The role of serotonin in depression A historical roundup and future

• 28 October 2024

Received: 30 October 2023 | Revised: 26 February 2024 | Accepted: 27 February 2024
DOI: 10.1111/jnc.16097
R E VI EW
The role of serotonin in depression—A historical roundup and
future directions
Svenja Bremshey1,2 | Juliana Groß1 | Kim Renken1 | Olivia Andrea Masseck1
This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in
any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.
© 2024 The Authors. Journal of Neurochemistry published by John Wiley & Sons Ltd on behalf of International Society for Neurochemistry.
Abbreviations: 5-HIAA,
5-hydroxyindoleacetic
acid; 5-HT,
serotonin, 5-hydroxytryptamin;
5-HTIAA,
5-hydroxyindoleacetic
acid; 5-HTR,
serotonin receptor; 5-HTT,
5-hydroxytryptamin
transporter; 5-HTTLPR,
44 bp repeat polymorphism in the 5-htt
linked polymorphic region; AMY, amygdala; AN, affective network; BDNF, brain-derived
neurotrophic factor; cAMP,
cyclic adenosine monophosphate; CCN, cognitive control network; ChR2, channelrhodopsin 2; DA, dopamine; DBS, deep brain stimulation; dlPFC, dorsolateral prefrontal cortex; DMN,
default mode network; DMT, 5-methoxy-
n,
n-dimethyltryptamine;
DOPAC, 3, 4-dihydroxyphenylacetic
acid; DREADDs, designer receptors exclusively activated by designer drugs;
DRN, dorsal raphe nucleus; DSM, the diagnostic and statistical manual of mental disorders; FDA, food and drug administration; FLIM, fluorescence lifetime imaging microscopy; fMRI,
functional magnetic resonance imaging; GFP, green fluorescent protein; Gi/o, inhibitory G-protein;
GPCR, G-protein
coupled receptors; Gq, stimulatory G-protein;
Gs, stimulatory
G-protein;
GWAS, genome-wide
association studies; GxE studies, gene–environment interaction studies; HIP, hippocampus; IGF-1,
insulin-like
growth factor-1;
IL, infralimbic cortex;
IPC, inferior parietal cortex; KO, knock-out;
LSD, lysergic acid diethylamide; MAO, monoamine oxidase; MDD, major depressive disorder; mPFC, medial prefrontal cortex; MRN, median
raphe nucleus; mTor, mammalian target of rapamycin; NA, noradrenaline; NMDA, glutamatergic n-methyl-
d-
aspartate;
OFC, orbitofrontal cortex; Opto-MASS,
optogenetic microwell
array screening system; OR, odds ratio; PBP, periplasmic binding protein; PCC, posterior cingulate cortex; PET, positron-emission-
tomography;
PFC, prefrontal cortex; PrL, prelimbic
cortex; RN, reward network; SNP, single nucleotide polymorphism; SNRI, serotonine noradrenaline reuptake inhibitor; SSRI, selective serotonin reuptake inhibitor; TCA, tricyclic
antidepressant; TPH, tryptophane; TPH2, tryptophane hydroxylase 2; vACC, ventral anterior cingulate cortex; VEGF, vascular endothelial growth factor; vlPFC, ventrolateral prefrontal
cortex; vmPFC, ventromedial prefrontal cortex; VNTR, variable-number-
tandem-
repeat
region in the second intron.
1Synthetic Biology, University of Bremen,
Bremen, Germany
2Neuropharmacology, University of
Bremen, Bremen, Germany
Correspondence
Olivia Andrea Masseck, Synthetic Biology,
University of Bremen, Bremen 28359,
Germany.
Email: masseck@uni-bremen.de
Abstract
Depression is one of the most common psychiatric disorders worldwide, affecting
approximately 280 million people, with probably much higher unrecorded cases.
Depression is associated with symptoms such as anhedonia, feelings of hopelessness,
sleep disturbances, and even suicidal thoughts. Tragically, more than 700 000 people
commit suicide each year. Although depression has been studied for many decades,
the exact mechanisms that lead to depression are still unknown, and available treatments
only help a fraction of patients. In the late 1960s, the serotonin hypothesis
was published, suggesting that serotonin is the key player in depressive disorders.
However, this hypothesis is being increasingly doubted as there is evidence for the
influence of other neurotransmitters, such as noradrenaline, glutamate, and dopamine,
as well as larger systemic causes such as altered activity in the limbic network or
inflammatory processes. In this narrative review, we aim to contribute to the ongoing
debate on the involvement of serotonin in depression. We will review the evolution of
antidepressant treatments, systemic research on depression over the years, and future
research applications that will help to bridge the gap between systemic research
and neurotransmitter dynamics using biosensors. These new tools in combination
with systemic applications, will in the future provide a deeper understanding of the
serotonergic dynamics in depression.
K E YWORDS
depression, antidepressants, mechanisms, serotonin, systems, biosensors

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