Inhibition/activation in bipolar disorder: validation of the Multidimensional Assessment of Thymic States scale (MAThyS).

BACKGROUND: One of the major issues in clinical practice is the accurate differential diagnosis between mixed states and depression, often leading to inappropriate prescriptions of antidepressants in mixed states, and as a consequence, increasing the risk of manic switch and suicide. In order to better define the spectrum of mixed states, it may be useful to develop a dimensional approach. In this context, the MAThyS (Multidimensional Assessment of Thymic States) scale was built to assess activation/inhibition levels in all bipolar mood episodes, and to determine whether a clinical description in terms of activation/inhibition can help better define bipolar states with which both manic and depressive symptoms are associated. The aim of this paper is the validation of the MAThyS scale in 141 bipolar patients in acute states (manic, hypomanic, mixed, or depressive). METHODS: The validation of the MAThyS scale was the primary outcome of this 24-week, phase III, open-label, olanzapine single-arm clinical trial. Principal component, factorial analysis, and Cronbach's coefficient calculation (internal consistency) were performed. Concurrent validity (correlations with 17-item Hamilton Depression Rating Scale [HAMD-17], Hamilton Anxiety Rating Scale [HAMA], and Young Mania Rating Scale [YMRS]) and responsiveness to the clinical intervention were assessed (change in MAThyS scale and effect size) at 6 and 24 weeks. RESULTS: Scree plot of eigenvalues identified a 2-dimension structure ("activation/inhibition level" and "emotional component"). Psychometric properties were good: Cronbach's coefficient was >0.9. Concurrent validity was good with low correlation (-0.19) with the HAMA scale and a higher correlation at baseline with the YMRS (0.72) and HAMD-17(-0.43). As expected, the activation state was predominant in manic, hypomanic, and mixed states while inhibition was predominant in depressive states. MAThyS score improvement was observed (effect size: -0.3 at 6 and 24 weeks). CONCLUSIONS: The MAThyS demonstrated good psychometric properties. The MAThyS scale may help clinicians to better discriminate and follow bipolar episodes, especially the broad spectrum of mixed episodes.

Striatal and extrastriatal dopamine transporter in cannabis and tobacco addiction: a high-resolution PET study.

The dopamine (DA) system is known to be involved in the reward and dependence mechanisms of addiction. However, modifications in dopaminergic neurotransmission associated with long-term tobacco and cannabis use have been poorly documented in vivo. In order to assess striatal and extrastriatal dopamine transporter (DAT) availability in tobacco and cannabis addiction, three groups of male age-matched subjects were compared: 11 healthy non-smoker subjects, 14 tobacco-dependent smokers (17.6 ± 5.3 cigarettes/day for 12.1 ± 8.5 years) and 13 cannabis and tobacco smokers (CTS) (4.8 ± 5.3 cannabis joints/day for 8.7 ± 3.9 years). DAT availability was examined in positron emission tomography (HRRT) with a high resolution research tomograph after injection of [11C]PE2I, a selective DAT radioligand. Region of interest and voxel-by-voxel approaches using a simplified reference tissue model were performed for the between-group comparison of DAT availability. Measurements in the dorsal striatum from both analyses were concordant and showed a mean 20% lower DAT availability in drug users compared with controls. Whole-brain analysis also revealed lower DAT availability in the ventral striatum, the midbrain, the middle cingulate and the thalamus (ranging from -15 to -30%). The DAT availability was slightly lower in all regions in CTS than in subjects who smoke tobacco only, but the difference does not reach a significant level. These results support the existence of a decrease in DAT availability associated with tobacco and cannabis addictions involving all dopaminergic brain circuits. These findings are consistent with the idea of a global decrease in cerebral DA activity in dependent subjects.

Suicidal attempts in bipolar disorder: results from an observational study (EMBLEM).

OBJECTIVES: To compare patients with and without a history of suicidal attempts in a large cohort of patients with bipolar disorder and to identify variables that are associated with suicidal behavior. METHODS: European Mania in Bipolar Longitudinal Evaluation of Medication (EMBLEM) is a two-year, prospective, observational study that enrolled 3,684 adult patients with bipolar disorder and initiated or changed oral treatment for an acute manic/mixed episode. Of those, 2,416 patients were eligible for the two-year follow-up. Only baseline characteristics were studied in the present study, included sociodemographic data, psychiatric history and comorbidities, history of suicide attempts, history of substance use problems, compliance with treatment, inpatient admissions, and functional status. Symptom severity was assessed using the Clinical Global Impression-Bipolar Disorder (CGI-BP) scale, the Young Mania Rating Scale (YMRS), and the 5-item Hamilton Depression Rating Scale (HAMD-5). A logistic regression model identified baseline variables independently associated with a history of suicidal behavior. RESULTS: Of the 2,219 patients who provided data on their lifetime history of suicide attempts, 663 (29.9%) had a history of suicidal behavior (at least one attempt). Baseline factors associated with a history of suicidal behavior included female gender, a history of alcohol abuse, a history of substance abuse, young age at first treatment for a mood episode, longer disease duration, greater depressive symptom severity (HAMD-5 total score), current benzodiazepine use, higher overall symptom severity (CGI-BP: mania and overall score), and poor compliance. CONCLUSIONS: These factors may be considered as potential characteristics to identify subjects at risk for suicidal behavior throughout the course of bipolar disorder.

Dual diagnosis: prevalence, risk factors, and relationship with suicide risk in a nationwide sample of French prisoners.

BACKGROUND: Axis I psychiatric disorders (PD) and substance use disorders (SUD) are common in prison, but only few studies have focused on their association in this setting. Dual diagnosis (DD) (the co-occurrence of a SUD and any axis I disorder) is known to have a poorer prognosis and to require more intense supportive care. OBJECTIVES: The objectives of this study were (1) to describe prisoners with DD (prevalence and characteristics); (2) to compare DD prisoners with 3 other groups of prisoners: no diagnosis (ND), SUD alone, or other isolated PD; and (3) to evaluate the impact of DD on suicide risk in prison. METHOD: A random stratified strategy was used to select 23 various types of prisons and 998 prisoners. Diagnoses were assessed using a unique procedure, each prisoner being evaluated by 2 psychiatrists, 1 junior, using a structured interview (MINI 5 plus), and 1 senior, using an open clinical interview. Following interviews, clinicians met to establish a list of diagnoses. Cloninger's temperament and character inventory was also used. RESULTS: Of the prisoners, 26.3% had a DD. DD prevalence was almost 80% in prisoners with SUD, while only one-third of the prisoners with an axis I PD had co-morbid SUD. No significant differences were observed in drug use patterns between DD and SUD without co-morbid PDs. DD showed the strongest association with suicide risk [OR = 5.7 (1.7-4.6)]. CONCLUSION: DD is very frequent in prison and is a major risk factor for suicide. Systematic psychiatric/SUD screening of prisoners with either a SUD or an axis I PD should be encouraged.

Mixed states vs. pure mania in the French sample of the EMBLEM study: results at baseline and 24 months--European mania in bipolar longitudinal evaluation of medication.

BACKGROUND: To describe the clinical course and treatment patterns over 24 months of patients experiencing an acute manic/mixed episode within the standard course of care. METHODS: EMBLEM was a 2-year European prospective, observational study on outcomes of patients experiencing a manic/mixed episode. Adults with bipolar disorder were enrolled within the standard course of care as in/outpatients if they initiated or changed oral medication for treatment of acute mania. After completing 12 weeks of acute phase, patients were assessed every 3-6 months during the maintenance phase. We present the 24 month results, with subgroup analysis for mixed states (MS) and pure mania (PM). These subgroup analyses are driven by the high proportion of antidepressants prescribed in this cohort. RESULTS: In France, 771 patients were eligible for the maintenance phase. 69% of patients completed the follow up over 24 months. The mean age was 45.5 years (sd = 13.6) with 57% of women. 504 (66%) patients were experiencing a PM and 262 (34%) a MS at baseline. The main significant differences in MS vs. PM at baseline were: a higher rate of women, and in the previous 12 months, a higher frequency of episodes (manic/mixed and depressive), more suicide attempts, more rapid cycling, fewer social activities and more work impairment. Over the 24 months of follow-up the MS group had a significantly lower recovery than PM (36% vs. 46%, p = 0.006). Overall, 42% of all patients were started on monotherapy and 58% on combination therapy; of those 35% and 30% respectively remained on their initial medication throughout the 24 months. At baseline, 36% were treated with an antidepressant, this proportion remains high throughout the follow-up period, with a significantly higher rate for MS vs. PM at 24 months (55% vs. 27%, p < 0.001). CONCLUSION: In this large sample, MS occur frequently (34%), they are more severe at baseline and have a worse functional prognosis than PM. Although antidepressants are not recommended in MS and PM, they were frequently prescribed at baseline and are maintained during the 24 months of follow-up.

Pathways to substance-related disorder: a structural model approach exploring the influence of temperament, character, and childhood adversity in a national cohort of prisoners.

AIMS: Using Cloninger's model of personality, we aimed to specify the relative influence of the more biologically determined variables, temperament and character and more environmentally driven influence, childhood adversity in the development of addiction; and to compare patterns found among alcoholics with those found among drug addicts. METHODS: We studied a group of prisoners, at a high risk of substance abuse and past history of childhood adversity. Using a stratified random strategy we selected (i) 23 prisons among the different types of prison in France, (ii) 998 prisoners. Each prisoner was assessed by two psychiatrists--one junior, using a structured interview (MINI 5 plus), and one senior, completing the procedure with an open clinical interview. At the end of the interview the clinicians met and agreed on a list of diagnoses. Cloninger's Temperament and Character Inventory was used to measure personality. Structural equations models, which have been advocated to disentangle the respective influence of complex risk factors, were used. RESULTS: The "novelty seeking" temperament was a crucial vulnerability factor, for both alcoholics and drug addicts, in the same proportion. Character and childhood adversity played a significant part only in the development of drug abuse. CONCLUSIONS: In a prison population, a common biological loaded factor, novelty seeking is found both at the core of alcohol- and drug-related disorder whereas environmentally loaded factors play a greater role in drug problems.

Comparison of self-reports and biological measures for alcohol, tobacco, and illicit drugs consumption in psychiatric inpatients.

BACKGROUND: Asking psychiatric in-patients about their drug consumption is unlikely to yield reliable results, particularly where alcohol and illicit drug use is involved. The main aim of this study was to compare spontaneous self-reports of drug use in hospitalized psychiatric patients to biological measures of same. A secondary aim was to determine which personal factors were associated with the use of tobacco, alcohol, and illicit drugs as indicated by these biological measures. METHODS: The consumption of substances was investigated using biological measures (urine cotinine, cannabis, opiates, cocaine, amphetamines and barbiturates; blood carbohydrate-deficient transferrin [CDT] and gamma-glutamyl transferase [GGT]) in 486 consecutively admitted psychiatric patients, one day following their hospitalization. Patients' self-reports of alcohol, tobacco and illicit drugs consumption were recorded. Socio-professional and familial data were also recorded. RESULTS: The results show a low correlation between biological measures and self-reported consumption of alcohol and illicit drugs. Fifty-two percent of the patients under-reported their consumption of illicit drugs (kappa=.47). Patients with schizophrenia and personality disorders were more likely to disclose their illicit drug consumption relative to patients suffering from mood disorders and alcohol dependence. Fifty-six percent of patients underreported alcohol use, as evaluated by CDT (kappa=.2), and 37% underreported when using the CDT+GGT measure as an indicator. Smoking appeared to be reported adequately. In the study we observed a strong negative correlation between cannabis use and age, a strong correlation between tobacco and cannabis use, and correlations between tobacco, cannabis and alcohol consumption. CONCLUSION: This study is the first to compare self-reports and biological measures of alcohol, tobacco and illicit drug uses in a large sample of inpatients suffering from various categories of psychiatric illnesses, allowing for cross-diagnosis comparisons.

Mixed states with predominant manic or depressive symptoms: baseline characteristics and 24-month outcomes of the EMBLEM cohort.

BACKGROUND: While factors associated with mixed states have been extensively studied, data are scant regarding the clinical heterogeneity of mixed states. The EMBLEM study was a prospective, observational study on patients with manic and mixed states. We describe and compare baseline characteristics and 24-month clinical course of mixed states with predominant depressive symptoms (MSDS) and mixed states with predominant manic symptoms (MSMS). METHODS: Adult inpatients/outpatients with bipolar disorder were enrolled within the standard course of care if they initiated or changed oral medication for acute mania or mixed states. A logistic regression was used to identify the baseline factors associated with each polarity. Comparisons with mixed episode without symptom predominance (OMS) were performed for informational purpose only. RESULTS: About 573 mixed patients were analyzed (23.7% of the cohort): 59.5% (n=341) had MSMS, 11.9% (n=68) had MSDS, and 28.6% (n=164) had OMS. At baseline, hallucinations/delusions during the index episode, inpatient status, high CGI-BP overall score, and low education level were more often associated with MSMS versus MSDS. Alcohol abuse or dependence and selective serotonin reuptake inhibitor (SSRI) or benzodiazepine use at inclusion were significantly more frequent with MSDS. MSDS had a significantly lower 24-month recurrence rate than MSMS; MSMS experienced more switches to mania whereas MSDS switched more to depression. LIMITATIONS: The post hoc dimensional definitions in the study require caution in the interpretation of the results. CONCLUSION: These results present evidence of clinical heterogeneity within mixed states. Predominant manic or depressive symptoms within mixed episode could influence clinicians' decisions in term of hospitalization, treatment, and perception of bipolar severity.

Young Mania Rating Scale: how to interpret the numbers? Determination of a severity threshold and of the minimal clinically significant difference in the EMBLEM cohort.

The aim of this analysis was to identify Young Mania Rating Scale (YMRS) meaningful benchmarks for clinicians (severity threshold, minimal clinically significant difference [MCSD]) using the Clinical Global Impressions Bipolar (CGI-BP) mania scale, to provide a clinical perspective to randomized clinical trials (RCTs) results. We used the cohort of patients with acute manic/mixed state of bipolar disorders (N = 3459) included in the European Mania in Bipolar Longitudinal Evaluation of Medication (EMBLEM) study. A receiver-operating characteristic analysis was performed on randomly selected patients to determine the YMRS optimal severity threshold with CGI-BP mania score ≥ "Markedly ill" defining severity. The MCSD (clinically meaningful change in score relative to one point difference in CGI-BP mania for outcome measures) of YMRS, was assessed with a linear regression on baseline data. At baseline, YMRS mean score was 26.4 (±9.9), CGI-BP mania mean score was 4.8 (±1.0) and 61.7% of patients had a score ≥ 5. The optimal YMRS severity threshold of 25 (positive predictive value [PPV] = 83.0%; negative predictive value [NPV] = 66.0%) was determined. In this cohort, a YMRS score of 20 (typical cutoff for RCTs inclusion criteria) corresponds to a PPV of 74.6% and to a NPV of 77.6%, meaning that the majority of patients included would be classified as severely ill. The YMRS minimal clinically significant difference was 6.6 points.

Association between ABCB1 C3435T polymorphism and increased risk of cannabis dependence.

Prolonged cannabis use has a significant impact on health and well-being. Genetic factors are known to influence cannabis dependence, but few specific genetic markers have been identified. ABCB1 polymorphisms are known to modify drug pharmacokinetics but have yet to be studied for their role in generating and maintaining cannabis dependence. The objective of this study is to determine if ABCB1 C3435T polymorphism may represent an independent genetic marker for cannabis dependence risk. An open bi-centric association study was conducted in two French Addiction Centres. Caucasian patients diagnosed with isolated cannabis dependence were compared with healthy age-matched controls for socio-demographic, clinical and genetic data using chi-square test, Fisher's exact test, or Mann-Whitney U test. Independent association between ABCB1 C3435T SNP marker and cannabis dependence was evaluated using multiple logistic regression analysis. Versus controls (n=40), patients with cannabis dependence (n=40) had a significantly higher 3435C allele frequency (62.5% versus 43.8% respectively, P=0.017) and CC genotype (50% versus 20%, P=0.005, OR=4.00 [1.50-10.60]). Multiple logistic regression analysis of the C3435T SNP and variables identified in univariate analyses indicated that the CC genotype was independently associated with cannabis dependence (P=0.045, OR=6.61 [1.05-46.58]). This is the first time a significant specific genetic marker has been shown in cannabis dependence. ABCB1 polymorphisms may alter Delta9THC distribution, its psychoactive effects and individual vulnerability to dependence. These results pave the way to a new pharmacogenetic hypothesis in cannabis dependence.

Prevalence and factors associated with alcohol and drug-related disorders in prison: a French national study.

BACKGROUND: Most studies measuring substance-use disorders in prisons focus on incoming or on remand prisoners and are generally restricted to drugs. However, there is evidence that substance use initiation or continuation occurs in prison, and that alcohol use is common. The aim of this study is 1) to assess prevalence of both drug and alcohol abuse and dependence (DAD/AAD) in a national randomised cohort of French prisoners, short or long-term sentence 2) to assess the risk factors associated with DAD/AAD in prison. a stratified random strategy was used to select 1) 23 prisons among the different types of prison 2) 998 prisoners. Diagnoses were assessed according to a standardized procedure, each prisoner being assessed by two psychiatrists, one junior, using a structured interview (MINI 5 plus), and one senior, completing the procedure with an open clinical interview. At the end of the interview the clinicians met and agreed on a list of diagnoses. Cloninger's Temperament and Character Inventory (TCI) was also used. RESULTS: More than a third of prisoners presented either AAD or DAD in the last 12 months. Cannabis was the most frequent drug and just under a fifth of prisoners had AAD. AAD and DAD were clearly different for the following: socio-demographic variables, childhood history, imprisonment characteristics, psychiatric comorbidity and Cloninger's TCI. Profiles of AAD in prison are similar to type II alcoholism. CONCLUSION: Regular screening of AAD/DAD in prison, and specific treatment programmes taking into account differences between prisoners with an AAD and prisoners with a DAD should be a public health priority in prison.

Predictive factors of the number and the dose of anti-psychotics in a cohort of schizophrenic patients.

BACKGROUND: Anti-psychotic prescription in schizophrenia is characterised in Europe by frequent associations and high doses. Nevertheless, few longitudinal epidemiological studies have explored anti-psychotic prescriptions. AIM: (1) To describe the evolution of prescription patterns across time; (2) to determine risk factors for prescription of high doses of anti-psychotics and for anti-psychotic combinations. MATERIALS AND METHODS: Three thousand four hundred seventy three subjects were included in 1993. Data collected in 1993 and subsequently in 1996 and 1999, provided information on demographics, clinical status and prescription. In 1996, the response rate was 68.5% and 56.7% in 1999. RESULTS: The number of anti-psychotics prescribed slightly decreased across time, while doses remained high for one-third of the patients. The factors predicting dose were: dose at previous evaluation, class of anti-psychotic and clinical severity. The factors predicting the number of anti-psychotics were: previous number and class of anti-psychotic and clinical severity. CONCLUSION: Higher dosage and combinations were related more to physicians' habits than to patient characteristics, as is frequently observed in chronic disease.