4- serotonin, mood and depression Flashcards
serotonergic systems
-where do they originate
-serotonergic axons
-what does it play a role in
The main serotonergic systems
originate in the brainstem:
Raphe nuclei.
- Serotonergic axons project
very widely throughout the
brain.
cell bodies very localised but effects are widely distributed - Serotonin plays a role in
mood, memory, sleep,
appetite, pain perception &
temperature regulation.
the serotonergic neuron
-synthesis by
-after release into synapse
-removed from synapse by
Serotonin (5-HT ) is
synthesized from tryptophan
(dietary amino acid (taken from what we eat)) & stored
in vesicles
(in 2 stages , converted from tryptophan to 5HTP to 5HT
- when action potential comes along, release into synapse,and after reease
serotonin engages with
receptors on receiving (post-
synaptic) neuron - Serotonin is removed from
synapse by reuptake
transporters on pre-
synaptic neuron
how is 5HT synthesised by tryptophan?
serotonin = 5-hydroxytryptamine = 5-HT
5HT is synthesised from tryptophan by two enzymes
tryptophan (from diet) — 5HTP —- 5HT
what is Acute Tryptophan depletion (ATD)
ATD is an experimental procedure used to reduce levels of
serotonin in the brain.
How is ATD carried out
deplete the precursor - hasn’t got enough building blocks
Participants follow low protein diet for ~24 hours & then ingest a
drink containing concentrated mixture of different amino acids, but no tryptophan.
- The body uses available amino acids to synthesize required
proteins & this uses up available tryptophan in body, since there was none in the drink - The reduced availability of tryptophan then leads to reduced
serotonin synthesis in brain. - The physiological effects are maximal after ~ 5 hours.
what is the result of acute tryptophan depletion
The reduced availability of tryptophan then leads to reduced
serotonin synthesis in brain.
-physiological effects are maximal after 5 hours
tryptophan manipulations and mood
-tryptophan depletion (ATD)
Tryptophan depletion (ATD) (reduced serotonin):
– associated with negative mood (also, increased irritability & aggression) in some healthy participants & those with history of mood disorders (incl. reappearance of symptoms)
Tryptophan supplementation (increased serotonin)
-affect on mood
Tryptophan supplementation (increased serotonin):
– associated with positive mood (also, reduced irritability & aggression) in some healthy participants & those with history of mood disorders
tryptophan manipulations and mood
- in depletion and supplementation the effects ….
-in both cases , these effects vary widely between individuals
-it is not yet well understood what differentiates those who respond and those who do not (poss. genetic factors)
what drugs increase serotonergic activity
-buspirone
-SSRI antidepressants
How does buspirone increase serotonergic activity
direct 5-HT receptor agonist
(acts directly on the receptors in post synaptic cell that would normally have serotonin bind with them and cause effects - buspirone is a similar enough shape
- mainly used to reduce anxiety, sometimes for treatment of
depression
how do SSRI (selective serotonin reuptake inhibitor) antidepressants increase serotonergic activity
-types
SSRI antidepressants –
* inhibit 5-HT reuptake from synapse
(serotonin gets released and act and then normally gets taken back up- but ssri inhibit the proteins that normally take it back uo- there is more of it left in the synapse
- seven different SSRIs currently available in UK
- e.g. fluoxetine (= Prozac, 1986), sertraline (= Zoloft, 1991),
paroxetine (= Seroxat, 1992), citalopram (= Cipramil, 1998
SSRI antidepressants- how do they work
SSRI = selective serotonin reuptake inhibitor
- Blocks reuptake of 5-HT, so concentration increases & more
receptors are activated - Most common drug treatment for major depressive illnesses;
also used to treat anxiety disorder
Stahl (2000). Placebo-controlled comparison of the selective serotonin reuptake inhibitors citalopram and sertraline
results
Effects of two different SSRIs on Hamilton Depression Rating scores
in randomized, double-blind, placebo-controlled study of 316 patients with major depressive disorder
-depression goes down after some time
-there is no condition where the drug wasn’t prescribed
debate over efficacy and side effects
Cipriani et al., 2018, The
Lancet
Large meta-analysis concluded
that antidepressants were more
effective than placebo in
placebo-controlled RCTs.
– Efficacy was scored as response
rate: number of patients with
>=50% reduction in depression
score using standard scale
large ____ differences i response to SSRIS and a risk of…
Large individual differences in response to SSRIs, and a risk of
side effects (e.g. Moncrieff, Epidemiology & Psychiatric Sciences, 2019)
do we know how well do placebo controls work when testing
what are the effects of SSRIs in healthy (non depressed) subjects
As with ATD, effects of SSRIs in non-depressed subjects are seen mainly in changes in subjective feelings of hostility, aggression & irritability.
- Compared to placebo, increasing levels of 5-HT with SSRIs in non-depressed subjects reduces reported hostility & irritability…
- …and increases social affiliation & co-operative
behaviours.
effects of 20mg/ day SSRI (paroxetine) in normal volunteers (Knutson et al (1998)
-study
Co-operative behaviour scores
were assigned from a two-person
problem-solving task (two people had to do this together
- In each pair, one participant had
placebo & one had SSRI - Behaviour filmed by hidden camera & video scorers blind to condition
- Participants given SSRI were scored significantly higher for co-operative
behaviour at one week
-people on ssri getting less hostile
-people on placebo getting more hostile
what is the link between serotonin and impulsive agression
he low serotonin hypothesis of impulsive (or reactive) aggression has a long history and is supported by studies carried out in humans & other animals (rats, monkeys)
- SSRIs are also commonly used to reduce levels of aggression in psychiatric conditions (e.g.
schizophrenia, bipolar disorder, borderline personality disorder)
Acute effects of SSRIs on moral judgement
Crockett et al (2010) –
responses to moral dilemmas
(e.g. ‘trolley problems’)
describe the study
study where they asked participants to respond to moral problems (a)push the switch , so one person dies instead of five etc)
b) push the man, so one person dies instead of five
double-blind, within-subjects
design with three conditions
(tested on three different days,
in counter-balanced order):
o placebo
o SSRI (citalopram)
o noradrenaline reuptake
inhibitor (atomoxetine, also
used as an antidepressant)
In each test session, 15 different moral dilemmas were
presented in text form, each ending with a question about carrying out a particular action (“Is it acceptable to…?”).
Response = press “Yes” or “No” key.
- A different (randomised) set of moral dilemmas were used
for each session, to avoid repetition effects
Crockett et al (2010) –
responses to moral dilemmas
(e.g. ‘trolley problems’
results
SSRI (citalopram) reduced acceptability of harming one
person to save many…
* …compared to both placebo and atomoxetine (with no significant difference between placebo and atomoxetine.
When participants were categorized into two groups based on a questionnaire measure of empathy, effect of SSRI was larger in the high
empathy group than in the low empathy group
* This suggests that individual differences in empathy and
‘harm aversion’ may also be
related to serotonin.
link between serotonin and facial expression processing
how does 5htp affect speed / accuracy of responses
[Harmer & Cowen (2013). “It’s the way that you look at it” – a cognitive neuropsychological account
of SSRI action in depression.
‘Identify emotion as
quickly as possible
(while intensity
increase’ shown images of people’s emotions
cute 5-HT manipulations affect speed & accuracy of responses:
– SSRI: enhances facial expression
recognition (particularly happiness),
without changing mood!! (see later…)
– ATD: impairs facial expression
recognition (particularly happiness
Can the acute effects of SSRIs help
to explain the delayed clinical
effects?
-the immediate affects
-since antidepressants take a while to kick in as they tell you
-why are the affects on mood taking weeks, where as the facial expression effect for example is rapid
what are the cognitive biases in depression
Memory – depressed subjects show superior memory for negative information (compared to positive or neutral) in broad range of tasks (autobiographical recall, memory
for word lists, implicit memory, etc.).
- Attention – e.g. depressed subjects take longer to name colours of negative words (e.g. lonely, hostile, useless)compared to positive words (e.g. lovely, honest, useful) in ‘emotional’ Stroop tasks.
- Facial expression processing – e.g. depressed subjects more likely to interpret neutral or ambiguous expressions as being negative.
-what are negative ‘low level’ biases
-negative biases may contribute to risk of….
-cognitive biases are important therapeutic targets in..
Negative ‘low-level’ (perceptual / attentional) cognitive biases are related to negative ‘high-level’ beliefs about self, world & others (Beck’s dysfunctional schemas).
- Negative cognitive biases may contribute to risk of developing depression and act to maintain a current depressed state.
- Cognitive biases are important therapeutic targets in cognitive therapies for mood disorders.
processing of emotional facial expressions
-harmer et al 2006
Harmer et al. (2006) found effects of taking Citalopram, versus placebo, after 7 days:
self-rated hostility perception & behaviour
amygdala response to fearful faces (implicit)
recognition of fearful faces (explicit)
- Importantly, these acute effects occur without any change
in subjective mood)
memory for emotional words
Harmer et al (2009) tested
incidental memory for words
presented in a categorization task
- Healthy comparison subjects
showed better recall for positive
(versus negative) words. Prior to
treatment, depressed patients did
not - Acute effect of antidepressant
(compared to placebo) in
depressed patients: significant
increase in recall of positive (but
not negative) words
From acute cognitive effects to delayed therapeutic effects
Changes in cognition and/or social behaviour may be the basis for antidepressant effects of SSRIs.
– It might be that SSRIs & other antidepressants do not affect
mood directly.
– Instead, they might change how the brain processes emotional
information by eliminating/reversing ‘low-level’ perceptual & cognitive biases
– Hence, they might provide a ‘bottom-up’ mechanism for changing ‘high-level’ dysfunctional thoughts & beliefs.
– This could explain the delay between physiological changes in
5-HT levels (within minutes or hours) & changes in self-reported
mood (after days or weeks of treatment). [See: Harmer & Cowen (2013), Warren et al (2015)]
Converging effects of SSRI and cognitive
therapy
Cognitive psychotherapy (e.g. CBT) takes a ‘top-down’
approach – aim is to teach ‘metacognitive skills’ for
identifying/modifying dysfunctional thoughts & beliefs
(called ‘negative schemata’ in CBT).
* Hence, combination therapy (antidepressant plus
psychotherapy) may be more effective than either on its own
