DISCUSSION
obesity, sleep abnormalities, psychiatric, dysbiosis, cognitive deficits, neuroinflammation, mood behavior, cognitive impairment, inflammation, edema, bipolar disorder, weight gain, Cognitive impairments, schizophrenia, pro‐inflammatory, diabetes, bipolar disorder(van den Berg, mania, Alzheimer's cognitive impairment, memory impairment, manic, bipolar disorders, tumor necrosis, TNF‐α, lipid dysfunction, Mood disorders, a decrease in executive function, depressive, MR, Morton & Murray, hypertension
OBESITY, DISEASE PROGRESSION, TUMOR NECROSIS, FLUID RETENTION, INFLAMMATION, EDEMA, MEDICATION SIDE EFFECTS, NEUROGENIC HYPERTENSION, OXIDATIVE STRESS, HYPERTENSION, CORTEX, DIABETES
In this clinical trial, patients with bipolar disorder requiring hospitalization during a manic episode who received spironolactone showed a significant improvement in cognitive status compared to the placebo group at the end of 8 weeks of the study. This was while there was no statistically significant difference between the two groups receiving spironolactone and placebo in terms of other investigated variables such as mood state, sleep quality, appetite, and body mass index at the end of 8 weeks. No side effects were observed during the clinical trial. Based on our knowledge, this is the first clinical trial to investigate the usefulness of spironolactone as an MR antagonist, with all its systemic effects on fluid and electrolyte regulation, control of inflammatory status and oxidative stress, and regulation of the HPA axis and circadian rhythm on mood, cognition, sleep quality, and body mass index in patients with bipolar disorder in manic episodes.Mood disorders are accompanied by chronic systemic inflammation and increased plasma levels of pro‐inflammatory cytokines such as tumor necrosis factor‐alpha (TNF‐α) and interleukin‐6 (IL‐6). These pro‐inflammatory factors regulate mood behavior and cognition by affecting the level of neurotransmitters and activating stress‐responsive endocrine axes (Bauer & Teixeira, The point emphasized in our study, as the first clinical trial that investigated the effect of spironolactone as an MR antagonist on the cognitive deficits of patients with bipolar disorder in manic episodes, is the effectiveness of this medication in improving the cognitive deficits of these patients after 8 weeks in comparison with the control group.Extensive or selective persistent cognitive deficits in cognitive domains such as verbal memory, attention, executive function, and psychomotor speed are seen in a significant percentage of patients with bipolar disorders and are one of the important treatment goals in this group of patients to improve social and occupational performance, reduce social costs related to lost work productivity, and enhance the quality of life (Miskowiak et al., A decrease in brain‐derived neurotrophic factor (BDNF) serum levels has been reported during the mania episode of patients with bipolar disorder, along with a decrease in executive function and verbal memory. Cognitive impairments can be associated with the aggravation of this decrease in blood level (Mora et al., In a study with a mouse model of Alzheimer's cognitive impairment, the use of MR antagonists (spironolactone and eplerenone) was associated with improved cognitive status. The authors reported changes such as increased BDNF and decreased TNF‐α in the frontal cortex and hippocampus as the main factors involved in this process which may be associated with the activation of the Nrf2‐dependent antioxidant system and the reduction of neuroinflammation (Chen et al., Also, there is a relationship between sleep abnormalities and cognition in patients with bipolar disorder (Burgess et al., In our study, the use of spironolactone was associated with the benefit and improvement of sleep quality at the end of the fourth week of the mood episode compared to the placebo, although the durability of this effect was not seen in the eighth week of the study.Sleep problems in patients with bipolar disorder have a high prevalence, are highly distressing and destructive (Morton & Murray, While the glucocorticoid receptor (GR) and its ligand, cortisol, are considered circadian clock regulators, according to new studies, MR also can play a role in circadian clock gene expression and timing regulation (Kanki & Young, According to some studies, inflammation may be associated with weaker cognitive outcomes in bipolar disorder, and high CRP has been associated with some low cognitive indices in this group of patients (Millett et al., Based on the studies conducted in patients with hypertension and diabetes, treatment with spironolactone is accompanied by a decrease in the serum levels of many inflammatory markers such as CRP and TNF‐α (Lin et al., In a study on mice, the use of spironolactone as an antagonist of NRG1‐ERBB4 signaling was associated with the improvement of working memory impairment by reversing the hyperphosphorylation of activated Erbb4 (NRG1 and its cognate receptor ERBB4 are considered as schizophrenia risk genes and altered NRG‐ERBB4 signaling is associated with positive, negative, and cognitive symptoms) (Wehr et al., In this way, an important part of the effect of spironolactone on the cognitive function of patients with bipolar disorder in the episode of mania in our study may be caused by the different mechanisms mentioned above.Many psychiatric disturbances including bipolar disorder are deeply affected by the activity of the HPA axis, and at the same time, they also have a reciprocal effect on this neuroendocrine system (Trinetti et al., Some studies reported increased hair cortisol concentrations as a sign of increased HPA activity in manic episodes of bipolar disorder(van den Berg et al., On the other hand, systemic inflammation with damage to the blood–brain barrier and increasing its permeability causes the access of inflammatory mediators to the brain and local activation of glial cells and neuroinflammation, which continues with a series of disturbances in the regulation of the HPA axis, serotonin and melatonin neuroreceptor system, and neurogenesis (Hennion et al., Based on the available evidence, the RAAS may play a role in regulating the HPA axis (Kakehi et al., In another clinical trial in which our group investigated the effect of spironolactone on the negative symptoms of patients with schizophrenia, the regulation of HPA activity by spironolactone was proposed as the main reason for the clinical effects of this medication treatment (Zandifar et al., In a study by Hochman et al., the relationship between relative fluid retention and manic episodes in bipolar disorder was reported. They found a significant decrease in serum fluid balance indices during manic episodes compared to depressive episodes in the form of lower concentrations of hematocrit, sodium, and serum albumin (Hochman et al., In this way, the use of spironolactone may improve the psychiatric symptoms of patients with bipolar disorder in manic episodes by creating fluid and electrolyte balance and reducing edema along with correcting the established state and preventing the reactions mentioned above. Also, the expression and function of GR and MR in the hippocampus are strongly regulated by serotonin (5‐HT) in the middle raphe nucleus, and stress is one of the effective factors in this receptor change through such a mechanism. The balance between these receptors in this center plays an important role in controlling emotional states (Wu et al., As mentioned, this result was not obtained at the end of 8 weeks of our study, and no difference was found in terms of the intensity of psychiatric symptoms between the two groups receiving spironolactone and placebo. In this way, conducting similar studies with larger sample sizes and using different doses of spironolactone may be beneficial in completing the present study.On the other hand, gut microbial dysbiosis is effective in disease progression and cognitive impairment in bipolar disorder (Dai et al., In a study on rats in a genetic model of neurogenic hypertension, spironolactone was associated with the improvement of intestinal dysbiosis. In this study, spironolactone restored the ratio of Firmicutes/Bacteroidetes and the population of acetate‐producing bacteria to normal levels and reduced the percentage of intestinal aerobic bacteria (González‐Correa et al., In examining another aspect of the problems associated with bipolar disorder, points such as obesity, increased appetite, and weight gain can be mentioned due to underlying multifactorial reasons such as medication side effects, disturbances in the neuro‐endocrinal system, and other influencing factors such as genetic variants which have a high prevalence in these patients (Platzer et al., Ghrelin, as an appetite‐stimulating peptide, is associated with an increase in appetitive feeding behaviors and the frequency of eating meals. Such an effect occurs when ghrelin passes through the blood–brain barrier and affects body weight regulation centers such as the hypothalamus and the mesolimbic reward system (Cummings, In a study in rats, the use of spironolactone as a metabolic modulator was associated with protection against lipid dysfunction (Areloegbe et al., The possible lack of influence of spironolactone on body mass index and the absence of side effects of weight gain can be associated with benefits in patients with bipolar disorder due to the inappropriate metabolic status of these patients. In our study, there was no significant difference in terms of body mass index and appetite between the two groups receiving spironolactone and placebo.