Antidepressants

Question 1

What is depression?

Answer 1

●Depression (major depressive disorder) is a pathologic state,
●which is expressed by a decreased mood for no less than 2 weeks with a loss of interest,
a decrease of activity,
the feeling of being guilty.

●The main danger of depressions is the risk of suicides.

Question 2

The main conceptions of the pathogenesis of depressions.

Answer 2

●Monoaminergic conception
●Neurotrophic conception

Question 3

Monoaminergic conception?

Answer 3

●Develop due to the decrease of the levels of monoamines
(serotonin and norepinephrine)
in the CNS.

Question 4

Neurotrophic conception?

Answer 4

●Depressions can be linked to the decreased activity of the brain-derived neurotrophic factor (BDNF).
●BDNF
is a protein which belongs to the family of growth factors.

●The high concentrations of the BDNFS are detected in the brain cortex and hippocampus.

●It contributes to the survival of the existing neurons and
stimulates the growth and differentiation of new neurons.

●Almost all of the antidepressants influence the number of monoamines
in the brain and/or the effects of the monoamines.

●On the other hand,
a long-term treatment by the antidepressants increases the number of the BDNFS
(the beneficial effect of antidepressants also develops in the long-term treatment, after 2-3 weeks).

●Genetically determined polymorphism
of the BDNF significantly influences the effect of the antidepressants.

●There are evidences about the interaction between the monoamines and the BDNF.

●It was shown that the increase of monoamines during the treatment by antidepressants leads to the activation of the transcription of the BDNF gene.

Question 5

Classificaton of antidepressants.

Answer 5

● non-selective serotonin and norepinephrine reuptake inhibitors
(tri-cyclic and tetracyclic antidepressants):
amitriptyline,
imipramine,
desipramine,
nortriptyline,
maprotiline,
amoxapine;

●selective serotonin reuptake inhibitors:
fluoxetine,
paroxetine,
sertraline,
escitalopram;

●selective serotonin and norepinephrine reuptake inhibitors: venlafaxine,
duloxetine;

●MAO inhibitors:
- irreversible:
》nialamide, 》tranylcypromine;
- reversible:
》moclobemide;

● other (atypical) antidepressants: mirtazapine,
trazodone,
bupropion,
agomelatine.

Question 6

The most common mechanisms of the action of antidepressants?

Answer 6

●The inhibition of the reuptake of serotonin and/or norepinephrine.

●the inhibition of the metabolism of serotonin and norepinephrine
by MAO. (Fig. 24).

》Both these mechanisms contribute to the increased number of these neurotransmitters in the synapse.

Question 7

Tricyclic antidepressants?

Answer 7

●These drugs have a complicated influence on the CNS.
●They inhibit the reuptake of both serotonin and norepinephrine,
also
they block some receptors in the CNS and the peripheral tissues:
muscarinic cholinoceptors,
alpha adrenoceptors,
histamine H, receptors.

Question 8

Adverse effects of tricyclic antidepressants?

Answer 8

●sedation
(the most prominent for amitriptyline, the less prominent for protriptyline and desipramine);

●antimuscarinic effect
(dry mouth,
cycloplegia,
increase of ocular pressure,
constipation,
urinary retention);

●cardiovascular effects
(orthostatic hypotension due to the block of alpha adrenoceptors, arrhythmias due to the block of Na* channels).

●The tricyclic antidepressants have a low therapeutic index
(can be used for suicidal purposes).

●》Symptoms of acute poisoning by the tricyclic antidepressants:
▪︎arrhythmias;
▪︎ seizures;
▪︎signs of muscarinic receptors blockade (agitation, delirium, dry mouth
and skin, mydriasis, fever, bowel and bladder paralysis).

Question 9

The treatment of poisoning by the tricyclic antidepressants?

Answer 9

●antiarrhythmics
(lidocaine,
phenytoin,
propranolol intravenously;
other antiarrhythmics are contraindicated).

●Intravenous injection of sodium bicarbonate was also shown to improve the outcome of poisoning by tricyclic antidepressants
》The mechanism is not clear, but it was proposed that sodium bicarbonate uncouples molecules of the antidepressants from Na+ channels.
》The cardiovascular & respiratory function must be monitored.

Question 10

Selective serotonin reuptake inhibitors
(SSRIs)?

Answer 10

●These drugs inhibit the reuptake of serotonin without a significant influence on the norepinephrine reuptake.

●In comparison with the tricyclic antidepressants, they induce fewer adverse effects:
》They do not induce sedative and antimuscarinic effects,
》do not influence significantly the cardiovascular system.
Also, SSRIs have a
》high therapeutic index (a low risk of overdosing).

Now SSRIs are the most commonly administered antidepressants.

The distinctive feature of the pharmacokinetics of fluoxetine is that this drug is converted in the liver to the metabolite norfluoxetine,
which is active and
has very long half-elimination time (approximately 180 hours).

》Other SSRIs have a shorter duration of the action.

Question 11

Discontinuation syndrome?

Answer 11

●Discontinuation syndrome can be observed after the rapid withdrawal of SSRIs,
Its symptoms include
anxiety,
dizziness,
Impaired coordination,
Insomnia or hypersomnia,
tremor,
sensory disturbances (paresthesias, shock-like electrical sensations).

This syndrome is less prominent for fluoxetine
due to the long duration of the action.

Question 12

Serotonin syndrome?

Answer 12

●Serotonin syndrome is the dangerous interaction that is possible
if SSRIs are administered with MAO inhibitors and some other serotonin-
potentiating drugs
(buspirone, sumatriptan, ergotamine, amphetamine).

●It is caused by the excessive stimulation of the serotonin receptors in the CNS.
●The symptoms of serotonin syndrome include
tremor,
seizures,
hypertension,
high fever,
confusion;
in severe cases, coma and death follow.

●For the treatment of this syndrome, the antagonist of serotonin 5-HT₂ receptors cyproheptadine can be administered,
also diazepam for relieving seizures is given intravenously.

For the prevention of the serotonin syndrome,
MAO inhibitors can be administered
no earlier than 4-5 weeks after the
withdrawal of fluoxetine and
2 weeks after the withdrawal of other SSRIs.

Question 13

Selective serotonin & norepinephrine reuptake inhibitors (SSNRIs)

Answer 13

●These drugs inhibit the reuptake of both serotonin and norepinephrine,
but,
unlike tricyclic antidepressants, SSNRIs do not interact with any receptors.

●Also, in comparison with tricyclic antidepressants, SSNRIs
cause less adverse effects and
have a higher therapeutic index.

●The adverse effects are almost similar to the selective serotonin reuptake inhibitors (including sexual disorders); additionally,
●they can cause some effects explained by the increased effects of ▪︎norepinephrine:
▪︎hypertension,
▪︎tachycardia,
▪︎symptoms of CNS activation (insomnia, agitation).

●Discontinuation syndrome similar to that of the SSRIs was described, especially for venlafaxine.
●Serotonin syndrome also can be observed if the SSNRIs are combined
with serotonin-potentiating drugs.

Question 14

MAO Inhibitors?

Answer 14

●MAO inhibitors increase the amount of norepinephrine and serotonin in synapses due to the inhibition of their inactivation by MAO.

●The irreversible MAO inhibitors form covalent bond with this enzyme, so they have a long duration of the action (2-3 weeks), which does not depend on half-elimination time.

Question 15

Irreversible MAO inhibitors?

Answer 15

Rarely used now due to many adverse effects:
●CNS stimulation (nervousness, insomnia),
●cardiovascular effects (hypertension, tachycardia).

They also have a dangerous interaction with the food containing tyramine (“cheese syndrome”).
Normally, tyramine is inactivated in the intestine by intestinal MAO.

●In presence of irreversible MAO inhibitors,
tyramine is absorbed from the gastrointestinal tract and causes severe hypertension
(tyramine is an indirectly acting adrenomimetic, contributing to the release of norepinephrine to the synaptic cleft and activation of the adrenergic receptors).

●So, the use of food containing a high
amount of tyramine
(aged cheese,
beer,
soy products,
chocolate,
bananas, etc.) is dangerous for the patients taking irreversible MAO inhibitors.

●The irreversible MAO inhibitors can interact with many drugs, especially with serotonin-potentiating drugs:
tramadol,
dextromethorphan,
other antidepressants (especially SSRIs).

●The serotonin syndrome can occur if these drugs are combined with MAO inhibitors (see above).

●Also, it is dangerous to administer these antidepressants together with the indirectly acting or mixed acting adrenergic agonists (ephedrine), because
a dangerous increase of the blood pressure can develop.

Question 16

Reversible MAO inhibitors?

Answer 16

●Tolerated better.
●The interaction with food is not observed.
●The risk of serotonin syndrome is relatively low.

Question 17

List out other antidepressants.

Answer 17

Mirtazapine
Trazodone
Bupropion
Agomelatine

Question 18

Mirtazapine?

Answer 18

●Blocks
▪︎presynaptic alpha-2 adrenergic receptors &
▪︎serotonin 5-HT₂ receptors.

●The block of these receptors leads to
▪︎the increased release of serotonin, ▪︎norepinephrine and dopamine to the synaptic cleft.

●The distinctive features of mirtazapine include
▪︎low toxicity,
▪︎a prominent sedative effect,
▪︎a more rapid beginning of antidepressant effect
(1 week vs 2-3 weeks for other antidepressants).

●It does not cause sexual disorders. Mirtazapine also
possesses antiemetic properties
due to
the block of serotonin 5-HT3 receptors.

Question 19

Trazodone?

Answer 19

●an antagonist of
serotonin 5-HT2A and
5-HT2c receptors.

●a weak inhibitor of serotonin reuptake.
●It is known that the block of 5-HT2c
receptors
leads to the increase of the effects of norepinephrine and dopamine in the CNS.

●It has prominent sedative and alpha-blocking properties.

●The specific adverse effect is priapism (long-lasting painful erection, which
can lead to the gangrene of the penis).

Question 20

Bupropion?

Answer 20

●An inhibitor of the reuptake of norepinephrine and dopamine.

●It has some stimulating effect on the CNS,
it does not induce sedation.
It is also a non-competitive antagonist of the nicotinic cholinoceptors
and
is effective in the treatment of nicotine dependence.

●It does not cause sexual dysfunction.

●Caution:
bupropion can cause epileptic seizures.

Question 21

Agomelatine?

Answer 21

●Is a new antidepressant.
●Is an agonist of the melatonin receptor.
(It is used in Europe, but not approved in the USA)

Question 22

Choice of antidepressants?

Answer 22

●The treatment usually starts with less toxic and safer antidepressants: SSRIs, SSNRIS or some other newer antidepressants (especially mirtazapine).

●If these drugs are not effective, we can
administer older and more toxic drugs (tricyclic antidepressants).

●The irreversible MAO inhibitors are administered very rarely.
Only in case of resistance to other antidepressants.

Question 23

Other pathological conditions,
Which can be treated by antidepressants?

Answer 23

●Pain syndrome
●Anxiety disorders
●appetite disorders

Question 24

Pain syndromes. (Treated by antidepressants)?

Answer 24

●tricyclic antidepressants are used to relieve chronic neuropathic pain
(the pain caused by the damage of neurons or sensory nerve endings. among the most common causes of this pain there are
▪︎diabetes mellitus,
▪︎herpes zoster,
▪︎cancer).

●Recently SSNRIs were showed to be effective in this condition
(duloxetine is officially approved
for this purpose)

Question 25

Anxiety disorders? (Treated by antidepressants)

Answer 25

●SSRIs and SSNRIs are effective and can
be administered in some kinds of anxiety disorders
(generalized anxiety, panic disorders).

●In comparison with anxiolytics, they do not act so rapidly,
but can be more effective in long-term treatment.

Question 26

Appetite disorders? (Treatment by antidepressants)

Answer 26

●It is known that serotonin is a physiological inhibitors of the appetite center in the hypothalamus, so SSRIs (especially fluoxetine) are used in bulimia.