Celecoxib is a prescription medication that inhibits Cycloxygenase-2 (COX-2), an enzyme that increases inflammation. Research evidence has shown that early treatment with celecoxib may improve symptoms in the early stages of schizophrenia.
For more on NAC research and outcomes in schizophrenia please consider viewing the archived presentation:
“New Options in the Treatment of Negative and Cognitive Symptoms in Schizophrenia – PART 2”
Schizophrenia and Inflammation
Treatment with neuroleptic medications in the early stages of schizophrenia may slow progression of the illness. This positive effect upon disease progression may be true of Celecoxib as well.
Inflammation in the body and brain is common in schizophrenia. Even in the early stages of the disorder, layered and interrelated inflammatory markers have repeatedly been shown to be elevated. This inflammatory process is part of the development of schizophrenia per se, and is not the simple result of the medications used to treat the disorder as has previously been postulated.
It is also clear that inflammatory processes impact the illness and may worsen symptoms over time. In fact, inflammation may actually be both the cause and effect of at least some of the changes that occur in schizophrenia. Decreasing inflammation should a primary treatment goal in any treatment model that conceives of schizophrenia as a progressive, inflammatory, neurodevelopmental disorder.
Research using Celecoxib in the early stages of this disorder is promising. While broader interventions aimed to decrease inflammatory processes in the early stages of the disorder are likely to become standard of care over the next decade, Celecoxib is available now and is used by some psychiatrists treating schizophrenia.
Celecoxib is an anti-inflammatory medication that blocks the Cycloxygenase-2 (COX-2) enzyme. COX-2 is a stress-phase enzyme that increases in amount and activity with tissue injury. While at some level, inflammation is required for healing, in many disease states the inflammation actually becomes the cause rather than a solution to tissue injury. In these circumstances COX-2 inhibitors have a role to play in mitigating this destructive process.
COX-2 is related to COX-1, however the latter enzyme is involved in many other messenging systems that are unrelated to inflammation. By blocking only COX-2, Celecoxib preferentially affects only inflamed tissue and turns down the inflammatory process only where it is an issue. In the brain, Celecoxib may help reduces inflammatory processes that cause ongoing injury and insult to brain tissue.
The Kynurenic Acid Hypothesis
Though COX-2 inhibitors may be helpful in schizophrenia, COX-2 may not be the heart of the problem. Brain inflammation through viruses may increase the production of Kynurenic Acid by shifting immune response towards Type 2 over Type 1. Viral Inflammation can shift towards a Type 2 immune response over Type I and this may help to explain the established viral risk factors for schizophrenia (e.g., The Flu Virus and Schizophrenia). Celecoxib may help reverse this complicated process.
Increased Type 2 immune response inhibits Indoleamine Dioxygenase (IDO), which normally participates in Tryptophan metabolism. Activity of Trypophan 2,3-Dioxygenase (TDO) increases on balance, and Kynurenic Acid (KA) levels rise as a result. While many brain cells can process these changes appropriately, Astrocytes lack the enzyme kynurenine hydroxylase, which helps to break down KA. A metabolic back up occurs and KA levels rise in the brain and CSF (Muller and Schwartz 2006).
Kynurenic Acid is known to block NMDA Receptors and Alpha7 Nicotinic Receptors, both of signficant importance in the symptoms of schziophrenia. KA blocks the NMDA Receptor at the Glycine Site even in low concentrations (Schwartz et al. 1990). It also blocks the Alpha7 Nicotinic Receptor (Hilmas et al. 2001), which is heavily involved in memory and intellect. Increasing Kynurenic Acid levels with pharmacological manipulation even appears to mimic patterns seen with PCP (a model of schizophrenia), including increased Nigral Dopaminergic Activity (Erhardt et al. 2001b).
Finally, Kynurenic Acid has been shown to be high in the CSF of individuals with schizophrenia (Erhardt et al. 2001a). Nilsson et al. (2005) reported 37% higher levels of KA males with schizophrenia (1.45 nM) compared to controls (1.06 nM). Furthermore, they saw 44% increases in drug-naive, first episode patients, thus this is clearly not an effect of medications use to treat schizophrenia.
The “Kynurenic Acid Hypothesis of Schizophrenia” may be the best explanation we currently have to describe the interrelation of Inflammation, NMDA Receptors and the symptoms of schizophrenia.
Celecoxib is often ignored as a treatment option in the early stages of the illness due to the perception of risk in the general medical community. Unfortunately, this perception may lead to an assessment of risks versus benefits that is often inaccurate in individuals acutely developing schizophrenia.
The risks associated with celecoxib pertain to the heart (myocardial infarction, hypertension and failure) or the gastrointestinal tract. But, they are not absolute. They are relative to an individual’s baseline risk profile. On average, these risk profiles are very low in an individual developing schizophrenia in their early 20’s. At this age, increasing a individual’s already very low risk by a small fraction is arguably a negligible issue. This is especially true in comparison to the potential benefits offered by Celecoxib in the early stages of the disorder.
In a review of the relative safety of NSAIDS (e.g., ibuprofen, ketoprofen) versus COX-2 Inhibitors (e.g., celecoxib, lumiracoxib) Moodley (2008) is clear that COX-2 Inhibitors have substantially reduced risk of causing serious gastrointestinal complications, though they can occur in vulnerable populations.
It also appears that Celecoxib is less likely to increase the relative risk of a cardiac event. In assessing risks associated with COX-2 inhibitors he states:
“One needs to take into account the underlying baseline cardiovascular risk of the populations being compared. . . . When the overall risk of cardiovascular complications is relatively low and an anti-inflammatory agent is required, current evidence suggests that celecoxib is an agent of choice because of its lower cardiovascular toxicity potential compared to NSAIDs and other COXIBs.”
Research based dosing of Celecoxib (CelebrexTM) is at 200 mg twice per day. It is often started at a lower dose of 100 mg twice per day to test tolerance.
Beneficial antipsychotic effects of celecoxib add-on therapy compared to risperidone alone in schizophrenia.
Müller N, Riedel M, Scheppach C, Brandstätter B, Sokullu S, Krampe K, Ulmschneider M, Engel RR, Möller HJ, Schwarz MJ. Am J Psychiatry. 2002 Jun;159(6):1029-34.
Description: Compared Celecoxib to Placebo when added to Risperidone in patients with acute exacerbation of schizophrenia
Design: Five-week trial with 50 patients. Double blind, placebo controlled. Outcomes measured on PANSS. Risperidone (flexible dosing) + Celecoxib 400 mg/day vs. Placebo.
Results: Study showed a small but significant reduction in PANSS scores with Celecoxib compared to Placebo.
Considerations: Study only 5 weeks long, which may be an insufficient period to assess mental status changes related to chronic inflammation. Torrey and Davis (2012) state that a reanalysis of the data showed that the largest benefits occurred in those individuals in the early stages of their condition.
Celecoxib as adjunctive therapy in schizophrenia: a double-blind, randomized and placebo-controlled trial.
Akhondzadeh S, Tabatabaee M, Amini H, Ahmadi Abhari SA, Abbasi SH, Behnam B. Schizophr Res. 2007 Feb;90(1-3):179-85. Epub 2007 Jan 8.
Description: Compared Celecoxib to Placebo when added to Risperidone in patients with acute exacerbation of schizophrenia.
Design: Eight-week trial with 60 patients, Double blind, placebo controlled. Outcomes measured on PANSS. Risperidone 6 mg/day + Celecoxib 200 mg BID or Placebo
Results: Study showed significantly reduced PANSS Positive and Total symptom sub-scale scores with Celecoxib compared to Placebo. PANSS Total Scores were reduced by 43.7 points with Celecoxib compared to 29.2 points with Placebo. This constitutes a 50% improvement over Risperidone alone.
Celecoxib treatment in an early stage of schizophrenia: results of a randomized, double-blind, placebo-controlled trial of celecoxib augmentation of amisulpride treatment.
Müller N, Krause D, Dehning S, Musil R, Schennach-Wolff R, Obermeier M, Möller HJ, Klauss V, Schwarz MJ, Riedel M.Schizophr Res. 2010 Aug;121(1-3):118-24. Epub 2010 May 31.
Description: Study compared Celecoxib to Placebo added to the atypical antipsychotic Amisulpride in patients in first psychotic episode.
Design: Six-week trial with 60 patients. Double blind, placebo controlled. Amisulpride (200-1000 mg/day) + Celecoxib 200 mg BID or Placebo
Results: Significantly better outcomes were seen with Celecoxib compared to Placebo. PANSS Global Scale (p=0.05), the PANSS Negative Scale (p=0.03) and the PANSS Total scale (P=0.002) all improved. Clinical Global Impression Scale (CGI) improved as well (p<0.001)
Considerations: Because this study only included individuals with first episode psychosis it strongly supports the hypothesis that early intervention with the anti-inflammatory Celecoxib is most likely to result in positive outcomes.
Celecoxib augmentation of continuously ill patients with schizophrenia.
Rapaport MH, Delrahim KK, Bresee CJ, Maddux RE, Ahmadpour O, Dolnak D. Biol Psychiatry. 2005 Jun 15;57(12):1594-6.
Description: Compared Celecoxib to Placebo added to flexible antipsychotic regimen in chronic patients with schizophrenia.
Design: Nine-week trial with 38 patients. Double blind, placebo controlled. Antipsychotic + Celecoxib 200 mg BID or Placebo
Results: Negative. No benefits were seen.
Considerations: This study was performed with patients with average duration of illness of 20 years. Negative findings support the hypothesis that Celecoxib is best used early in the progression of the disorder.