Psychopharmacology and Treatment Protocols for Primary Care Physicians in the Treatment of Adolescent Depression

Dr. David L Sellen

Abstract

Major depression affects 3 to 5 percent of children and adolescents. Depression negatively impacts growth and development, school performance, and peer or family relationships and may lead to suicide. Biomedical and psychosocial risk factors include a family history of depression, female sex, childhood abuse or neglect, stressful life events, and chronic illness. Diagnostic criteria for depression in children and adolescents are essentially the same as those for adults; however, symptom expression may vary with developmental stage, and some children and adolescents may have difficulty identifying and describing internal mood states. Safe and effective treatment requires accurate diagnosis, suicide risk assessment, and use of evidence-based therapies. Current literature supports use of cognitive behavior therapy for mild to moderate childhood depression. If cognitive behavior therapy is unavailable, an antidepressant may be considered. Antidepressants, preferably in conjunction with cognitive behavior therapy, may be considered for severe depression. Tricyclic antidepressants generally are ineffective and may have serious adverse effects. Evidence for the effectiveness of selective serotonin reuptake inhibitors is limited. Fluoxetine is approved for the treatment of depression in children eight to 17 years of age. All antidepressants have a black box warning because of the risk of suicidal behavior. If an antidepressant is warranted, the risk/benefit ratio should be evaluated, the parent or guardian should be educated about the risks, and the patient should be monitored closely (i.e., weekly for the first month and every other week during the second month) for treatment-emergent suicidality. Before an antidepressant is initiated, a safety plan should be in place. This includes an agreement with the patient and the family that the patient will be kept safe and will contact a responsible adult if suicidal urges are too strong, and assurance of the availability of the treating physician or proxy 24 hours a day to manage emergencies.

Introduction

At any given time, up to 15 percent of children and adolescents have some symptoms of depression. Five percent of those nine to 17 years of age meet the criteria for major depressive disorder,1,2 and 3 percent of adolescents have dysthymic disorder.³ The incidence of depressive disorders markedly increases after puberty. By 14 years of age, depressive disorders are more than twice as common in girls as in boys, possibly because of differences in coping styles or hormonal changes during puberty.⁴ Adolescent depressive disorders often have a chronic, waxing and-waning course, and there is a two- to fourfold risk of depression persisting into adulthood._5,6 Depression impacts growth and development, school performance, and peer or family relationships, and it can be fatal. Major depressive disorder is a leading cause of youth suicidal behavior and suicide.^7,8

More than 70 percent of children and adolescents with depressive disorders or other serious mood disorders do not receive appropriate diagnosis and treatment.⁹ Possible reasons for this may be the stigma attached to these disorders, an atypical presentation, a lack of adequate child mental health training for health care professionals, an inadequate number of child psychiatrists, and inequalities in mental health care insurance.

Underdiagnosis and undertreatment are greater problems in children younger than seven years, in part because of this age group’s limited ability to communicate negative emotions and thoughts with language and consequent tendency toward somatization. Thus, young children with depression may present with general aches and pains, headaches, or stomachaches. Additionally, if a parent has major depressive disorder, he or she may minimize the child’s depressive symptoms through a lack of awareness or an unwillingness to recognize symptoms that may be similar to his or her own.

Approximately two thirds of children and adolescents with major depressive disorder also have another mental disorder.¹⁵ It is essential that physicians recognize and treat associated psychiatric comorbidities; the most common of these are dysthymic disorder, anxiety disorders, attention-deficit/hyperactivity disorder, oppositional defiant disorder, and substance use disorder.

Screening

It is unclear whether routinely screening all children and adolescents for depression is beneficial in the primary care setting.¹⁶ Physicians who choose to screen may use the Children’s Depression Inventory (CDI), a reliable and valid self-rating scale for boys and girls seven to 17 years of age.^17-19 The CDI scale requires a first-grade reading level; it is available in long (27-item) and short (10-item) forms and in parent and teacher versions. Each item on the scale is scored from 0 to 2 according to the presence or absence of symptoms in the previous two weeks: 0 indicates symptom absence, 1 indicates mild symptoms, and 2 indicates a definite symptom. The raw score is plotted on a scoring grid and converted to a T-score. A raw score greater than 20 on the long form or greater than 7 on the short form and a T-score greater than 65 are clinically significant.

Presentation

Juvenile depression may manifest in different forms. As stated above, children younger than seven years may not be able to describe their internal mood state and may express their distress through vague somatic symptoms or pain. Irritable mood may be the cause of angry, hostile behavior. Impaired attention, poor concentration, and anxiety may resemble attention-deficit/hyperactivity disorder, and substance abuse may be a means of self medication for depression.

Diagnosis

Diagnosis of primary depressive mood disorders (Table 2) requires that physicians rule out depression from medical causes, such as endocrinopathies, malignancies, chronic diseases, infectious mononucleosis, anemia, and vitamin deficiency (especially folic acid), ¹⁰ and from medications, such as isotretinoin (Accutane).¹³ If any of these causes are present, the condition is referred to as secondary depressive mood disorder or depressive mood disorder secondary to medical conditions. Lack of improvement following treatment or medication discontinuation warrants further evaluation and treatment.

Major depressive disorder is the most severe of the depressive mood disorders. The Diagnostic and Statistical Manual of Mental Disorders, 4th ed., criteria for diagnosing major depressive disorder in children and adolescents are similar to those for adults (Table 3).^20-24

 If substance abuse is present, an independent diagnosis of major depression requires the presence of depression before substance abuse or during periods of remission. Concurrent treatment of substance use disorder and depression is needed to improve outcomes for both.²⁵  

Adjustment disorder with depressed mood is the most common depressive mood disorder in children and adolescents. Symptoms start within three months of an identifiable stressor (e.g., loss of a relationship), with distress in excess of what would be expected and interference with social, occupational, or school functioning. Symptoms should not meet criteria for another psychiatric disorder, are not caused by bereavement, and do not last longer than six months after the stressor has stopped.

Dysthymic disorder is a chronic, milder form of depression characterized by a depressed or irritable mood (indicated subjectively or described by others) present for more days than not for at least one year (as opposed to two years for adults). Two of the following additional symptoms also are required: changes in appetite, sleep difficulty, fatigue, low self-esteem, poor concentration or difficulty with making decisions, and feelings of hopelessness.²⁰About 70 percent of children and adolescents with dysthymic disorder eventually develop major depression.²⁶

Diagnosis of minor depression requires the presence of two out of the nine symptoms for major depression (Table 3), one being depressed mood or decreased interest, and a time course similar to that of major depression. If present between the episodes of major depression, minor depression can be a risk factor for relapse.²⁰

Atypical depression is characterized by hypersomnia, increased appetite with carbohydrate craving, weight gain, interpersonal rejection sensitivity, feeling of heaviness in the arms and legs, and reactivity of mood.²⁰ It is relatively common in children and adolescents.²⁷

 Presence of depressed mood, increased sleep, decreased appetite, and social isolation between October and February of two consecutive years suggests seasonal affective disorder.

Although less common, bipolar disorder is an important differential diagnosis. In 40 percent of children and adolescents with bipolar disorder, the illness begins with a major depressive episode.² Risk factors for bipolar disorder are acute and early onset of depression, presence of psychotic symptoms (e.g., hallucinations), significant psychomotor slowing, family history of bipolar disorder, any mood disorder in three consecutive generations of family members, and antidepressant induced mania.²⁸ Physicians should maintain a higher level of surveillance in patients at greater risk of bipolar disorder.

In severe major depression with psychosis, auditory hallucinations (often criticizing the patient) rather than delusions (as occur in adults) are present. This age-related variability in psychotic symptoms may be a result of differences in cognitive maturation. Treatment of major depressive disorder with psychosis requires the combination of an antidepressant and an antipsychotic medication.²⁹ Patients with this disorder are at a greater risk of suicide and often require inpatient psychiatric admission.

Suicide Risk Assessment

During the first visit, physicians should assess the suicide risk of patients with depression and decide on the most appropriate treatment venue. Depressive disorders are the most common diagnoses present in all suicides. Twenty percent of teenager seriously contemplate suicide, ³⁰ and 8 percent attempt it.³¹ In 2001, there were 1,833 suicides in children and adolescents 10 to 18 years of age; and in 2000, suicide was the third leading cause of death among those 10 to 19 years of age.³¹

Suicidal communication in any form must be taken seriously. Documentation of suicide risk should include high-risk and protective factors for suicide (Table 4).1,^30-36 Patients with multiple high-risk factors should be referred to a child and adolescent psychiatrist. However, patients with low-risk and protective factors (e.g., a close, warm, supportive family; religious beliefs against suicide; a positive future outlook) are less likely to harm themselves³² and may be treated as outpatients.

Parents or guardians should be asked to remove firearms and toxic substances, including nonprescription medications, from the patient’s environment and to provide appropriate supervision, especially during crises in the child’s life. They should be made aware of the suicide risk that exists during the early phases of antidepressant treatment and the need for additional supervision.

Treatment

Treatment options depend on the clinical situation and include cognitive behavior therapy alone or with antidepressants. The risk/benefit ratio of antidepressant use should be considered. Physicians choosing to prescribe antidepressants must obtain fully informed consent and closely monitor clinical progress, behavioral activation (e.g., impulsivity, daring, silliness, agitation), and suicidality, especially in the initial stages of treatment.²⁹ Follow-up should take place each week during the first month and every other week during the second month; subsequent frequency of follow-up visits should be determined by the clinical care needs of the patient. The choice of an antidepressant also may be guided by patient or family history of antidepressant response; side-effect profile; and drug-drug, drug-disease, and drug-food interactions.

COGNITIVE BEHAVIOR THERAPY AND COUNSELING

Cognitive behavior therapy is effective for mild to moderate childhood depression.^18,37-39 It entails reality-based challenges to pervasive, automatic, negative, distorted thoughts, with the goal of helping patients steer out of a negative view of themselves, the past, and the future. Interpersonal psychotherapy is directed at resolving grief, coming to terms with interpersonal role transitions or role disputes, and correcting interpersonal skill deficits.¹⁸

Office-based counseling may involve: (1) educating patients about healthy coping skills, problem solving, conflict resolution, social and assertiveness skills, and relaxation techniques; (2) educating parents about realistic, age-appropriate expectations and nonjudgmental, noncritical patterns of communication; and (3) supporting healthy behaviors, healthy psychological defenses, and healthy relationships.

ANTIDEPRESSANTS

The effectiveness and safety of various medications for depression in children and adolescents have been systematically studied and reviewed.^18,37-51 Tricyclic antidepressants are ineffective in children and have limited effectiveness in adolescents, with safety concerns in both groups.^18,40,41 There also is limited evidence for the effectiveness of selective serotonin reuptake inhibitors (SSRIs). In a systematic review of published and unpublished trials of SSRIs, published reports suggested favorable risk/benefit profiles for some SSRIs, but the addition of unpublished data shifted the risk/benefit ratio toward unfavorable, with the exception of fluoxetine (Prozac).⁴² In children and adolescents, there is limited or no evidence evaluating the use of lithium, monoamine oxidase inhibitors, St. John’s wort, and venlafaxine (Effexor).¹⁸ Most trials assessing the use of SSRIs in children and adolescents are of short duration, have small numbers of participants, and are industry-sponsored, thus limiting their ability to detect or report major adverse events.

Furthermore, there are high placebo response rates and methodologic flaws in studies supporting SSRI use.^43,52 For example, although one study indicated that fluoxetine plus cognitive behavior therapy was the best choice, the success of fluoxetine was found only in the unblended arms of the study: the blinded arms showed no better response than with placebo.³⁹ Finally, most studies are underpowered to address the outcome of suicide. Concerns about the effectiveness, adverse effects (Table 5), ¹⁸ and safety of antidepressant use have led to important regulatory changes in several countries. Of particular concern is the association of the drugs with increased suicidal behavior.⁵³ For example, the U.S. Food and Drug Administration (FDA) counsels against using paroxetine (Paxil) in children and adolescents because of effectiveness and safety concerns.⁵⁴ The Committee on Safety of Medicines in the United Kingdom analyzed SSRIs and considers the risk/benefit ratio to be favorable only for fluoxetine.⁴⁴ Additionally, fluoxetine is the only SSRI approved by the FDA for the treatment of depression in children eight to 17 years of age. Fluoxetine therefore may be considered for the treatment of moderate to severe depression in children. However, current evidence is inadequate to determine whether safety and effectiveness concerns represent a class effect or individual drug properties; thus, all antidepressants have a black box warning for increased risk of suicidal thoughts and behavior in children and adolescents being treated for depression.⁵⁵

Before initiating an antidepressant, physicians should ensure that a safety plan is in place. This includes an agreement with the patient and the family that the patient will be kept safe and will contact a responsible adult if suicidal urges are too strong, and assurance of the availability of the treating physician or proxy 24 hours a day to manage emergencies.