lecture 4- serotonin, mood and depression

Question 1

where does the main serotonergic system originate in the brainstem?

Answer 1

the raphe nuclei

Question 2

state- serotonergic axons project very widely throughout the brain

Question 3

what does serotonin play a role in?

Answer 3

serotonin plays a role in mood, memory, sleep, appetite, pain perception &
temperature regulation.

Question 4

the serotonergic neuron

Answer 4

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

Question 5

serotonin =

Answer 5

serotonin = 5-hydroxytryptamine = 5-HT

Question 6

what is 5-HT synthesized from?

Answer 6

5-HT is synthesized from tryptophan by two enzymes

tryptophan => 5-HTP (5-hydroxytryptopham) => 5-HT

Question 7

acute tryptophan depletion (ATD)

Answer 7

• 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.

Question 8

Tryptophan depletion (ATD) (reduced serotonin):

Answer 8

– associated with negative mood (also, increased irritability & aggression) in
some healthy participants & those with history of mood disorders (incl.
reappearance of symptoms)

Question 9

tryptophan supplementation (increased serotonin):

Answer 9

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

Question 10

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)

Question 11

drugs that increase serotonergic activity:

Answer 11

• buspirone
• SSRI antidepressants

Question 11

Buspirone –

Answer 11

• direct 5-HT receptor agonist
• mainly used to reduce anxiety, sometimes for treatment of depression

Question 12

ssris antidepressants

Answer 12

• 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

Question 12

SSRI antidepressants –

Answer 12

• 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)

Question 13

stahl (2000)

Answer 13

• 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.

Question 14

Debate over efficacy & side effects

Answer 14

• 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)

Question 15

effects of SSRIs in healthy (non-depressed) subjects

Answer 15

• 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 16

knutson et al. (1998)

Answer 16

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

Question 17

Serotonin & impulsive aggression

Answer 17

• 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)

Question 18

acute effect of SSRIs on moral judgement- crockett et al (2010)

Answer 18

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.

Question 19

serotonin and facial expression processing

Answer 19

• 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)

Question 20

cognitive biases in depression

Answer 20

• 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 21

cognitive biases in depression cont

Answer 21

• 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 22

processing of emotional facial expressions:

Answer 22

• 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)

Question 23

memory for emotional words: harmer et al (2009)

Answer 23

• 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 24

From acute cognitive effects to delayed
therapeutic effects

Answer 24

• 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).

Question 25

Converging effects of SSRI and cognitive
therapy

Answer 25

• 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.