DISCUSSION
deficit syndrome, schizophrenia, cognitive dysfunction
DISEASES, CORTEX
As far as we know, our study is the first randomized, double‐blind, placebo‐controlled trial that assessing the efficacy and safety of pentoxifylline as PDE inhibitor in alleviating the negative symptoms in chronic schizophrenia. Patients received pentoxifylline showed significant enhancement in PANSS negative, general psychopathology, and total subscale scores relatively to placebo group, but regarding the PANSS positive, the results were non‐significant. Our results could be clinically significant since negative symptoms are principal predictors for further functional impairment in patients suffering from schizophrenia and the current antipsychotics alone do not satisfactorily alleviate these symptoms.A Previous report proved that PDEs are highly expressed in the brain particularly in the striatum, hippocampus, caudate‐putamen, and cortex, which are known to be involved in neuropsychiatric diseases including cognitive dysfunction and negative symptoms in schizophrenia.Additionally, the pentoxifylline group's improvement may be attributed to the drug's anti‐inflammatory properties, which led to a significant drop in TNF‐α, and IL‐6 serum levels compared to baseline and patients taking a placebo. Pentoxifylline can also inhibit the production of cytokines and other biomolecules that are responsible for inflammatory cascade, decrease the neutrophil to lymphocyte ratio and thereby reinstating regulatory T cells/T helper‐17 (Treg/Th17) lymphocytes.The inflammatory activation of astrocytes can increase kynurenic acid production that results in a decrease in the levels of dopamine, acetylcholine, gamma‐aminobutyric acid, and glutamate.Although these encouraging outcomes of our study regarding the safety and efficacy of pentoxifylline in management of negative symptoms of schizophrenia, it had some limitations. We had no guide to make an unambiguous conclusion about the best dosage because this was the first clinical research of pentoxifylline in patients with schizophrenia. Furthermore, the small sample size and the short duration are considered probable limitations of this study. Even yet, PANSS is the “gold standard measure of treatment efficacy” since it offers objective evaluation of clinical response to pharmacological therapy. It still has the flaw of not specifically covering all deficit syndrome, cognitive function, and negative symptom domains.