Celecoxib and Schizophrenia – Research Abstracts

Akhondzadeh S, Tabatabaee M, Amini H, Ahmadi Abhari SA, Abbasi SH, Behnam B. Celecoxib as adjunctive therapy in schizophrenia: a double-blind, randomized and placebo-controlled trial. Schizophr Res. 2007 Feb;90(1-3):179-85. Epub 2007 Jan 8.

Some evidence suggests that the pathophysiology of schizophrenia is associated with the abnormal immune system, and cytokines may be important in schizophrenia. Cyclooxygenase-2 (COX-2) inhibitors such as celecoxib reduce the production of proinflammatory cytokines including Th1-like cytokines. Indeed, COX-2 inhibitors rebalance type-1 and type-2 immune response. The purpose of the present investigation was to assess the efficacy of celecoxib as an adjuvant agent in the treatment of chronic schizophrenia in an eight-week, double-blind and placebo-controlled trial. Eligible participants in this study were 60 patients with chronic schizophrenia. All patients were inpatients and were in the active phase of the illness, and met DSM-IV criteria for schizophrenia. Patients were allocated in a random fashion, 30 to risperidone 6 mg/day plus celecoxib 400 mg/day (200 mg bid) (morning and evening) and 30 to risperidone 6 mg/day plus placebo. Although both protocols significantly decreased the score of the positive, negative and general psychopathological symptoms over the trial period, the combination of risperidone and celecoxib showed a significant superiority over risperidone alone in the treatment of positive symptoms, general psychopathology symptoms as well as PANSS total scores. The means Extrapyramidal Symptoms Rating Scale for the placebo group were higher than in the celecoxib group over the trial. However, the differences were not significant. The results of this study suggest that celecoxib may be an effective adjuvant agent in the management of patients with chronic schizophrenia and anti-inflammatory therapies should be further investigated.

Erhardt S, Blennow K, Nordin C, Skogh E, Lindström LH, Engberg G.  Kynurenic acid levels are elevated in the cerebrospinal fluid of patients with schizophrenia. Neurosci Lett. 2001a Nov 2;313(1-2):96-8.

Kynurenic acid is an endogenous glutamate antagonist with a preferential action at the glycine-site of the N-methyl D-aspartate-receptor. Mounting evidence indicate that the compound is significantly involved in basal neurophysiological processes in the brain. In the present investigation, cerebrospinal fluid (CSF) level of kynurenic acid was analyzed in 28 male schizophrenic patients and 17 male healthy controls by means of high pressure liquid chromatography and fluorescence detection. Schizophrenic patients showed elevated CSF levels of kynurenic acid (1.67+/-0.27 nM) compared to the control group (0.97+/-0.07 nM). Furthermore, CSF levels of kynurenic acid in schizophrenic patients were also found to correlate with age. The present finding is indicative of a contribution of kynurenic acid in the pathogenesis of schizophrenia.

Erhardt S, Oberg H, Mathé JM, Engberg G. Pharmacological elevation of endogenous kynurenic acid levels activates nigral dopamine neurons.  Amino Acids. 2001b;20(4):353-62.

Inhibitors of kynurenine 3-hydroxylase have previously been used to increase endogenous levels of kynurenic acid, an excitatory amino acid receptor antagonist. In the present electrophysiological study PNU 156561A was utilized to elevate endogenous concentrations of kynurenic acid and subsequent effects on the firing pattern of dopamine (DA) neurons of rat substantia nigra (SN) were analyzed. Pretreatment with PNU 156561A (40 mg/kg, i.v., 5-7 h) caused a five-fold increase in endogenous kynurenic acid levels in whole brain five to seven hours after administration and also evoked a significant increase in firing rate and bursting activity of nigral DA neurons. The results of the present study show that a moderate increase in endogenous kynurenic acid levels produces significant actions on the tonic glutamatergic control of the firing pattern of nigral DA neurons, and implicate kynurenine 3-hydroxylase inhibitors as novel antiparkinsonian agents

Moodley I.  Review of the cardiovascular safety of COXIBs compared to NSAIDS. Cardiovasc J Afr. 2008 Mar-Apr;19(2):102-7.

There is no doubt that NSAIDs and COXIBS are the mainstay for managing pain and inflammation in arthritis. Overall, at therapeutically equivalent doses, both NSAIDs and COXIBs provide equivalent analgesic and anti-inflammatory efficacy. However, the gastrointestinal risk associated with NSAIDs is considerable. More recently, the cardiovascular risk associated with NSAIDs and COXIBs has become a concern. Most patients, particularly the young, can benefit from NSAIDs without the risk of serious adverse gastrointestinal or cardiovascular events. However, patients with a previous history of serious gastrointestinal complications and the elderly, who could be at risk, do require alternatives. COXIBs have significant benefits over NSAIDs in reducing the incidence of serious gastrointestinal complications (perforations, ulcers and gastric bleeding). Currently two oral COXIBs are available, celecoxib and lumiracoxib, and one parenteral COXIB, parecoxib. Celecoxib has been on the market for longer and has the largest body of evidence. The older NSAIDs, such as meloxicam, with preferential COX-2 inhibition do not have good long-term evidence of reducing the incidence of serious gastrointestinal complications. However, these agents do have evidence of tolerability, ie, reducing the less-serious gastrointestinal effects, mainly dyspepsia. The South African Rheumatoid Arthritis Association’s guidelines, amended in November 2005 recommend COXIBs for elderly patients (> 60 years) with previous gastropathy and those on warfarin and/or corticosteroids, providing they do not have contra-indications. However, caution is advised when prescribing COXIBs for patients with risk factors for heart disease. These recommendations are very similar to those made by the National Institute for Clinical Excellence (NICE). In addition, it should be noted that for those patients without any cardiovascular complications but with gastrointestinal risk factors or on aspirin, it may be necessary to add a proton pump inhibitor (PPI). PPIs, however, provide little benefit for bleeding and ulceration of the lower intestine. One consequence of this low-grade bleeding is anaemia and a general feeling of malaise in patients with rheumatic disease. Current evidence suggests that COXIBs such as rofecoxib and celecoxib do not increase small intestinal permeability and that celecoxib does not cause lower intestinal bleeding and may be of benefit to those patients with lower gastrointestinal complications. In patients at risk for cardiovascular complications, both NSAIDs and COXIBs have been shown to increase the risk of myocardial infarctions (MI), hypertension and heart failure. Studies comparing COXIBs and non-specific NSAIDs should, however, be interpreted with caution. One needs to take into account the underlying baseline cardiovascular risk of the populations being compared. COXIBs appear to be prescribed preferentially to patients who were at an increased risk of cardiovascular events compared with patients prescribed non-specific NSAIDs. 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.

Muller N, Schwarz M. Schizophrenia as an inflammation-mediated dysbalance of glutamatergic neurotransmission. Neurotox Res. 2006 Oct;10(2):131-48.

This overview tries to bridge the gap between psychoneuroimmunological findings and recent results from pharmacological, neurochemical and genetic studies in schizophrenia. Schizophrenia is a disorder of dopaminergic neurotransmission, but modulation of the dopaminergic system by glutamatergic neurotransmission seems to play a key role. This view is supported by genetic findings of the neuregulin- and dysbindin genes, which have functional impact on the glutamatergic system. Glutamatergic hypofunction, however, is mediated by the N-methyl-D-aspartate (NMDA)-receptor antagonism. The only endogenous NMDA receptor antagonist identified up to now is kynurenic acid (KYNA). Despite the NMDA receptor antagonism, KYNA also blocks, in lower doses, the nicotinergic acetycholine receptor, i.e., increased KYNA levels can explain psychotic symptoms and cognitive deterioration. KYNA levels are described to be higher in the cerebrospinal fluid (CSF) and in critical central nervous system (CNS) regions of schizophrenics as compared to controls. Another line of evidence suggests that a (prenatal) infection is involved in the pathogenesis of schizophrenia. Due to an early sensitization process of the immune system or to a (chronic) infection, which is not cleared through the immune response, an immune imbalance between the type-1 and the type-2 immune responses takes place in schizophrenia. The type-1 response is partially inhibited, while the type-2 response is over-activated. This immune constellation is associated with inhibition of the enzyme indoleamine dioxygenase (IDO), because IDO – located in astrocytes and microglial cells – is inhibited by type-2 cytokines. IDO catalyzes the first step in tryptophan metabolism, the degradation from tryptophan to kynurenine, as does tryptophan 2,3-dioxygenase (TDO). Due to the inhibition of IDO, tryptophan-kynurenine is predominantly metabolized by TDO, which is located in astrocytes, not in microglial or other CNS cells. In schizophrenia, astrocytes in particular are activated, as increased levels of S100B appear. Additionally, they do not have the enzymatic equipment for the normal metabolism-route of tryptophan. Due to the lack of kynurenine hydroxylase (KYN-OHase) in astrocytes, KYNA accumulates in the CNS, while the metabolic pathway in microglial cells is blocked. Accordingly, an increase of TDO activity has been observed in critical CNS regions of schizophrenics. These mechanisms result in an accumulation of KYNA in critical CNS regions. Thus, the immune-mediated glutamatergic-dopaminergic dysregulation may lead to the clinical symptoms of schizophrenia. Therapeutic consequences, e.g., the use of anti-inflammatory cyclo-oxygenase-2 inhibitors, which can also decrease KYNA directly, are discussed.

Müller N, Riedel M, Scheppach C, Brandstätter B, Sokullu S, Krampe K, Ulmschneider M, Engel RR, Möller HJ, Schwarz MJ. Beneficial antipsychotic effects of celecoxib add-on therapy compared to risperidone alone in schizophrenia.  Am J Psychiatry. 2002 Jun;159(6):1029-34.

Abnormalities in the immune system in schizophrenia have been described. However, important findings such as high levels of activating cytokines in the CSF and signs of CNS inflammation have been controversial. The authors conducted a trial of the new selective cyclooxygenase-2 inhibitor celecoxib, an immunomodulatory drug, in schizophrenic patients to evaluate its therapeutic effects. METHOD: In a prospective, double-blind evaluation, 50 patients with an acute exacerbation of schizophrenia were randomly assigned to either risperidone plus celecoxib or risperidone plus placebo. After a washout period, 25 patients received 2-6 mg/day of risperidone plus placebo and 25 received risperidone plus 400 mg/day of celecoxib for 5 weeks. The treatment effect was calculated by analysis of covariance. There were no significant differences between groups in age, sex, duration or severity of disease or psychopathology, or risperidone dose or plasma level. RESULTS: Over 5 weeks, both groups of patients showed significant improvement in scores on the Positive and Negative Syndrome Scale and on all subscales. However, the celecoxib group showed significantly greater improvement in the total score. CONCLUSIONS: Additional treatment with celecoxib has significant positive effects on the therapeutic action of risperidone with regard to total schizophrenia psychopathology. Moreover, the fact that treatment with an immunomodulatory drug showed beneficial effects on schizophrenia symptoms indicates that immune dysfunction in schizophrenia is not just an epiphenomenon but is related to the pathomechanism of the disorder. However, a nonimmunological therapeutic effect of celecoxib mediated by the N-methyl-D-aspartic acid receptor has to be taken into account.

Müller N, Krause D, Dehning S, Musil R, Schennach-Wolff R, Obermeier M, Möller HJ, Klauss V, Schwarz MJ, Riedel M. Celecoxib treatment in an early stage of schizophrenia: results of a randomized, double-blind, placebo-controlled trial of celecoxib augmentation of amisulpride treatment.  Schizophr Res. 2010 Aug;121(1-3):118-24. Epub 2010 May 31.

Recent trials support the hypothesis of the role of inflammation in the pathogenesis of schizophrenia. The overall therapeutic benefit of anti-inflammatory medication, in particular cyclo-oxygenase-2 (COX-2) inhibitors in schizophrenia, is still controversial. There are suggestions that therapy with COX-2 inhibitors may influence the early stages of the disease. Taking these findings into account, we conducted a double-blind, placebo-controlled, randomized trial of celecoxib augmentation to amisulpride treatment in patients with a first manifestation of schizophrenia. Forty-nine patients diagnosed with schizophrenia were randomly assigned. They were treated either with amisulpride (200-1000 mg) plus celecoxib (400 mg) or amisulpride (200-1000 mg) plus placebo. Inclusion criterion was the diagnosis of schizophrenia during the past two years according to DSM-IV. The trial lasted six weeks. At weekly intervals an assessment of the psychopathology was performed using the Positive and Negative Symptom Scale (PANSS) and the Global Clinical Impression Scale (CGI). A significantly better outcome was observed in the patient group treated with amisulpride plus celecoxib compared to the group with amisulpride plus placebo (PANSS negative: p=0.03; PANSS global; p=0.05 and PANSS total: p=0.02). In addition, ratings by the CGI scale during therapy with amisulpride and celecoxib showed a significantly better result (p< or =0.001). A significantly superior therapeutic effect could be observed in the celecoxib group compared to placebo in the treatment of early stage schizophrenia. This is the first time an improvement in patients’ negative symptoms has been demonstrated with celecoxib. In future, further trials are needed to investigate the effect of COX-2 inhibitors on prodromal and negative symptoms of schizophrenia.

Nilsson LK, Linderholm KR, Engberg G, Paulson L, Blennow K, Lindström LH, Nordin C, Karanti A, Persson P, Erhardt S. Elevated levels of kynurenic acid in the cerebrospinal fluid of male patients with schizophrenia. Schizophr Res. 2005 Dec 15;80(2-3):315-22. Epub 2005 Aug 25.

Previous studies have shown that endogenous brain levels of kynurenic acid (KYNA), a glutamate receptor antagonist, are elevated in patients with schizophrenia. Here we analyse KYNA in the cerebrospinal fluid (CSF) from a large cohort, including male healthy controls (n=49) and male patients with schizophrenia (n=90). We found that male patients with schizophrenia had significantly higher levels of CSF KYNA compared to healthy male controls (1.45 nM+/-0.10 vs. 1.06 nM+/-0.06 in the control group). Furthermore, when the patients with schizophrenia were divided into subgroups we found that CSF KYNA levels were significantly elevated in drug-naïve, first episode patients (1.53 nM+/-0.19, n=37) and in patients undergoing treatment with antipsychotic drugs (1.53 nM+/-0.17, n=34) compared to healthy male controls. No elevated CSF KYNA levels were detected in drug-free patients with schizophrenia, i.e. patients previously undergoing antipsychotic medications but drug-free at time of sampling (1.16 nM+/-0.10, n=19). Present results confirm that CSF KYNA concentration is elevated in patients with schizophrenia and are consistent with the hypothesis that KYNA contributes to the pathophysiology of the disease.

Rapaport MH, Delrahim KK, Bresee CJ, Maddux RE, Ahmadpour O, Dolnak D. Celecoxib augmentation of continuously ill patients with schizophrenia. Biol Psychiatry. 2005 Jun 15;57(12):1594-6.

Previous reports have demonstrated a beneficial effect of celecoxib adjunctive therapy for patients with an acute exacerbation of schizophrenia. We investigated the effects of celecoxib augmentation of atypical antipsychotic medications for continuously symptomatic outpatient subjects with schizophrenia to further extend these findings. We hypothesized that celecoxib augmentation therapy would improve psychopathology ratings compared with placebo. METHODS: Thirty-eight symptomatic outpatient subjects meeting DSM-IV criteria for schizophrenia and on a stable dose of an atypical antipsychotic medication for at least three months were randomized to receive 8 weeks of double blind placebo or celecoxib (400 mg/day) augmentation. Measures of psychopathology, functional disability, and extrapyramidal side effects were performed throughout the study. RESULTS: The treatment cohorts did not differ on any of the clinical outcome measures. CONCLUSIONS: Celecoxib augmentation of continuously ill outpatient subjects with schizophrenia did not improve clinical symptoms or measures of disability.

Swartz KJ, During MJ, Freese A, Beal MF. J  Cerebral synthesis and release of kynurenic acid: an endogenous antagonist of excitatory amino acid receptors. Neurosci. 1990 Sep;10(9):2965-73.

Excitatory amino acid (EAA)-mediated synaptic transmission is the most prevalent excitatory system within the mammalian brain. Activation of EAA receptors has been postulated to contribute to neuronal cell death in stroke, epilepsy, hypoglycemia, and Huntington’s disease. Kynurenic acid is an endogenous substance that inhibits EAA receptors and may therefore influence important physiologic and pathologic processes. The release of intracerebrally synthesized kynurenic acid into the extracellular fluid (ECF), where it may act at EAA receptors, has not been established in vivo. We studied the synthesis and release of kynurenic acid in the rat striatum using intracerebral microdialysis coupled with high performance liquid chromatography and fluorescence detection. The basal ECF concentration of kynurenic acid in the rat corpus striatum was 17.1 +/- 1.1 nM. Peripheral administration of the immediate biosynthetic precursor of kynurenic acid, L-kynurenine, resulted in marked dose-dependent increases in striatal ECF concentrations of kynurenic acid, peaking at 2-2.5 hr. The highest dose of L-kynurenine (100 mg/kg), administered peripherally, resulted in a 108-fold increase in plasma kynurenic acid levels and a 37-fold increase in cerebral ECF levels. Peripheral administration of kynurenic acid, at a dose that caused plasma levels to increase 430-fold, resulted in only 4-fold increases in striatal ECF concentrations. The precursor responsiveness of striatal ECF kynurenic acid to peripherally infused L-kynurenine was blocked by the central application (via the dialysis probe) of aminooxyacetic acid, an inhibitor of the immediate synthetic enzyme for kynurenic acid, kynurenine aminotransferase. Administration of L-tryptophan was less effective than L-kynurenine in increasing ECF kynurenic acid concentrations and did so at a considerably later time interval (6 hr).(ABSTRACT TRUNCATED AT 250 WORDS)

Torrey EF, Davis JM.  Adjunct treatments for schizophrenia and bipolar disorder: what to try when you are out of ideas. Clin Schizophr Relat Psychoses. 2012 Jan;5(4):208-216.

The pharmacologic treatment of schizophrenia and bipolar disorder leaves much to be desired. Repurposed drugs, which are approved for other medical conditions, represent an underutilized therapeutic resource for patients who have not responded to other drugs. Using experience gained from a decade of repurposed drug studies by the Stanley Medical Research Institute and search of the literature, we have identified nine such drugs for which there is some evidence of efficacy for schizophrenia and/or bipolar disorder. These include: aspirin; celecoxib; estrogen/raloxifene; folate; minocycline; mirtazapine; omega-3 fatty acids; pramipexole; and, pregnenolone. The evidence of efficacy is reviewed for each drug. Because there is little or no financial incentive for pharmaceutical companies to promote such drugs, there is a paucity of definitive trials, and these drugs are less widely known than they deserve to be. Biomarker studies should also be carried out to identify subgroups of patients who do respond to these drugs.

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