Celecoxib Adjunctive Treatment to Antipsychotics in Schizophrenia: A Review of Randomized Clinical Add-On Trials
Schizophrenia is a severe, chronic and debilitating mental disorder. Past literature has reported various hypotheses about the psychopathology of schizophrenia. Recently, a growing literature has been trying to explain the role of inflammation in the etiopathogenesis of schizophrenia. In the past, numerous immune modulation and anti-inflammatory treatment options have been proposed for schizophrenia, but sometimes the results were inconsistent. Electronic search was carried out in November 2015. PubMed and Scopus databases have been used to find studies to introduce in this review. Only randomized-placebo-controlled add-on trials were taken into account. In this way, six articles were obtained for the discussion. Celecoxib showed beneficial effects mostly in early stages of schizophrenia. In chronic schizophrenia, the data are controversial, possibly in part for methodological reasons.
Schizophrenia is a severe, chronic, and debilitating mental disorder . The adult prevalence is approximately 1%, but schizophrenics constitute close to 10% of the permanently disabled population .
Past literature has reported various hypotheses about the psychopathology of the schizophrenia. The dopamine hypothesis has tried to explain positive, negative, and cognitive symptoms of the schizophrenia suggesting different alterations of the dopamine activity in different brain regions [3–5]. The glutamate hypothesis suggested that phencyclidine and ketamine block of the N-methyl-D-aspartate receptor induced positive, negative, and cognitive symptoms [6–12]. The cytokine alterations in schizophrenics are consistent with the glutamate hypothesis of schizophrenia [13–17]. In fact, proinflammatory cytokines may influence dopaminergic and glutamatergic pathways and cognitive processes that are implicated in schizophrenia. Recently, alterations in the central gamma-aminobutyric acid and in the cholinergic systems have been proposed to be relevant for cognitive functions in schizophrenia [18–20].
A growing literature has been trying to explain the role of the inflammation in the pathophysiology of the schizophrenia. Emerging literature suggest that infectious exposures (e.g., influenza, genital reproductive infections, Toxoplasma gondii, and herpes simplex virus type 2) during the prenatal period may contribute to the etiopathogenesis of the schizophrenia [21–26]. Interesting data comes from animal studies of the maternal immune activation model of the schizophrenia. In animals, cytokines generated during the pregnancy may cross the placenta and blood-brain barrier and contribute to the oxidative stress [27–29].
A recent meta-analysis  has highlighted higher proinflammatory cytokines (IL-6, TNF-alpha, TGF-beta, and IFN-gamma) in acutely relapsed inpatients and in first-episode psychosis compared to controls. On the other hand, anti-inflammatory cytokine IL-10 levels were lower only in acutely relapsed patients with respect to controls.
The inflammatory hypothesis of the schizophrenia psychopathology has been supported by peripheral and central inflammatory signs in schizophrenic patients. Elevated proinflammatory factors, such as prostaglandin E2 (PGE2), C-reactive protein (CRP), interleukin- (IL-) 1beta, IL- 6, IL-8, and tumor necrosis factor- (TNF-) alpha, have been reported in serum/plasma levels (for recent reviews, see [31–33]).
Established correlations are that proinflammatory cytokines impair negative symptoms of schizophrenia [34, 35], deficiency in sustained attention , and psychomotor retardation . Some authors have highlighted a positive correlation between the severity of cognitive deficit and increased levels of inflammatory markers in schizophrenic patients [38–40]. Proinflammatory cytokines have a role in altering the synthesis and the release of dopamine and noradrenalin [41–43]. This activity may play a role in the emergence of positive symptoms, but the studies have not found a significant correlation between positive symptoms and enhanced proinflammatory cytokines levels [44–46].
There are some evidences that antipsychotics may induce immune-modulatory effects [47–49]. Long-term treatment with antipsychotics exerts concomitant augmentation of anti-inflammatory cytokines (sIL-1RA, sIL-2R, and IL-10) [50–55] and a reduction of proinflammatory ones (IL-1beta, IL-6, sIL-6R, and TNF-alpha) [56–59]. Interestingly, second-generation antipsychotics may be more efficacious than first generations in enhancing anti-inflammatory cytokines (reviewed in [60, 61]). Moreover, some authors have reported that, in drug resistant schizophrenia patients, immune abnormalities cannot be normalized .
Past literatures have reported decreases in volume of the central nervous system in schizophrenia, already during the first episode, especially in schizophrenics with a poor outcome [63, 64]. Moreover, some authors have showed a relationship between brain volume, IL-1, and IL-6 [65, 66]. Numerous imaging studies have reported microglia activation and alteration in astrocytes population in the brains of recent onset and chronic schizophrenics, supporting the neuroinflammation hypothesis [67–69]. Some small postmortem studies have indicated an increased immunoreactive microglia in schizophrenic patients [70–72].
The tryptophan metabolism has been hypothesized to have a role in the etiopathogenesis of the schizophrenia. In fact, increased levels of kynurenic acid have been found in particular brain regions of schizophrenics [73–75]. Moreover antipsychotic treatments have an impact on kynurenic acid levels in humans and rats .
In the past, numerous immune modulation and anti-inflammatory treatment options have been proposed for schizophrenia, but sometimes the results were inconsistent. Between the immune modulation options, authors proposed omega-3 fatty acids [77–81], erythropoietin [82, 83], tetracycline antibiotic , minocycline [85–89], azithromycin , and valacyclovir . Between the anti-inflammatory options, some trials were conducted with acetylsalicylic acid [92, 93], neurosteroids, and pregnenolone [94–96]. Recently, N-acetyl-cysteine add-on to anti-inflammatory agents has been tried [97, 98]. Emerging and promising adjunctive treatments for schizophrenia are represented by hormones (e.g., estrogen and oxytocin) [99–101], glutamatergic (e.g., glycine and d-serine) [102, 103], and nicotinergic compounds (e.g., varenicline and galantamine) [104, 105] and cannabidiol  (for an extensive review, see ).
2. Materials and Methods
Electronic search was carried out in November 2015. PubMed and Scopus databases have been used to find studies to introduce in this review. Keywords used in the search process were represented by “celecoxib add-on to antipsychotics”, “celecoxib adjunctive treatment to antipsychotics”, “celecoxib treatment for schizophrenia”, and “celecoxib treatment for schizophrenics”. Moreover, also studies found by hand search have been obtained to be included in this paper. Only randomized-placebo-controlled add-on trials were taken into account. In this way, six articles were obtained for the discussion.
There are two variants of cyclooxygenase (COX) enzyme: COX-1 and COX-2. Celecoxib is a selective inhibitor of COX-2. Both variants function in the promotion of inflammation, pain, and fever, but only COX-2 plays an important role in the central nervous system . Contrary to COX-1 inhibitors which could cause psychotic symptoms and cognitive dysfunctions, the therapeutic effect of celecoxib in schizophrenia is represented by the COX-2 inhibitor-mediated decrease of kynurenine levels .
Effects of celecoxib have been studied in add-on to risperidone, to olanzapine in one study, and to amisulpride in another. Only one study used constant doses of antipsychotics , the others used flexible doses. In each trial, 400 mg/day of celecoxib was administered. Durations of trials were different between studies, except for two. Even if the subjects enrolled in the studies were all schizophrenics, some differences have to be highlighted. In fact, two studies enrolled first manifestation schizophrenics [111, 113], whilst the others recruited continuously ill or chronic in active phase patients.
Four studies showed at least partial benefit in the celecoxib add-on treatment to antipsychotics groups based on the Positive and Negative Syndrome Scale (PANSS)  or Clinical Global Impressions scale (CGI) . Even if two studies were conducted in particular patient populations (Chinese first manifestation and Iranian chronic schizophrenics) [111, 112], the adjunctive celecoxib treatment reported similar benefits than other populations.
Since previous trials had been performed with risperidone, Müller et al.  decided to add celecoxib to amisulpride. A significantly better outcome in both positive and negative symptoms was observed in the group treated with adjunctive celecoxib compared to the placebo group. For the first time, a pronounced effect by celecoxib on schizophrenic negative symptoms was demonstrated , even if the particular effect of amisulpride on these symptoms is well known .
Two studies have not shown any therapeutic effect [109, 110], maybe due to the patient selection (refractory schizophrenia) and the different antipsychotics utilized (risperidone and olanzapine) and the duration of the trials. In fact, in animal studies observed that the effects of celecoxib on cytokines and behavioural symptoms depend on the time of administration of celecoxib . Moreover, since first episodes of schizophrenia are easier to treat than recurrent manifestation , these negative reports may have been due to chronic conditions.
A recent and useful meta-analysis  has investigated five randomized clinical trials reporting data on 264 patients in treatment with Non-Steroid Anti-Inflammatory Drugs (NSAID) augmentation to antipsychotics in schizophrenia. The authors calculated the effect of NSAIDs on symptom severity measured with the Positive and Negative Syndrome Scale (PANSS) . Likewise to our review, NSAID adjunctive treatment to antipsychotics showed a moderate beneficial effect on total symptom severity as well as on positive symptoms in schizophrenia and a small effect on negative symptoms in schizophrenia.
Very recently, Baheti et al.  have conducted an open-labeled, prospective, 6-week controlled trial to evaluate the effect of celecoxib as add-on to olanzapine therapy in acute exacerbation schizophrenics. Beneficial effects in positive, negative, and general psychopathology and total scores on PANSS have been reported, maybe for the short-term period of the trial and for the use of ICD-10 criteria for the diagnosis of schizophrenia.
Side effects were not significantly different between groups. Two trials used biperiden and lorazepam to treat extrapyramidal and anxiety side effects [108, 112]. Drop-out rates were different between trials. Even if the number of patients who dropped out from the trial was low, data are contrasting (major in celecoxib group , major in placebo group [112, 113]). Other studies have not reported drop-out rates [109–111].
Since inflammation has been correlated with the development of insulin resistance and metabolic disturbances , which are frequent in schizophrenics increased also by the antipsychotics , the use of anti-inflammatory agents may be very useful in future treatments.
In recent years, innovative therapies for autoimmune diseases have provided futuristic candidate agents for the cytokine based treatment of the schizophrenia. These treatment are based on antibodies or antibody components against cytokines or cytokine receptors [125–127].
A growing literature has been trying to explain the role of the inflammatory process in the pathophysiology of the schizophrenia. In the past, numerous studies have proposed anti-inflammatory treatment for schizophrenics, but sometimes results were inconsistent. Recently some trials have studied the effects of celecoxib add-on to risperidone, to olanzapine, and to amisulpride. Celecoxib showed beneficial effects mostly in early stages of the schizophrenia. In chronic schizophrenics the data are controversial, possibly in part for methodological reasons. In the authors’ opinion, future research should investigate celecoxib alone in the treatment of schizophrenia symptoms to better evaluate the schizophrenia inflammatory hypothesis and the real effect of the COX-2 inhibitor.
This paper was entirely funded by the authors, and no pharmaceutical companies were informed of or were involved in the review. All authors have contributed to this review with equal efforts.
The authors declare that they have no competing interests.
J. H. Krystal, L. P. Karper, J. P. Seibyl et al., “Subanesthetic effects of the noncompetitive NMDA antagonist, ketamine, in humans: psychotomimetic, perceptual, cognitive, and neuroendocrine responses,” Archives of General Psychiatry, vol. 51, no. 3, pp. 199–214, 1994.View at: Publisher Site | Google Scholar
V. Tancredi, M. D'Antuono, C. Cafè et al., “The inhibitory effects of interleukin-6 on synaptic plasticity in the rat hippocampus are associated with an inhibition of mitogen-activated protein kinase ERK,” Journal of Neurochemistry, vol. 75, no. 2, pp. 634–643, 2000.View at: Publisher Site | Google Scholar
C. J. Heyser, E. Masliah, A. Samimi, I. L. Campbell, and L. H. Gold, “Progressive decline in avoidance learning paralleled by inflammatory neurodegeneration in transgenic mice expressing interleukin 6 in the brain,” Proceedings of the National Academy of Sciences of the United States of America, vol. 94, no. 4, pp. 1500–1505, 1997.View at: Publisher Site | Google Scholar
L. Yan, R. K. Ohls, C. Rosa, M. Shah, D. S. Richards, and R. D. Christensen, “Maternal and umbilical serum concentrations of granulocyte colony-stimulating factor and its messenger RNA during clinical chorioamnionitis,” Obstetrics and Gynecology, vol. 86, no. 3, pp. 428–432, 1995.View at: Publisher Site | Google Scholar
J. M. Holden, J. E. Meyers-Manor, J. B. Overmier, E. Gahtan, W. Sweeney, and H. Miller, “Lipopolysaccharide-induced immune activation impairs attention but has little effect on short-term working memory,” Behavioural Brain Research, vol. 194, no. 2, pp. 138–145, 2008.View at: Publisher Site | Google Scholar
F. Dickerson, C. Stallings, A. Origoni, J. Boronow, and R. Yolken, “C-reactive protein is associated with the severity of cognitive impairment but not of psychiatric symptoms in individuals with schizophrenia,” Schizophrenia Research, vol. 93, no. 1–3, pp. 261–265, 2007.View at: Publisher Site | Google Scholar
L. Liu, F. Jia, G. Yuan et al., “Tyrosine hydroxylase, interleukin-1β and tumor necrosis factor-α are overexpressed in peripheral blood mononuclear cells from schizophrenia patients as determined by semi-quantitative analysis,” Psychiatry Research, vol. 176, no. 1, pp. 1–7, 2010.View at: Publisher Site | Google Scholar
X. Y. Zhang, D. F. Zhou, L. Y. Cao, G. Y. Wu, and Y. C. Shen, “Cortisol and cytokines in chronic and treatment-resistant patients with schizophrenia: association with psychopathology and response to antipsychotics,” Neuropsychopharmacology, vol. 30, no. 8, pp. 1532–1538, 2005.View at: Publisher Site | Google Scholar
M. Ozek, K. Toreci, I. Akkok, and Z. Guvener, “Influence of therapy on antibody-formation,” Psychopharmacologia, vol. 21, pp. 401–412, 1971.View at: Google Scholar
I. Wilke, V. Arolt, M. Rothermundt, C. Weitzsch, M. Hornberg, and H. Kirchner, “Investigations of cytokine production in whole blood cultures of paranoid and residual schizophrenic patients,” European Archives of Psychiatry and Clinical Neuroscience, vol. 246, no. 5, pp. 279–284, 1996.View at: Publisher Site | Google Scholar
N. Müller, M. Empl, M. Riedel, M. Schwarz, and M. Ackenheil, “Neuroleptic treatment increases soluble IL-2 receptors and decreases soluble IL-6 receptors in schizophrenia,” European Archives of Psychiatry and Clinical Neuroscience, vol. 247, no. 6, pp. 308–313, 1997.View at: Publisher Site | Google Scholar
H. Sugino, T. Futamura, Y. Mitsumoto, K. Maeda, and Y. Marunaka, “Atypical antipsychotics suppress production of proinflammatory cytokines and up-regulate interleukin-10 in lipopolysaccharide-treated mice,” Progress in Neuro-Psychopharmacology and Biological Psychiatry, vol. 33, no. 2, pp. 303–307, 2009.View at: Publisher Site | Google Scholar
N. Gogtay, A. Lu, A. D. Leow et al., “Three-dimensional brain growth abnormalities in childhood-onset schizophrenia visualized by using tensor-based morphometry,” Proceedings of the National Academy of Sciences of the United States of America, vol. 105, no. 41, pp. 15979–15984, 2008.View at: Publisher Site | Google Scholar
J. K. Yao, S. Magan, A. F. Sonel, J. A. Gurklis, R. Sanders, and R. D. Reddy, “Effects of omega-3 fatty acid on platelet serotonin responsivity in patients with schizophrenia,” Prostaglandins, Leukotrienes and Essential Fatty Acids, vol. 71, no. 3, pp. 171–176, 2004.View at: Publisher Site | Google Scholar
W. S. Fenton, F. Dickerson, J. Boronow, J. R. Hibbeln, and M. Knable, “A placebo-controlled trial of omega-3 fatty acid (ethyl eicosapentaenoic acid) supplementation for residual symptoms and cognitive impairment in schizophrenia,” The American Journal of Psychiatry, vol. 158, no. 12, pp. 2071–2074, 2001.View at: Publisher Site | Google Scholar
C. Chaves, C. R. Marque, I. B. Chaudhry et al., “Short-term improvement by minocycline added to olanzapine antipsychotic treatment in paranoid schizophrenia,” Schizophrenia Bulletin, vol. 35, pp. 354–355, 2009.View at: Google Scholar
I. B. Chaudhry, J. Hallak, N. Husain et al., “Minocycline benefits negative symptoms in early schizophrenia: a randomised double-blind placebo-controlled clinical trial in patients on standard treatment,” Journal of Psychopharmacology, vol. 26, no. 9, pp. 1185–1193, 2012.View at: Publisher Site | Google Scholar
F. B. Dickerson, C. R. Stallings, J. J. Boronow, A. E. Origoni, and R. H. Yolken, “A double-blind trial of adjunctive azithromycin in individuals with schizophrenia who are seropositive for Toxoplasma gondii,” Schizophrenia Research, vol. 112, no. 1–3, pp. 198–199, 2009.View at: Publisher Site | Google Scholar
F. B. Dickerson, C. R. Stallings, J. J. Boronow, A. E. Origoni, A. Sullens, and R. H. Yolken, “Double blind trial of adjunctive valacyclovir in individuals with schizophrenia who are seropositive for cytomegalovirus,” Schizophrenia Research, vol. 107, no. 2-3, pp. 147–149, 2009.View at: Publisher Site | Google Scholar
W. Laan, D. E. Grobbee, J.-P. Selten, C. J. Heijnen, R. S. Kahn, and H. Burger, “Adjuvant aspirin therapy reduces symptoms of schizophrenia spectrum disorders: results from a randomized, double-blind, placebo-controlled trial,” Journal of Clinical Psychiatry, vol. 71, no. 5, pp. 520–527, 2010.View at: Publisher Site | Google Scholar
M. Weiser, S. Burshtein, L. Fodoreanu et al., “A randomized trial administering aspirin, minocycline or pramipexole vs placebo as add-on to antipsychotics in patients with schizophrenia or schizoaffective disorder,” Neuropsychopharmacology, vol. 28, pp. 314–446, 2012.View at: Google Scholar
M. S. Ritsner, A. Gibel, T. Shleifer et al., “Pregnenolone and dehydroepiandrosterone as an adjunctive treatment in schizophrenia and schizoaffective disorder: an 8-week, double-blind, randomized, controlled, 2-center, parallel-group trial,” Journal of Clinical Psychiatry, vol. 71, no. 10, pp. 1351–1362, 2010.View at: Publisher Site | Google Scholar
E. Ghafari, M. Fararouie, H. G. Shirazi, A. Farhangfar, F. Ghaderi, and A. Mohammadi, “Combination of estrogen and antipsychotics in the treatment of women with chronic schizophrenia: a double-blind, randomized, placebo-controlled clinical trial,” Clinical Schizophrenia and Related Psychoses, vol. 6, no. 4, pp. 172–176, 2013.View at: Publisher Site | Google Scholar
C. M. Gibson, D. L. Penn, K. L. Smedley, J. Leserman, T. Elliott, and C. A. Pedersen, “A pilot six-week randomized controlled trial of oxytocin on social cognition and social skills in schizophrenia,” Schizophrenia Research, vol. 156, no. 2-3, pp. 261–265, 2014.View at: Publisher Site | Google Scholar
F. Rappart and N. Müller, “Celecoxib add-on therapy does not have beneficial antipsychotic effects over risperidone alone in schizophrenia,” Neuropsychopharmacology, vol. 29, no. 1, p. 222, 2004.View at: Google Scholar
Y. Zhang, D. Chun Chen, Y. Long Tan, and D. F. Zhou, “A double-blind, placebo-controlled trial of celecoxib added to risperidone in first-episode and drug-naive patients with schizophrenia,” European Archives of Psychiatry and Clinical Neuroscience, vol. 256, no. 2, p. 50, 2006.View at: Google Scholar
S. Akhondzadeh, M. Tabatabaee, H. Amini, S. A. Ahmadi Abhari, S. H. Abbasi, and B. Behnam, “Celecoxib as adjunctive therapy in schizophrenia: a double-blind, randomized and placebo-controlled trial,” Schizophrenia Research, vol. 90, no. 1–3, pp. 179–185, 2007.View at: Publisher Site | Google Scholar
N. Müller, D. Krause, S. Dehning et al., “Celecoxib treatment in an early stage of schizophrenia: results of a randomized, double-blind, placebo-controlled trial of celecoxib augmentation of amisulpride treatment,” Schizophrenia Research, vol. 121, no. 1–3, pp. 118–124, 2010.View at: Publisher Site | Google Scholar
W. Guy, “Clinical global impressions,” in ECDEU Assessment Manual for Psychopharmacology, Revised (DHEW Publ No ADM 76-338), pp. 218–222, National Institute of Mental Health, Rockville, Md, USA, 1976.View at: Google Scholar
P. Casolini, A. Catalani, A. R. Zuena, and L. Angelucci, “Inhibition of COX-2 reduces the age-dependent increase of hippocampal inflammatory markers, corticosterone secretion, and behavioral impairments in the rat,” Journal of Neuroscience Research, vol. 68, no. 3, pp. 337–343, 2002.View at: Publisher Site | Google Scholar
C. L. Raison, R. E. Rutherford, B. J. Woolwine et al., “A randomized controlled trial of the tumor necrosis factor antagonist infliximab for treatment-resistant depression: the role of baseline inflammatory biomarkers,” JAMA Psychiatry, vol. 70, no. 1, pp. 31–41, 2013.View at: Publisher Site | Google Scholar