Mechanistic and Genetic Causes of Depression and the Effect of SSRIs on the
Serotonergic Pathway
Ashley Nicole Phares
Introduction
Depression is a very common disorder and
up to 20% of the population in the United States
suffers from this condition, with twice as many
females diagnosed as males (15,16). Studies have
shown that 40-50% of depression risk is genetic,
while the other portion consists of non-genetic
factors like viral infection, emotional trauma, and
stress (16). Diagnosis requires the suffering of a
major depressive episode marked by several
specific symptoms, including depressed mood and
loss of interest (14). The hippocampus is generally
considered the prominent site for the generation and
treatment of depression, though abnormalities
related to the disorder also extended far beyond this
region (16). These include two major serotonergic
pathways in the brain that are located in the
projections ascending from the medial and dorsal
raphe and the descending projections from the
caudal raphe into the spinal cord (18). Research has
established a pathophysiological role of serotonin,
also known as 5-hydoxytryptamine (5-HT), in
depression (22, 8). In humans, serotonin expressing
neurons are highly localized to the spinal cord and
brainstem in clusters. In these collections, neurons
send out axons whose terminals contain serotonin
and innervate many different areas throughout the
brain (22). If part of the serotonergic pathway is
disrupted, the signaling system will not operate
correctly and will therefore likely lead to
depression.
But how might this pathway be disrupted?
As mentioned previously, genetics play a large role
in determining risk for depression (16). If mutations
occur in genes coding for elements of the pathway,
there is a stronger likelihood for depressive
tendencies (16, 3). Yet while genes predispose
many people to depression, others may be affected
by epigenetic mechanisms (21). For instance, longterm alterations associated with depression are also
thought to stem from adverse experiences early in
life (14, 10). Early environmental stressors result in
an enhanced biologic stress mechanism (21).
Synergistically, stress and genetic risk initiate a
cascade that disrupts the dynamic serotonergic
system through neurobiological transformations.
Other factors may include high levels of the stress
hormone cortisol, or imbalanced densities of
glucocorticoid and/or mineral corticoid receptors
(14). In fact, increased levels of glucocorticoid
downregulate hippocampus 5-HT, and many
patients diagnosed with depression exhibit enlarged
adrenal glands. Although it is difficult to reduce the
many emotional and physical symptoms of
depression to one prominent cause, the most widely
acknowledged source of this condition is indeed an
imbalance of the neurotransmitter, serotonin. Solid
evidence has shown that low serotonergic activity is
directly linked to major depression disorder (10).
The Mechanics of the Serotonergic Pathway
(Figure A)
We know that, when altered, the
serotonergic pathway can cause depression, but
what is its normal function and how does it work?
Typically, 5-HT governs autonomic operations,
influences learning and memory, and affects
behavior and mood (12). When serotonin is released
by the pre-synaptic cell into the synaptic cleft, it
binds to one of its distinct subtypes of 5-HT
receptors, resulting in a signal transduction cascade.
The serotonergic neurotransmission is terminated
when 5-HT is rapidly re-uptaken into the presynaptic terminus. The re-uptake is controlled by
the serotonin transporter, or SERT (12). [See Figure
A]
The brain synthesizes serotonin from the
amino acid L-tryptophan. This amino acid comes
mainly from the diet and must travel across the
blood-brain barrier by active transport in order to
reach the brain (18). L-tryptophan metabolism is a
highly regulated physiological process (19).
Tryptophan hydroxylase (TPH) is the rate-limiting
enzyme in the biosynthetic pathway for serotonin.
Its role is to convert the tryptophan amino acid into
5-hydroxytryptophan (5-HTP) which in turn is
decarboxylated to 5-HT (3). [See Figure B] Levels
of serotonin are linked to levels of L-tryptophan,
which change with both diet and levels of
competing amino acids (18). Pre-cursor loading and
increased intake of tryptophan can increase
serotonin concentrations (9). Tryptophan depletion
leads to decreased levels of 5-HT and often
depression (18).
(Figure B)
Serotonin receptors are the targets for the 5HT neurotransmitter and are primarily located on
the surface of the post-synaptic terminal (11).
Research has established that there are at least seven
distinct receptor families, each with multiple subtypes (18). These include 5-HT1A, 5-HT1D, 5HT3, and most importantly, 5-HT2A, 5-HT2B, and
5-HT2C which each affect a distinct neural system
(22, 13). Direct-acting agonists and antagonists
often show selective affinity for a specific family
and subtype of receptor (9). Perhaps the most
studied subtype of receptors is the 5-HT2C (11).
This subtype is widely distributed throughout the
brain and is considered a member of the class A Gprotein-coupled receptor homodimers which act in
intracellular signaling pathways (11, 20). It couples
to G alpha q, phospholipase D, and arachidonic acid
metabolism. 5-HT2C receptors function as
homodimers, regardless as to whether they are in
the active of inactive conformation. These two
conformations result from receptor isoforms
produced by RNA editing (11). 5-HT also acts on
some pre-synaptic receptors, such as 5-HT1B/1D
and 5-HT1A, which act in a negative feedback
mechanism. When bound by a neurotransmitter,
they inhibit firing rates, therefore decreasing the
amount of serotonin released into the synaptic cleft
(18).
The serotonin transporter mediates the reuptake of the neurotransmitter from the synaptic
cleft, back to the pre-synaptic nerve terminal (12). It
is found on serotonin neuron processes, nerve
terminals, and also platelets and its density varies
according to location (3). The SERT is an integral
membrane protein that belongs to the Na+/Cldependant family that transports metabolites and
neurotransmitters, as well as moves monoamines
and amino acids through the lipid bi-layer (12). The
human serotonin transporter is a twelve membranespanning protein that is affectively a neuronal
uptake pump for 5-HT (22). Many different
mechanisms, such as protein kinase C triggered
internalization, control SERT activity. It has been
found that with prolonged administration of
serotonin re-uptake inhibitors, adaptive changes in
SERT mRNA and protein levels occur (12). Each of
these parts of the serotonergic pathway are integral
to the working system and if altered, will likely
result in an increased risk for depression.
Genetic Mutations to the Serotonergic Pathway
Components
Evidence of genetic causation comes from
observation of a link between depression and family
history, twin comparisons, and twin adoption
studies (3). Also, as stated before, epidemiological
studies have shown that 40-50% of depression risk
is derived from genetic variation (16). Since each of
the components of the 5-HT pathway are so
essential for correct function, if any mutations occur
in genes coding for a part of the serotonergic
system, problems are bound to occur (3). Thus,
genes related to this system are prime targets for
investigation in the search for the causes of
depression (3, 15). Polymorphisms in these genes
can contribute to altered forms, or isoforms, that
display different levels of wildtype functionality
(3).
Worthy of study, are the polymorphisms of
the serotonin biosynthetic enzyme, tryptophan
hydroxylase, or TPH. Since alteration in 5-HT
neurotransmission is implicated in depression, it
makes sense to look at this important member of
serotonin’s synthetic pathway. The TPH gene is
located on chromosome 11 and two polymorphisms
in intron seven have been detected, which are in a
tight linkage disequilibrium. These consist of A to
C substitutions in either nucleotide 779 or 218. Less
TPH is not apparent in the dorsal raphe nucleus of
depressed suicide victims, which predicts that this
enzyme protein may be altered in the isoforms so as
to have less activity (3).
Altered levels of 5-HT receptors are often
reported in depression (1). For example, a reduced
number of serotonin receptors has been observed in
the post-mortem hippocampus of depressed suicides
(10). This eludes that genes coding for the 5-HT
receptors are also prime targets for study (2, 3).
Two polymorphisms for the 5-HT1B receptor have
been detected at nucleotides 129 and 161. These
involve silent mutations of a C to a T and a G to a C
respectively. These polymorphisms were found at
similar frequencies in normal and depressed
patients, but exhibit a lower level of binding in the
latter. Studies have also detected an uncommon
substitution of a phenylalanine residue for a
cysteine (3). Polymorphisms have additionally been
found in genes coding for 5-HT2C receptors.
Recent studies have shown that life stress increases
production of 5-HT2C receptor isoforms, which
have reduced 5-HT sensitivity. Moreover, genetics
and life stress early on are synergistic in producing
more of these receptor isoforms (5). Two prominent
polymorphisms have been seen in the 5-HT2A
receptor gene. In one, a T is changed to a C at
nucleotide 102 and in the other, an A is replaced by
a G at 1438. Other less frequent polymorphisms of
5-HT2A were observed as well (3). However,
strong evidence showing that alterations in this
subtype result in increased risk for depression have
not been shown (15).
The human gene for the serotonin
transporter is located on chromosome 17. It has
been found that less 5-HTT expression and binding
may result from a 44 bp insertion/deletion in the 5’
regulatory region adjacent to the promoter. It
appears that this polymorphism results in a
decreased number of binding sites (3). There is
mounting evidence that single nucleotide and
simple repeat sequence polymorphisms in coding
and regulatory genes of the serotonergic pathway
can result in a significant difference in the
functionality of the system (7).
Mutations
associated with the genes coding for components of
the 5-HT pathway, no matter how small, are
certainly worthy of investigation for the role they
likely play in the increased risk for depression.
The Effect of SSRIs on the Serotonergic Pathway
Much research has been done in order to
find mechanisms to treat the causes and symptoms
of depression. One of the major solutions to this
search has been the discovery and implementation
of selective serotonin reuptake inhibitors (SSRIs).
SSRIs were developed to target and inhibit the
serotonin transporter, or neuronal uptake pump.
This mechanism involves altering the 5-HT system
in order to increase the level of neurotransmitter in
the synaptic cleft (22, 23). [See Figure C] Inhibition
of the transporter yields an increase of serotonin in
the synapse, and therefore an increased activation of
the presynaptic inhibitory receptors. Over the period
of about three weeks, the negative feedback
mechanism achieves a therapeutic effect (18).
Imipramine was the first compound shown
to block the reuptake of serotonin by the
transporters
and
since
then
citalopram,
fluvoxamine, fluoxetine, paroxetine, sertraline,
duloxetine, and others have been added to that list
(22, 7, 17). SSRIs have common serotonin agonists
that meditate their effects. As far as affecting the
uptake pump, SSRIs have proven to be selective.
They affect particular receptors that in turn affect a
multitude of particular neural systems; hence, no
SSRI works exactly the same (22). Selective
serotonin reuptake inhibitors vary in elimination
half-life, selectivity for serotonin ratios, and affinity
for the 5-HT receptor (18). In order to be effective,
regular levels of serotonin must still be available.
This was shown by administering depletion of
tryptophan, the precursor of serotonin, and
observing the effects of the SSRIs. Without
adequate serotonin being produced, the SSRIs had
no positive effect (4, 18). In fact, serotonin
depletion leads to reoccurrence of symptoms in up
to 80% of patients (22).
depression that are just waiting to be discovered and
refined.
(Figure D)
Conclusion
(Figure C)
With continuous exposure to SSRIs,
postsynaptic receptors in the brain often become
desensitized. It is hypothesized that this may
specifically focus on the 5-HT1A autoreceptors in
the midbrain raphe nucleus, increasing serotonin in
critical brain regions (22). Application of
monoamine reuptake inhibitors leads to an increase
in cAMP (cyclic adenosine 3-5 monophosphatase)
activation, which turns on protein kinase A, which
in turn regulates target genes. This leads to an
increase in BDNF synthesis (brain-derived
neurotrophic factor) which is a primary
neurotrophin of the hippocampus which promotes
cellular resilience and long-term potentiation (14).
[See Figure D] SSRIs bring relief for many patients
suffering from depression by altering an important
step in the serotonergic pathway. Possibilities still
remain for different, and possibly more effective,
ways of treating the causes and symptoms of
Depression is a common disorder that
plagues a large percentage of the population. One of
the main causes of this condition has been linked to
alterations in the serotonergic pathway for
neurotransmission. Negative outcomes often occur
when mechanistic and genetic changes produce a
change in the 5-HT system, resulting in an
increased risk for depression. Through increased
understanding of the serotonin pathway and the
genetics governing its components and function,
treatments such as SSRIs, can and will continue to
be developed and perfected in order to treat the
causes and symptoms of depression.
References
1 Albert, P.R., Lemonde, S. (2004) 5-HT1A receptors, gene
repression, and depression: guilt by association.
Neuroscientist. 10(6): 575-93.
2 Anguelova, M., Benkelfat, C., Turecki, G. (2003) A
systematic review of association studies investigating
genes coding for serotonin receptors and the
serotonin transporter: I. Affective disorders. Mol
Psychiatry. 8(6): 574-91.
3 Arango, V., Huang, Y., Underwood, M.D., Mann, J.J.
(2003) Genetics of the serotonergic system in suicidal
behavior. Journal of Psychiatric Research. 37: 375386.
4 Argyropoulos, S.V., Hood, S.D., Adrover, M., Bell, C.J.,
Rich, A.S., Nash, J.R., Rich, N.C., Witchel, H.J.,
Nutt, D.J. (2004) Tryptophan depletion reverses the
therapeutic effect of selective serotonin reuptake
inhibitors in social anxiety disorder. Biol Psychiatry.
56(7): 503-9.
5 Bhansali, P., Dunning, J., Singer, S.E., David, L., Schmauss,
C. (2007) Early life stress alters adult serotonin 2C
receptor pre-mRNA editing and expression of the
alpha subunit of the heterotrimeric G-protien Gq.
Journal of Neuroscience. 27(6): 1467-1473.
6 Dell’Osso, B., Allen, A., Hollander, E. (2005) Fluvoxamine:
a selective serotonin re-uptake inhibitor for the
treatment of obsessive compulsive disorder. Expert
Opin Pharmacother. 6(15): 2727-40.
7 D’Souza, U.M., Craig, I.W. (2006) Functional
polymorphisms in dopamine and serotonin pathway
genes. Hum Mutat. 27(1): 1-13.
8 Freeman, S.L., Glatzle, J., Robin, C.S., Valdellon, M.,
Sternini, C., Sharp, J.W., Raybould, H.E. (2006)
Ligand-induced 5-HT3 receptor internalization in
enteric neurons in rat ileum.
Gastroenterology.131(1): 97-107.
9 Fuller, R.W. (1991) Role of serotonin in therapy of
depression and related disorders. J Clin Psychiatry.
52 Suppl: 52-7.
10 Graeff, F.G., Guimaraes, F.S., De Andrade, T.G.C.S.,
Deakin, J.F.W. (1996) Role of 5-HT in stress,
anxiety, and depression. Pharmacology Biochemistry
and Behavior 54(1): 129-141.
11 Herrick-Davis, K., Grinde, E., Weaver, B.A. (2006)
Serotonin 5-HT2C receptor homodimerization is not
regulated by agonist or inverse agonist treatment.
European Journal of Pharmacology. 568: 45-53.
12 Jess, U., El Far, O., Kirsch, J., Betz, H. (2002) Interaction
of the C-terminal region of the rat serotonin
transporter with MacMARCKS modulates 5-HT
uptake regulation by protein kinase C. Biochemical
and Biophysical Research Communications. 294:
272-279.
13 Leysen, J.E. (2004) 5-HT2 receptors. Curr Drug Targets
CNS Neurol Disord. 3(1): 11-26.
14 Maletic, V., Robinson, M., Oakes, T., Iyenger, S., Ball,
S.G., Russell, J. (2007) Neurobiology of depression:
an integrated view of key findings. Int J Clin Prac.
61(12): 2030-40.
15 Minov, C., Baghai, T.C., Schule, C., Zwanger, P.,
Schwartz, M.J., Zill, P., Rupprecht, R., Bondy, B.
(2001) Serotonin-2A-receptor and –transporter
polymorphisms: lack of association in patients with
major depression. Neuroscience. Letters. 303: 119122.
16 Nestler, E.J., Barrot, M., DiLeone, R.J., Eisch, A.J., Gold,
S.J., Monteggia, L.M. (2002) Neurobiology of
depression. Neuron. Vol. 34: 13-25.
17 Norman, T.R. (2005) Prospects for the treatment of
depression. Aust N Z J Psychiatry. 40(5): 394-401.
18 Nutt, D.J., Forshall, S., Bell, C., Rich, A., Sandford, J.,
Nash, J., Argyropoulos, S. (1999) Mechanisms of
action of selective serotonin reuptake inhibitors in the
treatment of psychiatric disorders. Eur. NeuroPsychopharmacology. 9 Suppl. 3: S81-S86.
19 Ruddick, J.P., Evans, A.K., Nutt., D.J., Lightman, S.L.,
Rook, G.A., Lowry, C.A. (2006) Tryptophan
metabolism in the central nervous system: medical
implications. Expert Rev Mol Med. 8(20): 1-27.
20 Serretti, A., Artioli, P., De Ronchi, D. (2004) The 5-HT2C
receptor as a target for mood disorders. Expert Opin
Ther Targets. 8(1):15-23.
21 Shelton, R.C. (2007) The molecular neurobiology of
depression. Psychiatr Clin North Am. 30(1): 1-11.
22 Vaswani, M., Linda, F.K., Ramesh, S. (2003) Role of
selective serotonin reuptake inhibitors in psychiatric
disorders: a comprehensive review. Progress in
Neuro- Psychopharmacology & Biological
Psychiatry. 27: 85-102.
23 Weizman, A., Weizman, R. (2000) Serotonin transporter
polymorphism and response to SSRIs in major
depression and relevance to anxiety disorders and
substance abuse. Pharmacogenomics. 1(3): 335-41.
Ashley is a junior double majoring in biology and
classics with a minor in the Blount Undergraduate
Initiative. She has researched for three years in the
Caldwell genetics lab using the C. elegans model
organism. During her freshman year, she worked
on the genetic causes of Parkinson’s disease, but
now focuses on the study of cancer mechanisms.
After graduation, Ashley will pursue a career in
dentistry.