[The link between aggressive behavior and depression in adolescence. A cross-sectional study conducted in the psychiatric emergency unit at the Sainte-Anne hospital]. / Lien entre comportements agressifs et vécu dépressif chez l'adolescent. Une étude transversale menée au centre psychiatrique d'orientation et d'accueil de l'hôpital Sainte-Anne.

INTRODUCTION: The link between depression and aggressive behavior in adults has been found in many studies. In adolescents, this relationship is still controversial. Several studies point out that irritability is a key symptom in adolescent depressed. Few studies have analyzed precisely the kind of aggressive behavior. This study sets out to assess the relationship between aggressive behavior and depressive affects in adolescents. We also pay attention in this population to hopelessness feelings, anxiety, global functioning and the type of aggressive behavior. METHOD: This is a descriptive and observational cross-sectional study. Data was collected from 49 successive adolescents admitted for a 24-hour evaluation in the emergency department of the Sainte-Anne psychiatric hospital. The inclusion period was from February to April 2012, with age limits between 15 and 18. For each patient, the clinician completed with the parents or other caregivers the Modified Overt Aggressive Scale (MOAS) searching for existence of aggressive behavior in the week prior to the consultation. The population was divided into two groups: P- group when the MOAS score was < 3 and the P+ group when the MOAS score was ≥ 3. The Global Assessment of Functioning Scale and Adolescent Depression Rating Scale for clinicians (ADRSc) were also completed. Each patient completed the self-report Buss-Perry Aggression Questionnaire (QA), the Beck Hopelessness scale and the Adolescent Depression Rating Scale for patients (ADRSp). RESULTS: Forty-nine adolescents with a median age of 16 years and 4 months participated. The first reason for consultation was depressive symptoms, followed by disruptive behavior. The analysis was conducted on 39 questionnaires. The demographic profile of the two groups was similar. We did not find any significant difference between the groups P+ and P- on ADRSc scores and secondary criteria. However, we found higher scores in the QA in the more depressed patient, especially a higher hostility score in this sample. In the subgroup analysis: as expected self-aggressive behavior was associated with a higher depression score, more hospitalization and a poor global functioning score. Surprisingly, the patients who showed physical aggression against others had a better prognosis and lower depression scores. DISCUSSION: The study did not conclude on the link between aggressive behavior and depression in this population. The adolescent hostility appears more characteristic of depression compared to other dimensions of aggressivity (anger, verbal aggression, physical aggression) in adolescents. Physical aggression against others appeared not only less typical in depression but was also associated with a better global functioning. Clinicians should pay particular attention to the kind of aggressive behavior in clinical evaluations of adolescents in an emergency context.

[Decision of emergency involuntary hospitalization: categorical or dimensional approach?]. / La décision d'hospitalisation sans consentement aux urgences: approche dimensionnelle ou catégorielle?

BACKGROUND: In 2005, in its recommendations on the modalities of decision making for compulsory hospitalization, the French Health High Authority (HAS) had already stressed the need for rapid implementation of studies and epidemiological analyses on the subject to compensate the lack of adequate data in France. The new French law of July 5, 2011, on the rights and protection of persons under psychiatric care, establishes a judicial review of decisions for compulsory hospitalization. Therefore, healthcare professionals need to better define and characterize the criteria for such decisions, especially in their relation to psychopathology. The concept of capacity to consent to treatment includes the ability to understand (to receive information about the disease), the ability to appreciate (to weigh the risks and benefits of treatment), the ability to reason (determining the best choice rationally) and the ability to freely express a decision. However, assessment tools of capacity to consent to treatment seem to fail to predict the modality of hospitalization. OBJECTIVE: This study examined the impact of clinical and contextual characteristics on the decision in emergency services to admit patients to compulsory inpatient psychiatric units. METHOD: Data was collected from 442 successive patients admitted to hospital for care from five psychiatric emergency facilities in Paris and covered sociodemographic information, previous hospitalizations, recent course of care, clinical diagnosis, Global Assessment of Functioning scale (GAF) and Insight measured by the Q8 Bourgeois questionnaire. Patients were also assessed based on criteria established by the HAS for the severity of mental disorders and the necessity of emergency care. RESULTS: Multivariable logistic regression shows that diagnosis does not affect the decision of hospitalization. Agitation, aggressiveness toward others, being married as well as being referred by a doctor or family are all factors that increase the risk of involuntary hospitalization. Last, low Q8 and GAF scores are strong predictors for compulsory admission. CONCLUSION: Our study shows a dimensional rather than categorical assessment of patients by clinicians. Assessment of insight is the main operational criterion used by clinicians in our study. This supports using insight and GAF evaluation in clinical practice to clarify assessment and decision-making in an emergency setting regarding compulsory hospitalization.

[The practice of restraint in a psychiatric emergency unit]. / Pratique de la contention dans un service d'urgences psychiatriques.

The practice of physical restraint is relatively frequent in medical emergency and geriatric units. Its use in psychiatry is controversial. Although distinct, it is often associated with seclusion, as a response to or prevention of agitated mentally ill patients'behavior. A detailed review of the literature shows the scarceness of work defining the exclusive use of restraint without seclusion. We report a naturalistic study over 6 Months, covering 76 cases having required restraint. The study of the international literature concerns nursing care, geriatric, child-adolescent psychiatric and adult psychiatric reviews. The restraint is a usual practice in general care like emergency, intensive care or geriatric units in order to prevent the patients from falling or to administrate certain care. Legal action has been reported as a consequence of lack of information or agreement of the family. The psychiatric use of restraint is conceived as an additional measure to seclusion, which is a controversial procedure from a therapeutic point of view as well as because of its long duration of application. The practice of restraint described in French literature, from Pinel (in to Daumézon and from French hospital regulations to "transparency forms", seems to be more easily accepted for its short duration and its careful prescription in order to maintain relations with the patients, including agitated children. We made a 6 Months retrospective study in a Parisian psychiatric emergency unit receiving an average of 30 patients a day. The rate of restraint is 1.4%. The objective was to describe the main clinical, epidemiological and situational characteristics and to define quality criteria concerning restraint regarding to the existing standards. We had at our disposal a restraint protocol in order to avoid its prescription as a punishment or for the comfort or the convenience of an insufficient staff. The decision of the restraint is directly prescribed by a physician or decided in emergency by the nurses and then rapidly confirmed by medical prescription. In short, most restrained patients are male, the average age is 32 Years old, and the diagnoses associated with restraint in order of frequency are schizophrenia, personality disorders, acute psychotic episodes, manic episodes and toxic abuses. The main early-warning signs are aggressiveness, delusions, opposition, paranoiac thoughts and distrust. The average duration is 2 hours with continuous clinical supervision and a relational contact maintained. Our study confirms the notion of cumulate restraint days. Actually, 43% of the restraints happen on the same day as others do. The high rate on those days could be as Fischer hypothesized the result of instinctive, aggressive and sexual release of the staff, as well as the consequence of an increase in anxiety and agitation of the other patients. The legal framework is more the duty of assistance to a person in danger than constrained hospitalization, which is not systematically pronounced. No injury or somatic complication occurred during restraint. Neither complaint from the patient or his family nor sick leave of staff was recorded. The specific use of restraint can be compared to the existing standards for using the seclusion room. Among those standards only 1 of 23 criteria was not verified. The others was applicable or without object. The therapeutic use of restraint requires the development of specific quality standards, and the existing criteria concerning seclusion represent a necessary but insufficient answer. We emphasize the need to take into account the early warning signs, a response to the cumulative restraint days, as well as a satisfaction study on patients and the feasibility of such a study in an emergency service.

[Antipsychotics in bipolar disorders]. / Antipsychotiques et troubles bipolaires.

This article is a review of the various treatments that are currently available, in particular in France, for the treatment of bipolar disorders. This article specifically addresses the use of novel antipsychotic agents as alternative therapy to a lithium therapy and/or the use of conventional antipsychotics. The prevalence of bipolar disorder over a lifetime is around 1% of the general population. Bipolar disorder consists of alternating depressive and manic episodes. It mainly affects younger subjects, and is often associated with alcohol and drug addictions. There are two main subtypes of bipolar disorder. According to the DSM IV-R, type 1 of bipolar disorder is characterised when at least one manic episode (or a mixed episode) has been diagnosed. Type 2 of bipolar disorder is related to patients enduring recurrent depressive episodes but no manic episode. Type 2 affects women more frequently as opposed to type 1 affecting individuals of both sexes. Manic-depressive disorder (or cyclo-thymic disorder) appears in relation to patients who has never suffered manic episode, mixed episode or severe depressive episode but have undergone numerous periods with some symptoms of depression and hypomanic symptoms over a two-year period during which any asymptomatic periods last no longer than two months. The average age of the person going through a first episode (often a depressive one) is 20 years-old. Untreated bipolar patients may endure more than ten manic or depressive episodes. Finally, in relation to 10 to 20% of patients, the bipolar disorder will turn into a fast cycle form, either spontaneously or as a result of certain medical treatments. Psychiatrists are now able to initiate various treating strategies which are most likely to be effective as a result of the identification of clinical subtypes of the bipolar disorder. Lithium therapy has been effectively and acutely used for patients with pure or elated mania and its prophylaxis. However, lithium medication may worsen depressive symptoms when used for a long term maintenance therapy. Additionally, mixed mania, rapid cycling type patients and bipolar disorder associated with substance abuse do not respond well to lithium therapy. In addition to the lithium therapy or in place of a lithium therapy, one can report the frequent use of antipsychotic agents in respect of patients with bipolar disorder during both the acute and maintenance phases of treatment. Antipsychotic agents have been used for almost forty years and may be used in combination with a lithium therapy. Conventional antipsychotics are effective but they may induce late dyskinesia, weight gain, sedation, sexual dysfunction and depression. These adverse side effects often lead to non compliance in particular in circumstances where antipsychotic agents are combined with a lithium therapy. A number of alternative somatic treatment approaches have been reported for patients who do not respond well or who are intolerant to lithium therapy. As such, valproate has received regulatory approval for the acute treatment of mania and carbamazepine has been indicated for this condition in a number of countries. Divalproex (Depakote) has recently obtained the authorization to market in France and may be prescribed for manic states or hypomanic states that do not tolerate lithium therapy or for which lithium therapy is contraindicated. A number of other anticonvulsants (lamotrigine, gabapentin and topiramate) are currently being tested. Because of the side effects of the conventional antipsychotic agents, atypical antipsychotic agents are currently on trial and appear to be of interest in the treatment of bipolar disorders. Currently, a number of prospective studies are available with clozapine, risperidone and olanzapine in the treatment of bipolar disorder. Most are short-term studies. Recent randomised, double-blind, placebo-controlled studies have shown clozapine, risperidone and olanzapine to be effective with antimanic and antidepressive effects, both as monotherapy and as add-on maintenance therapy with lithium or valproate. They also have a favorable side effect profile and a positive effect on overall functioning. Similarly, valproate combined with antipsychotics provides greater improvement in mania than antipsychotic medication alone and results in lower dosage of the antipsychotic medication. There is currently no double-blind study regarding the use of clozapine for bipolar disorders. However, based on the results of a number of open-label studies, clozapine appears to be effective in relation to schizo-affective and bipolar patients including those with rapid cycling or those who respond inadequately to mood stabilizers, carbamazepine, valproate or conventional antipsychotics. Clozapine seems to be more appropriate for bipolar and schizo-affective patients than schizophrenics. In particular, studies show that patients with manic and mixed-psychotic state of illness are better responders than patients with major depressive syndromes. Four open studies suggest the efficacy of clozapine in the maintenance treatment of bipolar disorder and three prospective, open-label studies show the efficacy of clozapine in the manic state of the illness. However, the number of patients in the studies was not important and these studies are not controlled. Clozapine has also adverse side affects, one of which consisting of a major risk of agranulocytosis and, potentially, death. In addition, clozapine has been shown to produce significant weight gain and sialorrhea as well as significant anticholinergic effects. As a result, clozapine should not be prescribed in the first place. As opposed to clozapine, there are open-label reports and controlled studies in respect of risperidone and olanzapine. Two recent double-blind studies of acute mania found olanzapine to be more effective than placebo. Based on these two studies, olanzapine has recently been approved for the indication of mania. The effects of olanzapine and divalproex in the treatment of mania have also been compared in a large randomized clinical trial. The olanzapine treatment group had significantly greater mean improvement of mania ratings and a significantly greater proportion of patients achieving protocol-defined remission. Significantly more weight gain and cases of dry mouth, increased appetite and somnolence were reported with olanzapine while more cases of nausea were reported with divalproex. The comparison of olanzapine with lithium for the treatment of mania has also been the subject of a double-blind randomized controlled trial. That study shows no differences between the two drugs. While these studies support the idea that olanzapine has direct acute anti-manic effects, a number of authors are of the opinion that olanzapine may have specific prophylactic mood-stabilizing properties. Olanzapine would appear to be effective in the maintenance treatment, as it exhibited both antimanic and antidepressant effects. Systematic trials have shown that risperidone may be effective and safe in the treatment of acute mania, as an add-on therapy with lithium or valproate (open studies and two controlled double-blind studies) and as monotherapy (open studies). In an open, multi-center, 6-month study, risperidone seems to be effective and safe as long-term adjunctive therapy in treatment-resistant bipolar and schizo-affective disorders, with no exacerbation of manic symptoms. Risperidone had few adverse side effects (and where there were any, they were mostly mild), mostly consisting of APS and weight gain. A naturalistic comparison of clozapine, risperidone and olanzapine in the treatment of bipolar disorder suggests that the efficacy and tolerability of the three treatments are similar. One major differentiation factor of these drugs appears to be weight gain, particularly between olanzapine and risperidone. However, this may partially be caused by the use of mood-stabilizing agents. Bipolar and schizo-affective patients now require combination therapy approach because of the cyclic nature of these disorders. Many studies report the combination of mood-stabilizing agents with conventional antipsychotics and atypical antipsychotics. Combination therapies produce a number of adverse side effects. Atypical antipsychotics (other than clozapine) are now rated as first-line agents for adjunctive treatment of mania because they produce less adverse side effects. Atypical antipsychotics are also rated as first-line agents for combined treatment of psychotic depression and they are strongly preferred when an antipsychotic is required for long-term maintenance.

Evaluation of SQ 34,514: pharmacokinetics and efficacy in experimental herpesvirus infections in mice.

The new antiviral nucleoside SQ 34,514 [(1R-1 alpha, 2 beta, 3 alpha)-2-amino-9- [2,3-bis(hydroxymethyl)cyclobutyl]-6H-purin-6-one], the active R isomer of racemic SQ 33,054 (cyclobut-G), was evaluated for efficacy in the treatment of herpesvirus infections in mice. SQ 34,514 was orally efficacious in a herpes simplex virus type 1 (HSV-1) systemic infection, an intracerebral HSV-2 infection, a vaginally induced HSV-2 infection in ovariectomized mice, and in a systemic murine cytomegalovirus infection. SQ 34,514 compared favorably with acyclovir and ganciclovir in the treatment of these experimental infections. In mice, SQ 34,514 had an oral bioavailability of 80% based on urinary excretion. SQ 34,514 may have potential value in the therapy of HSV and cytomegalovirus infections in humans.

Synthesis and antiviral activity of enantiomeric forms of cyclobutyl nucleoside analogues.

The syntheses of the enantiomeric cyclobutyl guanine nucleoside analogues [1R-1 alpha, 2 beta, 3 alpha]- and [1S-1 alpha, 2 beta, 3 alpha]-2- amino-9-[2,3-bis(hydroxymethyl)cyclobutyl]-6H-purin-6-one (7 and 8, respectively) and the enantiomeric cyclobutyl adenine analogues [1R-1 alpha, 2 beta, 3 alpha]- and [1S-1 alpha, 2 beta, 3 alpha]-6-amino-9-[2,3-bis(hydroxymethyl) cyclobutyl]purine (9 and 10, respectively) are described. trans-3,3-Diethoxy-1,2-cyclobutanedicarboxylic acid (14) was coupled with R-(-)-2-phenylglycinol to provide a mixture of diastereomeric bis-amides, 15a and 15b, which was readily separated by crystallization. Conversion of each bis-amide to the corresponding diol enantiomer, 16a and 16b, respectively, was effected by a facile three-step sequence in high overall yield. Homochiral diol 16a was converted in a straightforward manner to 7 and 9, and homochiral diol 16b was similarly converted to the corresponding optical isomers 8 and 10. Compounds 7 and 9, which mimic the absolute configuration of natural nucleosides, are highly active against a range of herpesviruses in vitro while the isomers of opposite configuration, 8 and 10, are devoid of antiherpes activity. The corresponding triphosphates of 7 and 8 (7-TP and 8-TP) were prepared enzymatically. Compound 7-TP selectively inhibits HSV-1 DNA polymerase, compared to human (HeLa) DNA polymerase, while 8-TP is much less inhibitory than 7-TP against both types of enzymes. Compounds 7 and 9 are efficacious in a mouse cytomegalovirus model infection.

(+-)-(1 alpha,2 beta,3 alpha)-9-[2,3-bis(hydroxymethyl)-cyclobutyl] guanine [(+-)-BHCG or SQ 33,054]: a potent and selective inhibitor of herpesviruses.

(+-)-(1 alpha,2 beta,3 alpha)-9-[2,3-bis(hydroxymethyl)cyclobutyl] guanine [(+-)-BHCG or SQ 33,054] is a newly synthesized nucleoside analog with potent and selective antiviral activity against members of the herpesvirus group, including human cytomegalovirus. The activity against a thymidine kinase deficient HSV-2 mutant was 25-fold poorer than against the parent virus, suggesting that phosphorylation is an important prerequisite for antiviral activity against HSV-2. (+-)-BHCG is readily phosphorylated by purified HSV-1 thymidine kinase, and BHCG triphosphate synthesized enzymatically is a selective inhibitor of HSV-1 DNA polymerase. (+-)-BHCG did not inhibit host cell growth at concentrations at least 1000-fold higher than HSV-2 inhibitory concentrations. Subcutaneous administration of (+-)-BHCG was protective against HSV-1 systemic infections in mice. BHCG is an exciting antiviral agent and represents a new class of nucleoside analogs.

The determinants of mothers' knowledge of the Down syndrome before genetic counseling: part II.

Mothers coming for genetic counseling because they have an infant with the Down syndrome (DS) vary in their amount of knowledge about the cause, recurrence risk, and options for dealing with the recurrence risk. The purpose of this work has been to determine some predictors of the variability in mothers' knowledge of the DS before coming to genetic counseling. Data were collected before counseling through a detailed interview concerning mothers' knowledge of the DS, their demographic background, fertility plan, and attitude toward family planing. These data were "reduced" by multiple-regression analysis, to 7 variables used in a prediction equation for mothers' level of pre-knowledge attainment. These variables were then used to construct a model which was tested by path analysis. Results of analyses showed that about 2/3 of the variance in mothers' pre-knowledge of the DS could be accounted for by 5 independent variables: 1) time from diagnosis to counseling session, 2) date of counseling session, 3) nonreporting of emotional upset, 4) education-occupational status (EOS), and 5) utilization of birth control methods. These findings led to the conclusion that what occurs before counseling is of importance for the outcome of genetic counseling, as measured by the genetic information acquired by the counselees. Some precounseling precedures are suggested on how genetic counselors might be able to gain more control over the important factors that occur before actual counseling.

PIP: There is great variability among mothers coming for genetic counseling because they have an infant with Down syndrome. Data were collected from 47 mothers of children with this disease who had reported to Indiana University Medical Center or Methodist Hospital of Indiana for genetic counseling. It was found that the mothers varied in their knowledge of the disease, the cause, recurrence risk, and options for dealing with a recurrence. Precounseling information was collected on the mothers' knowledge, their demographic backgrounds, fertility plans, and attitude toward family planning. 2/3 of the variance in the mothers' preknowledge could be accounted for by 5 independent variables: 1) the elapsed time between diagnosis and counseling; 2) the data of the counseling session; 3) nonreporting of emotional upset; 4) educational/occupational status; and 5) use of birth control methods. The relationships among these variables is diagrammed. As a result of this study, it was recommended that more precounseling education regarding the disease be provided and that more time elapse between the diagnosis and the counseling session to allow the parents time to educate themselves. These 2 improvements in the counseling process might improve the levels of information and the attitudes gained from the session.

Development of instruments to measure counselees' knowledge of Down syndrome.

Since approximately 10% of counselees coming to genetics clinics are concerned with Down syndrome, the development of short measures of knowledge of Down syndrome for evaluation could have widespread application. The purpose of this study was to design efficient, self-administered questionnaires of simple vocabulary to measure knowledge and understanding of Down syndrome before and after genetic counseling. Twenty-six previously piloted questions were administered to nurses, graduate students in Medical Genetics, special education teachers, and parents of children with Down syndrome (n = 126). A coefficient alpha of 0.842 indicated strong reliability. The content of the questionnaire was distributed into three categories: genetic knowledge, recurrence risk, and prenatal diagnosis. From the items (1) which had less than 85% correct responses, and (2) which fell into just one of the three categories, 12 questions were selected as a post-test (coefficient alpha of 0.749). Eight additional questions were then extracted (coefficient alpha of 0.56) as a pretest. The pretest predicted 53.3% of the variance of the post-test. The use of these instruments before and after counseling can be an aid in evaluating counseling and in comparing various approaches for effectiveness.