Table 2 Summary of emerging evidence of different medications with anti-inflammatory and antioxidant action used in SCZ

Nonsteroidal anti-inflammatory agents

Aspirin

Inhibits COX enzymes.

reduces inflammatory mediators.

Two RCTs had modest improvements in symptoms.

[173, 174]

Celecoxib

Inhibits COX-2 enzyme.

Inhibits conversion of arachidonic acid to prostaglandins.

Five RCTs had mixed results.

Minocycline

Inhibits inflammatory enzymes include NO synthase and 5-lipoxygenase.

Seven RCTs. Modest benefits on negative symptoms.

[174]

Antioxidants, free radical scavengers, and nutrients

N-Acetylcysteine

Reduces hydroxyl radicals; modulates synthesis and degradation of anti- and pro-inflammatory cytokines.

Two RCTs. Modest benefit in negative symptoms over placebo.

[174,175,176,177]

Vitamin C (l-ascorbic acid)

Antioxidant effect.

One RCT. Vitamin C improved symptoms vs. placebo.

Vitamin E (tocopherols and tocotrienols)

Increases intracellular glutathione and antioxidant potential.

11 RCTs in tardive dyskinesia patients with no significant benefit.

Melatonin (N-acetyl-5methoxy tryptamine)

Mitochondrial and antioxidant protection. Activates antioxidant enzymes and inhibits NO synthases and lipoxygenases.

Two RCTs: improved sleep and mood. No specific antipsychotic effects.

Cotinine

Anti-inflammatory positive allosteric modulator of nicotinic cholinergic receptors.

No studies.

Omega-3 PUFAs

It modulates microglial activity in the expression of TNF-α, IL-6, NO synthase, and COX-2; inhibits peroxidation (antioxidant).

Eight trials with only two positive effects but had no significant.

Largest trial for the prevention of psychosis was negative.

[174]

[176]

L-Theanine

AMPA and Kainic acid receptors antagonist, weak agonist of NMDA receptors.

One RCT for anxiety symptoms.

[175]

Gluten-free diet

Avoids gliadin and prolamins (wheat gluten, barley, and rye) that cause damaging antibodies.

Equivocal findings. Results vary across studies.

Biologicals

Tocilizumab

Targets specific cytokine. Anti-IL-6 receptor antibody.

One RCT. No benefit as no crossing for blood-brain barrier.

[178, 179]

Peroxisome proliferator-activated receptors (PPARs)

Rosiglitazone, Pioglitazone

Nuclear receptors activate gene expression and intracellular anti-inflammatory responses.

Rosiglitazone: one clozapine study, no improvement in negative or overall symptoms.

[180]

Pioglitazone: one RCT showed improvement in negative symptoms and overall scores.

Neuroprotectors

Davunetide

neuroprotective and lowers TNF-α.

Two-dose davunetide trial. No benefit.

[181]

Hormones

Estrogens

lower antioxidative stress via microglia activation, TNF-α, and NO reduction.

Seven studies, reduced positive symptoms among females.

[174]

Herbals and probiotics

Medicinal herbs, Ginger, turmeric, Ginkgo biloba

Blocking microglia-mediated neuro-inflammation. Reducing PGE2, IL-1β, and TNF-α via downregulating COX-2, p38MAPK, and NF-kB expression.

One RCT found Ginkgo increased response in refractory patients.

[175]

Probiotics

Probiotic trials aim to address SCZ-associated GI and microbial issues, with mixed results.

[182, 183]