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Psychopharmacological properties and therapeutic profile of the antidepressant venlafaxine

Abstract

Major depression (MD) is one of the most common psychiatric disorders worldwide. Currently, the first-line treatment for MD targets the serotonin system but these drugs, notably the selective serotonin reuptake inhibitors, usually need 4 to 6 weeks before the benefit is felt and a significant proportion of patients shows an unsatisfactory response. Numerous treatments have been developed to circumvent these issues as venlafaxine, a mixed serotonin-norepinephrine reuptake inhibitor that binds and blocks both the SERT and NET transporters. Despite this pharmacological profile, it is difficult to have a valuable insight into its ability to produce more robust efficacy than single-acting agents. In this review, we provide an in-depth characterization of the pharmacological properties of venlafaxine from in vitro data to preclinical and clinical efficacy in depressed patients and animal models of depression to propose an indirect comparison with the most common antidepressants. Preclinical studies show that the antidepressant effect of venlafaxine is often associated with an enhancement of serotonergic neurotransmission at low doses. High doses of venlafaxine, which elicit a concomitant increase in 5-HT and NE tone, is associated with changes in different forms of plasticity in discrete brain areas. In particular, the hippocampus appears to play a crucial role in venlafaxine-mediated antidepressant effects notably by regulating processes such as adult hippocampal neurogenesis or the excitatory/inhibitory balance. Overall, depending on the dose used, venlafaxine shows a high efficacy on depressive-like symptoms in relevant animal models but to the same extent as common antidepressants. However, these data are counterbalanced by a lower tolerance. In conclusion, venlafaxine appears to be one of the most effective treatments for treatment of major depression. Still, direct comparative studies are warranted to provide definitive conclusions about its superiority.

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Abbreviations

5-HT:

5-hydrotryptamine or serotonin

5-HT1A:

Serotonin 1A receptor

5-HT1B:

Serotonin 1B receptor

[5-HT]ext :

Extracellular serotonin

BDNF:

Brain-derived neurotrophic factor

CA3:

Ammon’s horn 3

cFST:

Chronic forced swim test

CI:

Confidence interval

CNS:

Central nervous system

CORT:

Corticosterone

CSD:

Chronic social defeat

DA:

Dopamine

DAT:

Dopamine transporter

[DA]ext :

Extracellular dopamine

DRN:

Dorsal raphe nucleus

ED50:

Median effective dose

EPM:

Elevated plus maze

EZM:

Elevated zero maze

FST:

Forced swim test

HDRS:

Hamilton depressive rating scale

HPA:

Hypothalamic–pituitary–adrenal axis

LC:

Locus coeruleus

LPS:

Lipopolysaccharide

MADRS:

Montgomery-Asberg depression rating scale

MD:

Mean difference

MDD:

Major depressive disorder

MED:

Minimal effective dose

MMP:

Matrix metalloproteinase

MS:

Maternal separation

NE:

Norepinephrine or noradrenaline

NET:

Norepinephrine transporter

[NE]ext :

Extracellular norepinephrine

NNT:

Number needed to treat

NRI:

Norepinephrine reuptake inhibitor

NSF:

Novelty-suppressed feeding

OB:

Olfactory bulbectomy

OCT2:

Organic cation transporter 2

OF:

Open field

OR:

Odds ratio

OVX:

Ovariectomy

PNN:

Perineuronal net

POCD:

Post-operative cognitive dysfunction

PV:

Parvalbumine

RCT:

Randomized clinical trial

RR:

Risk ratio

RT50:

Recovery time 50

SERT:

Serotonin transporter

SMD:

Standard mean difference

SNRI:

Serotonin-noradrenaline reuptake inhibitor

SPT:

Sucrose preference test

SSRI:

Selective serotonin reuptake inhibitor

ST:

Splash test

TCA:

Tricyclic antidepressant

TST:

Tail suspension test

UCMS:

Unpredictable chronic mild stress

VTA:

Ventral tegmental area

WHO:

World Health Organization

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B.P. Guiard and C. Rampon designed the study. B. Coutens and A. Yrondi managed the literature searches and wrote the first draft of the manuscript. All authors contributed to and have approved the final manuscript.

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Coutens, B., Yrondi, A., Rampon, C. et al. Psychopharmacological properties and therapeutic profile of the antidepressant venlafaxine. Psychopharmacology 239, 2735–2752 (2022). https://doi.org/10.1007/s00213-022-06203-8

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Keywords

  • Venlafaxine
  • 5-HT
  • NE
  • Major depression disorder
  • Antidepressants