Introduction to Treating Depression in Children and Adolescents

JOSEPH M. REY

BORIS BIRMAHER

KEY POINTS

There is a need to train frontline providers to recognize and manage depressive illnesses and to educate them in scientifically proven treatments.
To understand the research literature fully, it is useful to be familiar with the meaning of technical terms such as response, remission, relapse, number needed to treat or harm, augmentation treatment, and treatment resistance.
Not causing harm or ensuring that benefits of treatment outweigh the risks is the first principle of bioethics.
Informing patients and parents about the benefits and risks of interventions is at the core of ethical practice. Without that, informed consent is not possible.
Not obtaining children’s assent or cooperation often leads to adherence problems and can scuttle the best laid treatment plans.
Off-label prescribing poses an extra burden on practitioners who need to be particularly careful explaining what off-label implies, its potential risks and benefits.
Prescribing a psychotropic drug can in itself have an important psychological impact.
Research on the placebo effect, large in major depression, highlights the importance of a good therapeutic relationship for better outcomes.
Supportive management is probably a better option than watchful waiting and likely to be more acceptable to clinicians and parents.
Prescribing antidepressants implies an obligation in the prescriber to monitor side effects and response adequately.
Patients treated with antidepressants are often undertreated (e.g., remain at a low dose for too long or continue on an ineffective medication with only partial improvement) or not treated for long enough.
Apart from preventing relapse and recurrence, an important function of continuation treatment is to achieve further improvement among partial responders.
According to controlled trial data, clinicians can expect that up to 42% of depressed youth who initially respond will relapse or have a recurrence between 12 and 36 weeks in spite of adequate treatment.
Ignoring family psychopathology may result in nonresponse to treatment, crises, and relapse or recurrence of the illness. This may require referring parents for treatment in their own right.

Introduction

“The burden of suffering experienced by children with mental health needs and their families has created a health crisis in this country. Growing numbers of children are suffering needlessly because their emotional, behavioral, and developmental needs are not being met”1 (p. 1). The U.S. Surgeon’s General report on children’s mental health begins with these words, which can rightly be applied to the situation in most countries and in particular to depressive illness. To remediate this state of affairs in the United States, one of the goals for the future agreed on was to train frontline
providers to recognize and manage mental health issues, and educate them in scientifically proven treatments1( p. 8)—goals relevant for most countries. These worthy aspirations were outlined in 2000; almost 10 years later we learn that there is still much room for improvement. For example, in spite of—probably unrealistic—recommendations by the U.S. Food and Drug Administration (FDA) that depressed children and adolescents should be seen often at the beginning of treatment, only 5% had the recommended number of visits.2 Chapters 1, 19, and 24 highlight that there are not enough trained professionals, physicians and nonphysicians, to meet the treatment needs of depressed youth worldwide. In the United States, two thirds of the prescriptions of antidepressants for depressed youth between 1998 and 2005 were written by nonpsychiatrists,2 stressing the importance of improving the knowledge and skills of primary care professionals (see Chapter 19).

DEFINITIONS

Table 4.1 summarizes the definitions of response, partial response, remission, relapse, recurrence, phases of treatment, as well as terms used to describe various types or aspects of treatment relevant to everyday practice. These concepts are often referred to in the chapters that follow and in research reports; practitioners need to be familiar with their meaning to interpret research data correctly.

TABLE 4.1 DEFINITION OF TERMS OFTEN USED IN THE TREATMENT OF MAJOR DEPRESSION

Outcome^a
Response	After onset of treatment, if the patient shows no symptoms or a significant reduction in depressive symptoms for at least 2 weeks.
Partial response	The youth no longer fulfills criteria for MDD, but clinically relevant depressive symptoms or some functional impairment remain.
Sustained response	When patient is very much improved or very improved in at least two assess- ments conducted 6 weeks apart.
Remission	When there has been a period of >2 weeks but <2 months with no or very mild depressive symptoms and no or minimal functional impairment.
Recovery	Absence of significant symptoms of depression (e.g., no more than one or two mild symptoms) for >2 months and no functional impairment.
Relapse	When symptoms and impairment meeting criteria for a major depressive episode reappear during a period of remission (i.e., <2 months after symptoms subsided).
Recurrence	When symptoms and impairment severe enough to meet criteria for a major depressive episode return during a period of recovery (i.e., >2 months after symptoms subsided). This can be considered a new episode of the illness.
Treatment resistance	There is no wide agreement about a definition of resistance to treatment. Chapter 16 proposes that a patient should be deemed treatment-resistant when symptoms meeting criteria for MDD and functional impairment persist after 8 to 12 weeks of optimal treatment (pharmacological, CBT, or IPT) and a further 8 to 12 weeks of an alternative antidepressant or augmentation therapy with other medication or evidence-based psychotherapy.
Number needed to treat (NNT)	The number of individuals who need to be treated to prevent one additional case or bad outcome (i.e., resolution of a depressive episode). Data from RCTs are required to compute NNT, which is equal to one divided by the rate or response in the control group minus the rate of response in the treatment group (this is also called “absolute risk reduction”). For example, the TADS study²⁵ reported that 71% of participants treated with fluoxetine plus CBT were much or very much improved; the result for placebo was 35%. In this case NNT = 1/(0.35–0.71) = 2.7. That is, three patients (it is customary to round to the next whole number) will need to be treated with fluoxetine combined with CBT for one patient to show much or very much improvement. The lower the NNT, the more effective the intervention.
Number needed to harm (NNH)	NNH indicates how many patients need to be exposed to a risk factor (e.g., medication) to cause harm in one patient who would not have been harmed otherwise. NNH is calculated similarly to NNT with the difference that NNH refers to an unwanted effect; it also requires data from RCTs. NNH is the inverse of attributable risk (that is, the rate of an unwanted effect in those tak- ing placebo minus the rate in those treated with the medication). NNH equals one divided by the rate in nonexposed minus rate in exposed. For example, the same TADS study²⁵ reported that 11.9% of participants treated with fluoxetine alone had reported some harm-related event, compared with 5.4% for placebo. In this case NNH = 1/(0.119−0.054) = 15.4. That is, 15 depressed patients will need to be treated with fluoxetine for one patient to suffer a harm-related event attributed to the medication. In the case of NNH, the higher the number, the safer the intervention.
Phases of Treatment^a
Acute	The initial phase of treatment, which aims to achieve response and ultimately remission. It usually last 6 to 12 weeks.
Continuation	Once response or remission is achieved, treatment (pharmacologic, booster ses- sions of psychosocial treatments) is continued in all depressed youths to consol- idate the gains of the acute phase, further symptom reduction, and to avoid relapses. This phase usually lasts 3 to 9 months.
Maintenance	After a patient has recovered, maintenance treatment (pharmacologic, booster sessions of psychosocial treatments) is used to prevent recurrences in patients with a recurring or chronic disorder. Duration varies, but it can be indefinite.
Types of Treatment
First line	Appropriately safe treatments whose efficacy is supported by several, consistent RCTs, such as fluoxetine (Chapter 6), CBT (Chapter 8), and IPT (Chapter 9).
Second line	Treatments whose effectiveness has not been demonstrated by RCTs (e.g., escitalopram, dynamic psychotherapy) or have greater risks or side effects than first-line treatments (e.g., ECT). Second-line treatments are justified when first-line treatments have been ineffective or could not be tolerated (Chapters 6 and 16).
Optimization	Increasing the medication or psychotherapy to a maximum tolerable dose or lengthening the duration of treatment. This is the first strategy that should be considered to improve response (Chapters 6 and 16).
Switching	Changing one treatment, which has been ineffective or not tolerated, for another. Switching can be from psychotherapy to medication, from medication to psychotherapy, from one type of psychotherapy to another, and from one medication to another. In the case of medication, switching usually requires stopping or cross-tapering (reducing gradually one drug while the other is pro- gressively introduced) (Chapter16).
Augmentation	When two or more treatments that target the same symptoms or illness are combined to achieve synergy of action and a better response (Chapter 6). Both psychological (e.g., CBT) and pharmacologic (e.g., fluoxetine) treatments can be combined to improve outcome. Different classes of drugs can also be com- bined to augment response (e.g., an SSRI and lithium). The main risk of aug- mentation is increasing side effects (Chapters 6 and 14) and cost.
Adjunct treatments	Adjunctive agents generally target specific symptoms (e.g., sleep, agitation) with the expectation that once the depression improves, the adjunct treatment will no longer be required. For example, trazodone and mirtazapine are often used as adjunct and transient treatments for insomnia. The main risk of using adjunctive treatments is increasing side effects (Chapters 6 and 14) and cost.
Off-label	When medications are prescribed for indications or in patient groups (e.g., child- ren, elderly) other than those approved by the regulatory bodies. Regrettably, most drugs are not formally licensed for use in children, resulting in much off- label prescription in pediatric patients (Chapter 6). Because regulatory bodies (such as the FDA in the United States, EMEA for the European Union) may approve specific medications or not, what is considered off-label prescription can vary from country to country. Off-label use, although legal, places added responsibilities on the prescriber.
Generic drugs	Generic medications are drugs produced and distributed after the patent pro- tection (20 years for pharmaceuticals) afforded to the original developer has expired (e.g., fluoxetine). Generics are assumed to have identical properties to the original brand but usually are substantially cheaper.
^aModified from the American Academy of Child and Adolescent Psychiatry Practice Parameters for the Assessment and Treatment of Children and Adolescents with Depressive Disorder. ¹⁸
CBT, cognitive behavior therapy; ECT, electroconvulsive therapy; EMEA, European Medicines Agency; FDA, Food and Drug Administration; IPT, interpersonal psychotherapy; MDD, major depressive disorder; RCTs, randomized controlled trials; SSRI, selective serotonin reuptake inhibitor; TADS, Treatment for Adolescents with Depression Study.

ETHICAL ISSUES

The chapters that follow largely focus on “what to do” when treating pediatric depression. However, it is also important to highlight the ethical aspects of treatment and what to avoid. The key issues of confidentiality and safety are not discussed here because they are dealt with in most chapters of the book applied to the specific topics.

“PRIMUN NON NOCERE”

Not causing harm or, at the very least, ensuring that benefits of treatment far outweigh the risks, is one of the principles of bioethics (nonmaleficence—the duty not to inflict harm).3 That is, to recommend a treatment, the chances of helping patients with it should be higher than the probability of harming them; in other words, the risk/benefit ratio should be favorable.

Clinicians often use too narrow a gauge to appraise benefit versus risk. The potential gains from an intervention must be considered not only against the direct unwanted effects (e.g., akathisia, suicidal thoughts) but also against the financial and emotional cost, stigma, and inconvenience of treatment. Some of these costs are relevant to psychosocial treatments such as cognitive behavior therapy (CBT), interpersonal psychotherapy (IPT), dynamic, and family therapies, in which unwanted effects are often ignored when in fact the financial and time demands of treatment (e.g., missing time at work for parents, missing school or activities for children) can cause stress, particularly in already stretched families, and may undermine the sometimes marginal benefits of treatment. This can be a problem also in specialist services in which small parcels of the treatment plan are farmed out to various members of the multidisciplinary team, all needing a share of patients’ and families’ time for investigative and therapeutic input (discussed also in Chapter 5). When weighing the risks, the wider implications of not treating the depressive episode need to be considered also. Apart from the ongoing suffering and distress, these include potential deleterious outcomes such as suicide, school failure, and substance use.

Errors or poor judgment in delivering treatment are not the only ways in which we may harm our patients. This can happen in other, more subtle forms, such as through inadequate assessment, by neglecting to involve the child or family actively, haphazard and ad hoc decisions, not tailoring treatment to the needs and circumstances of the individual patient, and by impatience resulting in unnecessary changes to treatment, to name a few. Clinical experience, patient complaints, and malpractice suits repeatedly show that many flawed treatment decisions stem from an inadequate assessment resulting in misdiagnosis, lack of awareness of comorbid conditions, or ignorance of concurrent or
previous treatments or side effects. As highlighted in Chapter 3 and other parts of the book, a good initial evaluation is the basis for sound treatment planning.

INFORMED CONSENT

“We were not told”—that selective serotonin reuptake inhibitors (SSRIs) may increase the risk for suicidal behavior—was the main complaint voiced by angry parents whose children they believed had committed suicide as a result of treatment with SSRIs during hearings by the Food and Drug Administration, which subsequently resulted in “black box” warnings.4 Probably parents were not told because at that time clinicians did not know themselves, and this matter is still unresolved,5,6,7 although “it is much more likely that suicidal behavior leads to treatment than that treatment leads to suicidal behavior”8 (see also Chapters 6 and 14). Telling patients and parents about the benefits and risks of interventions is at the core of ethical practice. Without that, they will be able to only give “uninformed” consent.

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