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Depressive disorders

Childhood and adolescent major depressive disorder (MDD) is a


prevalent, familial, and recurrent condition that generally continues
episodically into adulthood. Childhood depression seems to be evident
at earlier ages in successive cohorts and often occurs with comorbid
psychiatric disorders, increased risk for suicide, substance abuse, and
behavior problems. Children and adolescents with depression
frequently have poor psychosocial, academic, and family functioning.

Pathophysiology
Several areas of the brain are involved in mood functions. Sleep,
appetite, and memory are commonly disturbed in persons with
depression. Except for the pituitary, all cerebral components
responsible for these functions are broadly considered to be a part of
the limbic system; all components normally receive signals from
neurons that secrete serotonin or norepinephrine or from neurons of
both types. Reductions in the activity of circuits that use serotonin and
norepinephrine are thought to contribute to depression.

Frequency
United States
Reported prevalence rates for depression in children and adolescents
vary. Differences may be due to different populations sampled and
variable criteria used.
In 1988, Kashani and Sherman conducted epidemiologic studies in the
United States that revealed the incidence of depression to be 0.9% in
preschool-aged children, 1.9% in school-aged children, and 4.7% in
adolescents.1 A study of a randomly selected sample of high school
students revealed that 22.3% of females and 11.4% of male high
school students reported one current or lifetime episode of unipolar
depression. The percentage of male and female students with 2 or
more episodes was 4.9% and 1.6%, respectively. In 1997, Garrison et
al conducted a study of adolescents aged 11-16 years in the
southeastern United States and found that the 1-year incidence of
major depression was 3.3%.2

As these studies demonstrate, the occurrence of depression is not


rare and is encountered regularly in pediatric and psychiatric practice.
International
Available data on the international incidence of major depression in
children and adolescents are sparse. Reported adult prevalence rates
generally mirror those of the United States.
Helgason examined the entire Icelandic birth cohort of 1895-97 with
periodic follow-up until cohort individuals reached age 74-76 years.
The lifetime estimates of risk for any affective disorder were 14.8% for
females and 9.8% for males.
The Stirling County Study, which began shortly after World War II,
offers a 40-year perspective of the prevalence and incidence of
psychiatric disorders among an adult population in Atlantic, Canada. In
2000, Murphy et al found the overall prevalence of depression
remained stable at 5% across 3 separate samples in 1952, 1970, and
1992.3 They reported a redistribution in the most recent sample that
indicated prevalence had shifted from older to younger persons and
that the female-to-male ratio had increased.
In 1999, a European study by Copeland et al sought to assess the
prevalence of depression in 9 European nations in order to design
intervention for elderly persons who were depressed.4 They found
widely ranging prevalences in their study centers. Prevalence for
females was higher than for males. They found no constant
association between prevalence and age. Meta-analysis revealed an
overall prevalence of 12.3% and sex frequencies of 14.1% for females
and 8.6% for males.
According to Jablensky in 1981, the World Health Organization (WHO)
collaborative study on the assessment of depressive disorders
examined depressive patients in Canada, Iran, Japan, and Switzerland
and found considerable similarity in depressive symptomatology
across cultures.5

Mortality/Morbidity
As many as 15% of those with depression or bipolar disorder commit
suicide each year. In 1996, the Centers for Disease Control and
Prevention (CDC) listed suicide as the ninth leading cause of death in
the United States, accounting for 30,862 deaths. Many believe this
number is a gross underestimate. For example, children's deaths are
often ruled as accidental when the intent of the deceased is not
apparent. The feasibility of suicide among children is frequently
unthinkable, even to health professionals. Because mood disorders,
such as depression, substantially increase the risk of suicide, suicidal
behavior is a matter of serious concern for clinicians who deal with the
mental health problems of children and adolescents. The incidence of
suicide attempts reaches a peak during the mid adolescent years; the
mortality rate from suicide increases steadily through the teenage
years; suicide is the third leading cause of death in that age group.
Risk factors for completed suicide include the presence of a major
mood disorder, occurrence of command auditory hallucinations, use of
substances, and evidence of specific plans and an attempt to prevent
discovery. Major depression with psychotic features, such as
hallucinations, places an individual at increased risk of harm to
themselves or others. Psychosis and risk of harm to self or others are
indications for hospitalization.

Race
Cultural norms associated with differing racial and ethnic groups can
affect the experience and reporting of symptoms of depression. For
example, in some cultures, depression may be experienced largely in
somatic terms, in place of sadness or guilt. Several studies point
toward the role of culture in childhood and adolescent depression. For
example, the stress of acculturation was found to have a role in the
increased incidence of depressive symptoms and suicidal ideation
among Hispanic youths.
In an epidemiologic study of youths aged 12-17 years in Los Angeles
County in 1998, Siegel et al found that Hispanic youths reported more
symptoms of depression, independent of socioeconomic status, when
compared with white, African American, or Asian American
adolescents, using the Children's Depression Inventory (CDI).6 This
study also found significant effects of social class on depression. As
income decreased, the average level of depression increased.
More extensive studies of ethnic subpopulations of adolescents who
are depressed are needed. The Diagnostic and Statistical Manual of
Mental Disorders, Fourth Edition (DSM-IV) states that a symptom
should not be dismissed because it is part of a cultural norm.7
Likewise, culturally distinctive experiences (eg, fear of being hexed or
bewitched; experience of visitations from the dead) should be
distinguished from actual hallucinations or delusions that may be part
of a major depressive episode with psychotic features.

Sex
Sex issues and depression in youths has been the subject of much
research. In 1998, Hankin et al conducted a prospective, 10-year,
longitudinal study of preadolescents through young adulthood and
found that the most critical time for sex differences to emerge is the
period when adolescents are aged 15-18 years.8 During this period,
the increase of the overall rates of depression and onset of new cases
of depression peak. The rates of depression increase dramatically for
both sexes, and the rate of depression in females grows to twice the
prevalence rate for males. No sex differences are noted for depression
symptom severity or recurrence.

Age
Evidence suggests that the presentation of some symptoms may
change with age. Symptoms, such as somatic complaints, irritability,
and social withdrawal, are more common in children, whereas
psychomotor retardation, hypersomnia, and delusions are less
common prior to puberty than in adolescence and adulthood.

Clinical
History
The Diagnostic and Statistical Manual of Mental Disorders, Third
Edition (DSM-III); the Diagnostic and Statistical Manual of Mental
Disorders, Third Edition Revised (DSM-III-R); and the DSM-IV use the
same basic criteria to diagnose depression in adults and children. A
few small adjustments were made to the diagnostic criteria to account
for the differences in age and stage of development in adults and
children.
The DSM-IV diagnostic criteria for depressive disorders are the same
for children and adolescents as they are for adults, with small
exceptions stated as notations to the criteria.

• The DSM-IV defines a major depressive episode as a


syndrome in which at least 5 of the following symptoms have
been present during the same 2-week period:
o Depressed mood (for children and adolescents, this
also can be an irritable mood)
o Diminished interest or loss of pleasure in almost all
activities
o Sleep disturbance
o Weight change or appetite disturbance (for children
this can be failure to achieve expected weight gain)
o Decreased concentration or indecisiveness
o Suicidal ideation or thoughts of death
o Psychomotor agitation or retardation
o Fatigue or loss of energy
o Feelings of worthlessness or inappropriate guilt
• At least one of the symptoms must be diminished
interest/pleasure or depressed mood. The symptoms must
cause significant distress or impairment of functioning in social,
occupational, or other important areas. Depression should not
have been precipitated by the direct action of a substance or the
result of a medical condition and should not be better explained
by bereavement or schizoaffective disorder. Additionally, a major
depressive episode should not be superimposed on
schizophrenia, schizophreniform disorder, delusional disorder, or
a psychotic disorder not otherwise specified.
• Depressive disorders can be rated as mild, moderate, or
severe. The disorder can also occur with or without psychotic
symptoms, which can be mood congruent or incongruent.
Depressive disorders can be determined to be in full or partial
remission. When an episode lasts more than 2 consecutive
years, the depression should be diagnosed as chronic.
Depression may also have melancholic features. Either a loss of
pleasure in almost all activities or a lack of reactivity to usually
pleasurable stimuli are present. Additionally, at least 3 of the
following are required:
o A depressed mood that is distinctly different from the
kind felt when a loved one is deceased
o Depression that is worse in the morning
o Waking up 2 hours earlier than usual
o Observable psychomotor retardation or agitation
o Significant weight loss or anorexia
o Excessive or inappropriate guilt
• Depressive episodes can also be present with catatonic
features that require at least 2 of the following, as illustrated in
the DSM-IV:
o Motoric immobility in the form of catalepsy or stupor
o Motor overactivity that seems purposeless and not
in response to external stimuli
o Extreme negativism or mutism
o Voluntary movement peculiarities such a posturing,
grimacing, stereotypy, and mannerisms
o Echolalia or echopraxia
• The seasonality of a depressive disorder can also be
specified. To diagnose a seasonal mood disorder, a regular
temporal relationship should exist between the depression and a
particular time of year. An individual should demonstrate at least
2 episodes of depressive disturbance in the prior 2 years, and
seasonal episodes should substantially outnumber nonseasonal
episodes. Diagnosing seasonal affective disorder in children is
difficult because they experience the recurrent universal stressor
of beginning school every autumn. Also, a young child might
present with an apparent seasonal depressive disorder but not
yet have had prior episodes.
• A depression may also be identified as having atypical
features. Characteristics of this subtype are mood reactivity and
exclusion of melancholic and catatonic subtypes in addition to 2
or more of the following for the a period of at least 2 weeks:
o Increase in appetite or significant weight gain
o Increased sleep
o Feelings of heaviness in arms or legs
o A pattern of long-standing interpersonal rejection
sensitivity that extends far beyond the mood disturbance
episodes and results in significant impairment in social or
occupational functioning
• The DSM-IV also includes a category for depressive
disorders not otherwise specified. This category includes
disorders with features of depression that do not meet criteria for
a specific mood disorder or adjustment disorder with depressed
mood. Examples include a depressive episode superimposed on
residual schizophrenia, a recurrent mild depressive disturbance
that does not meet criteria for dysthymia, or non–stress-related
episodes that do not meet the criteria for a major depressive
episode. Consult the DSM-IV for further details as to the
diagnostic criteria for depressive disorders not otherwise
specified.

Physical

• A complete mental health evaluation should always


include a medical evaluation.
• Organic etiologies that might imitate a depressive disorder
must be ruled out.
• Conditions believed to mimic depressive disorders fall into
the major general categories, including the following:
o Infection
o Medication
o Endocrine disorder
o Tumor
o Neurologic disorder
o Miscellaneous disorder

Causes
Whether ego-damaging experiences or biological processes cause
depression remains the topic of some debate. The final common
pathways to depression involve biochemical changes in the brain.

• Neuroimaging
o A recently discovered abnormality in an area of the
brain that helps to control emotional reactions contributes
to a new understanding of why persons develop
depression and other affective disturbances. By using
positron emission tomographic (PET) images, researchers
found an area of the prefrontal cortex with an abnormally
diminished activity in patients with unipolar depression and
bipolar depression. This region is related to emotional
response and has widespread connections with other
areas of the brain. These other areas are responsible for
the regulation of dopamine, noradrenaline, and serotonin,
which have important roles in the regulation of mood. PET
imaging provides the means for the study of receptor
volume and the effect a compound may have on
receptors; however, PET is problematic for use with
children and adolescents because it requires complex
equipment and uses radiation.
o MRI, magnetic resonance spectroscopy (MRS), and
magnetoencephalography (MEG) are best suited to study
the structural, physiological, and developmental brain
abnormalities in youths because they do not involve
ionizing radiation or radioactive isotopes. To date, few
neuroimaging studies have been performed in depressed
youths. In 1996, Steingard et al observed 65 latency-aged
children and adolescents who were hospitalized with
depression.9 MRI was used to compare depressed patients
with 18 hospitalized psychiatric controls who did not have
a depressive disorder. Depressed youths had a
significantly smaller ratio of frontal lobe volume to total
cerebral volume and a significantly larger ratio of lateral
ventricular volume to total cerebral volume than controls.
The researchers in this study suggest that these
alterations in cerebral volumes may suggest a role for the
frontal lobes in the development of early-onset depression.
o In 1998, Tutus et al observed adolescents with MDD
using single-photon emission tomography (SPET) in order
to examine cerebral perfusion and any association
between perfusion indices and clinical variables.10
Fourteen adolescent outpatients (aged 11-15 y) with MDD
and 11 age-matched controls were studied. Significant
differences were found between the perfusion index
values of untreated depressed patients and those of the
controls. The findings were indicative of relatively reduced
perfusion in the left anterofrontal and left temporal cortical
areas. They suggest that adolescents with MDD may have
regional blood flow deficits in left anterofrontal and left
temporal cortical regions with greater right-left perfusion
asymmetry compared with healthy controls.
• Neuroendocrine abnormalities
o In 1996, De Bellis et al studied neuroendocrine
changes in prepubertal children who were depressed.11
They examined nocturnal secretion of adrenocorticotropin
(ACTH), cortisol, growth hormone (GH), and prolactin in
the depressed groups and control groups, respectively.
Prepubertal children who were depressed had lower
cortisol secretion during the first 4 hours of sleep than did
children in the control group. ACTH, GH, and prolactin
secretion did not differ between the 2 groups.
o Possible abnormalities of the neurotransmitter
systems remain under investigation. In 1999, Nobile et al
found that human platelet 5-HT (serotonin) uptake is
differentially influenced in nondepressed and depressed
children by a common genetic variant of the promotor
region of 5-HTT.12 In 1997, Birmaher et al found that, prior
to onset of affective illness, children who were at high risk
had the same pattern of neuroendocrine response to 5-
hydroxy-L-tryptophan (L-5-HTP) challenge as did children
with major depression.13 These findings could constitute
the identification of a trait marker for depression in
children.
• Genetic studies: Several studies of adults who are
depressed, such as those reported by Akiskal and Weller in
198914 and Weissman et al in 1984,15 suggest a genetic
component in the etiology of depressive disorders.
• Parent-child relation model
o This model conceptualizes depression as the result
of poor parent-child interaction. Adults with depression
report low paternal involvement and high maternal
overprotection during early childhood. Troubled
relationships with parents, siblings, and peers are
common in children and adolescents with affective illness.
A child who is affectively ill often has a parent who is
affectively ill. For children to report abuse and/or neglect
by their parent(s) who is affectively ill is not uncommon.
o In 1991, Hammen et al reported a significant
temporal association between mother and child.16 They
found that children with substantial stress exposure who
also had symptomatic mothers were significantly more
depressed than children who were exposed to comparable
levels of stress only.
• Cohort effect: In 1987, Klerman and Gershon reported a
progressive increase in the lifetime cases of major depression
over the last 70 years. They found high rates of affective
disorders among relatives, with a younger age of onset in
successive cohorts.

Differential Diagnoses
Anxiety Disorder: Generalized Anxiety
Attention Deficit Hyperactivity Disorder
Child Abuse & Neglect: Posttraumatic Stress Disorder
Mood Disorder: Bipolar Disorder
Mood Disorder: Dysthymic Disorder

Other Problems to Be Considered


Major depressive disorder is diagnosed when the required DSM-IV
symptoms are present and other disorders have been ruled out.
Symptom clusters, such as seasonality, atypical symptoms, psychosis,
or hypomania, characterize different subtypes of depression. Identify
these subtypes because they require different modes of treatment.

In youths, manic and depressive symptoms may be mixed (mixed


episode), which is a common presentation of bipolar disorder among
youths. Hypomanic symptoms may be quite brief at the onset of
bipolar disorder and may be disregarded. Comorbid symptoms of
attention deficit hyperactivity disorder (ADHD), anxiety, posttraumatic
stress disorder, substance abuse, and sleep disorders are often
overlooked and require careful assessment and treatment. Consider
the diagnosis and treatment of youths with subclinical depression
because these children are at high risk to develop depression, and
early intervention may be beneficial.

Other conditions to be considered include the following:

• Medication reaction or substance abuse


• Organic disease presenting as depressive disorder
Workup
Laboratory Studies

• Include a CBC count with differential in the initial


laboratory evaluation to rule out infection and anemia.
• Assay electrolytes, BUN, creatinine clearance, creatinine,
and urine osmolality to exclude renal disorders.
• When using tricyclic antidepressants or lithium carbonate,
monitor plasma levels to measure compliance and to avoid
toxicity.
• Evaluate urine osmolality and creatinine clearance
periodically during lithium treatment.

Other Tests

• Consider EEG evaluation for patients with a history or


presentation that is suggestive of seizure disorder.
• Perform ECG prior to treatment with a tricyclic
antidepressant.
• Perform liver function tests and thyroid function tests
(triiodothyronine [T3], thyroxine [T4], and thyroid-stimulating
hormone [TSH]) to rule out thyroid disease.
• In 1985, Weller et al report that a properly performed
dexamethasone suppression test (DST) can be helpful to
confirm a clinical diagnosis of depression and may be useful in
monitoring treatment response during follow-up.17 The overall
sensitivity of the DST is 70% in prepubertal children and 47% in
adolescents.
• CDI is a simple test that may assist in detecting
occurrence and degree of childhood depression.

Treatment
Medical Care
Opinions vary about whether cognitive-behavioral psychotherapy,
pharmacotherapy, or a combination of both should be offered as first-
line treatment for children and adolescents with MDD. Safety is always
the first concern in the evaluation of MDD in children and adolescents.
Cognitive-behavioral therapy has been shown in multiple randomized
clinical trials to be effective in the treatment of mild-to-moderate MDDs
in children and adolescents. Evidence from randomized clinical trials
suggests efficacy in the treatment of moderate-to-severe MDD using 3
selective serotonin reuptake inhibitors (SSRIs): fluoxetine, sertraline,
and citalopram.
Overall, the choice of the initial acute therapy depends on the severity,
number of prior episodes, chronicity, subtype, age of the patient,
contextual issues (eg, family conflict, academic problems, exposure to
negative life events), compliance with treatment, previous response to
treatment, and the motivation of the patient and family for treatment. In
mild cases, psychosocial interventions are often recommended as
first-line treatments, whereas, in the most severe cases, medication in
addition to psychotherapeutic intervention is often recommended.
Treatment of a child or adolescent who is depressed should occur
within a biopsychosocial context. Such an approach includes the
psychotherapies (eg, individual, family, group), medication
management, social skills training, and educational assessment and
planning. The clinician should choose a treatment setting prior to
initiation of a treatment plan. The clinician must carefully assess the
risk for suicide in any child who is depressed. If a child is obsessed
with thoughts of suicide or has definite plans, the patient must be
hospitalized. Also, the clinician should weigh factors, such as the
child's ability to function and the stability of the family plus any history
of previous suicide attempts, when determining whether or not to
hospitalize a child or adolescent.
Psychotherapy appears to be a useful initial acute treatment for mild-
to-moderate depression. Cognitive-behavioral therapy has been
extensively studied, and other forms of psychotherapy, such as
psychodynamic psychotherapy, interpersonal psychotherapy, and
family therapy, have been found to be effective and are used clinically.
More studies that compare the complementary and differential effects
of these therapies are needed.
Antidepressant medications may be indicated for children and
adolescents with nonrapid cycling bipolar depression, psychotic
depression, depression with severe symptoms that prevent effective
psychotherapy, and depression that does not respond to
psychotherapy; however, given the psychosocial context in which
depression occurs, pharmacotherapy is insufficient as the only
treatment. Even when the patient's mood has been stabilized using a
medication-only treatment, evidence suggests that the environmental
and social problems associated with MDD remain, preventing the
necessary full stabilization.
Combined treatment increases the likelihood not only of mitigating
depressive symptomatology but also increases the likelihood of
increasing self-esteem, coping skills, and adaptive strategies and
improving family and peer relationships. Psychodynamic
psychotherapy, interpersonal therapy, cognitive-behavioral therapy,
behavior therapy, family therapy, supportive psychotherapy, and group
psychotherapy have all been used for the treatment of youths with
MDD.
Many clinicians have found psychodynamic psychotherapy useful in
the treatment of depression in youths. Controlled studies using
psychodynamic psychotherapy for the treatment of depression in
children and adolescents are particularly difficult to design and
expensive to conduct but are greatly needed. Psychodynamic
psychotherapy can help youths understand themselves, identify
feelings, improve self-esteem, change maladaptive patterns of
behavior, interact more effectively with others, and cope with ongoing
and past conflicts.
Interpersonal therapy focuses on problem areas of grief, interpersonal
roles, disputes, role transitions, and interpersonal difficulties. In a 1996
study, Mufson and Fairbanks found that interpersonal therapy may be
useful in the acute treatment of adolescents with MDD.18 They also
found the rate of relapse to be relatively low after acute interpersonal
therapy treatment.

Cognitive-behavioral therapy is one of the most frequently studied


psychotherapy treatments. Its use in treating MDD is based on the
premise that patients who are depressed have a distorted view of
themselves, the world, and the future. These cognitive distortions
contribute to their depression and can be identified and counteracted
with cognitive-behavioral therapy. In nonclinical samples, 4 studies
have shown group cognitive-behavioral therapy to be better than no
intervention for children and adolescents in the reduction of depressive
symptomatology and improvement of self-esteem.

In most clinical samples, cognitive-behavioral therapy was found to be


superior to other manualized treatments, including relaxation training
and family and supportive therapy; however, all clinical studies of
cognitive-behavioral therapy found a high rate of relapse on follow-up,
suggesting the need for continuation treatment. Given the high rate of
relapse and recurrence of depression, continuation therapy is
recommended for all patients for at least 6-12 months.
During the continuation phase, observe patients at least monthly,
depending on clinical status, functioning, support systems,
environmental stressors, motivation for treatment, and the presence of
comorbid psychiatric or other medical disorders. In this phase,
psychotherapy can be used not only to consolidate the skills learned
during the acute phase and help patients cope with the psychosocial
sequelae of the depression but also to address the antecedents,
contextual factors, environmental stressors, and intrapsychic conflicts
that may contribute to a relapse. If the patient is taking
antidepressants, psychotherapy can be used to foster medication
compliance. The only continuation study in depressed youths suggests
that monthly cognitive-behavioral therapy sessions may be effective to
prevent relapses of depression in adolescents.19
Several factors appear to be related to the response to psychotherapy,
including age at onset of depression, severity of depression, presence
of comorbid psychiatric disorders (eg, anxiety, dysthymia, substance
abuse), lack of support, parental psychopathology, family conflict,
exposure to stressful life events, socioeconomic status, quality of
treatment, therapist's expertise, and motivation of both patient and
therapist. A combination of the particular elements of cognitive-
behavioral therapy, interpersonal therapy, psychodynamic
psychotherapy, and other psychotherapies may be brought together in
the best interests of the patient. In 1997, Brent et al reported that
individual supportive treatment was found to be considerably less
efficacious than cognitive-behavioral therapy in adolescents who were
depressed.20
Adolescents whose parents suffer from depression are at increased
risk of developing depressive disorders. Garber et al (2009) studied
316 adolescents whose parents were diagnosed with current or prior
depressive disorders. The adolescents had a past history of
depression, current elevated but subdiagnostic depressive symptoms,
or both. The objective was to determine if the effects of a group
cognitive behavioral prevention program prevented depression onset
compared with usual care. Rate and hazard ratio were lower among
adolescents participating in a cognitive behavioral program than in
those who underwent usual care. Adolescents participating in a
cognitive behavioral program also self-reported greater improvement
in depressive symptoms than those who underwent usual care. These
effects were not observed in adolescents with a currently depressed
parent, and, in these adolescents, the cognitive behavioral program
was not shown to be more effective than usual care in preventing
depression.21

Medication
Studies on the use of medications for youths with MDD are few, and
some have methodologic problems. Additionally, very few
pharmacokinetics studies have been performed in children. The few
studies in children have focused on the effects of tricyclic
antidepressants (TCAs), with few studies addressing SSRIs. Other
antidepressants, including heterocyclics (eg, amoxapine, maprotiline),
monoamine oxidase inhibitors (MAOIs), bupropion, venlafaxine, and
nefazodone, have been found to be effective in the treatment of adults
who are depressed.
The clinician needs to inform parents and patients about adverse
effects, the dose, the timing of therapeutic effect, and the danger of
overdose, particularly with TCAs, before initiating pharmacologic
treatment. Parents should take responsibility for medication storage
and administration, especially with younger children and children at
risk for suicide. Because of the potential of the TCAs to induce a fatal
overdose, the clinician must carefully determine the exact amount of
medication to be prescribed at each appointment.
The TCAs require a baseline ECG, resting blood pressure, and pulse.
Weight should also be frequently documented. No laboratory tests are
currently indicated before or during the administration of the SSRIs.
No other tests are indicated in a healthy child before starting
antidepressants.
Because of reports that SSRIs are effective for the treatment of youths
with MDD and because of reports that SSRIs have a relatively safe
adverse effect profile, very low lethality after overdose, and only once
daily administration, the clinician may support the use of the SSRIs as
first-line medications.
Open studies, such as those in 1997 by Leonard et al22 and Rey-
Sanchez and Gutierrez-Casares,23 have reported 70-90% response to
the SSRIs in the treatment of adolescents with MDD. Also in 1997,
Emslie et al conducted an 8-week double-blind study of the treatment
of a large sample of youths with MDD and showed that children and
adolescents responded significantly better to fluoxetine than to
placebo (58% vs 32%).24 Despite the significant response to fluoxetine,
many patients had only partial improvement; only 31% achieved full
remission.
A possible explanation for the partial response is that the effective
treatment may involve variation in dose or length of treatment. Also,
the ideal treatment likely involves a combination of pharmacologic and
psychosocial interventions. Except for lower initial doses, the
administration of SSRIs in children and adolescents is similar to the
treatment protocols used for adult patients. The clinician should treat
patients with adequate and tolerable doses for at least 4 weeks. At 4
weeks, if the patient has not shown even minimal improvement, the
clinician should consider increasing the dose. If, at this time, the
patient shows improvement, the dose can be continued for at least 6
weeks. On the contrary, if no improvement is apparent at 6 weeks,
other treatment strategies should be considered.
The clinician must cautiously apply this recommendation; whether
longer trials with SSRIs increase the number of patients with late
improvement is not clear. The SSRIs possess a relatively flat dose-
response curve, suggesting that maximal clinical response may be
achieved at minimum effective doses; therefore, adequate time must
be allowed for clinical response and frequent early dose adjustments
must be avoided. Blood levels are rarely indicated in clinical settings,
but they may help clarify concerns about toxicity or medical
compliance.
The adverse effects of all SSRIs in children are similar to those in
adults. They are dose-dependent and may subside with time. SSRIs
may induce mania, hypomania, and behavioral activation, in which
patients become impulsive, silly, agitated, and daring. Other adverse
effects include GI symptoms, restlessness, diaphoresis, headaches,
akathisia, bruising, and changes in appetite, sleep, and sexual
functioning. The long-term adverse effects of SSRIs are not yet
known.

A small number of case reports, such as those by King et al in 199425


and Teicher et al in 1993,26 have described a putative association
between SSRI administration and increased suicidality (perhaps linked
to behavioral activation or akathisia). However, although such
phenomena may have occurred in a small number of cases, several
studies suggest that SSRIs, like other antidepressants, generally
reduce the risk of suicide in adult patients who are depressed.
SSRIs are greatly preferred over the other classes of antidepressants.
Because the adverse effect profile of SSRIs is less prominent,
improved compliance is promoted. SSRIs do not have the cardiac
arrhythmia risk associated with TCAs. Arrhythmia risk is especially
pertinent in overdose, and suicide risk must always be considered
when treating a child or adolescent with mood disorder.
Physicians are advised to be aware of the following information and
use appropriate caution when considering treatment with SSRIs in the
pediatric population.
In December 2003, the UK Medicines and Healthcare Products
Regulatory Agency (MHRA) issued an advisory that most SSRIs are
not suitable for use by persons younger than 18 years for treatment of
"depressive illness." After review, this agency decided that the risks to
pediatric patients outweigh the benefits of treatment with SSRIs,
except fluoxetine (Prozac), which appears to have a positive risk-
benefit ratio in the treatment of depressive illness in patients younger
than 18 years.
In October 2003, the US Food and Drug Administration (FDA) issued a
public health advisory regarding reports of suicidality in pediatric
patients being treated with antidepressant medications for major
depressive disorder. This advisory reported suicidality (both ideation
and attempts) in clinical trials of various antidepressant drugs in
pediatric patients. The FDA has asked that additional studies be
performed because suicidality occurred in both treated and untreated
patients with major depression and, thus, could not be definitively
linked to drug treatment.
In September 2004, the results of an FDA analysis suggested that the
risk of emergent suicidality in children and adolescents taking SSRIs
was real. The FDA advisors (Columbia University) recommended the
following:

• A "black-box" warning label be placed on all


antidepressants, indicating that they increase the risk of suicidal
thinking and behavior (suicidality)
• A patient information sheet (Medication Guide)
be provided to the patient and their caregiver with every
prescription
• The results of controlled pediatric trials of depression be
included in the labeling for antidepressant drugs

The committees recommended that the products not be


contraindicated in the United States because access was important for
those who could benefit from them. For more information, see the FDA
Statement on Recommendations of the Psychopharmacologic Drugs
and Pediatric Advisory Committees.
This remains a controversial issue. Some studies have argued that a
decline in youth suicide rates coincided, to a striking extent, with
significant increases in the prescription of antidepressants (mostly
SSRIs) to adolescents.27,28,29 The Treatment for Adolescents with
Depression Study (TADS) also lends support for fluoxetine's efficacy in
adolescent depression, notably the combined use of fluoxetine with
cognitive-behavioral therapy.30 Data from the TADS study also
suggested a possible protective effect of cognitive behavioral therapy
against suicidality when used in combination with fluoxetine.
Additionally, a study of more than 65,000 children and adults treated
for depression between 1992 and 2003 by the Group Health
Cooperative in Seattle found that suicide risk declines, not rises, with
the use of antidepressants.31 This is the largest study to date to
address this issue.
Currently, evidence does not suggest that obsessive-compulsive
disorder (OCD) and other anxiety disorders treated with SSRIs are
associated with an increased risk of suicide.
Abrupt discontinuation of SSRIs with shorter half-lives, such as
paroxetine, may induce withdrawal symptoms, some of which may
mimic a relapse or recurrence of a depressive episode (eg, tiredness,
irritability, severe somatic symptoms). The withdrawal symptoms can
appear after as few as 6-8 weeks of SSRI treatment. For clinical
practice and education, the FDA has recommended that physicians
who prescribe these medications should closely monitor patients with
observation that "would generally include at least weekly face-to-face
contact during the first 4 weeks of treatment" with specific visit
intervals specified after those 4 weeks.32
Awareness of possible interactions with other medications is
important. To varying degrees, the SSRIs inhibit the metabolism of
several medications that are metabolized by the diverse clusters of
hepatic cytochrome P450 isoenzymes (eg, TCAs, neuroleptics,
antiarrhythmics, benzodiazepines, carbamazepine, theophylline,
warfarin, terfenadine [removed from United States market]). In
addition, interactions of SSRIs with other serotonergic medications,
particularly MAOIs, may induce the serotonergic syndrome, marked by
agitation, confusion, and hyperthermia. SSRIs also have a high rate of
protein binding, which can lead to increased therapeutic or toxic
effects of other protein-bound medications. MAOIs should not be
administered less than 5 weeks after discontinuation of fluoxetine and
less than 2 weeks for other SSRIs. Also, the clinician should not
prescribe SSRIs within 2 weeks after stopping the MAOIs.
Although open studies using TCAs suggest their usefulness in treating
youths with MDD, several randomized controlled studies have shown
50-60% response to both TCAs (nortriptyline, desipramine,
amitriptyline) and placebo. Consider these results with caution
because of methodologic limitations, including small sample sizes,
short-duration trials, and inclusion of patients with mild depression and
comorbid disorders that may have had good responses to placebo.
TCAs are no longer considered the first-line treatment for youths with
depressive disorders; however, individual cases may respond better to
TCAs than to other medications. TCAs may also be useful for youths
with comorbid ADHD, enuresis, and narcolepsy, as well as for
augmentation strategies. When using TCAs, the clinician should
monitor plasma levels to measure compliance and to avoid toxicity.

Selective serotonin reuptake inhibitor (SSRI)


antidepressants
These are a relatively new group of medicines used to treat emotional
and behavior problems, including depression, panic disorder,
obsessive-compulsive disorder, bulimia, and posttraumatic stress
disorder in adults. These medications are beginning to be used to treat
the same problems in children and adolescents. Serotonin is a
chemical that exists naturally in the brain. The SSRIs increase brain
serotonin to reference range levels. SSRIs include, but are not limited
to, the following medications: fluoxetine, paroxetine, sertraline,
citalopram, and fluvoxamine.

Follow-up
Further Inpatient Care

• Major depression with psychotic features, such as


hallucinations, places an individual at increased risk of harm to
themselves or others and is an indication for hospitalization.
• The real possibility and potential for suicide with concrete
planning by the patient warrants hospitalization.
• Suicide recidivism is another potential cause for
hospitalization.
• The failure of the family support system when confronting
depression with suicidal ideation again may be a strong indicator
for temporary hospitalization in an attempt to stabilize and
improve family functioning.
• Risk factors for completed suicide include the presence of
a major mood disorder, occurrence of command auditory
hallucinations, use of substances, and evidence of plans to
prevent discovery, as well as patient perception of failure of the
issues that precipitated suicidal thinking to change. This lack of
action tends to escalate the patients' sense of hopelessness.

Further Outpatient Care

• See Treatment.

Complications
• Because of individual variation in the pharmacokinetics of
TCAs, monitoring plasma concentration is helpful to determining
optimal dosage. A plasma level of 150-250 mg/mL is considered
the range of therapeutic effectiveness, although an upper level
in children has not been established.
• Perform ECG before starting TCA therapy.
• Be alert to changes in the patient that might signify a
switch from a depressive state to a manic state. Childhood-onset
depression is commonly a precursor of bipolar disorder.
• TCAs in large doses can be lethal and should be avoided
in youths who are at risk for suicidal behaviors.

Prognosis

• According to the American Academy of Child and


Adolescent Psychiatry practice parameters for depressive
disorders in childhood and adolescence, a history of a previous
depressive episode, subsyndromal symptoms of depression,
dysthymia, and anxiety disorders increase the risk for future
depression.33 Familial, social, and environmental factors appear
to play significant roles in the course of depressive illness in
children and youths. Good evidence indicates that depression
can be recurrently noted in families from generation to
generation. Thus, a thorough family history is quite important.
• In 1999, in a 9-year study of an epidemiologic sample of
776 adolescents, Pine and associates found that symptoms of
major depression in adolescence strongly predicted adult
episodes of major depression.34

Patient Education

• Educating parents about children's emotional problems is


very important. Education is known to result in better compliance
with treatment and to improve parents' understanding toward
their children. Patients should be educated in a manner
congruent with individual development, level of impairment, and
clinician judgment.
• The clinician should instruct parents and others in the
homes of depressed youths to remove firearms from their
homes to decrease the risk of suicide. Household medications
also should not be accessible to depressed youths.
• For excellent patient education resources, visit
eMedicine's Depression Center, Substance Abuse Center, and
Antidepressants Center. Also, see eMedicine's patient education
articles Depression, Substance Abuse, and Understanding
Antidepressant Medications.

Miscellaneous
Medicolegal Pitfalls

• Risk assessment of patients who are depressed should be


ongoing.
• The clinician must have a safety plan in place for patients
with suicidal ideation that includes no access to medications or
other means of self-harm plus constant supervision.
• Consider hospitalization for patients for whom an effective
safety plan and supervision is not feasible and for those patients
and families unable or unlikely to comply with treatment
recommendations.
• Do not use TCAs as a first-line treatment for patients with
suicidal ideation.
• Documentation should support clinical decision-making.