lecture 4- serotonin, mood and depression Flashcards
where does the main serotonergic system originate in the brainstem?
the raphe nuclei
state- serotonergic axons project very widely throughout the brain
what does serotonin play a role in?
serotonin plays a role in mood, memory, sleep, appetite, pain perception &
temperature regulation.
the serotonergic neuron
tryptophan =>5-HTP => 5HT
Serotonin (5-HT ) is synthesized from tryptophan (dietary amino acid) & stored
in vesicles
- After release into synapse, serotonin engages with receptors on receiving (post-
synaptic) neuron - Serotonin is removed from synapse by reuptake transporters on pre- synaptic neuron
serotonin =
serotonin = 5-hydroxytryptamine = 5-HT
what is 5-HT synthesized from?
5-HT is synthesized from tryptophan by two enzymes
tryptophan => 5-HTP (5-hydroxytryptopham) => 5-HT
acute tryptophan depletion (ATD)
- ATD is an experimental procedure used to reduce levels of serotonin in the brain.
- 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.
- The reduced availability of tryptophan then leads to reduced serotonin synthesis in brain.
- The physiological effects are maximal after ~ 5 hours.
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):
– associated with positive mood (also, reduced irritability & aggression) in some
healthy participants & those with history of mood disorders
state- 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)
drugs that increase serotonergic activity:
- buspirone
- SSRI antidepressants
Buspirone –
- direct 5-HT receptor agonist
- mainly used to reduce anxiety, sometimes for treatment of depression
ssris antidepressants
- 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 disorders
SSRI antidepressants –
- inhibit 5-HT reuptake from synapse
- seven different SSRIs currently available in UK
- e.g. fluoxetine (= Prozac, 1986), sertraline (= Zoloft, 1991), paroxetine (= Seroxat, 1992), citalopram (= Cipramil, 1998)
stahl (2000)
- Effects of two different SSRIs on Hamilton Depression Rating scores in randomized, double-blind, placebo-controlled study of 316 patients with major depressive disorder –
- sertraline v. placebo: p < .05 at
weeks 12, 20 & 24 - citalopram v. placebo: p < .01 at
weeks 4 to 24 - stahl (2000) Placebo-controlled comparison of the selective serotonin reuptake inhibitors citalopram and sertraline. Biological Psychiatry 48, 894-901.
Debate over efficacy & side effects
- Cipriani et al., 2018, The
Lancet Link
– 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 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 psychoactive substances? (e.g. Moncrieff, World Psychiatry, 2015)
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.
knutson et al. (1998)
Effects of 20mg/day SSRI (paroxetine) in normal volunteers –
Self-rated hostility
(p < .05 at 1 and 4 weeks)
Self-rated hostility
(p < .05 at 1 and 4 weeks)
- Co-operative behaviour scores
were assigned from a two-person
problem-solving task - 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
Serotonin & impulsive aggression
- The 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 effect of SSRIs on moral judgement- crockett et al (2010)
moral dilemmas- trolley problems- a) push the switch, so one person dies instead of five
b) push the man, so one person dies instead of 5
- 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.
- 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.
serotonin and facial expression processing
- Acute 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)
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.
cognitive biases in depression cont
- 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) found effects of taking Citalopram, versus placebo, after 7 days:
decreases in…
- 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) (in healthy participants)
memory for emotional words: harmer et al (2009)
- 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).
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.
