Combined treatment of myo-inositol and d-chiro-inositol (80:1) as a therapeutic approach to restore inositol eumetabolism in patients with bipolar disorder taking lithium and valproic acid.

OBJECTIVE: Patients with bipolar disorder (BD) experience a poor quality of life (QoL) and a weak adherence to the therapy due to the various side effects occurring during the pharmacological therapy. To date clinicians have no tools to intervene on such effects, considering them as an unavoidable part of the therapy. This review paves the way for a step forward in the management of patients with BD bridging the therapeutic gap in clinical practice. MATERIALS AND METHODS: We reviewed the literature, searching through different databases (MEDLINE, Scopus, Google Scholar). We used different keywords, including bipolar disorder, lithium and valproic acid, inositol role in bipolar disorder, side effects, inositol depletion, supplementation of inositols under lithium treatment, inositol role in metabolism, hypothyroidism, renal and cardiac functionality. In particular, we narrowed the search down to English literature, excluding works before 1980s. Regarding clinical studies, we included case reports and both preclinical and clinical studies, especially only those exhibiting a control group. The outcome of the database search was to highlight the threat of side effects and the relationship with inositol lower levels, paving the way for a step forward in the management of patients with BD. RESULTS: Based on the collected evidence, the combined administration of myo-inositol (myo-ins) and d-chiro-inositol (d-chiro-ins) is strongly recommended in order to restore levels and metabolism of inositols. Previous studies pointed out the beneficial effects of inositols in recovering pathological conditions, like polycystic ovary syndrome (PCOS), hypothyroidism, weight gain, cardiac functionality, being all these conditions related to the depletion of inositols. Furthermore, a controlled dosage of inositols, up to 6 grams/daily, may reduce the side effects caused by lithium therapy, without hindering its central therapeutic role on patients' mood. CONCLUSIONS: Considering the iatrogenic depletion of inositols, the tailored ratio 80:1 in favour of myo-ins, may become a safe and effective strategy to counteract side effects, by providing a large amount of myo-ins and an adequate one of d-chiro-ins. The clinical dosage of inositols used as dietary supplementation is 4 grams/daily, and it may allow the recovery of the side effects and improve patients' QoL, without reducing the central therapeutic effect of the pharmacological therapy.

Identifying the Most Important Consultation-Liaison Psychiatry Publications in 2020 Using a Novel Literature Assessment Instrument.

BACKGROUND: As the science of consultation-liaison psychiatry advances, the Academy of Consultation-Liaison Psychiatry's Guidelines and Evidence-Based Medicine Subcommittee reviews articles of interest to help academy members remain familiar with the latest in evidence-based practice. OBJECTIVE: We identify the 10 most important articles for clinical practice in consultation-liaison psychiatry from 2020 using the new Importance and Quality instrument for assessing scientific literature. METHODS: The subcommittee published annotated abstracts for 97 articles on the academy website in 2020. Reviewers then rated all articles on clinical importance to practice and quality of scholarship using the Importance and Quality instrument. We describe the 10 articles with the highest aggregate scores and analyze the reliability of Importance and Quality instrument. RESULTS: Twenty-four raters identified the top 10 scoring articles of 2020. These articles provide practical guidance on key areas of consultation-liaison psychiatry including management of COVID-19, lithium treatment for complex patients, medical risks among patients with severe mental illness, and substance use disorders in medical settings. The assessment instrument demonstrated good to excellent interrater reliability. CONCLUSION: These articles offer valuable guidance for consultation-liaison psychiatrists regardless of their practice area. Collaborative literature reviews with standardized assessments help clinicians deliver evidence-based care and foster a high standard of practice across the specialty.

[Effects of Chinese herbal medicine Xifeng Capsule on multidrug resistance-associated protein 1 expression in hippocampus and cortex of rats with lithium-pilocarpine-induced epilepsy].

OBJECTIVE: To study the effects of Xifeng Capsule, a compound traditional Chinese herbal medicine, combined with carbamazepine on spontaneous epileptic seizure induced by lithium and pilocarpine in rats and the expression level of multidrug resistance-associated protein 1 (MRP1). METHODS: Lithium and pilocarpine were used to induce epilepsies in rats. All epileptic rats were randomly divided into model, high-dose Xifeng Capsule, medium-dose Xifeng Capsule, low-dose Xifeng Capsule, high-dose Xifeng Capsule plus carbamazepine (CBZ) (combined high-dose group), high-dose Xifeng Capsule plus half dose of CBZ (combined low-dose group) and CBZ groups with 10 rats in each group. And another 10 normal rats served as control. After treating 28 d, immunohistochemical method was used to detect the MRP1 expression in cortex and hippocampus of the epileptic rats. RESULTS: MRP1 expression in hippocampus of the treated groups was higher than that of the normal control group, with wider range and darker positive particles, but was lower than that of the model group. In the cortical areas, the differences between the combined high-dose group or the combined low-dose group and the model group were statistically significant (P<0.05). Regardless of the hippocampus CA1, CA3, gyrus or cortical areas, the influence of high-dose Xifeng Capsule on MRP1 distribution was superior to that of low-dose Xifeng Capsule; Xifeng Capsule combined with CBZ had better effects than low-dose Xifeng Capsule, medium-dose Xifeng Capsule and CBZ used alone (P<0.05). CONCLUSION: Xifeng Capsule used alone or combined with CBZ can effectively inhibit MRP1 expression in hippocampus and cortex of epileptic rats.

Effects of alcohol, lithium, and homocysteine on nonmuscle myosin-II in the mouse placenta and human trophoblasts.

OBJECTIVE: Mouse embryonic exposure to alcohol, lithium, and homocysteine results in intrauterine growth restriction (IUGR) and cardiac defects. Our present study focused on the placental effects. We analyzed the hypothesis that expression of nonmuscle myosin (NMM)-II isoforms involved in cell motility, mechanosensing, and extracellular matrix assembly are altered by the 3 factors in human trophoblast (HTR8/SVneo) cells in vitro and in the mouse placenta in vivo. STUDY DESIGN: After exposure during gastrulation to alcohol, homocysteine, or lithium, ultrasonography defined embryos exhibiting abnormal placental blood flow. RESULTS: NMM-IIA/NMM-IIB are differentially expressed in trophoblasts and in mouse placental vascular endothelial cells under pathological conditions. Misexpression of NMM-IIA/NMM-IIB in the affected placentas continued stably to midgestation but can be prevented by folate and myoinositol supplementation. CONCLUSION: It is concluded that folate and myoinositol initiated early in mouse pregnancy can restore NMM-II expression, permit normal placentation/embryogenesis, and prevent IUGR induced by alcohol, lithium, and homocysteine.

[Fucus vesiculosus induced hyperthyroidism in a patient undergoing concomitant treatment with lithium]. / Hipertiroidismo inducido por la ingestión de Fucus vesiculosus en un paciente en tratamiento concomitante con litio.

INTRODUCTION: Fucus vesiculosus is a marine alga rich in iodine, which is being used in alternative medicine as a laxative, diuretic, and as a complement for weight loss diets. CASE REPORT: We report the case of a 60-year old male patient, diagnosed with bipolar disorder and under treatment with lithium concomitantly with a herbal preparation, including Fucus vesiculosus, as a laxative. He developed hyperthyroidism that remitted once the herbal preparation was withdrawn. CONCLUSION: Fucus vesiculosus may cause hyperthyroidism given its high iodine content. Herbal preparations should be taken in account when treating a patient due to the possibility of adverse effects and interactions with other drugs.

Assessment of medication adherence in a cohort of patients with bipolar disorder.

INTRODUCTION: This study aimed to identify factors associated with medication adherence in bipolar disorder (BPD) patients. METHODS: EMBLEM is a 2-year, prospective, observational study on the outcomes of BPD patients initiating or changing treatment for a manic/mixed episode. Data were collected at baseline, during the first 12 weeks of treatment (acute phase) and up to 24 months of follow-up (maintenance phase). Adherence was assessed by investigators at every visit. Repeated measures logistic regression analyses identified variables associated with adherence. RESULTS: Of 1,831 patients included in the analysis, 76.6% were adherent and 23.4% were non-adherent with their BPD medication during the maintenance phase. Patients were more likely to be adherent if they had insight into their illness at week 12. Patients were less likely to be adherent if they had cannabis abuse/dependence during the acute phase, work impairment or higher CGI hallucinations/delusions at baseline DISCUSSION: Psychotic symptoms, poor insight, cannabis abuse/dependence and work impairment are negatively related to medication adherence during maintenance therapy of bipolar disorder. Patients with these characteristics may need a different therapeutic approach.

Effects of psychotropics on glycosylated hemoglobin (HbA1c) in a cohort of bipolar patients.

OBJECTIVES: Research suggests that certain psychotropics may induce glucose regulatory dysfunction. Hyperglycemia increases levels of glycosylated hemoglobin (HbA1c). This study investigated the relationship between psychotropic use and concentrations of HbA1c in bipolar patients who were presumably non-diabetic. METHODS: Analysis was conducted on 76,671 patients with bipolar disorder (BPD) from the Integrated Health Care Information Services (IHCIS). Included were 381 patients with at least two measurements of HbA1c taken between January 1, 1997 and June 30, 2002. Individuals with only 1 HbA1c measure, diagnosed with type 1 or type 2 diabetes according to the International Classification of Diseases (ICD-9), and/or who were using any anti-diabetes medication were excluded from the cohort. We compared HbA1c levels from first to final HbA1c measurements. The types of psychotropic medications used by the patients were examined. RESULTS: A total of 197 (51.9%) BPD patients had an abnormal initial HbA1c test result (defined as HbA1c>7). Thirty patients were taking antipsychotics, 24 mood stabilizers (anticonvulsants), 10 lithium, 51 antidepressants and 116 a combination of medications. A total of 150 patients were not taking psychotropic medications. HbA1c levels declined significantly in patients taking psychotropic medication(s) [mean=7.5, standard deviation (SD)=2.1% versus mean=7.0, SD=1.8%; p<0.001] and in patients not taking psychotropic medication(s) (mean=7.4, SD=2.0% versus mean=7.0, SD=1.9%; p<0.001). The only exception to this finding was among patients taking antipsychotics, where there was a slight increase (not statistically significant) during this period (mean=7.0, SD=1.8% versus mean=7.2, SD=3.7%; p=0.791). CONCLUSIONS: These results support findings suggesting an increased risk of type 2 diabetes in BPD patients. Mood stabilizers (anticonvulsants), antidepressants and lithium in monotherapy and combination were associated with a decrease in HbA1c levels. Although not statistically significant, antipsychotic medications were associated with an increase in HbA1c in this population.

Treatment of agitation and aggression in bipolar mania: efficacy of quetiapine.

OBJECTIVE: Agitation and aggression are potentially disruptive and dangerous features of bipolar mania. This analysis evaluated the effects of quetiapine on agitation and aggression in patients with bipolar I mania. METHODS: Four double-blind, randomized, controlled trials were conducted using similar protocols; 407 patients with bipolar I mania were randomized to quetiapine monotherapy (200-800 mg/day) or placebo for 12 weeks, and 402 patients were randomized to quetiapine (200-800 mg/day) or placebo in combination with lithium (Li) or divalproex (DVP) for 3 or 6 weeks. Measurements of agitation included the Positive and Negative Syndrome Scale (PANSS) Activation subscale, PANSS Supplemental Aggression Risk subscale scores, and Young Mania Rating Scale (YMRS) items relevant to agitation. RESULTS: Initial reductions in both the PANSS Activation and PANSS Supplemental Aggression Risk subscale scores were noted by Day 4 with quetiapine and placebo. The reduction in PANSS Activation subscale scores was significantly greater with quetiapine monotherapy than placebo first at Day 21 (-3.5 versus -1.4, P<0.001) and also at Day 84 (-4.8 versus -1.2, P<0.001). The improvement in PANSS Supplemental Aggression Risk subscale score was significantly greater with quetiapine monotherapy than placebo by Day 14 (P<0.01) and all time points thereafter including Day 21 (-4.0 versus -1.8, P<0.001) and Day 84 (-5.6 versus -1.7, P<0.001). In combination therapy, the mean improvement in PANSS Activation subscale score at Day 21 was numerically but not significantly different with QTP+Li/DVP than PBO+Li/DVP (-4.2 versus -3.2, P=0.087). The mean PANSS Supplemental Aggression Risk subscale scores were significantly improved at Day 21 with QTP+Li/DVP versus PBO+Li/DVP (-5.05 versus -3.69, P<0.05). CONCLUSIONS: Quetiapine is an effective and appropriate treatment choice in managing agitation and aggression associated with bipolar mania.

Quetiapine in the treatment of acute bipolar mania: efficacy across a broad range of symptoms.

OBJECTIVE: An ideal antimanic therapy is well tolerated and offers full multidimensional symptom relief. The efficacy of quetiapine in the treatment of acute bipolar mania has previously been established. This post-hoc analysis aims to extend our understanding of quetiapine's antimanic efficacy by evaluating its therapeutic effect across the full spectrum of manic symptoms. METHODS: Patient-level data from four similar, randomized, double-blind, placebo-controlled trials evaluating the efficacy and safety of quetiapine in bipolar disorder patients with DSM-IV acute mania were combined. Two trials investigated quetiapine as monotherapy (twice daily) and two trials assessed the combination of quetiapine with either lithium (Li) or divalproex (DVP). Changes in scores on the total Young Mania Rating Scale (YMRS), and on each of the 11 items comprising the YMRS, were the primary measures of interest in this analysis. Changes in the Supplemental Aggression and Agitation subscales of the Positive and Negative Syndrome Scale (PANSS) were secondary measures analyzed. RESULTS: Quetiapine as monotherapy, or in combination with Li or DVP, was a highly effective treatment for acute mania, as shown by overall change scores in the total YMRS. Patients treated with quetiapine monotherapy exhibited a significantly greater reduction (versus placebo) in YMRS total scores at Day 4 (-3.5 versus -2.2; p=0.021), with an increasing between-group difference reported throughout the duration of the trials at Day 21 (-13.6 versus -7.8; p<0.001) and at study endpoint on Day 84 (-19.0 versus -9.6; p<0.001). Quetiapine was also superior in efficacy to placebo on all categorical (i.e., response and remission rates) and secondary outcome parameters. On each of the 11 YMRS items, including the double-weighted core manic items, quetiapine was significantly superior to placebo (p<0.05). Effect sizes at Day 84 ranged from 0.37 to 0.61. Quetiapine in combination with Li/DVP offered a significant benefit over Li/DVP monotherapy, starting at Day 7 (p<0.05) and continuing to the primary study endpoint on Day 21 (p=0.01). Four of 11 YMRS items improved significantly more on quetiapine combination therapy than on Li/DVP monotherapy. The efficacy of quetiapine in these trials appeared independent of baseline disease severity, the presence of psychosis, and treatment-emergent sedation/somnolence. Quetiapine monotherapy produced significantly greater improvement than placebo on the PANSS Activation and the PANSS Supplemental Aggression Risk subscale scores. Similar findings were obtained with quetiapine combined with Li or DVP. CONCLUSIONS: Patients with bipolar disorder may report severe and complex manic symptoms. The results herein indicate that quetiapine is efficacious across the multiple dimensions of mania, including medically serious symptoms commonly encountered in practice.

Adverse drug interactions involving common prescription and over-the-counter analgesic agents.

BACKGROUND: Eight analgesic preparations with approved indications for acute pain were among the top 200 drugs prescribed in the United States in 2006. In addition, an estimated 36 million Americans use over-the-counter (OTC) analgesics daily. Given this volume of use, it is not surprising that a number of drug interactions involving analgesic drugs have been reported. OBJECTIVES: This article examines the pharmacologic factors that enhance the clinical relevance of potential drug interactions and reviews the literature on drug interactions involving the most commonly used analgesic preparations in the United States. METHODS: A PubMed search was conducted for English-language articles published between January 1967 and July 2007. Among the search terms were drug interactions, acetaminophen, aspirin, ibuprofen, naproxen, celecoxib, NSAIDs, hydrocodone, oxycodone, codeine, tramadol, OTC analgesics, alcohol, ethanol, antihypertensive drugs, methotrexate, warfarin, SSRIs, paroxetine, fluoxetine, sertraline, citalopram, serotonin syndrome, MAOIs, and overdose. Controlled clinical trials, case-control studies, and case reports were included in the review. RESULTS: A number of case reports and well-controlled clinical trials were identified that provided evidence of the relatively well known drug-drug interactions between prescription/OTC NSAIDs and alcohol, antihypertensive drugs, high-dose methotrexate, and lithium, as well as between frequently prescribed narcotics and other central nervous system depressants. In contrast, the ability of recent alcohol ingestion to exacerbate the hepatotoxic potential of therapeutic doses of acetaminophen is not supported by either case reports or clinical research. Use of ibuprofen according to OTC guidelines in patients taking cardioprotective doses of aspirin does not appear to interfere with aspirin's antiplatelet activity, whereas chronic prescription use of ibuprofen and other NSAIDs may interfere. Low-dose aspirin intake appears to abolish the gastroprotective effects of cyclooxygenase-2-selective inhibitors, including celecoxib. There is evidence of other less well known and potentially clinically significant drug-drug interactions, including the ability of selective serotonin reuptake inhibitors to inhibit the analgesic activity of tramadol and codeine through inhibition of their metabolic activation, to induce serotonin syndrome when used chronically in the presence of high doses of tramadol through synergistic serotonergic action, and to increase the potential for gastrointestinal bleeding associated with NSAID therapy through additive or supra-additive antiplatelet activity. CONCLUSIONS: Considering the widespread use of analgesic agents, the overall incidence of serious drug-drug interactions involving these agents has been relatively low. The most serious interactions usually involved other interacting drugs with low therapeutic indices or chronic and/or high-dose use of an analgesic and the interacting drug.