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Research Agenda for Depression and Bipolar Disorder 

Research Agenda for Depression and Bipolar Disorder
Research Agenda for Depression and Bipolar Disorder
Treating and Preventing Adolescent Mental Health Disorders: What We Know and What We Don't Know. A Research Agenda for Improving the Mental Health of Our Youth


The Disorder

What We Know

Basic knowledge about major depressive disorder (MDD) in adolescence has begun to accumulate over the past two decades. Most importantly, MDD is now no longer seen primarily as a disorder of the middle-aged and elderly. It is clear that MDD often begins in adolescence and has a serious impact on the adolescent's development into adulthood. In contrast, prepubertal onset is less common, with a higher proportion of males who experience mood reactivity, irritability, dysphoria, and comorbidity with disruptive disorder. Adolescent MDD is chronic and recurrent, sharing diagnostic features with those of adult MDD, including high comorbidity with anxiety and substance abuse disorders, and risk for suicide. Adolescent MDD is associated with a lack of social development and skills, withdrawal from peers, and poor school performance.

Information on risk factors for the development of adolescent MDD has also begun to emerge. The most consistent risk factors for MDD in both adolescents and adults are female gender (2-to 3-fold increased risk) and a family history of MDD. Offspring of depressed parents are at increased risk (2-to 4-fold) for depression. A previous episode is a major risk factor for the occurrence of additional episodes; over 50% of adolescents with MDD have a recurrence within 5 years, and MDD episodes often continue into adulthood. This confers an increased risk of suicide attempts and psychiatric and medical hospitalizations. Adverse family environments, especially the absence of supportive interactions, poor parental bonding, poor primary attachments, and harsh discipline, are also risk factors that contribute to both the onset and recurrence of adolescent MDD. Negative cognitions about the self appear to mediate the relation between stressful life events and the occurrence of depressive symptoms.

Biologically, there are abnormalities in hypothalamic–pituitary–adrenal (HPA) axis activity in adolescence similar to those found in adults, as well as thyroid dysfunction.

What We Do Not Know

We have only begun to characterize the possible adverse effects of depression on brain structure and function. We have limited data on brain plasticity and neurogenesis. In addition, the way in which treatment interventions (psychosocial and/or psychopharmacological) impact brain plasticity and neurogenesis is unknown. No specific genes have yet been identified that are unequivocally associated with MDD, regardless of age of onset.

Although there appears to be a clear link between life events and depression, we do not know the mechanisms by which stress increases an individual's vulnerability to depression or the genetic and environmental factors that influence vulnerability or resilience. Furthermore, it is known that various forms of stressors often precede mood disorders, but it is not known why only some individuals exposed to these stressors become depressed. There is some evidence that a patient's response to an external stressor may be moderated by the individual's genetic constitution, by possessing a functional polymorphism in the promoter region of the serotonin transporter gene. Some evidence has pointed to negative cognitive appraisals of the self and life events as mediators of the relation between stress and depression, but these factors do not appear to tell the whole story. Thus, other mediators are likely. Moreover, we know little about the ways in which such negative cognitions develop in adolescence, and whether they can be prevented.

The biological mechanisms that mediate the relation between life events and risk of MDD in adolescents are also not known. We do not know whether the presence of adolescent depression is a risk factor for the development of other medical diseases and how its presence may affect the course of the medical illness. In addition, we do not know if treatment and/or prevention of depression decreases the potential impact and severity of the expressed medical illness.

Research Priorities: What We Need to Know

Research on adolescent MDD needs to proceed on many fronts. To facilitate research across broad aspects of the disorder, we propose that highest priority be given to the following areas:

  • Studies of the prodromal phase of child and adolescent mood disorders. Such research would allow for better identification of the illness and how it evolves over time to its full clinical course.

  • Integrative studies of the range of possible psychological, sociological, familial, and biological variables that contribute to the development of adolescent depression. By identifying which variables are most important and contribute the most to the development of adolescent MDD, we can target treatment and prevention efforts to such risk factors and yield the best outcomes.

  • Examination of the mediational links between environmental stressors, cognitive and personality variables, genetics, biological systems, and depressive symptoms. Uncovering these links will provide information on the causal chain of events that leads to the clinical disorder, and suggest avenues for the further development of new treatments and preventive programs.


What We Know

As found in the adult depression treatment literature, cognitive behavioral treatment (CBT) and interpersonal therapy for youth depression appears to be more efficacious than no treatment, wait-list control, or attention placebo controls. In addition, there is preliminary evidence suggesting that attachment-based family therapy may be useful for the treatment of adolescent depression. To date, the only medications that have demonstrated safety and efficacy in double-blind, placebo-controlled trials for children and adolescents with major depression are the selective serotonin reuptake inhibitors (SSRIs). Fluoxetine was the first SSRI and the only one with federal Food and Drug Administration (FDA) approval for the treatment of pediatric depression. Recently, the National Institute of Mental Health (NIMH) funded study entitled “Treatment of Adolescents with Depression Study” (TADS) showed that 71% of patients responded well to combination treatment of CBT with fluoxetine compared with 61% who received fluoxetine alone, 43% who received CBT alone, and 35% of those treated with placebo. The study also reported that patients became significantly less suicidal regardless of the treatment they received. In addition, after reviewing 24 double-blind, placebo-controlled pediatric trials using antidepressants, an FDA panel has determined that SSRIs may carry an increased risk of suicidal ideation or behaviors for a small proportion of users (perhaps 2% or 3%). The FDA has labeled all antidepressants with a warning about the potential risk of increased suicidal thinking and behavior and the need for close medical monitoring, particularly in the first month of treatment and when the medication dose is adjusted. The FDA expects physicians to educate patients and families about the risks and benefits of these medications and to watch for behavioral changes in the child, such as irritability, aggression, and impulsivity. In spite of these concerns, antidepressants can be very effective in treating mood and anxiety disorders in this group.

What We Do Not Know

Although initial treatment studies have been promising, many patients continue to have clinically significant levels of depression after psychotherapy and medication treatment, and most patients experience at least one recurrence of depression within 5 years of treatment termination. Thus, we know little about achieving remission and favorable long-term outcomes in adolescent MDD populations. Presently, the TADS program is continuing to follow children over a one-year period after completing the acute phase of the study. This will provide much needed information about long-term treatment outcomes for adolescents with depression. Moreover, we do not know which specific psychosocial or pharmacologic treatments are most efficacious and for which patients. In addition, there is little known about the efficacy of sequencing or combining various treatments. There is no information regarding the management of partial and nonresponse in the treat ment of adolescent depression. We have limited information about the optimal length of time for any of these treatments and how to maintain the treatment response once achieved by using such options as booster sessions and/or varying the length of medication treatment. There is also little information on how our present treatments that target adolescent depression impact comorbid psychiatric disorders such as substance abuse, disruptive disorders, and anxiety disorders.

Research Priorities: What We Need to Know

We have identified a number of high-priority topics for treatment research on MDD in adolescence:

  • There is a need for more research into the safety and efficacy of SSRIs. The benefits vs. risks of using SSRIs with adolescents should be carefully assessed in such studies.

  • Future studies need to have adequate statistical power to determine the efficacy and safety of antidepressants in both child and adolescent populations.

  • There is a particular need to research the use of antidepressant treatment in suicidal adolescents. Independent, federally funded centers should be established to evaluate treatment to prevent suicide.

  • Long-term studies of antidepressants are required to evaluate their safety profile in children. This information will enable a risk/ benefit analysis of extended antidepressant use. In addition, maintenance studies are needed to guide optimal medication treatment duration.

  • There is a need for antidepressants studies focussing on remission of symptoms and full functional recovery, rather than just treatment response.

  • The development and testing of interventions that focus on maternal depression and family discord might be an effective way of preventing adolescent depression.

  • Additional treatment research such as the TADS program is needed to explore further the acute efficacy of combination treatment, with a particular focus on determining which subpopulation of patients will do best with monotherapy vs. combined treatment.

  • Treatment research is needed on refractory and chronic conditions, such as “double depression” in adolescence. These chronic disorders may respond better to combinations of medication and CBT than to either monotherapy alone, as suggested by comparable data on adults with chronic depression.

  • Interventions designed to improve outcome in patients with poor prognostic risk factors need to be examined.

  • There is little in the literature about the transportability of manualized treatments to the community settings; this important issue needs to be addressed.


What We Know

A number of promising strategies for the prevention of childhood and adolescent depression have emerged over the past decade. Of special significance is the fact that these emerging prevention strategies make a point of taking the developmental level of participants into account. The evaluated preventive strategies are based primarily on cognitive-behavioral and family-educational approaches, with the focus of reducing risk factors and enhancing protective and resiliency factors associated with depression in youth. Rigorous standards for the development and evaluation of manual-based preventive approaches have been introduced, and these innovations have greatly facilitated research in this area.

To date, we have initial evidence that these prevention programs are more effective than both no treatment and usual care (staying in existing treatment or patients seeking treatment on their own) in reducing future episodes of MDD. These effects are particularly evident for those at highest risk of MDD and for those with the greatest severity of depressive symptoms.

What We Do Not Know

Despite the promising studies on prevention of depression, much remains to be learned. There are not enough data about the timing of preventive interventions or about the appropriate setting for such interventions to be assured that the expected outcomes occur for the targeted population. Most studies have used samples that include adolescents who have had previous episodes of MDD (high-risk samples). Thus, we know little about the prevention of first episodes of MDD. Long-term follow-up data are scarce but crucial to understanding whether preventive interventions have an impact on the occurrence of MDD episodes into adulthood.

Research Priorities: What We Need to Know

Prevention research is in its infancy; therefore, a number of basic studies are sorely needed. These include the following:

  • More prevention programs based on the full range of risk factors for MDD need to be developed and tested.

  • Comparisons among existing preventive programs need to be conducted.

  • Further research on the active ingredients of preventive programs and the mediators of change should be performed.

  • We need to examine prevention programs in different contexts with an awareness of cultural, racial, and ethnic differences.

  • We need to learn how to disseminate prevention programs so that they reach the families most at need and at risk. This is especially a challenge because of the lack of sophisticated delivery systems of prevention programs.

  • The impact of prevention programs for individuals with different types of risk factors for MDD needs to be evaluated.


The Disorder

What We Know

We now know that variants, or precursors, of bipolar disorder may be more common in adolescence than previously thought. There is a growing consensus that youth who are afflicted with severe affective dysregulation, high levels of agitation, aggression, and dyscontrol may be suffering from an early form of bipolar disorder. This issue has received increased scientific attention, as is evident in the scheduling of two NIMH workshops on bipolar disorder in children and adolescents and in exhaustive reviews that have supported the validity of the disorder in youth.

Bipolar disorder is highly heritable. There are several loci of the human genome that have been associated with the disorder.

What We Do Not Know

We know little about how to accurately identify the early signs and symptoms of bipolar disorder in youth. This challenge of early disorder identification has limited epidemiologic information on this illness. There is still controversy over the definition of early-onset mania; this is complicated by the fact that this disorder is highly comorbid with other psychiatric disorders. In particular, we know little about the overlap of attention deficit hyperactivity disorder (ADHD) and conduct disorder with bipolar disorder in youth.

We also do not know whether pediatric bipolar disorder differs from the adult form of the disorder. Related to this, there is little information on the adult course of pediatric-onset mania. Other than a likely genetic contribution, little is known about the risk factors for the development of bipolar disorder in youth.

Research Priorities: What We Need to Know

Several priorities for research can be suggested:

  • Most importantly, additional epidemiologic studies are needed to determine the prevalence of pediatric and adolescent bipolar disorder.

  • Long-term longitudinal studies are needed to clarify the relation of adolescent onset of symptoms to the course of bipolar disorder in adulthood. These data would assist with informing us about the clinical course and acute and long-term treatment outcome.

  • The relationship of comorbid disorders such as ADHD and conduct disorder to juvenile-onset bipolar disorder needs to be further evaluated.


What We Know

As learned from treatment of adults diagnosed with bipolar disorder, the complexity of this illness in adolescents requires a combination of medication and psychosocial interventions to effectively reduce the burden of the illness. We also know that patients who respond to a given acute pharmacotherapy regimen continue to benefit from ongoing treatment with the medication that led to successful symptom amelioration.

What We Do Not Know

There are very few controlled studies of specific psychosocial or pharmacologic interventions for pediatric bipolar disorder. Psychosocial interventions specifically targeting adolescent bipolar disorder are just now starting to evolve. There are few studies of maintenance treatment, which is essential for this disorder. For both psychosocial and pharmacologic treatments, there is minimal empirical evidence to clearly inform the clinician as to what types of treatment combinations are most effective for the adolescent suffering from bipolar disorder. It may be that combination pharmacotherapy with more than one mood-stabilizing agent may be a rational approach for some youth who have manic, hypomanic, depressed, or mixed states.

There are also limited data on the impact of long-term exposure to psychotropic compounds on the developing brain. We also do not have studies of the side effects that arise from medication treatment over a long period of time.

Research Priorities: What We Need to Know

Treatment studies of highest priority would include the following:

  • More, and larger, efficacy studies of medications and psychosocial treatments are urgently needed.

  • Whether treatment should begin with drug monotherapy or a combination of medications, or medication plus psychotherapy, should be a topic of further study.

  • Treatment of nonresponders to standard bipolar treatment should be evaluated.

  • Studies of maintenance pharmacotherapy and psychotherapy are sorely needed.

  • Given the chronicity of this disorder and the high risk for these patients to die from suicide, there needs to be research on the development of prevention programs that would target patients at risk for this disorder that have an impact on prevention of suicide, the most serious consequence of the illness.


What We Know and Do Not Know

Unfortunately, we know almost nothing about the prevention of bipolar disorder in youth. One factor hindering prevention research is the challenge of making an accurate diagnosis. Not until we can accurately identify high-risk cases and the emergence of the actual disorder in adolescence can studies on prevention begin. At this point in time, even if we could properly identify a target population and clinical end point, we do not yet know how best to design and evaluate preventive strategies for this disorder.

Research Priorities: What We Need to Know

As mentioned above, scientific advancement in accurately characterizing the early signs and full emergence of bipolar disorder in youth is a crucial first step. The next step is further research on risk factors for the development of bipolar disorder in youth. Once these goals have been accomplished, we need to design and evaluate preventive programs that target such risk factors. Although such preventive studies are in the future, they represent one of the more important directions for alleviating the burden of this serious and potentially debilitating disorder in adulthood.

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