Search

Depression is a prevalent, highly debilitating mental disorder affecting up to 15% of the population at least once in their lifetime, with huge costs for society. Neurobiological mechanisms of depression are still not well known, although there is consensus about interplay between genetic and environmental factors. Antidepressant medications are frequently used in depression, but at least 50% of patients are poor responders, even to more recently discovered medications. Furthermore, clinical response only occurs following weeks to months of treatment and only chronic treatment is effective, suggesting that actions beyond the rapidly occurring effect of enhancing monoaminergic systems, such as adaptation of these systems, are responsible for the effects of antidepressants. Recent studies indicate that an impairment of synaptic plasticity (neurogenesis, axon branching, dendritogenesis and synaptogenesis) in specific areas of the CNS, particularly the hippocampus, may be a core factor in the pathophysiology of depression. The abnormal neural plasticity may be related to alterations in the levels of neurotrophic factors, namely brain-derived neurotrophic factor (BDNF), which play a central role in plasticity. As BDNF is repressed by stress, epigenetic regulation of the BDNF gene may play an important role in depression. The hippocampus is smaller in depressed patients, although it is unclear whether smaller size is a consequence of depression or a pre-existing, vulnerability marker for depression. Environmental stressors triggering activation of the hypothalamic-pituitary-adrenal axis cause the brain to be exposed to corticosteroids, affecting neurobehavioural functions with a strong downregulation of hippocampal neurogenesis, and are a major risk factor for depression. Antidepressant treatment increases BDNF levels, stimulates neurogenesis and reverses the inhibitory effects of stress, but this effect is evident only after 3-4 weeks of administration, the time course for maturation of new neurons. The ablation of hippocampal neurogenesis blocks the behavioural effects of antidepressants in animal models. The above findings suggest new possible targets for the pharmacotherapy of depression such as neurotrophic factors, their receptors and related intracellular signalling cascades; agents counteracting the effects of stress on hippocampal neurogenesis (including antagonists of corticosteroids, inflammatory cytokines and their receptors); and agents facilitating the activation of gene expression and increasing the transcription of neurotrophins in the brain. [ABSTRACT FROM AUTHOR]

Background: Pervasive developmental disorders (PDDs) are severe psychiatric disorders characterized by impairment in social interactions, in verbal and non-verbal communication, and by restricted and stereotyped patterns of interest and behaviour, with onset in the first 3 years of life. The appropriate use of pharmacotherapy can improve some aberrant symptoms and behaviours and increase the person's response to non-pharmacological interventions.Objective: To describe clinical outcomes, or symptom changes, and adverse effects during naturalistic treatment with aripiprazole monotherapy in children with PDDs and severe behavioural disorders (such as aggression against self and/or others, hostility, hyperactivity, severe impulsiveness).Method: This retrospective naturalistic study included 34 patients (23 males and 11 females, age range 4.5-15 years, mean age 10.2 +/- 3.3 years), admitted during 2006-2007, diagnosed according to DSM-IV criteria and followed up for 4-12 months (mean 7.0 +/- 3.6 months). Outcome measures were three global measures of clinical and functional impairment and improvement from baseline: the Clinical Global Impression-Severity (CGI-S) and CGI-Improvement (CGI-I) scales; the Children's Global Assessment Scale (C-GAS); and the Childhood Autism Rating Scale (CARS), a specific measure of PDD symptoms.Results: The mean baseline CGI-S was 5.7 +/- 0.8 (markedly ill/severely ill). The mean final dosage of aripiprazole was 8.1 +/- 4.9 mg/day. At the endpoint, 11 patients (32.4%) were 'much improved' or 'very much improved' (CGI-I score of 1 or 2), 12 patients (35.3%) were 'minimally improved' (CGI-I score of 3) and 10 (29.4%) were 'unchanged' or 'worsened' (CGI-I score of 4 or 5). C-GAS and CARS scores significantly improved (p < 0.0001, effect sizes 0.59 and 0.62, respectively). Nine patients (26.5%) experienced moderate to severe agitation, which was associated with self-injurious behaviours in five of these patients, and five patients presented with sleep disorders. Twelve patients (35.3%) discontinued medication during the follow-up because of lack of efficacy or adverse effects.Conclusions: In these severely impaired children with PDDs, aripiprazole monotherapy was associated with a significant improvement in maladaptive behaviours in one-third of patients. Agitation and insomnia were the most frequent adverse effects. Further controlled studies in larger samples to explore possible predictors of efficacy are warranted. [ABSTRACT FROM AUTHOR]

Background: The most severe forms of conduct disorder (CD) are disabling conditions, often resistant to treatment and likely to evolve into antisocial behaviours. Mood stabilizers and atypical antipsychotics are often used to treat severe cases of CD, as are antidepressants and psychostimulants less frequently, despite a relative lack of efficacy data. Use of lithium in hospitalized children and adolescents with CD has been evaluated in a small number of studies.Aim: To explore the efficacy and tolerability of lithium (administered either as monotherapy or in association with atypical antipsychotics) in children and adolescents with CD and to identify variables associated with positive or negative responses to such treatment.Methods: This retrospective study included 60 consecutive patients (46 males and 14 females; range 8-17 years; mean age 14.2 +/- 2.4 years) who were treated with lithium for CD diagnosed on the basis of the Kiddie-Schedule for Affective Disorders and Schizophrenia-Present and Lifetime (K-SADS-PL) clinical interview and the DSM-IV criteria for CD. The sample consisted of 44 inpatients (who remained in hospital during the first 2 or 3 weeks of treatment and were then assessed as outpatients) and 16 outpatients; the follow-up period was 6-12 months (mean 8.4 +/- 2.2 months). While all patients were initially treated with lithium, an atypical antipsychotic could be added if necessary to achieve satisfactory control of symptoms. Outcome measures included the Modified Overt Aggression Scale (MOAS), the Clinical Global Impression-Severity (CGI-S) and Clinical Global Impression-Improvement (CGI-I) scales, and the Aggression Questionnaire (which assessed the type of aggression, i.e. predatory vs affective). Patients were considered responders to pharmacological treatment at the end of the follow-up period if they satisfied all of the following criteria: >or=50% decrease in MOAS score, CGI-I score of 1 or 2 ('very much improved' or 'much improved') and CGI-S score of 0.8 indicates good treatment efficacy).Results: At the end of follow-up, 29 of 60 patients (48.3%) were classified as responders (10 receiving lithium monotherapy and 19 receiving lithium plus atypical antipsychotic therapy). For the sample as a whole, mean total MOAS score improved significantly (p < 0.001) and the effect size (pre- vs post-treatment) was 1.03. Mean MOAS verbal, and physical towards objects and other persons aggression scores, both in patients taking lithium as monotherapy and those also taking an add-on atypical antipsychotic, also improved significantly (p < 0.001) and the effect size was >or=0.80 for all items. Improvement in mean MOAS self-aggression score (p < 0.001) and an effect size of 0.59 was found when an atypical antipsychotic was added to lithium therapy. Predictors of a positive response to treatment were less severe disease at baseline, lower MOAS aggression scores and an impulsive (affective, nonpredatory) type of aggression. Gastrointestinal adverse effects, polydipsia and increased urinary frequency, tremor and increased thyroid stimulating hormone levels were the most frequently reported adverse effects. Two patients discontinued treatment because of adverse effects (vomiting and thyroid dysfunction).Conclusion: Lithium alone or in combination with an atypical antipsychotic may reduce aggressive behaviours in children and adolescents with CD. The adverse effects of such therapy are relatively common but rarely severe. [ABSTRACT FROM AUTHOR]

This paper provides an overview of the phenomenology, longitudinal outcome data, assessment and management of separation anxiety disorder (SAD) in children and adolescents. SAD is qualitatively different from early worries, and is characterised by an abnormal reactivity to real or imagined separation from attachment figures, which significantly interferes with daily activities and developmental tasks. Different epidemiological studies indicate a prevalence of 4 to 5% in children and adolescents. In contrast to other anxiety disorders, 50 to 75% of children with SAD come from homes of low socioeconomic status. The severity of symptomatology ranges from anticipatory uneasiness to full-blown anxiety about separation, but children are usually brought to the clinician when SAD results in school refusal or somatic symptoms. School refusal is reported in about 75% of children with SAD, and SAD is reported to occur in up to 80% of children with school refusal. Longitudinal studies have suggested that childhood SAD may be a risk factor for other anxiety disorders, but whether this link is specific to, for example, panic disorder and agoraphobia, or whether SAD represents a general factor of vulnerability for a broad range of anxiety disorders is still debated. Most relevant data are reported on nonpharmacological treatments (psychoeducational, behavioural, cognitive-behavioural, family and psychodynamic), and these are the first choice approach in SAD. Controlled studies show efficacy of cognitive-behavioural therapy in children with anxiety disorders and specifically in SAD-school phobia, supporting this approach as the best proven treatment. Pharmacotherapy should be used in addition to behavioural or psychotherapeutic intervention when the child's symptoms have failed to respond to those treatments, and he/she is significantly impaired by the symptoms. Selective serotonin (5-hydroxytryptamine; 5-HT) reuptake inhibitors (SSRI) have a good adverse effect profile and may be considered as first choice drugs in SAD. When different SSRIs fail to improve symptomatology, a trial with a tricyclic antidepressant (TCA) is indicated, with careful monitoring of cardiac functioning. Because of the adverse effect profile and the potential for abuse and dependence, benzodiazepines should be used only when a rapid reduction of symptomatology is needed, until the SSRI or the TCA have begun to be effective (few weeks). Buspirone should be considered in children who have not responded to other treatments. Further research is needed to confirm efficacy of newer antidepressants (venlafaxine, mirtazapine, nefazodone) in childhood anxiety disorders. [ABSTRACT FROM AUTHOR]

Sleep problems are a common complaint in children/adolescents with autism spectrum disorder (ASD). Correctly diagnosing and treating sleep problems in individuals with ASD is key, as they can add to the psychosocial burden of the disorder and exacerbate associated symptoms, such as inattention or irritability. Here, we provide an overview of the epidemiology, diagnosis, and management of sleep problems/disorders in children and adolescents with ASD. This narrative review is mainly informed by a systematic search in PubMed and PsycInfo (last search: 10 October 2019) of available pertinent meta-analyses. We also searched for randomized controlled trials (RCTs) published after the search date of available meta-analyses. As for the epidemiology of sleep disorders in ASD, recent meta-analytic evidence shows a pooled prevalence of 13% (95% confidence interval [CI] 9-17) in the ASD population, compared with 3.7% in the general population. In terms of diagnosis of sleep disorders, it should be based on standardized criteria [e.g., the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) or third edition of the International Classification of Sleep Disorders (ICSD)]; clinicians should bear in mind that the communication difficulties presented by individuals with ASD may make the diagnostic process more challenging. Regarding the treatment, a meta-analysis of behavioral interventions, including only three RCTs, found significant effects in terms of increase in total sleep time (24.41 min, 95% CI 5.71-43.11, P = 0.01), decrease in sleep-onset latency (- 18.31 min, 95% CI - 30.84 to - 5.77, P = 0.004), and a significant effect on sleep efficiency (5.59, 95% CI 0.87-10.31, P = 0.02), albeit the risk of bias of the included studies was rated "high" in relation to issues with the blinding. The bulk of the evidence for the pharmacological treatment is for melatonin, with a meta-analysis of five double-blind RCTs showing a large effect size, favoring melatonin, in sleep duration (44 min compared with placebo, Hedge's g 1.07 [95% CI 0.49-1.65]) and sleep-onset latency (39 min compared with placebo, Hedge's g - 2.46 [95% CI - 1.96 to - 2.98]). We conclude that additional RCTs are desperately needed to support the management of sleep disorders in ASD with an evidence-based, precision medicine approach.

Psychostimulants are the recommended first-line pharmacological treatment for attention-deficit/hyperactivity disorder (ADHD). Methylphenidate is one of the most commonly used psychostimulants worldwide. Given that immediate-release and/or tablet/capsule formulations may decrease adherence to methylphenidate treatment, several drug companies have been developing novel long-acting and/or liquid/chewable formulations that may improve adherence as well as (for long-acting formulations) reduce abuse potential, decrease stigma associated with multiple administrations per day, and decrease the potential for adverse effects related to dosage peak. Here, we review the pharmacokinetics, efficacy, and tolerability of novel formulations of methylphenidate that are in development or have been approved by the US FDA or European Medicines Agency (EMA) in the last 5 years. We searched the websites of the FDA, EMA, ClinicalTrials.gov, and the pertinent drug companies. We also searched PubMed, Ovid databases (MEDLINE, PsycINFO, Embase + Embase classic), and ISI Web of Knowledge (Web of Science [Science Citation Index Expanded], Biological Abstracts, Biosis, Food Science and Technology Abstracts) to retrieve any additional pertinent information. We found data from trials for the following compounds: (1) methylphenidate extended-release oral suspension (MEROS; NWP06, Quillivant™); (2) methylphenidate extended-release chewable capsules (NWP09, QuilliChew ER™); (3) methylphenidate hydrochloride extended-release capsules (Aptensio XR™); (4) methylphenidate extended-release orally disintegrating tablets (XR-ODT; NT-0102, Cotempla™); (5) ORADUR technology (once-daily tamper-resistant formulation) methylphenidate sustained release (SR); and (6) methylphenidate modified-release (HLD-200; Bejorna™). Overall, available evidence based on trials suggests these compounds have good efficacy and tolerability. Future research should further explore the effectiveness and tolerability of these new formulations as well as their potential to improve adherence to treatment in the 'real world' via pragmatic trials.

Attention-deficit hyperactivity disorder (ADHD) is one of the most common neurobehavioural disorders in children. It has been shown that as many as 85% of patients with ADHD have at least one psychiatric co-morbidity, and approximately 60% have at least two. Atomoxetine is a specific, noradrenergic reuptake inhibitor that provides an effective treatment option for patients with ADHD and co-morbid conditions. The efficacy of atomoxetine in treating ADHD appears to be unaffected by the presence of co-morbid conditions. Therapy with atomoxetine has been associated with statistically significant improvements in symptoms of oppositional defiant disorder in most, but not all, studies. Limited data suggest this agent may have potential in improving co-occurring symptoms of anxiety and may be useful in patients with co-morbid conditions such as tics or Tourette's syndrome. The tolerability profile of atomoxetine in patients with ADHD and co-morbid conditions was similar to that of patients with uncomplicated ADHD. Atomoxetine was well tolerated, with adverse events generally mild and transient; the most frequent adverse events in patients with ADHD included abdominal pain, decreased appetite, nausea and vomiting. The favourable safety and efficacy profile of atomoxetine makes it a promising treatment for patients with ADHD and associated co-morbidities.

Background: Pediatric obsessive-compulsive disorder (OCD) can cause substantial impairment in academic, social and family functioning. Even though cognitive-behavioural therapy (CBT) is an effective treatment, the pharmacological option has to be taken into consideration. Effectiveness of serotonin reuptake inhibitors (SRIs) has been supported by several double-blind, placebo-controlled studies., Objective: To report the response to pharmacotherapy in children and adolescents with OCD naturalistically followed up and treated with SRIs., Methods: From a consecutive series of 257 patients (174 males and 83 females; mean age 13.6+/-2.7 years) diagnosed with OCD following a clinical interview according to DSM-IV criteria, 37 children improved significantly after psychotherapy and were excluded. The remaining 220 patients were included in the study., Results: Eighty-nine patients (40.5%) were managed with SRI monotherapy and 131 with an SRI in combination with another medication. Compared with those who needed polypharmacy, patients managed with SRI monotherapy were younger at the time of the first consultation, had less severe symptoms at baseline, and more frequently presented with co-occurring anxiety and depressive disorders, while patients receiving polypharmacy presented with higher rates of bipolar disorder, tic disorder and disruptive behaviour disorders. 135 patients (61.4%) achieved a positive clinical response and were considered responders. When differences between responders and nonresponders at the end of follow-up were considered, irrespective of the pharmacological treatment (monotherapy or polypharmacy), responders had less severe disease at baseline, were younger at the time of the first consultation, more frequently presented with the contamination/cleaning phenotype and less frequently presented with the hoarding phenotype. Treatment refractoriness was associated with higher rates of conduct disorder and bipolar disorder, and lower rates of generalized anxiety disorder and panic disorder. Forty-three children received therapy with an atypical antipsychotic as an augmenting strategy, and 25 of these children (58.1%) became responders. Responders to augmentation were less severely impaired at baseline, while different subtypes of OCD were similar between responders and nonresponders, as were patterns of co-morbidity., Conclusion: Our study suggests that putative variables associated with response to pharmacological treatment of paediatric OCD can be defined, and can help improve treatment strategies.

Awareness of childhood-onset schizophrenia is rapidly increasing, with a more precise definition now available of the clinical picture and early signs, the outcome and the treatment strategies. Premorbid developmental impairments, including language, motor and social deficits, are more frequent and more pronounced in earlier- than in later-onset forms of schizophrenia. This 'pan-dysmaturation' is reported from the first months of life in more than half of the children who will develop childhood-onset schizophrenia, and it suggests a more severe and early disruption of brain development compared with the adolescent- and adult-onset disorder. The insidious onset in at least 75% of children, the high rates of premorbid problems and the hesitancy on the part of clinicians to make a diagnosis of schizophrenia in a child usually delay the recognition of the syndrome. Elementary auditory hallucinations are the most frequent positive symptom, while visual and tactile hallucinations are rarer. Delusions are less complex than in adolescents and are usually related to childhood themes. Negative symptoms are largely predominant, namely flat or inappropriate affect. A marked deterioration from the previous level of functioning is present in all these children, and an impaired outcome is reported in approximately 50-60% of them. The main diagnostic challenges are with differentiating childhood-onset schizophrenia from affective disorders (both depression and bipolar disorder) with psychotic symptoms, pervasive developmental disorders and severe personality disorders. Post-traumatic stress disorder and obsessive-compulsive disorder without insight may also be misdiagnosed as schizophrenia. Furthermore, approximately 10% of children from the community report nonpsychotic hallucinations or delusions. Finally, children with atypical psychotic features that do not strictly fit diagnostic criteria for schizophrenia have been described, and new labels have been proposed to categorise these clinical patterns, such as multidimensionally impaired disorder and multiple complex developmental disorder. In the context of a multimodal approach, including behavioral, social, scholastic and familial interventions, a pharmacological treatment is usually the core treatment. Available experience from the few controlled studies, open studies and case reports on pharmacotherapy in children with schizophrenia aged <12 years is critically analysed in this review, with particular reference to the use of atypical antipsychotics in clinical practice. To date, the major evidence supports the efficacy of risperidone and olanzapine, while clozapine seems an effective option in treatment-refractory cases. Published experience with newer atypical antipsychotics (quetiapine, ziprasidone, aripiprazole) is still lacking in this age range. Safety data (namely extrapyramidal symptoms, weight gain, hyperprolactinaemia, haematological adverse effects, seizures, hepatotoxicity, metabolic effects, neuroleptic malignant syndrome and cardiovascular effects) are reviewed and discussed, along with strategies for management.

Pervasive developmental disorders (PDDs) are severe psychiatric disorders characterised by impaired social interaction, reduced verbal and nonverbal communication, and restricted and stereotyped patterns of interest and behaviour, with onset in the first 3 years of life. As part of a multimodal approach that includes educational and behavioural interventions, appropriate use of pharmacotherapy in patients with PDDs can improve some symptoms and behaviours and increase the patient's response to nonpharmacological interventions. Pharmacotherapy is aimed at stabilising the dysregulated systems that are thought to underlie the abnormal behaviours, namely the serotonergic and dopaminergic systems.This paper critically reviews the available literature on the pharmacotherapy of PDDs in children and adolescents. Pharmacological, efficacy and safety data on drugs acting on serotonin (serotonergic agents such as clomipramine, fluoxetine, paroxetine, sertraline, citalopram and fluvoxamine), on both serotonin and norepinephrine (venlafaxine and mirtazapine), dopamine (dopamine-blocking antipsychotics such as haloperidol and pimozide), and on both serotonin and dopamine (atypical antipsychotics such as clozapine, risperidone, olanzapine, quetiapine and ziprasidone) are presented. The paper concludes with a brief discussion of other psychotropic medications, such as the opioid antagonists, alpha-adrenoceptor agonists (clonidine and guanfacine), psychostimulants, mood stabilisers, glutamatergic compounds (lamotrigine, amantadine), buspirone, and secretin. Available evidence suggests that atypical antipsychotics (mainly risperidone and olanzapine) are particularly indicated when more serious behavioural symptoms, such as aggression, self-injurious behaviours and hyperactivity, are prominent. Serotonergic agents may be effective in children with repetitive phenomena or affective symptoms. Social relatedness is more frequently refractory to both atypical antipsychotics and serotonergic agents. Further research into the drug treatment of PDDs, including placebo-controlled trials and long-term, naturalistic follow-up studies of large samples of patients of different age ranges, is warranted.