[Early intervention in bipolar affective disorders: Why, when and how]. / Intervenir précocement dans les stades débutants du trouble bipolaire : pourquoi, quand et comment.

OBJECTIVES: Bipolar disorder (BD) is a chronic and severe psychiatric disease. There are often significant delays prior to diagnosis, and only 30 to 40 % of patients will experience complete remission. Since BD occurs most often at a young age, the disorder can seriously obstruct future socio-professional development and integration. Vulnerability-stress model of BD is considered to be the result of an interaction between vulnerability genes and environmental risk factors, which leads to the onset of the disorder most often in late adolescence or early adulthood. The clinical "staging" model of BD situates the subject in a clinical continuum of varying degrees of severity (at-risk status, first episode, full-blown BD). Given the demonstrated effectiveness of early intervention in the early stages of psychotic disorder, we posit that early intervention for early stages of BD (i.e. at-risk status and first episode mania or hypomania) would reduce the duration of untreated illness and optimize the chances of therapeutic response and recovery. METHODS: We conducted a narrative review of the literature to gather updated data on: (1) features of early stages: risk factors, at-risk symptoms, clinical specificities of the first manic episode; (2) early screening: targeted populations and psychometric tools; (3) early treatment: settings and therapeutic approaches for the early stages of BD. RESULTS: (1) Features of early stages: among genetic risk factors, we highlighted the diagnosis of BD in relatives and affective temperament including as cyclothymic, depressive, anxious and dysphoric. Regarding prenatal environmental risk, we identified peripartum factors such as maternal stress, smoking and viral infections, prematurity and cesarean delivery. Later in the neurodevelopmental course, stressful events and child psychiatric disorders are recognized as increasing the risk of developing BD in adolescence. At-risk symptoms could be classified as "distal" with early but aspecific expressions including anxiety, depression, sleep disturbance, decreased cognitive performance, and more specific "proximal" symptoms which correspond to subsyndromic hypomanic symptoms that increase in intensity as the first episode of BD approaches. Specific clinical expressions have been described to assess the risk of BD in individuals with depression. Irritability, mixed and psychotic features are often observed in the first manic episode. (2) Early screening: some individuals with higher risk need special attention for screening, such as children of people with BD. Indeed, it is shown that children with at least one parent with BD have around 50 % risk of developing BD during adolescence or early adulthood. Groups of individuals presenting other risk factors, experiencing an early stage of psychosis or depressive disorders should also be considered as targeted populations for BD screening. Three questionnaires have been validated to screen for the presence of at-risk symptoms of BD: the Hypomanic Personality Scale, the Child Behavior Checklist-Paediatric Bipolar Disorder, and the General Behavior Inventory. In parallel, ultra-high risk criteria for bipolar affective disorder ("bipolar at-risk") distinguishing three categories of at-risk states for BD have been developed. (3) Early treatment: clinical overlap between first psychotic and manic episode and the various trajectories of the at-risk status have led early intervention services (EIS) for psychosis to reach out for people with an early stage of BD. EIS offers complete biopsychosocial evaluations involving a psychiatric examination, semi-structured interviews, neuropsychological assessments and complementary biological and neuroimaging investigations. Key components of EIS are a youth-friendly approach, specialized and intensive care and client-centered case management model. Pharmaceutical treatments for at-risk individuals are essentially symptomatic, while guidelines recommend the use of a non-antipsychotic mood stabilizer as first-line monotherapy for the first manic or hypomanic episode. Non-pharmacological approaches including psychoeducation, psychotherapy and rehabilitation have proven efficacy and should be considered for both at-risk and first episode of BD. CONCLUSIONS: EIS for psychosis might consider developing and implementing screening and treatment approaches for individuals experiencing an early stage of BD. Several opportunities for progress on early intervention in the early stages of BD can be drawn. Training first-line practitioners to identify at-risk subjects would be relevant to optimize screening of this population. Biomarkers including functional and structural imaging measures of specific cortical regions and inflammation proteins including IL-6 rates constitute promising leads for predicting the risk of transition to full-blown BD. From a therapeutic perspective, the use of neuroprotective agents such as folic acid has shown particularly encouraging results in delaying the emergence of BD. Large-scale studies and long-term follow-up are still needed to achieve consensus in the use of screening and treatment tools. The development of specific recommendations for the early stages of BD is warranted.

Increased risk of suicide attempt in bipolar patients with severe tobacco dependence.

BACKGROUND: The aim of our study was to investigate, in bipolar patients, the association between tobacco status (use and dependence) and history of suicide attempt, and to assess the possible role of inflammation as a missing link in the association between smoking status and history of suicide attempt. METHODS: A total of 453 adult bipolar out-patients recruited in the French FondaMental Advanced Centres of Expertise for Bipolar Disorder were divided into two subgroups: 274 patients without past history of suicide attempt (non-SA), and 179 patients with a past history of suicide attempt (SA). Tobacco use and dependence, psychiatric and somatic comorbidities, history of childhood abuse, family history of suicide were assessed. Fasting blood tests yielded samples collected for the measurement of high sensitivity (hs-)CRP. RESULTS: The risk of suicide attempt increased with smoking dependence. Notably, bipolar patients with a history of suicide attempt were three times more likely to have severe tobacco dependence, independently of confounding factors. However, we failed to find arguments promoting the hypothesis of inflammatory markers (through hs-CRP measure) in the link between tobacco dependence and suicidal behavior. CONCLUSIONS: We found a significant association between severe tobacco dependence and history of suicide attempt, but not with level of CRP, independently of confusing factors. Longitudinal studies taken into account all these potential confusing factors are needed to confirm our results.

Inhibitory control and error monitoring by human subthalamic neurons.

The subthalamic nucleus (STN) has been shown to be implicated in the control of voluntary action, especially during tasks involving conflicting choice alternatives or rapid response suppression. However, the precise role of the STN during nonmotor functions remains controversial. First, we tested whether functionally distinct neuronal populations support different executive control functions (such as inhibitory control or error monitoring) even within a single subterritory of the STN. We used microelectrode recordings during deep brain stimulation surgery to study extracellular activity of the putative associative-limbic part of the STN while patients with severe obsessive-compulsive disorder performed a stop-signal task. Second, 2-4 days after the surgery, local field potential recordings of STN were used to test the hypothesis that STN oscillations may also reflect executive control signals. Extracellular recordings revealed three functionally distinct neuronal populations: the first one fired selectively before and during motor responses, the second one selectively increased their firing rate during successful inhibitory control, and the last one fired selectively during error monitoring. Furthermore, we found that beta band activity (15-35 Hz) rapidly increased during correct and incorrect behavioral stopping. Taken together, our results provide critical electrophysiological support for the hypothesized role of the STN in the integration of motor and cognitive-executive control functions.

[Psychosurgical treatment of malignant OCD: three case-reports]. / Traitement psychochirurgical des TOC malins: à propos de trois cas.

Surgery can be proposed for some patients affected by psychiatric diseases such as severe, disabling and refractory affective disorders (depression), OCD and chronic anxiety states. It can be performed after a period of evolution of minimum 5 Years and after all other classical treatments have failed. For the last Years, different stereotactic techniques have been used: capsulotomy, cingulotomy, subcaudate tractotomy and limbic leukotomy, performed by radiofrequency thermolesions or radiosurgery (g rays). In the case of OCD, these procedures are supposed to affect some of the neural circuits between the frontal lobes and different structures of the limbic system, considered as central to OCD symptoms. As they cause smaller cerebral lesions than earlier surgical techniques (mostly open surgery techniques), modern stereotactic approaches have less clinical side effects, primarily less deficit in emotional reactivity and motivation. This type of treatment offers some hope to patients seriously disabled by OCD. These surgeries and especially their main side effects are mentioned briefly in this Article. The most current indications for psychosurgery are severe OCD and chronic major depressive disorder. The level of stress should be significant and assessed by clinical and social functioning scale scores (for the OCD: Y-BOCS>25, GAF>50). Patients affected by demential disorders, sociopathic or paranoiac personality disorder, substance abuse should be excluded as well as patients aged 65 Years over and less than 18 Years. Several studies evaluating the results of the surgical treatment showed significant improvement in 54% of cases. and a moderate improvement in 27% of them. These results seem unchanged a few Years later in 56% of cases. Despite the lack of controlled trials of neurosurgery and several bias in published reports, evidence suggests that the condition of intractable OCD patients may improve after this surgery. Although capsulotomy and cingulotomy are mainly used, the superiority of any of these four surgical techniques has not been established yet. In this Article, we reported 3 "malignant" OCD cases treated by different psychosurgery techniques: 2 of the cases showed a clinical improvement, whereas the third did not -benefit from surgery. All of them were suffering of OCD since childhood with a gradual clinical impairment, unless the -second patient who presented a severe impairment following an accident causing a ten-day coma. In all three cases social consequences of OCD were important: negative socio-professional and family-life consequences and depressive complication with suicide risk. All patients remained unresponsive or showed a very transient reaction to the other forms of therapy, including varied pharmacotherapy (potentiation pharmacotherapy strategies included), intensive psychotherapy, behavioural therapy and electro-convulsive therapy. Pre- and post-operative assessment included neurological, radiological, psychometric and neuropsychological examination. The free and informed consent of the patient was always required before surgery, notifying the nature of the procedure, the potential risks and outcome. The first patient benefited of a bilateral anterior cingulotomy by thermocoagulation in stereotactic conditions, followed, four years later, by a second complementary one because of a relapse which occurred a few months after the first intervention. A clinical improvement was noticed over a period of two years, though it was not sufficient according to the patient. The second patient benefited of a stereotactic cingulotomy associated with a limbic leucotomy: it was initially efficient on OCD as well as on thymic symptoms. Nevertheless the positive evolution on OCD is not perceived by the patient and has not been assessed until now by clinical rating scales. Anterior cingulotomy is undergone in the third case, who showed a significant improvement. Despite clomipramine administered secondary to the surgery, a slight relapse of obsessive ideas was noticed six months later. The postoperative side effects were transient and regressive after a few months; they were observed especially in the case of tractotomy (oedema and transient frontal syndrome). On the whole, morbidity seemed more important with extensive lesions, whereas recurrence rate may be higher with smaller lesions. We did not observe any consequences on personality or on cognitive functions of these patients. No additional -deficits were observed after surgery. Further research is needed in order to determine the optimal site and size of the lesions in terms of efficacy and safety. Although psychosurgery is still controversial from an ethical view point, this treatment appears to be an ultimate solution for these severe disabled patients. Psychosurgery is a safe and relatively effective treatment which should be carried out by an expert multidisciplinary team in these disorders; surgery should be considered as part of an entire treatment program including an appropriate psychiatric rehabilitation part. Research in this field is currently focused on MRI-guided basal ganglia stimulation techniques which would allow to target specific structures in a reversible way.

[Plasma levels of metapramine and its 3 major metabolites in patients with depression. Results and preliminary interpretations]. / Concentrations plasmatiques de la métapramine et de ses trois principaux métabolites chez des patients déprimés. Résultats et interprétations préliminaires.

Metapramine (Timaxel) and his three major metabolites (19148 RP, 23669 RP, 19749 RP) have been determined in the plasma of 18 depressed inpatients treated by the antidepressant drug (12 women and 6 men; 7 are smokers and 11 non-smokers). In a steady state, interindividual variability is very important, especially for 23669 RP. No significant correlation exists between normalized doses (mg.kg-1) and normalized plasma concentrations (ng.ml-1/dose mg.kg-1) of metapramine or anyone of its metabolites. The plasma metabolic ratios reveal also important intraindividual and interindividual variability. Two populations of patients seem to exist: extensive metabolizers and relatively poor metabolizers, without apparent clinical consequence because 23669 RP shows an antidepressant activity. Women seem, with equal normalized doses, to exhibit higher plasma levels of unchanged metapramine than men, due to a lower protein-binding rather than to a more active metabolism. In patients who received a poly-medication smoking seems not to induce desmethylation of metapramine. The plasma metabolic ratios, compared by the analysis of variance and the Wilcoxon distribution-free test, are significatively influenced by sex and not by tobacco-smoking.