Treatment-emergent adverse events from selective serotonin reuptake inhibitors by age group: children versus adolescents

OBJECTIVE: The aim of this study was to report the frequency of common treatment-emergent adverse events (AEs) from selective serotonin reuptake inhibitors (SSRIs) in children, adolescents, and adults. METHOD: AE data were obtained from all published double-blind, placebo-controlled SSRI studies of children and adolescents that separated AE findings by age group. The AE findings were pooled for purposes of age-group comparisons. Double-blind, placebo-controlled SSRI studies of adolescents (n = 2) and of adults identified in systematically identified trials (n = 22) were assessed to compare patterns and rates across the age span. Other reports, primarily from the published SSRI literature, were added to clarify the findings presented. RESULTS: Activation and vomiting SSRI AEs were 2- to 3-fold more prevalent in children than in adolescents, and their rate was lowest in adults. Somnolence as a SSRI AE was uncommon in children; its rate increased with advancing age. Insomnia and nausea were common SSRI AEs across the age span. Activation AEs were a frequent reason for discontinuation from SSRI clinical trials in preadolescents, whereas somnolence, nausea, and insomnia AEs were the most common reasons for trial discontinuations in adults. CONCLUSIONS: Children are particularly vulnerable to specific AEs from certain medications, such as SSRIs. It is likely that the level of children's biological immaturity explains part of this phenomenon.     

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.     

Serotonin-norepinephrine reuptake inhibitors in the treatment of obsessive-compulsive disorder: A critical review

OBJECTIVE: To critically review the antiobsessional properties of serotonin-norepinephrine reuptake inhibitors (SNRIs) (venlafaxine and clomipramine) in the treatment of obsessive-compulsive disorder (OCD) as an alternative to selective serotonin reuptake inhibitors (SSRIs), which are currently considered the first-line treatment of OCD. DATA SOURCES: A MEDLINE search was performed to identify clinical trials with the SNRIs venlafaxine and clomipramine published from 1996 to 2004 (keywords: SNRIs, venlafaxine, duloxetine, and clomipramine, each matched individually with the term OCD), focusing on the best-designed studies for inclusion. DATA SYNTHESIS: Much of the literature about SNRIs in OCD supports the efficacy of these compounds in the treatment of OCD. However, double-blind, placebo-controlled studies with venlafaxine are lacking, and the most relevant studies consist of active comparison trials between SNRIs and SSRIs. In these studies, SNRIs seem to be as effective as SSRIs in OCD; SNRIs might be preferred for patients with certain types of treatment-resistant OCD or those with particular comorbid conditions. A large number of placebo-controlled and active comparison trials with clomipramine document efficacy in OCD, and meta-analytic studies suggest a small superiority over SSRIs. Compared with clomipramine, the SNRI venlafaxine showed fewer side effects and better tolerability. CONCLUSION: The SNRIs may represent a valid alternative to the SSRIs, particularly in specific cases. Double-blind, placebo-controlled studies are, however, needed to confirm the positive findings reported by several studies with venlafaxine.     

Treatment outcome and outcome associations in children with pervasive developmental disorders treated with selective serotonin reuptake inhibitors: a chart review

PURPOSE: The aim of this study was to determine the outcome and predictors of outcome with selective serotonin reuptake inhibitors (SSRIs) in outpatient children and adolescents with pervasive developmental disorders (PDDs). METHOD: Clinic charts were reviewed for 89 outpatient youths with a Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV) diagnosis of a PDD who were treated with SSRIs. Response was determined using the Clinical Global Impressions (CGI) scale. Side-effect and demographic data, including family history, were recorded. RESULTS: Forty-four point nine percent (44.9%) were determined to be much improved and considered responders. Fifty-four percent (54%) of the subjects demonstrated activation side effects. In 35.4% of these subjects, the activation side effects led to drug discontinuation. Pearson chi-squared and regression analysis demonstrated an association between SSRI response and a family history of PDD. There were no significant associations between clinical variables and activation side effects. CONCLUSIONS: SSRI treatment led to modest response rate in this group of youths with PDDs. Activation side effects were frequent, often leading to treatment dropouts. Potential outcome associations include a family history of PDDs.     

A double-blind placebo-controlled pilot study of olanzapine in childhood/adolescent pervasive developmental disorder

Atypical antipsychotics have been shown to improve disruptive and repetitive behaviors in pervasive developmental disorders (PDDs), but they require assessment of potential side effects. This is the first placebo-controlled trial of olanzapine in the treatment of children and adolescents with PDD. Eleven patients with a diagnosis of either autism, Asperger's syndrome, or PDD not otherwise specified (PDD-NOS) and aged 6-14 years were randomized into an 8-week double-blind, placebo-controlled, parallel treatment study with olanzapine. There was a significant linear trend x group interaction on the Clinical Global Impressions- Improvement (CGI-I) and 50% on olanzapine versus 20% on placebo were responders. Olanzapine was associated with significant weight gain (7.5 +/- 4.8 lbs vs. 1.5 +/- 1.5 lbs on placebo). Olanzapine may be a promising treatment for improving global functioning of PDDs, but the risk of significant weight gain remains a concern. Additional studies are needed to determine the efficacy and safety of olanzapine in the treatment of children with PDD.     

Research Units on Pediatric Psychopharmacology (RUPP) Autism Network. Background and rationale for an initial controlled study of risperidone

This article has reviewed the background and rationale for the choice of risperidone as the first drug to be studied by the RUPP Autism Network. Risperidone has potent effects on 5-HT and DA neuronal systems, both of which have been implicated in the pathophysiology of autism. Unlike the typical antipsychotics, haloperidol and pimozide, which have been shown to be effective for reducing many of the maladaptive behaviors associated with autism, risperidone's 5-HT2A/DA D2 ratio of receptor blockade appears to produce a lower risk of acute and chronic extrapyramidal side effects, as well as enhanced efficacy for the "negative" symptoms of autism. Indirect clinical and preclinical evidence supports the use of risperidone to treat impaired social behavior, interfering repetitive phenomena, and aggression, targets of pharmacotherapy for many patients with autism. Numerous published open-label trials in children and adolescents with autism and related PDDs and one double-blind, placebo-controlled study in adults suggest that risperidone has promise for the treatment of children and adolescents with autism. Because most of these studies have been short-term, open-label trials in small samples, however, a large-scale controlled study of risperidone in children and adolescents with autism is needed to confirm these results. Finally, because it is likely that children who demonstrate short-term benefit from risperidone will remain on the medication indefinitely, the longer-term effectiveness and safety of risperidone in this population also needs to be determined. The design of this study and the assessments used are described separately.     

Peripheral and central neurochemical effects of the selective serotonin reuptake inhibitors (SSRIs) in humans and nonhuman primates: assessing bioeffect and mechanisms of action

It is clear that selective serotonin reuptake inhibitors (SSRIs) act powerfully to inhibit serotonin (5-hydroxytryptamine, 5-HT) uptake centrally and peripherally. However, there are a number of critical unanswered questions concerning the effects of the drugs in adults and children. The influence of age and duration of treatment on the extent of uptake inhibition and on the enhancement of central serotonergic functioning are unclear. In addition, the relationship of these factors and effects to the therapeutic and adverse effects of the SSRIs remain to be clarified. The general clinical utility of platelet 5-HT measurement is reviewed and studies assessing central and peripheral uptake blockade in infants and children and non-human primates are discussed. Recent investigations of central neurochemical effects of the SSRIs in primates assessed through measurement of 5-HT and related compounds in cisternal cerebrospinal fluid (CSF) of the rhesus monkey are presented. In summary, the studies described have found that: human fetal exposure to SSRIs has substantial effects on 5-HT transport in utero; exposure to SSRIs through breastmilk of mothers treated for postpartum depression usually has negligible effects on 5-HT uptake; prescribed SSRIs appear to exert similar effects on 5-HT transporter blockade in children and adults; and rapid and sustained increases are seen in monkey cisternal CSF levels of 5-HT upon initiation of SSRI administration. The implications of the observations in terms of behavioral effects, clinical practice, and underlying mechanisms of action of the SSRIs are discussed.     

Does elimination of placebo responders in a placebo run‐in increase the treatment effect in randomized clinical trials? A meta‐analytic evaluation

The use of a placebo run-in phase, in which placebo responders are withdrawn from a study before random assignment to treatment condition, has been criticized as favoring the active treatment in clinical trials. We compared the effect size of randomized, placebo-controlled clinical trials (in the treatment of depression with selective serotonin reuptake inhibitors [SSRIs]) that include a placebo run-in phase with those that do not, using a meta-analytic approach. This study differed from earlier meta-analytic studies in that it considered only SSRIs and included only studies using continuous measures of depression, allowing for a more refined assessment of effect size. An extensive literature search identified 43 datasets published between 1980 and 2000 comparing placebo with SSRI and using a continuous measure of depression (usually the Hamilton Depression Rating Scale). We included only studies of at least 6 weeks' duration focusing on treatment for primary acute major depression in adults 18-65 years of age. Studies focusing on depression in specific medical illnesses were not included. Analysis of efficacy was based on 3047 subjects treated with an SSRI antidepressant and 3740 subjects treated with a placebo. There was no statistically significant difference in effect size between the clinical trials that had a placebo run-in phase followed by withdrawal of placebo responders and those trials that did not. Despite the lack of a statistically significant difference between studies of withdrawing early placebo responders and those not using this procedure, this approach is likely to continue to be used widely because it produces large absolute effect sizes. It is recommended that future studies clearly describe these procedures and report the number of subjects dropped from the study for early placebo response and other reasons.     

Citalopram therapy for depression: a review of 10 years of European experience and data from U.S. clinical trials

BACKGROUND: This review summarizes and evaluates clinical experience with citalopram, the latest selective serotonin reuptake inhibitor (SSRI) to be approved for the treatment of depression in the United States. DATA SOURCES: Published reports of randomized, double-blind, controlled clinical studies of citalopram were retrieved using a MEDLINE literature search. Search terms included citalopram, SSRI, TCA (tricylic antidepressant), depression, and clinical. For each study, data on antidepressant efficacy and adverse events were evaluated. Pharmacokinetic studies and case reports were reviewed to supplement the evaluation of citalopram's safety and tolerability. Data presented at major medical conferences and published in abstract form also were reviewed. STUDY FINDINGS: Thirty randomized, double-blind, controlled studies of the antidepressant efficacy of citalopram were located and reviewed. In 11 studies, citalopram was compared with placebo (1 of these studies also included comparison with another SSRI). In 4 additional studies, the efficacy of citalopram in preventing depression relapse or recurrence was investigated. In another 11 studies (including 1 meta-analysis of published and unpublished trials), citalopram was compared with tricyclic and tetracyclic antidepressants. Finally, results are available from 4 studies in which citalopram was compared with other SSRIs. A placebo-controlled study of citalopram for the treatment of panic disorder was reviewed for data on long-term adverse events. CONCLUSION: Data published over the last decade suggest that citalopram is (1) superior to placebo in the treatment of depression, (2) has efficacy similar to that of the tricyclic and tetracyclic antidepressants and to other SSRIs, and (3) is safe and well tolerated in the therapeutic dose range of 20 to 60 mg/day. Distinct from some other agents in its class, citalopram exhibits linear pharmacokinetics and minimal drug interaction potential. These features make citalopram an attractive agent for the treatment of depression, especially among the elderly and patients with comorbid illness.     

Pharmacotherapy of irritability in pervasive developmental disorders

Children and adolescents diagnosed with autism and related pervasive developmental disorders (PDDs) often sustain irritability, including aggression, self-injurious behavior, and tantrums. Research to date supports the use of the atypical antipsychotics as a first-line pharmacologic treatment for this target symptom domain in PDDs. Currently, the atypical antipsychotic risperidone is the only medication approved by the US Food and Drug Administration for irritability in youth with autism. Additional large-scale, placebo-controlled studies of other medications are needed to determine their efficacy for the treatment of irritability in this diagnostic group.     

Controversy revisited: Selective serotonin reuptake inhibitors in paediatric depression.

BACKGROUND: Selective serotonin reuptake inhibitors (SSRIs) are currently controversial treatments for paediatric depression. There have been several publications on the subject during recent years. This article summarizes their findings and provides some original thoughts, suggestions, and perspectives. METHODS: Important and relevant articles presenting original data and published in leading journals during 2003-2005 were identified through a PubMed search. Articles instructive in content were selected. A narrative sequence is used to review the field, build arguments, and propound views. RESULTS: Ten principal and several other auxiliary studies were identified for scrutiny. The findings of these studies suggest that published clinical trials of SSRIs in paediatric depression have overstated the antidepressant benefits and understated the risks of suicidal ideation and behaviour arising with treatment; the unpublished clinical trial data are even more unfavourable. Nevertheless, the clinical, epidemiological, and forensic data do suggest overall safety and efficacy of the SSRIs, amongst which fluoxetine may have the best risk-benefit profile. CONCLUSIONS: Psychotherapeutic interventions may not always be feasible or effective, especially when depression is more severe. The failure to prescribe a drug may, at the very least, lead to the loss of the placebo effect. It is therefore suggested that, if the diagnosis of unipolar depression is confident, appropriate doses of fluoxetine may be prescribed to depressed children and adolescents; the use of rescue medication to treat emergent agitation is important, and augmentation with psychotherapy may further improve outcomes. The monitoring of indices of growth may also be necessary.     

Pharmacological treatment options for autism spectrum disorders in children and adolescents

Autism and other pervasive developmental disorders (PDDs) are frequently associated with dysfunctional behaviors and are characterized by deficits in socialization, communication, and behavioral rigidity. Despite the absence of a pharmacological cure for PDDs, many of the dysfunctional, coinciding behaviors may be treated pharmacologically. This article reviews what is known about the efficacy and tolerability of pharmacological interventions for the treatment of children and adolescents suffering from autistic spectrum disorders.     

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.     

Atomoxetine for the treatment of attention-deficit/hyperactivity disorder

Atomoxetine is a selective noradrenaline reuptake inhibitor that has been studied for use in the treatment of attention-deficit/hyperactivity disorder (ADHD). In vitro, ex vivo and in vivo studies have shown that atomoxetine is a highly selective antagonist of the presynaptic norepinephrine transporter with little or no affinity for other noradrenergic receptors or other neurotransmitter transporters or receptors. So far, two open-label and seven randomised, double-blind, placebo-controlled, clinical trials have been published, six in youths and three in adults. Each of these trials has shown a positive response as measured by the primary efficacy measures, the ADHD-IV Rating Scale (ADHD RS) or the Conners Adult ADHD Rating Scale (CAARS). Atomoxetine has generally been well tolerated. The most common treatment-related adverse event was decreased appetite. Atomoxetine shows no abuse potential and is not a controlled substance in the US. In November of 2002 the FDA approved atomoxetine for use in the US for the treatment of ADHD in children, adolescents and adults. Atomoxetine is the first nonstimulant approved by the FDA for the treatment of ADHD and the first medication approved for the treatment of adult ADHD.     

Comparison of response to a selective serotonin reuptake inhibitor in children,adolescents, and adults with posttraumatic stress disorder

BACKGROUND: Although the pathophysiology of posttraumatic stress disorder (PTSD) is considered multifactorial, empirical evidence suggests that serotonergic dysregulation may characterize the disorder. The efficacy of the selective serotonin reuptake inhibitors (SSRIs) in treating essential symptoms (re-experiencing, avoidance, numbing, hyperarousal) in both adults and children is likely to involve potentiation of this neurotransmitter. OBJECTIVE: This study compared outcome in an 8-week open trial of citalopram (an SSRI) in children/adolescents and adults with a Diagnostic and Statistical Manual of Mental Disorders (4th ed.) diagnosis of PTSD. METHODS: Twenty-four children/adolescents and 14 adults assessed for PTSD severity at baseline were followed up on citalopram treatment (20-40 mg/day) at two-weekly intervals over 8 weeks. The Clinician-Adminstered PTSD Scale (CAPS) and the Clinical Global Improvement Scale (CGI) were used as outcome measures. RESULTS: Although there were no significant differences in outcome measures between children/adolescents (n = 24) and adults (n = 14), both groups had significant reductions in mean CAPS total scores, symptom cluster scores, and CGI ratings at endpoint. CONCLUSION: Although the SSRIs have established efficacy and safety in the treatment of adult PTSD, literature on their use in child and adolescent PTSD is sparse. Controlled data are needed to support the clinical perception that SSRIs are agents of choice in the treatment of pediatric PTSD.     

A retrospective assessment of citalopram in children and adolescents with pervasive developmental disorders

Although selective serotonin reuptake inhibitors have been used to treat symptoms of aggression and anxiety in children and adolescents with pervasive developmental disorders (PDDs), there are no published reports of the use of citalopram in this population. The purpose of this study was to examine the benefits and adverse effects of citalopram in a group of children and adolescents with PDDs. Target behaviors included aggression, anxiety, stereotypies, and preoccupations. Seventeen patients with PDDs (14 with autistic disorder, three with Asperger's disorder) (mean age = 9.4 +/- 2.9 years; range 4-15 years) were treated with citalopram for at least 2 months (mean duration of treatment = 7.4 +/- 5.3 months; range 1-15 months). Treatment was initiated at a low dose (5 mg daily) and was increased by 5 mg weekly as tolerated and as necessary. The mean final dose was 19.7 +/- 7.8 mg (range 5-40 mg). Outcome was based on a consensus between clinician and parents, using the Improvement item of the Clinical Global Impressions Scale as a guide. Ten (59%) children were judged to be much improved or very much improved regarding target behaviors. Core symptoms of PDDs (social interactions, communication) did not show clinically significant improvement. Citalopram was generally well tolerated, although four patients developed treatment-limiting adverse effects: two with increased agitation, one with insomnia, and one with possible tics. The results of this case series suggest that citalopram has beneficial effects on some interfering behaviors associated with PDDs with few adverse effects. Controlled trials are warranted.     

Risperidone-induced prolactin elevation in a prospective study of children, adolescents, and adults with mental retardation and pervasive developmental disorders

OBJECTIVE: Risperidone is widely prescribed for aggression and self-injury in children, adolescents, and adults with mental retardation (MR) and pervasive developmental disorders (PDD). Risperidone elevates prolactin more than other atypical antipsychotic medications. Females may show greater prolactin elevation than males. METHOD: In this relatively long-term study of risperidone efficacy and safety for aggression and self-injury in children, adolescents, and adults with MR and PDDs, serum prolactin was measured in a 21-subject subset during the course of a double-blind, placebo-controlled trial. Prolactin was measured in ng/mL at baseline, once during acute treatment, and once during maintenance. RESULTS: In children and adolescents (n=10), mean age of 12.5 years, prolactin increased from mean 13.2+/-8.6 at baseline to 31.0+/-11.6 acutely and remained elevated at 37.9+/-10.4 in maintenance. In adults, mean age of 35.3 years, prolactin increased more markedly from 11.6+/-7.4 baseline (n=11) to 93.3+/-54.2 acutely but decreased to 67.8+/-62.9 in maintenance (n=7). Prolactin remained significantly elevated above normal in all subjects for at least 26 weeks. Mean prolactin of adult females, while similar to that of adult males at baseline, was 2.2 times male levels acutely and 3.7 times greater in maintenance. CONCLUSION: In this small subset, mean prolactin elevation persisted for at least 26 weeks. In adults, females showed significantly greater elevations than males.     

Is Rett syndrome a subtype of pervasive developmental disorders?

The author reviews the issue on whether Rett syndrome (RS) is a subtype of pervasive developmental disorders (PDDs). More than 200 articles of RS have been published in the last 10 years. Internal and external validities of RS have been established by several independent studies. There remains the question whether RS presents clinical features that meet the total criteria for PDDs. The available data seem to support the idea of classifying RS as a subtype of PDDs in the DSM-IV.The views expressed in this article are those of the author and do not represent the official positions of the DSM-IV Task Forces, Work Groups, or the American Psychiatric Association.     

Selective serotonin reuptake inhibitors in pediatric depression: is the balance between benefits and risks favorable?

Recent controversies surrounding the use of selective serotonin reuptake inhibitors (SSRIs) have highlighted the need to reassess potential benefits, as well as potential risks of this class of medications in the treatment of pediatric depression. The recent availability of data from meta-analyses of published and unpublished antidepressant trials, epidemiological studies, and the Treatment for Adolescents with Depression Study (TADS) has facilitated a reanalysis of this risk/benefit relationship. Despite reviewing similar data, various regulatory agencies have arrived at rather disparate conclusions regarding the data, resulting in continued controversy. Although all groups appear to agree that careful assessment, education regarding risks, and closer monitoring are essential for SSRIs, only the U.S. Food and Drug Administration (FDA) and the U.K. Medicine and Health Care Products Regulatory Agency maintain that an acceptable risk/benefit relationship exists for fluoxetine. The European Medicines Agency concluded that the SSRIs should not be used in the treatment of depression in children and adolescents. The authors of this review have taken into consideration many of these same data and offer a critical discussion of the pros and cons of SSRIs in pediatric depression. The authors have concluded that SSRIs -- in particular, fluoxetine -- do have a role in the treatment of pediatric depression.