M. Adida

Lithium toxicity profile: a systematic review and meta-analysis

BACKGROUND Lithium is a widely used and effective treatment for mood disorders. There has been concern about its safety but no adequate synthesis of the evidence for adverse effects. We aimed to undertake a clinically informative, systematic toxicity profile of lithium. METHODS We undertook a systematic review and meta-analysis of randomised controlled trials and observational studies. We searched electronic databases, specialist journals, reference lists, textbooks, and conference abstracts. We used a hierarchy of evidence which considered randomised controlled trials, cohort studies, case-control studies, and case reports that included patients with mood disorders given lithium. Outcome measures were renal, thyroid, and parathyroid function; weight change; skin disorders; hair disorders; and teratogenicity. FINDINGS We screened 5988 abstracts for eligibility and included 385 studies in the analysis. On average, glomerular filtration rate was reduced by -6·22 mL/min (95% CI -14·65 to 2·20, p=0·148) and urinary concentrating ability by 15% of normal maximum (weighted mean difference -158·43 mOsm/kg, 95% CI -229·78 to -87·07, p<0·0001). Lithium might increase risk of renal failure, but the absolute risk was small (18 of 3369 [0·5%] patients received renal replacement therapy). The prevalence of clinical hypothyroidism was increased in patients taking lithium compared with those given placebo (odds ratio [OR] 5·78, 95% CI 2·00-16·67; p=0·001), and thyroid stimulating hormone was increased on average by 4·00 iU/mL (95% CI 3·90-4·10, p<0·0001). Lithium treatment was associated with increased blood calcium (+0·09 mmol/L, 95% CI 0·02-0·17, p=0·009), and parathyroid hormone (+7·32 pg/mL, 3·42-11·23, p<0·0001). Patients receiving lithium gained more weight than did those receiving placebo (OR 1·89, 1·27-2·82, p=0·002), but not those receiving olanzapine (0·32, 0·21-0·49, p<0·0001). We recorded no significant increased risk of congenital malformations, alopecia, or skin disorders. INTERPRETATION Lithium is associated with increased risk of reduced urinary concentrating ability, hypothyroidism, hyperparathyroidism, and weight gain. There is little evidence for a clinically significant reduction in renal function in most patients, and the risk of end-stage renal failure is low. The risk of congenital malformations is uncertain; the balance of risks should be considered before lithium is withdrawn during pregnancy. Because of the consistent finding of a high prevalence of hyperparathyroidism, calcium concentrations should be checked before and during treatment. FUNDING National Institute for Health Research Programme Grant for Applied Research.

Risk factors associated with lifetime suicide attempts in bipolar I patients: findings from a French National Cohort.

Risk factors that may be associated with suicide attempts in bipolar disorder are still a matter of debate. We compared demographic, illness course, clinical, and temperamental features of suicide attempters vs those of nonattempters in a large sample of bipolar I patients admitted for an index manic episode. One thousand ninety patients (attempters = 382, nonattempters = 708) were included in the study. Multivariate analysis evidenced 8 risk factors associated with lifetime suicide attempts as follows: multiple hospitalizations, depressive or mixed polarity of first episode, presence of stressful life events before illness onset, younger age at onset, no free intervals between episodes, female sex, higher number of previous episodes, and cyclothymic temperament. These characteristics may help identify subjects at risk for suicide attempt throughout the course of bipolar disorder. We finally propose to integrate such characteristics into a stress-diathesis model of suicidal behavior, adapted to bipolar patients.

Lack of insight may predict impaired decision making in manic patients.

OBJECTIVES The tendency to engage in risky behaviours is a core feature of the manic episodes of bipolar disorder. The aim of this study was to establish whether this characteristic can be quantified with a laboratory measure of decision making [the Iowa Gambling Task (IGT)] and to determine clinical correlates of the IGT performance in mania. METHODS Inpatients with acute mania (n = 45) and healthy volunteers (n = 45) were assessed on the IGT. Affective symptomatology was assessed with the Young Mania Rating Scale and Hamilton Depression Rating Scale, and item scores were subjected to factor analysis. Multivariate regression was used to assess clinical predictors of impaired decision making in the manic patients. RESULTS On the IGT, manic patients selected more cards from the risky decks than healthy controls, and showed little capacity to learn from incurred losses. In a multivariate analysis, impaired decision making ability in the manic patients was significantly predicted by a symptom factor associated with lack of insight. CONCLUSIONS Manic patients clearly show defects in decision making, which are strongly related to their lack of insight. Neural circuitry supporting effective decision making, including the ventromedial prefrontal cortex and somatosensory cortex, may be implicated in the pathophysiology of acute mania.

Investigation of impulsivity in a sample of treatment-seeking pathological gamblers: a multidimensional perspective.

Numerous studies have shown that problem gambling is characterised by lack of impulse control. However, they have often been conducted without considering the multifaceted nature of impulsivity and related psychological mechanisms. The current study aims to disentangle which impulsivity facets are altered in pathological gambling. Twenty treatment-seeking pathological gamblers (PGs) and 20 matched control participants completed a self-reported questionnaire measuring the various facets of impulsive behaviours (UPPS Impulsive Behaviour Scale), as well as two laboratory tasks assessing inhibitory control (the go-stop task) and tolerance for delayed rewards (single key impulsivity paradigm). Compared with matched controls, PGs exhibited higher urgency, lower premeditation, impairment in prepotent inhibition, and lower tolerance towards delayed rewards. Nevertheless, complementary profile analyses showed that impulsivity-related deficits found in PGs are highly heterogeneous, and that some PGs are neither impulsive in the impulsivity facets assessed nor impaired in the cognitive mechanisms measured. These findings underscore (1) the necessity to disentangle the construct of impulsivity into lower-order components and (2) that further studies should take into account, in addition to impulsivity-related mechanisms, other psychological factors potentially involved in pathological gambling.

Suicidal behaviour in a French Cohort of major depressive patients: Characteristics of attempters and nonattempters

BACKGROUND Epidemiological and clinical studies indicate that major depressive disorder is the leading cause of suicidal behaviour and that bipolar II subjects carry the highest risk. Identification of risk factors is therefore essential to prevent suicide in this population. METHODS As part of the EPIDEP National Multisite French Study of 493 consecutive DSM-IV major depressive patients evaluated in at least two semi-structured interviews 1month apart, 155 (33.7%) were classified as suicide attempters, and 295 (66.3%) as nonattempters, after exclusion of bipolar I patients. RESULTS Compared to nonattempters, attempters had a longer duration of illness, longer delays before seeking help and correct diagnosis and a higher number of previous episodes; they were more frequently rapid cyclers, with fewer free intervals between episodes. Lifetime suicide attempts were associated with more comorbid bulimia and substance abuse. Bipolar II spectrum disorders, depressive, cyclothymic and irritable temperaments were overrepresented in attempters, as well as family history of both affective disorder and suicide attempts. The following independent variables were associated with lifetime suicide attempts: higher number of previous depressive episodes, multiple hospitalizations, cyclothymic temperament, rapid cycling and earlier age at onset. LIMITATIONS Retrospective design, recall bias, lack of sample homogeneity, and insufficient assessment of hypomanic features during index depression. CONCLUSIONS In major depressive disorders, family history, age at onset, illness course, comorbidity and cyclothymic temperament alongside other indices of bipolarity may help predict suicidal behaviour. Longer delays to seeking help and diagnosis in attempters emphasize the importance of early recognition of bipolar spectrum disorders.

Psychopathological Correlates of Lifetime Anxiety Comorbidity in Bipolar I Patients: Findings from a French National Cohort

Background: Despite numerous studies on the comorbidity of bipolar and anxiety disorders, there is no satisfactory psychopathological model for their overlap. Method: 1,090 hospitalized patients meeting DSM-IV criteria for a manic episode of bipolar I disorder were subtyped according to the presence or not of lifetime anxiety comorbidity and assessed for demographic, illness course, clinical, associated condition, temperament, and treatment characteristics. Results: Lifetime anxiety comorbidity, defined as presence of at least one anxiety disorder in lifetime, was found in 27.2% (n = 297) of the sample. Compared to patients without such a comorbidity (n = 793), those who had it experienced a higher number of mood episodes and suicide attempts in the previous year, more stressors, organic disorders and less free intervals; furthermore, they showed more temperaments with depressive features and complex treatment. At study entry, they also experienced manic episodes with higher levels of depression, psychosis and hostility. The following independent variables were associated with lifetime anxiety comorbidity: higher scores on the Montgomery-Åsberg Depression Rating Scale, depressive temperament, irritable temperament, higher scores on the Scale for the Assessment of Positive Symptoms, episodes without free intervals and at least one stressor before the index episode. Conclusions: Factors associated with lifetime anxiety comorbidity in bipolar I patients may be integrated into a comprehensive diathesis-stress model emphasizing the role of irritable temperament as a source of mood instability and stress, and interacting with other temperamental characteristics to trigger the outbreak of both anxiety and bipolar symptoms.

Characteristics and profiles of bipolar I patients according to age-at-onset: findings from an admixture analysis.

BACKGROUND Many studies have used admixture analysis to separate age-at-onset (AAO) subgroups in bipolar patients, but few have looked at the phenomenological characteristics of these subgroups, in order to find out phenotypic markers. METHODS Admixture analysis was applied to identify the model best fitting the observed AAO distribution of a sample of 1082 consecutive DSM-IV bipolar I manic inpatients who were assessed for demographic, clinical, course of illness, comorbidity, and temperamental characteristics. RESULTS The model best fitting the observed distribution of AAO was a mixture of three Gaussian distributions. We could identify three AAO subgroups: early, intermediate, and late age-at-onset (EAO, IAO, and LAO, respectively). Patients in the EAO subgroup were more often single young males exhibiting severe mania with psychotic features, a subcontinuous course of illness with substance use and panic comorbidity, more suicide attempts, and temperamental components sharing hypomanic features. Patients with LAO showed a less severe picture with more depressive temperamental components, alcohol use and comorbid general medical conditions. A less typical phenotype was present in IAO patients. LIMITATIONS The following are the limitations of this study: retrospective design, and bias toward preferential enrollment of patients with manic predominant polarity. CONCLUSIONS This study confirms that bipolar I disorder can be subdivided into three subgroups based on AAO distribution and shows that patients from these subgroups differ in phenotypes.

Factors associated with rapid cycling in bipolar I manic patients: findings from a French national study.

INTRODUCTION Despite numerous explanatory hypotheses, few studies have involved a large national clinical sample examining risk factors in the occurrence of rapid cycling during the course of bipolar illness. METHODS From 1,090 manic bipolar I disorder inpatients included in a multicenter national study in France, 958 could be classified as rapid or nonrapid cyclers and assessed for demographic, illness course, clinical, psychometric, temperament, comorbidity, and treatment characteristics. RESULTS Rapid cycling bipolar disorder occurred in 9% (n=86) of the study group. Compared to nonrapid cyclers (n=872), patients with rapid cycling experienced the onset of their illness at a younger age, a higher number of prior episodes, more depression during the first episode, and more suicide attempts. At study entry, they also experienced manic episodes with more depressive and anxious symptoms, but less psychotic features. The following independent variables were associated with rapid cycling: longer duration of illness, antidepressant treatment, episodes with no free intervals, cyclothymic temperament, lower scores on the Scale for Assessment of Positive Symptoms and presence of thyroid disorder. Retrospective study limited to bipolar I disorder inpatients; several factors previously associated with rapid cycling were not assessed. CONCLUSION Our findings may confirm previous descriptions, according to which rapid cycling develops later in the course of illness following a sensitization process triggered by antidepressant use or thyroid dysfunction, in patients with a depression-mania-free interval course, and cyclothymic temperament.

Relationship of suicide rates to economic variables in Europe: 2000-2011

BACKGROUND It is unclear whether there is a direct link between economic crises and changes in suicide rates. AIMS The Lopez-Ibor Foundation launched an initiative to study the possible impact of the economic crisis on European suicide rates. METHOD Data was gathered and analysed from 29 European countries and included the number of deaths by suicide in men and women, the unemployment rate, the gross domestic product (GDP) per capita, the annual economic growth rate and inflation. RESULTS There was a strong correlation between suicide rates and all economic indices except GPD per capita in men but only a correlation with unemployment in women. However, the increase in suicide rates occurred several months before the economic crisis emerged. CONCLUSIONS Overall, this study confirms a general relationship between the economic environment and suicide rates; however, it does not support there being a clear causal relationship between the current economic crisis and an increase in the suicide rate.

Self-assessment and characteristics of mixed depression in the French national EPIDEP study.

BACKGROUND Studies on mixed depression have been conducted so far on the basis of DSM-IV manic symptoms, i.e., a list of 7 symptoms which may provide limited information on the subsyndromal features associated with a full depressive episode. METHODS As part of the EPIDEP National Multisite French Study of 493 consecutive DSM-IV major depressive patients evaluated in at least two semi-structured interviews 1 month apart, 102 (23.8%) were classified as mixed depressives (≥3 hypomanic symptoms), and 146 (34%) as pure depressives (0 hypomanic symptom), after exclusion of bipolar I patients; hypomanic symptoms were assessed with the Multiple Visual Analog Scales of Bipolarity (MVAS-BP, 26 items) of Ahearn-Carroll in a self assessment format. A narrower definition of mixed depression, resting on those MVAS-BP items referring to DSM-IV hypomanic symptoms was also tested, as a sensitivity analysis. RESULTS Compared to pure depressives, mixed depressive patients had more psychotic symptoms, atypical features and suicide attempts during their index episode; their illness course was characterized by early age at onset, frequent episodes, rapid cycling, and comorbidities. Mixed depressive patients were more frequently bipolar with a family history of bipolar disorder, alcohol abuse, and suicide. A dose-response relationship was found between intradepression hypomania and several clinical features, including temperament measures. The following independent variables were associated with mixed depression: hyperthymic temperament, cyclothymic temperament, irritable temperament, and alcohol abuse. Using the narrower definition of mixed depression missed risk factors such as suicidality and comorbidities. LIMITATIONS The following are the limitations of this study: retrospective design, recall bias, lack of sample homogeneity, no cross-validation of findings by hetero-evaluation of hypomanic symptoms. CONCLUSIONS EPIDEP data showed the feasibility and face validity of self-assessment of intradepressive hypomania. They replicated previous findings on the severity and high suicidal risk of mixed depression profile. They confirmed, for mixed depression, that mixed states occur when mood episodes are superimposed upon temperaments of opposite polarity. They finally suggested that a definition of mixed depression only based on DSM-IV-TR hypomanic symptoms may not allow to identify the most unstable subforms of the entity.