Acta Psychiatr Scand 2019: 139: 401–403 © 2019 John Wiley & Sons A/S.
Wiley & Sons A/S. Published by John Wiley & Sons Ltd
All rights reserved
DOI: 10.1111/acps.13031
Editorial
Has the time come to treat depression with
anti-inflammatory medication?
Introduction
A meta-analysis by K€ ohler-Forsberg et al. (1)
involving nearly 10 000 patients, published in the
current issue of Acta Psychiatrica Scandinavica,
shows that anti-inflammatory treatment can
reduce depressive symptoms, as well as increase
remission and response rates in patients with
depression. The observed effect sizes were large for
three classes of anti-inflammatory medications:
NSAIDs, corticosteroids, and cytokine inhibitors,
with a near-doubling of effect size resulting from
the add-on, and there was minimal heterogeneity
in the results for these medications. In fact, the
added effect size resulting from the anti-inflamma-
tory agents added to antidepressants was larger
than that reported in studies of the effects of
antidepressants alone (2).
Is there any reason to be surprised by these
results? Perhaps not, if we keep in mind that meta-
analyses have previously established that patients
with depression indeed have increased levels of
inflammation in the blood (3, 4). There are also
several well-established biological mechanisms by
which peripheral inflammation can reach the
brain, induce neuroinflammation, and alter neuro-
transmission, thereby generating depressive symp-
toms (5, 6).
Some of the first observations indicating that
inflammation can cause depressive symptoms came
from clinical studies in patients who received inter-
feron (IFN)-based immunotherapies to treat con-
ditions such as cancer and hepatitis. The patients
developed depressive symptoms and sometimes
active suicidal behaviour at an increased rate (7).
In fact, at least 25% of patients receiving IFN
treatment will develop depression after starting the
treatment (8).
In a person who is experiencing peripheral
inflammation, cytokines and other inflammatory
factors can reach the brain by passive diffusion
across areas with high blood–brain barrier (BBB)
permeability, such as the median eminence of the
hypothalamus. Cytokine receptors in this region
ACTA PSYCHIATRICA SCANDINAVICA
initiate some of the first responses to sickness/in-
flammation, including fever, malaise, appetite
changes, and fatigue, often referred to as neu-
rovegetative symptoms (9). Moreover, inflamma-
tory factors can actively be transported across the
BBB to reach other brain regions, and inflamma-
tion can also spread throughout the brain parench-
yma. The resident macrophages of the brain,
microglial cells, become activated upon cytokine
stimulation and start secreting their own arsenal of
proinflammatory molecules. Some of these neuro-
chemicals will not only exacerbate inflammation,
but also bind directly to microglial and neuronal
cytokine receptors and alter neurotransmission
(10). Inflammation also induces downstream meta-
bolic pathways in the brain. For example, the
kynurenine pathway breaks down tryptophan into
metabolites with effects on glutamate
neurotransmission. When this pathway is overacti-
vated by inflammation, serotonin levels are
reduced, as a consequence of shunting the break-
down of tryptophan down the kynurenine path-
way, limiting serotonin production (11, 12). The
metabolism of several other neurotransmitters,
including dopamine, is also greatly impacted by
neuroinflammation (13). Additional supportive
evidence for a role of inflammation in depression
comes from epidemiological studies showing an
increased risk of depression in groups of patients
that suffer from somatic inflammatory disorders,
such as rheumatoid arthritis, cardiovascular dis-
ease, and diabetes, and the benefits of anti-inflam-
matory treatments on their mood symptoms (14,
15).
Thus, there is now a large body of scientific evi-
dence implicating inflammation in depression,
including causative mechanistic studies, epidemio-
logical and associative studies, and, as in the cur-
rent meta-analysis by K€ ohler-Forsberg (1),
positive effects from clinical trials using anti-
inflammatory therapies to treat depression. Cur-
rently, the critical questions are as follows: What
more is needed before there can be consensus as to
401
Editorial
whether depression is an inflammatory disorder, and
before the clinical guidelines to treat depressive
patients will include anti-inflammatory agents?
Before a novel treatment can be approved for
clinical use, rigorous preclinical and clinical trials
are required. For many anti-inflammatory treat-
ments, including the NSAIDs and corticosteroids,
these requirements have already been fulfilled, as
they have been tested and approved for safety and
efficacy in humans to treat a wide variety of
somatic inflammatory conditions. For several of
these medications, the safety profiles are very well
established after decades of use in humans, and
many can be purchased over the counter without
any need for a prescription. In order to be
approved for clinical use for a new indication, the
treatments also need to show efficacy in clinical tri-
als targeting the particular condition, in this case,
depression. The anti-inflammatory treatments,
shown to be effective in treating depression in the
studies described in the meta-analysis by K€ ohler-
Forsberg, et al., should then be tested in large-
scale, multicenter, randomized, and placebo-con-
trolled trials (RCTs) involving several hundreds to
thousands of participants. After testing whether
anti-inflammatory agents are effective in treating
depression in well-controlled studies at such a
large-scale, governmental agencies in the respective
countries could move forward to approve the anti-
inflammatory drugs in question for the new indica-
tion, depression.
This path might seem both straight forward and
warranted at this point in time, considering the
wealth of experimental data supporting the use of
anti-inflammatory agents in depression. However,
phase III trials are expensive, in the range of 20–
30 million dollars or more, each, to conduct (16).
Only drugs with a high likelihood of generating
future profit are put through phase III trials. In the
case of the traditionally used, safe and tolerable
anti-inflammatory agents that are already on the
market, there is no financial incentive for the phar-
maceutical industry to conduct these costly, large-
scale RCTs. Rather, they are more likely to fund
newly discovered immunotherapies with a poorly
characterized safety profile, as such novel
immunomodulatory treatments can be patented
and monetized. Therefore, putting the well-estab-
lished OTC anti-inflammatory treatments through
phase III clinical trials for use in depression is
something that will likely need to be funded by
governmental authorities.
An important question brought up in the
meta-analysis by K€ ohler-Forsberg et al. (1) is
whether all patients with depression suffer from
inflammation and therefore would benefit from
402
anti-inflammatory treatment as a general recom-
mendation, or whether the inflammation extends
only to certain population groups. Some studies
indeed indicate that subgroups of depressive
patients, including patients with postpartum
depression or suicidal depression, may exhibit par-
ticularly high levels of inflammation (17, 18). If
preselection of patients based on increased periph-
eral inflammation would be implemented for sub-
sequent anti-inflammatory treatment, several
candidate peripheral markers could be employed
based on current evidence, including cytokines IL-
6 and TNF-alpha, and acute phase proteins CRP
and SAA (19–21). However, it is not yet well
established whether the degree of inflammation
that can be measured in blood matches ongoing
inflammation in the central nervous system (CNS).
Thus, it could be that inflammatory mechanisms
are activated in the brains of all patients with
depression, even if the markers only are elevated in
the periphery of some patients. It is also possible
that while inflammatory markers are elevated in
many patients, only those with a genetic suscepti-
bility to inflammation and depression go on to
develop a depressed phenotype. Interestingly, the
meta-analysis by K€ ohler-Forsberg (1) indicates
that depressive patients in general would benefit
from the anti-inflammatory treatment, without
any preselection of specific subgroups. Thus, the
meta-analysis did not attempt to divide the studies
based on subgroups or indications of ongoing
inflammation and still detected effect sizes that
were larger than those observed for the conven-
tional antidepressive treatments.
The meta-analysis by K€ ohler-Forsberg et al.
(1) comes with some limitations. One of the
most important is the likelihood of bias in the
studies. The studies were all small to medium in
size, and the anti-inflammatory agents tested
were of several different classes, making the
studies heterogeneous. In addition, duration of
treatment was also variable. For example, the
two corticosteroid treatment studies were ultra-
short, only 2 and 4 days, while all other studies
were longer than 6 weeks. However, the most
commonly used treatment was the use of
NSAIDs as an add-on (all studies but one used
celecoxib), with 13 studies and over 4000 partic-
ipants included, making the results regarding
this anti-inflammatory agent particularly robust,
with an effect size of 0.40.
Conclusion
In summary, current experimental evidence points
to a causative role for inflammatory mechanisms

in depression. The meta-analysis by K€ ohler-Fors-
berg et al. (1) shows that anti-inflammatory treat-
ment, both as monotherapy and as an add-on to
antidepressants, has a strong beneficial effect.
There is a clear incentive for future large RCTs in
order to test the use of anti-inflammatory drugs for
treating depression. However, the responsibility to
fund these RCTs will likely fall on federal or foun-
dation sources of funding. In 2017, the World
Health Organization announced that depression
was the leading cause of suffering and disability
worldwide which means novel treatments are
needed now more than ever (22). Perhaps finally
the time has come for large-scale trials of anti-
inflammatories in depression?
Declaration of interest
Dr. Achtyes has received research support from Alkermes,
AssurEx, Astellas, Avanir, Biogen, Boehringer Ingelheim,
Janssen, Network180, Neurocrine Biosciences, Novartis,
Otsuka, Pfizer, Priority Health, Takeda, and Vanguard
Research Group and has served on advisory boards for Alker-
mes, Indivior, Janssen, Neurocrine Biosciences, Roche, and
the Vanguard Research Group. Dr Brundin has received fund-
ing from the National Institutes of Health and the Michael J
Fox Foundation for research projects studying the role of
inflammation in neuropsychiatric disorders.
L. Brundin1,2, E. Achtyes2,3
1
Center for Neurodegenerative Science, Van Andel Research
Institute, 2Division of Psychiatry and Behavioral Medicine,
Michigan State University College of Human Medicine, and
3
Pine Rest Christian Mental Health Services, Grand Rapids,
MI, USA
E-mail: Lena.Brundin@vai.org, Eric.Achtyes@pinerest.org
References
1. K€ohler-Forsberg O, Nicolaisen LC, Hjorthøj C, Nordentoft
M, Mors O, Benros ME. Efficacy of anti-inflammatory
treatment on major depressive disorder or depressive
symptoms: meta-analysis of clinical trials. Acta Psychiatr
Scand 2019;139:404–419.
2. Cipriani A, Furukawa TA, Salanti G et al. Comparative
efficacy and acceptability of 21 antidepressant drugs for
the acute treatment of adults with major depressive disor-
der: a systematic review and network meta-analysis. Lan-
cet 2018;391:1357–1366.
3. Dowlati Y, Herrmann N, Swardfager W et al. A meta-ana-
lysis of cytokines in major depression. Biol Psychiatry
2010;67:446–457.
4. K€ohler CA, Freitas TH, Maes M et al. Peripheral cytokine
and chemokine alterations in depression: a meta-analysis
of 82 studies. Acta Psychiatr Scand 2017;135:373–387.
5. Swain M, D’Mello C. Immune-to-brain communication
pathways in inflammation-associated sickness and depres-
sion. Curr Top Behav Neurosci 2016;31:73–94.
Editorial
6. Miller AH, Raison CL. The role of inflammation in
depression: from evolutionary imperative to modern treat-
ment target. Nat Rev Immunol 2016;16:22–34.
7. Lucaciu LA, Dumitrascu DL. Depression and suicide idea-
tion in chronic hepatitis C patients untreated and treated
with interferon: prevalence, prevention, and treatment.
Ann Gastroenterol 2015;28:440–447.
8. Udina M, Castellvı P, Moreno-Espa~na J et al. Interferon-
induced depression in chronic hepatitis C: a systematic
review and meta-analysis. J Clin Psychiatry 2012;73:1128–
1138.
9. McCusker RH, Kelley KW. Immune-neural connections:
how the immune system’s response to infectious agents
influences behavior. J Exp Biol 2013;216:84–98.
10. Rothaug M, Becker-Pauly C, Rose-John S. The role of
interleukin-6 signaling in nervous tissue. Biochim Biophys
Acta 2016;1863:1218–1227.
11. Bay-Richter C, Linderholm KR, Lim CK et al. A role for
inflammatory metabolites as modulators of the glutamate
N-methyl-D-aspartate receptor in depression and suicidal-
ity. Brain Behav Immun 2015;43:110–117.
12. Haroon E, Miller AH. Inflammation effects on brain glu-
tamate in depression: mechanistic considerations and
treatment implications. Curr Top Behav Neurosci
2017;31:173–198.
13. Miller AH, Haroon E, Raison CL, Felger JC. Cytokine
targets in the brain: impact on neurotransmitters and neu-
rocircuits. Depress Anxiety 2013;30:297–306.
14. Nerurkar L, Siebert S, McInnes IB, Cavanagh J. Rheuma-
toid arthritis and depression: an inflammatory perspective.
Lancet Psychiatry 2019;6:164–173.
15. Kappelmann N, Lewis G, Dantzer R, Jones PB, Khandaker
GM. Antidepressant activity of anti-cytokine treatment: a
systematic review and meta-analysis of clinical trials of
chronic inflammatory conditions. Mol Psychiatry
2018;23:335–343.
16. Mullard A. How much do phase III trials cost? Nat Rev
Drug Disc 2018;17:777.
17. Osborne LM, Monk C. Perinatal depression–the fourth
inflammatory morbidity of pregnancy? Theory and
literature review. Psychoneuroendocrinology 2013;38:
1929–1952.
18. Brundin L, Bryleva EY, Thirtamara RK. Role of inflam-
mation in suicide: from mechanisms to treatment. Neu-
ropsychopharmacology 2017;42:271–283.
19. Lamers F, Milaneschi Y, Smit JH, Schoevers RA, Witten-
berg G, Penninx BWJH. Longitudinal association between
depression and inflammatory markers: results from the
Netherlands study of depression and anxiety. Biol Psy-
chiatry 2019. https://doi.org/10.1016/j.biopsych.2018.12.
020
20. Bryleva EY, Keaton SA, Grit J et al. The acute-phase
mediator serum amyloid A is associated with symptoms of
depression and fatigue. Acta Psychiatr Scand 2017;135:
409–418.
21. Felger JC, Haroon E, Patel TA et al. What does plasma
CRP tell us about peripheral and central inflammation in
depression? Mol Psychiatry 2018. https://doi.org/10.1038/
s41380-018-0096-3
22. WHO. Depression, let’s talk says WHO as depression tops
list of causes of ill health. 2017; WHO News letters. http://
www.who.int/mediacentre/news/releases/2017/world-hea
lth-day/en/.
403