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CHAPTER 5
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Neurochemistry
of Mood Disorders
Charles F. Gillespie, M.D., Ph.D.
Depression and maniaare ancient diseases. Contemporary descriptions of
the clinical phenomenology of depression and mania resonate with the antiquarian
writings of the Greek physician Hippocrates (ca. 460–377
Galen (ca. 129–199
A.D.), and the Arabic physician Ishaq Ibn Imran (ca. 848–906 A.D.). Independent of
culture, the central features of depression, or rather depressive disorders, include pro
found feelings of despondency paired with a loss of will and of the capacity to experience pleasure. By contrast, mania is characterized by feelings of elation or irritability, accompanied by elevated energy and drive coupled with a radically enhanced
sense of personal agency.
Historical conceptualizations of the biology of depression, then called melancholia,
and states of mania were rooted in the humoral theory of disease and emphasized im
balances of the four humors, such as an excess of black bile leading to melancholia,
the historical description of a present-day subtype of severe depression. Modern-era
theories, beginning in the 1950s, of the neurochemical pathophysiology of mood disorders have been structured predominantly around a core of monoamine neurotransmitters: norepinephrine and dopamine, which are catecholamines, and serotonin,
which is an indoleamine. In more recent decades, clinical investigation has extended
to the role of a neuropeptide, corticotropin-releasing hormone, and two amino acid
neurotransmitters, GABA and glutamate, in the pathophysiology of mood disorders.
Comprehensive and critical treatment of this topic, which spans nearly seven decades
of clinical studies of patients with unipolar depression and bipolar disorders, is impossible in the space available. Therefore, emphasis in this chapter is placed on coverage of replicated findings and outcomes assessed by meta-analyses.
A.D.), the Turkish physician Aretaeus of Cappadocia (fl. ca. 150
B.C.), the Roman physician
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Monoamines: Serotonin, Norepinephrine,
and Dopamine
The serendipitous discovery of the first antidepressant medication, the monoamine
oxidase inhibitor (MAOI) iproniazid (Crane 1956), which inhibits the catabolism of
monoamines, and soon thereafter the discovery of the first tricyclic antidepressant
(TCA), imipramine (Kuhn 1957), which inhibits the reuptake of monoamines from the
synapse, demonstrated the antidepressant, and in some cases mania-inducing, effects
of medications acting on monoamines. Reports of the depressogenic effects of reser
pine and related compounds, medications used at the time for treatment of hypertension, further fueled interest in the mood-altering effects of medications affecting
monoaminergic neurotransmission (Freis 1954; Lemieux et al. 1956). Administration
of reserpine leads to depletion of monoamines from the presynaptic terminals of neu
rons, resulting in depression for some but not all hypertensive patients. This effect is
in contrast with the monoamine-increasing and mood-elevating effects of MAOIs and
TCAs observed in patients with depression.
Clinical observations of the effects of MAOIs, TCAs, and reserpine on mood, in
conjunction with their corresponding pharmacological effects on monoaminergic
neurotransmission, formed the intellectual foundation of the monoamine hypothesis
of mood disorders. In its initial form, the monoamine hypothesis focused on deficient
presynaptic function of monoaminergic neurons and included component hypothe
ses regarding the manner in which decreased or increased neurotransmission of the
catecholamine neurotransmitters norepinephrine and dopamine (Bunney and Davis
1965; Schildkraut 1965) and the indoleamine neurotransmitter serotonin (Coppen
1968; Lapin and Oxenkrug 1969) results in depression or mania. Over time, the monoamine hypothesis has gone through iterative revision and expansion to postulate
roles for altered postsynaptic function, including changes in receptor density and sen
sitivity, as opposed to simply pathogenic presynaptic function manifesting as relative
deficiency of neurotransmitter release (reviewed in Racagni and Popoli 2008).
In the sections below, I review findings from clinical studies of monoamine metabolites, transporter proteins, and receptors, as well as experimental depletion studies.
Topical reviews are provided for each section. Other resources provide comprehensive
reviews of norepinephrine (Ressler and Nemeroff 1999), the interaction of serotonin
and norepinephrine (Ressler and Nemeroff 2000), and dopamine (Ashok et al. 2017;
Dunlop and Nemeroff 2007).
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Metabolite Studies
Numerous cross-sectional case-control investigations of the principal metabolites of
serotonin (5-hydroxyindoleacetic acid [5-HIAA]), norepinephrine (3-methoxy-4hydroxyphenylglycol [MHPG]), and dopamine (homovanillic acid [HVA]) have been
conducted using samples of plasma, urine, and cerebrospinal fluid (CSF) from pa
tients with unipolar depression, depressed or manic patients with bipolar disorder,
patients with other psychiatric disorders such as schizophrenia, and healthy individuals serving as controls. The scientific rationale for these investigations is that the levels of these metabolites indirectly reflect the aggregate steady-state presynaptic activ-
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ity of their respective parent neurotransmitter systems and hence dysfunction representative of unipolar depression or the manic or depressive episodes of bipolar disorder, for example.
A well-replicated finding from this line of investigation is the association of low
CSF 5-HIAA with attempted suicide or death by suicide, often impulsive and involv
ing violent means (Asberg et al. 1976). This finding has proven to be remarkably robust
and is supported by a meta-analysis of 27 studies (Lester 1995). Notably, the associa
tion of low CSF 5-HIAA with suicidal behavior is not specific to mood disorders and
is observed across a variety of psychiatric disorders (reviewed in Asberg 1997).
In contrast to the association observed between reduced concentrations of CSF 5HIAA and violent suicide, studies of CSF monoamine metabolites have been largely
inconsistent with respect to their relationship with unipolar depression or the manic
or depressive phases of bipolar disorder. A structured review and meta-analysis of 23
studies (Pech et al. 2018) failed to find an association between unipolar depression and
CSF levels of 5-HIAA and MHPG, although a weak association was identified between
lower CSF HVA and unipolar depression. Similarly, a structured review of eight stud
ies (Knorr et al. 2018) examining the relationship between CSF monoamine metabolite levels and depression or mania in patients with bipolar disorder also identified a
pattern of inconsistent replication, as well as sample and methodological heteroge
neity.
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Transporter Studies
The serotonin transporter (SERT/SLC6A4) is found in the blood on platelets, where it
facilitates concentration of serotonin (5-hydroxytryptamine [5-HT]) from the plasma
role in clearance of 5-HT from the synapse (Lesch et al. 1993). Reduction in the number
of SERT binding sites was first observed in platelet assays of patients with depression
(Briley et al. 1980). This initial finding was subsequently replicated (Kaplan and
Mann 1982; Nemeroff et al. 1988a), and a later meta-analysis of 70 studies demon
strated significant reduction in SERT binding sites on platelets from patients with unipolar depression compared with healthy control subjects (Ellis and Salmond 1994).
Postmortem studies of the brain have found either no differences or a reduced density of SERT binding in the frontal cortex of individuals who have died by suicide (reviewed in Stockmeier 2003). Data from in vivo radioligand studies using PET have
been mixed, with findings of higher, lower, and no difference in levels of SERT binding
across brain regions in samples of unipolar and bipolar depressed patients relative to
controls (reviewed in Savitz and Drevets 2013). Binding specificity of radioligands,
sample composition, and prior/current treatment status likely contribute to the range
of findings.
More recently, data from a meta-analysis of 27 in vivo imaging and 25 postmortem
studies (Kambeitz and Howes 2015) showed significant reductions in SERT binding
sites within the striatum, amygdala, and brain stem of patients with depression compared with healthy control subjects within the meta-analysis of in vivo imaging studies. Conversely, no significant differences in SERT binding sites were observed between
patients who died by suicide and control subjects in the meta-analysis of 25 postmortem studies.
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The norepinephrine transporter (NET/SLC6A2) was the first monoamine transporter to be cloned (Pacholczyk et al. 1991) and is responsible for the reuptake of norepinephrine from the synapse back into the presynaptic neuron (reviewed in Lin and
Madras 2006). In vivo imaging studies using PET have produced conflicting results.
Increased NET binding is found within the prefrontal region of the thalamus in medication-naïve patients with unipolar depression; however, no effect of depression is
observed on the extent of NET binding within the locus coeruleus (Moriguchi et al.
2017). NET binding within the locus coeruleus was found to be lower in a mixed sam
ple of depressed patients with bipolar I disorder, bipolar II disorder, or unipolar major depressive disorder relative to healthy controls (Yatham et al. 2018).
The dopamine transporter (DAT/SLC6A3) is responsible for the reuptake of dopamine released during phasic firing of dopaminergic neurons (Mulvihill 2019) back
into the presynaptic neuron (reviewed in Lin and Madras 2006). Data from in vivo
studies, almost exclusively using single-photon emission computed tomography
(SPECT), are conflicting and demonstrate higher, lower, and no difference in levels of
DAT binding in patients with unipolar depression compared with healthy control
subjects (Camardese et al. 2014). The heterogeneity of radioligands and sample com
position likely contribute to the range of findings. Not surprisingly, a meta-analysis
of 12 in vivo SPECT and PET studies of striatal DAT binding failed to find an effect of
depression on DAT binding in the striatum (Li et al. 2015).
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Receptor Studies
A significant body of research has demonstrated dysregulation of the serotonin 1A receptor (5-HT
5-HT
receptors have inhibitory effects and function as presynaptic autoreceptors lo-
1A
calized to the soma of serotonergic neurons and as postsynaptic heteroceptors. In vivo
studies (reviewed in Savitz and Drevets 2013) using PET have generally found re
duced binding of 5-HT
bic regions in samples composed of patients with unipolar and bipolar depression.
Finally, a meta-analysis of 10 in vivo imaging studies supports the finding of reduced
5-HT
binding within the mesiotemporal cortex as well as the hippocampus, raphe
1A
nuclei, insula, anterior cingulate cortex, and occipital cortex of patients with unipolar
depression (Wang et al. 2016).
Accumulating evidence indicates that 5-HT
in the pathophysiology of depression (reviewed in Tiger et al. 2018). Like 5-HT
ceptors, 5-HT
neurons and as heteroceptors on the terminals of nonserotonergic neurons. Preclinical and clinical data indicate that 5-HT
influenced by p11 (Svenningsson et al. 2006), a multifunctional calcium-binding protein (Svenningsson et al. 2013). Reduced levels of 5-HT
in the prefrontal cortex, orbitofrontal cortex, and hippocampus of patients who have
died by suicide (Anisman et al. 2008). Similarly, data from in vivo imaging studies us
ing PET have demonstrated reduced binding of 5-HT
striatum/ventral pallidum (Murrough et al. 2011) and anterior cingulate cortex, subgenual prefrontal cortex, and hippocampus (Tiger et al. 2016) of patients with unipolar depression.
) system in patients with depression (reviewed in Kaufman et al. 2016).
1A
receptors within the dorsal raphe and in the cortical and lim-
1A
receptors also have a significant role
1B
receptors function as autoreceptors on the terminals of serotonergic
1B
receptor localization and function is heavily
1B
mRNA have been reported
1B
receptors within the ventral
1B
1A
re-
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5-HT2A receptors are located on platelets and localized postsynaptically within the
brain. Increased platelet 5-HT
receptor binding has been observed in nonsuicidal
2A
patients with unipolar and bipolar depression and in suicidal patients more generally
in some studies (reviewed in Pandey 2013) but not in others (reviewed in Müller-Oer
linghausen et al. 2004). In vivo studies (reviewed in Savitz and Drevets 2013) using
PET to examine 5-HT
results with increases, decreases, and findings of no differences in 5-HT
receptor binding within the brain have produced conflicting
2A
receptor
2A
binding between controls and patients with unipolar depression. Postmortem studies
of 5-HT
receptor binding within the brains of individuals who died by suicide have
2A
also produced mixed results, with some studies demonstrating increased binding rel
ative to controls and other studies finding no differences between groups (reviewed
in Pandey 2013). Methodological differences may contribute to the discrepant find
ings. Studies using levels of mRNA and 5-HT
consistently demonstrate increased expression of 5-HT
receptor protein as study outcomes
2A
receptors in the brains of in-
2A
dividuals who have died by suicide, whereas the findings from radioligand studies
are mixed.
A large body of data provides evidence for a major role of α
ceptors (α
-ARs and β-ARs) in the pathophysiology of mood disorders and suicide
2
- and β-adrenergic re-
2
(reviewed in Cottingham and Wang 2012; Pandey 2013). Adrenergic receptors have
been measured in peripheral assays using platelets and lymphocytes and in brain assays using postmortem samples. An increased density of platelet α
-ARs has been
2
consistently observed in samples of patients with unipolar depression when radiola
beled α
state of the receptor, are used. Similarly, an increased density of α
-AR agonist assays, which preferentially bind to the affinity conformational
2
-ARs, assessed with
2
radiolabeled agonist assays, has been reported within the frontal cortex, temporal
cortex, hippocampus, hypothalamus, and locus coeruleus of individuals who have
died by suicide. The literature examining β-AR binding in the brain is complex. Early
studies reported increased β-AR binding in the frontal cortex (Mann et al. 1986; Mey
erson et al. 1982) and temporal cortex (Arango et al. 1990) of individuals who died by
suicide, which conflicted with other reports of reduced β-AR binding in the frontal
cortex of antidepressant-treated patients who died by suicide (De Paermentier et al.
1991). More recently, the effects of depression and antidepressant treatment on β-AR
and α
2014). Increased β-AR and α
jects. Conversely, β
-AR binding were examined in subjects who died by suicide (Rivero et al.
2
-AR binding was observed in antidepressant-free sub-
2
-AR binding was reduced and α2-AR binding remained elevated
1
in antidepressant-treated subjects. Considered together, the data demonstrate the
effects of depression on upregulation of β-ARs and α
pressant medications on downregulation of β
-AR and resistance of α2-ARs to medi-
1
-ARs and the effects of antide-
2
cation effects.
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Depletion Studies
The development of pharmacological and dietary methods to acutely and selectively
deplete monoaminergic neurotransmitters facilitated the development of a large
body of research examining the effects of 5-HT and norepinephrine (NE)/dopamine
(DA) depletion on mood in a variety of clinical research samples, including healthy
individuals, individuals with a family history of depression, and patients with a his-
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tory of depression responsive to serotonergic or noradrenergic antidepressants (reviewed in Delgado 2004). Considered as a whole, these investigations produced
mixed results. A meta-analysis of 45 acute tryptophan depletion and 8 acute phenyl
alanine/tyrosine depletion studies (Ruhé et al. 2007) found no support for an effect of
5-HT or NE/DA depletion on mood in healthy controls. Conversely, depletion of
5-HT or NE/DA acutely reduced mood by a small but significant degree in healthy
controls with a family history of depression. In drug-free patients with remitted depression, depletion of 5-HT resulted in a moderate decrease in mood, but no effect on
mood was observed following NE/DA depletion. Finally, depletion of 5-HT was
found to result in relapse of depressed mood only in patients with remitted depres
sion who previously responded to serotonergic antidepressants.
Corticotropin-Releasing Hormone
In addition to its role in regulation of the hypothalamic-pituitary-adrenal axis, corticotropin-releasing hormone (CRH) also acts as a neurotransmitter coordinating the
behavioral, autonomic, endocrine, and immune responses to stress and has a central
role in the pathogenesis of major depressive disorder (reviewed in Waters et al. 2015).
Elevated CSF concentrations of CRH have been reported in patients with depression
(Nemeroff et al. 1984) and reviewed in Hartline et al. (1996). Postmortem findings
from individuals who died by suicide include increased transcription (Raadsheer et
al. 1995) and expression (Raadsheer et al. 1994) of CRH, elevated concentrations of
CSF CRH (Arató et al. 1989), decreased expression of CRH
the frontal cortex (Merali et al. 2004), and increased CRH concentrations and de
creased density of CRH receptors within the frontal cortex (Merali et al. 2006; Nemeroff et al. 1988b). Successful treatment of depression using either electroconvulsive
therapy (Nemeroff et al. 1991) or antidepressants (De Bellis et al. 1993; Veith et al.
1993) reduces the high pretreatment concentrations of CSF CRH. Conversely, per
sistently elevated CSF CRH in depressed patients with symptomatic improvement is
associated with early relapse of depression (Banki et al. 1992).
receptor mRNA within
1
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Gamma-Aminobutyric Acid
GABA is an amino acid derivative of glutamate and is the primary inhibitory neurotransmitter within the brain. Several lines of imaging, physiological, and postmortem data are consistent with a pivotal role for altered GABAergic neurotransmission
in the pathophysiology of mood disorders (reviewed in Duman et al. 2019; Prévot and
Sibille 2021). Reduced levels of GABA were first observed in the CSF of patients with
unipolar depression 40 years ago (Gold et al. 1980). This finding was subsequently
replicated (Gerner and Hare 1981; Gerner et al. 1984; Kasa et al. 1982) and extended
to medication-free, euthymic patients with bipolar disorder (Berrettini et al. 1983).
More recently, data from two meta-analyses (Godfrey et al. 2018; Schür et al. 2016) of
in vivo magnetic resonance spectroscopy (MRS) studies indicate that levels of GABA
are reduced in the cortex of patients with depression. In addition, functional studies
of GABAergic neurotransmission using transcranial magnetic stimulation (TMS) in
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patients with depression have demonstrated impairment of GABAergic neurotransmission using analysis of short- and long-interval cortical inhibition and the cortical
silent period (Bajbouj et al. 2006; Levinson et al. 2010), implicating both ionotropic
(GABA
et al. 2013). Furthermore, reduced levels of the GABAsynthetic enzyme glutamic acid
decarboxylase 67 (GAD67) have been reported in the prefrontal cortex of individuals
with major depressive disorder (Karolewicz et al. 2010). Finally, data from large gene
expression studies of individuals who died by suicide have demonstrated changes in
the expression of GABA and glutamate receptors associated with depression (Chou
dary et al. 2005; Klempan et al. 2009: Sequeira et al. 2007, 2009).
) and metabotropic (GABAB) receptors in this process (Fee et al. 2017; Radhu
A
Glutamate
Glutamate is the principal excitatory neurotransmitter in the brain. A growing body
of evidence suggests that disruption in glutamatergic neurotransmission plays a cen
tral role in the pathophysiology of depression (reviewed in Duman et al. 2019; Lener
et al. 2017; Sanacora et al. 2012). Stress reactivity may be one pathway through which
this occurs. Exposure to acute stress results in increased levels of extracellular glutamate within the prefrontal cortex and hippocampus, and it has been hypothesized
that this in turn leads to excitotoxicity driven by glutamatergic activation of extrasyn
aptic N-methylcortex and hippocampus (reviewed in Popoli et al. 2011).
Data from a systematic review and meta-analysis of in vivo proton MRS studies indicate that glutamate and related metabolites are reduced within the frontal cortex of
individuals with major depressive disorder (Moriguchi et al. 2019). Reduction in the
level of cortical glutamate may be related to the loss of glial cells, which play a key
role in the reuptake and recycling of glutamate (Hamidi et al. 2004; Ongür et al. 1998;
Rajkowska and Miguel-Hidalgo 2007). Imaging studies combining MRS and func
tional MRI have demonstrated that glutamate levels in the medial prefrontal cortex
are associated with the extent of connectivity to subcortical regions (Duncan et al.
2013) and that reduced glutamate levels in the subgenual anterior cingulate cortex are
associated with reduced connectivity in the insula (Horn et al. 2010) and reduced re
sponses to emotionally salient stimuli in depressed patients with predominant anhedonia (Walter et al. 2009). Data from postmortem studies have demonstrated reduced
levels of the NR2A and NR2B subunits of the NMDA receptor (Feyissa et al. 2009) and
reductions in synaptic markers and increased loss of synapses (Kang et al. 2012) within
the dorsolateral prefrontal cortex of patients with unipolar depression.
D-aspartate (NMDA) receptors, resulting in atrophy of the prefrontal
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Conclusion
In this brief chapter, I have provided an overview of clinical and experimental research findings related to the neurochemical pathophysiology of unipolar and bipolar mood disorders. Despite the enormous volume of translational and clinical
research on the biological basis of mood disorders, the fundamental causes of these
disorders remain unclear. Philosophically, there has been a shift from reductionist,
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single-neurotransmitter models of mood disorder pathophysiology to complex and
hierarchical models of pathophysiology emphasizing the impact of genetics, develop
mental and adult exposure to environmental stress, sex differences, role of neuroplasticity and neurotrophic processes, and contributions from the immune and endocrine
systems (reviewed in Duman et al. 2019; Miller et al. 2017). Broadly speaking, chal
lenges to progress have included the variety of mood states (and their putative subtypes) to study—that is, euthymic (unipolar vs. bipolar), depressed (unipolar vs.
bipolar), manic, and mixed—along with a reliance, driven by practical consider
ations, on cross-sectional instead of longitudinal studies. Future research in the form
of interdisciplinary “team science,” involving the recruitment of large samples, use of
consistent case definitions, and use of longitudinal methods, may have a transforma
tive impact on the understanding of mood disorders.
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