Spatial learning and memory impairment and increased locomotion in a transgenic amyloid precursor protein mouse model of Alzheimer's disease

A well-known example for gene x environment interactions in psychiatry is the one involving the low activity (s) allelic variant of the serotonin transporter (5-HTT) promoter polymorphism (5-HTTLPR) that in the context of stress increases risk for depression. In analogy, 5-HTT knockout rodents are highly responsive to early life, but also adult external stressors, albeit conflicting data have been obtained. In our study on emotion and cognition using homozygous 5-HTT knockout (5-HTT^−/−) and wild-type (5-HTT^+/+) rats we have been confronted with animal facility construction, which were associated with severe lifetime stress (noise and vibrations). To assess the impact of construction stress on well-established 5-HTT^−/− rat phenotypes we conducted ad hoc analyses of 5-HTT^−/− and 5-HTT^+/+ rats that grew up before and during the construction. The reproductive capacity of the parents of the experimental 5-HTT^+/− rats was significantly decreased. Further, 5-HTT^−/− anxiety-related phenotypes in the elevated plus maze and social interaction tests were abolished after construction noise exposure, due to increased anxiety in 5-HTT^+/+ rats and decreased anxiety in 5-HTT^−/− rats (social interaction test only). In addition, reversal learning was improved in 5-HTT^+/+ and, to a milder extent, decreased in 5-HTT^−/− rats. Finally, construction stress genotype-independently increased behavioural despair in the forced swim test. In conclusion, severe construction stress induces 5-HTT genotype-dependent ‘for-better-and-for-worse’ effects. These data importantly contribute to the understanding of 5-HTT gene x environment interactions and show the risk of losing genotype effects by construction stress.     

Pharmacologic treatment of anxiety disorders in children and adolescents

This article reviews the pharmacologic treatment of anxiety disorders in children and adolescents. These disorders are quite common and can be considered a "silent epidemic" because they are more often reported by the children and adolescents than by their parents. Tricyclic antidepressants (TCAs), benzodiazepines, buspirone, and selective serotonin reuptake inhibitors (SSRIs) have been used to treat anxiety disorders in children and adolescents with varying degrees of success. Considering safety and efficacy, the SSRIs appear to be the first-line treatment for anxiety disorders in youth, but more studies are needed to confirm preliminary results. Tricyclic antidepressants and benzodiazepines may be considered when the child has not responded to SSRIs or when adverse effects have exceeded benefits. Although nonpharmacologic approaches for the treatment of anxiety in children and adolescents are beyond the scope of this article, their importance is to be underscored and they should be considered as part of the treatment plan. Over the next decade, research data will be generated regarding the treatment of anxiety disorders in youth. Ongoing research studies include the use of fluoxetine (B. Birmaher, personal communication, 1999) and fluvoxamine (J. Walkup, personal communication, 1999) for the treatment of generalized anxiety disorder, separation anxiety disorder, or social phobia; and buspirone for generalized anxiety disorder in children. Despite these efforts, there is a need for more studies to examine the safety and efficacy of different pharmacologic treatments, as well as longitudinal studies to monitor for long-term tolerability and side effects. Pharmacokinetic studies for children and adolescents will provide information on the metabolism and absorption of these medications and delineate the developmental differences between children and adolescents when compared to adults. Finally, and perhaps most importantly, studies that compare medication, psychosocial treatments, and their combination are needed.     

The selective serotonin reuptake inhibitors controversy in the treatment of depression in children

Antidepressants are widely prescribed for children and adolescents, although data regarding their safety and efficacy are limited. The objective of this article is to review the origins of the controversy regarding the current use of selective serotonin reuptake inhibitors (SSRIs) in children and adolescents. Two chief concerns drive the controversy: 1) the discovery of an increased risk of suicidal behaviors in those treated with SSRIs and 2) the efficacy of SSRIs in childhood and adolescent major depression is unclear. Various factors may account for the reported differences in outcomes for SSRI treatment in children and adolescents compared to adults. The past decade has shown a significant drop in the rate of adolescent suicide, which coincides with the onset of the use of these medications. Therefore, a reduction in the use of SSRIs in children and adolescents should be considered carefully.     

Selective serotonin reuptake inhibitors for children and adolescents

The controlled studies of selective serotonin reuptake inhibitors (SSRIs) in pediatric psychopharmacology research lag behind the controlled studies of SSRIs in adults. As a result, widespread use of SSRIs in the treatment of child and adolescent psychiatric disorders is in stark contrast to the paucity of research data. Recent changes in the research climate (including support from the National Institute of Mental Health, the Food and Drug Administration, and industry) have encouraged welldesigned SSRI studies in pediatric psychopharmacology, and will ultimately provide needed information to guide treatment. This paper reviews the best available data from pediatric SSRI trials, including 10 double-blind placebo-controlled trials, and two abstracts of open-label continuation studies of SSRIs associated with large pediatric efficacy studies. Adverse events (AEs) of SSRIs in children and adolescents are discussed in reference to available pediatric studies. Recent pharmacokinetic studies of SSRIs in children and adolescents are reviewed. Future SSRI research strategies are also discussed.     

Developmental effects of SSRIs: lessons learned from animal studies.

Selective serotonin reuptake inhibitors (SSRIs) are utilized in the treatment of depression in pregnant and lactating women. SSRIs may be passed to the fetus through the placenta and the neonate through breastfeeding, potentially exposing them to SSRIs during peri- and postnatal development. However, the long-term effects of this SSRI exposure are still largely unknown. The simplicity and genetic amenability of model organisms provides a critical experimental advantage compared to studies with humans. This review will assess the current research done in animals that sheds light on the role of serotonin during development and the possible effects of SSRIs. Experimental studies in rodents show that administration of SSRIs during a key developmental window creates changes in brain circuitry and maladaptive behaviors that persist into adulthood. Similar changes result from the inhibition of the serotonin transporter or monoamine oxidase, implicating these two regulators of serotonin signaling in developmental changes. Understanding the role of serotonin in brain development is critical to identifying the possible effects of SSRI exposure.     

Therapeutic drug monitoring in child and adolescent psychiatry

Psychopharmacotherapy in children and adolescents is characterized by an increased susceptibility for adverse events and an increased risk of ineffective treatment due to specific age-dependent and developmental characteristics in comparison to adults. Dosing in paediatric psychiatric patients requires careful handling, since the dose recommendations for adults can not simply be extrapolated to minors because of pharmacokinetic and pharmacodynamic differences. In addition, psychopharmacotherapy in children and adolescents is hampered by lack of high quality evidence on efficacy and safety in many indications and subsequently a high degree of off-label use. Therapeutic Drug Monitoring (TDM) is an established and useful tool in psychiatry to individualize and optimize the outcomes (efficacy/safety balance) of psychopharmacological drug treatment in the individual patient by dose adjustments based upon measured serum concentrations. In children and adolescents the administration of psychotropic drugs is a general indication for performing TDM. However, TDM studies specific in these age groups are necessary to identify age and indication specific therapeutic ranges of serum concentrations. Systematic collection of data on drug exposure, serum concentrations and clinical characteristics as well as outcomes can generate such practice-based evidence. A German-Swiss-Austrian competence network for TDM in child and adolescent psychiatry using a multi-centre internet-based data infrastructure was founded to document and collect demographic, safety and efficacy data as well as blood concentrations of psychotropic drugs in children and adolescents (further information: www.tdm-kjp.com).     

Fluoxetine treatment of prepubescent rats produces a selective functional reduction in the 5-HT2A receptor-mediated stimulation of oxytocin

Various childhood mood disorders are being treated with serotonin selective reuptake inhibitors (SSRIs) such as fluoxetine (Prozac(R)), yet limited data are available on their effects on serotonergic systems prior to maturation. This study investigated the effects of chronic fluoxetine treatment on 5-HT2A serotonin receptor-mediated neuroendocrine responses in young male rats. Prepubescent male rats were treated with saline or fluoxetine (10 mg/kg/day, i.p.) for 14 days, a treatment regimen producing maximal changes in postsynaptic 5-HT2A function in adults. Eighteen hours post-treatment, the rats received saline or increasing doses (0.5, 2.0, or 5.0 mg/kg, i.p.) of the 5-HT2 receptor agonist (+/-)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane HCl ((+/-)-DOI). Trunk blood was obtained to determine changes in oxytocin, ACTH, corticosterone, and renin responses. Fluoxetine produced a small ( approximately 6%) but significant reduction in body weight gain, but no changes were observed in basal hormone levels. In both saline- and fluoxetine-treated rats, (+/-)-DOI increased plasma oxytocin levels in a dose-dependent manner. However, the magnitude of the oxytocin responses to all doses of (+/-)-DOI were markedly attenuated ( approximately 50%) in the fluoxetine-treated rats, indicating a functional reduction in the E(max) of 5-HT(2A) receptor-mediated oxytocin responses. In contrast, fluoxetine did not alter the (+/-)-DOI-induced increases in plasma ACTH, corticosterone, or renin. These data provide the first demonstration of selective neuroadaptive responses in 55-HT2A serotonin receptor function due to prepubescent treatment with fluoxetine. These data may be clinically relevant with respect to the use of selective serotonin reuptake inhibitors in children and adolescents.     

Early life stress triggers sustained changes in histone deacetylase expression and histone H4 modifications that alter responsiveness to adolescent antidepressant treatment

Early life stress can elicit long-lasting changes in gene expression and behavior. Recent studies on rodents suggest that these lasting effects depend on the genetic background. Whether epigenetic factors also play a role remains to be investigated. Here we exposed the stress-susceptible mouse strain Balb/c and the more resilient strain C57Bl/6 to a powerful early life stress paradigm, infant maternal separation. In Balb/c mice, infant maternal separation led to decreased expression of mRNA encoding the histone deacetylases (HDACs) 1, 3, 7, 8, and 10 in the forebrain neocortex in adulthood, an effect accompanied by increased expression of acetylated histone H4 proteins, especially acetylated H4K12 protein. These changes in HDAC expression and histone modifications were not detected in C57Bl/6 mice exposed to early life stress. Moreover, a reversal of the H4K12 hyperacetylation detected in infant maternally separated Balb/c mice (achieved with chronic adolescent treatment with a low dose of theophylline that only activates HDACs) worsened the abnormal emotional phenotype resulting from this early life stress exposure. In contrast, fluoxetine, a drug with potent antidepressant efficacy in infant maternally separated Balb/c mice, potentiated all histone modifications triggered by early life stress. Moreover, in non-stressed Balb/c mice, co-administration of an HDAC inhibitor and fluoxetine, but not fluoxetine alone, elicited antidepressant effects and also triggered changes in histone H4 expression that were similar to those provoked by fluoxetine treatment of mice exposed to early life stress. These results suggest that Balb/c mice develop epigenetic modifications after early life stress exposure that, in terms of the emotive phenotype, are of adaptive nature, and that enhance the efficacy of antidepressant drugs.     

SSRIs类药物治疗儿童少年情绪障碍229例疗效观察

目的 了解SSRIs类药物在儿童少年情绪障碍治疗中的疗效与副反应。方法 自制调查表,回顾分析229例应用SSRIs类药物治疗儿童少年情绪障碍的各项资料。结果 药物平均起效时间16.6天。平均有效剂量:舍曲林30.8 mg,氟西汀与帕罗西汀均接近于20 mg。总有效率62.9％(脱落32.8％),副作用发生率11.8％(脱落18.5％)。结论 SSRIs类药物起效时间仍未短于2周,疗效与环类抗抑郁剂不相上下,而服用方便,副作用轻,在治疗儿童情绪障碍中前景广阔。     

Fluoxetine promotes gliogenesis during neural differentiation in mouse embryonic stem cells

Selective serotonin reuptake inhibitors (SSRIs) are commonly prescribed for treatment of mood disorders and depression, even during pregnancy and lactation. SSRIs are thought to be much safer than tricyclic antidepressants, with a low risk of embryonic toxicity. Several recent studies, however, have reported that fetal exposure to SSRIs increases the risk of adverse effects during fetal and neonatal development. This is consistent with our previous finding that fluoxetine, a prototypical SSRI, profoundly affected the viability of cultured embryonic stem (ES) cells as well as their ability to differentiate into cardiomyocytes. Furthermore, we found that fluoxetine induced fluctuations in ectodermal marker gene expression during ES cell differentiation, which suggests that fluoxetine may affect neural development. In the present study, we investigated the effects of fluoxetine on the process of differentiation from ES cells into neural cells using the stromal cell‐derived inducing activity (SDIA) method. Fluoxetine treatment was found to enhance the expression of glial marker genes following neural differentiation, as observed by immunocytochemical analysis or quantitative RT‐PCR. The promoter activity of glial marker genes was also significantly enhanced when cells were treated with fluoxetine, as observed by luciferase reporter assay. The expression of neuronal markers during ES cell differentiation into neural cells, on the other hand, was inhibited by fluoxetine treatment. In addition, FACS analysis revealed an increased population of glial cells in the differentiating ES cells treated with fluoxetine. These results suggest that fluoxetine could facilitate the differentiation of mouse ES cells into glial cell lineage, which may affect fetal neural development. © 2010 Wiley‐Liss, Inc.     

Sertraline and fluoxetine: safe treatments for children and adolescents with epilepsy and depression

OBJECTIVE: Depression is frequent, underdiagnosed, and untreated in people with epilepsy. The lack of treatment is partially explained by the concerns over the proconvulsive effects of psychoactive drugs. There are few studies on the effects of selective serotonin reuptake inhibitors (SSRIs) in adults with epilepsy and none in children. The main purpose of the present study was to analyze the impact of SSRIs on the severity and frequency of seizures in children and adolescents with epilepsy and major depressive disorders. In addition, we also evaluated the efficacy of SSRIs in the treatment of depressive symptoms and side effects other than seizure aggravation. METHODS: Monthly frequency of seizures was recorded in the 3-6 months preceding the introduction of SSRIs. According to the criteria proposed by A.M. Kanner, A.M. Kozak and M. Frey (Epilepsy Behav 2000;1:100-5), a positive correlation between introduction of SSRIs and seizure worsening should be considered in the following circumstances: (1) occurrence of de novo generalized tonic-clonic (GTC) seizures; (2) recurrence of GTC seizures following a period of at least 1 year without such episodes; and (3) increase in monthly seizure frequency compared with that reported before introduction of SSRIs. Seizure worsening was considered as probably caused by an SSRI when the increase in monthly frequency occurred in a period up to 3 months after the beginning of SSRI use. RESULTS: Thirty-six children with epilepsy had a depressive disorder. Seizures worsened in two patients. Among this group of patients with depression, all had an improvement in their depressive symptoms. One patient taking fluoxetine had a facial rash and one patient taking sertraline had gastrointestinal disorders. These conditions improved, with total remission, when fluoxetine was replaced with sertraline and vice versa. CONCLUSION: In this sample of children and adolescents with epilepsy and depressive disorders, we observed that SSRIs are a good therapeutic option, considering their efficacy in remission of depressive symptoms, their few adverse effects, and their maintenance of satisfactory seizure control. Treatment of depression should be considered relevant in the treatment of patients with epilepsy.     

Acute selective serotonin reuptake inhibitors increase conditioned fear expression: blockade with a 5-HT(2C) receptor antagonist.

BACKGROUND: Selective serotonin reuptake inhibitors (SSRIs) effectively treat various anxiety disorders, although symptoms of anxiety are often exacerbated during early stages of treatment. We previously reported that acute treatment with the SSRI citalopram enhances the acquisition of auditory fear conditioning, which is consistent with the initial anxiogenic effects reported clinically. Here, we extend our findings by assessing the effects of acute SSRI treatment on the expression of previously acquired conditioned fear. METHODS: Rats underwent fear conditioning drug-free. Tone-evoked fear responses were tested after drug treatment the following day. This protocol more closely resembles the clinical setting than pre-conditioning treatment, because it evaluates effects of treatment on a pre-existing fear rather than on the formation of a new fear memory. RESULTS: A single pre-testing injection of the SSRIs citalopram or fluoxetine significantly increased fear expression. There was no effect of the antidepressant tianeptine or the norepinephrine reuptake inhibitor tomoxetine, indicating that this effect is specific to SSRIs. The SSRI-induced enhancement in fear expression was not blocked by tropisetron, a 5-HT(3) receptor antagonist, but was blocked by SB 242084, a specific 5-HT(2C) receptor antagonist. CONCLUSIONS: Enhanced activation of 5-HT(2C) receptors might be a mechanism for the anxiogenic effects of SSRIs observed initially during treatment.     

Evidence of a progressive motor dysfunction in Mucopolysaccharidosis type I mice

Selective serotonin re-uptake inhibitors are increasingly used for the treatment of adolescents with behavioural disorders. However, the effect of this class of drugs during this sensitive period of brain development has not been extensively investigated. In this study we examine the effect of subchronic treatment with the selective serotonin re-uptake inhibitor, fluoxetine (10 mg/kg/day, i.p.) throughout adolescence (postnatal day 28-60) on learning and memory in the rat. Learning and memory were assessed at two time points: during adolescence, while the animals were being treated with fluoxetine and in young adulthood, 40 days after the termination of fluoxetine treatment. Fluoxetine treated rats were compared to a saline injected control group with respect to spatial navigation in the water maze, object recognition and object-in-place recognition memory. Additionally open field behaviour was examined. In adolescent rats fluoxetine treatment impaired water-maze probe trial performance and object recognition at intertrial intervals of 15 and 60 min, while leaving object-in-place recognition memory unaffected. In the open field the fluoxetine treated animals displayed reduced exploratory activity and higher levels of anxiety. Training the animals to a new platform position in young adulthood showed that the rats that had been treated with fluoxetine during adolescence were significantly slower to acquire this new spatial information. Adolescent fluoxetine treatment had no effect on cell proliferation in dorsal dentate gyrus and subgranular zone in young adulthood. This calls for further studies examining the long-term effects of this class of antidepressants on adolescent brain development and behaviour.     

Selective serotonin reuptake inhibitor and venlafaxine use in children and adolescents with major depressive disorder: a systematic review of published randomized controlled trials.

OBJECTIVE: This review critiques published randomized placebo-controlled trials pertaining to the efficacy and safety of selective serotonin reuptake inhibitors (SSRIs) and venlafaxine in the treatment of major depressive disorder in children and adolescents. METHOD: Medline was searched for articles meeting defined inclusion criteria. The following key terms were used: depressive disorders, antidepressive agents, fluoxetine, paroxetine, sertraline, citalopram, fluvoxamine, venlafaxine, child, and adolescent. RESULTS: Six articles met inclusion criteria. Only 2 studies claim efficacy by significant results in primary outcomes; both have since been contested in further analysis. Not one study adequately examines safety, particularly with respect to whether a link exists between antidepressant use and induction of suicidal ideation or attempts. CONCLUSION: Published studies on SSRI or venlafaxine use in children and adolescents are inconclusive with respect to safety and efficacy, owing to inappropriate claims of efficacy, lack of improvement in global functioning scores, nonstandardized data collection regarding adverse effects, exclusion of suicidal subjects in the recruitment process, grouping of children and adolescents together, small sample sizes, conflict of interest posed by pharmaceutical company sponsorship, and publishing bias. Future investigators should consider these factors when developing study designs.     

Treating children and adolescents with selective serotonin reuptake inhibitors: how long is appropriate?

This article addresses a key question on the use of selective serotonin reuptake inhibitors (SSRIs) among children and adolescents. As briefly reviewed, recent randomized controlled trials have established the safety and efficacy of SSRIs in the acute treatment of major depression and anxiety disorders among children and adolescents. Major questions emerge in light of these data concerning the potential risks and benefits of long-term SSRI use among children and adolescents who receive significant short-term benefits from SSRI treatment. The current review summarizes research on longitudinal outcomes, neuroscience, and psychopharmacology to formulate a set of preliminary recommendations on long-term SSRI use. A review of data in these areas supports three conclusions. First, for children who achieve marked reduction in anxiety or depressive symptoms on an SSRI, clinicians should consider recommending a medication-free trial. Second, when indicated, this medication-free trial should coincide with the first low-stress period occurring after 1 year of continual SSRI treatment. Third, SSRI treatment should be reinitiated in children who exhibit signs of relapse during this medication-free trial.     

Brain serotonin transporter availability predicts treatment response to selective serotonin reuptake inhibitors.

BACKGROUND: Few studies have investigated the predictive value of central serotonin transporter (SERT) availability for treatment response to serotonin reuptake inhibitors (SSRIs). This study used brain imaging to examine the relationship between pretreatment brain SERT availability and transporter occupancy by SSRIs with treatment response in two independent depressed populations. METHODS: Study 1: Twenty-three patients with major depression underwent a single photon emission computed tomography (SPECT) measurement of brain SERT availability using [123I]beta-CIT ([123I]methyl 3beta-(4-iodophenyl) tropane-2beta-carboxylate. The SERT availability was correlated with treatment response to fluoxetine (20 mg/day) assessed with weekly Hamilton Depression Rating Scale (HDRS) for 6 weeks. Study 2: The second group included 10 depressed patients who received 6 weeks of paroxetine treatment (20 mg/day) and serial SPECT scans (baseline, during, and after the treatment). RESULTS: In Study 1, higher pretreatment diencephalic SERT availability significantly predicted better treatment response 4 weeks later. Similar results were found in Study 2 and supported Study 1 findings. The data showed that greater occupancy of diencephalic transporters by paroxetine correlated with better treatment response. CONCLUSIONS: Higher pretreatment availability and greater occupancy of SERT in diencephalon may predict better treatment course in response to SSRIs.     

Pharmacological analysis of zebrafish (Danio rerio) scototaxis

The scototaxis test has been introduced recently to assess anxiety-like phenotypes in fish, including zebrafish. Parametric analyses suggest that scototaxis represents an approach-avoidance conflict, which hints at anxiety. In this model, white avoidance represents anxiety-like behavior, while the number of shuttling events represents activity. Acute or chronic fluoxetine, buspirone, benzodiazepines, ethanol, caffeine and dizocilpine were assessed using the light-dark box (scototaxis) test in zebrafish. Acute fluoxetine treatment did not alter white avoidance, but altered locomotion in the higher dose; chronic treatment (2 weeks), on the other hand, produced an anxiolytic effect with no locomotor outcomes. The benzodiazepines produced a hormetic (inverted U-shaped) dose-response profile, with intermediate doses producing anxiolysis and no effect at higher doses; clonazepam, a high-potency benzodiazepine agonist, produced a locomotor impairment at the highest dose. Buspirone produced an anxiolytic profile, without locomotor impairments. Moclobemide did not produce behavioral effects. Ethanol also produced a hormetic profile in white avoidance, with locomotor activation in 0.5% concentration. Caffeine produced an anxiogenic profile, without locomotor effects. These results suggest that the light-dark box is sensitive to anxiolytic and anxiogenic drugs in zebrafish.     

Methylphenidate effects in the young brain: friend or foe?

Attention deficit hyperactivity disorder (ADHD) is one of the most prevalent neuropsychiatry disorders in children and adolescents, and methylphenidate (MPH) is a first-line stimulant drug available worldwide for its treatment. Despite the proven therapeutic efficacy, concerns have been raised regarding the possible consequences of chronic MPH exposure during childhood and adolescence. Disturbances in the neurodevelopment at these crucial stages are major concerns given the unknown future life consequences.This review is focused on the long-term adverse effects of MPH to the brain biochemistry. Reports conducted with young and/or adolescent animals and studies with humans are reviewed in the context of long-term consequences after early life-exposure. MPH pharmacokinetics is also reviewed as there are differences among laboratory animals and humans that may be relevant to extrapolate the findings.Studies reveal that exposure to MPH in laboratory animals during young and/or adolescent ages can impact the brain, but the outcomes are dependent on MPH dose, treatment period, and animal’s age. Importantly, the female sex is largely overlooked in both animal and human studies. Unfortunately, human reports that evaluate adults following adolescent or child exposure to MPH are very scarce. In general, human data indicates that MPH is generally safe, although it can promote several brain changes in early ages. Even so, there is a lack of long course patient evaluation to clearly establish whether MPH-induced changes are friendly or foe to the brain and more human studies are needed to assess the adult brain changes that arise from early MPH treatment.     

Suizidalität bei depressiven Kindern und Jugendlichen unter Behandlung mit selektiven Serotoninwiederaufnahmehemmern

Due to concerns that selective serotonin reuptake inhibitors (SSRI) might be associated with an increased risk of suicidal ideation and suicide attempts in depressive children and adolescents, treatment with these drugs is controversial. All available data from randomised controlled trials on SSRIs treating depression in these age groups were examined regarding efficacy and suicidality. Results suggest that fluoxetine and, less clearly, sertraline are effective in such treatment. A meta-analysis yielded no statistically significant difference between treatment with SSRI and placebo with regard to the occurrence of suicidal behavior. Following evidence-based criteria, the risk:benefit ratio is favourable for fluoxetine and sertraline. Their use in the pharmacotherapy of depressive children and adolescents is indicated.