4- serotonin, mood and depression

Question 1

serotonergic systems
-where do they originate
-serotonergic axons
-what does it play a role in

Answer 1

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.

Question 2

the serotonergic neuron
-synthesis by
-after release into synapse
-removed from synapse by

Answer 2

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

Question 3

how is 5HT synthesised by tryptophan?

Answer 3

serotonin = 5-hydroxytryptamine = 5-HT

5HT is synthesised from tryptophan by two enzymes

tryptophan (from diet) — 5HTP —- 5HT

Question 4

what is Acute Tryptophan depletion (ATD)

Answer 4

ATD is an experimental procedure used to reduce levels of
serotonin in the brain.

Question 5

How is ATD carried out

Answer 5

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.

Question 6

what is the result of acute tryptophan depletion

Answer 6

The reduced availability of tryptophan then leads to reduced
serotonin synthesis in brain.

-physiological effects are maximal after 5 hours

Question 7

tryptophan manipulations and mood
-tryptophan depletion (ATD)

Answer 7

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)

Question 8

Tryptophan supplementation (increased serotonin)
-affect on mood

Answer 8

Tryptophan supplementation (increased serotonin):

– associated with positive mood (also, reduced irritability & aggression) in some healthy participants & those with history of mood disorders

Question 9

tryptophan manipulations and mood
- in depletion and supplementation the effects ….

Answer 9

-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)

Question 10

what drugs increase serotonergic activity

Answer 10

-buspirone
-SSRI antidepressants

Question 11

How does buspirone increase serotonergic activity

Answer 11

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

Question 12

how do SSRI (selective serotonin reuptake inhibitor) antidepressants increase serotonergic activity
-types

Answer 12

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

Question 13

SSRI antidepressants- how do they work

Answer 13

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

Question 14

Stahl (2000). Placebo-controlled comparison of the selective serotonin reuptake inhibitors citalopram and sertraline
results

Answer 14

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

Question 15

debate over efficacy and side effects
Cipriani et al., 2018, The
Lancet

Answer 15

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

Question 16

large ____ differences i response to SSRIS and a risk of…

Answer 16

Large individual differences in response to SSRIs, and a risk of
side effects (e.g. Moncrieff, Epidemiology & Psychiatric Sciences, 2019)

Question 17

do we know how well do placebo controls work when testing

Question 18

what are the effects of SSRIs in healthy (non depressed) subjects

Answer 18

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.

Question 19

effects of 20mg/ day SSRI (paroxetine) in normal volunteers (Knutson et al (1998)
-study

Answer 19

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

Question 20

what is the link between serotonin and impulsive agression

Answer 20

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)

Question 21

Acute effects of SSRIs on moral judgement
Crockett et al (2010) –
responses to moral dilemmas
(e.g. ‘trolley problems’)
describe the study

Answer 21

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

Question 22

Crockett et al (2010) –
responses to moral dilemmas
(e.g. ‘trolley problems’
results

Answer 22

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.

Question 23

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.

Answer 23

‘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

Question 24

Can the acute effects of SSRIs help
to explain the delayed clinical
effects?

Answer 24

-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

Question 25

what are the cognitive biases in depression

Answer 25

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.

Question 26

-what are negative ‘low level’ biases
-negative biases may contribute to risk of….
-cognitive biases are important therapeutic targets in..

Answer 26

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.

Question 27

processing of emotional facial expressions
-harmer et al 2006

Answer 27

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)

Question 28

memory for emotional words

Answer 28

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

Question 29

From acute cognitive effects to delayed therapeutic effects

Answer 29

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)]

Question 30

Converging effects of SSRI and cognitive
therapy

Answer 30

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