1.2 Theories of depression (deel 2)

Question 1

Waar gaat artikel Moncrieff over?

Moncrieff at al. (2022)

Answer 1

• Serotonin theory
• Moncrieff vindt geen bewijs voor deze theorie als onderliggend aan depressie.

Question 2

Serotonin theory

Moncrieff at al. (2022)

Answer 2

Abnormalities in the brain chemicals (serotonin in this case) has an effect on depression, which justified the usage of antidepressants.

Question 3

What is another explanation for the effects of antidepressants?

Moncrieff at al. (2022)

Answer 3

• Placebo effect.
• Or their ability to blunt or limit emotions.

Question 4

What are 5 areas that support serotonin hypothesis

Moncrieff at al. (2022)

Uit eerdere onderzoeken, niet wat Moncrieff heeft gevonden

Answer 4

1. If there were lower levels of serotonin and serotonin metabolite (5-HIAA) in body fluids in depression.
2. If serotonin receptor levels were different in people with depression
3. If there were higher levels of serotonin transporter (SERT) in people with depression (low synaptic serotonin levels)
4. If a decrease in tryptophan (which lowers available serotonin) would trigger depression.
5. If there was an interaction between the SERT gene and stress in depression (SERT gene-environment interaction).

Question 5

Results

Serotonin and 5-HIAA

Moncrieff at al. (2022)

Answer 5

Serotonin is metabolized to 5-HIAA.

Serotoninlevels can be tested in: blood, plasma, urine and cerebrospinal fluid (ideal place to test, but risky).

No evidence of a link between 5-HIAA concentrations and depression was found

Antidepressants were linked to lower serotonin levels, whether person had or did not have depression.

Question 6

Results

Receptors (5-HT1A)

Moncrieff at al. (2022)

Answer 6

5-HT1A receptors decrease presynaptic release of serotonin.

Increased activity of 5-HT1A expected in people with depression.

Majority found no difference of 5-HT1A between people with/without depression, OR lower levels of 5-HT1A in people with depression
- A lower level would suggest there is a higher concentration of serotonin in people with depression.

Question 7

Serotonin transporter (SERT)

Moncrieff at al. (2022)

Answer 7

SERT transports serotonin out of synapse, decreasing its availability in this area.

SSRIs are assumed to work by inhibiting SERT, therefore increasing serotonin levels in the synapse.

The amount of SERT is expected to be higher in people with depression.

Reviews: antidepressants reduced SERT, depression is linked with high serotonin activity

Question 8

Depletion studies (tryptophan)

Moncrieff at al. (2022)

Answer 8

Decreased tryptophan assumed to decrease serotonin levels.

Lower mood was found after a decrease in tryptophan in people with depression.

Decrease in tryptophan didn’t affect individuals without depression.

Overall, mainly mixed results

Question 9

SERT gene and gene-stress interaction

Moncrieff at al. (2022)

Answer 9

Lower SERT level produces higher synaptic serotonin levels.

Depression might be triggered if the short version of SERT gene and stressful life event is present.

Early studies found interaction, however, recent high quality studies did not

Question 10

Overall results

Moncrieff at al. (2022)

5

Answer 10

1. No evidence of link between 5-HIAA concentrations and depression.
2. Higher concentration of serotonin in people with depression
3. Amount of SERT is expected to be higher in people with depression
4. Mixed results from depletion studies
5. Depression might be triggered if the short version of SERT gene and stressful life event is present, mixed results.

Question 11

Waar gaat artikel Jacobsen over?

Jacobsen (2023)

Answer 11

Kritiek op Moncrieff
- Factual errors of Moncrieff
- Selective quotes from cited literature
- Data is misinterpreted (SSRIs may decrease rather than increase serotonin)

Question 12

Further errors

5-HT1A receptors

Jacobsen (2023)

Answer 12

They suggest that a drop in 5-HT1A receptor in depression could mean more serotonin outside cells –> this is uncertain.

They state: that reduced 5-HT1A receptors after antidepressants might be the body’s response to lower serotonin, but little evidence to support this

Question 13

Further errors

Tryptophan

Jacobsen (2023)

Answer 13

They state: decrease tryptophan has little effect on mood for healthy people.

However, in people taking SSRIs, tryptophan decrease causes depression again, so high serotonin is crucial for continued antidepressant use.

They didn’t state results that were against their idea of high serotonin activity causing depression.

Question 14

Further errors

Reduces plasma

Jacobsen (2023)

Answer 14

They mention that reduced plasma serotonin after SSRI usage as a proof of less brain serotonin.

This means that there is less serotonin in the blood, not in the brain.

Question 15

Conclusion

Jacobsen (2023)

Answer 15

Moncrieff provides little innovative information. The selective conclusions from the literature and the questionable conclusions drawn may not contribute positively to scientific discussions or benefit patients.

Question 16

Waar gaat artikel Jauhar over?

Jauhar (2023)

Answer 16

• Methodological weaknesses of study Moncrieff

Question 17

How are umbrella reviews usually organized?

Jauhar (2023)

Answer 17

Usually split their studies into previous meta-analyses/systematic reviews of primary studies vs. umbrella reviews of meta-analyses/systematic reviews.

Moncrieff summarized all studies together (selectively excluding some) –> interpretation unreliable

Question 18

Quality of evidence used

Jauhar (2023)

Answer 18

• Define quality of evidence based on at least 2 authors and the direction of the effect agreeing.
• Chosen meta-analyses were not very similar to the studies they were comparing them to.
• Unclear why only studies involving antidepressants with positive outcomes were selected.

Question 19

Tryptophan

Jauhar (2023)

Answer 19

Mentioned: individuals with depression had slight greater decrease in mood after tryptophan decrease, but most participants were on antidepressants.

However, in the meta-analysis they refer to, impact of tryptophan decrease on mood in depressed indi not taking antidepressants showed a great effect size.

–> This means that tryptophan decrease is related to serotonin in individuals prone to depression and those who have recovered through SSRIs

Moncrieff reference many negative isolated studies on healthy participants to create an impression that tryptophan decrease has no impact

Question 20

Other mistakes

Jauhar (2023)

Answer 20

• Misinterpreting molecular imaging evidence
• Stating that brain areas where SERT binding effects were detected were not consistent, when the findings in various brain regions are, in fact, consistent.

Question 21

Conclusion

Jauhar (2023)

Answer 21

1. Methodology of the review lacks consistency for an umbrella review
2. There is bias stemming from the use of selective criteria and results interpretation
3. Complexities of neuroscience and neuropsychopharmacology were not consideredm so valid and reliable conclusions can’t be drawn.

Question 22

What should have been concluded?

Jauhar (2023)

Answer 22

1. Tryptophan decrease indicated the involvement of serotonin in those vulnerable to or experiencing depression.
2. Molecular imaging suggests that there are disturbances in the system.