAO-A selective, reversible MAOIs (e.g. moclobemide).

 Amines (e.g. tyramine) in foods (e.g. cheese) are usually broken down by MAO in the intestines and liver.  MAOIs can lead to accumulation of tyramine and a sympathomimetic effect.
 Dangerous food interactions with MAO blockers (e.g. acute hypertension).

Tyramine is taken up into adrenergic terminals and competes with NA for the vesicular compartment.

Question 3

Non-selective TCA for SERT/NET:

Answer 3

Non-selective for SERT/NET:

Imipramine, Amitriptyline, nortriptyline

Question 4

Selective TCA for NET:

Answer 4

Selective for NET:

Desipramine

Question 5

TCA ADR

Answer 5

 Sedation
•Due to H1 histamine receptor antagonism
•Tolerance to sedation can develop in 1-2 weeks

 Postural hypotension
•Due to α-adrenoceptor sympathetic block

 Dry mouth, blurred vision, constipation
•Due to muscarinic receptor antagonism

 Risk of drug induced cardiac dysrhythmias
•Perhaps due to block of HERG potassium channel

Question 6

blockage of HERG potassium channels

Answer 6

TCA ADR

Block of HERG can lead to prolongation of the cardiac ventricular action potential resulting in drug-induced long QT syndrome (LQTS), which can result in fatal arrhythmias.

Question 7

TCA PK

Answer 7

 Drug-drug interactions
•Plasma protein bound
•Rely on hepatic metabolism for elimination

Question 8

SSRI adv

Answer 8

Low affinity for α adrenoceptors ——–>
Lack of cardiovascular effects, safer in overdose

Lack of effect at histamine receptors ————–>
Reduced sedation

Low affinity for muscarinic cholinergic receptors ——–>
Minimal anticholinergic side effects (e.g. dry mouth and constipation)

Overall SSRIs are safer in overdose and less side effects lead to better compliance.

 Adverse effects of TCAs lead to prescription of subtherapeutic doses.
 Improved adverse effect profile of SSRIs leads to better compliance and so prescription of more adequate doses.

basically good

1) efficacy
2) safety
3) tolerability

1st line therapy. but not perfect…..
• Only 2/3 get remission
• Adverse effects especially at start
• Discontinuation can be a problem in some

Question 9

SSRI ADR

Answer 9

 Nausea
 Insomnia
 Sexual dysfunction

N AND I
- May be discontinuation/rebound symptoms of withdrawal when plasma levels of drug

 SSRI-induced sexual dysfunction
 Men = delayed ejaculation
 Women = delayed or blocked orgasm (anorgasmia)
 Reported by up to 50% of patients on SSRIs
 But rarely [<10%] leads to discontinuation
 Due to increased stimulation of 5HT2 receptors

Question 10

SSRI citalopram

Answer 10

Citalopram still has some histamine receptor antagonism leading to sedation.

Question 11

prevent SSRI-induced sexual dysfunction by giving ___________________

Answer 11

Cyproheptadine or other 5HT2 blockers

can be given to prevent SSRI-induced sexual dysfunction

Question 12

SSRI DDI

Answer 12

1) serotonin syndrome 
 Severe reaction can result from drug-drug interactions with other drugs increasing serotoninergic activity (e.g. MAOIs). 
 Effects include: 
 tremor 
 hyperthermia 
 cardiovascular collapse

Question 13

ADR of NARI

Answer 13

Reboxetine

 New drug so adverse effects not well described.
 Dry mouth (11 %)
 Constipation (9 %)
 Insomnia (approx. 9 %)
- Probably due to increased noradrenergic activity in the central nervous system.
 Tachycardia (approx. 3%)
- Probably due to increased availability of NA at sympathetic “fright, flight or fight” synapses.

Question 14

SNRI ADV

Answer 14

Venlafaxine

 Different structure to TCAs and fewer adverse effects than TCAs.
 Claimed to work slightly faster than other antidepressants.
 Claimed to work better in treatment-resistant patients

Question 15

SNRI ADR

Answer 15

 Serotoninergic adverse effects similar to SSRIs:
 Nausea
 Insomnia
 Sexual dysfunction
 “Serotonin syndrome” when combined with other serotoninergic drugs and MAOIs.
 Withdrawal effects may be more common and stronger than for SSRIs and TCAs.

Question 16

other antidepression

Answer 16

 Mirtazapine: a norepinephrine and specific serotonin antidepressant (NaSSA). Antagonist of adrenergic α2 autoreceptors and 5-HT2C receptor, among others.

 Bupropion: a norepinephrine-dopamine reuptake inhibitor (NDRI).

 Agomelatine: agonist of melatonin MT1 and MT2 receptors, less TCA / SSRI-associated side-effects, also helps in sleep disorders.

 Ketamine: a glutamate NMDA receptor antagonist used as an anesthetic, currently evaluated for rapid-onset antidepressant effect.

Question 17

Relative effects of antidepressants on monoamine uptake

Answer 17

5-HT selectivity

SSRIs
- Escitalopram
- Citalopram
- Sertraline
- Paroxetine
- Fluoxetine
- Clomipramine (TCA)
- Venlafaxine
(MIDDLE)
- Amitriptyline (TCA)
- Imipramine (TCA)
- Nortriptyline (TCA)
- Desipramine (TCA)
-Lofepramine (TCA)
- Reboxetine (NARI)
- Maprotiline (NARI)

TCAs
NARIs
NA selectivity