Section two – how we think antidepressants work
a.
How we think the symptoms of depression happen
People with depression usually have problems with low mood, poor sleep, poor appetite, loss of
energy and interest or pleasure. Depression affects about 1 in 30 people every year.
The main theory about how these symptoms happen is the so-called ‘monoamine hypothesis’.
We know that:
 Serotonin and noradrenaline are transmitters in the brain
 Serotonin and noradrenaline are involved with the control of sleep and wake, emotions,
mood, arousal, drive, temperature regulation and how hungry we feel
 If a person has too little serotonin and noradrenaline in the parts of the brain that control
mood, this will lead to too little activity. That part of the brain may become slower and less
effective. This would lower mood
 What causes this is not fully known but some sorts of stress may lead to lower levels of
serotonin and noradrenaline
 It will also depend on how that person’s brain reacts. It may be that they naturally have
less serotonin or noradrenaline than other people. It might also be that under some types
of stress their brain may react by having less serotonin or noradrenaline
 Transmitters other than serotonin and noradrenaline are probably also involved.
‘Normal’ communication between cells
‘Less’ communication between cells e.g. as in depression
There are many ideas about how the symptoms of depression might occur. These include:
 Genetics
 How the brain develops
 Nurture (i.e. how we are bought up)
 How we react to what happens to us.
There are probably many causes and in each person there may be a combination of these.
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a.
How we think the symptoms of depression happen (Part 2)
This section is a bit complicated. You may want to miss this at the moment and come back to it later. And it’s not
even known for certain. But it is an attempt to explain something very complex in a fairly simple way.
There is a possible spiral of events:
1. You are under a stress you can’t cope with (you may not even know about it)
2. This activates the HPA axis (which helps us react to and protect from stress)
3. This releases CRF (Corticotropin Releasing Factor)
4. This leads to the brain releasing ACTH (Adrenocorticotropic Hormone)
5. This leads to release of cortisol – cortisol maintains your metabolism and immune response and we know its
levels are higher in people with depression
6. This leads to the release of noradrenaline and serotonin being reduced
7. This leads to a lower mood and you become less able to cope with stresses
8. And then you start again at (1).
How therapies may help
 Antidepressants can help by boosting serotonin and noradrenaline. This can help make positive thoughts easy
to have and improve how you can cope with life
 Talking Therapies can help challenge negative thoughts. This can help the person cope with the stresses they
may come under
 Support can help reduce the stresses as well.
There are also many other symptoms where boosting serotonin seems to help. In PTSD, OCD
and bulimia nervosa we don’t really know what happens in the brain. However, it is clear that
only higher doses of medicines such as the SSRIs help reduce symptoms so the effect may be
different to depression. In anxiety lower doses usually help.
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b.
How we think antidepressants work
Medicines usually called antidepressants can also be used to help the symptoms of many other conditions e.g. anxiety, PTSD,
OCD, eating disorders, panic and social anxiety.
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Normal nerve activity, with the usual strength messages being
passed.
Reduced nerve activity e.g. as in depression, with lower strength
or downbeat messages. If too little serotonin or noradrenaline
leads to the symptoms of depression then boosting serotonin or
noradrenaline should help to reduce the symptoms.
One way to do this is to block the reuptake or recycling of
serotonin or noradrenaline. This is what most antidepressants do.
If the recycling is blocked it boosts the amount of serotonin or
noradrenaline in the synapse.
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How this works is that the next message is as downbeat as it was
before. Serotonin or noradrenaline is released but the message is
weaker than before depression set in.
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Most antidepressants block the reuptake of serotonin or
noradrenaline so there is some spare serotonin or noradrenaline
hanging around in the synapse.
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The next downbeat impulse that comes along releases serotonin
or noradrenaline as normal. But it combines with the serotonin or
noradrenaline still hanging around from the last message.
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The new message is thus stronger because it has some extra
transmitter from the last message. So, the activity in that part of
the brain is increased, boosting the messages.
The important thing to remember is that antidepressants probably mainly work by correcting
the effect of having too little transmitter. They are NOT STIMULANTS. Antidepressants also
have many other effects in the brain and some of these may be how they work for e.g.
depression.
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c. How we think the specific antidepressants work
SSRIs (including citalopram, escitalopram, fluvoxamine, fluoxetine, paroxetine and sertraline)
 The SSRIs boost the amount of serotonin in the synapses by blocking its recycling or
reuptake back into the nerve endings. They have little or no effect on other transmitters
 You might guess this from what SSRI stands for: Selective Serotonin Reuptake Inhibitors
Mirtazapine (Zispin®)
 Mirtazapine increases the amount of both serotonin and noradrenaline at nerve endings
 It also blocks two types of serotonin receptor (5HT2 and 5HT3). This means you don’t feel
sick, and doesn’t cause agitation or sexual problems
 It also blocks some histamine receptors. This means you can feel quite sleepy when you
start taking it, but at least it helps treat any hay fever or allergies! It can also lead to weight
gain in some people.
Venlafaxine (Efexor®, Efexor XL®)
 At doses up to about 150mg a day, venlafaxine blocks the reuptake of serotonin
 At doses above about 150mg a day, venlafaxine blocks the reuptake of both serotonin and
noradrenaline
 At doses above about 225mg a day, venlafaxine blocks the reuptake of dopamine as well.
Duloxetine (Cymbalta®)
 Duloxetine blocks the reuptake of both serotonin and noradrenaline at all doses.
Reboxetine (Edronax®)
 Reboxetine blocks the reuptake of noradrenaline only
 This means you do not get the effects from serotonin e.g. feeling sick, agitation or sexual
problems
 However, to be fair, it doesn’t seem to be quite as effective as the SSRIs.
Trazodone (Molipaxin®)
 Trazodone blocks the reuptake of serotonin just like the SSRIs
 It also has an effect on some other serotonin receptors and a little on histamine, which may
give some different side effects.
Agomelatine (Valdoxan®)
 Agomelatine is unusual in that it boosts melatonin receptors in the brain and only has a
small (but important) effect on serotonin receptors
 This means it helps you sleep and you don’t get the same side effects as from medicines
that affect the reuptake of serotonin e.g. no sickness, agitation, sexual problems.
MAOIs
See a separate section.
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d. How and why you can get side effects from antidepressants
The side effects you get will depend on which of the transmitters in the brain are affected.
Serotonin:
If a medicine boosts the effect of serotonin then this can boost the effect in the area of the
brain that controls mood. But also in other areas e.g. the ones that control ‘satiety’ (how much
food you eat), how well you sleep (the so-called ‘sleep-wake cycle’) and sexual activity.
Too much serotonin in some parts of the brain can make you:
 Feel sick
 Feel less hungry
 Get headaches or migraines
 Feel sleepier or not sleeping as well
 Have problems having an orgasm or low desire.
Noradrenaline:
If a medicine boosts the effect of noradrenaline then this can boost the effect in the area of the
brain that controls mood. But also in other areas too.
Too much noradrenaline in some parts of the brain can:
 Make you feel restless, anxious, irritable and stressed
 Make you find it hard to sleep
 Increase your heart rate and blood pressure.
Dopamine:
If a medicine boosts the effect of dopamine then this can boost the effect in the area of the
brain that controls mood. But also in other areas too.
Too much dopamine in some parts of the brain can make you:
 Feel overexcited, aggressive, euphoric, high or psychotic
 Feel nauseous or sick.
Histamine:
 Histamine is produced by the brain to keep us awake
 If a medicine also blocks histamine in the brain, then this can make you feel sleepy. This is
the same as if you take one of the older antihistamines such as chlorphenamine (also called
Piriton®, chlorpheniramine or dexchlorpheniramine) or promethazine for hay fever or allergy.
The newer antihistamines such as cetirizine don’t get into the brain so don’t cause the same
sleepiness
 In the body histamine reduces inflammation and allergies
 Blocking histamine might also lead to some weight gain.
Acetylcholine:
If a medicine also blocks acetylcholine, then this can make you feel a bit slow, sleepy and
confused. You may also get a dry mouth, blurred vision, finding it hard to wee and poo.
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e. How we think the MAOIs work
Another way of doing this is to stop the breakdown of transmitters. This is what the MAOIs do.
They block or inhibit the monoamine oxidase enzyme (MAO). This doesn’t now break down the
transmitter, so the next time an impulse comes along, there is more transmitter, a stronger
message is passed, and activity in that part of the brain is increased.
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‘Normal’ nerve activity
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‘Reduced’ nerve activity e.g. as in depression.
If too little serotonin or noradrenaline produces the symptoms of
depression then boosting these should help to reduce the
symptoms.
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One way to do this is the block the breakdown of these
transmitters. This is what MAOIs do.
How this works is that the next message is downbeat as before.
Transmitter is released but the message is reduced in strength.
The MAOI blocks the breakdown of the transmitter so there is lots
of spare transmitter hanging around.
The next impulse that comes along releases transmitter as normal.
But it combines with the transmitter still hanging around from last
message because it wasn’t broken down.
The new message is thus stronger and activity in that part of the
brain is increased.
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f. How and why you can get side effects from MAOIs
Some antidepressants e.g. the tricyclics, block the reuptake of serotonin and noradrenaline.
Others mainly block the reuptake of just serotonin e.g. the SSRIs. The MAOIs block the
monoamine enzyme which breaks down noradrenaline, serotonin and some other transmitters.
They are Monoamine Oxidase Inhibitors.
Unfortunately, the MAOIs also block an enzyme in the body which breaks down other
compounds. One of these is an amino acid called tyramine. Tyramine is an essential compound
which the body needs, and is found in many foods. However, if you have too much tyramine in
the body, it can make your blood pressure rise. Foods such as cheese, yeast and meat extracts
etc contain lots of tyramine. If you eat any of these foods while taking an MAOI, your body can
not break down (or metabolise) the tyramine. You then get an excess of tyramine in the body,
which increases your blood pressure very quickly. This can at cause headaches initially but can
be very dangerous and has caused some very serious reactions.
The MAOIs also affect other transmitters, which are broken down by the MAO enzyme.
 Affecting your noradrenaline may also sometimes upset your blood pressure e.g. you may
feel dizzy when you stand up etc.
g. Some key facts about antidepressants
 The symptoms of depression may be caused by an imbalance of chemicals in the brain,
probably reduced levels of serotonin and noradrenaline
 Sometimes the symptoms of depression can occur in what are called Adjustment Disorders,
where someone has problems adapting or adjusting to work, home or lifestyle changes.
 The symptoms of some other conditions, especially PTSD, anxiety and OCD, also seem to be
at least partly caused by a lack of serotonin and/or noradrenaline
 Antidepressants can help correct any such imbalances in the brain
 Antidepressants are not stimulants
 They do not work by altering your personality
 They are not addictive, not abused and are not habit forming (but you should not stop
taking them suddenly)
 They do not usually lose their effect if you keep taking them. It is possible that in about 1 in
10 people depression can come back again, but it is not clear why this happens
 ‘Antidepressants’ can also help treat many symptoms other than depression e.g. premenstrual syndrome or tension, PTSD, OCD, anxiety, aggression and premature ejaculation
 Overall antidepressants quite clearly reduce feelings of self-harm and suicidal thoughts.
However, it seems that these feelings can increase in a few people. This may be because
some people can feel a bit restless when starting antidepressants and this can be
uncomfortable. To try to get over this possible problem, it is often best to start with a lower
dose for a few days and then increase.
The small print: This booklet is to help you understand about how we think medicines may work for mental health problems.
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