C-Reactive Protein Alterations in Bipolar Disorder: A Meta-Analysis
Abstract
OBJECTIVE: There is growing evidence that bipolar disorder (BD) is associated with inflammation, including abnormal levels of acute-phase C-reactive protein (CRP). Our meta-analysis was conducted to estimate the size of the association between CRP levels and BD, accounting also for subgroup differences (mood phases and treatment). DATA SOURCES: MEDLINE, EMBASE, PsycINFO, and ISI Web of Science and references of identified articles were searched up to June 2013 using the keywords (bipolar disorder) AND (C-reactive protein OR CRP). STUDY SELECTION: English language studies measuring blood levels of CRP in patients with BD and control subjects were selected, 136 abstracts were reviewed, 20 articles retrieved, and 11 studies included. DATA EXTRACTION: Two independent reviewers extracted data. All studies were included in the primary analyses, and between-group differences for subanalyses were also reported. This meta-analysis was performed using random-effects models. RESULTS: Eleven studies comprising 1,618 subjects were eligible for inclusion. Overall, CRP levels were significantly elevated in patients with BD versus controls (standardized mean difference [SMD] = 0.39; 95% CI, 0.24 to 0.55; P < .0001). CRP levels were significantly higher in manic (SMD = 0.73; 95% CI, 0.44 to 1.02; P < .001) and euthymic (SMD = 0.26; 95% CI, 0.01 to 0.51; P = .04), but not in depressed (SMD = 0.28; 95% CI, -0.17 to 0.73; P = .22) patients with BD compared to controls. CRP levels were unrelated to use of lithium or antipsychotic medication. CONCLUSIONS: This meta-analysis supports an association between increased CRP levels and BD. Given that an elevated level of CRP is a marker of low-grade inflammation and a risk factor for cardiovascular and malignant diseases, measurement of CRP level might be relevant to the clinical care of bipolar patients.
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Inflammatory processes have been linked to psychopathology as shown in meta-analyses of depression, BPD, psychosis, and PTSD.
“In addition to a host of physical health consequences, these inflammatory processes have been linked to psychopathology as shown in meta-analyses of depression (Howren et al. 2009), BPD (Dargél et al. 2015), psychosis (Miller et al. 2011), and PTSD (Passos et al. 2015).”
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The depression state has conflicting results for CRP.
“But the depression state has conflicting results43,44.”
From Inflammation-related biomarkers in major psychiatric disorders: a cross-disorder assessment of reproducibility and specificity in 43 meta-analyses (2019) · cites this paper as [44]
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“GSK3 activation is also associated with oxidative stress and in fl ammation, both of which have been reported to be elevated in bipolar disorder patients [82 – 85].”
BackgroundKulacaoglu, F., Yıldırım, Y. E., Aslan, M., & İzci, F. (2023) · Nordic Journal of Psychiatry · doi:10.1080/08039488.2022.2116106 · Cited by 18 · see citing works
“According to a recent meta-analysis, CRP levels were found to be higher mostly in mania, and later in depressive and euthymic period of BD [32].”
MethodKnight, E. L., Engeland, C. G., Yocum, A. K., Abu-Mohammad, A., Bertram, H. S., Vest, E., McInnis, M. G., & Saunders, E. F. H. (2023) · Brain Behavior & Immunity - Health · doi:10.1016/j.bbih.2023.100613 · Cited by 18 · see citing works
Johansson, V., Jakobsson, J., Fortgang, R. G., Zetterberg, H., Blennow, K., Cannon, T. D., Hultman, C. M., Wetterberg, L., & Landén, M. (2016) · European Archives of Psychiatry and Clinical Neuroscience · doi:10.1007/s00406-016-0759-5 · Cited by 18 · see citing works
Kendirlioglu, B. K., Özperçin, P. Ü., Yüksel, Ö., Sözen, Ş., Cihnioğlu, R., Kalelioğlu, T., İlnem, M. C., & Karamustafalıoğlu, N. (2019) · Nordic Journal of Psychiatry · doi:10.1080/08039488.2019.1673480 · Cited by 18 · see citing works
“[6] but this was not the case in depressive state [5].”
BackgroundEarly Life Stress, Neuroinflammation, and Psychiatric Illness of Adulthood
Shin, S. H., & Kim, Y. (2023) · Advances in experimental medicine and biology · doi:10.1007/978-981-19-7376-5_6 · Cited by 18 · see citing works
Badrfam, R., Mostafavi, S., Khaleghi, A., Akhondzadeh, S., Zandifar, A., Farid, M., Khonsari, N. M., & Mohammadi, M. R. (2021) · Brain and Behavior · doi:10.1002/brb3.2394 · Cited by 17 · see citing works
“…previous sections, bipolar disorder, especially in recurrent conditions such as the mania phase, causes inflammation (Rosenblat &McIntyre, 2016), increased levels of inflammatory factors (Dargél et al., 2015), and elevated levels of homocysteine (Salagre et al., 2017) as a pro-inflammatory factor.”
BackgroundKöhler-Forsberg, O., Sylvia, L., Deckersbach, T., Ostacher, M. J., McInnis, M., Iosifescu, D., Bowden, C., McElroy, S., Calabrese, J., Thase, M., et al. (2018) · Acta Neuropsychiatrica · doi:10.1017/neu.2017.34 · Cited by 15 · see citing works
C-Reactive Protein (CRP): A Potent Inflammation Biomarker in Psychiatric Disorders
Orsolini, L., Pompili, S., & Volpe, U. (2023) · Advances in experimental medicine and biology · doi:10.1007/978-981-19-7376-5_7 · Cited by 17 · see citing works
Raison, C. L., SIU, C. O., Pikalov, A., Tocco, M., & Loebel, A. D. (2019) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2019.12.010 · Cited by 16 · see citing works
“The role of inflammation in adult mood disorders has been examined more extensively in unipolar depression than in bipolar disorder; however significant data indicate that changes in immune function are at least as common in bipolar as in unipolar conditions, and that both manic and depressive phases of the illness ar…”
BackgroundSanchez-Autet, M., Arranz, B., Sierra, P., Safont, G., Garcia-Blanco, A., de la Fuente, L., Garriga, M., Marín, L., & García-Portilla, M. P. (2022) · The World Journal of Biological Psychiatry · doi:10.1080/15622975.2021.2013089 · Cited by 15 · see citing works
“Regarding CRP levels in BD, two meta-analysis (Darg el et al. 2015; Fernandes et al. 2016) and recent studies have found high CRP concentrations in different mood states (Munkholm et al. 2018) and in BD patients with high emotional hyper-reactivity and activation levels (Darg el et al. 2018, 2019).”
BackgroundResultInfluentialRhee, S. J., Lee, H., & Ahn, Y. M. (2021) · Scientific Reports · doi:10.1038/s41598-021-99312-x · Cited by 15 · see citing works
Figueroa‐Hall, L. K., Xu, B., Kuplicki, R., Ford, B. N., Burrows, K., Teague, T. K., Sen, S., Yeh, H., Irwin, M. R., Savitz, J. B., et al. (2022) · Translational Psychiatry · doi:10.1038/s41398-022-02049-y · Cited by 15 · see citing works
“Several studies have reported no association between mood stabilizer use (lithium, valproic acid, and lamotrigine) and CRP concentrations [75, 76].”
BackgroundShao, S., Zou, Y. Z., Kennedy, K. G., Dimick, M. K., MacIntosh, B. J., & Goldstein, B. I. (2023) · The International Journal of Neuropsychopharmacology · doi:10.1093/ijnp/pyad063 · Cited by 16 · see citing works
“…dysregulation is evident among both adults and youth with BD, particularly during symptomatic episodes (Bai et al., 2014; Avramopoulos et al., 2015; Dargel et al., 2015; Goldstein et al., 2015; Uyanik et al., 2015; Hatch et al., 2017), with implications for both physical and mental health…”
BackgroundBrouillet, J. Z., Boltri, M., Lengvenytė, A., Lajnef, M., Richard, J., Barrau, C., Strumila, R., Coyac, M., Wu, C., Boukouaci, W., et al. (2023) · Journal of Affective Disorders Reports · doi:10.1016/j.jadr.2023.100624 · Cited by 14 · see citing works
Self-citationPlasma GDF15 level is elevated in psychosis and inversely correlated with severity
Kumar, P., Millischer, V., Villaescusa, J. C., Nilsson, I. A. K., Östenson, C., Schalling, M., Ösby, U., & Lavebratt, C. (2017) · Scientific Reports · doi:10.1038/s41598-017-07503-2 · Cited by 16 · see citing works
Effects of infliximab on brain neurochemistry of adults with bipolar depression
Mansur, R. B., Subramaniapillai, M., Lee, Y. L., Pan, Z., Carmona, N. E., Shekotikhina, M., Iacobucci, M., Rodrigues, N. B., Nasri, F., Rosenblat, J. D., et al. (2020) · Journal of Affective Disorders · doi:10.1016/j.jad.2020.11.128 · Cited by 15 · see citing works
Joe, P., Clemente, J. C., Piras, E., Wallach, D. S., Robinson‐Papp, J., Boka, E., Remsen, B., Bonner, M., Kimhy, D., Goetz, D. M., et al. (2021) · Schizophrenia Research · doi:10.1016/j.schres.2021.09.019 · Cited by 14 · see citing works
Caldirola, D., Daccò, S., Cuniberti, F., Grassi, M., Lorusso, S., Diaferia, G., & Perna, G. (2021) · Journal of Psychosomatic Research · doi:10.1016/j.jpsychores.2021.110604 · Cited by 13 · see citing works
Orsolini, L., Ricci, L., Pompili, S., Cicolini, A., & Volpe, U. (2023) · Journal of Affective Disorders · doi:10.1016/j.jad.2023.04.004 · Cited by 13 · see citing works
Lee, S., Lee, K. H., Park, K. M., Park, S. J., Kim, W. J., Lee, J., Kronbichler, A., Smith, L., Solmi, M., Stubbs, B., et al. (2021) · Psychological Medicine · doi:10.1017/s0033291721003767 · Cited by 14 · see citing works
Bagaric, T., Mihaljević-Peleš, A., Hanžek, M. S., Živković, M., Kozmar, A., & Rogić, D. (2024) · Current Issues in Molecular Biology · doi:10.3390/cimb46050275 · Cited by 13 · see citing works
“Biomarkers such as lL-6 [18–21], CRP [22,23], albumin [24,25], and zinc [26–29] have been subject of numerous studies aimed to shed light into complex interplay between inflammatory process and depressive symptoms.”
BackgroundDoes CRP predict outcome in bipolar disorder in regular outpatient care?
Balukova, S. M., Haarman, B. C. M., der Lek, R. F. R., & Schoevers, R. A. (2016) · International Journal of Bipolar Disorders · doi:10.1186/s40345-016-0055-3 · Cited by 12 · see citing works
C-reactive protein as a potential biomarker in psychiatric practice: Are we there yet?
Baysak, E., Güden, D. S., Arıcıoğlu, F., & Halaris, A. E. (2021) · The World Journal of Biological Psychiatry · doi:10.1080/15622975.2021.1961502 · Cited by 10 · see citing works
“Meta-analysis (Darg el et al. 2015) (continued) there are clinical studies showing pre-treatment CRP levels might predict differential response to antidepressant treatments.”
BackgroundChen, S., Chen, G., Li, Y., Yue, Y., Zhu, Z., Li, L., Jiang, W., Shen, Z., Wang, T., Hou, Z., et al. (2022) · European Archives of Psychiatry and Clinical Neuroscience · doi:10.1007/s00406-022-01540-3 · Cited by 12 · see citing works
“Significantly increased serum CRP levels were discovered here in all disease groups, which is consistent with the results of numbers of meta-analyses and systematic reviews in patients with MDD, SZ, and BPD [36, 65–69].”
ResultBipolar spectrum disorders in neurologic disorders
Digiovanni, A., Ajdinaj, P., Russo, M., Sensi, S. L., ONOFRJ, M. C., & Thomas, A. (2022) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2022.1046471 · Cited by 10 · see citing works
“These levels increase more during the manic phase than during depression or euthymia (152, 154).”
BackgroundCoello, K., Pedersen, H. H., Munkholm, K., Kjærstad, H. L., Stanislaus, S., Ostrowski, S. R., Faurholt‐Jepsen, M., Miskowiak, K. W., Frikke‐Schmidt, R., Vinberg, M., et al. (2024) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2024.03.029 · Cited by 10 · see citing works
Bruun, C. F., Zarp, J., Forman, J. L., Coello, K., Miskowiak, K. W., Vinberg, M., Faurholt‐Jepsen, M., & Kessing, L. V. (2024) · BMJ Open · doi:10.1136/bmjopen-2024-084105 · Cited by 10 · see citing works
Cynthia Marie-claire, A., Courtin, C., Curis, E., Bouaziz-Amar, É., Laplanche, J., Jacob, A., Étain, B., Blanchard, A., & Bellivier, F. (2019) · Journal of Neuroimmunology · doi:10.1016/j.jneuroim.2019.576993 · Cited by 10 · see citing works
“Numerous biological markers related to the immune and inflammatory systems have been reported as abnormal in BD, mainly in the direction of an elevation of central and peripheral markers of inflammation (Dargél et al., 2015; Modabbernia et al., 2013), therefore suggesting an association between BD and a chronic low gr…”
BackgroundChudal, R., Sourander, A., Surcel, H., Sucksdorff, D., Hinkka‐Yli‐Salomäki, S., & Brown, A. S. (2016) · Journal of Affective Disorders · doi:10.1016/j.jad.2016.08.056 · Cited by 10 · see citing works
“Studies of adult patients with BPD have also revealed elevations in peripheral CRP levels (Dargél et al., 2015).”
Background
- Authors
- Dargél, A. A., Godin, O., Kapczinski, F., Kupfer, D. J., & Leboyer, M.
- Affiliations
- Hôpital Albert-Chenevier (FR)
- Venue
- The Journal of Clinical Psychiatry
- Publisher
- Physicians Postgraduate Press, Inc
- Published
- 2015-02-25
- Volume
- 76
- Issue
- 02
- Pages
- 142-150
- ISSN
- 0160-6689 (ISSN-L)
- OpenAlex
- W1974846472
- Cited by
- 155
- References
- 0
- Citations by year
- 2026: 6 · 2025: 5 · 2024: 6 · 2023: 14 · 2022: 13 · 2021: 18 · 2020: 14 · 2019: 13 · 2018: 14 · 2017: 17 · 2016: 29 · 2015: 6
- FWCI
- 17.84
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- The Journal of Clinical Psychiatry (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Agence Nationale de la Recherche (ANR-11-IDEX-0004)
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Bipolar Disorder and Treatment
- Life Sciences › Neuroscience › Biological Psychiatry › Tryptophan and brain disorders
- Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
- Keywords
- bipolar disorder, C-reactive protein, inflammation, acute phase proteins, manic episodes, euthymic state, depressive episodes, lithium, antipsychotic drugs, cardiovascular risk
- MeSH terms
- Affect, Bipolar Disorder, C-Reactive Protein, Humans, Predictive Value of Tests, Biomarkers
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