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Background: Glycogen synthase kinase-3 (GSK-3) inhibition by lithium has been well established in vitro, but proof that this biochemical effect mediates lithium's beneficial action in patients with bipolar disorder is lacking. We studied whether lymphocyte GSK-3β activity measured indirectly in lithium- or valproate (VPA)-treated euthymic patients with bipolar disorder is different from controls., Methods: Lymphocyte total and Ser-9-phospho-GSK-3β (inactive) levels were measured by Western blotting. Forty-seven patients with bipolar disorder and 32 age- and sex-matched control subjects were studied., Results: No significant differences were found between lithium- and VPA-treated patients and controls in phospho-GSK-3β, total GSK-3β, or their ratio., Conclusions: The data do not support the concept that in vivo, during chronic treatment of bipolar illness, GSK-3β is inhibited either by lithium or by VPA.

Lithium is the gold-standard treatment for bipolar disorder, a severe mental illness. A large body of evidence suggests that inflammation plays a role in the pathogenesis of bipolar disorder and that mood stabilizers exhibit anti-inflammatory properties. However, contradicting findings have also been reported. In this study, we examined the effects of lithium on LPS-induced inflammation in rat primary glia cells. Cells were pre-treated with lithium (1 or 10 mM) for 6 or 24 h, after which, inflammation was induced by the addition of LPS (for another 18 h) to the culture medium. Thereafter, medium was collected and cells were harvested for further analyses. Levels of TNF-α, IL1-β and PGE(2) were determined by ELISA and NO levels by the Griess reaction assay. Expression levels of cyclooxygenase-2 (COX-2) and inducible NO synthase (iNOS) were examined by Western blot analysis. We found that pre-treatment with lithium 10 mM (but not 1 mM) significantly reduced LPS-induced secretion of TNF-α, IL1-β, PGE(2) and NO. In addition, lithium significantly reduced the expression of COX-2 and iNOS. These findings indicate that lithium exhibits a potent anti-inflammatory effect. However, it's important to emphasize that this effect was obtained mainly under treatment with an extra-therapeutic concentration of the drug.

Bipolar affective disorder is a chronic, severe, debilitating illness affecting 1-2% of the population. Valproate, along with lithium and carbamazepine, are the only drugs for which long-term efficacy has been established. However, these drugs are ineffective for, and not well tolerated by, a large number of patients and are also associated with teratogenicity and reproductive defects. Therefore, there is a substantial need to develop more effective anti-bipolar drugs. We have previously shown that valproate, like lithium, decreases intracellular inositol, which supports the inositol depletion hypothesis. We employed inositol depletion in yeast as a screening tool to identify potential new anti-bipolar medications. We show here that hexanoic acid, heptanoic acid, octanoic acid, nonanoic acid, decanoic acid, ethylhexanoate, and methyloctanoate decrease intracellular inositol levels and increase the expression of INO1, the gene encoding myo-inositol-3-phosphate synthase (MIPS). Similar to valproate, these inositol-depleting carboxylic acids inhibited MIPS indirectly. A correlation was shown between cell growth inhibition and the increase in INO1 expression by the carboxylic acids, factors that were reversed in the presence of inositol. Inositol depletion in yeast may be exploited as an easy and inexpensive screening test for potential new inositol depleting anti-bipolar drugs.

Background: Bipolar disorder (BPD) is a severe and chronic illness, with a lifetime prevalence of approximately 1.5%. Despite the availability of some mood stabilizing drugs including lithium, valproate (valproic acid), lamotrigine and carbamazepine, BPD is characterized by high rates of recurrence, as treatment with these and other drugs is ineffective for and not well-tolerated by a significant percentage of patients. Most drugs currently used for the maintenance treatment of BPD are anticonvulsants (e.g., valproate, carbamazepine and lamotrigine)., Objectives: The aim of this paper is to review the studies characterizing the anticonvulsant efficacy of valproate-like carboxylic acids and related compounds, some of which may have potential for the treatment of manic-depressive illness., Results: The data reviewed herein demonstrate clearly that some dietary fatty acids and other valproate-like carboxylic acids exhibit potent anticonvulsant activity, and may thus be candidates for mood stabilizing treatment options for BPD.

Mounting evidence suggests that immune-system dysfunction and inflammation play a role in the pathophysiology and treatment of mood-disorders in general and of bipolar disorder in particular. The current study examined the effects of chronic low-dose aspirin and low-dose lithium (Li) treatment on plasma and brain interleukin-6 and tumor necrosis factor-α production in lipopolysaccharide (LPS)-treated rats. Rats were fed regular or Li-containing food (0.1%) for six weeks. Low-dose aspirin (1 mg/kg) was administered alone or together with Li. On days 21 and 42 rats were injected with 1 mg/kg LPS or saline. Two h later body temperature was measured and rats were sacrificed. Blood samples, the frontal-cortex, hippocampus, and the hypothalamus were extracted. To assess the therapeutic potential of the combined treatment, rats were administered the same Li + aspirin protocol without LPS. We found that the chronic combined treatment attenuated LPS-induced hypothermia and significantly reduced plasma and brain cytokine level elevation, implicating the potential neuroinflammatory diminution purportedly present among the mentally ill. The combined treatment also significantly decreased immobility time and increased struggling time in the forced swim test, suggestive of an antidepressant-like effect. This preclinical evidence provides a potential approach for treating inflammation-related mental illness. [ABSTRACT FROM AUTHOR]

Abstract: Aims: To screen for inositol-depleting valproate-like compounds as potential mood stabilizing drugs. Main methods: We exploited the yeast Saccharomyces cerevisiae, as a model in which inositol de novo synthesis has been extensively characterized, to test the effects of ethyl butyrate (EB), 2-ethyl-butyric acid, sodium butyrate, and n-propyl hexanoate on inositol biosynthesis. Cell growth was followed by measuring the optical density of the cultures (spectrophotometrically), RNA abundance was determined by Northern blot analysis, intracellular inositol was measured by a fluorometric assay, and 1-d-myo-inositol-3-phosphate synthase activity was examined using a chromatographic method. Key findings: Of the tested compounds, only EB exhibited an inositol-depleting effect. The inositol-depleting effect of EB was achieved without significant adverse effect on cell growth, pointing to lesser toxicity compared to valproate. Significance: These results indicate that EB is a potential candidate for mood-stabilizing therapy. [Copyright &y& Elsevier]

Despite established efficacy in bipolar disorder patients, lithium (Li) therapy has serious side effects, particularly chronic kidney disease. We examined the safety and behavioral effects of combined chronic low-dose aspirin plus low-dose Li in rats to explore the toxicity and therapeutic potential of this treatment. Rats were fed regular or Li-containing food (0.1% [low-dose, LLD-Li] or 0.2% [standard-dose, STD-Li]) for six weeks. Low-dose aspirin (1 mg/kg) was administered alone or together with Li. Renal function and gastric mucosal integrity were assessed. The effects of the combination treatment were evaluated in depression-like and anxiety-like behavioral models. Co-treatment with aspirin did not alter plasma Li levels. Chronic STD-Li treatment resulted in significant polyuria and polydipsia, elevated blood levels of creatinine and cystatin C, and increased levels of kidney nephrin and podocin—all suggestive of impaired renal function. Aspirin co-treatment significantly damped STD-Li-induced impairments in kidney parameters. There were no gastric ulcers or blood loss in any treatment group. Combined aspirin and LLD-Li resulted in a significant increase in sucrose consumption, and in the time spent in the open arms of an elevated plus-maze compared with the LLD-Li only group, suggestive of antidepressant-like and anxiolytic-like effects, respectively. Thus, we demonstrate that low-dose aspirin mitigated the typical renal side effects of STD-Li dose and enhanced the beneficial behavioral effects of LLD-Li therapy without aggravating its toxicity. [ABSTRACT FROM AUTHOR]

Valproate is the most widely prescribed antiepileptic drug worldwide, and it is also used in the treatment of bipolar affective disorder, migraine headache and cancer. However, the therapeutic mechanism of action of valproate in these illness states is not understood. This article reviews the pharmacological effects of valproate that may explain its therapeutic efficacy. It focuses on the hypothesis that inhibition of glycogen synthase kinase-3 by valproate is a crucial therapeutic mechanism of this drug in the treatment of bipolar affective disorder. Other cellular pathways and signaling molecules that are targets of valproate (such as inositol de novo biosynthesis, histone deacetylase, protein kinase C, γ-aminobutyric acid, the extracellular signal-regulated kinase pathway and others) are also discussed. [ABSTRACT FROM AUTHOR]

Bipolar affective disorder is a severe and chronic disabling illness affecting 1.5% of the general population. Lithium, valproate and other mood stabilizers are used to treat bipolar disorder; however, these are ineffective for, and not tolerated by, a significant percentage of patients, underscoring the urgent need for better medications. Although not universally accepted, the inositol-depletion hypothesis is one of the main hypotheses suggested to explain the therapeutic mechanism of mood-stabilizing drugs. This paper reviews the relevance of the inositol-depletion hypothesis, paying special attention to the inhibition of inositol de novo synthesis by valproate. It also discusses inositol supplementation as a treatment strategy for multiple neurological disorders, including prophylactic use against valproate-induced neural tube defects. [ABSTRACT FROM AUTHOR]

Millions of people around the world suffer from psychiatric illnesses, causing unbearable burden and immense distress to patients and their families. Accumulating evidence suggests that inflammation may contribute to the pathophysiology of psychiatric disorders such as major depression and bipolar disorder. Copious studies have consistently shown that patients with mood disorders have increased levels of plasma tumor necrosis factor (TNF)-α. Given these findings, selective anti-TNF-α compounds were tested as a potential therapeutic strategy for mood disorders. This mini-review summarizes the results of studies that examined the mood-modulating effects of anti-TNF-α drugs. [ABSTRACT FROM AUTHOR]

According to the World Health Organization, the major psychiatric and neurodevelopmental disorders include major depression, bipolar disorder, schizophrenia, and autism spectrum disorder. The potential role of inflammation in the onset and progression of these disorders is increasingly being studied. The use of non-steroidal anti-inflammatory drugs (NSAIDs), well-known cyclooxygenase (COX) inhibitors, combined with first-choice specific drugs have been long investigated. The adjunctive administration of COX inhibitors to classic clinical treatments seems to improve the prognosis of people who suffer from psychiatric disorders. In this review, a broad overview of the use of COX inhibitors in the treatment of inflammation-based psychiatric disorders is provided. For this purpose, a critical analysis of the use of COX inhibitors in the last ten years of clinical trials of the major psychiatric disorders was carried out. [ABSTRACT FROM AUTHOR]