Metabolomic analysis to detect urinary molecular changes associated with bipolar depression.

Bipolar disorder (BD) is a debilitating mental disorder with complex clinical manifestations and low diagnostic accuracy. Depressive episodes are most common in the course of BD with high comorbidity and suicide rates, which present greater clinical challenges than mania and hypomania episodes. However, there are no objective biomarkers for bipolar depression. The aim of this study was to detect urinary metabolite biomarkers that could be useful for the diagnosis of bipolar depression. Nuclear magnetic resonance spectroscopy was used to profile urine samples of patients with bipolar depression (n = 37) and healthy volunteers (n = 48). Data were analyzed using Orthogonal Partial Least Square Discriminant Analysis and t-test. Differential metabolites were identified (VIP > 1 and p < 0.05), and further analyzed using Metabo Analyst 3.0 to identify associated metabolic pathways. In total, we identified seven metabolites differentially expressed in patients with BD and healthy controls. Compared with healthy group, the levels of betaine, glycerol, hippuric acid, indole sulfate, trimethylamine oxide, and urea in urine samples of BD patients were significantly higher, while the level of inositol was significantly lower. Most of these small molecules are related to lipid metabolism and gut microbiota metabolism. These differential metabolites could provide critical insight into the pathological mechanisms of bipolar depression. The results of this study provide a meaningful reference for similar and further studies in the future.

Aripiprazole causing false positive urine amphetamine drug screen in an adult patient with bipolar disorder.

There has been only a few reports regarding aripiprazole causing false positive urine amphetamine drug screens, exclusively on children accidently ingesting aripiprazole. Herein, we present the first reported case of a 40 year old woman affected by Bipolar I Disorder, treated with aripirazole at therapeutic oral dose ranging from 15 mg/day to 30 mg/day, in the context of a depressive episode with mixed and psychotic features, showing a false positive urine amphetamine drug screen. We document the relationship between aripiprazole-dose, plasma concentration and amphetamines values in toxicologic urine examinations over time. Awareness of potential false positive urine amphetamine drug screens during aripiprazole treatment can condition therapeutic choices and prevent legal implications.

Urinary metabolite signature in bipolar disorder patients during depressive episode.

The first few episodes of bipolar disorder (BD) are highly likely to be depressive. This phenomenon causes many BD patients to be misdiagnosed as having major depression. Therefore, it is very important to correctly diagnose BD patients during depressive episode. Here, we conducted this study to identify potential biomarkers for young and middle-aged BD patients during depressive episode. Both gas chromatography-mass spectroscopy (GC-MS) and nuclear magnetic resonance (NMR) spectroscopy were used to profile the urine samples from the recruited subjects. In total, 13 differential metabolites responsible for the discrimination between healthy controls (HCs) and patients were identified. Most differential metabolites had a close relationship with energy homeostasis. Meanwhile, a panel consisting of five differential metabolites was identified. This panel could effectively distinguish the patients from HCs with an AUC of 0.998 in the training set and 0.974 in the testing set. Our findings on one hand could be helpful in developing an objective diagnostic method for young and middle-aged BD patients during depressive episode; on the other hand could provide critical insight into the pathological mechanism of BD and the biological mechanisms responsible for the transformation of different episodes.

Association of functioning and quality of life with objective and subjective measures of sleep and biological rhythms in major depressive and bipolar disorder.

OBJECTIVE: Disruptions in biological rhythms and sleep are a core aspect of mood disorders, with sleep and rhythm changes frequently occurring prior to and during mood episodes. Wrist-worn actigraphs are increasingly utilized to measure ambulatory activity rhythm and sleep patterns. METHODS: A comprehensive study using subjective and objective measures of sleep and biological rhythms was conducted in 111 participants (40 healthy volunteers [HC], 38 with major depressive disorder [MDD] and 33 with bipolar disorder [BD]). Participants completed 15-day actigraphy and first-morning urine samples to measure 6-sulfatoxymelatonin levels. Sleep and biological rhythm questionnaires were administered: Biological Rhythms Interview of Assessment in Neuropsychiatry (BRIAN), Munich Chronotype Questionnaire (MCTQ), Pittsburgh Sleep Quality Index (PSQI) and Epworth Sleepiness Scale (ESS). Actigraph data were analyzed for sleep and daily activity rhythms, light exposure and likelihood of transitioning between rest and activity states. RESULTS: Mood groups had worse subjective sleep quality (PSQI) and biological rhythm disruption (BRIAN) and higher objective mean nighttime activity than controls. Participants with BD had longer total sleep time, higher circadian quotient and lower 6-sulfatoxymelatonin levels than HC group. The MDD group had longer sleep onset latency and higher daytime probability of transitioning from rest to activity than HCs. Mood groups displayed later mean timing of light exposure. Multiple linear regression analysis with BRIAN scores, circadian quotient, mean nighttime activity during rest and daytime probability of transitioning from activity to rest explained 43% of variance in quality-of-life scores. BRIAN scores, total sleep time and probability of transitioning from activity to rest explained 52% of variance in functioning (all p < 0.05). CONCLUSIONS: Disruption in biological rhythms is associated with poorer functioning and quality of life in bipolar and MDD. Investigating biological rhythms and sleep using actigraphy variables, urinary 6-sulfatoxymelatonin and subjective measures provide evidence of widespread sleep and circadian system disruptions in mood disorders.

Population pharmacokinetic modeling of sustained release lithium in the serum, erythrocytes and urine of patients with bipolar disorder.

PURPOSE: Lithium (Li), the first-line treatment of bipolar disorder, was first developed as an immediate-release form with a routine therapeutic drug monitoring 12 h after the last dose. In Europe, the most commonly prescribed form is a sustained release (srLi). Yet no pharmacokinetics (PK) study has been published of srLi, administered once a day, in adults. The present study describes srLi PK in the serum and erythrocytes of bipolar patients. METHODS: To assess srLi PK, we studied prospectively 17 French bipolar patients on a median dose of 1000 mg (600-1600) for at least 2 years. Serum (S), erythrocyte (E) concentrations, and urinary (U) amount were collected over 8 h after 15 days of morning intake using monitoring electronic medical system (MEMs). Population PK parameters were estimated using the SAEM algorithm (MONOLIX 4.3.3 software). RESULTS: Using a population approach, we built a PK population model of srLi including one S compartment (VS = 23.0 L, ClS = 1.21 L h-1), one E compartment (VE = 64.7 L, ClSE = 3.63 L h-1, ClES = 9.46 L h-1), and one U compartment (F = 0.62) and estimate the ratio of concentrations to Li in E over S at 0.38 with 27% between-subject variability. CONCLUSION: This is a PK model of srLi once a day in bipolar patients using a population approach simultaneously describing Li concentrations in serum, erythrocytes, and urine which provide an estimate of the ratio of concentration in erythrocyte over serum and its between-subject variability (BSV).

A multisystem composite biomarker as a preliminary diagnostic test in bipolar disorder.

OBJECTIVE: Diagnosis and management of bipolar disorder (BD) are limited by the absence of available laboratory tests. We aimed to combine data from different molecular levels and tissues into a composite diagnostic and state biomarker. METHODS: Expression levels of 19 candidate genes in peripheral blood, plasma levels of BDNF, NT-3, IL-6 and IL-18, leukocyte counts, and urinary markers of oxidative damage to DNA and RNA were measured in 37 adult rapid-cycling patients with BD in different affective states during a 6- to 12-month period and in 40 age- and gender-matched healthy individuals in a longitudinal, repeated measures design comprising a total of 211 samples. A composite biomarker was constructed using data-driven variable selection. RESULTS: The composite biomarker discriminated between patients with BD and healthy control individuals with an area under the receiver operating characteristic curve (AUC) of 0.83 and a sensitivity of 73% and specificity of 71% corresponding with a moderately accurate test. Discrimination between manic and depressive states had a moderate accuracy, with an AUC of 0.82 and a sensitivity of 92% and a specificity of 40%. CONCLUSION: Combining individual biomarkers across tissues and molecular systems could be a promising avenue for research in biomarker models in BD.

Elevated levels of 8-oxoGuo and 8-oxodG in individuals with severe mental illness - An autopsy-based study.

Elevated systemic oxidative stress levels of 8-oxoGuo and 8-oxodG have been reported in individuals with severe mental illness (SMI). As no previous studies have addressed the link between local levels of 8-oxoGuo and 8-oxodG in the central nervous system (CNS), measured in cerebrospinal fluid (CSF), and urinary systemic levels, we employed autopsy-based material to elucidate this aspect. Additionally, we investigated the impact of 8-oxoGuo and 8-oxodG levels on the prevalence of somatic co-morbidities. Based on post mortem samples from deceased individuals with SMI (N = 107), we found significantly elevated urinary levels of both 8-oxoGuo and 8-oxodG compared to mentally healthy living controls. While we found an association between urinary and CSF 8-oxodG levels (r = 0.50, P < 0.001), a similar correlation was not evident for 8-oxoGuo (r = 0.15, P = 0.16). Additionally, the two r-values were significantly different (P < 0.001). Neither marker in urine or CSF was associated with obesity-related variables, metabolic syndrome or type 2 diabetes. The post mortem interval did not affect the results, but the agonal phase seemingly introduced bias. This study provided novel insights into the cellular oxidative stress levels in individuals with SMI. We demonstrated that increased oxidative stress locally and systemically is correlated and is a clear phenomenon in SMI. Although post mortem measurements contain some weaknesses, our study indicates DNA as the main site of oxidative stress modifications in the CNS in SMI. This may provide novel opportunities for treatment modalities. Additionally, our study demonstrated the applicability of post mortem material investigating systemic and local 8-oxoGuo and 8-oxodG levels.

Metabolomics of Major Depressive Disorder and Bipolar Disorder: Overview and Future Perspective.

Major depressive disorder (MDD) and bipolar disorder (BD) are the most common mood disorders. They are etiologically related, but clinically distinct psychiatric illnesses. Their shared clinical features result in high rates of misdiagnosis due to a lack of biomarkers that allow their differentiation. BD is more frequently misdiagnosed as MDD because of overlapping symptomology, often later onset of mania, and frequent occurrence of depressive episodes in patients with BD. Misdiagnosis is also increased when patients with BD present symptoms indicative of a clinically significant depressive episode, but are premorbid for manic symptoms, or previous manic states not recognized. Therefore, the development of specific biomarkers for these disorders would be invaluable for establishing the correct diagnosis and treatment of MDD and BD. This chapter presents an overview and future perspective of the identification of biomarkers for mood disorders using metabolomics.

Performance of the biological rhythms interview for assessment in neuropsychiatry: An item response theory and actigraphy analysis.

BACKGROUND: Biological rhythm disturbances are widely associated with the pathophysiology of mood disorders. The Biological Rhythms Interview for Assessment in Neuropsychiatry (BRIAN) is a self-report that indexes rhythm disturbance in sleep, activity, social and eating patterns. The aim of this study was to perform an Item Response Theory (IRT) analysis of the BRIAN and investigate its associations with objective sleep and rhythm disturbance measures. METHODS: 103 subjects (31 bipolar, 32 major depression and 40 healthy volunteers) wore an actiwatch for fifteen days, and completed a first morning urine sample and the BRIAN on day 15. IRT analysis assessed individual BRIAN items and their relationship to total score. Individual actiwatch records were processed to produce a sequence of transitions between rest/activity, and a likelihood of transitioning between states was calculated to investigate sleep-wake dynamics. Cosinor analysis produced daily activity rhythms (DARs). Spearman correlations were used to assess the association between sleep/DAR variables and the BRIAN. RESULTS: IRT analyses showed that 11 of 18 BRIAN items displayed a high level of discrimination between item options across a range of BRIAN total scores. Total BRIAN score correlated with wake after sleep onset, total activity count during sleep, and urinary 6-sulphatoxymelatonin. BRIAN Activity domain correlated with the daytime transition probability from rest to activity. LIMITATIONS: The sample size may have been underpowered for the graded-response model employed in IRT. The study lacked an objective comparison for BRIAN eating and social domain. CONCLUSION: The present study reveals the BRIAN displays promising external validity compared to objective parameters of circadian rhythmicity.

Increased DNA and RNA damage by oxidation in patients with bipolar I disorder.

The mechanisms underlying bipolar disorder (BD) and the associated medical burden are unclear. Damage generated by oxidation of nucleosides may be implicated in BD pathophysiology; however, evidence from in vivo studies is limited and the extent of state-related alterations is unclear. This prospective study investigated for we believe the first time the damage generated by oxidation of DNA and RNA strictly in patients with type I BD in a manic or mixed state and subsequent episodes and remission compared with healthy control subjects. Urinary excretion of 8-oxo-deoxyguanosine (8-oxodG) and 8-oxo-guanosine (8-oxoGuo), valid markers of whole-body DNA and RNA damage by oxidation, respectively, was measured in 54 patients with BD I and in 35 healthy control subjects using a modified ultraperformance liquid chromatography and mass spectrometry assay. Repeated measurements were evaluated in various affective phases during a 6- to 12-month period and compared with repeated measurements in healthy control subjects. Independent of lifestyle and demographic variables, a 34% (P<0.0001) increase in RNA damage by oxidation across all affective states, including euthymia, was found in patients with BD I compared with healthy control subjects. Increases in DNA and RNA oxidation of 18% (P<0.0001) and 8% (P=0.02), respectively, were found in manic/hypomanic states compared with euthymia, and levels of 8-oxodG decreased 15% (P<0.0001) from a manic or mixed episode to remission. The results indicate a role for DNA and RNA damage by oxidation in BD pathophysiology and a potential for urinary 8-oxodG and 8-oxoGuo to function as biological markers of diagnosis, state and treatment response in BD.

Divergent Urinary Metabolic Phenotypes between Major Depressive Disorder and Bipolar Disorder Identified by a Combined GC-MS and NMR Spectroscopic Metabonomic Approach.

Bipolar disorder (BD) is a complex debilitating mental disorder that is often misdiagnosed as major depressive disorder (MDD). Therefore, a large percentage of BD subjects are incorrectly treated with antidepressants in clinical practice. To address this challenge, objective laboratory-based tests are needed to discriminate BD from MDD patients. Here, a combined gas chromatography-mass spectrometry (GC-MS)-based and nuclear magnetic resonance (NMR) spectroscopic-based metabonomic approach was performed to profile urine samples from 76 MDD and 43 BD subjects (training set) to identify the differential metabolites. Samples from 126 healthy controls were included as metabolic controls. A candidate biomarker panel was identified by further analyzing these differential metabolites. A testing set of, 50 MDD and 28 BD subjects was then used to independently validate the diagnostic efficacy of the identified panel using an area under the receiver operating characteristic curve (AUC). A total of 20 differential metabolites responsible for the discrimination between MDD and BD subjects were identified. A panel consisting of six candidate urinary metabolite biomarkers (propionate, formate, (R*,S*)2,3-dihydroxybutanoic acid, 2,4-dihydroxypyrimidine, phenylalanine, and ß-alanine) was identified. This panel could distinguish BD from MDD subjects with an AUC of 0.913 and 0.896 in the training and testing sets, respectively. These results reveal divergent urinary metabolic phenotypes between MDD and BD. The identified urinary biomarkers can aid in the future development of an objective laboratory-based diagnostic test for distinguishing BD from MDD patients.

Elevated levels of urinary markers of oxidatively generated DNA and RNA damage in bipolar disorder.

OBJECTIVES: The pathophysiological mechanisms underlying bipolar disorder and its multi-system nature are unclear. Oxidatively generated damage to nucleosides has been demonstrated in metabolic disorders; however, the extent to which this occurs in bipolar disorder in vivo is unknown. We investigated oxidatively generated damage to DNA and RNA in patients with bipolar disorder and its relationship with the affective phase compared with healthy control subjects. METHODS: Urinary excretion of 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG) and 8-oxo-7,8-dihydroguanosine (8-oxoGuo), markers of oxidatively generated DNA and RNA damage, respectively, was measured in 37 rapid cycling patients with bipolar disorder and in 40 age- and gender-matched healthy control subjects. Employing a longitudinal design, repeated measurements of both markers were evaluated in various affective phases in patients with bipolar disorder during a six- to 12-month period and compared with repeated measurements in healthy control subjects. RESULTS: In linear mixed models, adjusting for demographical, metabolic, and lifestyle factors, the excretion of 8-oxodG and 8-oxoGuo was significantly elevated in euthymic patients with bipolar disorder compared with healthy control subjects, with increases of 40% (p < 0.0005) and 43% (p < 0.0005), respectively. The increased oxidatively generated nucleoside damage was present through all affective phases of the illness, with no significant difference between affective states. CONCLUSIONS: Our results indicate that bipolar disorder is associated with increased oxidatively generated damage to nucleosides. The findings could suggest a role for oxidatively generated damage to DNA and RNA as a molecular mechanism contributing to the increased risk of medical disorders, shortened life expectancy, and the progressive course of illness observed in bipolar disorder.

Combined application of NMR- and GC-MS-based metabonomics yields a superior urinary biomarker panel for bipolar disorder.

Bipolar disorder (BD) is a debilitating mental disorder that cannot be diagnosed by objective laboratory-based modalities. Our previous studies have independently used nuclear magnetic resonance (NMR)-based and gas chromatography-mass spectrometry (GC-MS)-based metabonomic methods to characterize the urinary metabolic profiles of BD subjects and healthy controls (HC). However, the combined application of NMR spectroscopy and GC-MS may identify a more comprehensive metabolite panel than any single metabonomic platform alone. Therefore, here we applied a dual platform (NMR spectroscopy and GC-MS) that generated a panel of five metabolite biomarkers for BD-four GC-MS-derived metabolites and one NMR-derived metabolite. This composite biomarker panel could effectively discriminate BD subjects from HC, achieving an area under receiver operating characteristic curve (AUC) values of 0.974 in a training set and 0.964 in a test set. Moreover, the diagnostic performance of this panel was significantly superior to the previous single platform-derived metabolite panels. Thus, the urinary biomarker panel identified here shows promise as an effective diagnostic tool for BD. These findings also demonstrate the complementary nature of NMR spectroscopy and GC-MS for metabonomic analysis, suggesting that the combination of NMR spectroscopy and GC-MS can identify a more comprehensive metabolite panel than applying each platform in isolation.

The McGill Geriatric Lithium-Induced Diabetes Insipidus Clinical Study (McGLIDICS).

OBJECTIVE: Despite being a common and potentially serious condition, nephrogenic diabetes insipidus (NDI) remains poorly understood in older lithium users. Our main objective was to compare the prevalence of NDI symptoms and decreased urine osmolality ([UOsm] < 300 milli-Osmoles [mOsm/kg]) among geriatric and adult lithium users. We also assessed NDI symptoms, serum sodium (Na+), and urine specific gravity (USG) as possible surrogate measures of decreased UOsm, and ascertained whether potential etiologic factors independently correlated with decreased UOsm. METHOD: This was a cross-sectional study of 100 consecutive outpatients treated with lithium from 6 tertiary care clinics, of which 45 were geriatric (aged 65 years and older) and 55 adult (aged 18 to 64 years). Patients completed a symptom questionnaire and underwent laboratory tests, including UOsm, serum Na+, and USG. RESULTS: Geriatric and adult lithium users had similar rates of decreased UOsm (12.5%, compared with 17.9%, P = 0.74), but geriatric patients reported less symptoms (P < 0.05). Although UOsm did not correlate with symptoms or current serum Na+, USG of less than 1.010 was suggestive of UOsm of less than 300 mOsm/kg. Age, lithium duration, and serum lithium level were independently associated with UOsm. CONCLUSIONS: The prevalence of decreased UOsm is similar in geriatric and adult lithium users, but older patients are less likely to report urinary and thirst symptoms. Although subjective symptoms do not correlate with UOsm, USG may be a cost-efficient clinical surrogate measure for UOsm. We suggest clinicians increase their vigilance for decreased UOsm, especially in lithium users with advanced age, longer duration of lithium exposure, and higher lithium levels. This may potentially prevent lithium intoxication, falls, hypernatremic events, and renal dysfunction.

2,4-Dihydroxypyrimidine is a potential urinary metabolite biomarker for diagnosing bipolar disorder.

Bipolar disorder (BD) is a common and debilitating mental disorder. However, there are no biomarkers available to aid in the diagnosis of this disorder. Here, we used a gas chromatography-mass spectrometry (GC-MS) based metabonomic method to characterize the urinary metabolic profiling of BD subjects and healthy controls to identify and validate urinary metabolite biomarkers for BD. Multivariate statistical analysis was used to visualize group discrimination and identify differentially expressed urinary metabolites in BD subjects relative to the healthy controls. Multivariate statistical analysis showed that the BD group was significantly distinguishable from the healthy control. Totally, 37 urinary metabolites responsible for discriminating BD subjects from healthy controls were identified. Interestingly, of 37 differential metabolites, 2,4-dihydroxypyrimidine was identified as an effective diagnostic biomarker for BD, yielding an area under the receiver operating characteristic curve (AUC) of 0.889 in the training samples (45 BD subjects and 61 healthy controls) and 0.805 in the test samples (26 BD subjects and 33 healthy controls). Our findings suggest that 2,4-dihydroxypyrimidine is a promising candidate urinary biomarker for BD, which may facilitate development of a urine-based diagnostic test for BD.

Lower estimated glomerular filtration rates in patients on long term lithium: a comparative study and a meta-analysis of literature.

BACKGROUND: Several studies have shown that long-term lithium use is associated with a subtle decline in estimated glomerular filtration rate. This study compared mean estimated glomerular filtration rates (eGFR) in patients on long term lithium, against matched controls. METHODS: Patients with bipolar affective disorder, who are on lithium (for at least a year), were compared against controls that were matched (1:1) for age, gender and presence or absence of diabetes or hypertension. The eGFR was calculated from creatinine values according to the 'modification of diet in renal disease study' (MDRD) formula and was compared between cases and controls. A meta-analysis was performed to compare our findings with similar studies in literature. RESULTS: Forty seven patients met the inclusion criteria. They were matched with 47 controls. The eGFR values of lithium users were significantly lower (p = 0.04) compared to controls. This difference persisted between the subgroup of lithium users without comorbidities (diabetes and hypertension) and their controls but disappeared for lithium users with comorbidities and their controls. Nonetheless, lithium users had lower eGFR values in both subgroups. A meta-analysis of 9 studies showed a significant lowering in the glomerular filtration rate in lithium users compared to controls [mean difference -10.3 ml/min (95% confidence interval: -15.13 to -5.55, p < 0.0001)]. CONCLUSIONS: Lithium causes a subtle decline in glomerular filtration rate; renal function needs to be monitored in patients on lithium treatment.

Trace elements in bipolar disorder.

INTRODUCTION: Trace elements may play an important role in bipolar disorders. The objective of this study is to determine serum copper and zinc, blood lead and cadmium and urine lead, cadmium and thallium concentrations in patients diagnosed with bipolar disorders and to compare these levels with those of a healthy control group. MATERIALS AND METHODS: A total of 25 patients diagnosed with bipolar disorder and 29 healthy subjects participated in this study. Serum copper and zinc concentrations were measured using flame atomic absorption spectrometry; the blood lead and cadmium concentrations were measured by electrothermal atomization atomic absorption spectrometry with Zeeman background correction; urine lead, cadmium and thallium concentrations were measured by inductively coupled plasma mass spectrometry. RESULTS: Median blood and urine lead and cadmium levels were significantly higher among the bipolar patients than among the control group: Blood lead (µg/dL): patient median: 3.00 (IQR: 1.40-4.20); control median (µg/dL): 2.20 (IQR: 0.90-3.00) p=0.040. Blood cadmium (µg/L): patient median: 0.39 (IQR: 0.10-1.15); control median: 0.10 (IQR: 0.10-0.17) p<0.001. The median of cadmium (µg/L) in patients who smoked (1.20 IQR: 0.44-2.30) was higher than that in non-smokers (0.12 IQR: 0.10-0.34) p<0.001. There was a statistically significant increase (p=0.001) in zinc levels among patients in the manic phase (mean 111.28, SD: 33.36 µg/dL) with respect to the control group (mean 86.07, SD: 12.39 µg/dL). CONCLUSIONS: The results suggest that there could be higher levels of some toxic trace elements in the group of patients with bipolar disorder than in the healthy control group.

Elevated urinary ADAM12 protein levels in lithium-treated bipolar patients.

ADAM (A Disintegrin And Metalloprotease)12 is a member of a family of integral membrane and secreted glycoproteins. ADAM12 has recently been detected in urine. In the present study we measured ADAM12 protein levels in urine from bipolar patients vs. healthy controls. Nineteen bipolar patients and 22 matched-control subjects were studied. Urine samples were concentrated and Western-blot analysis used to determine ADAM12 protein levels. The 92 kDa form of urine ADAM12 protein levels were highly elevated in Li-treated bipolar patients compared with normal controls. The 68 kDa form of urine ADAM12 protein levels did not differ. Future experiments are needed to explore a potential link between ADAM12 protein level elevation and lithium response.

Effects of short- and long-term lithium treatment on kidney functioning in patients with bipolar mood disorder.

Lithium (Li) carbonate has been reported to be able to cause some reversible functional changes in the kidney. In this study, the authors aimed to investigate whether the duration of Li treatment is the primary determinant of the changes in renal functioning due to the Li treatment. For this purpose, 10 Li-naïve (mean age+/-S.D.: 34.50+/-4.85), 10 short-term (mean age+/-S.D.: 31.77+/-7.61) and 10 long-term (mean age+/-S.D.: 36.60+/-10.15) Li-treated bipolar patients were included in the study. Serum blood urea nitrogen (BUN) and creatinine, urine creatinine levels, creatinine clearance, urine osmolality before and after 8-h water deprivation and urine osmolality after desmopressin injection were measured in all patients. Serum BUN and creatinine levels were within the normal limits and not statistically different among the groups. Creatinine clearance of the long-term Li-treated group was significantly lower than both that of the Li-naïve group and that of the short-term Li-treated group. After 8-h water deprivation and also after desmopressin injection, no difference was found among the groups in terms of urine osmolality. However, when each patient was evaluated individually in terms of their renal concentrating ability, partial nephrogenic diabetes insipidus was diagnosed in four patients on long-term and in two patients on short-term Li treatment. To our surprise, hypothalamic diabetes insipidus was also diagnosed in other two patients on long-term Li treatment. These results demonstrate that long-term Li treatment may cause impairment in renal concentrating ability, some of which may originate from the effects of Li on vasopressin on hypothalamic level, and a decrease in glomerular filtration rate (GFR). In the light of these data, we can conclude that long-term administration of Li may be a risk factor for Li-induced renal impairment, which is a progressive effect in nature.

Quetiapine in bipolar disorder and cocaine dependence.

OBJECTIVE: Bipolar disorder is associated with the highest rates of substance abuse of any psychiatric illness. Therefore, treatments that stabilize mood and decrease drug use or cravings are of great interest. Atypical antipsychotics are in widespread use in patients with bipolar disorder. However, minimal data are available on their use in bipolar patients with comorbid substance abuse. METHODS: Open-label, add-on, quetiapine therapy was examined for 12 weeks in 17 outpatients with bipolar disorder and cocaine dependence. Subjects were evaluated with a structured clinical interview; Hamilton Depression Rating (HDRS), Young Mania Rating (YMRS), Brief Psychiatric Rating (BPRS) scales; and Cocaine Craving Questionnaire (CCQ). Urine samples and self-reported drug use were also obtained. Data were analyzed using a last observation carried forward method on all subjects given medication at baseline. RESULTS: Significant improvement from baseline to exit was observed in HDRS, YMRS, BPRS and CCQ scores (p < or = 0.05). Dollars spent on cocaine and days/week of cocaine use decreased non-significantly, and urine drug screens did not change significantly from baseline to exit. Quetiapine was well tolerated, with no subjects to our knowledge discontinuing because of side-effects. CONCLUSIONS: The use of quetiapine was associated with substantial improvement in psychiatric symptoms and cocaine cravings. The findings are promising and suggest larger controlled trials of quetiapine are needed in this population.