Attention-deficit/hyperactivity disorder (ADHD) symptoms and suicidality in children: The mediating role of depression, irritability and anxiety symptoms.

BACKGROUND: Attention-deficit/hyperactivity disorder (ADHD) is associated with increased suicidality risk. Yet, potential mechanisms transmitting the effect of ADHD to suicidality remain unclear. We investigated whether depression, irritability and anxiety symptoms mediate between ADHD symptoms and suicidality. METHODS: ADHD, depression, irritability and anxiety symptoms as well as suicidality (composited of suicidal ideation, attempts or self-harm) were measured in an outpatient clinic for ADHD (N = 1,516, 6-17 years old, 61.1% diagnosed with ADHD) using parent and teacher questionnaires. Multiple mediator models adjusted for age, sex and psychosocial adversities were constructed separately for parent- and teacher-report. RESULTS: Parents reported higher rates of suicidality than did teachers (12.1% and 3.8%, p < .001). Suicidality was associated with parent (OR = 1.10, 95%CI: 1.07-1.14) and teacher (OR = 1.08, 95%CI: 1.03-1.15) reported ADHD symptoms. The association between ADHD symptoms and suicidality was mediated by both parent- and teacher-reported depression (39.1% and 45.3% of total effect, respectively) and irritability symptoms (36.8% and 38.4% of total effect, respectively). Anxiety symptoms mediated between ADHD and suicidality for parent- but not teacher-report (19.0% of total effect). No direct effect of ADHD symptoms was found once depression, irritability and anxiety were controlled. LIMITATIONS: The cross-sectional design limits the ability to determine causal order between mediators and outcome. CONCLUSIONS: Our results confirmed the association between ADHD symptoms and suicidality. However, this association was indirect and fully mediated by symptoms of depression, irritability and anxiety. Assessing these symptoms may enable an estimate of suicidality and help managing suicidal risk in ADHD.

Clinical Features of Pediatric Complex Regional Pain Syndrome: A 5-Year Retrospective Chart Review.

OBJECTIVES: Complex regional pain syndrome (CRPS) is a painful condition of a limb characterized by a constellation of symptoms. Little is known about the clinical features of pediatric CRPS, with fewer than a dozen studies published to date. The aim of this study was to explore the clinical course of pediatric CRPS, with emphasis on clinical features and disease outcomes. A secondary aim was to discern differences in clinical features of pediatric CRPS with and without related movement disorders, and between children who had a favorable and unfavorable outcome. MATERIALS AND METHODS: We carried out a retrospective chart review of children with CRPS who presented to a pediatric Chronic Pain Clinic in Canada over a 5-year period (2012 to 2016). RESULTS: The study identified 59 children with CRPS (mean age: 12.7±2.5; 74.6% female; 72.9% lower extremity). In total, 87% (n=48) of children experienced complete resolution or significant improvement of CRPS, with a relapse rate of 15%. Overall, 25% (n=15) had a CRPS-related movement disorder. There were no differences in the clinical features of pediatric CRPS with or without related movement disorders. Children who experienced a favorable outcome had a significantly shorter symptom duration at the initial visit in comparison with children who experienced an unfavorable outcome. DISCUSSION: In this cohort, pediatric CRPS was most common in girls around the age of 12, usually in the lower extremity, and most experienced a favorable outcome. Further research is needed to better understand the prognosis and relapse rate of pediatric CRPS.

PANDAS/PANS in childhood: Controversies and evidence.

Since first defined in 1998, paediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS) and its later, broader iteration, paediatric acute-onset neuropsychiatric syndrome (PANS), have garnered significant attention and controversy. The role of streptococcal infection in children with explosive onset obsessive-compulsive disorder and new onset tics, the natural history of this entity, and the role of symptomatic and disease-modifying therapies, including antibiotics, immunotherapy, and psychoactive drugs, are all issues that have yet to be definitively addressed. While definitive proof of the autoimmune hypothesis of PANDAS is lacking, given the heightened attention to this entity and apparent rise in use of this diagnostic category, addressing questions around diagnosis, treatment, and etiology is imperative. In this paper, we review current working definitions of PANDAS/PANS, discuss published evidence for interventions related to this entity, and propose a clinical approach to children presenting with acute symptoms satisfying criteria for PANDAS/PANS.

Glutamate Genetics in Obsessive-Compulsive Disorder: A Review.

OBJECTIVE: Obsessive-compulsive disorder (OCD) is common and debilitating with patients exhibiting persistent intrusive thoughts (obsessions), repetitive ritualistic behaviours (compulsions) and anxiety. While it is known that OCD is highly heritable, the specific genetic risk factors for OCD are still largely unknown. The etiology of OCD has also not been fully elucidated but there is growing evidence that glutamate signaling dysfunction in the cortico-striatal-thalamo-cortical (CSTC) circuitry plays a role in its pathogenesis. METHODS: We conducted a focused review of recent literature on the role of glutamate genes in OCD. RESULTS: There have been several recent discoveries in the SAPAP (DLGAP) family, SLC1A1, and GRIN/GRIK families of proteins related to OCD. CONCLUSION: There is growing evidence supporting a role for genetic variation leading to dysfunctional glutamate signaling in OCD. Based on this new evidence we hypothesize that sustained glutamatergic neurotransmission in key areas of the brain may be contributing to the etiology of OCD.

OBJECTIF: Le trouble obsessionnel-compulsif (TOC) est commun et débilitant chez les patients qui présentent des pensées intrusives (obsessions) persistantes, des comportements rituels répétitifs (compulsions) et de l'anxiété. Bien que l'on sache que le TOC est fortement héréditaire, les facteurs de risque génétique spécifiques du TOC sont encore largement inconnus. L'étiologie du TOC n'a pas non plus été encore pleinement élucidée, mais il apparaît de plus en plus que le glutamate qui signale une dysfonction dans le circuit cortico-striatal-thalamo-cortical (CSTC) joue un rôle dans sa pathogenèse. MÉTHODES: Nous avons mené une revue ciblée de la littérature récente sur le rôle des gènes du glutamate dans le TOC. RÉSULTATS: Il y a eu plusieurs découvertes récentes dans la famille SAPAP (DLGAP), les familles de protéines SLC1A1, et GRIN/GRIK liées au TOC. CONCLUSION: Les preuves s'accumulent à l'appui du rôle d'une variation génétique menant à un signal dysfonctionnel du glutamate dans le TOC. Selon ces nouvelles preuves, nous émettons l'hypothèse que la neurotransmission glutamatergique soutenue dans les principales régions du cerveau peut contribuer à l'étiologie du TOC.

A review of the role of serotonin system genes in obsessive-compulsive disorder.

Obsessive-compulsive disorder (OCD) is a debilitating neuropsychiatric disorder that causes the patient to experience intrusive thoughts and/or to carry out repetitive, ritualized behaviors that are time consuming and impairing. OCD is familial and heritable. The genetic factors responsible for pathogenesis, however, remain largely unknown despite the numerous candidate gene studies conducted. Based on efficacy of serotonin reuptake inhibitors (SRIs) in treating OCD, serotonin system genes have been a dominant focus in OCD candidate gene studies. We review the most commonly studied candidate serotonin system gene variants (specifically in SLC6A4, HTR2A, HTR1B, and HTR2C) and their association with OCD. Although findings to date are mixed, serotonin transporter polymorphism 5-HTTLPR and HTR2A polymorphism rs6311 (or rs6313) are most consistently associated with OCD. Mixed findings may be the result of genetic complexity and phenotypic heterogeneity that future studies should account for. Homogenous patient subgroups reflecting OCD symptom dimensions, OCD subtypes, and sex should be used for gene discovery.

Pharmacogenetics of citalopram-related side effects in children with depression and/or anxiety disorders.

Pharmacogenetic approach to antidepressant (AD) response is a promising avenue toward individualizing AD treatment. This is particularly relevant in pediatric populations because of concerns about the suicide risk of serotonin selective reuptake inhibitors (SSRIs), resulting in a black-box warning. However, to date, no specific gene or polymorphism has been consistently implicated as a marker of AD side effect (SE) in the pediatric population. The aim of this study was to examine the association between polymorphisms in genes related to the serotonergic system and citalopram SE's in children and adolescents with major depressive disorder (MDD)/dysthymia and/or anxiety disorders. Outpatients (N = 87, 44 % males), aged 7-18 years with a DSM-IV-TR diagnosis of MDD/dysthymia and/or an anxiety disorder were treated in an 8-week open trial with 20-40 mg/day of citalopram. SE's were rated using a questionnaire devised specifically for this study. Association analysis between known/candidate genetic variants in three genes (5-HTR2A, 5-HTR1Dß, 5-HTR2C) and SE's was conducted. Agitation was more common in boys than girls (male:female 42.1 vs. 18.7 %, χ 2 = 5.61, df = 1, p = 0.018). Subjects with 5-HTR1Dß CC genotype showed more agitation vs. both CG and GG genotypes (CC:CG:GG 71.4 vs. 33.3 vs. 18.1 %, χ 2 = 8.99, df = 2, p = 0.011). The 5-HTR1Dß CC genotype was associated with more reports of agitation. It has been suggested that agitation may be an intermediate phenotype to suicidal behavior. Thus, it seems that 5-HTR1Dß polymorphism may be involved in citalopram-related agitation in children and adolescents treated for depression and/or anxiety.

The Danieli Inventory of Multigenerational Legacies of Trauma, Part II: Reparative Adaptational Impacts.

The impacts of the Holocaust on children of survivors have been widely investigated. However, consensus is limited, and no validated measures have been tailored with or to them. We aimed to develop and validate a scale that measures these specific impacts (Part II of the Danieli Inventory of Multigenerational Legacies of Trauma). We studied 484 adult children of survivors who participated in a cross-sectional web-based survey in English or Hebrew; of these, 191 participated in a clinical interview. Exploratory factor analyses of 58 items to reduce and refine the measure yielded a 36-item scale, Reparative Adaptational Impacts, that had excellent internal consistency (α = .91) and congruence between English and Hebrew versions (φ ≥ .95). Associations between impacts and SCID-based diagnoses of major depressive episode, posttraumatic stress disorder, and generalized anxiety disorder were moderate to strong (ds = 0.48-0.89). Strong associations also emerged between severity of offspring's reparative adaptational impacts and intensity of their parents' posttrauma adaptational styles (Multiple R = .72), with intensity of victim style, especially the mother's, having the strongest effect (ß = .31-.33). Having both research and clinical relevance for assessing Holocaust survivors' offspring, future studies might investigate the scale's generalizability to other populations affected by mass trauma.

Effects of long-term valproic acid treatment on hematological and biochemical parameters in adolescent psychiatric inpatients: a retrospective naturalistic study.

The objective of this study was to determine the long-term hematological and biochemical side effects of valproic acid (VPA) in psychiatric adolescent inpatients. A retrospective naturalistic study design was used. Participants were psychiatric inpatients treated with VPA, alone or in combination with other medications. Electronic medical files were reviewed for changes in hematological and biochemical parameters following a course of VPA treatment. One hundred and four adolescents aged 12-18 (mean 15.76±1.58) years fulfilled the study criteria. The mean blood level and duration of VPA treatment were 65.81±22.18 mcg/ml and 98.57±135.94 days, respectively. The mean levels of thyroid-stimulating hormones and triglyceride levels increased significantly from the first to the last measurement. Platelet count decreased significantly following VPA treatment. No correlation was observed between these parameters and age, duration of treatment, or VPA levels. No serious adverse events were reported. Long-term VPA treatment in adolescents with psychiatric disorders is associated with significant increases in triglyceride levels. Moreover, VPA-treated adolescent psychiatric inpatients may be at risk of developing pituitary-thyroid axis dysregulation and decreased platelet count. Therefore, baseline measurement of thyroid functions and metabolic and hematological parameters and monitoring throughout the treatment are recommended.

Short-term effects of lithium on white blood cell counts and on levels of serum thyroid-stimulating hormone and creatinine in adolescent inpatients: a retrospective naturalistic study.

OBJECTIVE: The purpose of this study was to determine if the known side effects of lithium in adults may be generalized to younger patients with psychiatric disorders. METHODS: A retrospective naturalistic study design was used. Data were collected from the database of a tertiary pediatric medical center covering the years 1994-2010. Included were patients hospitalized for bipolar and non-bipolar disorders and treated with lithium, alone or in combination with other medications. The electronic medical files were reviewed for changes in thyroid and kidney function and for hematological parameters during the course of treatment. RESULTS: Sixty-one patients 12.5-20.4 years of age (mean 16.94±1.66) met the study criteria: 33 with bipolar disorder and 28 with a non-bipolar disorder. Mean duration of lithium treatment (mean lithium blood level, 0.73±0.24 mEq/L) was 193.68±254.35 days. Mean levels of thyroid-stimulating hormones (TSH) rose significantly from baseline to last measurement (3.16±2.68 vs. 1.52±0.92 mU/L; paired t=-5.19, df=50, p<0.001); in 25% of patients, TSH levels at the last measurement were above normal (≥4 mU/L). Only one patient developed TSH values >10 mU/L (the threshold considered clinically significant). Positive correlation was found between pre- and posttreatment TSH levels (Pearson's r=0.60; n=51, p<0.05). White blood cell count (WBC) also increased significantly following lithium treatment (7195±2151 vs. 7944±2096 cells/mm(3); t=2.83, df=60, p=0.006). No significant changes were noted in serum creatinine levels. There was no difference in these parameters between patients treated with lithium alone or in combination with other medications. CONCLUSIONS: Lithium treatment in adolescents with bipolar or non-bipolar disorders is associated with a significant increase in blood TSH levels and WBC count. Lithium-treated adolescent inpatients with a high basal TSH level may be at risk of developing pituitary-thyroid axis dysregulation. Therefore, baseline measurement of thyroid functions and serial monitoring throughout treatment are recommended.

[Pharmacogenetics and anxiety disorders: analysis of recent findings].

Anxiety disorders are chronic disorders appearing with a high frequency in the general population and causing much distress to those suffering from them. The current common treatment consists of antidepressants, primarily from the serotonin-selective-reuptake-inhibitor (SSRI) class. However, despite the relative effectiveness of these medications the patients' responses vary widely with one third not responding at all. While we do not currently have the ability to predict who will respond positively to the medication, it is hoped that genetic research will make it possible to prospectively identify responders and thus help avoid failed treatment attempts and side-effects. The field of pharmacogenetics is divided into pharmaco-kinetics (genetic factors that influence the drug metabolism in the body) and pharmco-dynamics (genetic factors that affect the response to the drug at the level of the receptors/transporters/enzymes in the target organs). Contrary to the treatment of depression, there is little research available on the pharmacogenetics of anxiety disorders and the existing research coincides with the studies on depression. The primary pharmacogenetic-dynamic findings are related to serotonergic genes of which those with the long allele of the serotonin transporter gene (5-HTTLPR) are expected to respond positively to treatment, and the same is true regarding genetic variants of several serotonin receptors. The pharmacogenetic-kinetic findings focus on the CYP450 enzyme system. The hope is that with the progression of the pharmacogenetic research new genetic variants will be discovered which, when combined with the clinical characteristics of those suffering from anxiety disorders, will enable the development of novel treatment algorithms to be customized for each patient.

Additive effects of 5-HTTLPR (serotonin transporter) and tryptophan hydroxylase 2 G-703T gene polymorphisms on the clinical response to citalopram among children and adolescents with depression and anxiety disorders.

OBJECTIVE: The purpose of this study was to evaluate the association between polymorphisms in two serotonin pathway genes and the clinical response to citalopram among children and adolescents with depression and/or anxiety disorders. METHODS: Eighty-three children and adolescents with depression and/or anxiety disorders were treated with citalopram for 8 weeks. We assessed the association between the response to citalopram and polymorphisms in the tryptophan hydroxylase-2 (TPH2) and the serotonin transporter gene. The polymorphisms included single nucleotide polymorphisms (SNPs) in the transcriptional control region (G-703T) of the TPH2 gene and the serotonin transporter gene-linked promoter region (5-HTTLPR). RESULTS: Fifty patients of the 83 (60.2%) achieved satisfactory response (Clinical Global Impressions - Improvement ≤2). We observed an additive effect of the two genes on the clinical response to citalopram. Patients carrying the combination of TPH2 -703G and the 5-HTTLPR L alleles were the most likely to respond (80%). In contrast, patients carrying the combination of TPH2 -703T and the 5-HTTLPR S alleles were least likely to respond (31%). The other patients (with -703G/5-HTTLPR S and -703T/5-HTTLPR L alleles) showed intermediate response (67%). CONCLUSIONS: This finding suggests that 5-HTTLPR and TPH2 genes may act in concert to modulate the clinical response to citalopram among children and adolescents with depression and/or anxiety disorders.

Duloxetine contributing to a successful multimodal treatment program for peripheral femoral neuropathy and comorbid 'reactive depression' in an adolescent.

In the United States, duloxetine has been approved for the treatment of major depressive disorder, diabetic peripheral neuropathic pain and fibromyalgia in the adult population. Data regarding the use of duloxetine in the pediatric population, however, are very limited. Femoral nerve injury is a rare complication of cardiac catheterization. In the case described, duloxetine contributed to a successful multimodal treatment program for peripheral neuropathic pain due to femoral neuropathy in an adolescent with 'reactive depression' and conversion symptoms. To the best of the authors' knowledge, the present article is only the third such report on this dual use of duloxetine in children and adolescents, and the first report of such treatment following femoral neuropathy induced by cardiac catheterization.

Anti-inflammatory drugs as moderators of antidepressant effects, especially those of the selective serotonin-reuptake inhibitor class.

Large studies examining remission rates obtained by antidepressants have yielded somewhat dismal results. In the well-reported Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study, only 36.8% of patients exhibited remission with the selective serotonin-reuptake inhibitor (SSRI) citalopram and the cumulative remission rate was 67% after multiple treatments were attempted. Warner-Schmidt et al. recently published an interesting paper that suggests specific mechanisms by which anti-inflammatory drugs inhibit the antidepressant effects of SSRIs. They employed well-established mouse models of depression: the tail suspension test and the forced swim test. In their experiment, ibuprofen significantly attenuated the antidepressant-like effects of SSRIs in both tests. The authors also presented data from the STAR*D study itself. These data - demonstrating higher remission rates for depressed patients receiving citalopram without concomitant NSAIDs (55.2%) than those receiving citalopram with NSAIDs (44.5%) - serve to illustrate the potential hindering effects of anti-inflammatory drugs.

Effectiveness and tolerability of citalopram for the treatment of depression and anxiety disorders in children and adolescents: an open-label study.

To assess the effectiveness and tolerability of citalopram for the acute treatment of children and adolescents suffering from depression and/or anxiety disorders. As much as 78 outpatients, aged 7-18 years with a diagnosis of depressive and/or anxiety disorder, completed an 8-week open trial with citalopram (20-40 mg/day). Outcome, side effects and suicidality were assessed weekly to bi-weekly using appropriate rating scales. At endpoint 56% of subjects were found to be responders (Clinical Global Impression-Improvement [CGI-I] Scale

Pharmacogenetics of selective serotonin reuptake inhibitors in pediatric depression and anxiety.

Selective serotonin reuptake inhibitors (SSRIs) are now an accepted and widely used first-line treatment for pediatric depression and anxiety. However, the data indicate that SSRI treatment achieves a clinical response in only 55-60% of children, and some may develop drug-induced suicidal behavior. Clinicians have no reliable tools to help them identify in advance those youths who are not likely to respond to an SSRI, or who are likely to develop SSRI-induced suicidality. Pharmacogenetic research attempts to identify genetic markers that are associated with response and side-effect profile. This review covers all the pharmacogenetic studies conducted as yet on pediatric samples and compares them with available data on adult samples. An emphasis is put on serotonergic genes such as the serotonin transporter (5-HTT) and additional genes known to be active in the CNS.

Serotonin transporter polymorphism (5-HTTLPR) and citalopram effectiveness and side effects in children with depression and/or anxiety disorders.

OBJECTIVE: The aim of this study was to examine the association between polymorphism in the serotonin transporter gene and citalopram effectiveness and side effects in children and adolescents with major depressive disorder (MDD) and/or anxiety disorders. METHODS: Outpatients, aged 7- 18 years with a Diagnostic and Statistical Manual of Mental Disorders, 4th edition, text revision (DSM-IV-TR) MDD and/or anxiety disorder were treated in an 8-week open trial with 20-40 mg/day of citalopram. Subjects were genotyped with respect to short (s) versus long (l) forms of the 5-HTTLPR polymorphism of the serotonin transporter, and the relationship between genotype and outcome and side effects was assessed. RESULTS: Subjects with 5-HTTLPR ss genotype showed a less vigorous response with regard to depressive symptoms measured by the Children's Depression Rating Scale-Revised (CDRS-R) scores over time compared to subjects with sl/ll genotypes (beta = 0.67, z = 2.02, p = 0.04). In addition, the 5-HTTLPR ss group exhibited lower rates of agitation compared to those with sl/ll genotype (6.3% vs. 32.8%, p = 0.05). Also, subjects with 5-HTTLPR ss genotype had consistently higher scores of suicidality at each week compared to the sl/ll group (beta = 0.76, z = 2.04, p = 0.04) as measured by item number 13 of the CDRS-R. CONCLUSIONS: The 5-HTTLPR ss genotype was associated with a poorer clinical response with regard to depressive symptoms as well with fewer reports of agitation. The 5-HTTLPR polymorphism may be a genetic marker of response to citalopram in children and adolescents with depression and/or anxiety.