Recent Advances in Prepubertal Mood Disorders: Phenomenology and Treatment

John R. Pruett Jr; Joan L. Luby

Curr Opin Psychiatry. 2004;17(1) 

Abstract and Introduction

Purpose of Review: This review examines advances over the last year in the field of prepubertal mood disorders.
Recent Findings: In bipolar affective disorder, general consensus has been established for a phenotype distinct from but co-morbid with attention deficit hyperactivity disorder. Pharmacological trials have provided some support for the safety and efficacy of combination pharmacotherapies. Debate has continued about the possible roles of selective serotonin reuptake inhibitors and stimulants in 'switching' children from an episode of depression to mania. Work on the phenomenology of prepubertal major depressive disorder has identified a preschool phenotype. Double-blind placebo-controlled studies have increased the evidence base for use of fluoxetine in the treatment of major depressive disorder. Few controlled studies have explored the efficacy of psychotherapies. Results from general psychiatry underscore the developmental importance of identification of childhood mood disorders: providing evidence for gene-environment interactions in the pathogenesis of major depressive disorder, suggesting vulnerable periods for environmental insults, and raising the disturbing possibility that untreated major depressive disorder is detrimental to the brain.
Summary: Despite significant progress there remains a striking paucity of data to direct clinical practice in the treatment of prepubertal mood disorders. Data are badly needed to clarify the risk-benefit ratio in circumstances in which potential side effects are not fully understood and the consequences of not treating may, themselves, be detrimental. Further revisions of the early phenomenology of major depressive disorder and bipolar affective disorder will provide the basis for future treatment trials and further studies of etiology and neurobiology.

Numerous studies of the phenomenology of childhood bipolar affective disorder (BP) have established validity for a childhood phenotype (e.g.)[1,2]. These investigations have changed the landscape of child mental health by including bipolar disorder in the differential diagnosis of affective dysregulation. As a result of these data, there has been increasing public health awareness and widespread clinical recognition that childhood BP is a severe illness, characterized by a stable and relapsing course, co-morbidity with attention deficit hyperactivity disorder (ADHD), mixed states, and continuous rapid or ultradian mood cycling (for review, see [1]). Despite the convergence of evidence, the remaining controversies were salient themes in the literature over the last year. They include questions about the breadth of the diagnostic category for children and whether childhood BP is narrowly defined by Diagnostic and statistical manual of mental disorders (DSM)-IV BP type-I (comparable to the adult nosology) or more broadly defined as 'BP NOS'. Related debates concern the relationship between childhood BP and ADHD as overlapping versus co-morbid conditions. Finally, is the prepubertal BP phenotype an early and developmentally adjusted form of adult BP evidenced by continuity with the adult disorder or a unique diagnostic entity?

Empirical evidence and clinical consensus about the existence of major depressive disorder (MDD) in children and adolescents has been present for more than two decades. These data, as well as longitudinal follow-up studies demonstrating continuity with the adult disorder, revolutionized public health attention to childhood MDD, which is now a commonly identified and treated disorder in children of 6 years and older. Building upon this foundation, the current focus of investigation and debate has now shifted to early identification, prevention, and effective treatment (e.g.).[3*,4] Irritability was added to sadness in the DSM-IV as a cardinal symptom specific to childhood manifestations of MDD.[5] More recently, investigators studying the phenomenology of childhood MDD have attempted to identify and characterize the disorder in even younger children.[6**,7**,8] Heightened awareness of the severity and chronicity of childhood MDD, increasing evidence for safety and efficacy of treatments in childhood, and evolving concern about the deleterious effects of untreated MDD on the central nervous system highlight the importance of identification and treatment of MDD at the earliest possible developmental stage.

Bipolar Affective Disorder: Phenomenology

In recent work on prepubertalr BP phenomenology, the importance of the symptom of irritability has been a controversial issue. Irritability is a DSM-IV symptom of adult mania.[5] Irritability, however, presents as a more protean and nonspecific marker in several childhood mental disorders (e.g. disruptive behavior disorders). Geller et al.[9**,10**] suggested that reliance on irritability as a central marker contributes to diagnostic inaccuracy in childhood BP. Geller and colleagues[9**] investigated DSM-IV BP symptom prevalence in prepubertal and early adolescent patients. They found that elation, grandiosity, flight of ideas or racing thoughts, decreased need for sleep, and hypersexuality were symptoms that best discriminated childhood BP from ADHD and normal controls. They required the presence of elation or grandiosity for the diagnosis of BP to enhance specificity and to control for overlapping symptoms of ADHD. They found that, while irritability was a very common symptom of mania, it was also highly nonspecific. In their sample, 72% of children with ADHD demonstrated irritability in contrast to BP children who demonstrated rapid cycling, elation, depression, and irritability.[9**] Several reviews published over the last year have addressed these diagnostic controversies.[11**,12*,13,14**]

Kent and Craddock[12*] analyzed existing data to investigate the relationship between childhood BP and ADHD. They addressed the question of whether BP and ADHD are unique diagnostic entities or different manifestations of one disorder. They concluded that current evidence does not support a relationship between the DSM-IV categories of BP and ADHD in children. Existing data, however, do support a relationship between some BP and ADHD symptoms. They emphasize the importance of developmentally modified DSM-IV BP criteria for children to clarify the clinical distinction of these disorders in young populations.

Finally, Geller and colleagues[15**] reported on a prospective follow-up study of prepubertal and early adolescent BP. In a 2-year period 65.2% of their sample recovered but 55.2% relapsed, with mean times to recovery and relapse of 36.0 and 28.6 weeks, respectively. Notably, psychosocial factors emerged as important variables impacting risk for relapse, with intact family as a protective factor and low maternal warmth as a risk factor.[15**] Review of data, from their ongoing prospective study of 93 participants with childhood or early adolescent onset BP, supports the view that childhood BP is a more severe illness than adult BP. They suggested that typical pediatric BP more closely resembles more malignant forms of the adult disorder, with rapid and continuous cycling, mixed states, and treatment resistance.[14**]

While a significant body of data has converged to paint a clearer clinical picture of childhood BP, there remains a serious paucity of data to inform clinical treatment decisions. This review period provided current and comprehensive reviews[16*,17**,18] of the limited state of knowledge about treatment for BP children and adolescents. Weller and colleagues[17**] discussed existing data (both open-label and placebo-controlled studies, as well as anecdotal clinical evidence) for a comprehensive list of agents. Wagner[18] noted that, to date, only one group has studied a mood stabilizer in adolescent BP in a randomized, double-blind, placebo-controlled fashion. This study found that lithium was effective in the treatment of adolescent BP with co-morbid substance dependence.[19] Wagner and colleagues[20*] recently performed an open-label study of divalproex in children and adolescents with BP and reported that 61% of children showed an improvement of 50% or more in mania symptoms. Notably, 68% experienced mild to moderate adverse events, although no clinically significant alterations in laboratory values were found.

Investigations of combination pharmacotherapy for pediatric BP have also been provided over the last year.[21*,22*] Kowatch and colleagues[21*] studied 53 children who completed acute treatment with a single mood stabilizer. In a 16-week open-label extension phase, nonresponders underwent switching or augmentation. Eighty percent (n=16) of children studied responded to combinations of two mood stabilizers. This suggests that, similar to treatment of some forms of adult BP, BP children may require multiple medications.[21*] Importantly in the same study, Kowatch et al. also investigated the use of stimulants for treatment of co-morbid ADHD. They found that the use of stimulants concurrent with mood stabilizers ameliorated ADHD symptoms and did not exacerbate mood symptoms. While studies of whether stimulants 'unmask' or precipitate mania remain controversial, recent data suggest that this is not a common occurrence (e.g.,[23*] and for a commentary, see)[24*]. In the other combination drug trial, Findling and colleagues[22*] showed that children and adolescents with BP may be safely and effectively treated with a combination of lithium and divalproex. This group reported significant improvements in all outcome measures at weeks 8 and 20. History of psychosis and acute psychosis were more common in nonremitters. Lithium levels were significantly higher in remitters than in nonremitters.[22*]

In keeping with the dearth of treatment data, there have been no published studies of the feasibility and efficacy of psychosocial interventions for children with BP. Fristad and colleagues[25*] reviewed the theoretical support for targeting expressed emotion and family concordance to improve outcome in children with BP. Based on this, Fristad et al.[25*] are conducting the second randomized controlled trial of multifamily psycho educational groups and the first randomized trial of individual family psycho education for families of children with BP. Based on the importance of maternal warmth and other family factors on rates of recovery and relapse in pediatric BP,[15**] such investigations are warranted and may prove important.

Geller and colleagues[26] previously found that in 72 children with prepubertal major depressive disorder (MDD), 48.6% 'switched' to some form of BP by adulthood. At issue is whether this outcome reflects the natural course of the disorder, or whether this is iatrogenic and a result of exposing sensitive individuals to stimulants or antidepressants. Naturalistic follow-up studies and treatment trials are needed to specifically address this question. Luby and Mrakotsky[27*] found higher rates of restlessness in preschoolers with MDD and a family history of BP than in those with MDD and no BP family history, suggesting a very young population with markers of risk for later switching to mania. High rates of prescribing and new investigations have highlighted these concerns about the potential for unwanted 'activation' or induction of 'switching' in response to use of antidepressant medications in BP (or MDD) children.[28] In a retrospective chart review, Wilens et al.[29*] found evidence for psychiatric adverse events in 22% of 82 children treated with selective serotonin reuptake inhibitors (SSRIs). This group found that sleep disturbance and agitation were the most common adverse events, typically occurring within the first 3 months of treatment. Adverse events that emerged early also resolved more rapidly with discontinuation. Forty-four percent of patients (n=18) had psychiatric adverse events on rechallenge. Galanter et al.[23*] showed that children with ADHD and manic symptoms responded to methylphenidate without an increased rate of adverse events during a 1-month trial. Craney and Geller[24*] have pointed out that their own longitudinal data show no relationship between either antidepressant or stimulant use on recovery or relapse in pediatric BP.[15**]

A valid phenotype for prepubertal BP has set the foundation for future neurobiological studies of this disorder. Two reviews this year addressed the state of neuroimaging in pediatric BP.[30*,31] Studies are few and preliminary. In this past year, two groups used proton magnetic resonance spectroscopy to explore potential chemical differences between the brains of BP children and others.[32,33] Future work may shed light on the robustness, specificity, and functional significance of these findings. In another intriguing experiment, Moore and colleagues[34*] used lithium-7 magnetic resonance spectroscopy to show that younger children (youngest age=7 years) had lower brain-to-serum lithium concentration ratios than older children. They described positive linear correlations between serum and brain lithium concentrations, and between age and brain-to-serum lithium ratios. This raises the important question about whether children need higher serum lithium levels than adults to reach therapeutic (brain) lithium levels. This promising field is just in its infancy.

Major Depressive Disorder: Early Phenomenology/Early Identification/Prevention

Luby and colleagues[6**] provided the first demonstration that preschool MDD is characterized by 'typical' symptoms and signs (e.g. sadness/irritability, anhedonia and neurovegetative signs) instead of previously theorized 'masked' symptoms. These investigators found that sadness or irritability was highly sensitive and anhedonia was a highly specific symptom of preschool MDD, while 'masked symptoms' (e.g. somatic) occurred but were less frequently observed.[6**] They also found that some symptoms were evident in thematic play content as reported by parents. Luby and colleagues[7**] also demonstrated that the DSM-IV duration criterion[5] captured only a subset of the most severely ill preschoolers and failed to capture a larger symptomatic group. This investigation provided evidence for a clinically significant depressive syndrome in children as young as 3 years of age. Such findings highlight the need to assess for developmentally translated symptom states to identify the disorder at this early age. In convergence with these data, Mol Lous et al.[8] found reliable markers for depression in young children's play. They found that depressed 3- to 6-year-olds showed less symbolic play, less coherent play, and more nonplay behavior than nondepressed children.

While childhood MDD has been recognized for some time, efficacy of pharmacotherapeutic treatment was not established until the development of SSRIs. Two recent studies have expanded the evidence base for use of these drugs in depressed children.[35**,36*] Fluoxetine is now the only antidepressant with two randomized placebo-controlled studies supporting its efficacy for childhood MDD.[35**] Emslie and colleagues[35**] showed superiority of fluoxetine over placebo in 122 children and 97 adolescents randomized to drug or placebo during a 9-week treatment trial in which few adverse reactions were observed. Importantly, their dose titration data showed statistical significance at 1 week, when fluoxetine dose was at only 10 mg/day. In keeping with these promising results, Baumgartner and colleagues[36*] published a retrospective chart review of 17 children and adolescents with depressive or anxiety disorders treated with citalopram and found that this drug was effective and well tolerated.

In the last year, several informative reviews of the pharmacotherapy for childhood MDD have been published.[37**,38,39*] This evidence points to the critical importance of maintaining a developmental approach to the treatment of childhood MDD. For example, Findling and colleagues[37**] reviewed the data showing a clear lack of efficacy for tricyclic antidepressants, drugs with established efficacy in treating adult MDD, in childhood depression. The largest body of positive efficacy data to date exists for fluoxetine.[37**] These authors highlight the limited data supporting the use of other SSRI antidepressants in childhood MDD; they also review numerous alternative treatments.[37**] Diler and Avci's review[38] cites a need for treatment maintenance guidelines for childhood MDD and suggests 'start low and go slow' (p. 470) with the goal of achieving a 6-month symptom-free period. Pine[39*] reviewed existing data that support recommendations for a medication-free trial at a time of low stress, after marked symptom reduction and 1 year of continued SSRI treatment, with re-initiation at relapse. Pine suggests that randomized maintenance trials are a necessary next step. Regarding other somatic treatments, Russell and colleagues[40*] reported a notable case in which electroconvulsive therapy proved to be a safe and life-saving intervention for a 9-year-old girl with catatonic depression.

Two reviews examined the small database on psychotherapeutic treatment for childhood MDD, including cognitive behavioral therapy and interpersonal and family therapies.[41**,42] Sherrill and Kovacs[41**] noted that there have been less than 10 controlled, peer-reviewed publications on psychotherapy for youths with depression. Their metaanalysis described solid and promising evidence for goal-oriented behavioral therapy and relationship-focused therapy (50-87% recovered) versus 'generic' (21-75% recovered for generic/supportive) or no treatment (5-48% recovered). They also noted that most of the data came from adolescents, highlighting the need for further studies in depressed children. A recent controlled study of psychodynamic psychotherapy[43*] showed immediate and delayed benefits for children with DSM-IV depressive and anxiety disorders. In this study Muratori and colleagues randomized 58 children to time-limited psychodynamic psychotherapy or community services. The psychodynamic psychotherapy treated children showed significant benefits for both of these internalizing disorders as well as externalizing symptoms at both 6 months and at 2 years.[43*] This promising work demonstrates the feasibility and need for future controlled studies of psychotherapies in childhood affective disorders.

In light of existing data discussed above that support the use of SSRIs as the drugs of choice for childhood MDD, the recent report of GlaxoSmithKline's internal data suggesting increased suicidal ideation and unclear efficacy for paroxetine is concerning (discussed in)[44*,45*,46,47*]. The UK Committee on Safety of Medicines banned paroxetine for use in depression in children under 18, and the US Food and Drug Administration recommended, 'that Paxil not be used in children and adolescents for the treatment of MDD'.[48*] During the writing of this review, this single issue has been the most frequent topic of calls from community primary care physicians to one author (JRP) when on-call. In light of prior evidence supporting the safety and efficacy of SSRIs, further controlled studies are urgently needed so that clinicians can make better-informed decisions about using SSRIs other than fluoxetine for childhood MDD.

Several publications from the general literature are included in this review due to their contribution to understanding the importance of early identification and prevention of childhood MDD. In a large longitudinal community sample, Caspi et al.[49**] recently investigated gene-environment interactions in the risk for MDD. Examining environmental interactions with functional polymorphisms of the serotonin transporter (5-HTT) gene, they found that individuals with one or two short alleles of the 5-HTT promoter polymorphism had a higher frequency of depression in response to life stress than those with two copies of the long allele.[49**] This exciting finding provides the most specific and robust evidence to date of the long suspected gene-environment interaction in risk for MDD. Penza et al.[50**] reviewed the accumulating body of evidence supporting the idea that early childhood stress (e.g. abuse) can permanently alter the major neuroendocrine stress-response system, leading to neurodevelopmental changes that may later increase the risk of MDD and anxiety disorders. These alterations in the hypothalamic-pituitary-adrenal axis may lead to structural brain changes such as atrophy of the hippocampus (again, see review)[50**]. Finally, Sheline and colleagues[51**] used structural magnetic resonance imaging to show that the duration of untreated depression correlates with the magnitude of hippocampal volume loss in women with recurrent depression. They discussed how this finding implies a neuroprotective effect for antidepressant medication.[51**] These are extremely important considerations when weighing the potential risks and benefits of (long-term) antidepressant treatment in children with MDD.

Conclusion

This year advanced knowledge about the phenomenology and treatment of prepubertal mood disorders. Refining prepubertal MDD and BP phenotypes has provided another step toward better understanding risks and benefits for pharmacological and psychotherapeutic interventions. Disturbing questions about potential differential safety and efficacy profiles of SSRIs echo lessons learned from previous trials with tricyclic antidepressants in children: medications that are effective for adults with MDD and BP may not work the same in children. Yet the emerging evidence suggests mood disorders may have long-lasting neurodevelopmental sequelae, highlighting the critical importance of early identification, prevention, and treatment.

References

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  40. * Russell PS, Tharyan P, Kumar K, Cherian A. Electro convulsive therapy in a pre-pubertal child with severe depression. J Postgrad Med 2002; 48:290-291. This is an important case report that underscores the need for further study of electroconvulsive therapy in childhood MDD.

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  43. * Muratori F, Picchi L, Bruni G, et al. A two-year follow-up of psychodynamic psychotherapy for internalizing disorders in children. J Am Acad Child Adolescent Psychiatry 2003; 42:331-339. These authors reported exciting findings about psychodynamic psychotherapy in children with internalizing disorders.

  44. * Waechter F. Paroxetine must not be given to patients under 18. BMJ 2003; 326:1282. This brief report addresses the Medicines and Healthcare Products Regulatory Agency's recommendations for UK pediatric patients on paroxetine.

  45. * Abbott A. British panel bans use of antidepressant to treat children. Nature 2003; 423:792. This brief report summarizes emerging concerns about efficacy and increased suicidal thinking in children on paroxetine.

  46. Bachtold D. Drug safety: conflict-of-interest allegations derail inquiry into antidepressant's 'dark side'. Science 2003; 300:33.

  47. * The Medical Letter, Inc. Are SSRIs safe for children? The Medical Letter on Drugs and Therapeutics 2003; 45:53-54. This report provides a balanced discussion about the risks of stopping versus continuing treatment with paroxetine.

  48. * US Food and Drug Administration. FDA statement regarding the anti-depressant Paxil for pediatric population. FDA Talk Paper 2003; T03-T43. http://www.fda.gov/bbs/topics/ANSWERS/2003/ANS01230.html. [(Accessed 19 June 2003)] This web report provides the official US Food and Drug Administration recommendation about Paxil in children.

  49. ** Caspi A, Sugden K, Moffitt TE, et al. Influence of life stress on depression: moderation by a polymorphism in the 5-HTT gene. Science 2003; 301:386-389. This important paper provides data that in part explain a long-presumed gene-environment interaction in the pathogenesis of depression. It provides one explanation for why stress may contribute to depression in some people but not in others.

  50. ** Penza KM, Heim C, Nemeroff CB. Neurobiological effects of childhood abuse: implications for the pathophysiology of depression and anxiety. Arch Women Ment Health 2003; 6:15-22. These authors provided a thorough and readable review of a critically important topic. The discussions raise the hypothesis of a critical period for susceptibility to environmental insult on neuroendocrine systems implicated in depression and anxiety.

  51. ** Sheline YI, Gado MH, Kraemer HC. Untreated depression and hippocampal volume loss. Am J Psychiatry 2003; 160:1516-1518. These investigators found evidence for structural brain changes resulting from untreated depression. This is an important work when pondering risks and benefits of treating childhood MDD.