REVIEW ARTICLE

The inflammation hypothesis in geriatric depression

George S. Alexopoulos,y and Sarah Shizuko Morimotoz
Weill Cornell Institute of Geriatric Psychiatry, White Plains, New York, USA
Correspondence to: G. S. Alexopoulos, E-mail: gsalexop@med.cornell.edu
y
S.P. Tobin and A.M. Cooper Professor, Director, Weill-Cornell Institute of Geriatric Psychiatry, White Plains, New York.
z
Research Fellow, Weill-Cornell Institute of Geriatric Psychiatry, White Plains, New York.

Background: A large body of research has focused on ‘‘mediating mechanisms’’ and predisposing brain
abnormalities to geriatric depression, but little is known about its etiology. This paper examines whether
age-related and comorbid disease-related immune deregulation is an etiologic contributor to geriatric
depression.
Methods: This article reviews findings on neuroinflammation during the aging process and depression as
well as studies of anti-inflammatory actions of classical antidepressants and antidepressant actions of
anti-inflammatory agents.
Results: Aging results in increased peripheral immune responses, impaired peripheral-CNS immune
communication, and a shift of the CNS into a pro-inflammatory state. These exaggerated and prolonged
immune responses may lead to changes in the function of emotional and cognitive networks pertinent to
geriatric depression and to behavioral changes reminiscent of the depressive and cognitive symptoms of
geriatric depression. Some antidepressants may reduce the expression of inflammation markers. Limited
data suggest that some anti-inflammatory agents may have antidepressant properties.
Conclusions: A synthesis of available findings suggests that aging-related and comorbid disease-related
inflammatory processes may promote changes in the neural systems predisposing to geriatric depression
or facilitating metabolic changes that mediate depressive syndromes. The ‘‘inflammation hypothesis’’ in
geriatric depression cannot be tested in its entirety, but it can lead to testable hypotheses and data on
mechanisms by which inflammatory processes promote geriatric depression. The significance of such an
effort is that it may lead to a novel treatment development model bringing to bear recent advances of
anti-inflammatory pharmacology to the treatment of depressed elderly patients. Copyright # 2011 John
Wiley & Sons, Ltd.
Key words: immunity; aging; depression; geriatrics
History: Received 10 September 2010; Accepted 10 November 2010; Published online 2 March 2011 in Wiley Online Library
(wileyonlinelibrary.com).
DOI: 10.1002/gps.2672

Introduction

A model intended to organize research in geriatric more likely to develop in predisposed persons with
depression proposed that factors contributing to this abnormalities in brain structures responsible for
disorder be divided into ‘‘mediating mechanisms’’, emotional regulation including those of the cognitive
‘‘predisposing brain abnormalities’’ and ‘‘etiological control network (dorsal anterior cingulate and the
contributors’’(Alexopoulos 2005). According to this lateral prefrontal cortex), the emotional control system
model the symptoms and signs of geriatric depression (dorsal and rostral anterior cingulate and amygdala),
are mediated by metabolic brain changes; hypometa- and the hippocampus. Aging and disease-related
bolism in several dorsal neocortical structures and processes may serve as etiological factors by either
hypermetabolism in some ventral limbic structures directly promoting metabolic changes mediating
(Alexopoulos 2002). These metabolic changes are the depressive syndrome, or by increasing brain

Copyright # 2011 John Wiley & Sons, Ltd. Int J Geriatr Psychiatry 2011; 26: 1109–1118.
1110 G. S. Alexopoulos and S. S. Morimoto

abnormalities predisposing to geriatric depression. In oxygen and nitrogen free radicals, neurotransmitters
addition, chronic stress may lead to depression by and proteolytic enzymes (Giulian et al., 1986;
promoting abnormal processes at each of the three Gehrmann et al., 1993; Banati and Graeber 1994;
levels, i.e., mediating mechanisms, predisposing ab- Jones et al., 2008). Microglia recruit and activate
normalities, and etiological contributors. A large body astrocytes (Blasko et al., 2004), which also produce
of research has focused on mediating mechanisms and cytokines and chemokines, metabolize extracellular
predisposing brain abnormalities (emotional and neurotransmitters, and support damaged neurons
cognitive control systems) to geriatric depression but through neurotrophic substances (Darlington 2005).
much less attention has been given to their etiology. The activation of microglia can be both neuroprotec-
Abnormal immune responses have been hypothes- tive and neurotoxic (Kreutzberg 1996). Microglia
ized to contribute to development of depressive facilitate the return to homeostasis once an insult is
symptoms and signs (Maes, 2010). Despite encoura- contained by participating in tissue repair, by
ging findings, the immune hypothesis of depression removing offending agents and cytokines, and by
has led to few attempts at novel antidepressant secreting injury-healing factors. However, excessive
treatment development. This paper reviews findings activation of microglia can be cytotoxic through the
on the effects of both aging and aging-related processes release of excitatory amino acids and cytokines (Dilger
on CNS immunity with the goal of examining whether and Johnson 2008).
inflammatory processes are likely contributors to brain Cytokines are polypeptides central to the function of
changes predisposing to depression or mediating both the CNS and the peripheral immune system
geriatric depression syndromes. (Wang et al., 2002). In the CNS, they are mainly
produced by microglia and astroglia though all CNS
cells are capable of cytokine production (Wang et al.,
CNS immune regulation 2002). Cytokines can be broadly grouped into related
families including tumor necrosis factor (TNF),
Historically, the CNS has been considered an immune- interleukin (IL), interferon (INF), colony stimulating
privileged organ, as it lacks a lymphatic system and is factor (CSF), and transforming growth factor (TGF)
somewhat shielded from the circulatory system by the (Wang et al., 2002). Cytokines are part of the
blood–brain barrier (Hwang et al., 2009; Lucin and homeostatic apparatus, able to participate in removal
Wyss-Coray 2009). However, it is now understood that of damaged cells as well as in repair and neuror-
the CNS has its own immune system that is distinct egeneration processes. However, depending on the
from but interacts with the immune system of the magnitude, length, and timing of their induction,
periphery. Communication of peripheral immune cytokines can exact severe tissue damage and have been
responses to the CNS leads to changes in both the implicated in some neurodegenerative and immune
CNS immune responses and in behavior (Blalock disorders as well as in stroke (Wang et al., 2002).
1994). Cytokines play a central role in the system by which
The CNS immune system is regulated by both the peripheral immune system communicates with the
macroglial and microglial cells. The first line of CNS CNS (Dilger and Johnson 2008). They may enter the
immune defense are microglia (Kreutzberg 1996), CNS through areas of blood–brain barrier that are
comprising 5% to 20% of the total CNS glial cell highly permeable or through active transport (Banks
population. Most of the time, microglia exist in a 2001). Cytokines may also bind to receptors within
quiescent phase (Kreutzberg 1996). However, some cerebral blood vessels and induce the production of
microglia reside in a ‘‘primed’’ state characterized by second messengers that, then, diffuse into the brain
shortened processes, and expression of cell surface (Maier and Watkins 2003). Finally, peripheral cyto-
markers. These microglia are similar to activated kines may directly stimulate vagal and trigeminal
microglia but do not secrete significant cytokines. afferent fibers and trigger production of cytokines in
However, primed microglia can be rapidly induced and the CNS (Maier et al., 1998; Goehler et al., 2000;
lead to greater cytokine production than non-primed Romeo et al., 2001).
microglia. Stimulation with an antigen activates
microglia and leads to retraction of cellular processes, Aging of CNS immunity
changes in surface marker expression, and the release
of cytokines. Further activation turns microglia into The aging process shifts the organism into a pro-
phagocytes, similar to macrophages in the periphery. inflammatory state. This shift is mediated by increased
Activated microglia secrete cytokines, growth factors, immune responses in the periphery, disruption of the

Copyright # 2011 John Wiley & Sons, Ltd. Int J Geriatr Psychiatry 2011; 26: 1109–1118.
Inflammation hypothesis in geriatric depression 1111

periphery-CNS immune communication, and an role of immune regulation in the pathogenesis of

increased and discordant CNS response. More than depression. In his ground breaking work, Maes and his
half of the genes upregulated during late life are genes co-workers suggested that depression is characterized
regulating inflammatory processes (Lee et al., 2000; Lu by cell-mediated immune activation (Maes et al., 1990;
et al., 2004; Lucin and Wyss-Coray 2009). Maes 1993; Maes et al., 1993) Support for this
Aging disrupts the peripheral immune system hypothesis was provided by increases in the numbers
leading to excessive innate immune activity (Gruver and percentages of T cells with activation markers,
et al., 2007). Disruption in the periphery-CNS enhanced stimulated production of INF-g, higher
immune communication further contributes to a neopterin and soluble TNF receptor-1 or 2 levels,
pro-inflammatory shift of CNS. As a consequence, induction of indoleamine 2,3 deoxygenase (IDO), and
peripheral immune stimulation produces a dispropor- glucocorticoid resistance in immune cells (Maes).
tional CNS inflammatory response in older adults, Additional markers of immune activation have also
leaving some older adults in a chronic state of been identified in depression. These include increased
neuroinflammation characterized by continuous pro- numbers of neutrophils and monocytes, increased
duction of pro-inflammatory cytokines (Ye and prostaglandin E2, haptoglobin, and C-reactive protein
Johnson 1999; Dilger and Johnson 2008). (CRP) in the peripheral blood of depressed patients
The pro-inflammatory shift of the aging CNS is (Calabrese et al., 1986; Joyce et al., 1992; Sluzewska
characterized by increased numbers of both activated et al., 1996; Maes et al., 1997).
and primed microglia, continuous production of pro- Peripheral cytokines have been studied in younger
inflammatory cytokines, and decreases in antiinflam- adult major depression. A meta-analysis of community
matory molecules (Sparkman and Johnson 2008). and clinical samples found evidence that serum levels
Dystrophic changes in microglia result in morpho- of IL-6, IL-1, IL-1ra, and CRP are associated with
logical changes including atrophic or fragmented depressive symptoms (Howren et al., 2009). The
processes, diminished phagocytic function, reduced associations between cytokines and depression were
ability to secrete neurotrophic factors, and increased stronger in clinical samples with high severity of
production of inflammatory proteins (Streit et al., depression than community samples suggesting a
2008). Activated microglia have a shorter life span than ‘‘dose-effect relationship’’. A more recent meta-
quiescent microglia (Streit et al., 2008) but are analysis evaluated findings of 24 studies of unstimu-
replenished by mitosis of parenchymal microglia, or lated levels of cytokines in patients with major
by migration of bone marrow progenitor cells during depression (Dowlati et al., 2010). This study concluded
injury or inflammation (Graeber et al., 1988; Flugel that there are significantly higher concentrations of
et al., 2001). Interestingly, the mitotic ability of IL-6 and TNF-a in depressed compared to control
microglia, is not reduced, and may even be enhanced in subjects, but either no evidence or inconclusive
late life (Conde and Streit 2006). However, increased evidence of differences in IL-1b, IL-4, IL-2, IL-8,
mitosis, along with increased activation, may promote IL-6, IL-10, and INF-g.
further production of senescent microglia (Streit et al., Peripheral cytokines levels have also been investi-
2008). gated in both older depressed and older community
In summary, aging renders microglia hypervigilant, residents. The rationale of these studies has been that
and prone to excessive and prolonged release of pro-inflammatory cytokines can contribute to the
cytokines IL-1b, IL-6, and TNF-a when challenged by development of depressive symptoms and induce
immune stimuli (Wei et al., 1992; Ershler 1993; Ershler stress-reactive hormonal and brain neurotransmitter
et al., 1993; Hager et al., 1994; Godbout and Johnson changes similar to those of depression.
2006; Maggio et al., 2006). Activation of microglia There have been five epidemiologic studies focused
places a burden on the cells metabolic mechanisms. on the relationship of peripheral cytokines to depres-
The end results of these processes are neuron loss, sive symptoms in older adults (Dentino et al., 1999;
inefficient clearance of neurotoxic molecules, and Penninx et al., 2003; Tiemeier et al., 2003; Bremmer
reduction of neurogenesis (Carpentier and Palmer et al., 2008; Milaneschi et al., 2009). The most
2009; Lucin and Wyss-Coray 2009). consistent finding has been an association of elevated
IL-6 with depressive symptoms after controlling for
Inflammatory indices in geriatric depression likely confounding variables (Dentino et al., 1999;
Penninx et al., 2003; Tiemeier et al., 2003; Bremmer
The relationship between immune, endocrine and et al., 2008). In the health, aging, and body com-
neurotransmitter functions generated interest in the position sample, the association between IL-6 serum

Copyright # 2011 John Wiley & Sons, Ltd. Int J Geriatr Psychiatry 2011; 26: 1109–1118.
1112 G. S. Alexopoulos and S. S. Morimoto

level and depressive symptoms was stronger in older Circulating inflammatory cytokines are elevated in
men than in older women (Penninx et al., 2003). In the conditions comorbid with geriatric depression. Serum
Rotterdam Study sample, high IL-6 levels were found levels of IL-1 have been correlated with various aspects
in older adults with depressive disorders with similar of cardiovascular disease and its outcomes (Aposto-
IL-6 serum levels among those with dysthymia, minor lakis et al., 2008). In vitro studies have demonstrated
or major depression (Tiemeier et al., 2003). The that IL-1a, IL-1b, and IL-18 have atherogenic proper-
association of IL-6 elevation with major depression was ties including up-regulation of adhesion molecules,
confirmed by the Longitudinal Aging Study Amster- activation of macrophages, and smooth muscle
dam (LASA) (Bremmer et al., 2008). Finally, the proliferation (Apostolakis et al., 2008). Other cyto-
InCHIANTI study observed an elevation of IL-1ra in kines have been implicated as well. In the sample of
older adults with depressive symptoms. Moreover, the Health, Aging, and Body Composition Study,
high IL-1ra levels were a risk factor for developing increased IL-6 and TNF-a levels in the periphery were
depressive symptoms during a 6-year follow-up a risk factor of subclinical and clinical cardiovascular
(Milaneschi et al., 2009). disease (Cesari et al., 2003). These findings have been
Studies of patients with depressive disorders indicate confirmed by others (Kritchevsky et al., 2005). IL-6
elevated IL-1b levels in geriatric major depression and TNF-a are both acute-phase proteins. In the
although some disagreement exists. An early study periphery, IL-6 is secreted by macrophages and
found no significant differences in peripheral IL-1b, monocytes and leads to proliferation of B cells
IL-6, and TNF-a between older women with major (Hodgkin et al., 1988; Mayer et al., 1991). TNF-a is
depression and normal female controls (Brambilla and secreted by macrophages, mast cells, and natural killer
Maggioni, 1998). However, a well designed study cells and is associated with release of pro-inflammatory
observed that older adults with major depression, but cytokines and prostaglandins from macrophages
not those with subsyndromal depression, had higher (Lindemann 1991). Finally, increased inflammatory
IL-1b serum levels than similarly aged controls indices (plasma IL-6) are associated with development
(Thomas et al., 2005). A functional polymorphism of cognitive impairment, disability and mortality in
in the promoter region of the IL-1b gene (IL-1b- late life (Ferrucci et al., 1999; Harris et al., 1999;
511c/t) is associated with age of early onset of geriatric Weaver et al., 2002; Roubenoff et al., 2003; Maggio
depression (Hwang et al., 2009). IL-1b was correlated et al., 2006).
with severity of depression (Thomas et al., 2005). In Stress, a precipitant of depression, promotes
other studies of depressed elderly patients, several inflammation in both aged animals and humans.
inflammatory markers (plasma: TNF-a, IL-6, and IL- Stress can activate microglia and upregulate the
1b) were correlated with the severity of depressive expression of cell surface antigens such as major
symptoms overall (Diniz et al., 2010a,b; Grassi- histocompatability complex (MHC) class II (Frank
Oliveira et al., 2009) as well as cognitive symptoms et al., 2007). Chronic stress further exacerbates age-
of depression (Gimeno et al., 2009). In addition, IL-6 is related increases in inflammation (Buchanan et al.,
associated with increased suicide risk, with the highest 2008). In addition, earlier exposure to a particular
levels of IL-6 correlating with the most violent suicide stressor can prime microglia and increase its inflam-
attempts (Lindqvist et al., 2009). matory responses to subsequent encounters with that
Peripheral cytokines have been found to be elevated stressor (Johnson et al., 2002; Frank et al., 2007).
in older adults at risk for depression. Caregiving for External stressors have been associated with increases
an ill relative increases both depressive symptoms in circulating IL-1b and IL-6 and in cognitive
and inflammatory markers in the elderly. In cross- impairment in elderly patients (Sparkman and
sectional studies, family caregivers of dementia Johnson, 2008).
patients had higher levels of circulating IL-6 than Most of the evidence linking inflammation to
age-matched controls (Lutgendorf et al., 1999). geriatric depression with inflammation is based on
Studies have indicated that not only are circulating measures of peripheral inflammatory markers. It is
cytokine levels higher, but the response to immune difficult for these large molecules to cross the blood–
challenge lasts longer in stressed elderly populations. brain barrier. Peripheral immune responses may be
Specifically, elderly caregivers had a prolonged followed by CNS immune changes through the
elevation in IL-6 of up to four weeks following periphery-CNS communication system. Thus, a pro-
influenza vaccine, where as there was no IL-6 change inflammatory state of the periphery can serve as a
in non-caregiving age matched controls (Harris stimulus for direct studies of the CNS inflammatory
et al., 1999). status in geriatric depression. Such studies are feasible

Copyright # 2011 John Wiley & Sons, Ltd. Int J Geriatr Psychiatry 2011; 26: 1109–1118.
Inflammation hypothesis in geriatric depression 1113

in humans because several PET ligands are now et al., 2003). In older animals, IL-6 is concentrated in
available permitting in vivo assessment of activated the hippocampus, cerebral cortex and cerebellum
microglia. compared with younger cohorts (Ye and Johnson 1999;
Ye and Johnson 2001).
In normal adults, the inflammatory response to
Putative immune mechanisms in geriatric immune challenge may lead to changes in the function
depression of emotional networks. Enhanced activity of the
subgenual anterior cingulate cortex and reduced
Several mechanisms may explain the relationship of functional connectivity of the subgenual anterior
pro-inflammatory cytokines to depression. High cingulate with the amygdala, medial prefrontal cortex,
plasma IL-6 levels were associated with lower and nucleus accumbens during emotional face
hippocampal gray matter in adults aged 30–56 years processing was shown to be modulated by a peripheral
(Marsland et al., 2008). TNF-a exerts a similar inflammatory response (IL-6) (Harrison et al., 2009).
antineurogenic effect through interaction with the Moreover, a SNP encoding IL-1b has been associated
TNF-R1 receptor (Nakajima et al., 1998; Cacci et al., with both reduced activity of the anterior cingulate and
2005; Iosif et al., 2006). Inflammatory blockade the amygdala in response to emotional probes and with
restores adult hippocampal neurogenesis (Monje poor response of major depression to antidepressants
et al., 2003). Another mechanism by which pro- (Baune et al., 2010). In addition, patients treated with
inflammatory proteins may lead to depression is the cytokine INF-a exhibited greater dorsal anterior
through induction of the IDO enzyme. IL-6, TNF-a, cingulate activation than controls (Capuron et al.,
and INF-g increase the expression of idoleamine 2,3- 2005); dysfunction of the anterior cingulate has been
dioxygenase (IDO) in peripheral and central immune documented in geriatric depression. These findings
cells. Activated IDO increases kynurenine production suggest a complex interaction between aging, neuroin-
from dietary tryptophan and as a consequence reduces flammation, and stress such that aging may exacerbate
the synthesis of serotonin (Heyes et al., 1992; Mellor the effects of stress in the CNS leading to behavioral
and Munn, 1999); reduction of serotonin is thought to and cognitive changes similar to those characteristic of
be a central mechanism in depression. Moreover, depressive syndromes.
increase in metabolic products of kynurenine such as
quinolinic acid serves as an NMDA receptor agonist
promoting hippocampal neuronal damage and apop- The role of antidepressants
tosis (Schwarcz et al., 1983; Stone and Behan 2007).
Aging is associated with changes in immune There are limited data on the effect of antidepressants
responses. In aged mice, lipopolysaccharide injections on inflammatory processes. Evidence of a relationship
resulted in prolonged sickness behavior compared to between antidepressants and antiiflammatory pro-
younger adult mice, exaggerated neuroinflammatory cesses comes from both preclinical and clinical studies.
response with stronger induction of peripheral and Animal studies suggest tricyclic antidepressants
brain IDO and increased turnover in brain serotonin (TCA) may reduce the production of some pro-
(Godbout et al., 2005). Discordant central inflamma- inflammatory and increase the production of antiin-
tory responses can have damaging effects to an flammatory cytokines. Administration of lipopolysa-
organism due to the behavioral effects and neurotoxi- charide to animals induces ‘‘sickness behavior’’, a
city of brain pro-inflammatory cytokines (Dilger and behavioral state with several common symptoms with
Johnson 2008). depression (Yirmiya et al., 1996). ‘‘Sickness behavior’’
Aging of the brain’s inflammatory responses may as well as TNF-a production can be attenuated by
lead to abnormalities in neural systems related to the pretreatment with desipramine (Shen et al., 1999),
development of depressive syndromes. In aged rodents, although paroxetine, and venlafaxine had no signifi-
glial cultures from brain sections, including those of cant effects (Shen et al., 1999). In an animal model of
areas related to mood processing, have increased anhedonia, pretreatment with TCA reduced patho-
inflammatory responses (cytokines IL-6, IL-1b, and logical behavior. This effect was accompanied by an
TNF-a) compared to younger animals after lipopo- increase in the antiinflammatory cytokine IL-10
lysaccharide challenge (Ye and Johnson 1999; Terao (Kubera et al., 1998, 2000a,b, 2001). In the olfactory
et al., 2002). The cerebral cortex of aged mice bulbectomy model of depression, pre-treatment with
spontaneously produces higher levels of IL-6 than desipramine decreased the production of the proin-
the cortex of adult animals (Ye and Johnson 2001; Xie flammatory cytokines TNF-a and IL-1b. In animal

Copyright # 2011 John Wiley & Sons, Ltd. Int J Geriatr Psychiatry 2011; 26: 1109–1118.
1114 G. S. Alexopoulos and S. S. Morimoto

models of inflammatory diseases septic shock and kines in animal models of inflammation. Changes in
asthma, the antidepressants fluoxetine and desipra- some cytokines may occur in depressed patients treated
mine reduced release of TNF-a (Roumestan et al., with some antidepressants but the relationship of
2007). pretreatment levels to antidepressant response remains
In vitro human studies on the effect of antidepress- unclear. These observations are based mainly on
ants on cytokine production have yielded contra- exploratory studies and need confirmation.
dictory findings. In cell cultures of healthy volunteers,
various antidepressants suppressed pro-inflammatory
cytokine production. The antidepressants used in these The role of antiinflammatory agents
studies were moclobemide (Lin et al., 2000), clomi-
pramine, sertaline, trazodone (Maes et al., 1999), Despite the conceptual appeal of the inflammation
imipramine, and mianserine (Szuster-Ciesielska et al., theory of depression, few studies have investigated the
2003). However, in cell cultures of depressed patients, role of antiinflammatory agents. However, numerous
imipramine, venlafaxine, 5-hydroxy-tryptophan, and a antiinflammatory agents have become available
combination of fluoxetine and 5-hydroxy-tryptophan recently though limited data exists on their use or
increased IL-6, but not TNF-a production (Szuster- effects in psychiatric disorders. What follows sum-
Ciesielska et al., 2003). marizes studies of antiinflammatory agents in neuro-
Open pharmacological studies and case series psychiatric disorders pertinent to depression.
suggest that antidepressants influence indices of Minocycline, a semi-synthetic, second-generation
inflammation, although the direction is unclear. In a tetracycline analog crosses the blood–brain barrier and
small number of depressed patients, fluoxetine and has antiinflammatory, antiapoptotic, and antioxidant
TCA reduced plasma levels of IL-6 (Maes et al., 1997; properties in addition to its bacteriostatic action. The
Basterzi et al., 2005). In another small sample, antiinflammatory effects are both direct and indirect
antidepressants decreased IL-12 and increased trans- through suppression of microglia activation and
forming growth factor beta-1 (TGF b-1) after six weeks proliferation and subsequent release of cytokines
of treatment (Lee and Kim 2006). Yet another study IL-1b, IL-6, and TNF-a as well as expression of
showed that antidepressants led to a decrease of the chemokines such as macrophage inflammatory protein
pro-inflammatory cytokines IL-2, IL-6, and TNF- b1 1a, INF-inducible protein 10, chemokine receptor 3 as
but did not influence INF-g, IL-4, and TNF-a (Kim well as suppressing the activity of matric metallopro-
et al., 2007). teases, which disrupt the blood–brain barrier (Plane
Pre-treatment cytokine plasma levels may influence et al., 2010; Chen et al., 2000). Minocycline inhibits
the response to antidepressants. SSRI resistant patients apoptosis by reducing mitochondrial calcium over-
had higher TNF-a plasma levels while euthymic load, stabilizing mitochondrial membrane, and inhi-
patients with history of depression had TNF-a levels biting release of cytochrome c and other apoptotic
similar to those of normal controls (O’Brien et al., agents, ultimately resulting in decreased activation of
2007). Depressed non-responders to escitalopram caspases 1 and 3 and lower nuclear damage. An
TNF-a plasma levels had higher TNF-a levels than additional antiapoptotic effect of minocycline may be
responders but their levels were similar to normal mediated by upregulation of the antiapoptotic factor
controls (Eller et al., 2008). These relationships were BCL-2. The antioxidant effect of minocycline may be
most pronounced in males. TNF-a increased in mediated in part by inhibition of cyclo-oxygenase 2
treatment responders during the escitalopram trial induced nitric oxide synthetase and nicotinamide
and reached the levels of normal subjects. Responders adenine dinuceotide phosphate oxidase. Finally,
to escitalopram had greater reduction in the soluble minocycline inhibits poly-ADP polymerase 1 (PAR
IL-2 receptor than depressed non-responders to 1), a molecule that when activated by DNA damage,
escitalopram (Eller et al., 2008). However, others contributes to excitotoxicity.
failed to detect significant changes in soluble IL-2 Various experimental models of brain insult suggest
receptor levels during antidepressant treatment (Maes that minocycline may have neuroprotective properties.
et al., 1995; Kagaya et al., 2001; Mikova et al., 2001), Minocycline may reduce inflammatory indices, brain
although higher soluble IL-2 receptor serum concen- cell damage and even improve abnormal behavior in
trations were found after treatment in non-responders models of stroke, Parkinson’s disease, Huntington’s
(Mikova et al., 2001). disease Alzheimer’s disease multiple sclerosis, and
In summary, some, but not all, antidepressants may amyotrophic lateral sclerosis (Plane et al., 2010).
reduce ‘‘sickness behavior’’ and production of cyto- However, minocycline was found ineffective or

Copyright # 2011 John Wiley & Sons, Ltd. Int J Geriatr Psychiatry 2011; 26: 1109–1118.
Inflammation hypothesis in geriatric depression 1115

neurotoxic in some animal models especially when The ’’inflammation hypothesis’’ in geriatric
very high dosages were used. depression
Animal studies and anecdotal data suggest that
minocycline may possess antiinflammatory properties. We propose that aging-related and disease-related
Minocycline has been shown to reduce immobility processes result in CNS inflammatory changes that
in mice on the forced swim test, an accepted may contribute to the etiology of at least some
behavioral model of depression (Molina-Hernandez depressive syndromes. Depressed older adults have
et al., 2008). In this same study, a combination of lower familial prevalence of mood disorders than
subthreshold doses of minocycline synergized the younger adults and greater cognitive symptoms,
antidepressant actions of sub-threshold doses of the structural brain abnormalities, medical morbidity,
TCA desipramine (Molina-Hernandez et al., 2008). disability, and mortality (Alexopoulos and Kelly,
Anecdotal evidence suggests that minocycline may 2009). Some of these medical and cognitive events
augment the action of antidepressants in major are thought to predispose patients to geriatric
depressive disorder (Pae et al., 2008). An open depression and may be fueled by a CNS pro-
(Miyaoka et al., 2008) and a placebo-controlled inflammatory state. Accordingly, we suggest that
treatment trial (Levkovitz et al., 2010) showed that immune processes are likely to promote changes in
addition of minocycline to an antipsychotic regimen the emotional and cognitive neural systems predis-
improved symptoms of schizophrenia. Specifically, posing to geriatric depression or facilitate the
minocycline reduced overall psychotic and negative metabolic brain changes mediating the depressive
symptoms, and improved working memory, cognitive syndrome in late life. We base this assertion on
flexibility, and planning in the placebo-controlled converging findings suggesting that:
study (Levkovitz et al., 2010). While these studies
have limitations, they provide the rationale for (1) Aging results in increased peripheral immune
studying the efficacy of minocycline in geriatric responses, impaired peripheral-CNS immune
depression, a disorder with brain abnormalities likely communication, and a shift of the CNS into a
to be contributed to at least in part by inflammatory pro-inflammatory state with exaggerated and pro-
processes. longed responses to immune challenge.
Etanercept, a soluble TNF-a receptor, prevents (2) Exaggerated and prolonged immune responses of
TNF-a mediated cellular response by competitively the CNS can influence the function of some of the
inhibiting the interaction of TNF-a with cell-surface emotional and cognitive networks pertinent to
receptors. Etanercept 50 mg twice weekly reduced geriatric depression.
symptoms of depression in a placebo-controlled study (3) Aging of the brain’s inflammatory responses leads
of patients with psoriasis (Tyring et al., 2006). While to behavioral changes reminiscent of the depressive
this study had a large number of subjects, only 42 had and cognitive symptoms of geriatric depression.
major depression. (4) Some antidepressants reduce the expression of
The cyclo-oxygenase-2 inhibitor celecoxib has been several inflammation markers in the periphery.
found to augment the efficacy of reboxetine, and (5) Limited data suggest that some antiinflammatory
fluoxetine in patients with major depression (Muller agents may have antidepressant properties.
et al., 2006; Akhondzadeh et al., 2009). In study of
osteoarthritis patients, the cyclo-oxygenase -2 inhibi- Testing the inflammation hypothesis in
tor rofecoxib reduced symptoms of depression and geriatric depression
improved cognition (Collantes-Estevez et al., 2003).
The putative mechanism of celecoxib’s action is Available findings provide a ‘‘signal’’ of a relationship
inhibition of prostaglandin E2 (PGE2). PGE2 stimu- between aging of the brain’s immune system, medical
lated production of IL-6 is increased in depression comorbidity increasing the brain’s pro-inflammatory
(Frommberger et al., 1997; Song et al., 1998). state and geriatric depression. However, many ques-
In vitro studies have shown greater PGE2 produc- tions remain to be answered, including:
tion by lymphocytes of depressed patients com-
pared to control subjects (Linnoila et al., 1983). (1) Is the aging- and disease-related CNS pro-inflam-
Moreover, increased PGE2 has been documented in matory state, indeed, an etiological factor of some
the saliva, serum and cerebrospinal fluid of depressed geriatric depressive syndromes or a consequence of
patients (Nishino et al., 1989; Akhondzadeh et al., the pathophysiological changes of depression? If
2009). CNS inflammation is etiologically related to ger-

Copyright # 2011 John Wiley & Sons, Ltd. Int J Geriatr Psychiatry 2011; 26: 1109–1118.
1116 G. S. Alexopoulos and S. S. Morimoto

iatric depression, what position does it occupy in some of these questions and may hopefully lead to a
the chain of biological events leading to the syn- novel treatment model.
drome?
(2) Do aging and disease-related CNS pro-inflamma-
tory states influence the short-term- or long-term
Disclosures
course of geriatric depression?
(3) Is the pro-inflammatory state in aging related to a
Dr. Alexopoulos has received grant support by Forest
specific depressive symptom set or to abnormalities
Pharmaceuticals, holds equity of Johnson and John-
of specific cognitive or emotional networks that
son, and has served in the Speakers Bureau of Forest,
function abnormally in depression?
(4)
Astra Zeneca, Lilly, Merck, BMS, and Novartis.
Do older persons with structural or functional
Dr. Morimoto: None.
brain abnormalities predisposing to poor anti-
depressant response have increased indices of
inflammation?
(5) Do high pretreatment levels of inflammation Acknowledgements
indices influence response to antidepressants?
(6) Is improvement of geriatric depression accom- This work was supported by NIMH grants T32
panied by reduction of inflammatory markers? MH19132, R01 MH079414, and P30 MH085943 to
(7) Which antiinflammatory agents, if any, have anti- Dr. Alexopoulos.
depressant action and which such agents can aug-
ment the action of conventional antidepressants in
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