A double-blind, randomized, placebo-controlled pilot trial of atorvastatin for nephrogenic diabetes insipidus in lithium users.

OBJECTIVE: Lithium remains an important treatment for mood disorders but is associated with kidney disease. Nephrogenic diabetes insipidus (NDI) is associated with up to 3-fold risk of incident chronic kidney disease among lithium users. There are limited randomized controlled trials (RCT) for treatments of lithium-induced NDI, and existing therapies can be poorly tolerated. Therefore, novel treatments are needed for lithium-induced NDI. METHOD: We conducted a 12-week double-blind pilot RCT to assess the feasibility and efficacy of 20 mg/d atorvastatin vs placebo in the treatment of NDI in chronic lithium users. Patients, recruited between September 2017 and October 2018, were aged 18 to 85, currently on a stable dose of lithium, and determined to have NDI. RESULTS: Urinary osmolality (UOsm) at 12 weeks adjusted for baseline was not statistically different between groups (+39.6 mOsm/kg [95% CI, -35.3, 114.5] in atorvastatin compared to placebo groups). Secondary outcomes of fluid intake and aquaporin-2 excretions at 12 weeks adjusted for baseline were -0.13 L [95% CI, -0.54, 0.28] and 98.68 [95% CI, -190.34, 387.70], respectively. A moderate effect size was observed for improvements in baseline UOsm by ≥100 mOsm/kg at 12 weeks in patients who received atorvastatin compared to placebo (38.45% (10/26) vs 22.58% (7/31); Cohen's d = 0.66). CONCLUSION: Among lithium users with NDI, atorvastatin 20 mg/d did not significantly improve urinary osmolality compared to placebo over a 12-week period. Larger confirmatory trials with longer follow-up periods may help to further assess the effects of statins on NDI, especially within patients with more severe NDI.

Irregular eating patterns associate with hypomanic symptoms in bipolar disorders.

Objective: We present novel dimensional methods to describe the timing of eating in psychopathology. We focused on the relationship between current mood in bipolar disorder (BD) and the stability of the temporal pattern of daily eating events. Methods: Consenting BD patients (n = 69) from an outpatient, tertiary care clinic completed hourly charts of mood and eating for two weeks. Mood was also evaluated with Montgomery-Åsberg Depression Rating Scale (MADRS) and Young Mania Rating Scale (YMRS). Results: Illustrative displays, or eatograms, enabling visualization of all recorded eating events were used to guide assessment of the temporal structure of eating across the two week assessment period. We computed indices to quantify irregularities in timing of eating, namely IFRQ, ITIM and IINT for the variability of frequency, timing, and interval of eating events, respectively. In this cohort, irregular temporal pattern of eating correlated with hypomanic symptoms (YMRS with IFRQ, Spearman rank order rh = 0.28, p = .019, with ITIM, rh = 0.44, p < .001, and with IINT rh = 0.38, p = .001), but not depressive symptoms or anthropometric measures. Conclusions: Our data suggest a link between the instability of the temporal order of daily eating and mood. The dimensional measures for eating pattern introduced here enable future investigations of correlations with psychopathology.

Atorvastatin in the treatment of Lithium-induced nephrogenic diabetes insipidus: the protocol of a randomized controlled trial.

BACKGROUND: Lithium is the gold-standard treatment for bipolar disorder, is highly effective in treating major depressive disorder, and has anti-suicidal properties. However, clinicians are increasingly avoiding lithium largely due to fears of renal toxicity. Nephrogenic Diabetes Insipidus (NDI) occurs in 15-20% of lithium users and predicts a 2-3 times increased risk of chronic kidney disease (CKD). We recently found that use of statins is associated with lower NDI risk in a cross-sectional study. In this current paper, we describe the methodology of a randomized controlled trial (RCT) to treat lithium-induced NDI using atorvastatin. METHODS: We will conduct a 12-week, double-blind placebo-controlled RCT of atorvastatin for lithium-induced NDI at McGill University, Montreal, Canada. We will recruit 60 current lithium users, aged 18-85, who have indicators of NDI, which we defined as urine osmolality (UOsm) < 600 mOsm/kg after 10-h fluid restriction. We will randomize patients to atorvastatin (20 mg/day) or placebo for 12 weeks. We will examine whether this improves measures of NDI: UOsm and aquaporin (AQP2) excretion at 12-week follow-up, adjusted for baseline. RESULTS: Not applicable. CONCLUSION: The aim of this clinical trial is to provide preliminary data about the efficacy of atorvastatin in treating NDI. If successful, lithium could theoretically be used more safely in patients with a reduced subsequent risk of CKD, hypernatremia, and acute kidney injury (AKI). If future definitive trials confirm this, this could potentially allow more patients to benefit from lithium, while minimizing renal risk. TRIAL REGISTRATION: ClinicalTrials.gov NCT02967653 . Registered in February 2017.

The Canadian Network for Mood and Anxiety Treatments (CANMAT) task force recommendations for the management of patients with mood disorders and comorbid substance use disorders.

BACKGROUND: Mood disorders, especially bipolar disorder (BD), frequently are associated with substance use disorders (SUDs). There are well-designed trials for the treatment of SUDs in the absence of a comorbid condition. However, one cannot generalize these study results to individuals with comorbid mood disorders, because therapeutic efficacy and/or safety and tolerability profiles may differ with the presence of the comorbid disorder. Therefore, a review of the available evidence is needed to provide guidance to clinicians facing the challenges of treating patients with comorbid mood disorders and SUDs. METHODS: We reviewed the literature published between January 1966 and November 2010 by using the following search strategies on PubMed. Search terms were bipolar disorder or depressive disorder, major (to exclude depression, postpartum; dysthymic disorder; cyclothymic disorder; and seasonal affective disorder) cross-referenced with alcohol or drug or substance and abuse or dependence or disorder. When possible, a level of evidence was determined for each treatment using the framework of previous Canadian Network for Mood and Anxiety Treatments recommendations. The lack of evidence-based literature limited the authors' ability to generate treatment recommendations that were strictly evidence based, and as such, recommendations were often based on the authors' opinion. RESULTS: Even though a large number of treatments were investigated for alcohol use disorder (AUD), none have been sufficiently studied to justify the attribution of level 1 evidence in comorbid AUD with major depressive disorder (MDD) or BD. The available data allows us to generate first-choice recommendations for AUD comorbid with MDD and only third-choice recommendations for cocaine, heroin, and opiate SUD comorbid with MDD. No recommendations were possible for cannabis, amphetamines, methamphetamines, or polysubstance SUD comorbid with MDD. First-choice recommendations were possible for alcohol, cannabis, and cocaine SUD comorbid with BD and only second-choice recommendations for heroin, amphetamine, methamphetamine, and polysubstance SUD comorbid with BD. No recommendations were possible for opiate SUD comorbid with BD. Finally, psychotherapies certainly are considered an essential component of the overall treatment of SUDs comorbid with mood disorders. However, further well-designed studies are needed in order to properly assess their potential role in specific SUDs comorbid with a mood disorder. CONCLUSIONS: Although certain treatments show promise in the management of mood disorders comorbid with SUDs, additional well-designed studies are needed to properly assess their potential role in specific SUDs comorbid with a mood disorder.

Dissociative symptoms as measured by the Cambridge Depersonalization Scale in patients with a bipolar disorder.

BACKGROUND: The Cambridge Depersonalization Scale (CDS) characterizes the quality, frequency, and duration of dissociative symptoms. While the psychometric properties of the CDS have been evaluated in primary dissociative disorder, this has been insufficiently addressed among other psychiatric patient groups such as patients with a bipolar disorder (BD). METHODS: Outpatients with variable mood (n = 73) responded to a survey that assessed dissociative symptoms and other characteristics. We used factor analysis and McDonald's omega to evaluate psychometric properties of the CDS, and correlations with other characteristics. RESULTS: Previously suggested multifactorial models of the CDS were not supported, but the single-dimensional model fit both dichotomized (p = 0.31, CFI = 0.99, RMSEA = 0.02, ECV 70%) and trichotomized CDS responses (p = 0.06, CFI = 0.96, RMSEA = 0.04, ECV 47%). The CDS showed high internal consistency (ω = 0.96). CDS factor scores correlated with symptom severity on the Quick Inventory for Depressive Symptoms (QIDS-SR-16) (ρ = 0.59), the Social Phobia Inventory (ρ = 0.52), the American Association of Psychiatry Severity measure for Panic Disorders (ρ = 0.46), the Childhood Trauma Questionnaire (ρ = 0.44), and the Trauma Screening Questionnaire (ρ = 0.53). Two abbreviated versions of the CDS, retaining the best 14 or 7 items were proposed. LIMITATIONS: The sample size remained moderate. CONCLUSIONS: The CDS is a psychometrically sound, unidimensional measure with clinical impact to detect and characterize dissociative symptoms in BD patients. Establishing the reliability and validity of the abbreviated scales for screening necessitates further study.

Diagnosis of bipolar disorder in primary and secondary care: what have we learned over a 10-year period?

BACKGROUND: Studies suggest that misdiagnosis of bipolar disorders (BD) is frequent in primary care. This study aimed to evaluate agreement between referral for BD by general practitioners (GP) and BD diagnosis by secondary care psychiatrists, and to evaluate the impact of age, gender, and BD type on agreement. METHODS: The study was conducted at Hôpital du Sacré-Coeur de Montréal׳s "Module Evaluation/Liaison" (MEL), which establishes/clarifies psychiatric diagnoses requested mainly from GPs and directs patients to appropriate treatment and care. Socio-demographic variables, reason for referral, and psychiatric diagnosis were compiled for patients assessed from 1998 to 2010. GP-psychiatrist agreement was established for BD type, gender, and age group (18-25, 26-35, 36-45, >45) using Cohen׳s Kappa coefficient (Κ). RESULTS: From 1998 to 2010, MEL psychiatrists received 18,111 requests and carried out 10,492 (58%) assessments. There were 583 referrals for BD suspicion, while 640 assessments (6.1%) received a BD diagnosis (40.3% type I, 40.5% type II). The overall K was 0.35 (95% CI [0.31, 0.38]), and was significantly higher for type I than type II (I=0.35, 95% CI [0.30, 0.39]; II=0.25, 95% CI [0.21, 0.30]), though age group and gender had no impact. LIMITATIONS: Reasons for referral were converted into keywords and categories to facilitate agreement analyses. Only the main psychiatric diagnosis was available. CONCLUSIONS: Our study suggests diagnosing BD remains strenuous, regardless of age and gender, though BD type I seems better understood by primary care GPs. The true measure of BD diagnosis remains a critical issue in clinical practice.