allopurinol and Schizophrenia

There is accumulating evidence that progressive changes in brain structure and function take place as schizophrenia unfolds. Among many possible candidates, oxidative stress may be one of the mediators of neuroprogression, grey matter loss and subsequent cognitive and functional impairment. Antioxidants are exogenous or endogenous molecules that mitigate any form of oxidative stress or its consequences. They may act from directly scavenging free radicals to increasing anti-oxidative defences. There is evidence that current treatments impact oxidative pathways and may to some extent reverse pro-oxidative states in schizophrenia. The existing literature, however, indicates that these treatments do not fully restore the deficits in antioxidant levels or restore levels of oxidants in schizophrenia. As such, there has been interest in developing interventions aimed at restoring this oxidative balance beyond the benefits of antipsychotics in this direction. If antioxidants are to have a place in the treatment of this serious condition, the relevant and up-to-date information should be available to clinicians and investigators.. To evaluate the effect of antioxidants as add-on treatments to standard antipsychotic medication for improving acute psychotic episodes and core symptoms, and preventing relapse in people with schizophrenia.. We searched the Cochrane Schizophrenia Group's Study-Based Register of Trials which is based on regular searches of CINAHL, BIOSIS, AMED, Embase, PubMed, MEDLINE, PsycINFO, and registries of clinical trials. There are no language, time, document type, or publication status limitations for inclusion of records in the register. We ran this search in November 2010, and again on 8 January 2015. We also inspected references of all identified studies for further trials and contacted authors of trials for additional information.. We included reports if they were randomised controlled trials (RCTs) involving people with schizophrenia who had been allocated to either a substance with antioxidant potential or to a placebo as an adjunct to standard antipsychotic treatment.. We independently extracted data from these trials and we estimated risk ratios (RR) or mean differences (MD), with 95% confidence intervals (CI). We assessed risk of bias for included studies and created a 'Summary of findings' table using GRADE.. The review includes 22 RCTs of varying quality and sample size studying Ginkgo biloba, N-acetyl cysteine (NAC), allopurinol, dehydroepiandrosterone (DHEA), vitamin C, vitamin E or selegiline. Median follow-up was eight weeks. Only three studies including a minority of the participants reported our a priori selected primary outcome of clinically important response. Short-term data for this outcome (measured as at least 20% improvement in scores on Positive and Negative Syndrome Scale (PANSS)) were similar (3 RCTs, n = 229, RR 0.77, 95% CI 0.53 to 1.12, low quality evidence). Studies usually reported only endpoint psychopathology rating scale scores. Psychotic symptoms were lower in those using an adjunctive antioxidant according to the PANSS ( 7 RCTS, n = 584, MD -6.00, 95% CI -10.35 to -1.65, very low quality evidence) and the Brief Psychiatric Rating Scale (BPRS) (8 RCTS, n = 843, MD -3.20, 95% CI -5.63 to -0.78, low quality evidence). There was no overall short-term difference in leaving the study early (16 RCTs, n = 1584, RR 0.73, 95% CI 0.48 to 1.11, moderate quality evidence), or in general functioning (2 RCTs, n = 52, MD -1.11, 95% CI -8.07 to 5.86, low quality evidence). Adverse events were generally poorly reported. Three studies reported useable data for 'any serious adverse effect', results were equivocal (3 RCTs, n = 234, RR 0.65, 95% CI 0.19 to 2.27, low quality evidence). No evidence was available for relapse, quality of life or service use.. Although 22 trials could be included in this review, the evidence provided is limited and mostly not relevant to clinicians or consumers. Overall, although there was low risk of attrition and selective data reporting bias within the trials, the trials themselves were not adequately powered and need more substantial follow-up periods. There is a need for larger trials with longer periods of follow-up to be conducted. Outcomes should be meaningful for those with schizophrenia, and include measures of improvement and relapse (not just rating scale scores), functioning and quality of life and acceptability and, importantly, safety data.

Topics: Acetylcysteine; Allopurinol; Antioxidants; Antipsychotic Agents; Ascorbic Acid; Dehydroepiandrosterone; Drug Therapy, Combination; Free Radical Scavengers; Ginkgo biloba; Humans; Oxidative Stress; Randomized Controlled Trials as Topic; Schizophrenia; Selegiline; Vitamin E; Vitamins

To review the available literature evaluating the effectiveness of allopurinol for poorly responsive or treatment refractory schizophrenia.. Searches of MEDLINE (1966-October 2006), the Cochrane Library, and International Pharmaceutical Abstracts (1970-October 2006) were conducted using the terms allopurinol and schizophrenia. Limits were set to select studies conducted in humans.. All articles identified from the data sources were evaluated. All case reports or clinical trials located were included in the review.. Dopamine has been implicated for many years in the pathophysiology of schizophrenia, and the typical antipsychotics, via blockade of dopaminergic neurotransmission, have provided relief for patients with positive symptoms. However, because dopamine blockade does not relieve all symptoms of schizophrenia, it is now evident that many neurotransmitters may be involved in the pathogenesis of schizophrenia. Therefore, atypical antipsychotics, which target multiple neurotransmitters, have emerged as first-line therapies. An evolving body of evidence also supports a purinergic hypothesis for schizophrenia. Increased adenosinergic transmission is thought to reduce the affinity of dopamine agonists for dopamine receptors. Allopurinol, a xanthine oxidase inhibitor, may increase circulating pools of adenosine and may ultimately have antipsychotic and anxiolytic effects. Growing evidence for use of allopurinol as adjunctive therapy has been reported in both case reports and small clinical trials.. Clinical trials show that adjuvant allopurinol may provide benefit to patients who are poorly responsive to current treatments for schizophrenia. Allopurinol is well tolerated by most patients. However, larger, randomized clinical trials need to be performed to determine the magnitude of this benefit, whether allopurinol should be routinely used as adjuvant therapy to antipsychotics, and which patient population is most likely to benefit from allopurinol use. For patients with limited options, allopurinol in doses of 300 mg once or twice daily may improve psychotic symptoms, especially refractory positive symptoms.

Topics: Adjuvants, Pharmaceutic; Allopurinol; Antipsychotic Agents; Humans; Schizophrenia; Schizophrenic Psychology

Adenosine agonists produce behavioral effects similar to dopamine antagonists, hence increasing adenosine levels might improve symptoms of schizophrenia. This hypothesis is supported by three single-site studies indicating that allopurinol, which increases adenosine levels, improved symptoms in patients with schizophrenia. We performed a multi-center, 8-week RCT of allopurinol vs. placebo added to anti-psychotic medications in 248 patients with schizophrenia or schizoaffective disorder. Both groups showed improvement in the PANSS (effect size 1.13) and in clinical and cognitive measures. No difference was observed between groups in primary (t=0.01, p=0.992) or secondary outcome measures. These findings do not support allopurinol as a treatment for schizophrenia.

Topics: Adenosine; Adult; Allopurinol; Antipsychotic Agents; Drug Therapy, Combination; Enzyme Inhibitors; Female; Humans; Male; Middle Aged; Psychotic Disorders; Schizophrenia; Treatment Outcome; Xanthine Oxidase

To investigate if adjunctive allopurinol reduces symptoms in schizophrenia outpatients with persistent symptoms despite adequate pharmacotherapy.. N=59 schizophrenia outpatients were randomly assigned to receive adjunctive allopurinol 300 mg bid or identical-looking placebo for 8 weeks after a 2-week placebo run-in. Symptoms were assessed biweekly.. A total of n=51 patients completed the trial. Including all n=59 randomized patients, a total of 4 of 31 in the allopurinol group and 0 of 28 in the placebo group had at least a 20% reduction in total PANSS score at the final study visit (chi-square=3.88, p=.049). Among the n=51 completers, individuals in the allopurinol group rated themselves as more improved than did those in the placebo group (z=-2.24, p=.025). The allopurinol medication was well tolerated and there were not any adverse events attributed to the study medication.. Allopurinol may be an effective adjunctive medication for some patients with persistent schizophrenia.

Topics: Adult; Allopurinol; Ambulatory Care; Antimanic Agents; Antipsychotic Agents; Double-Blind Method; Drug Administration Schedule; Drug Therapy, Combination; Female; Humans; Male; Placebos; Psychiatric Status Rating Scales; Schizophrenia; Schizophrenic Psychology; Treatment Outcome

There is a large amount of data showing that adenosine plays a role opposite to dopamine in the brain. Adenosine agonists and antagonists produce behavioral effects similar to dopamine antagonists and dopamine agonists, respectively. Allopurinol, a well-known hypouricemic drug that inhibits xantine oxidase, has been used as an add-on drug in the treatment of poorly responsive schizophrenic patients. Indeed, the neuropsychiatric effects of allopurinol in schizophrenia have been suggested to be secondary to its inhibitory effect of purine degradation, enhancing adenosinergic activity. The purpose of the present investigation was to assess the efficacy of allopurinol as an adjuvant agent in the treatment of chronic schizophrenia in an 8-week double blind and placebo controlled trial. Eligible participations in the study were 46 patients with schizophrenia. All patients were inpatients and were in the active phase of the illness, and met DSM-IV criteria for chronic schizophrenia. Patients were allocated in a random fashion, 23 to haloperidol 15 mg/day plus allopurinol 300 mg/day and 23 to haloperidol 15 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 haloperidol and allopurinol showed a significant superiority over haloperidol alone in the treatment of positive symptoms, general psychopathology symptoms as well as PANSS total scores. The means of Extrapyramidal Symptoms Rating Scale for the placebo group were higher than in the allopurinol group over the trial, and the differences were significant in weeks 6 and 8. A significant difference was observed between the overall mean biperiden dosages in two groups. The results of this study suggest that allopurinol may be an effective adjuvant agent in the management of patients with chronic schizophrenia. Nevertheless, results of larger controlled trials are needed, before recommendations for a broad clinical application can be made.

Topics: Adult; Allopurinol; Antipsychotic Agents; Case-Control Studies; Dopamine Antagonists; Double-Blind Method; Drug Evaluation; Drug Therapy, Combination; Female; Haloperidol; Humans; Male; Placebos; Psychiatric Status Rating Scales; Schizophrenia; Time Factors; Treatment Outcome

To evaluate the xanthine oxidase inhibitor allopurinol as an adjuvant treatment for patients with moderately refractory schizophrenia, with the objective of increasing the endogenous pool of purines, including the neuro-modulator adenosine.. A double-blind, placebo-controlled, crossover clinical trial of add-on allopurinol (300 mg b.i.d.) for poorly responsive schizophrenia or schizoaffective disorder (DSM-IV criteria) was conducted. Thirty-five patients were enrolled, of whom 22 completed the 12 weeks of the study. Eighteen of these patients also completed a P50 evoked potential evaluation.. Allopurinol was well tolerated and produced significant improvement in Positive and Negative Syndrome Scale (PANSS) total, positive, negative, and general scores, particularly for positive symptoms compared with baseline and with placebo phase. Nine patients improved more than 20% in PANSS total score during allopurinol treatment, whereas none responded in the placebo phase. Responders had a shorter duration of illness than nonresponders. P50 auditory sensory gating failed to improve with allopurinol treatment.. Allopurinol was an effective and well-tolerated adjuvant treatment for poorly responsive schizophrenia, especially for refractory positive symptoms.

Topics: Adult; Allopurinol; Antipsychotic Agents; Cross-Over Studies; Double-Blind Method; Drug Therapy, Combination; Enzyme Inhibitors; Evoked Potentials, Auditory; Female; Humans; Male; Placebos; Psychiatric Status Rating Scales; Schizophrenia; Schizophrenic Psychology; Severity of Illness Index; Treatment Outcome; Xanthine Oxidase

Topics: Administration, Oral; Allopurinol; Child; Child Behavior Disorders; Clinical Trials as Topic; Diet Therapy; Dose-Response Relationship, Drug; Echolalia; Humans; Male; Placebos; Purines; Remission, Spontaneous; Schizophrenia; Schizophrenia, Childhood; Self Concept; Uric Acid; Xanthine Oxidase

Topics: Allopurinol; Antipsychotic Agents; Humans; Schizophrenia; Schizophrenic Psychology

Despite multiple trials of different adjuvant therapies to an antipsychotic regimen, there have been few promising results. Allopurinol may be one promising adjunctive therapy based on three randomized controlled trials.. To determine whether adjuvant allopurinol would be beneficial to a patient already on multiple trials of antipsychotics with no improvement.. Allopurinol was started with this particular patient who was on the inpatient unit for over three months with no prior improvement. Within two weeks of allopurinol adjuvant therapy, the patient showed significant improvement with regards to his positive and negative symptoms of schizophrenia (PANSS scores went from a score of 88 to a score of 41 two weeks later).. Despite some limitations of this particular case report, it is possible that allopurinol can play an effective role as an adjuvant to antipsychotic regimens in reducing the symptoms of schizophrenia.

Topics: Adult; Allopurinol; Antipsychotic Agents; Drug Resistance; Drug Therapy, Combination; Free Radical Scavengers; Humans; Male; Schizophrenia; Treatment Outcome

Acquired ichthyosis is a rare condition that can reveal an unsuspected haematological malignancy, thus allowing early diagnosis and management. If ichthyosis regresses under treatment for the haematological disorder, its recurrence reflects a turning point in the course of the disease and implies worsening of the prognosis.. The patients were examined at a joint dermatology/haematology consultation. The diagnosis of ichthyosis was based on clinical examination alone with no patients undergoing skin biopsy.. Our series included three men and two women aged 38 to 65 years consulting for a variety of reasons including asthenia, anaemia and adenopathy. Ichthyosis occurred 2 to 9 months after the initial symptoms of the blood disease. Lesions consisted of diffuse brown scales. The disease was associated with lymphadenopathy and biological inflammatory syndrome. Two patients were presenting non-Hodgkin lymphoma, one had Hodgkin's disease, one had chronic myeloid leukaemia in progression and one had an undifferentiated lymphomatous process. Treatment was based on chemotherapy and emollients. The ichthyosis progressed in step with the underlying malignancy in all cases, with regression being complete in three cases, partial in one case and absent in one case.. In rare cases, acquired ichthyosis reveals systemic disease, and may be of infectious, endocrine or drug origin; it may also be idiopathic. However, it is most often a paraneoplastic syndrome with cutaneous expression encountered during haematological malignancies. Because of the variety of causative blood dyscrasias, ichthyosis cannot be used to guide their diagnosis, although it remains a reliable monitoring tool.. Acquired ichthyosis should prompt the clinician to search for a neoplastic condition, primarily a haematological disorder, guided by other associated signs, given that in our study, skin lesions generally appear to precede signs of the blood disease.

Topics: Adult; Aged; Allopurinol; Anemia; Antibodies, Monoclonal, Murine-Derived; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Benzamides; Bleomycin; Cyclophosphamide; Doxorubicin; Etoposide; Female; Hematologic Neoplasms; Hodgkin Disease; Humans; Ichthyosis; Imatinib Mesylate; Leukemia, Myeloid, Accelerated Phase; Lung Neoplasms; Lymphoma, B-Cell; Male; Middle Aged; Paraneoplastic Syndromes; Parotid Neoplasms; Piperazines; Platelet Aggregation Inhibitors; Prednisone; Procarbazine; Pyrimidines; Retrospective Studies; Rituximab; Schizophrenia; Stomach Neoplasms; Vincristine

Mounting evidence shows that oxidative stress (OS) and the purine/adenosine system play a key role in the pathophysiology of schizophrenia. Lately, our group pointed out that not only antioxidants, but also the prooxidant system plays an important role in neuro-psychiatric disorders. Xanthine oxidase (XO) is an enzyme of special interest in this context, since it acts as a prooxidant, but its main product is a vastly important antioxidant, uric acid (UA). Furthermore, XO plays major part in the purine/adenosine metabolism, which has been hypothesised to play a role in schizophrenia as well.. We examined the activity of XO in the striato-cortico-limbic system of schizophrenic patients (SP) and controls using a commercially available activity assay.. We found decreased activity of XO in the occipital cortex and thalamus of patients with psychosis. Furthermore, XO shows a significant positive correlation with chlorpromazine equivalents in the putamen and the temporal cortex.. Nevertheless, our results might suggest a downregulation of cellular defence mechanisms in schizophrenia in several brain regions, which could account for neuronal alterations which have been described before. This demonstrates that more research is needed to fully understand the role of the complex enzyme XO in the pathophysiology of schizophrenia.

Topics: Aged; Aged, 80 and over; Case-Control Studies; Female; Humans; Male; Middle Aged; Occipital Lobe; Oxidative Stress; Schizophrenia; Thalamus; Xanthine Oxidase

Topics: Allopurinol; Antipsychotic Agents; Comorbidity; Drug Resistance; Electroconvulsive Therapy; Epilepsy; Hematoma, Subdural; Humans; Male; Middle Aged; Off-Label Use; Risk Factors; Schizophrenia; Time Factors

Topics: Adult; Allopurinol; Electroconvulsive Therapy; Gout Suppressants; Humans; Hyperuricemia; Male; Schizophrenia; Seizures

Omega-3 (omega-3) is an essential fatty acid (EFA) found in large amounts in fish oil. It contains eicosapentaenoic acid and docosahexaenoic acid (DHA). DHA is one of the building structures of membrane phospholipids of brain and necessary for continuity of neuronal functions. Evidences support the hypothesis that schizophrenia may be the result of increased reactive oxygen species mediated neuronal injury. Recent reports also suggest the protective effect of omega-3 EFA against neuropsychiatric disorders including schizophrenia. This study proposed to assess the changes in antioxidant enzyme and oxidant parameters in the corpus striatum (CS) of rats fed with omega-3 EFA diet (0.4g/kg/day) for 30 days. Eight control rats and nine rats fed with omega-3 were decapitated under ether anesthesia, and CS was removed immediately. Thiobarbituric acid-reactive substances (TBARS) and nitric oxide (NO) levels as well as total superoxide dismutase (t-SOD) and xanthine oxidase (XO) enzyme activities in the CS were measured. Rats treated with omega-3 EFA had significantly lower values of TBARS (P<0.001), NO (P<0.002) and XO (P<0.005) whereas higher values of t-SOD enzyme activity (P<0.002) than the control rats. These results indicate that omega-3 EFA rich fish oil diet reduces some oxidant parameters in CS. This may be revealed by means of reduced CS TBARS levels as an end product of lipid peroxidation of membranes in treated rats. Additionally, reduced XO activity and NO levels may support this notion. On the other hand, although the mechanism is not clear, omega-3 EFA may indirectly enhance the activity of antioxidant enzyme t-SOD. Taken together, this preliminary animal study provides strong support for a therapeutic effect of omega-3 EFA supplemented to classical neuroleptic regimen in the treatment of schizophrenic symptoms and tardive dyskinesia.

Topics: Animals; Antioxidants; Corpus Striatum; Dietary Fats; Fatty Acids, Essential; Fatty Acids, Omega-3; Fish Oils; Lipid Peroxidation; Nitric Oxide; Oxidants; Psychotic Disorders; Rats; Schizophrenia; Superoxide Dismutase; Thiobarbituric Acid Reactive Substances; Xanthine Oxidase

There is great evidence in recent years that oxygen free radicals play an important role in the pathophysiology of schizophrenia. The present study was performed to assess the changes in plasma nitric oxide (NO) and thiobarbituric acid-reactive substances (TBARS) levels, and superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), and xanthine oxidase (XO) activities in schizophrenic patients compared to age- and sex-matched normal controls. A hundred patients with schizophrenia and 51 healthy volunteers were included in the study. XO, SOD, and GSH-Px activities as well as NO and TBARS levels were estimated by standard biochemical techniques in the plasma of normal healthy controls and schizophrenia patients. In schizophrenia, increased plasma XO activity (P < .0001) and NO levels (P < .0001), decreased SOD activity (P < .0001), and unchanged GSH-Px activity were detected compared to control group. Plasma TBARS levels were increased in schizophrenic patients (P < .01), especially in the residual subtype. TBARS levels in nonsmoker schizophrenic patients were found to be higher than nonsmoker controls. Although TBARS levels in both patients and controls were found to be higher in smokers as compared to nonsmokers, it was not statistically significant. No effects of duration of the illness, gender, and low and high dose of daily neuroleptic treatment equivalent to chlorpromazine on oxidant and antioxidant parameters were observed. Because the dose and the duration of treatment with drugs have no influence on the results, it can be interpreted that the findings are more likely to be related mainly to the underlying disease. These findings indicated a possible role of increased oxidative stress and diminished enzymatic antioxidants, both of which may be relevant to the pathophysiology of schizophrenia. On the other hand, increased NO production by nitric oxide synthetases (NOSs) suggests a possible role of NO in the pathophysiological process of schizophrenia. These findings may also suggest some clues for the new treatment strategies with antioxidants and NO synthase (NOS) inhibitors in schizophrenia.

Topics: Adolescent; Adult; Antioxidants; Female; Glutathione Peroxidase; Humans; Male; Middle Aged; Nitric Oxide; Oxidants; Oxidative Stress; Schizophrenia; Statistics, Nonparametric; Superoxide Dismutase; Thiobarbituric Acid Reactive Substances; Xanthine Oxidase

Adenosine has been proposed to contribute to the pathophysiology of schizoprenia and as a target for therapeutic intervention. In the lack of direct adenosine agonists, allopurinol may indirectly elevate adenosine levels by inhibiting degradation of purines. We report two cases of poorly responsive schizophrenic patients who improved considerably with add-on allopurinol 300 mg/day. Their clear clinical improvement warrant further investigation of allopurinol, as well as other purinergic strategies, for the treatment of schizophrenia.

Topics: Adult; Allopurinol; Antipsychotic Agents; Drug Interactions; Drug Therapy, Combination; Humans; Male; Psychiatric Status Rating Scales; Schizophrenia; Schizophrenic Psychology; Treatment Outcome