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How (we think) medicines work, to help you…
Learn more about your
medicines
Introduction
Section one:
How the brain works (the brain, brain cells, synapses and transmitters)
Section two:
Sections available include how we think medicines work for:
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
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Depression, OCD, PTSD, anxiety, eating disorders, panic, social anxiety
Bipolar mood disorder
Psychosis and schizophrenia
Anxiety
Sleep and insomnia
Dementia and Alzheimer’s Disease
ADHD
Section three:
Tolerance, dependence and addiction
Combined help
The small print: This booklet is to help you understand about how we think medicines may work for mental health problems.
V01.10 [4-2017] ©2017 MisturaTM Enterprise Ltd (www.choiceandmedication.org). Choice and MedicationTM indemnity applies only to licensed subscribing
organisations and the personal use by that organisation’s service users and carers. Use by non-subscribing organisations is prohibited
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Introduction
The philosophical bit
The aim of this book is to help you to
understand medicines for mental health
problems a bit better. If you understand
how medicines might be working you may
then be able to use them better. And then
get the best out of them.
To the best of our current knowledge*
 Our universe started with a bit of a bang
about 18.8b years ago
 Our sun was formed about 4.6b years
ago
 The earth and moon were formed
shortly afterwards
 Life started developing and evolving on
our planet about 3.8b years ago
 There may have been several false starts
and there were several mass extinctions
(just like there is at the moment)
 Dinosaurs ruled the earth from 160m to
66.5m years ago
 Then, about 66.5m years ago, the 15Km
wide Chicxulub meteorite hit Mexico,
wiped out about 75% of all species,
ended the dinosaur era and created the
conditions for other mammals to take
over
 One of those mammals that evolved was
the humans. And we’ve taken over.
* To probably misquote Prof. Brian Cox, if you
measure something three different ways and the
answer is the same each time, it’s probably the
right answer. You can’t be 100% certain but you
can be pretty sure.
In terms of evolution, once we’re past
reproduction age, everything else is a bit of
a bonus. None of us live forever on earth –
very few of us will have many more than
100 trips round the sun.
So, as long as you can survive, differences
don’t matter much to the species as a
whole. They do to the individual, but not
overall. If parts of you are a bit different it
doesn’t really matter. Differences may even
be an advantage or a disadvantage.
How we are and what we look like depends
on many things:
1. Our genes
 We have up to about 20,000 genes (half
from each parent) on 23 chromosomes
 Genes control how we’re built e.g. sex,
hair colour, eyes etc.
 Some control which liver enzymes we
have – and these may change how we
react to some medicines.
 Some genes will control the structure
and receptors we have in our brain. Each
receptor has lots sub-types and variants
 Genes control many other things too.
Think of the humble Brussels sprout. What you think
of Brussels sprouts depends on whether or not you
can taste a chemical in them called PTC. If you can’t
taste PTC, you love sprouts. If you can, they taste
evil. Whether or not you can like them depends on
whether your genes code for a taste of PTC.
2. Environment, experience and time
Our environment e.g. family, upbringing, life
events, what we eat, illnesses and stress,
will mould how we grow and develop.
But what has this got to do with
medicines?
The biggest difference between people is
our brain. The brain is extraordinarily
complex. Each one is unique in billions of
ways. Sometimes it is wired up one way,
sometimes another.
The brain is also always changing over time
(minute to minute, day by day, month by
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month) and reacts to events and adapts to
these.
Not all of the changes are for the better in
the 21st Century, when we are all expected
to function fully all the time. And of course
as we get older things don’t always work as
well as they used to.
How we at C&M think of it is that if you
need to take a bit of a chemical to make the
body work better that’s a real bonus. And if
that is in the brain we shouldn’t think of it
any differently to physical health. Does
anyone have a stigma if they need a bit of
extra thyroid? Pain-killers for arthritis?
Drugs to reduce blood pressure? The same
should be true of the brain. If you feel
rubbish and something helps you feel better
or can cope better, that’s great. They’d
have loved that 200 years ago.
As someone once said to me “Life may not
be perfect on medicines but it’s a whole lot
better than without.”
Choice of medicines
The effects of all medicines are different
and depend on:
 Their chemical structure or shape, and
their chemical group
 The dose
 How and when it is taken e.g. timing
 Your genes.
The choice of medicines is based on:
 Drug – we have very little to guide us
yet on which one to choose
 Dose – getting the right balance
between the effects we want and the
ones we don’t want. You need enough
to reduce the symptoms without giving
you side effects that are worse than the
symptoms
 Side effects – which ones you get and
how you and your body can cope with
them.
Symptoms and problems will change with
time, so drugs and doses may need to be
changed or at least tweaked sometimes.
That’s not a failure, that’s life.
What this book is based on is huge amounts
of research over the years. We will try to
give you an overview of a very complicated
topic.
But, remember, you are unique. There is no
such thing as an average brain, just as
there isn’t an average for most things. Like
the Americans who designed an aircraft
pilot’s seat to fit the average airman size,
only to find that not a single pilot was
actually of “average” size!
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Section one – how the brain works
1.1 The brain
It may be that “Your head tells you that you need to take medication, but your heart says you
don't want to". In order to help you make your own decisions, it is useful to have an idea about
how medicines work. This is the aim of our booklet.
In order to try to understand a little about how medicines are thought to work, it is best to first
learn a few facts about the human brain. Each human being has:
One head and one brain.
Each brain has somewhere around 10,000,000,000 brain
cells. These brain cells are called neurones.
Each brain cell has many links or connections with other
brain cells. These are through nerve fibres (called axons).
These are the wiring that connects brain cells.
There are about 4 million miles of nerve fibres or axons in
each brain. That’s enough to stretch to the moon and back
eight times.
All nerve fibres have branches. Many can have up to
10,000 branches in them.
At the end of each nerve fibre is a junction with another
brain cell. These junctions are called synapses (circled in
the drawing).
As you can see, overall the brain is an extraordinarily complex part of the body.
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1.2 Synapses (the junctions between brain cells)
Synapses are very important because:
1. They are the way that brain cells talk to each other
2. Synapses are of the same basic design everywhere in the body e.g. in the brain, the heart,
the legs etc.
3. There are rather a lot of them in each brain - probably around 100,000,000,000
4. If we can get chemicals (e.g. medicines) into the gap between them in the brain, we can
affect the way in which brain cells talk to each other. We can calm messages down or boost
them.
 For example, caffeine, alcohol, paracetamol, some laxatives and triptans for migraine are
all chemicals that get into synapses and can calm down or boost messages in the brain.
A synapse looks a bit like this:
In the drawing you will see the following:
 Axons – these are nerve fibres. A neurone (brain call) has thousands of axons
 Transmitters - these are small chemicals used by brain cells as messengers. They are
stored in the vesicles in the nerve ending ready to be released. There is only one type in
each nerve ending. A transmitter that is used in the brain is called a neurotransmitter.
 Vesicles – these are the little packages that contain the transmitter.
 Receptors - these are structures on the surface of the receiving axon which have a slot
designed just for the transmitter. Think of it like this: if the transmitter is a key, receptors
are the lock into which they fit. A bit like a Yale key and a Yale lock.
 Enzymes - these surround the synapse and break down any spare transmitter that might
leak out. This stops any spare transmitter setting off the next nerve.
 Calcium channels – these control the action of glutamate and noradrenaline, which are the
main excitatory or alerting messengers. They speed up or slow down the effects of
glutamate and noradrenaline
 Reuptake pump – this sucks any spare or used transmitter back up into the nerve ending.
It can then be reused.
On the next page we’ll show you how it all works.
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1.3 What happens when a message is passed from one brain cell to
another
1
An electrical message or impulse is sent from the brain cell
down one of the nerve fibres towards the synapse. It travels
down the nerve fibre a bit like an electrical ‘Mexican Wave’.
Some messages travel at over 250 miles an hour. Others can be much
slower e.g. pressure at 150mph and pain at 2mph. This is why when you
stub your toe you feel the pressure just before the pain.
2
This message arrives at the synapse at the end of the nerve
ending. When it arrives it triggers the chemical transmitter to
be released from the vesicles in the nerve ending.
3
The transmitter travels across the gap from the first nerve
fibre to the next or receiving nerve fibre. The transmitter hits
a receptor on the other side. It fits into it just like a key fitting
into a lock.
4
When the transmitter hits the receptor, the receptor changes
shape. This is the trigger for changes inside the nerve ending.
These changes set off an electrical message in that nerve fibre
which then travels down the nerve fibre to the brain cell.
5
The message arrives at the brain cell, which then decides
what to do. Meanwhile, the synapse deals with the
transmitter.
6
Most of it is taken back up again into the nerve ending i.e. it is
recycled. This is called re-uptake. Some transmitter is broken
down by the enzymes.
7
The nerve fibre and synapse is then ready for next message.
Other things to know:
 Messages are only passed in one direction
 There is only one type of transmitter per synapse
 The transmitter allows an electrical message to be turned into a chemical message and back
into an electrical message
 When a receptor is hit by a receptor, there is usually a quick effect. There may also be a
slower effect sometimes that may affect the way the brain cell works.
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1.4 Transmitters or neurotransmitters
There are over about 100 different known transmitters in the brain, but about 10 of them do
99% of the work. These transmitters in the brain tend to be grouped together in pathways.
Each group or pathway seems to have specific roles in the brain.
Transmitter
The main things it seems to do
Some problems if it gets out of balance
Serotonin or
In the brain, serotonin helps control
Too much serotonin in the brain and you
5-HT
mood, emotions, sleep/wake, feeding may feel sick, less hungry, and get
and temperature.
headaches or migraines.
In the body, serotonin helps control
Too little in the brain and you may feel
blood pressure and your intestines.
depressed, suicidal and sleep badly.
Dopamine
The first pathway in the brain
Not enough dopamine in the first pathway
(there are three controls muscle tension. It tells the
and your muscles tighten up (e.g. as
main groups or muscles to relax.
happens in Parkinson’s Disease).
pathways of
The second pathway controls
Too much dopamine in the second pathway
dopamine
‘perceptions’ e.g. emotions, reward,
leads to an overactive brain i.e. too much
neurones in the drive, pleasure, appetite and deciding ‘perception’. You may see, hear or imagine
brain)
what is real or important.
things that are not real.
The third pathway controls a
Too little dopamine in this pathway and
hormone called prolactin.
your prolactin goes up. This leads to
stopping periods and starting breast milk
production.
Noradrenaline
In the body, noradrenaline controls
Too much noradrenaline and you may feel
(NA)
the heart and blood pressure.
anxious, jittery, panicky and shaky.
(also called
In the brain, it controls sleep,
Too little noradrenaline in the brain and
norepinephrine or
arousal, wakefulness, mood, focus,
you may feel depressed, sleepy and dizzy.
NE)
attention, emotion and drive.
Acetylcholine
In the body, acetylcholine passes the Too little in your body can give you a dry
(ACh)
messages that make muscles tighten mouth, blurred vision and constipation.
up. In the brain, it controls arousal,
If you have too little in the brain you may
memory, how well you learn tasks,
become confused, sleepy, slow at learning
and remember things.
and have a poor memory.
Histamine
In the brain it keeps us awake
Too little and we become sleepy
In the body it is part of the immune
Too much can lead to too much
system.
inflammation e.g. as in hay fever
Glutamate
Glutamate acts as an ‘accelerator’ or
Too much and you may become anxious
alerter in the brain
and some parts of your brain may become
overactive, psychotic or have seizures. Too
little and you become sleepy or sedated.
GABA (Gamma- GABA acts as a ‘brake’ in the brain,
Too much and you become sleepy,
AminoButyric
relaxes it and helps give it a sense of forgetful or sedated. Too little and you may
Acid)
well-being.
become anxious, restless and excited.
We don’t always know why but some of these transmitters can get out of balance e.g. you can
have too much or too little. This can then be the cause the symptoms.
Nearly all known mental health medicines act in one of several ways:
1. Block the receptors, to reduce the effects from having too much of a transmitter
2. Boost the message by e.g. by stimulating receptors or blocking the transmitters’ reuptake,
which increases their activity. This reverses the effect of having too little transmitter.
3. Block the enzymes - this stops the breakdown of transmitter, increasing how much is there.
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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.
01e4plu
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.
01e3
gfh
02c
01e3
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.
02f
Most antidepressants block the reuptake of serotonin or
noradrenaline so there is some spare serotonin or noradrenaline
hanging around in the synapse.
02h
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.
02i
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.
01e4
hgn
‘Normal’ nerve activity
01e3
‘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.
3e
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 and others
 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.
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Section two – how we think mood stabilisers work
a.
How we think the symptoms of bipolar happen
People with bipolar mood disorder or manic depression can suffer highs, lows and all stages in
between. The highs can be excited over-activity but can also include being irritable and
frustrated (hypomania) or be destructive and uncontrolled (mania). Lows can be any stage of
depression e.g. mild, moderate or severe. These stages can last a long time.
‘Normal’ nerve activity
01e4plus
‘Reduced’ nerve activity e.g. as in being low or depressed
01e3
‘Excess’ communication e.g. as in being high or manic/hypomanic
It is unclear exactly what happens in the brain to cause mania. One of the more logical ideas is
that the transmitters noradrenaline or dopamine are overactive or in ‘overdrive’.
We know that there are many changes in the brain with bipolar mood disorder but it is not
clear which are the important ones. The transmitters involved in the brain might be out of
balance:
 Dopamine may be overactive – this may be the cause of the delusions and paranoia
 Noradrenaline may be overactive – this may lead to general over-activity in mania and
underactive in depression. It may also be that the receptors become more or less sensitive
 Serotonin may be underactive – this may be part of the cause of the low moods. It might
also be that serotonin receptors become more or less sensitive, and this may be inherited.
http://www.choiceandmedication.org/nsft
b. How we think lithium works
Lithium is called a mood stabiliser. Lithium has been used since the 1950s to help people with
bipolar disorder or manic depression. It helps to stop the highs and the lows, or at least make
them occur less often and be less severe, so you can cope with them.
What seems to happen is that when a message is sent in the brain:
 The transmitter (e.g. noradrenaline) hits a receptor (e.g. a noradrenaline receptor)
 The message is passed to the inside of the cell:
 Firstly through a ‘G-protein’
 Then through a protein called PKC (Protein Kinase C)
 This then triggers the ‘inositol circuit’
 This is what then triggers the nerve message or impulse being passed on.
These G-proteins and PKC are known as ‘secondary messengers’.
It is known the G-proteins and PKC are overactive in people with bipolar who are high. The
opposite seems to be true in depression i.e. that G-proteins and PKC are underactive. Lithium
(and also sodium valproate) seems to regulate this over-activity or under-activity. They seem to
work mostly when G-proteins and PKC are overactive, acting a bit like a ‘speed regulator’. They
seem to adjust the activity downwards when people are high, and upwards when people are
low.
One way of looking at this is to think of it as a lock and key. Think of the transmitter as a key
and the receptor the lock. Normally the key goes into the lock, turns, the door opens, and the
message is passed. The door has an automatic spring on it, so it then swings shut and the key
falls out ready for the next message.
For lithium, the secondary messengers (the ones that pass the message from the receptor to
the inside of the cell) can either be over-active or under-active. This is a bit like the automatic
spring on a door being either too tight (hard to pass messages, so you feel depressed) or too
loose (too easy to pass messages, so you feel high).
Lithium seems to act as the maintenance guy on the secondary messengers. It oils the
automatic spring on the door so it doesn't get stuck shut or open, and tightens up the regulator
so it doesn't swing too easily. The whole system works more reliably and better, so you don't
swing from low to high as much.
Lithium has many other effects that might be important e.g. it leads to an increase in the
production of Bcl-2. Bcl-2 is known as a ‘neuroprotective protein’. Bcl-2 levels drop quickly
when you stop lithium. This may make the brain more vulnerable to stress. Lithium also boosts
the amount of grey cells in the brain.
http://www.choiceandmedication.org/nsft
c. How we think other mood stabilisers work
Sodium valproate (also called valproate, valproate semisodium, divalproex and
valproic acid) - Epilim®, Epilim Chrono®, Depakote®, Episenta®, Valpro® and many others
 Valproate may act a bit like lithium, through the secondary messengers such as PKC
 Valproate may also increase the time needed between messages so slows down ‘repetitive
firing’. Under normal circumstances this time between messages makes little difference. If
the brain is overactive lots of messages are sent in quick succession. Valproate slows the
number of messages back down to the normal level e.g. if the next message follows along
before the nerve has reset itself, the message can't be passed
 Valproate may also have an effect on GABA (the brain’s natural calmer). Valproate blocks
the GABA-T enzyme that breaks down GABA. This means that the effect of GABA is boosted
as there is more of it because less is broken down.
Carbamazepine (e.g. Tegretol®)
 This may have an effect on ‘kindling’, which makes sure that minor brain messages do not
get passed around in the brain, so only proper ones get through
 GABA is the brain’s main calming transmitter. Carbamazepine may also boost the effect of
GABA in the brain.
Lamotrigine (e.g. Lamictal®)
 Lamotrigine helps epilepsy by stopping sodium entering the nerve endings. This helps stop
too many random messages being passed and stabilises the brain
 It seems to be that lamotrigine may reduce the amount of glutamate in the brain.
Glutamate ‘excites’ the brain and so it may work by helping to calm the brain down (or get
it less ‘excited’) and make it more stable
 We don’t really know how lamotrigine helps stop bipolar depression coming back
Quetiapine (e.g. Seroquel and Seroquel XL®)
 Quetiapine helps reduce the symptoms of mania and helps stop it coming back
 It may do this in the same way that quetiapine reduces psychosis, by blocking dopamine
receptors in the brain
 We don’t really know how it works to help stop bipolar depression coming back. Quetiapine
has an effect on some serotonin receptors so it may work via these.
Olanzapine (e.g. Zyprexa®)
 Olanzapine helps reduce the symptoms of mania and helps stop it coming back
 It may do this in the same way that olanzapine reduces psychosis, by blocking dopamine
receptors in the brain
 We don’t really know quite how it works for bipolar depression.
Aripiprazole (e.g. Abilify®)
 Aripiprazole helps reduce the symptoms of mania and helps stop it coming back
 Aripiprazole may do this in the same way as it does for psychosis, by regulating dopamine
receptors so they don’t over-heat
 We don’t think it helps bipolar depression.
http://www.choiceandmedication.org/nsft
g. Some key facts about mood stabilisers
 The symptoms of bipolar might be caused by an imbalance of some chemicals in the brain
 Mood stabilisers can help correct any such imbalances in the brain
 Mood stabilisers do not work as tranquillisers, sedatives (although they can have some
calming effects, especially in mania) nor stimulants
 They do not work by altering your personality
 They are not addictive, not abused for their mood stabilising effects 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
 Taking mood stabilisers reliably for many years has been shown to reduce relapses and the
harm that can cause.
http://www.choiceandmedication.org/nsft
Section two – how we think antipsychotics work
a.
How we think the symptoms of psychosis happen
People with psychosis have problems with seeing things that aren’t there, hearing voices,
imagining things, and having terrifying thoughts. Psychosis can be a symptom of many
conditions e.g. schizophrenia, depression, anxiety and bipolar disorder.
The main theory about why this happens is the so-called ‘Dopamine Hypothesis’. Dopamine in
the brain helps you focus on things and trying to make sense of them. It then decides what is
important and what isn’t, and what to do about it. If it is overactive you can start to
concentrate more on something that might be a danger. Things become over-important and
more threatening. For example, seeing and hearing things that aren’t there (and thus thinking
they come from somewhere e.g. television, radio), imagining too much and misinterpreting
thoughts. You might start to think that the eyes on statues or paintings are following you
around.
Some of the reasons we know this are that:
 If you give a person a drug that increases the level or activity of dopamine in the brain, it
can produce the symptoms of psychosis. For example, amphetamines (‘Speed’), cannabis
and levodopa (used to treat Parkinson’s Disease) can sometimes do this
 If you reduce the level or activity of dopamine, it reduces the symptoms of psychosis
 People with psychosis have been shown to have more dopamine activity in their brain.
‘Normal’ communication
‘Excess’ communication e.g. as in psychosis
There are lots of other theories about the cause of schizophrenia e.g. genetics, stresses and
how the brain develops. There may in fact be many causes and in each person there may be a
combination of these. Apart from dopamine, other transmitters are probably also involved. It
might be that too much glutamate is the cause of the dopamine system becoming overactive.
http://www.choiceandmedication.org/nsft
a.
How we think the symptoms of psychosis happen (part 2)
This section is a bit complex. You may want to miss this at the moment and come back to it later. It is also an
attempt to explain something very complex in a simple way.
There is possibly a series of events that can lead to schizophrenia:
1. Someone may be born with a dopamine system in the brain that is a bit too overactive. Or may become
overactive as the brain develops or if things happen to it
2. The person may then come under stress and/or have a trigger. There are many things in the person’s
environment that cause stress (and who grows up without any stress?). These might include social isolation,
discrimination, moving to an inner city area with loss of friends or social support that can increase stress and
dopamine. There may then be a trigger e.g. an event of isolation, stress, drugs
3. That stress causes the dopamine system to become more active
4. That increases dopamine in the brain, which can then lead to psychosis
5. That psychosis increases stress and upset
6. That stress increases dopamine levels
7. And then you start again at (4) above.
How therapies may help
 Antipsychotics can help by reducing the effects of more dopamine in the brain. This might help stop
schizophrenia in the first place. It can also help reduce the symptoms when they are in full swing or when
they are not caused by schizophrenia.
 Talking Therapies can help the person cope with the stresses they may come under. This may reduce the
dopamine increase.
 Support can help reduce the stresses as well.
http://www.choiceandmedication.org/nsft
b. How we think antipsychotics work
We know that too much dopamine can produce the symptoms of psychosis. Thus, correcting
the effect of having too much dopamine should help to reduce the symptoms. One way of
doing this is the block dopamine receptors i.e. jam some of them up so they don’t work and
can’t pass too many messages. This is what antipsychotics do.
Normal nerve activity
Increased activity due to extra dopamine being released. We don’t
know for sure why this happens.
More dopamine hitting dopamine receptors means more and
stronger messages. This can mean parts of the brain become
overactive, which is where the psychosis comes from.
01e05
b
4i
Antipsychotics block dopamine receptors. This is a bit like putting
the wrong Yale key into a Yale lock – it goes in, doesn’t have any
effect and stops the proper key going in.
4ja
When the next over-excited message arrives it can’t hit all the
receptors because some are blocked.
4ka
Dopamine hits fewer receptors.
5cd
The result is not such an over-excited message, the brain is calmer
and the symptoms caused by too much dopamine are reduced. It
doesn’t cure anything but can help you live with it.
The important thing to remember is that antipsychotics probably mainly work by reducing the
effect of having too much dopamine. They are NOT TRANQUILLISERS, although they may
help you to feel calmer. They have a much more specific way of working than just sedating
you.
http://www.choiceandmedication.org/nsft
c. How we think that aripiprazole works
Aripiprazole seems to work in a slightly different way to other antipsychotics.
What it does the same as other antipsychotics:
 Aripiprazole blocks dopamine receptors and stops the excess dopamine over-stimulating
your brain
 This reduces the symptoms caused by this excess dopamine e.g. hallucinations, being
paranoid.
What it does differently:
 Aripiprazole blocks the receptors but at the same time partly stimulates or boosts them
 This is a bit like a key going into a lock and jamming it but also allowing the door to open a
little bit, allowing some messages to get through, but not too many
 It boosts the receptors up to about 30% (about a third) of normal.
What this means:
 Aripiprazole acts more like a regulator of dopamine
 It doesn’t have the same side effects as the other antipsychotics of just blocking dopamine
e.g. feeling sleepy, muscle stiffness and increased prolactin
 It can be quite a jolt to your brain when starting so it is always best to start slowly e.g. 5mg
or 10mg a day
 Aripiprazole seems to suit some people and not others.
http://www.choiceandmedication.org/nsft
d. How and why you can get side effects from antipsychotics
As we have seen, antipsychotics block dopamine receptors. They do this by fitting into the
receptor usually reserved for dopamine. When dopamine comes along, it cannot fit into the
receptor and cannot pass the message. It is a bit like putting the wrong Yale key into a Yale
lock. You can get the key in, but it doesn’t have any effect and stops the proper key going in.
Although antipsychotics mainly block dopamine receptors, they also affect other transmitter
systems e.g. acetylcholine, serotonin and histamine.
Dopamine:
 If a medicine blocks the effect of dopamine on some dopamine receptors in the area that
controls perceptions this can help reduce the symptoms caused by too much dopamine e.g.
delusions and hallucinations
 However, some antipsychotics block dopamine receptors in other parts of the brain as well
 If it blocks dopamine in the part of the brain that controls muscle tension this upsets your
muscle control, a bit like Parkinson’s disease, and you can get muscle stiffness and mild
shaking
 If it blocks dopamine in the part of the brain that controls a hormone called prolactin, then
more prolactin is released which confuses the body e.g. periods may stop or be irregular,
breasts produce milk.
Serotonin:
 If you block some serotonin receptors, it may have an effect on your appetite (making you
feel hungrier, less full when you’ve eaten) and hence weight gain can occur.
Noradrenaline:
 If a medicine blocks the effect of noradrenaline then this can sometimes upset your blood
pressure e.g. you may feel dizzy when you stand up quickly.
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
chlorpheniramine, Piriton® or dexchlorpheniramine) or promethazine (Phenergan®) for hay
fever or allergy. The newer antihistamines such as cetirizine don’t get into the brain so don’t
make you feel sleepy
 In the body histamine increases inflammation and allergy
 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.
It may also of course be that some of these other transmitter effects may actually help produce
a better effect or be part of how they work. However, no one has yet made a drug that has no
effect on dopamine but still helps psychosis in humans.
http://www.choiceandmedication.org/nsft
e. Some key facts about antipsychotics
 The symptoms of psychosis are probably caused by too much dopamine activity in the brain
 This produces overactivity in the part of the brain that controls seeing, hearing, and
imagining
 Symptoms of some other conditions also seem to be at least partly caused by extra
dopamine. Antipsychotics can help manage e.g. bipolar mood disorder (especially mania),
depression, personality disorders, poor sleep, aggression, some symptoms of dementia,
self-injurious behaviour, tics, Tourette’s Syndrome and ADHD
 Antipsychotics help reduce the effects of having too much dopamine
 Antipsychotics are not tranquillisers, although they may help you feel calmer
 They do not directly alter personality
 They are not addictive and are not habit forming, but if you stop taking them suddenly the
symptoms could come back
 They do not appear to lose their effect if you keep taking them
 If you stop antipsychotics, your symptoms may not return again for several months (and
indeed you may even feel better for a while) but may then come back again after three to
six months
 If you do become unwell again even when taking an antipsychotic, you will not be as unwell
as if you had not been taking one at all.
http://www.choiceandmedication.org/nsft
Section two – how we think medicines for anxiety work
a. How we think the symptoms of anxiety happen
People with anxiety can have a variety of symptoms. These can be divided into two main
groups; ‘psychological’ and ‘physical’:
 Psychological symptoms include fear, being irritable, not being able to concentrate, feeling
restless, being sensitive to noise, disturbed sleep (e.g. waking during the night, unpleasant
dreams) and poor memory (usually due to poor concentration)
 Physical symptoms are mainly due to increased muscle tension e.g. problems with the
stomach and guts (passing wind, loose bowels etc.), ‘central’ (blurred vision, dizziness, loss
of libido), breathing problems (tight chest, difficulty breathing), heart changes (palpitations,
heart pain, missed beats), tension (headache, tremor) and panic attacks (sudden episodes of
extreme anxiety/apprehension).
This is due to over-activity in several parts of the brain, often caused by some external pressure
or reason, and your brain’s reaction to this.
‘Normal’ communication
01e4
‘Excess’ communication e.g. as in anxiety
The transmitters involved include:
 GABA – this is the main calming transmitter. It may be less active and so the brain is
missing some of its natural calming systems
 Noradrenaline – this is generally an exciter transmitter. It may be overactive or underactive
in the wrong places
 Serotonin – this may be underactive in some parts of the brain
 Glutamate – this brain exciter may be over-exciting the brain
 GABA – this is the brain’s natural calmer, but may not be active enough.
http://www.choiceandmedication.org/nsft
b. How we think the benzodiazepine anxiolytics work
The benzodiazepine anxiolytics include lorazepam, diazepam, chlordiazepoxide, oxazepam and many more.
GABA is the brain’s natural calming agent. It acts as a ‘brake’ in the brain and keeps its activity
in check. When you are over-anxious, it may be that boosting the effects of GABA will help the
brain to calm down. Medicines such as the benzodiazepines work by boosting the calming
effects of GABA. This helps reduce the number of ‘worrying’ or stimulating messages being
passed. The benzodiazepines block GABA into its receptors, so the receptors are active for
longer, and the brain’s natural calming messages are stronger.
Normal nerve activity
When the brain is aroused, worried or anxious there are stronger
or more messages from extra transmitters being released.
These extra messages will mean that your brain will become even
more stimulated and aroused. This will increase the amount of
transmitter released, which will stimulate your brain more. And so
it goes on, round and round.
5d
Part of the brain’s natural calming system is a network of nerves
that release calming GABA. The benzodiazepines and some similar
medicines (drawn as red L shapes) jam GABA into its receptor.
5e
This means that when your brain releases GABA and it hits the
receptor, GABA stays on the receptor for longer, so has a longer
and stronger calming action.
The important thing to remember is that anxiolytics mainly work by boosting the brain’s natural
calming agents. They are NOT TRANQUILLISERS, although they may help you to feel
calmer. They have a much more specific way of working than just sedating you.
Some benzodiazepines are also used for helping manage epilepsy, as pre-medication before
operations, muscle relaxants, and to help sleep. The effect they will have will partly depend on
the dose, when you take it (day or night) and how you take it (e.g. tablets, liquids, injection
etc).
http://www.choiceandmedication.org/nsft
c. How and why you can get side effects from benzodiazepines
As we have seen, benzodiazepines block GABA onto its receptors. GABA is widespread
throughout the brain, and so a few of their side effects are due to this more generalised
calming e.g. confusion, poor balance and feeling sleepy. It should be possible to reduce these
effects by getting the dose just right for you. Some of the benzodiazepines (e.g. diazepam and
chlordiazepoxide) hang around in the body for quite a long time (up to a day or even longer)
before the body removes them. This can lead to a long effect, which can feel a bit like a
hangover the next morning.
d. How we think other treatments for anxiety work
There are other ways help control symptoms of anxiety. We know that having low levels of
serotonin in the brain can make you more anxious. It may be that noradrenaline levels may be
high or low i.e. having high levels of noradrenaline in the brain may make you more anxious.
We also know that a little sedation can help ‘take the edge off’ your symptoms so you can get
them under control.
SSRIs (e.g. citalopram, escitalopram, fluoxetine, paroxetine, sertraline)
 SSRIs increase the amount of serotonin at nerve endings (see the section on depression to
see how this works)
 The SSRIs may help anxiety by boosting serotonin, which may be low.
Venlafaxine (e.g. Efexor XL®) and duloxetine (e.g. Cymbalta®)
 These increase the amount of serotonin at nerve endings (see the section on depression to
see how that works)
 They both also increase the amount of noradrenaline at nerve endings (the same way that
SSRIs do for serotonin)
 Duloxetine blocks the reuptake of both serotonin and noradrenaline at all doses
 Venlafaxine at doses up to about 150mg a day, this blocks the reuptake of serotonin. At
doses above about 150mg a day, venlafaxine blocks the reuptake of both serotonin and
noradrenaline.
Pregabalin (e.g. Lyrica®)
 Glutamate and noradrenaline are two of the alerting transmitters or messengers in the brain
 What we think happens is that pregabalin seems to attach itself to the calcium channels on
the synapses which use glutamate or noradrenaline
 This slows down the messages and takes the edge off them
 This helps stop some of the messages getting overactive or too alerting.
Antipsychotics
 Many antipsychotics seem to have a calming effect, partly by causing a little sleepiness
 They may also have a minor ‘tranquillising’ effect.
Buspirone
 Buspirone seems to have an effect on one type of serotonin receptor (the 5HT1A one if you
really want to know!)
 We’re not very sure how this helps anxiety but whatever it does it takes a long time to do it.
It usually needs at least 4 weeks at the full dose to work.
http://www.choiceandmedication.org/nsft
e. A summary of some other facts you may want to know
The benzodiazepines are often used as ‘first-aid’ for anxiety. They are very useful and proper
for this. It is, however, quite difficult to find out how well these medicines work over the
longer-term. This is because anxiety often varies for reasons other than medicines. For
example, external pressures, stress, illnesses or change over time. If you decide you would like
to take a benzodiazepine for longer than a few weeks, you should discuss this with your doctor.
Talk about the risks of taking a benzodiazepine, and the risks of not taking a benzodiazepine
e.g. are you likely to use other drugs such as alcohol to calm your nerves?
Some people can get some withdrawal effects if they stop benzodiazepines suddenly, so when
the time comes to stop, it is best to reduce the dose slowly.
 The symptoms of anxiety can be reduced by increasing the strength of the brain’s natural
calming messages
 Anxiolytics help by boosting the brain’s natural calming messages
 Anxiolytics are not tranquillisers although they may help you feel calmer
 They do not directly alter personality
 They are not necessarily addictive. It is best to stop them slowly if taken for more than
about a month. Seek advice about this
 They do not appear to lose their anxiolytic effect if you keep taking them.
http://www.choiceandmedication.org/nsft
Section two – how we think hypnotics work
‘Hypnotics’ is the word used for sleeping tablets or capsules or other medicines to aid sleep.
a. How we think insomnia and sleep problems happen
Insomnia is a problem with sleep e.g. lack of sleep, problems getting off the sleep, staying
asleep, waking early or if the sleep is not refreshing.
Insomnia is more often a symptom of a condition rather than an illness itself. It can be caused
by a variety of reasons e.g. external (e.g. noise, comfort, light) and internal (e.g. stress,
physical illness, drugs, overwork, worry).
The principles of sleep hygiene should always be used before trying medicines. These include:
1. Cut caffeine intake, especially within 3-6 hours of bedtime.
2. Have a warm milky drink at bedtime
3. Have some exercise and keep regular habits and routines
4. Reduced daytime sleeping
For the full list look at our Handy Fact sheet on insomnia and sleep hygiene on our website.
‘Normal’ communication
01e4
‘Excessive’ communication keeps you awake
moa-01e5e
The result is that the brain becomes overactive, messages are passed round and this keeps you
awake. This could be due to not enough of GABA (the calmer), too much glutamate (the
exciter), or too much noradrenaline or serotonin.
http://www.choiceandmedication.org/nsft
b. How we think the benzodiazepines and Z-hypnotics work
The benzodiazepine hypnotics include lorazepam, nitrazepam and temazepam.
The Z-hypnotics include zopiclone and zolpidem.
GABA is the brain’s natural calming agent. It acts as a ‘brake’ in the brain and keeps its activity
in check. When you are over-anxious, it may be that boosting the effects of GABA will help the
brain to calm down and get to sleep. Medicines such as the benzodiazepines (e.g. temazepam,
nitrazepam, lorazepam) and zopiclone (and zolpidem) work by boost the calming effects of
GABA. This helps reduce the number of ‘worrying’ messages being passed and allow you to get
off to sleep. The benzodiazepines jam GABA into its receptors, so the receptors are activated
for longer, and the brain’s natural calming messages are stronger.
Normal nerve activity
When the brain is aroused, worried or anxious there is increased
activity from extra transmitters being released.
These extra messages will mean that your brain will become even
more stimulated and aroused. This will increase the amount of
transmitter released, which will stimulate your brain more. And so it
goes on, round and round.
Part of the brain’s natural calming system is a network of nerves that
release calming GABA. The benzodiazepines and Z-hypnotics (drawn
as red L shapes) jam GABA into its receptor.
This means that when your brain releases GABA and it hits the
receptor, GABA stays on the receptor for longer, so has a longer and
stronger calming action. This then calms the brain down and helps
you get to sleep.
http://www.choiceandmedication.org/nsft
c. How and why you can get side effects from benzodiazepines and Zhypnotics
As we have seen, anxiolytics block GABA onto its receptors. GABA is widespread throughout the
brain, and so a few side effects are due to this more generalised calming e.g. confusion, poor
balance and feeling sleepy. It should be possible to reduce these effects by getting the dose
just right for you.
Some of the benzodiazepines (e.g. diazepam and chlordiazepoxide) hang around in the body
for quite a long time (up to a day or even longer) before the body removes them. This can lead
to side effects that can last a while, and can feel a bit like a hangover the next morning.
d. How we think other treatments for insomnia work
Melatonin (e.g. Circadin®)
 Melatonin is the brain’s messenger and starts the process of falling asleep. Melatonin is
produced by the pituitary gland in the brain after it gets dark and the brain decides it is
time to go to sleep
 Not enough melatonin and you may find it harder to fall asleep
 Taking extra melatonin by mouth at night or at bedtime can help boost what melatonin you
have
 By the way, back-lit flat LED screens (computers, TVs, iPads) produce a blue light that
makes it harder for the brain to produce the melatonin it needs to help you go to sleep.
Antipsychotics (e.g. pericyazine, olanzapine, quetiapine)
 Many antipsychotics seem to have a calming effect, partly by causing a little sleepiness.
 They may also have a minor ‘tranquillising’ or calming effect
 Some antipsychotics (especially quetiapine, olanzapine, clozapine) also block histamine
receptors and can cause sleepiness through this.
Mirtazapine (e.g. Zispin®)
 Mirtazapine increases the amount of both serotonin and noradrenaline at nerve endings
 It also has an effect on some histamine receptors. This means you can feel quite sleepy
when you start taking it, and can help you get to sleep.
Trazodone (e.g. Molipaxin®)
 Trazodone blocks the reuptake of serotonin, like the SSRIs. However, it also has an effect
on some other serotonin receptors, which may give different side effects
http://www.choiceandmedication.org/nsft
Promethazine and diphenhydramine
 Promethazine and diphenhydramine are antihistamines i.e. they blocks the effects of
histamine in the body and brain
 Histamine is produced by your brain to help keep you awake
 If a medicine blocks histamine in the brain, then this can make you feel sleepy
 This is the same effect as if you take one of the older antihistamines such as
chlorphenamine (also called 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.
Chloral hydrate and chloral betaine
 Chloral causes sedation across the whole brain so it makes it easier to fall off to sleep.
e. A summary of some other facts you may want to know
The benzodiazepines are often used as ‘first-aid’ for anxiety. They are very useful and proper
for this. It is, however, quite difficult to find out how well benzodiazepines and Z-hypnotics
work for insomnia over the longer-term. This is because sleep often varies for reasons other
than medicines. For example, external pressures, stress, or illness. If you decide you would like
to take a hypnotic for longer than a few weeks, you should discuss this with your doctor. Talk
about the risks of taking a benzodiazepine, and the risks of not taking a benzodiazepine e.g.
are you likely to use other drugs such as alcohol to help you sleep?
Some people can get some withdrawal effects if they stop benzodiazepines or Z-hypnotics
suddenly e.g. ‘rebound insomnia’. When the time comes to stop, it is best to reduce the dose
slowly.
 Some hypnotics help by boosting the brain’s natural calming messages
 By boosting the strength of the brain’s natural calming messages hypnotics can calm the
brain at night
 Other hypnotics block the brain’s natural alerting messages
 By blocking the strength of the brain’s alerting messages hypnotics can stop the brain
keeping you alert and awake at night
 They do not directly alter personality
 They are not necessarily addictive, although you might end up psychologically relying on
them to get you to sleep. It is best to stop them slowly if taken for more than about a
month. Seek advice about this.
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Section two – how we think medicines for dementia and
Alzheimer’s disease work
a. How we think the symptoms of dementia and Alzheimer’s Disease
happen
People with dementia (Alzheimer’s Disease is one of the dementias) can have a range of
symptoms such as:
 Loss of memory
 Finding it hard to do familiar tasks
 Problems with language and speaking
 Not knowing what time it is and where they are
 Problems with abstract thinking
 Losing things
 Changes in mood, behaviour and personality
 Finding it hard to start to do things or even wanting to.
Acetylcholine is the chemical messenger or transmitter for the brain cells in the brain that run
the memory systems e.g. putting memories down and getting them back. It seems that in
Alzheimer’s Disease the brain loses the cells and connections that use acetylcholine in the
memory parts of the brain.
‘Normal’ communication
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‘Less’ communication between cells e.g. as in Alzheimer’s Disease
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There are many other things that happen to the brain in Alzheimer’s Disease. However, it
seems that loss of acetylcholine is the main cause of the memory problems.
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b. How we think the anticholinesterases work for Alzheimer’s Disease
The anticholinesterases include donepezil, galantamine and rivastigmine.
The anticholinesterases are sometimes also called the cholinesterase inhibitors.
Some of the symptoms of Alzheimer’s Disease e.g. loss of memory, seem to be due to a loss of
acetylcholine in the brain. The main medicines for Alzheimer’s Disease stop the breakdown of
acetylcholine. This increases the amount and helps the brain make the best of what it has got.
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Normal nerve activity.
N.B. Acetylcholine doesn’t have a regular reuptake system so you can’t have
any SSRI-type drugs for Alzheimer’s Disease. What happens is that
acetylcholine is broken down by the enzymes and part of that is then taken
back up again.
Reduced acetylcholine nerve activity can happen in dementia.
If there is too little acetylcholine the brain finds it harder to find
the memories. So, boosting acetylcholine should help the brain
make the most of what acetylcholine it has got.
One way to do this is the block the breakdown of acetylcholine by
enzymes. This is what the anticholinesterases do. They block the
acetylcholine esterase enzyme that breaks down acetylcholine.
Ac
h3bc
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How this works is that the next message is downbeat as before.
Acetylcholine is released but the message is reduced in strength.
Ac
h3g
The anticholinesterase blocks the breakdown of the acetylcholine.
There is then some spare acetylcholine hanging around.
The next impulse that comes along releases acetylcholine as usual.
But it combines with the acetylcholine still hanging around from
last message because it wasn’t broken down.
The new message is thus stronger. Activity in that part of the
brain is increased. This doesn’t actually cure anything but it helps
make the most of what is there. It is possible that doing this may
slow down the speed of the decline in Alzheimer’s Disease.
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c. How we think memantine works for Alzheimer’s Disease
Some of the symptoms of Alzheimer’s Disease e.g. loss of memory, seem to be due to a loss of
acetylcholine in the brain. However, it seems that there may be too much glutamate (the
brain’s exciter transmitter). Too much glutamate at one of the receptors (the NMDA one) can
damage brain cells by over stimulating them and then killing them off.
Normal nerve activity
Increased activity due to extra glutamate being released. We don’t
know for sure why this happens but the result is stronger messages.
4i
More glutamate hitting glutamate receptors means stronger messages.
This can mean parts of the brain are overactive, which is where the
damage comes from.
4i
Memantine blocks glutamate receptors. This is a bit like putting the
wrong Yale key into a Yale lock – it goes in, doesn’t have any effect
and you can’t get it out again easily.
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When the next over-excited message arrives it can’t hit all the
receptors because some are blocked.
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Glutamate hits fewer receptors.
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The result is that the brain cell doesn’t get too over-stimulated and
doesn’t get damaged. It doesn’t cure anything but can help reduce the
symptoms and decline.
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d. How and why you can get side effects from the anticholinesterases
Many medicines can be a bit like ‘blunderbuss’ treatments i.e. they hit the part that seems to
be wrong, but also hit lots of other parts, which aren’t wrong. The side effects you get from
medicines are from these extra ‘hits’.
In the body, acetylcholine passes the messages that make muscles contract:
 Too much in the stomach and intestine and you will probably feel sick or be sick and/or
suffer from diarrhoea
 Too much in the bladder and you will have trouble with passing water
 Too much in the heart and it will beat slower.
e. How and why you can get side effects from memantine
Too much glutamate in some parts of the brain can excite neurones until they die. Memantine
can help reduce the effect of too much glutamate.
If

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memantine blocks glutamate in other areas of the brain it might cause:
Sleepiness (not enough stimulation)
Exhaustion (not enough stimulation)
Headache
Memantine is also related to LSD so some people can get hallucinations.
f. Some other facts you may want to know about medicines for
dementia and Alzheimer’s Disease
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Sadly, they don’t cure anything. They might slow down the speed of the decline in
Alzheimer’s Disease but don’t stop it
Some of the main symptoms of Alzheimer’s Disease may be caused by a lack of
acetylcholine in some parts of the brain
o Anticholinesterases help boost acetylcholine in the brain by blocking its breakdown
o They can help make the most of what the brain has got
o When stopped the brain tends to go down to where it would have been had an
anticholinesterase never been taken
Memantine can also help manage some of the disturbed symptoms
Both of these can help reduce the need for antipsychotics
The medicines not stimulants, not sedatives and not tranquillisers
They do not alter personality
They are not addictive and are not habit forming.
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Section two – how we think medicines work for ADHD
a. How we think the symptoms of ADHD (Attention Deficit Hyperactivity
Disorder) happen
Dopamine and noradrenaline are two of the many chemical messengers in the brain. They play
a part in controlling concentration and reward. It seems that too little activity from dopamine
(and possibly noradrenaline) in some parts of the brain can mean the brain can’t focus on
anything and doesn’t feel calm.
‘Normal’ communication between cells
‘Less’ communication between cells e.g. as in ADHD
Not enough dopamine in the reward parts of the brain mean the brain may often be looking for
something exciting to boost dopamine (and noradrenaline) to make it feel normal. This can lead
to the symptoms of ADHD such as being easily distracted, impulsive, taking risks, smoking and
reward seeking.
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b. How we think the stimulant treatments work for ADHD
The stimulants include methylphenidate, dexamphetamine/dexamfetamine and lisdexamfetamine.
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Normal nerve activity
Too little activity in some parts of the brain e.g. the parts that help
it to concentrate, can mean the brain can’t focus on anything. It
seems that can also mean that the brain is constantly searching for
something exciting to boost dopamine and noradrenaline.
One way to help the brain is to block the reuptake (recycling) of
dopamine (or noradrenaline)
This is what the stimulants do. If the recycling is blocked it boosts
the amount of dopamine and noradrenaline.
Dexamfetamine (and lisdexamfetamine) may also increase the
amount of dopamine released.
How this works is that the next message is downbeat as before.
Dopamine and noradrenaline is released but is boosted by some
dopamine and noradrenaline left over from the previous message.
The message is thus stronger. By boosting dopamine and
noradrenaline this helps the brain feel more normal and helps it
concentrate.
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c. How and why you can get side effects from the stimulants
Not enough dopamine in some parts of the brain might lead to some of the symptoms of
ADHD. The stimulants help correct this. However, too much dopamine in other parts of the
brain might cause:
Stimulant effects:
 Reduced appetite (Anorexia)
 Aggression
 Poor sleep
 Feeling nervous.
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d. How we think atomoxetine works
Noradrenaline is vital in the areas of the brain that control or regulate attention, concentration,
mood and thinking. Atomoxetine increases the amount of this noradrenaline, which increases
attention and decreases impulsiveness and hyperactivity in people with ADHD. This effect on
noradrenaline can also boost dopamine, which might be lacking in ADHD. An important thing to
remember is that atomoxetine is NOT a stimulant.
01e4
Normal nerve activity
Too little noradrenaline activity in some parts of the brain e.g. the
parts that help it to concentrate, can mean the brain can’t focus on
anything. It seems that can also mean that the brain is constantly
searching for something exciting to boost it.
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One way to help the brain is to block the reuptake (recycling) of
noradrenaline. Increasing noradrenaline can also help increase
dopamine.
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This is what atomoxetine does. It blocks the reuptake of
noradrenaline. How this works is that the next message is
downbeat as before.
02f
The message arrives and noradrenaline is released.
This is boosted by some noradrenaline left over from the previous
message and from some stimulation of noradrenaline receptors.
More activity means more or stronger messages being passed. This
boosts noradrenaline, which in turn can boost dopamine (but not
enough to risk any abuse).
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Boosting noradrenaline and dopamine helps the brain feel more
normal and helps it concentrate.
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e. How and why you can get side effects from atomoxetine
Atomoxetine increases the amount of noradrenaline in the brain, and also some serotonin and
dopamine, which can help the symptoms.
Noradrenaline can be quite activating, including on the heart, and can lead to:
 Increased heart rate (although nearly all of the noradrenaline increase occurs in the brain)
 Loss of appetite (anorexia)
 Poor sleep
Too much serotonin can lead to:
 Nausea and vomiting.
You might also get more (or less) side effects if one of your liver enzymes (the one called
CYP2D6) breaks down atomoxetine slower or faster than other people. Having a slow or fast
CYP2D6 enzyme doesn’t normally make any difference at all but it can do if you are taking a
drug broken down by this enzyme.
A slow CYP2D6 enzyme:
 Is not common but varies depending where your genes have come from
 Occurs in about 2% (1 in 50) Turkish people, about 9% (1 in 11) white British Caucasians
(9%) through to 19% (1 in 5) black South Africans
 Will mean that your body will not break down atomoxetine as well, so you get higher levels
in the body for the same dose. This can lead to more side effects.
An ultra-fast CYP2D6 enzyme:
 Is generally even rarer but also varies depending where your genes have come from
 Occurs in about 1% (1 in 100) white British Caucasians, about 10% (1 in 10) Spanish
people through to about 30% (1 in 3) of Ethiopians
 Will breaks down atomoxetine really quickly and you get few side effects, but little effect.
f. Some other facts you may want to know about medicines for ADHD
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Drugs don’t cure ADHD but can help even out the balance of chemicals in the brain and
allow the person to concentrate and help school, work and driving
They do not increase the chances of someone abusing drugs later on. The opposite seems
to be true as it decreases the need for people with ADHD to self-medicate or treat
themselves with stimulants, cannabis etc
They do not seem to lose their effect, as long as you keep taking them. Younger people
may need higher doses as they get older and bigger
There are no known long-term side effects
Stimulants can be stopped and restarted
No one actually wants to give medicines to younger people if they are not needed but
younger people who have ADHD can be held back by their symptoms. This can have a lifelong effect on school, qualification, social skills and jobs. If ADHD medicines can help a
person get as good an education as possible that is good. The effects of a poor education
last a life-time.
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Section three – the wider picture
3.1 Tolerance, dependence and addiction
It is a common fear that many medicines used in mental health conditions are ‘addictive’. This
is not the case but is quite rightly a major concern for many people. This section will hopefully
explain why many of the medicines used in mental health care are not addictive.
If a medicine is addictive, or produce dependence, it will have at least four main features:
1. Tolerance: Do people need more of the drug to get the same effect?
2. Dependence: Do people crave or desire the drug?
3. Addiction: Do people get withdrawal symptoms if they stop the drug suddenly?
4. Reward: Does the drug give a reward or buzz within about an hour of being taken?
These come from the World Health Organisation (WHO). If we list some drugs that have an
effect the brain and look at these features we can see some differences:
Craving
Do people crave
or desire the
drug?
Alcohol
Caffeine
Amphetamines
Tolerance
Do people need
more of the
drug to get the
same effect?
Yes
Yes
Yes
Smoking
Yes
Yes
Cannabis
Yes
Yes
Cocaine
Yes
Yes
Heroin and
other opiates
Sleeping tablets
Yes
Yes
Sometimes
Sometimes
Benzodiazepines
Sometimes
Antidepressants
In about 1 in
20 people
Sometimes but
not always
No
Antipsychotics
No
No
Lithium
No
No
Yes
Yes
Yes
Addiction
Do people get
withdrawal symptoms if
they stop the drug
suddenly?
Yes e.g. ‘DTs’
Yes e.g. headaches
Yes e.g. tiredness, vivid
dreams
Yes e.g. anxiety, being
grumpy and hungry
Usually only after high
doses for a long time
Yes e.g. ‘the crash’,
depression, tiredness
Yes e.g. ‘cold turkey’
Reward
Does the drug give a
reward within about an
hour or so?
Sometimes e.g.
‘rebound’ insomnia
Sometimes (about 1 in
3 people)
Sometimes, but not
usually if done
gradually
Sometimes, but not if
done gradually
Not if done slowly over
4-12 weeks
Yes e.g. ‘rebound
hypertension’
The ‘reward’ is falling
asleep
Can be a reward of
sedation and calming
No
Medicines for
No
No
high blood
pressure
No
Yes
No
Chocolate *
* OK, chocolate isn’t a drug but lots of people say they are ‘addicted’ to it!
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Yes - reward
Yes - reward
Yes – quick reward
Yes – very quick reward
Yes – very quick reward
Yes – very quick reward
Yes – very quick reward
No, although there can
be some calming effect
No
No
Yes
If we look at this in a bit more detail:
1. Tolerance: i.e. the person gets used to an effect. For example if we live near a busy road
and get used to the sounds of cars, or we become less aware of physical sensations e.g.
contact lenses, a watch etc. Tolerance to a drug means that the person needs an ever
higher dose to get the same effect e.g. we may become tolerant to the sedative effects of a
drug.
2. Dependence: e.g. desire or craving. The person will crave another dose of the drug when
the previous one is wearing, or has worn, off.
3. Addiction: Withdrawal symptoms start when the drug wears off and go when the next
dose is taken. These must be a specific set of symptoms which are linked to that particular
drug.
4. Reward: A drug must have a reward or immediate effect. This effect usually has to happen
within an hour or so of taking something. If not, you can’t make the link between the drug
and the effect. If you get a buzz it reinforces the reward. It may seem a little obvious but it
is hard to be addicted to a drug if you don’t know you’ve taken it. The longer the gap
between taking something and the reward also means it is trickier to get the dose right.
As you can see, generally speaking:
 The known drugs of abuse are taken for their immediate effect and reward, but produce
craving, withdrawal symptoms and tolerance to their desired actions
 Just because a drug has withdrawal symptoms doesn’t mean it is addictive. If you suddenly
stop medicines for high blood pressure your blood pressure can suddenly shoot up
dangerously. Some treatments for stomach ulcers can have withdrawal symptoms
 Most prescribed mental health medicines do not cause craving, have no significant
withdrawal symptoms (with a few notable exceptions) and no tolerance to the desired
effects are seen
 Most of the mental health medicines are helping symptoms by correcting a known chemical
imbalance in the brain that causes the symptoms.
Regardless of this, we think that all medicines should, where possible, be started slowly and
stopped gradually or slowly. If you take anything important away from anyone suddenly, they
will feel strange for a while. Imagine suddenly not having your music, iPad, mobile phone,
computer, television, or family and friends? It’s a bit like stopping a car without your seat belt
on – you can do it quickly but it hurts. It’s much safer and more comfortable to slow down
gradually.
It is interesting that most ‘addictive’ drugs in the table increase the amount of dopamine in the
brain’s mesolimbic area. This part of the brain has the ‘reward’ or ‘pleasure’ centres:
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Opiates e.g. heroin, morphine, methadone – these stimulate opiate receptors, which
releases dopamine in the reward system
Cocaine - blocks the reuptake of dopamine in reward system
Nicotine - increases dopamine in parts of reward system by up to 8 times
Cannabis - stimulates cannabis receptors, which release dopamine in reward system
Amphetamines - release dopamine from nerve endings and directly stimulate dopamine
receptors in the reward system
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Alcohol has many effects across the whole brain e.g. reduces the effect of glutamate (the
exciting transmitter) and increases GABA (the calming transmitter) but also increases
dopamine in the reward centres
Caffeine blocks adenosine (another chemical transmitter in the brain – adenosine is a
calming transmitter) which boosts dopamine release
LSD and Ecstasy probably both stimulate or boost some serotonin receptors in the brain.
None of the usual medicines used in mental health care (such as antidepressants) release
dopamine in the mesolimbic system, so lack the ‘reward’ that the classic addictive drugs do.
The exception would be stimulants to treat hyperactivity, which are related to amphetamines.
In fact, antipsychotics block the effects of dopamine.
Many thanks to all the people and organisations who have helped over the years and continue to
help me try to get my head round …er… my head. This includes the College of Mental Health
Pharmacy, the British Association for Psychopharmacology and the speakers at the many
conferences I have been lucky enough to be invited to and to attend.
Stephen Bazire
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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