Table 2.

Clinical studies on use of anti-inflammatory drugs in treatment of psychiatric disorder. N: proband number, T: time frame, PANSS: Positive and Negative Symptom Score, SANS: Schedule for the Assessment of Negative Symptoms, and CGI score: clinical global impression score.

Treatment	Psychiatric disorder	Probands	Trial design	Outcome	Authors
Aspirin 1000 mg/day plus 40 mg/day pantoprazole, in addition to antipsychotic treatment	Schizophrenia	Patients with at least moderate symptom burden and a DSM-IV diagnosis for schizophrenia spectrum disorder for under 10 years N = 70	Randomized controlled trial T = 3 months	Mixed model improvement in overall psychopathology and in positive symptoms as measured by PANSS No differences in negative symptom or general scores	Laan et al., 2010 [158]
Aspirin 1000 mg/day plus 40 mg/day pantoprazole, in addition to antipsychotic treatment	Schizophrenia	Patients with moderate or above on CGI score, moderate score on two of PANSS items: delusions, hallucinatory behaviors, conceptual disorganization or suspiciousness/persecution, and/or a total PANSS negative symptoms score above 18 N = 400	Post hoc analysis of randomized controlled trial T = 16 weeks	Improvements in patients with high CRP levels	Weiser et al., 2014 [159]
Celecoxib 200 mg bid in addition to 2–6 mg/day risperidone	Schizophrenia	Patients with acute exacerbation of schizophrenia N = 50	Double-blind, Randomized Placebo-controlled T = 5 weeks	Significant improvement of positive symptoms	Müller et al., 2002 [160]
Celecoxib in addition to olanzapine	Schizophrenia	Patients with acute exacerbation of schizophrenia N = 94	Open-label, prospective, controlled T = 6 weeks	Improvement of positive, negative, and general psychopathology and total scores as measured by PANSS	Baheti et al., 2013 [161]
Celecoxib (200 mg bid) in addition to risperidone (200 mg/day)	Schizophrenia	inpatients diagnosed with active phase schizophrenia N = 60	Double-blind randomized placebo-controlled T = 8 weeks	Significant improvement regarding positive symptoms as measured by PANSS	Akhondzadeh et al., 2007 [162]
Celecoxib	Schizophrenia	Patients with a first manifestation of schizophrenia N = 49	Double-blind randomized placebo-controlled T = 6 weeks	Significant improvement regarding positive and negative symptoms as measured by PANSS	Müller et al., 2010 [163]
Celecoxib (400 mg/day) in addition to antipsychotic treatment	Schizophrenia	Outpatients with a DSM-IV diagnosis of schizophrenia, experiencing persistent symptoms despite treatment for 3 months N = 38	Double-blind, randomized, placebo-controlled, T = 8 weeks	No difference in outcome, as measured by PANSS	Rapaport et al. 2005 [164]
Concomitant intake of NSAID or paracetamol	Schizophrenia	Schizophrenia patients N = 2000	Retrospective investigation	Higher risk for relapse to active psychosis	Köhler et al., 2016 [165]
Previous NSAID use	Schizophrenia	Patients prescribed antipsychotics 82 cases, 359 controls	Case-control trial of antipsychotics prescription	Significant reduction of risk to develop psychosis when NSAID had been taken, but only in male individuals	Laan et al., 2007 [166]
Use of COX-2 inhibitors	Schizophrenia	Case events indicating schizophrenia exacerbation in patients using antipsychotics N = 1443	Nested case-control study T = previous 93 days	No increase of risk for schizophrenia exacerbation	Stolk et al., 2007 [167]
Minocycline in addition to usual treatment	Schizophrenia	Patients with early-stage schizophrenia N = 94	Double-blind, randomized, placebo-controlled T = 1 year	Significant improvement of negative symptoms as measured by PANSS	Chaudhry et al., 2012 [168]
Minocycline (200 mg/day) in addition to risperidone	Schizophrenia	Patients with DSM-IV diagnosis of early-phase (less than 5 years) schizophrenia who had been on a steady dosage of risperidone N = 93	Double-blind, randomized, placebo-controlled T = 16 weeks	Significant improvement in treatment response in the Scale for the Assessment of Negative Symptoms (SANS) total scores and PANSS for negative symptoms	Liu et al., 2014 [169]
Minocycline (200 mg/day)	Schizophrenia	Patients with DSM-IV diagnosis of schizophrenia, no treatment with therapeutics for one week before start of trial N = 43	Randomized, placebo-controlled T = 8 weeks	Significant decrease of SANS score after 8 weeks (though not 4 weeks) of treatment	Ghanizadeh et al., 2014 [170]
Minocycline (up to 200 mg/day) in addition to risperidone (up to 6 mg/day)	Schizophrenia	Chronic schizophrenia patients N = 40	Double-blind, randomized, placebo-controlled T = 8 weeks	Significant improvement of negative symptom as measured by PANSS	Khodaie-Ardakani et al., 2014 [171]
Minocycline	Schizophrenia	Early-phase schizophrenia patients N = 54	Double-blind, randomized, placebo-controlled T = 6 months	Significant improvement of negative symptoms and general outcome measured by PANSS, Clinical Global Impression (CGI) and insight score, and improvements of cognitive executive functions	Levkovitz et al., 2009 [172]
NSAID and paracetamol	Bipolar disorder	DSM-IV-TR diagnosis of bipolar disorder I or II and at least mild symptoms N = 482	Secondary analysis from the Bipolar CHOICE study T = 6 months	No difference as measured by CGI-BP	Köhler-Forsberg et al., 2017 [173]
Aspirin	Bipolar disorder	Patients taking lithium with erectile dysfunction N = 32	Double-blind, randomized, placebo-controlled T = 6 weeks	No differences in mania or depressive symptoms, significant improvement of erectile dysfunction	Saroukhani et al., 2013 [174]
Aspirin, low-dose of 30 or 80 mg per day and for an unspecified time or for more than 1, 45, 90, or 180 days, in addition to lithium	Bipolar disorder	Patients with at least five previous prescriptions for lithium and at least 1-year drug history N = 5145	Pharmacoepidemiological study on the PHARMO Record Linkage System (RLS) in the Netherlands T = 10 year period	Significantly fewer events of mood-stabilizer treatment alteration	Stolk et al., 2010 [175]
Celecoxib (400 mg/day)	Bipolar disorder	DSM-IV diagnosis of bipolar disorder during a depressive or mixed episode of the disease N = 28	Double-blind, randomized, placebo-controlled T = 6 weeks	Improvement of depressive symptoms (as measured by Hamilton Depression Rating Scale) found in the first week	Nery et al., 2008 [176]
Celecoxib in addition to sodium valproate	Bipolar disorder	Patients with diagnosis of acute bipolar mania with manic episode without psychotic features N = 46	Double-blind, randomized, placebo-controlled T = 6 weeks	Significantly higher remission rates as measured by young mania rating scale	Arabzadeh et al., 2015 [177]
Concomitant NSAID use in addition to escitalopram or nortriptyline	Depression	Patients with major depression disorder treated in the GENDEP study N = 811	Retrospective on the GENDEP study T = up to 12 weeks	No change of serotonin reuptake inhibitor treatment	Uher et al., 2012 [178]
Previous aspirin use as anti-platelet treatment	Depression	Men of older age (69–87 years) N = 5273	Retrospective analysis of aspirin use after assessment of mood disorder symptoms T = last 5 years	Significantly higher risk for depression in individuals who had used aspirin as antiplatelet agent drug in the past, but had stopped the treatment before the mood assessment (measured by Geriatric Depression scale)	Almeida et al., 2010 [179]
Regular aspirin or statin use in the past	Depression	Depression patients N = 1631	Population-based study T = last 6 months	No higher risk for development of depression	Glaus et al., 2015 [180]
Celecoxib in addition to antidepressants	Depression	Patients with depressive episodes N = 150	Meta-analysis of 4 randomized controlled trials	Improvements in Hamilton Rating Scale for Depression scores, remission and response rate	Na et al., 2014 [181]
Diclofenac (50 mg bid) versus celecoxib (200 mg bid)	Depression	Outpatients with breast cancer and concomitant depression N = 52	T = 6 weeks	Significant improvements by HDSR score in both, celecoxib significantly more successful than diclofenac, analgesic effect comparable	Mohammadinejad et al., 2015 [182]
Celecoxib (200 mg bid)	Depression	Patients with depression due to brucellosis N = 40	Double-blind, randomized, placebo-controlled T = 8 weeks	Significant improvements on HDRS	Jafari et al., 2015 [183]
Celecoxib (200 mg bid) or sodium naproxen (220 mg bid)	Depression	Individuals older than 70 years and with a family history of Alzheimer's disease (though without any cognitive dysfunction) N = 2312	Alzheimer's Disease Anti-Inflammatory Prevention Trial Yearly follow-up	No significant change in individual or overall depression score measured by 30-item Geriatric Depression Scale	Fields et al., 2012 [184]
Minocycline (150 mg/day) as adjunctive therapy to fluvoxamine, paroxetine, or sertraline	Depression	Inpatients with a DSM-IV diagnosis of major depression with psychotic features N = 25	Open-label study T = 6 weeks	Significant improvement of depressive and psychotic symptoms as measured by Hamilton Depression Rating Scale and Brief Psychiatric Rating Scale	Miyaoka et al., 2012 [185]
100 mg bid minocycline	Depression	HIV positive patients with mild-to-moderate scores of depression N = 46	Double-blind, randomized, placebo-controlled T = 6 weeks	Significant reduction of depression score (Hamilton Depression Rating Scale)	Emadi-Kouchak et al., 2016 [186]
Celecoxib 200 mg bid in addition to fluvoxamine	OCD	OCD outpatient N = 50	Double-blind, randomized, placebo-controlled T = 10 weeks	Significant improvement of symptoms	Shalbafan et al., 2015 [187]
N-Acetylcysteine (up to 2400 mg/day)	OCD	OCD patients, nonresponsive to serotonin reuptake inhibitors N = 48	Double-blind, randomized, placebo-controlled T = 12 weeks	15% higher response rate	Afshar et al., 2012 [188]
Minocycline (100 mg/day) in addition to serotonin reuptake inhibitor	OCD	Treatment-resistant outpatients with OCD N = 9	Open-label study T = 12 weeks	No significant improvements in outcome in cohort as a whole, more than 30% reduction of the Yale–Brown Obsessive Compulsive Scale	Rodriguez et al., 2010 [189]
Minocycline (100 mg bid) as add-on to fluvoxamine (100 mg/day for the first two 200 mg/day for the remaining 6 weeks of the trial)	OCD	OCD patients N = 102	Double-blind, randomized, placebo-controlled T = 10 weeks	Significantly higher treatment response rate (either complete or partial) measured by the Yale-Brown Obsessive compulsive scale. Specifically patients scored significantly lower in total and on the obsessive subscale	Esalatmanesh et al., 2016 [190]
Celecoxib (up to 300 mg/day) in addition to risperidone	Autism	Children with autistic disorder N = 40	Double-blind, randomized, placebo-controlled T = 10 weeks	Significant improvements of scores in irritability, social withdrawal, and stereotypy	Asadabadi et al., 2013 [191]
Minocycline (1.4 mg/kg body weight)	Autism	Children with autism spectrum disorder N = 11	Open-label T = 6 months	No clinical improvements (Clinical Global Impression Severity Scale, Clinical Global Impression Severity Scale Improvement, and Vineland Adaptive Behavior Scales)	Pardo et al., 2013 [192]