Download Depression

Investigating ‘emotion’ in humans
and animals to develop new
treatments for mood disorders
Dr Emma Robinson
Senior Research Fellow and RCUK Academic Fellow
What are mood disorders?
These are psychiatric disorders involving a
change in mood that is NOT appropriate
to the situation i.e. pathological
Examples of psychiatric disorders where mood
changes are a common feature:
• Depression
• Anxiety disorders
• Bipolar disorder
• Substance abuse
• Schizophrenia
Sometimes referred to as ‘affective disorder’ or to
have an ‘affective component’
What is depression
• Depression is the most common mood disorder
• Currently affect 1 in 5 people and female > male
• 2nd highest cause of death amongst persons aged 20•
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35
Overall mortality ~15%
WHO predict the rise in depression will mean it is the
leading cause of disability adjusted life years
Major impact on quality of life and productivity
(particularly in knowledge-based society)
High rates of alcohol and substance misuse, impact on
relationships and productivity.
Depression can be mild, moderate or severe (major
depressive disorder)
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•
•
•
•
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•
Treatment is with antidepressant drugs (available since
1950s)
Approximately 30% of patients fail to respond
Depression often goes undiagnosed and untreated. (only
1/3 are being treated
Depression is episodic with untreated episodes lasting 6
– 24 months followed by recovery (6months+ of
remission) or remission (all symptoms gone).
Peak onset of age 20 – 40. 2x more likely in women.
(increased risk (6 months) following child birth)
Married males low than unmarried, married women
higher than unmarried.
Much higher rate of depression in developed versus nondeveloped countries.
What are the symptoms of
depression?
“Some people say that depression feels like a black curtain of despair coming
down over their lives. Many people feel like they have no energy and can't
concentrate. Others feel irritable all the time for no apparent reason. The
symptoms vary from person to person, but if you feel "down" for more than
two weeks, and these feelings are interfering with your daily life, you may be
clinically depressed.” Ref: www.depression.com
Symptoms
• rumination of negative thought
• constant feelings of sadness, irritability, or tension
• decreased interest or pleasure in usual activities or hobbies
• loss of energy, feeling tired despite lack of activity
• a change in appetite, with significant weight loss or weight gain
• a change in sleeping patterns, such as difficulty sleeping, early morning awakening,
or sleeping too much
• restlessness or feeling slowed down
• decreased ability to make decisions or concentrate
• feelings of worthlessness, hopelessness, or guilt
• thoughts of suicide or death
What is the cause of depression?
Little definitive evidence for the cause or treatment
of depression has been achieved but:
• Disease of brain chemistry
• Neurotransmitter systems in certain brain areas or
circuits are not functioning optimally resulting in the
development of depressive symptoms
• Psychological and medical treatments can benefit
patients
• Drug treatments have delayed onset of action and must
be used for a prolonged period after initial recovery
What is the cause of depression?
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Family history. Genetics play an important part in depression. It can run in families
for generations.
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Trauma and stress. Things like financial problems, the breakup of a relationship, or
the death of a loved one can bring on depression. You can become depressed after
changes in your life, like starting a new job, graduating from school, or getting
married.
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Negative emotional bias. People who have low self-esteem and a negative outlook
are at higher risk of becoming depressed. These traits may actually be caused by
low-level depression (called dysthymia).
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Physical conditions. Serious medical conditions like heart disease, cancer, and HIV
can contribute to depression, partly because of the physical weakness and stress
they bring on. Depression can make medical conditions worse, since it weakens the
immune system and can make pain harder to bear. In some cases, depression can
be caused by medications used to treat medical conditions.
Other psychological disorders. Anxiety disorders, eating disorders, schizophrenia,
and (especially) substance abuse often appear along with depression.
Biology of depression
Problems occur at the level of nerve to nerve
communication
Brain areas involved in emotion are affected
Changes in the neurotransmitter serotonin is
strongly linked with depression
Storage
Release
(exocytosis)
Sp
Me
t
Na+ Channels
eci abol
fic
i
enz sm
ym
es
Synthesis
Overview of neurotransmission
Ca++ Channels
-ve
-ve
-ve
Pre-synaptic autoreceptor
e.g. alpha2-AR
Reuptake
+ve
SYNAPSE
K+ Channels
Post-synaptic receptor
*Antidepressant drugs target the synapse
Treatments for depression (and anxiety)
Storage
Release
(exocytosis)
t
Me
Sp
Ca++ Channels
-ve
-ve
-ve
Pre-synaptic autoreceptor
e.g. alpha2-AR
+ve
Reuptake
Antidepressant drug examples:
Amitrityline (1950s)
Fluoxetine (1990s)
Moclobemide (1990s)
Mirtazapine (1990s)
Na+ Channels
eci abol
fic
i
enz sm
ym
es
Synthesis
Aim: to reverse the impairment in nerve to communication
How: use a drug* to increase the level of neurotransmitter available in
the brain
BUT
These treatments are effective in only 60-70% of patients
Don’t really know why this works
Action is delayed by 4-6 wks
K+ Channels
Post-synaptic receptor
*the term ‘drug’ describes any chemical that can alter biology and includes medicines, research drugs, natural products etc
Research into depression
Scientific need
• Major socio-economic problem due to lack of understanding of
cause and treatment approaches
e.g. Why do some people respond and others do not?
• What is the cause of depression?
e.g. Which parts of the brain are involved?
Which chemical system in the brain are key?
• Why do some people get depression but others do not
e.g. Role of genes and family history
Role for environmental factors such as stress
• Can treatment be improved?
e.g. Reduce time for medicine to work
Increase the % of patients in which the treatment works
• Government and EU priority area
What can we study?
• Normal people
• How does a normal brain control emotion?
• Can a normal person be made depressed by changing their brain
chemistry?
• Patients
• How do their brains and brain chemistry differ from normal people?
• What changes in response to treatment?
• What exactly is depression?
• Animal studies
• How does depression arise?
• Are there new targets within the brain where a drug might help to treat
depression?
• Is this target safe?
Depleting brain transmitters in normal
subjects
Tryptophan hydroxylase
Competition
by large neutral
amino acids
L-tryptophan
5-HT
Protein
L-tryptophan
5-HTP
Blood brain
barrier
Dietary tryptophan
A transient reduction in brain serotonin
induces a relapse in negative mood
Good
Normal
range
Mood
Depressed
-24h
0
Low
tryptophan
diet
Time
(hours)
5
Tryptophan
depletion
Normal diet
What methods are used to measure emotional
processing and mood in humans?
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Questionnaires
Visual analogue scales
Processing of emotional faces
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Facial morphs
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Attentional bias
Emotional stroop test
Emotional words
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Recall
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Homophone test
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Emotional go/no-go
Facial morphs
Studies using emotional words are used to reveal impairments
in emotional processing in depression
Left: Emotional words used
to assess categorisation
Right: Emotional Stroop
measure latency to complete
a word and uses colour as a
distracter and a mixture of
happy, sad or neutral words.
Left: Neuropsychological tests are
combined with brain imaging studies to
reveal which area of the brain is involved in
emotional behaviour.
Brain imaging studies reveal a biological
basis to depression
Using deep brain stimulation in
treatment resistant depression
Using animals to study depression
Why?
Many questions that arise from human studies and/or
other areas of research cannot be answered using
human subjects but require an intact behaving
animal
For example
• Understand the basic biology of emotional behaviour
• Understand how neurones communicate
• Understand how current drugs work and design better
ones
• Test how effective a new drug might be before testing in
patients
• Assess safety
Animal emotion: a philosophical conundrum
“Recent work in the area of ethics and animals suggests that it is philosophically
legitimate to ascribe emotions to nonhuman animals. Furthermore, it is
sometimes argued that emotionality is a morally relevant psychological state
shared by humans and nonhumans. What is missing from the philosophical
literature that makes reference to emotions in nonhuman animals is an attempt
to clarify and defend some particular account of the nature of emotion, and the
role that emotions play in a characterization of human nature. I argue in this
paper that some analyses of emotion are more credible than others. Because
this is so, the thesis that humans and nonhumans share emotions may well be
a more difficult case to make than has been recognized thus far.”
(Beth Dixon)
“While the study of emotion is a respectable field, those who work in it are usually
academic psychologists who confine their studies to human emotions. The
standard reference work, The Oxford Companion to Animal Behaviour, advises
animal behaviorists that "One is well advised to study the behaviour, rather
than attempting to get at any underlying emotion".
(Jeffrey Moussaieff Masson)
Animals and emotion
Primates show a broad range of emotions but do other animals?
Can other species e.g. rodents provide a model
for human emotion?
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Most laboratory research uses rodents
What can a rat (or mouse) tell us about emotional
behaviour and depression?


1.
Motivational changes
2.
Reward sensitivity
3.
Emotion-related behaviour ?
Nature 266, 730 - 732 (21 April 1977); doi:10.1038/266730a0
Depression: a new animal model sensitive to antidepressant
treatments
R. D. PORSOLT*, M. LE PICHON & M. JALFRE*
Animal models of emotion-related
behaviour (testing cognitive affective bias)
• Pigs, rats and birds have been shown to
respond to ambiguous information in a positive
or negative bias depending on their intrinsic
emotional state
• Rats show a disappointment effect when they
expect a certain value of outcome but do not
receive it
• Rats will show a memory bias for an event which
occurred during positive emotional stimulation
Emotional tone discrimination task: a test of cognitive affective bias
for rats and humans
Cue start of trial
(e.g. Light on)
Figure 1: Representation of the
human and rodent emotional
tone discrimination task.
Training using ‘pure’ +ve and
-ve tones. Intermediate probe
tones are used to test emotional
bias.
Positive cue
Probe trial
Negative cue
Time out
Probability of positive lever response
Reward
Random
Aversive
reinforcement
outcome
(Reward, Aversive event
or time out)
X = gradient (a measure
of ‘response bias’)
X
+ ve CAB
- ve CAB
+ ve Cue
- ve Cue
Probe trial range
Figure 2: Theoretical effect of
+ve and –ve affective bias on
response bias in the emotional
tone discrimination task
AVOID
aversive
outcome
References
• Lopez and Murray, (1998) The global burden of disease,
1990-2020. Nature medicine, 4, 1241-1243.
• Doris et al., (1999) Depressive illness. Lancet, 354,
1369-1375.
• Slattery et al., (2004) Invited review: the evolution of
antidepressant mechanisms. Fundamental Clinical
Pharmacology, 18, 1-21