Cognitive pharmacology of depression Bill Deakin University of Manchester

My most highly cited paper (870 times)

5-HT depletion & chronic amphetamine mimic the effects of OFC lesions

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Acute TRP depletion Control

Delgado et al (1990)

HDRS

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Tryptophan depletion triggers relapse of depressive symptoms

• 36 experimental ATD studies in humans explicitly address the role of 5-HT in

response inhibition, punishment and reward.

• ATD did not cause disinhibition of responding in the absence of rewards or

punishments (9 studies).

• Remarkably, ATD lessened the ability of punishments (losing points or notional

money) to restrain behaviour without affecting reward processing in 7 studies.

• A major role for 5-HT in reward processing is unlikely but further tests are warranted

by some ATD findings.

My next most highly cited paper (745)

Keeps us out of trouble (anxiety) Dorsal raphe system (5HT2c; 1d) activated by distal threats symptom

Amygdala fear (PPE) GAD

Striatum avoidance retardation

(dopamine) reward suppression anhedonia

PAG don’t panic yet helplessness

Helps us cope if we get into it (adaptation & resilience) Median raphe system (5HT1A) activated by chronic aversion

Hippocampus (DMN) limit consolidation rumination

disconnection, DRN opponent process

•Does the 5HT2c antagonist agomelatine modulate reward processing?

•Does the SSRI escitalopram work on resilience (effort processing)?

•New evidence for a DRN opponent process

Salvador A1, Vinckier F5, Meyniel F5, Deakin JFW3, Harmer CJ2, Montejo AL4, Jabourian AP6, Gruget C7, Gabriel C7, Goodwin GM2, Gaillard R1

Effects of agomelatine compared to escitalopram on motivation in healthy male and female volunteers after 8 weeks of treatment

A specific role for serotonin in effort cost processing Florent Meyniel, Goodwin G.M., Deakin B, Cecilia Gabriel-Gracia, Céline Gruget, Mathias Pessiglione, Raphael Gaillard

Escitalopram induced tolerance to the cost of effort

5-HT immunohistochemistry wild -type Pet-/- knockout

Increased conditioned anxiety

Restrained unconditioned anxiety

When only the DRN system develops. Pet-/- KO mice

38% 95%

62% 95%

Conclusions

• CANTAB continues to make a massive contribution to cognitive pharmacology

• 5-HT is involved in behavioural adaptation to adversity

• Some cognitive effects of antidepressants may involve down regulation of 5-HT2 receptors

• Resilience and tolerance to adversity (eg effort) may be independent of the DRN -5-HT2c system and involve an extrasynaptic opponent process