Angèle Consoli

Adverse effects of second-generation antipsychotics in children and adolescents: a Bayesian meta-analysis.

Abstract In adults, second-generation antipsychotics (SGAs) have a low frequency of extrapyramidal syndrome (EPS) and a moderate frequency of metabolic adverse effects. Here we aimed to assess short-term adverse effects of SGAs in children and adolescents. We searched for relevant studies in MEDLINE and EMBASE (1996–2010), Food and Drug Administration and European Medicines Agency clinical trial registries, and reference lists of review articles. We found 41 were short-term (3–12 weeks) controlled studies that evaluated SGA adverse effects in youths. Using Bayesian meta-analysis, we analyzed odds ratios (ORs) or mean average effects. Numbers of arms (subjects) in the 41 trials were aripiprazole, 10 (n = 671); olanzapine, 14 (n = 413); quetiapine, 10 (n = 446); risperidone, 25 (n = 1040); ziprasidone, 4 (n = 228); clozapine, 5 (n = 79); and placebo/untreated, 23 (n = 1138), totaling 93 arms (4015 patients). Clozapine was assessed only for weight gain and somnolence. Compared with placebo, significant treatment-related increases were observed for weight gain with olanzapine (mean ± SD = 3.99 ± 0.42 kg; 95% credible interval, 3.17–4.84 kg), clozapine (2.38 ± 1.13 kg; 95% credible interval, 0.19–4.62 kg), risperidone (2.02 ± 0.32 kg; 95% credible interval, 1.39–2.66 kg), quetiapine (1.74 ± 0.38 kg; 95% credible interval, 0.99–2.5 kg), and aripiprazole (0.89 ± 0.32 kg; 95% credible interval, 0.26–1.51 kg); glucose levels with risperidone (3.7 ± 1.36 mg/dL; 95% credible interval, 1.08–6.42 mg/dL) and olanzapine (2.09 ± 1.08 mg/dL; 95% credible interval, 0.13–4.32 mg/dL); cholesterol levels with quetiapine (10.77 ± 2.14 mg/dL; 95% credible interval, 6.6–14.95 mg/dL) and olanzapine (4.46 ± 1.65 mg/dL; 95% credible interval, 1.24–7.73 mg/dL); triglyceride levels with olanzapine (20.18 ± 5.26 mg/dL; 95% credible interval, 9.85–30.53 mg/dL) and quetiapine (19.5 ± 3.92 mg/dL; 95% credible interval, 11.84–27.17 mg/dL); hyperprolactinemia with risperidone (OR, 38.63; 95% credible interval, 8.62–125.6), olanzapine (OR, 15.6; 95% credible interval, 4.39–41.1), and ziprasidone (OR, 9.35; 95% credible interval, 1.24–37.03); and EPS with ziprasidone (OR, 20.56; 95% credible interval, 3.53–68.94), olanzapine (OR, 6.36; 95% credible interval, 2.43–13.84), aripiprazole (OR, 3.79; 95% credible interval, 2.17–6.17), and risperidone (OR, 3.71; 95% credible interval, 2.18–6.02). All SGAs increased the risk of somnolence/sedation. We conclude that short-term metabolic effects and EPS are frequent in children treated with SGAs. Second-generation antipsychotics have distinct profiles of secondary effects, which should be considered in making treatment decisions.

Malignant catatonia due to anti-NMDA-receptor encephalitis in a 17-year-old girl: case report

Anti-NMDA-Receptor encephalitis is a severe form of encephalitis that was recently identified in the context of acute neuropsychiatric presentation. Here, we describe the case of a 17-year-old girl referred for an acute mania with psychotic features and a clinical picture deteriorated to a catatonic state. Positive diagnosis of anti-NMDA-receptor encephalitis suggested specific treatment. She improved after plasma exchange and immunosuppressive therapy. Post-cognitive sequelae (memory impairment) disappeared within 2-year follow-up and intensive cognitive rehabilitation.

Association of adolescent catatonia with increased mortality and morbidity: evidence from a prospective follow-up study.

This paper examined outcomes among youth with catatonic syndrome and determined whether the characteristics suggesting the relevance of chronic catatonic schizophrenia (CCS) at index episode remained stable at follow-up. From 1993 to 2004, 35 individuals aged 12 to 18 years were prospectively admitted for management of catatonic syndrome and followed up after discharge. Mean duration from discharge to follow-up was 3.9 years (range 1-10). Four patients were lost to follow-up. Among the remaining 31 subjects (mean age=19.5 years, range 15-26), life-time diagnosis using the Diagnostic Interview for Genetic Studies was unchanged in 28 patients, and included schizophrenia (all subtypes; N=20), major depressive episode (N=5), bipolar disorder type I (N=4) and brief psychotic episode (N=2). Mortality (all-cause Standardized Mortality Ratio=6266; 95% CI=1181-18,547) and morbidity were severe, with 3 deaths (including 2 suicides), 6 patients presenting with a causal organic condition and 14 subjects needing continuous psychiatric care. All males in the study (N=8) who had chronic catatonic schizophrenia at the index episode still had chronic catatonic signs at follow-up. Catatonia is one of the most severe psychiatric syndromes in adolescents. It is associated with a 60-fold increased risk of premature death, including suicide, when compared to the general population of same sex and age. This increased risk of premature death remains higher than the one measured in former adolescent psychiatric patients (all-cause SMR=221; 95% CI=156-303; Engqvist and Rydelius, 2006), or in schizophrenia irrespective to age and subtype (all-cause SMR=157; 95% CI=153-160; Harris and Barraclough, 1998).

Moderate clinical improvement with maintenance ECT in a 17-year-old boy with intractable catatonic schizophrenia

The use of electro-convulsive therapy (ECT) in adolescents is controversial, and few studies have been conducted to assess its efficacy and safety in this population. We report the case of a 19-year-old boy who received two series of ECT, one at 15 and another at 16, for intractable catatonic schizophrenia. Since the age of 17, he has required treatment combining clozapine and maintenance ECT. The course showed a sustained moderate improvement. The treatment permitted the patient to regain some autonomy with moderate adverse effects. ECT remains an uncommon treatment in adolescents, and the current case supports the view that it should not be banned in young people.

Treatments in child and adolescent bipolar disorders

The existence of bipolar disorder in adolescents is now clearly established. However, whether bipolarity exists in children is more controversial. We reviewed the literature on acute and prophylactic treatment of bipolar disorder in youths. The guidelines for the treatment of bipolar disorder in children and adolescents are generally similar to those applied in adult practice. But no evidence-based data support the use of mood stabilisers or antipsychotics since we only found two placebo-randomised controlled trials testing the efficacy of lithium in the paediatric literature. Therefore, we support the view that prescriptions should be limited to the most typical cases. In fact, the use of mood stabilisers or antipsychotics in the treatment of bipolar disorder in children and adolescents appears to be of limited use when a comorbid condition, such as attention deficit hyperactivity disorder, occurs unless aggressive behaviour is the target symptom.

Suicidal behaviors in depressed adolescents: role of perceived relationships in the family

ContextSuicide is the second leading cause of death in adolescents and young adults in Europe. Reducing suicides is therefore a key public health target. Previous studies have shown associations between suicidal behaviors, depression and family factors.ObjectiveTo assess the role of family factors in depression and suicidality in a large community-based sample of adolescents and to explore specific contributions (e.g. mother vs. father; conflict vs. no conflict; separation vs. no separation) taking into account other risk factors.MethodsA cross-sectional sample of adolescents aged 17 years was recruited in 2008. 36,757 French adolescents (18,593 girls and 18,164 boys) completed a questionnaire including socio-demographic characteristics, drug use, family variables, suicidal ideations and attempts. Current depression was assessed with the Adolescent Depression Rating Scale (ADRS). Adolescents were divided into 4 groups according to suicide risk severity (grade 1 = depressed without suicidal ideation and without suicide attempts, grade 2 = depressed with suicidal ideations and grade 3 = depressed with suicide attempts; grade 0 = control group). Multivariate regressions were applied to assess the Odds Ratio of potential risk factors comparing grade 1, 2 or 3 risk with grade 0.Results7.5% of adolescents (10.4% among girls vs. 4.5% among boys) had ADRS scores compatible with depression; 16.2% reported suicidal ideations in the past 12 months and 8.2% reported lifetime suicide attempts. Repeating a year in school was significantly associated to severity grade of suicide risk (1 and 3), as well as all substance use, tobacco use (severity grades 2 and 3) and marijuana use (severity grade 3), for girls and boys. After adjustment, negative relationships with either or both parents, and parents living together but with a negative relationship were significantly associated with suicide risk and/or depression in both genders (all risk grades), and Odds Ratios increased according to risk severity grade.ConclusionFamily discord and negative relationship with parents were associated with an increased suicide risk in depressed adolescents. So it appears essential to take intrafamilial relationships into account in depressed adolescents to prevent suicidal behaviours.

Electroconvulsive therapy in adolescents with the catatonia syndrome: efficacy and ethics.

Objectives: In child and adolescent psychiatry, catatonia is infrequent, but it is one of the most severe syndromes, characterized by the coexistence of psychic and motor symptoms. In this report, we explore the therapeutic experience with electroconvulsive therapy (ECT) in adolescents with catatonia. Methods: We review the literature (1985-2009) to clarify issues related to the use of ECT in child and adolescent patients with catatonia. Results: Electroconvulsive therapy is used as second-line management after high-dose benzodiazepine trials. Electroconvulsive therapy is an effective, safe, and useful procedure in the treatment of catatonic youngsters as reported in 59 patients. Ethical issues regarding the use of ECT are analyzed and their implications briefly discussed in the light of general medical ethics. Conclusions: Electroconvulsive therapy is a safe and effective treatment for catatonia in children and adolescents.

Acute behavioral crises in psychiatric inpatients with autism spectrum disorder (ASD): Recognition of concomitant medical or non-ASD psychiatric conditions predicts enhanced improvement

During adolescence, some individuals with autism spectrum disorder (ASD) engage in severe challenging behaviors, such as aggression, self-injury, disruption, agitation and tantrums. We aimed to assess risk factors associated with very acute behavioral crises in adolescents with ASD admitted to a dedicated neurobehavioral unit. We included retrospectively in 2008 and 2009 29 adolescents and young adults with ASD hospitalized for severe challenging behaviors and proposed a guideline (Perisse et al., 2010) that we applied prospectively for 29 patients recruited for the same indications between 2010 and 2012. In total, 58 patients were admitted (n=70 hospitalizations, mean age=15.66 (±4.07) years, 76% male). We systematically collected data describing socio-demographic characteristics, clinical variables (severity, presence of language, cognitive level), comorbid organic conditions, etiologic diagnosis of the episode, and treatments. We explored predictors of Global Assessment Functioning Scale (GAFS) score and duration of hospitalization at discharge. All but 2 patients exhibited severe autistic symptoms and intellectual disability (ID), and two-thirds had no functional verbal language. During the inpatient stay (mean=84.3 (±94.9) days), patients doubled on average their GAFS scores (mean=17.66 (±9.05) at admission vs. mean=31.4 (±9.48) at discharge). Most common etiologies for acute behavioral crises were organic causes [n=20 (28%), including epilepsy: n=10 (14%) and painful medical conditions: n=10 (14%)], environmental causes [n=17 (25%) including lack of treatment: n=11 (16%) and adjustment disorder: n=6 (9%)], and non-ASD psychiatric condition [n=33 (48%) including catatonia: n=5 (7%), major depressive episode: n=6 (9%), bipolar disorder: n=4 (6%), schizophrenia: n=6 (9%), other/unknown diagnosis: n=12 (17%)]. We found no influence of age, gender, socio-economic status, migration, level of ID, or history of seizure on improvement of GAFS score at discharge. Severity of autism at admission was the only negative predictor (p<.001). Painful medical conditions (p=.04), non-ASD psychiatric diagnoses (p=.001), prior usage of specialized ASD care programs (p=.004), functional language (p=.007), as well as a higher number of challenging behaviors upon admission (p=.001) were associated with higher GAFS scores at discharge. Clinical severity at admission, based on the number of challenging behaviors (r=.35, p=.003) and GAFS score (r=-.32, p=.008) was correlated with a longer inpatient stay. Longer hospitalization was however correlated (r=.27, p=.03) with higher GAFS score at discharge even after adjustment for confounding factors. Challenging behaviors among adolescents with ASD may stem from diverse risk factors, including environmental problems, comorbid acute psychiatric conditions, or somatic illness such as epilepsy or acute pain. The management of these behavioral challenges requires a unified, multidisciplinary approach.

Plasma Exchange in Patients with Stuporous Catatonia and Systemic Lupus Erythematosus

gomery-Asberg Depression Rating Scale, the Brief Psychiatric Rating Scale and the SLE Disease Activity Index (SLEDAI) [6] . Because of their clinical specificity, the CRS and the SLEDAI were the primary variables. For the comparison of preand postclinical scores, we used a nonparametric test which needs a minimum of 5 patients to reach a 0.05 significance. During the course of the study, 5 patients were admitted with SLE and catatonia. These 5 patients, all female, met the inclusion criteria. All of them (or their families on their behalf) agreed to PE. Three of the patients were teenagers who had been hospitalized for several weeks without any improvement, receiving a treatment regimen combining psychotropic medications, corticoids and immunosuppressors. Three patients exhibited life-threatening complications: 2 were severely malnourished and the third had a pulmonary infection and skin lesions due to immobility. One patient showed a severe renal involvement. The last patient was included because of resistance after 3 weeks of treatment. Table 1 summarizes the demographic, clinical and biological characteristics, and treatments of all subjects both before and after PE. All patients had severe depression with psychotic and catatonic features. The number of catatonic signs ranged from 6 to 12, with staring, negativism and withdrawal being present in all 5 patients, and catalepsy, stupor, mutism and refusal to eat in 4. Regarding SLE, the clinical and biological manifestations varied across individuals and included asthenia (n = 5), polyarthralgia (n = 3), renal involvement (n = 3), cutaneous lesions (n = 3), weight loss (n = 2), myalgia (n = 1), generalized adenopathy (n = 1) and melena (n = 1). One patient had an abnormal neurological examination limited to moderate ataxia. All patients had biological features of SLE. Routine biological and hematological tests showed anemia (n = 3), thrombocytopenia (n = 2), lymphopenia (n = 2) and proteinuria (n = 3). The cerebrospinal fluid showed biochemical abnormalities in 3 patients but none of them had monoclonal immunoglobulin G or cell increase. MRI scans showed abnormalities in 3 patients, including cortical atrophy (n = 2) and T 2 -weighted hyperintensities of the frontal lobes (n = 1). The mean number of PE that patients received was 7.2 (range: 3–11). We found a significant improvement for all clinical variables. Mean CRS and SLEDAI scores before PE were 15 (range: 11–16) and 18.8 (range: 12–22), respectively. Both scores dramatically decreased after PE to a mean of 1.2 (range: 0–6) and 3.4 (range: 0–12), respectively (Wilcoxon paired test: Z = –2.032, p = 0.042). In particular, 3 patients very much improved on the Clinical Global Impression Scale after the first week of PE. The biological variables paralleled clinical improvement. At follow-up, 4 patients were still doing well; in particular, all the teenagers were able to return to school with minimal treatment for SLE. The last patient (case 4) died in her local hospital as a consequence of a septic shock 3 months after discharge. To date, only a few case studies have reported the possible use of PE in neuropsychiatric SLE [7, 8], but catatonia was not explored. Therapeutic approaches to catatonia are mainly symptomatic. It is recommended (a) to use high doses of benzodiazepines or sedative drugs, and (b) to apply ECT in case of resistance or life-threatening conditions [1] . However, treatment of associated disorders may improve psychomotor symptoms as well. This is important when there are organic causes. Therefore, etiopathogenic investigations are mandatory when catatonia occurs [9] . In the cases studied here, benzodiazepines were inefficient, and ECT was not considered because of the associated SLE. The report that PE was an efficient treatment option for pediatric autoimmune neuropsychiatric disorders associCatatonia is a rare but severe psychiatric condition. The most frequent causes are psychiatric diseases (e.g. schizophrenia), but organic causes should be considered as well (e.g. Wilson’s disease) [1] . The recommended treatments are symptomatic and include the use of sedative drugs and electroconvulsive therapy (ECT) [1] . Although rare cases of catatonia have been described in systemic lupus erythematosus (SLE) [2] , catatonia was not included in the recent nomenclature of neuropsychiatric SLE [3] . In a recent report, we showed that plasma exchanges (PE) could be an efficient treatment option for catatonic manifestations of SLE, avoiding the use of ECT [4] . The aim of the present study was to assess the efficacy of PE for severely resistant patients with catatonia and SLE in an open trial. The consecutive patients were recruited at Pitié-Salpêtrière Hospital from 2001 to 2004. For inclusion, the diagnosis of SLE was based on the revised criteria of the American College of Rheumatology [3] . The diagnosis of catatonia was made based on at least two catatonic motor signs, or one catatonic motor sign (catalepsy, stupor, posturing, waxy flexibility, staring, stereotypies, psychomotor excitement, automatic compulsive movements, muscular rigidity, echopraxia) combined with a nonmotor catatonic symptom indicative of severely impaired behavioral and emotional functioning (withdrawal, mutism, mannerism, echolalia, incontinence, verbigeration, refusal to eat) [5] . Clinical examinations by a psychiatrist and a physician specializing in internal medicine were repeated as needed. Psychiatric diagnoses were based on DSM-IV criteria. Additional investigations always included routine hematological tests, immunological investigations, studies of cerebrospinal fluid, electroencephalography, and neuroimaging. All patients received a symptomatic psychiatric treatment (benzodiazepine for motor symptoms, antidepressant for depression, atypical neuroleptic for psychosis and mood stabilizer for bipolarity) combined with (a) high-dose intravenous methylprednisone (1 g/day ! 3) followed by oral prednisone (1 mg/kg/day), and (b) monthly pulse cyclophosphamide (0.7 g/m 2 ) or azathioprine (2– 3 mg/kg/day). In case of life-threatening conditions, severe complications of SLE or resistance to pharmacotherapy for 3 weeks, patients were asked to receive PE and written consent was obtained (from them or their families). PE (60 ml/kg) was given 2–3 times per week. Treatment efficacy was monitored using the Clinical Global Impression-Severity Scale, the Global Assessment of Functioning Scale, the modified Bush-Francis Catatonia Rating Scale (CRS) [5] , the Mont-

The Use of Oxytocin to Improve Feeding and Social Skills in Infants With Prader–Willi Syndrome

BACKGROUND AND OBJECTIVES: Patients with Prader–Willi syndrome (PWS) display poor feeding and social skills as infants and fewer hypothalamic oxytocin (OXT)-producing neurons were documented in adults. Animal data demonstrated that early treatment with OXT restores sucking after birth. Our aim is to reproduce these data in infants with PWS. METHODS: We conducted a phase 2 escalating dose study of a short course (7 days) of intranasal OXT administration. We enrolled 18 infants with PWS under 6 months old (6 infants in each step) who received 4 IU of OXT either every other day, daily, or twice daily. We investigated the tolerance and the effects on feeding and social skills and changes in circulating ghrelin and brain connectivity by functional MRI. RESULTS: No adverse events were reported. No dose effect was observed. Sucking assessed by the Neonatal Oral-Motor Scale was abnormal in all infants at baseline and normalized in 88% after treatment. The scores of Neonatal Oral-Motor Scale and videofluoroscopy of swallowing significantly decreased from 16 to 9 (P < .001) and from 18 to 12.5 (P < .001), respectively. Significant improvements in Clinical Global Impression scale scores, social withdrawal behavior, and mother–infant interactions were observed. We documented a significant increase in acylated ghrelin and connectivity of the right superior orbitofrontal network that correlated with changes in sucking and behavior. CONCLUSIONS: OXT is well tolerated in infants with PWS and improves feeding and social skills. These results open perspectives for early treatment in neurodevelopment diseases with feeding problems.