Depression As An Immunometabolic Disorder

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Depression As An Immunometabolic Disorder: Exploring Shared

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Article in Current Neuropharmacology · April 2020

DOI: 10.2174/1570159X18666200413144401
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Current Neuropharmacology, 2020, 18, 00-00 1
REVIEW ARTICLE
Depression as an Immunometabolic Disorder: Exploring Shared Pharma-

cotherapeutics with Cardiovascular Disease
Mervin Chávez-Castillo1,2, Manuel Nava2, Ángel Ortega2, Milagros Rojas2, Victoria Núñez2,
Juan Salazar2,*, Valmore Bermúdez3 and Joselyn Rojas-Quintero4
1
Psychiatric Hospital of Maracaibo. Maracaibo, Venezuela; 2Endocrine and Metabolic Diseases Research Center.
School of Medicine. University of Zulia. Maracaibo, Venezuela; 3Universidad Simón Bolívar, Facultad de Ciencias
de la Salud, Barranquilla, Colombia; 4Pulmonary and Critical Care Medicine Department, Brigham and Women’s
Hospital, Harvard Medical School, Boston, MA, USA
Abstract: Modern times have seen depression and cardiovascular disease (CVD) become notorious
public health concerns, corresponding to alarming proportions of morbidity, mortality, decreased
quality of life, and economic costs. Expanding comprehension of the pathogenesis of depression as
an immunometabolic disorder has identified numerous pathophysiologic phenomena in common
ARTICLE HISTORY
with CVD, including chronic inflammation, insulin resistance, and oxidative stress. These shared
components could be exploited to offer improved alternatives in the joint management of these
Received: January 07, 2020 conditions. Abundant preclinical and clinical data on the impact of established treatments for CVD
Revised: March 04, 2020
Accepted: April 16, 2020 in the management of depression have allowed for potential candidates to be proposed for the joint
management of depression and CVD as immunometabolic disorders. However, a large proportion
DOI: of the clinical investigation currently available exhibits marked methodological flaws which pre-
10.2174/1570159X18666200413144401
clude the formulation of concrete recommendations in many cases. This situation may be a reflec-
tion of pervasive problems present in clinical research in psychiatry, especially pertaining to study
homogeneity. Therefore, further high-quality research is essential in the future in this regard.
Keywords: Depression, cardiovascular disease, chronic inflammation, insulin resistance, oxidative stress, metabolism.
1. INTRODUCTION CVD-related mortality by up to 60% [5]. Moreover, they

share several pathophysiologic components, including
In recent years, depression has become one of the most
chronic low-grade inflammation, insulin resistance (IR), and
prominent conditions in daily clinical practice and is cur-
dysthrombogenesis [6]. The presence of these shared ele-
rently recognized as the leading cause of disability globally,
ments blurs the traditional distinction between mental and
amounting to extremely high direct and indirect financial physical illness, and could significantly change the manage-
costs, as well as representing a severe detriment to the qual-
ment standards of depression and CVD by posing the ques-
ity of life [1]. Interestingly, depression stands alongside car-
tion: How can the treatment of these conditions be integrated
diovascular disease (CVD) as some of the most prominent
on the basis of their common pathophysiologic components?
problems in public health at present, with CVD being the
This review aims to summarize current views on depression
first cause of mortality and morbidity worldwide [2]. The
as an immunometabolic disorder and its link with CVD, as
parallels in the epidemiology of these conditions have well as potential novel pharmacological options for their
sparked abundant research on their interrelated pathophysi-
joint management. A literature search was performed on
ology and clinical management.
PubMed, EMBASE, Scopus, ISI Web of Science, and Goo-
Although depression is notorious for frequently co- gle Scholar databases, from inception to January 2020.
occurring with a myriad of medical comorbidities [3], the
link with CVD appears to be particularly powerful, with 2. REVISITING DEPRESSION AS AN IMMUNO-
these entities sharing various risk factors such as chronic METABOLIC DISORDER
stress, physical inactivity, westernized dietary patterns and
2.1. From the Sparks to the Flame: Emphasis on Chronic
various metabolic alterations [4]—and depression increasing
Inflammation
Depression was historically conceived as an illness lim-
*Address correspondence to this author at the Endocrine and Metabolic ited to the brain-mind. However, in recent decades, accumu-
Diseases Research Center. School of Medicine. University of Zulia. Mara-
caibo 20th Avenue 4004, Venezuela; Tel/Fax: ++582617597279;
lating evidence has propelled a paradigm shift, where de-
E-mail: juanjsv18@hotmail.com pression is now understood as a systemic disease, with the
1570-159X/20 $65.00+.00 ©2020 Bentham Science Publishers

2 Current Neuropharmacology, 2020, Vol. 18, No. 0 Chávez-Castillo et al.
brain-mind and the body sharing a bidirectional relationship hyperactivation of microglia and neurotoxicity [16, 17]. As
[7]. Chronic inflammation (CI) has been identified as a key with all forms of CI, it is hypothesized to stem from the con-
common component in depression and multiple medical flation of extrinsic and intrinsic proinflammatory factors
conditions, including CVD, endocrine-metabolic disorders, (Fig. 1) [18, 19].
autoimmune disorders, cancer, and many others [8-11]. Al-
though inflammation is a key physiologic mechanism that A great body of research has documented the presence of
elevated circulating biomarkers of inflammation in partici-
aims to preserve homeostasis in the face of injury, it comes
pants with depression, including IL-1β, IL-6, IFNγ, TNFα
at the cost of profound disturbances in the functionality of
and acute-phase reactants, especially high-sensitivity C-
target tissues [12]. Classic examples of these include vascu-
Reactive Protein (hs-CRP), among others [20, 21]. Neuroin-
lar changes to allow exudate formation, such as increased
flammation and chronic stress are both powerful inducers of
endothelial adhesiveness and permeability in response to
cytokine signaling [13]. Nonetheless, all tissues are vulner- the neuroendocrine changes typical of depression, especially
sustained activation of sympathetic autonomous signaling
able to inflammation-induced changes, with each displaying
and the hypothalamus-pituitary-adrenal axis (HPAA) [22].
distinct patterns of dysfunction. Thus, systemic CI entails the
Notably, in non-depressed participants, acute and chronic
dysregulation of multiple organ systems [14].
stress, as well as increased inflammatory biomarkers have
The term “neuroinflammation” has been coined to de- been associated with “sickness behavior”, which features
scribe CI in the central nervous system (CNS), which in- many depressive characteristics, such as low mood, anhedo-
volves activation of microglia, astrocytes and oligodendro- nia, fatigue, and feeding and sleep disorders [18,23]. Indeed,
cytes, with the release of cytokines, chemokines, acute-phase neuroinflammation can significantly disrupt the metabolism
reactants, and other mediators [15]. Although neuroinflam- and signaling of monoamines—serotonin, norepinephrine
mation may be beneficial in the acute setting, for example, in and dopamine—the central neurotransmitters involved in the
the limitation of CNS infections; its persistence results in neurobiology of depression [24].
Fig. (1). Intrinsic and extrinsic etiologic factors of neuroinflammation. The additive and synergic effects of various intrinsic and extrinsic
factors results in chronic inflammation. Neuroinflammation in particular is associated with depression and other neuropsychiatric disorders.
(A higher resolution / colour version of this figure is available in the electronic copy of the article).
Depression as an Immunometabolic Disorder Current Neuropharmacology, 2020, Vol. 18, No. 0 3
Fig. (2). Molecular events associated with chronic inflammation in neurons. In neurons, chronic inflammation is associated with four major
pathophysiologic components: 1) Increased oxidative and nitrosative stress, which is associated with protein carbonylation and nitrosylation
as well as lipid peroxidation, which results in formation of neoepitopes and favors autoimmunity. Oxidative stress and nitrosative stress also
damages nuclear DNA and induces mitochondrial dysfunction. 2) Activation of stress-related intracellular signaling pathways, which pro-
mote apoptosis and disruptions in intracellular calcium homeostasis, worsen inflammation and oxidative stress, and impair neurotrophic sig-
nals. 3) Disruptions in monoamine metabolism, through activation of IDO, leading to kynurenine synthesis, which decreases serotonin avail-
ability and promotes excitotoxicity. 4) Excitotoxicity, promoted by kynurenine, disrupted calcium metabolism, and increased glutamate sig-
naling from glial cells. Abbreviations: Protein-CO: Protein carbonylation. Protein-NO: Protein nitrosylation. Lipid-OO-: Lipid peroxidation.
IKK: I kappa B Kinase. IkB: inhibitor kB protein. NFkB: Nuclear factor kappa B. MAPK: Mitogen-activated protein kinases. ERK: Extracel-
lular signal-regulated kinase. JNK: Jun N-terminal kinase. CREB: Cyclic AMP responsive element binding protein. Bcl-2: B-cell lymphoma-
2. IDO: Indoleamine 2,3-dioxygenase. TDO: Tryptophan 2,3-dioxygenase. ICH: Intracellular calcium homeostasis. IMM: Internal mitochon-
drial membrane. (A higher resolution / colour version of this figure is available in the electronic copy of the article).
At the molecular level, oxidative stress (OS), alterations creased expression of superoxide dismutase and glutathione
in intraneuronal signaling, disruptions in monoamine me- peroxidase [29, 30]. CI also involves hyperactivity of induc-
tabolism and excitotoxicity are the major pathophysiologic ible nitric oxide synthase (iNOS) with increased production
phenomena induced by CI in the context of depression (Fig. of nitric oxide and nitrosative stress (NS) by nitrosylation of
2). Oxidation of inflammatory mediators such as arachidonic proteins, membrane lipids and DNA [29, 31].
acid and its precursor, linoleic acid, entails increased produc-
tion of reactive oxygen species (ROS) [25-27], which can Proinflammatory cytokines, OS and NS act as alarm sig-
nals and can activate cellular stress-related kinases such as
cause membrane lipid peroxidation, DNA damage and pro-
JNK, p38 and IKK-kinase. These promote the nuclear trans-
tein carbonylation in neurons [28]. Patients with depression
location of NF-κB, a potent proinflammatory transcription
may be especially vulnerable to OS, with lower levels of
factor, thus worsening CI in a positive feedback loop [32-
antioxidant molecules such as glutathione, coenzyme Q10,
34]. Furthermore, patients with depression have been de-
and possibly zinc, vitamin A and vitamin D; as well as de-
scribed to exhibit significantly higher levels of IgM antibod-
ies against neoepitopes produced from CI, OS and NS [35]. clude decreased vagal tone with sympathetic hyperactivation,
Neuronal stress also potentiates signaling of the with increased non-selective α-adrenergic and β-adrenergic
ERK/CREB/Bcl-2 pathway, which promotes apoptosis, al- activity in the cardiovascular system [70, 71]. Platelet dys-
terations in intracellular calcium traffic, and release of cyto- function has also been described in depression, including
chrome C [36-38]. Neurons in the prefrontal cortex, anterior augmented intraplatelet traffic of calcium and other disrup-
cingulate cortex, amygdala and hippocampus may be par- tions in signaling, upregulation of α-adrenergic and 5HT2A
ticularly susceptible to these changes in depression [38-42]. receptors, P-selectin, glycoprotein IIb/IIIa and β-
Guan et al. reported prenatally stressed offspring rats to dis- thromboglobulin, and downregulation of serotonin transport-
play the decreased expression of these proteins in the pre- ers [72-74]. Indicators of endothelial dysfunction in de-
frontal cortex and hippocampus, in association with depres- pressed patients may improve with antidepressant therapy.
sion-like behavior [38]. Conversely, patients with depression López-Vílchez et al. found participants with depression to
may have impaired activity of Nrf-2, a transcription factor display higher levels of circulating endothelial cells, VCAM-
that promotes the expression of cytoprotective enzymes such 1 and soluble von Willebrand factor, which decreased gradu-
as thioredoxin reductase, glutathione peroxidase, glu- ally along 24 weeks in treatment with escitalopram [63].
tathione-S-transferase, haeme oxygenases, and others [43-
In addition, IR is a pivotal mediator between CI, CVD
45]. Indeed, imaging and postmortem studies have identified
and depression. IR, defined as decreased peripheral tissue
neuronal and glial modifications, as well as volumetric
changes in the hippocampus, amygdala, basal nuclei, the responsivity to insulin signaling [75], is promoted by proin-
flammatory mediators, particularly by inducing serine phos-
prefrontal cortex, and the anterior cingulate cortex, in asso-
phorylation of IRS-1 [76], as well as ectopic fat deposition in
ciation with cognitive impairment [46-48]. This structural
the liver and muscle tissue [77]. Typical hormonal changes
neurodegeneration is thought to be due to decreased signal-
of depression, such as increased catecholamine and gluco-
ing by neuroprotective mediators, such as the brain-derived
corticoid signaling, can also promote IR. This impact may be
neurotrophic factor (BDNF) and fibroblast growth factor
(FGF) [49-51]; which in turn are disrupted by the damaging most marked regarding the cognitive symptoms of depres-
sion, as described by Austin et al. in a cohort of 328 patients
environment promoted by CI and OS [52-54]. These altera-
[78]. This reduced sensitivity entails hyperinsulinemia,
tions in neurotrophic signaling may be reversible by antide-
which in turn yields deleterious effects on all organ systems,
pressant treatment [55-56]; and BDNF levels have been ob-
and predisposes to numerous cardiometabolic disturbances
served to rise in parallel with the improvement of depressive
such as obesity, hyperglycemia, dyslipidemia and hyperten-
symptoms in a clinical study by Piccinni et al. [57].
sion, among others [79]. In turn, these are all promoters of
Finally, in neurons, IFN-α, IFN-γ and TNF-α can activate CI, thus constituting a vicious cycle involving depression,
indoleamine 2,3-dioxygenase (IDO), which synthesizes CI, and IR (Fig. 3) [80].
kynurenine (KYN) from tryptophan, the precursor to sero-
Obesity is a powerful enhancer of IR and all its associ-
tonin, thus implicating decreased production of this mono-
ated disturbances. Adipose tissue has been recognized as an
amine. In addition, the metabolism of kynurenine yields qui-
immunologically active organ, through the secretion of
nolinic acid and kynurenic acid (KA), both of which promote
excitotoxicity by binding to NMDA receptors and promoting proinflammatory cytokines and adipokines: leptin, resistin
and adiponectin [81]. Leptin plays a physiological role,
glutamate release in glial cells [58]. Furthermore, KA may
where it promotes satiety in accordance with increasing adi-
impair dopamine release [59,60]. In patients with hepatitis C
pose tissue deposits. However, in obesity, leptin resistance is
undergoing therapy with IFN-α for 24 weeks, this treatment
a frequent finding, favoring an energetic imbalance towards
was associated not only with increased depressive symp-
excess [82]. Leptin also intervenes in the pathogenesis of
toms, but also increased KYN/tryptophan ratios, reflecting
higher IDO activity, as well as increased KYN/KA ratios, depression by potentiating HHPA activation [83] and pro-
moting the expression of IL-6 and TNFα [84]. Resistin and
corresponding to the degree of neurotoxicity involved [61].
adiponectin display opposite effects regarding CI and ener-
2.2. Feeding the Fire: Proinflammatory Neuroendocrine getic homeostasis, with the former being proinflammatory
Signaling and upregulated in obesity, and the latter being anti-
inflammatory and upregulated by weight loss, with de-
Certainly, the impact of CI on depression is hardly lim- creased expression in obesity [85]. Although the role of re-
ited to changes in the brain; it is widely recognized as a piv- sistin in depression remains obscure; adiponectin expression
otal pathophysiologic component in atherosclerosis, by po- has been found to be downregulated by glucocorticoid sig-
tentiating vascular chemotaxis, release of growth factors, and naling, which could further favor obesity and CI in depres-
proliferation of vascular smooth muscle cells, among other sion [86]. Altered adipokine levels have been widely re-
mechanisms. This underlines the shared mechanisms under- ported in depressed patients, especially increased leptin and
lying the pathogenesis of depression and CVD [62]. Partici- decreased adiponectin [87]. These mediators have been pro-
pants with depression also appear to have increased expres- posed as putative biomarkers for depression, though vari-
sion of VCAM-1 and other vascular adhesion and throm- ables such as the severity of depression and obesity may be
bogenic molecules in endothelial cells [63-67]. Hyperactiva- important confounders in this context as determined in a
tion of the HPAA and hypercortisolemia have been related to systematic review and meta-analysis by Carvalho et al. [88].
the downregulation of endothelial nitric oxide synthase Adipokines may be predictors of antidepressant therapy out-
(eNOS), impairing relaxation of vascular walls [68, 69]. comes, although similar concerns remain [89]. Because IR is
Other possible alterations of vascular tone in depression in- a natural stepping stone in the development of Type 2 Diabe-
Fig. (3). Relationship between chronic inflammation, insulin resistance and depression. Chronic inflammation, insulin resistance and depres-
sion constitute a positive feedback loop, each worsening each other through diverse disruptions in peripheral tissues and various cardiome-
tabolic disturbances. (A higher resolution / colour version of this figure is available in the electronic copy of the article).
tes Mellitus (DM2), and owing to the added psychosocial The sum of these CI- and IR-related risk factors results in
challenges by the disease [90], it is unsurprising that the endothelial dysfunction [104], which has also been associ-
prevalence of depression is two to three times greater in dia- ated with depression. Measures of endothelial dysfunction such
betic patients [91]. DM2 majorly enhances all pathophysi- as intima-media thickness and flow-mediated dilation have
ologic components related to IR, CI, and obesity [92], which been inversely correlated with the severity of depression
leads to potentiated neuroinflammation through the increased [105, 106]; highlighting the progressive impact of the immu-
OS and deleterious microvascular and macrovascular nometabolic disturbances in the evolution of depression.
changes [93]. Notoriously, brain structures involved in cir-
cuits related to suicidal behavior may be especially suscepti- 3. IMPACT OF ESTABLISHED TREATMENTS FOR
ble to damage in DM2 [91, 94, 95]. Hypertension is also CARDIOVASCULAR DISEASE IN THE MANAGE-
closely related to IR: Angiotensin II, a key mediator in the MENT OF DEPRESSION
renin-angiotensin-aldosterone system (RAAS) has been re-
ported to modulate neuroprotection via AT2 receptors in There have been significant advances in the elucidation
neurons [96-100]. In addition, activation of AT1 receptor of the mechanistic interplay between depression and CVD
favors CI and OS by triggering the release of TNFα and [4], and the effect of antidepressants on discrete cardiome-
other cytokines, activation of the NADPH-oxidase complex tabolic variables has been outlined [107]. Nevertheless, the
and NF-κB, and expression of iNOS and cyclooxygenase-2 effects of antidepressants on specific cardiovascular out-
(COX-2) [101-103]. comes remain undetermined [108]. The same is true for the
Table 1. Summary of key evidence regarding established treatments for cardiovascular disease in the management of depression.
Class Compounds (REF) Methodology Relevant Results
Anti-inflammatory treatment was associated with reduced

Systematic review and meta-analysis on 14
depressive symptoms (SMD, -0.34; 95% CI, -0.57 to -0.11;
trials (6262 participants), 10 with NSAIDs
NSAIDs, cytokine I2=90%). This was most prominent for celecoxib (SMD, -
and 4 with cytokine inhibitors assessing
inhibitors (113) 0.29; 95% CI, -0.49 to -0.08; I2=73%) on remission (OR,
their use for depression and depressive
Non- 7.89; 95% CI, 2.94 to 21.17; I2=0%) and response (OR, 6.59;
symptoms.
steroidal 95% CI, 2.24 to 19.42; I2=0%).
anti-
inflammatory Of the 21 patients who completed the study, 52.4% showed a
drugs Pilot open-label trial which included 24 significant response to the ASA + SSRI combination; and
patients with major depression who had 82% achieved remission by the end of the study. Significant
ASA + SSRI (117) not responded to treatment during at least 4 changes were observed in the HDRS ratings, with a baseline
weeks with an SSRI, and received add-on mean of 29.3±4.5 points, which decreased to 14.0±4.1 points
ASA 160 mg/day during 4 weeks. by day 7 (P<0.0001). This trend persisted until the end of the
study on day 28.
Randomized, placebo-controlled trial

Both groups obtained a significant reduction in HDRS scores,
which included 68 patients with major
Lovastatin + Fluoxet- although this was greater in the fluoxetine + lovastatin group.
depressive disorder who received up to 40
ine The fluoxetine + lovastatin group had a baseline mean HDRS
mg/day of fluoxetine + lovastatin 30
(124) score of 28.9±6.86 points, which decreased to 16.3±5.03 by
mg/day or fluoxetine + placebo for 6
week 6 (P<0.05).
weeks.
Statins
Patients treated with fluoxetine + simvastatin had a signifi-
Double-blind, placebo-controlled trial
cantly greater reduction in HDRS scores in comparison with
Simvastatin + which included 48 patients with moderate-
the fluoxetine + placebo group. The reductions in HDRS
Fluoxetine severe depression which received fluoxet-
scores for the former were of 8.04±4.09 by week 2 (P<0.01),
(125) ine 20-40 mg/day + simvastatin 20 mg/day
13.45±4.58 by week 4 (P<0.02), and 18.5±7.1 by week 6
or fluoxetine + placebo for 6 weeks.
(P<0.02). No adverse effects were reported during the study.
Systematic review and meta-analysis on 19

Pioglitazone was associated with reduced depressive symp-
trials (3369 participants), 9 with thia-
toms compared to controls (pooled effect size  =  -0.68 (95%
zoldinediones, 5 with metformin, 2 with
Various C.I. -1.12 to -0.24), p  =  .003, Nstudies  =  8, I2  =  83.2%); while
thiazolidenediones against metformin, 2
(128) metformin was compared to controls. Female sex was a pre-
with incretin-based therapies and 1 with
dictor for improvement of depressive symptoms with pioglita-
insulin, assessing their impact on depres-
zone.
sive symptoms.
In comparison with controls, pioglitazone was associated with

Meta-analysis with 4 randomized con-
Pioglitazone increased remission rates (27% versus 10%, I2=17.3%, fixed-
trolled trials comprising 161 patients with
Antidiabetic (131) effect model: [OR] =3.3, 95% confidence interval [95% CI;
a major depressive episode.
drugs 1.4; 7.8], P=0.008).
Administration of metformin was associated with a decrease

in MADRS (F1,112 = 26.43, p < 0.001) and HDRS-17
(F1,112 = 27.61, p < 0.001) scores compared to baseline. In
Double-blind, randomized, placebo-
addition, at week 24, patients on metformin showed a signifi-
controlled trial which included 58 patients
Metformin cant improvement in cognitive function; with improved WMS-
with depression and DM2 who received
(138) R scores in the verbal memory index (F1,112 = 22.19, p <
metformin 1-2 g/day or placebo for 24
0.001), visual memory index (F1,112 = 10.53, p < 0.01), gen-
weeks.
eral memory index (F1,112 = 4.27, p <0.05), attention and
concentration index (F1,112 = 12.62, p < 0.01), and delayed
memory index (F1,112 = 19.84, p < 0.001).
Preclinical study on rats subjected to an

unpredictable mild stress protocol which Treatment with Irbesartan + Fluoxetine decreased immobility
Irbesartan + Fluoxet- were treated with irbesartan 40 mg/kg time (166s, p<0.001) in the TST, whereas it increased swim-
Antihypertensive
ine and/or fluoxetine 25 mg/kg in monother- ming (184.16s, p<0.001) and climbing times (184.16s,
drugs
(145) apy or combination. Behavioral responses p<0.001) and decreased immobility time (8.5s, p<0.001) in the
were assessed with MFST and TST at MFST.
week 6.
(Table 1) contd….
Class Compounds (REF) Methodology Relevant Results
Omega-3 fatty acids appear to ameliorate depressive symp-

Meta-analysis which included 13 random-
toms in patients with MDD, especially at high doses, and in
ized, placebo-controlled trials with a total
patients who receive treatment with antidepressants. The over-
of 1233 adults with major depressive dis-
Polyunsaturated Omega-3 Fatty Acids all SMD was 0.172 (95% CI 0.018, 0.325; P=0.028) when
order who received supplemental omega-3
fatty acids (161) compared with placebo. Studies on participants with MDD
fatty acids. A meta-regression was per-
employing ⩾60% EPA yielded a highly significant SMD of
formed to evaluate the effects of the sup-
0.892 (95% CI 0.543, 1.241; P<0.001), compared to those
plement according to several variables.
with <60% EPA, which showed no effect.
Abbreviations: NSAIDs: Non-steroidal anti-inflammatory drugs; ASA: Acetylsalicylic acid; SSRI: Selective serotonin reuptake inhibitor; HDRS: Hamilton depression rating scale;
DM2: Type 2 diabetes mellitus; MADRS: Montgomery-Asberg depression rating scale; HDRS: Hamilton depression rating scale-17 items; WMS-R: Wechsler memory scale-revised;
MFST: Modified forced swim test; TST: Tail suspension test; MDD: Major depressive disorder; EPA: Eicosapentaenoic acid.
effects of cardiometabolic treatments on depression [109, −0.24) for symptom amelioration in depression [128]; and
110], remaining an equally provoking, yet uncertain field of another supports the role of pioglitazone in improving the
research (Table 1). probability of remission [131]. Indeed, numerous studies
have reported favorable results for the use of pioglitazone as
Non-steroidal anti-inflammatory drugs (NSAIDs) have
an adjuvant to antidepressants [132-134]. Indeed, there is
been posited as potentially useful modulators of CI in de- evidence that the antidepressant effect of pioglitazone is
pression due to their relatively selective pharmacodynamics
more perdurable when compared with other similar adju-
[111, 112]. Selective COX-2 inhibitors may be the most
vants, with trials as long as 24 weeks returning positive re-
promising in this regard. In a systematic review and meta-
sults [135]. However, it should be noted that these studies
analysis, celecoxib appeared to significantly decrease de-
mostly included individuals with obesity, DM2 and other
pressive symptoms without notable adverse effects, in con-
established metabolic disorders. Thus, the effects of pioglita-
trast with other NSAIDs and cytokine inhibitors [113]. Simi- zone in depression in more metabolically healthy partici-
lar findings have been supported by multiple trials [114-
pants remain to be ascertained.
116]. However, different NSAIDs appear to yield different
results in depression. In a pilot study on patients with treat- Metformin also has notorious anti-inflammatory activity,
ment-resistant depression (TRD), 52.4% of participants re- by decreasing expression of NF-κB via AMPK-dependent
sponded positively to the coadministration of acetylsalicylic and independent pathways, as well as improving energetic
acid with a selective serotonin reuptake inhibitor (SSRI) balance irrespective of the presence of DM2 and other meta-
[117]. In contrast, other studies with differing combinations bolic disturbances [136, 137]. In a 24-week double-blind,
of non-selective NSAIDs and SSRIs have failed to obtain placebo-controlled, randomized clinical trial of patients with
similar results [118-121]. At any rate, these findings should DM2, the administration of metformin significantly im-
be interpreted with caution, as the available trials were short proved depressive symptoms in comparison to placebo
and executed on younger participants. Indeed, the need for [138]. However, these results are not consistent across trials
optimization and uniformity of trial methodology is a recur- [139]; and pioglitazone may be a superior alternative: In a 6-
ring theme in the assessment of NSAIDs and several other week double-blind study on obese patients with depression
treatments for depression. and polycystic ovary syndrome and depression, monotherapy
Empirical evidence shows that the use of statins is asso- with pioglitazone granted greater improvement in depressive
ciated with a decreased risk of depression in adults [122]. symptoms than monotherapy with metformin [140]. Simi-
This effect has been hypothesized to be mediated by the re- larly to pioglitazone, the antidepressant potential of met-
duction of excitotoxicity and OS through antagonism of formin in metabolically healthy participants remains rather
NMDA receptors and IDO [123]. Several small, short, pla- unexplored. Research on other antidiabetic drugs—including
cebo-controlled trials have reported improved antidepressant glibenclamide [141], liraglutide [142], and sitagliptin
responses in participants treated with fluoxetine + lovastatin [143]—for depression remains chiefly in preclinical stages.
[124], fluoxetine + simvastatin [125], and citalopram + sim- Concerning antihypertensive drugs, amounting preclini-
vastatin [126]. Yet, again, future trials require larger samples cal and clinical evidence suggests a link between modulation
and longer duration to better ascertain the efficacy of statins of the RAAS to intervene in the pathophysiology of depres-
as antidepressant adjuvants. Clinical research on other hypol- sion [144-150]. Angiotensin-converting enzyme inhibitors
ipidemic drugs in depression is scarce, and preclinical find- (ACEI), and angiotensin-receptor blockers (ARB) may im-
ings seem discouraging [127]. pact depression by reducing CI and OS, and promoting neu-
A variety of antidiabetic drugs have also been evaluated rogenesis [148]. Out of all classes of antihypertensive drugs,
in depression [128]. Most research has focused on thia- only ACEI and ARB were associated with decreased risk for
zolidinediones, which have powerful anti-inflammatory ac- hospitalization related to a mood disorder in a large retro-
tivity via activation of PPAR-γ and downregulation of eNOS spective study by Boal et al. [149]. Likewise, in the HUNT
[129] and have shown antidepressant activity in rat and study from Norway, hypertensive patients treated with
mouse models [130]. In a meta-analysis, these drugs dis- ACEIs had lower odds of displaying symptoms of depression
played a pooled effect size of −0.68 (95% C.I. −1.12 to [150]. However, future studies accounting for confounders
such as disease severity, comorbidities and polypharmacy [160]. A meta-analysis by Martins et al. [161] found omega-
should clarify the true role of antihypertensive drugs as anti- 3 fatty acids to enhance antidepressant response, yet with
depressant adjuvants. great variability depending on EPA contents: Only studies
with EPA contents ≥60% showed significant antidepressant
Finally, in recent decades, omega-3 fatty acids received
effects, in contrast with studies using EPA contents <60%.
widespread acceptance as augmenting agents for antidepres- This highlights the importance of continuous evaluation of
sant therapy [151-154]. These molecules have been recog-
novel antidepressant alternatives in clinical settings.
nized due to their direct anti-inflammatory and antioxidant
properties [155]. They may also participate in the neurobiol-
4. POTENTIAL PHARMACOLOGICAL CANDIDATES
ogy of depression by modulating the expression and func-
FOR THE JOINT MANAGEMENT OF DEPRESSION
tionality of serotonin and dopamine receptors [156]. Never-
AND CARDIOVASCULAR DISEASE
theless, more recent meta-analyses have reframed the role of
these molecules for depression, with reports of small, non- In addition to the use of antidepressants for CVD and the
significant effect sizes [157-159]. The variable concentra- use of cardiometabolic treatments for depression, other
tions of eicosapentaenoic acid (EPA) in omega-3 prepara- pharmacological options have been studied in an effort to
tions may be an important intervening factor in this scenario attack both problems simultaneously. CI remains a prime
Table 2 Summary of key evidence regarding new pharmacological candidates for the joint management of depression and cardio-
vascular disease.
Class Compounds (REF) Methodology Relevant results
Multicentric, double-blind, randomized, placebo-

At week 12, treatment with ustekinumab was associated
controlled trial where 1230 patients with psoriasis
with significant reductions in HADS scores both in patients
Ustekinumab (164) who received ustekinumab 45 mg, ustekinumab
who received 45 mg (-1.7 ± 3.1) and 90 mg (-2.1 ± 3.4);
90 mg, or placebo for 24 weeks, and had their
P<0.001.
depressive and anxious symptoms evaluated.
Double-blind, randomized, placebo-controlled

Interleukin A significant reduction in depressive and anxious symptoms
trial with 380 patients with atopic dermatitis who
antagonists was observed at 16 weeks in patients treated with dupilumab
Dupilumab (165) were treated with dupilumab 100 mg, 200 mg or
(P<0.001), with 66.7-75% reductions in the treated groups
300 mg, or placebo for 16 weeks, and had their
vs 22.2% in the placebo groups.
depressive and anxious symptoms evaluated.
Double-blind, randomized, placebo-controlled,

Of patients with high-sensitivity C-reactive protein levels >5
12-week trial with 60 patients with major depres-
Infliximab (166) mg/L, 62% showed an improvement of ≥50% in depressive
sion who received three infusions of infliximab (5
symptoms as assessed with the HDRS.
mg/kg, at baseline and weeks 2 and 6) or placebo.
Systematic review including 65 studies on the use The grade of recommendation for depressive disorder was
Antioxidants NAC (171) of NAC for various neuropsychiatric disorders, of B. Authors highlight the need for further controlled studies
which 2 were on depressive disorder. and longer follow-up for assessing consistent improvement.
The pooled effect size was 0.49 inconsequential, with a non-

Systematic review and meta-analysis with 40 significant difference between folic acid and placebo
studies on various nutraceuticals, including 9 on (p=50.23; z=51.19, 95% confidence interval [CI], –0.31 to
Various (174)
folate, folinic acid, methylfolate, or a combination 1.29). Similarly, isolated analysis of methylfolate yielded a
of folic acid with vitamins B6 and B12. non-signifcant effect (p=50.25; z=51.15, 95% CI, –0.22 to
0.83).
Vitamins
A mean reduction of 8.5 points (58.2% decrease) was found
in patients’ PHQ-9 score (mean baseline PHQ-9 score=
Naturalistic clinical trial with 554 patients, of
14.6, mean follow-up PHQ-9 score= 6.1; P = .000). In
L-Methylfolate (175) which 502 received L-methylfolate as adjunctive
addition, 376 patients (67.9%) showed treatment response,
therapy, and 52 as monotherapy.
while 253 (45.7%) achieved remission after an average of
95 days in treatment.
All treatment arms showed a significant reduction in HDRS

Double-blind, randomized, placebo-controlled,
scores (p<0,001); with a reduction of mean scores from
Nutritional 12-week trial on 189 patients with MDD who
SAMe (185) 18.98 ± 5.09 to 12.79 ± 7.38 (p < 0.001) in the group treated
supplements were treated with SAMe 1600-3200 mg/d, escita-
with SAMe. Remission rates were 28% for SAMe, 28% for
lopram 10-20 mg/d or placebo.
escitalopram, and 17% for placebo.
Abbreviations: HADS: Hospital anxiety and depression scale; HDRS: Hamilton depression rating scale; NAC: N-acetylcysteine; PHQ-9: Patient Health Questionnaire-9; SAMe: S-
adenosylmethionine; MDD: Major depressive disorder.
therapeutic target in this context, with numerous other forms has raised concerns of increased cardiovascular risk, due to
of anti-inflammatory agents being studied in these circum- being a precursor of homocysteine [181]. In animal models,
stances (Table 2) [119]. Immunotherapy may be a frontrun- SAMe has been shown to increase the synthesis of mono-
ner in this regard, as it has been ascertained to diminish car- amines, modulate neurotransmission and improve membrane
diovascular risk in patients with rheumatoid arthritis and fluidity [182]. Although current findings suggest SAMe to
other similar conditions [162, 163]. Immunotherapy may be innocuous regarding cardiovascular risk [183], evidence
also be useful in depression: in a randomized, double-blind, regarding its efficacy for depression is inconsistent, and nu-
placebo-controlled, 24-week trial carried out on 1230 pa- merous studies have failed to show significant benefits to its
tients with moderate-severe psoriasis, treatment with usteki- use [184, 185].
numab, an IL-12 and IL-23 antagonist, was associated with
significant improvement of anxious and depressive symp- CONCLUSION
toms [164]. In a similar study on 380 patients with severe
The integration of the management of depression and
atopic dermatitis, the administration of dupilumab, an IL-4
CVD on the basis of their shared pathophysiologic compo-
antagonist, was also associated with a significant reduction
nents is an attractive prospect. However, great gaps in cur-
of anxious and depressive symptoms [165]. Indeed, to date,
rently available preclinical and clinical knowledge preclude
improvement of depression is a secondary outcome in most
the introduction of novel alternatives in this regard at this
trials assessing immunotherapeutics. Nevertheless, a small time. CI is undoubtedly the most appealing target in this con-
randomized, double-blind, placebo-controlled, 12-week trial
text. Although the need for further clinical investigation is
by Raison et al. [166] evaluating the use of TNFα antagonist
indisputable, researchers should mind the common research
infliximab for TRD reported more promising results. In this
design problems frequently seen in clinical psychiatry. In-
study, participants in the control group with initial hs-CRP
deed, beyond the necessity for more homogenized method-
levels >5 mg/L showed >50% improvement of depressive
ology and clear study outcomes, a wide spectrum of ques-
symptoms. Future studies should explore more in-depth the tions must be addressed earnestly, ranging from the practical,
utility of immunotherapy in populations with depression
in population selection and follow-up duration; to the con-
without other inflammatory comorbidities.
ceptual, including the very definition of TRD, remission and
Various nutritional supplements have also been studied in relapse [186, 187].
the management of depression. N-acetylcysteine (NAC) has
The resolution of these conundrums is necessary to im-
particularly ignited research interest given its role as an anti-
prove the quality of research in clinical psychiatry, and con-
oxidant by replenishing glutathione levels, as well as being sequently facilitate the introduction of revolutionizing thera-
an immunomodulator, and regulator of glutamate and dopa-
peutic measures in depression, CVD, and other associated
mine neurotransmission [167, 168]. Its antioxidant properties
conditions. In the meantime, lifestyle recommendations, in
have proved useful in the management of CVD [169, 170].
the form of sufficient physical activity and dietary modifica-
Current clinical evidence on NAC for depression is consid-
tions, may be invaluable, safe and useful tools in the treat-
ered only preliminary, with further confirmatory research
ment of depression, CVD, and many related immunome-
required, especially on the exploration of optimal dosing tabolic disorders.
schemes and candidate selection, as determined in a system-
atic review by Deepmala et al. [171]. Indeed, clinical out- CONSENT FOR PUBLICATION
comes remain equivocal, with trials reporting improvement
of depressive symptoms without changes in inflammatory Not applicable.
biomarkers [172]; or major uncertainty in regards to suffi-
cient and optimal duration of administration [173]. FUNDING
Finally, folate has also been studied substantially in the None.
context of depression. A large systematic review and meta-
analysis concluded that available data assessing folate, fo- CONFLICT OF INTEREST
linic acid and methylfolate on this matter are contradictory, The authors declare no conflict of interest, financial or
without any determinant evidence in favor of folate, and otherwise.
relatively more positive results for methylfolate [174]. Inter-
estingly, in isolated clinical trials methylfolate appears to be ACKNOWLEDGEMENTS
beneficial both alone and as adjunctive therapy [175, 176].
This should warrant further investigation, as in the National Declared none.
Health and Nutrition Examination Survey (NHANES),
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1. INTRODUCTION CVD-related mortality by up to 60% [5]. Moreover, they

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Class Compounds (REF) Methodology Relevant Results

Anti-inflammatory treatment was associated with reduced

Randomized, placebo-controlled trial

Systematic review and meta-analysis on 19

In comparison with controls, pioglitazone was associated with

Administration of metformin was associated with a decrease

Preclinical study on rats subjected to an

Class Compounds (REF) Methodology Relevant Results

Omega-3 fatty acids appear to ameliorate depressive symp-

Class Compounds (REF) Methodology Relevant results

Multicentric, double-blind, randomized, placebo-

Double-blind, randomized, placebo-controlled

Double-blind, randomized, placebo-controlled,

The pooled effect size was 0.49 inconsequential, with a non-

All treatment arms showed a significant reduction in HDRS

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