BackgroundAccumulating evidence shows that a propensity towards a pro-inflammatory status in the brain plays an important role in schizophrenia. Anti-inflammatory drugs might compensate this propensity. This study provides an update regarding the efficacy of agents with some anti-inflammatory actions for schizophrenia symptoms tested in randomized controlled trials (RCTs).MethodsPubMed, Embase, the National Institutes of Health website (http://www.clinicaltrials.gov), and the Cochrane Database of Systematic Reviews were systematically searched for RCTs that investigated clinical outcomes.ResultsOur search yielded 56 studies that provided information on the efficacy of the following components on symptom severity: aspirin, bexarotene, celecoxib, davunetide, dextromethorphan, estrogens, fatty acids, melatonin, minocycline, N-acetylcysteine (NAC), pioglitazone, piracetam, pregnenolone, statins, varenicline, and withania somnifera extract. The results of aspirin [mean weighted effect size (ES): 0.30; n = 270; 95% CI (CI) 0.06–0.54], estrogens (ES: 0.78; n = 723; CI 0.36–1.19), minocycline (ES: 0.40; n = 946; CI 0.11–0.68), and NAC (ES: 1.00; n = 442; CI 0.60–1.41) were significant in meta-analysis of at least two studies. Subgroup analysis yielded larger positive effects for first-episode psychosis (FEP) or early-phase schizophrenia studies. Bexarotene, celecoxib, davunetide, dextromethorphan, fatty acids, pregnenolone, statins, and varenicline showed no significant effect.ConclusionsSome, but not all agents with anti-inflammatory properties showed efficacy. Effective agents were aspirin, estrogens, minocycline, and NAC. We observed greater beneficial results on symptom severity in FEP or early-phase schizophrenia.

Objective Clozapine is the most effective antipsychotic for treatment refractory people with schizophrenia, yet many patients only partially respond. Accumulating preclinical and clinical data suggest benefits with minocycline. We tested adjunct minocycline to clozapine in a 10 week, double blind placebo-controlled trial. Primary outcomes tested were positive and cognitive symptoms, while avolition, anxiety/depression and negative symptoms were secondary outcomes. Methods Schizophrenia and schizoaffective participants (N=52) with persistent positive symptoms were randomized to receive adjunct minocycline (100 mg oral capsule twice daily) (N=29) or placebo (N=23). Results Brief Psychiatric Rating Scale (BPRS) psychosis factor (p=0.098, effect size ES=0.39) and BPRS total score (p=0.075, effect size 0.55) were not significant. A ≥30% change in total BPRS symptoms was observed in 7/28 (25%) among minocycline and 1/23 (4%) among placebo participants, respectively (p=0.044). Global cognitive function (MATRICS Consensus Cognitive Battery, MCCB) did not differ, although there was a significant variation in size of treatment effects among cognitive domains (p=0.03), with significant improvement in working memory favoring minocycline (p=0.023, ES 0.41). The SANS total score did not differ, but significant improvement in avolition with minocycline was noted (p=0.012, ES=0.34). Significant improvement in the BPRS anxiety/depression factor was observed with minocycline (p=0.028, ES=0.49). Minocycline was well tolerated with significantly fewer headaches and constipation compared to placebo. Conclusion Minocycline’s effect on the MCCB composite score and positive symptoms were not statistically significant. Significant improvements with minocycline were seen in working memory, avolition and anxiety/depressive symptoms in a chronic population with persistent symptoms. Larger studies are needed to validate these findings.

Schizophrenia is a chronic debilitating mental disorder that affects about 1% of the U.S population. The pathophysiology and etiology remain unknown, thus new treatment targets have been challenging and few novel treatments with new mechanisms of action have come to market in the past few decades. Increasing attention has been paid to the role of inflammation in schizophrenia and new data suggests that decreasing inflammation and inflammatory biomarkers may play some role in schizophrenia treatment. This review summarizes the clinical trial literature regarding medications that possess anti-inflammatory properties that have been tested for schizophrenia symptoms and covers such medications as nonsteroidal anti-inflammatory agents, such as the cyclooxygenase-2 (COX-2) inhibitors and aspirin, omega-3 fatty acids, neurosteroids and minocycline. Overall, there is accumulating evidence, albeit mostly adjunctive treatments, that agents working on inflammatory pathways have some benefits in people with schizophrenia. In the next few years the field will begin to see data on many treatments with anti-inflammatory properties that are currently under study. Hopefully advancements in understanding inflammation and effective treatments having anti-inflammatory properties may help revolutionize our understanding and provide new targets for prevention and treatment in schizophrenia.

The Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) and Treatment Units for Research on Neurocognition and Schizophrenia projects were designed to facilitate the development of new drugs for the treatment of cognitive impairments in people with schizophrenia. The MATRICS project identified three drug mechanisms of particular interest: dopaminergic, cholinergic, and glutamatergic. As a group, while people with schizophrenia have moderate cognitive impairment, it is the best predictor of long-term outcome. Unfortunately, there are no approved medications for cognitive impairment in this population. Hence, the development of new pharmacological approaches is critical for reducing illness-related disability. The combination of an acetylcholinesterase inhibitor (AChEI) and memantine is more effective than either medication alone to improve cognition in Alzheimer’s dementia. Galantamine is not only an AChEI, but also a positive allosteric modulator of the α4β2 and α7 nicotinic receptors. Hypofunction of N-methyl-D-aspartate (NMDA) receptors has been implicated in the pathophysiology of cognitive symptoms in schizophrenia and hence memantine may positively impact cognition. Memantine decreases the tonic NMDA current and galantamine enhances the action potential mediated by a postsynaptic NMDA current. This results in an increased signal transmission; therefore, a greater signal-to-noise ratio occurs with the combination than memantine alone. Galantamine improves the α-amino-3-hydroxy-5-methyl-4-isoxazol-propionate (AMPA)-mediated signaling which could be neuroprotective and may improve memory coding. The combination of galantamine and memantine may be particularly effective in schizophrenia in order to increase the selective cognition enhancement produced by either medication alone. In the future, multitarget-directed ligands may play a role in the treatment of complex diseases like schizophrenia.

Purpose/Background Negative symptoms and cognitive impairments tend to co-occur in people with schizophrenia. If their association with each other is due, in part, to shared pathophysiology, then this suggests that a single drug could potentially be effective for both domains. The current study was designed to examine this hypothesis. Methods/Procedures Fifty-eight participants with either DSM-IV-TR schizophrenia or schizoaffective disorder entered into a 6-week double-blind, placebo-controlled, double-dummy, randomized clinical trial of intranasal oxytocin and galantamine. Seventeen participants were randomized to intranasal oxytocin, 20 were randomized to galantamine and 21 were randomized to placebo. The Scale for the Assessment of Negative Symptoms total score was used to assess change in negative symptoms (the primary outcome measure for oxytocin). The MATRICS Consensus Cognitive Battery composite score was used to assess cognition (the primary outcome measure for galantamine). Findings/Results There were no significant group differences for negative symptoms (oxytocin versus placebo: F=0.19, df=2, 47.4, p=0.83; galantamine versus placebo: F=0.41, df=2, 52.5, p=0.67). There were no significant group differences for cognitive impairments (galantamine versus placebo: t= 0.71, df=40, p=0.48; oxytocin versus placebo: t= 0.50, df=40, p=0.62). There were also no significant group differences for the functional capacity or ancillary symptom measures. Implications/Conclusions The lack of an efficacy signal for either compound precluded our ability to test whether pharmacological treatment pathways for negative symptoms and cognitive impairments overlap or are independent. (clinicaltrials.gov trial number: NCT01012167)

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Abstract:Patients with post-traumatic stress disorder (PTSD) are frequently symptomatic despite being on medications currently approved by the US Food and Drug Administration for PTSD. There is evidence to support the notion that prazosin is effective for PTSD nightmares. However, PTSD-related nightmares often do not resolve completely on a low dose of prazosin. The capacity of prazosin to treat daytime symptoms of PTSD which are distressing to patients has not been well studied. Clinicians are reluctant to increase the dose of prazosin due to side effect concerns. To date, the highest reported dose of prazosin used for PTSD is 16 mg daily. We illustrate two case reports using high-dose (up to 30 and 45 mg) prazosin for PTSD with comorbid treatment-resistant mood disorders. We report that high-dose prazosin was safe, tolerable and effective for PTSD in adults. To our knowledge, this is the first case series to highlight the importance of using high-dose prazosin for the treatment of PTSD. In patients with partial response to currently available medications for PTSD, greater utilization of highdose prazosin for the management of PTSD may lead to better outcomes.