Мета-анализ: добавление НПВС к терапии антипсихотиками при шизофрении

Objective: To meta-analytically assess the efficacy and tolerability of nonsteroidal anti-inflammatory drugs (NSAIDs) vs placebo in schizophrenia. Method: Searching PubMed, PsycINFO, ISI Web of Science, and the US National Institute of Mental Health clinical trials registry from database inception to December 31, 2012, we conducted a systematic review/meta-analysis of randomized placebo-controlled studies assessing the efficacy of adjunctive NSAIDs. Primary outcome was the change in Positive and Negative Syndrome Scale (PANSS) total score. Secondary outcomes included change in PANSS positive and negative subscores, all-cause discontinuation, and tolerability outcomes. Random effects, pooled, standardized mean changes (Hedges’ g) and risk ratios were calculated. Results: Across 8 studies, including 3 unpublished reports (n = 774), the mean effect size for PANSS total score was −0.236 (95% CI: −0.484 to 0.012, P = .063, I2 = 60.6%), showing only trend-level superiority for NSAIDs over placebo. The mean effect sizes for the PANSS positive and negative scores were −0.189 (95% CI: −0.373 to −0.005, P = .044) and −0.026 (95% CI: −0.169 to 0.117, P = .72), respectively. The relative risk for all-cause discontinuation was 1.13 (95% CI: 0.794 to 1.599, P = .503). Significant superiority of NSAIDs over placebo regarding PANSS total scores was moderated by aspirin treatment (N = 2, P = .017), inpatient status (N = 4, P = .029), first-episode status (N = 2, P = .048), and (in meta-regression analyses) lower PANSS negative subscores (N = 6, P = .026). Interpretation: These results indicate that adjunctive NSAIDs for schizophrenia may not benefit patients treated with first-line antipsychotics judged by PANSS total score change. NSAIDs may have benefits for positive symptoms, but the effect was minimal/small. However, due to a limited database, further controlled studies are needed, especially in first-episode patients.

 Adjunctive Use of Nonsteroidal Anti-inflammatory Drugs for Schizophrenia: A Meta-analytic Investigation of Randomized Controlled Trials

Потенцирование антидепрессивного действия сертралина целекоксибом

Background
It has been proposed that the mechanism of the antidepressant effect of celecoxib is linked to its anti-inflammatory action and particularly its inhibitory effect on pro-inflammatory cytokines (e.g. interleukin-6(IL-6)). We measured changes in serum IL-6 concentrations and depressive symptoms following administration of celecoxib in patients with major depressive disorder (MDD).
Methods
In a randomized double-blind placebo-controlled study, 40 patients with MDD and Hamilton Depression Rating Scale—17 items (Ham-D) score ≥ 18 were randomly assigned to either celecoxib (200 mg twice daily) or placebo in addition to sertraline (200 mg/day) for 6 weeks. Outcome measures were serum IL-6 concentrations at baseline and week 6, and Ham-D scores at baseline and weeks 1, 2, 4, and 6.
Results
The celecoxib group showed significantly greater reduction in serum IL-6 concentrations (mean difference (95%CI) = 0.42(0.30 to 0.55) pg/ml, t(35) = 6.727, P < 0.001) as well as Ham-D scores (mean difference (95%CI) = 3.35(1.08 to 5.61), t(38) = 2.99, P = 0.005) than the placebo group. The patients in the celecoxib group experienced more response (95%) and remission (35%) than the placebo group (50% and 5%, P = 0.003 and 0.04 respectively). Baseline serum IL-6 levels were significantly correlated with baseline Ham-D scores (r = 0.378, P = 0.016). Significant correlation was observed between reduction of Ham-D scores and reduction of serum IL-6 levels at week 6 (r = 0.673, P < 0.001).
Limitations
We did not measure other inflammatory biomarkers.
Conclusions
We showed that the antidepressant activity of celecoxib might be linked to its capability of reducing IL-6 concentrations. Moreover, supporting previous studies we showed that celecoxib is both safe and effective as an adjunctive antidepressant

 Effect of celecoxib add-on treatment on symptoms and serum IL-6 concentrations in patients with major depressive disorder: Randomized double-blind placebo-controlled study

Влияние нестероидных противовоспалительных средств на антидепрессивное действие СИОЗС

Cytokines may be important in depression. These immunomodulators are produced by glial cells, regulate brain serotonin and noradrenergic systems, and activate the hypothalamic-pituitary-adrenal axis. Antidepressants increase levels of p11, a specific protein that regulates depression in rodent models and interacts with the serotonin receptor. To learn about possible interactions of antidepressants, cytokines, p11, and anti-inflammatory drugs (NSAIDs), researchers conducted experiments in mice and reanalyzed data from the large STAR*D study.

The selective serotonin reuptake inhibitors citalopram and fluoxetine increased p11 levels in mouse frontal cortex, but coadministered ibuprofen (IBU) or acetylsalicylic acid (ASA) blocked this increase. IBU lowered plasma citalopram levels. The tricyclic desipramine produced a small p11 increase, which was not affected by IBU or ASA. Antidepressant-related p11 increases were dependent on signaling by two cytokines (interferon-gamma and tumor necrosis factor-alpha). In a mouse model of depression, IBU, ASA, and acetaminophen prevented the behavioral response to SSRIs but not to antidepressants of other types.

Of STAR*D patients who took citalopram for 12 weeks, significantly fewer achieved remission if taking NSAIDs than if not taking NSAIDs (45% vs. 55%). Findings were similar in a comparison of other analgesic use with nonuse (37% vs. 54%).

Do Analgesics Interfere with Efficacy of Selective Serotonin Reuptake Inhibitors?

НПВС могут снижать эффективность СИОЗС

They then confirmed these effects in a human population. Depressed individuals who reported anti-inflammatory drug use were much less likely to have their symptoms relieved by an antidepressant than depressed patients who reported no anti-inflammatory drug use.

The effect was rather dramatic since, in the absence of any anti-inflammatory or analgesic use, 54 percent of patients responded to the antidepressant, wheh success rates dropped to approximately 40 percent for those who reported using anti-inflammatory agents.

Anti-Inflammatory Meds Can Reduce Antidepressant Effectiveness

Болезнь Паркинсона, иммунная система, воспаление

The team confirmed that a gene in the human leukocyte antigen (HLA) region was strongly linked with Parkinson’s disease; this region contains a large number of genes related to immune system function...
Nonsteroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen are protective against Parkinson’s disease, according to the study.

However, not everyone benefits from them to the same degree. The amount of risk reduction conferred by NSAIDs may vary widely depending on genetic differences, say the researchers.

Investigating the connection between Parkinson’s disease and inflammation, especially in the context of the variable genetic makeups of individuals, likely would lead to better, more selective medicines for treatment.

Parkinson’s May Be Linked to Immune System

Аспирин

If aspirin may be able to reduce schizophrenia symptoms, how might it do so? By correcting an imbalance in the production of pro-inflammatory and antiinflammatory cytokines by helper T cells, the researchers proposed. Other researchers have implicated such an imbalance in schizophrenia.

Aspirin Regimen May Help Counter Schizophrenia Symptoms

Аспирин при шизофрении

"Aspirin given as [an adjunct treatment] to regular antipsychotic treatment reduces the symptoms of schizophrenia spectrum disorders. The reduction is more pronounced in those with the more altered immune function. Inflammation may constitute a potential new target for antipsychotic drug development."

Aspirin for Schizophrenia?