Table 3.

Anti-inflammatory Treatments for Individuals with Psychotic Symptoms

Author	Year	Journal	Technique	Drug (dosage)	Reported Side Effects	Population	Major Finding	Strength of Association
Prasad et al.	2012	Schizophrenia Bulletin	18 weeks of double-blind placebo-controlled drug add-on trial comparing antipsychotics and valacyclovir to antipsychotics and placebo	valacyclovir (1.5 g twice daily orally) – antiherpes virus-specific medication for treatment of herpes-simplex virus, type 1 (HSV1)	Six subjects on placebo reported drooling, muscle tightness, mild tremors, akithisia, bloating, feeling tired, elbow pain, increased sex drive, insomnia, and leg cramps. Five subjects on valacyclovir reported constipation, stomach pain, motion sickness, occasional muscle twitch, tremor and upset stomach. All side effects were mild; none of the subjects required discontinuation of treatment.	24 HSV1 seropositive schizophrenia subjects (age 18–50) who were on stable doses of antipsychotics for at least 1 month and scored ≥ 4 on a least one item of the Positive and Negative Syndrome Scale (PANSS)	Valacyclovir group improved in verbal memory, working memory, and visual object learning compared to placebo group, but psychotic symptom severity did not improve	Cohen’s d effect sizes: Immediate verbal memory: d = 1.14 Working memory: d = .79; Visual object learning: d = .97
Amminger et al.	2010	Archives of General Psychiatry	Randomized, double-blind, placebo-controlled 12-week trial comparing omega-3 (ω-3) polyunsaturated fatty acids (PUFAs) to placebo	Long-chain omega-3 polyunsaturated fatty acids (1.2 g/d)	No statistically significant group differences in adverse events were observed between omega-3 PUFAs and placebo on the Udvalg for Kliniske Undersøgelser (side effect rating scale for psychotropic drugs)	81 individuals (age 13–25) at ultra-high risk of psychotic disorder	Long-chain omega-3 PUFAs significantly reduced cumulative risk of progression to full-threshold psychosis over a 12 month period, as well as total, positive, negative symptoms, and general symptoms, and improved functioning as assessed by the PANSS compared with placebo	12-month conversion rates to psychotic disorder: 4.9% in the ω-3 group and 27.5% in the placebo group Effect sizes for secondary outcomes: PANSS total, d = 0.70; PANSS positive, d = 0.69; PANSS negative, d = 0.52; PANSS general, d = .68; Global Assessment of Functioning (GAF), d = −.72; Montgomery Asberg Depression Rating Scale (MADRS), d = 0.32 (MADRS change not significant) Difference between groups in cumulative risk of progression to full-threshold psychosis: 22.6% (95% CI, 4.8 – 40.4)
Laan et al.	2010	Journal of Clinical Psychiatry	Randomized, double-blind placebo-controlled drug augmentation trial comparing antipsychotics and aspirin to antipsychotics and placebo	aspirin (acetylsalicylic acid) (1000 mg/d) – aselective cyclooxygenase (COX) inhibitor, nonsteroidal anti-inflammatory drug (NSAID). (Proton pump inhibitors, such as omeprazole, were additionally prescribed to reduce risk of mucosal gastric injury)	No substantial side effects were recorded – no serious gastric or bleeding events requiring medical attention were observed during the trial	70 antipsychotic-treated schizophrenia spectrum disorder inpatients and outpatients (age 18–55) from 10 psychiatric hospitals	Addition of aspirin to regular antipsychotic treatment substantially reduced total and positive symptoms as assessed with the PANSS	Significant results: PANSS total: d = .47; PANSS positive: d = .39 Non-significant results: PANSS negative: d = .26; PANSS general: d = .39
Levkovitz et al.	2010	Journal of Clinical Psychiatry	Longitudinal double-blind, randomized, placebo-controlled drug add-on trial comparing atypical antipsychotics and minocycline to atypical antipsychotics and placebo	minocycline (200 mg/d) – second-generation tetracycline antibiotic	In minocycline group, 2 patients had indigestion, 2 had pigmentation, and 1 attempted suicide. (In 4 of these 5 cases, minocycline treatment was discontinued, and patients were excluded from the study. In 1 case, in which the subject experienced mild pigmentation, treatment was continued as planned.) No adverse events occurred in the placebo group.	54 early-phase schizophrenia patients (age 18–35)	Minocycline add-on therapy was associated with improvements in negative symptoms and executive functioning	Reduction in Scale for Assessment of Negative Symptoms (SANS) score: r = .46 Change in executive functioning (composite score) of the Cambridge Neuropsychological Test Automated Battery (CANTAB): r = .47**
Müller et al.	2010	Schizophrenia Research	Double-blind, placebo-controlled, randomized trial of celecoxib augmentation to amisulpride treatment in patients with first-episode schizophrenia	celecoxib (400 mg/d) – selective COX-2 inhibitor, NSAID	No patient needed to be excluded from the trial due to side effects; bradycardia was seen in one patient in the placebo group, a well-known side effect of amulsipride. No important effect on cardiovascular function could be determined in this short-term trial from celecoxib	49 patients (age 19–49) with a first episode of schizophrenia (n = 42) or schizophreniform disorder (n = 7)	Significant improvements in PANSS negative, PANSS global, and PANSS total scores observed in the patient group treated with amisulpride plus celecoxib compared to the amisulpride plus placebo group	* PANSS total: d = .631; PANSS negative: d = .910; PANSS general: d = .503; PANSS positive (non-significant finding): d = .312
Akhondzadeh et al.	2007	Schizophrenia Research	Prospective, double-blind, placebo-controlled trial of celecoxib drug augmentation to risperidone treatment	celecoxib (400 mg/d) – selective COX-2 inhibitor, NSAID	No clinically important side effects were observed	60 inpatients (age 19–44) with chronic schizophrenia who were in the active phase of the disorder	After 8 weeks the risperidone plus celecoxib group showed significantly greater improvement in positive, general, and total PANSS scores compared to the risperidone plus placebo group	PANSS positive: d = .066; PANSS general: d = .073; PANSS total: d = .082
Rapaport et al.	2005	Biological Psychiatry	8-week prospective, double-blind, placebo-controlled drug augmentation trial comparing atypical antipsychotics and celecoxib to atypical antipsychotics and placebo	celecoxib (400 mg/d) – selective COX-2 inhibitor, NSAID	Celecoxib augmentation did not impact measures of extrapyramidal side effects, functioning, or any safety parameters	38 symptomatic outpatient schizophrenia subjects (age 19–67) who were on a stable dose of atypical antipsychotic medication for at least 3 months	Treatment cohorts did not differ on any of the clinical outcome measures and celecoxib augmentation did not improve clinical symptoms or measures of disability among continuously ill outpatient schizophrenia subjects	* Effect sizes for non-significant results: PANSS total: d = −.340; SANS: d = −.115; Clinical Global Impression – Severity (CGI-S): d = −.196; Calgary Depression Scale: d = −.038; Hamilton Anxiety Scale (HAM-A): d = −.225; Scale of Functioning: d = .513
Müller et al.	2004	European Archives of Psychiatry and Clinical Neuroscience	Double-blind, placebo-controlled, randomized trial comparing risperidone and celecoxib to risperidone and placebo	celecoxib (400 mg/d) – selective COX-2 inhibitor, NSAID	No clinically important side effects were observed	50 schizophrenia patients (age 18–65)	In the celecoxib, but not in the placebo group, decreases in CD19+ lymphocytes (markers of the immune-response type-2 related B-lymophocytes in the blood) were significantly associated with decreases on the PANSS negative scale; celecoxib group also displayed significantly higher levels of soluble interleukin-2 receptors (sIL-2R) (markers of the type-1 immune response)	Decreases in CD19+ lymphoctyes and PANSS negative scale score (r = 0.48 p < 0.03) Increases in sIL-2R in celecoxib group compared to placebo: (z = 2.28, p < .01)**
Müller et al.	2002	American Journal of Psychiatry	Prospective, double-blind, placebo-controlled, randomized trial comparing risperidone and celecoxib to risperidone and placebo	celecoxib (400 mg/d) – selective cyclooxygenase-2 (COX-2) inhibitor, NSAID	No clinically important side effects were observed (side effects that have previously been attributed to the administration of celecoxib, especially gastronintestinal problems, were not observed)	50 patients (age 18–65) with schizophrenia who had been hospitalized following acute exacerbation of their psychosis; all subjects received risperidone	After 5 weeks the risperidone plus celecoxib group showed significantly greater improvement in the PANSS total score compared to the risperidone plus placebo group	(F = 3.80, df = 1, 47, p = .05)**

^*Effect size or odds ratio not reported in paper. Calculated by authors based on available data reported in manuscripts.

^**No effect size or odds ratio reported