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Pediatric unipolar depression and pharmacotherapy: General principles

Pediatric unipolar depression and pharmacotherapy: General principles
Literature review current through: Jan 2024.
This topic last updated: Jan 30, 2024.

INTRODUCTION — For children and adolescents with unipolar depression who are receiving pharmacotherapy, outcomes may be improved by following several general principles [1-3].

This topic reviews the general principles of administering pharmacotherapy to pediatric patients with depressive disorders. Other topics provide an overview of treating pediatric depression, and discuss choosing a specific antidepressant for depressed youth, psychosocial treatments for adolescent depression, and the effect of antidepressant medications on suicide risk in children and adolescents.

(See "Overview of prevention and treatment for pediatric depression".)

(See "Pediatric unipolar depression and pharmacotherapy: Choosing a medication".)

(See "Pediatric unipolar depression: Psychotherapy".)

(See "Effect of antidepressants on suicide risk in children and adolescents".)

CHOOSING TREATMENT FOR PEDIATRIC UNIPOLAR DEPRESSION — Multiple treatment options, including pharmacotherapy and psychotherapy, are available for treating pediatric unipolar depression. (See "Overview of prevention and treatment for pediatric depression".)

PRESCRIBING PHARMACOTHERAPY — The sections below describe the general principles of prescribing medications for pediatric unipolar depression.

Indications — Pharmacotherapy for unipolar depression is indicated for children and adolescents with moderate to severe depressive syndromes that are diagnosed according to the American Psychiatric Association's Diagnostic and Statistical Manual, Fifth Edition, Text Revision (DSM-5-TR) [4] or the World Health Organization's International Classification of Diseases-11th Revision (ICD-11) [5]. Indications include:

Major depression (table 1)

Persistent depressive disorder (dysthymia) (table 2)

Other specified depressive disorder (eg, depressive symptoms with functional impairment)

Other indications for antidepressants include depressive symptoms that accompany disorders that are amenable to pharmacotherapy (eg, anxiety disorders), as well as depressive syndromes that do not respond to psychotherapy. Medications are generally not used for patients who have subsyndromal depressive symptoms (minor depression) [6].

Approach to the patient — When initiating pharmacotherapy for depressed children and adolescents, clinicians should (table 3) [3,7,8]:

Confirm the diagnosis of a unipolar depressive syndrome.

Help patients and families understand and accept pharmacotherapy by explaining the benefits and risks of antidepressants, as well as the risks of no treatment, and soliciting their preferences regarding different options.

Allow enough time for patients and families to review the information about antidepressants to make informed decisions. Pharmacotherapy is not an emergency medical treatment for depressed children and adolescents.

Although suicidal behavior is a medical emergency, the hurried administration of antidepressants has no role in the immediate, acute management of suicidal youth because antidepressants generally do not take effect for at least two to four weeks. (See "Suicidal ideation and behavior in children and adolescents: Evaluation and management".)

Establish that both the clinician and family need to monitor the patient. (See 'Monitoring' below.)

Conduct frequent interviews at the beginning of treatment (eg, once every week or two weeks), to foster the therapeutic alliance.

Education — Before pharmacotherapy is initiated for pediatric depression, clinicians, patients, and families should discuss the medication's benefits, safety risks, and potential side effects; the lag in onset of therapeutic effects; and criteria for discontinuation (table 4 and table 5) [9]. Education is part of obtaining assent from patients and informed consent from the parents or guardians. A useful resource for patients and parents that includes information about antidepressants, and is published by the American Academy of Child & Adolescent Psychiatry and the American Psychiatry Association, is entitled Depression: Parents' Medication Guide [7].

Education about pharmacotherapy should be developmentally appropriate for the patient's level of understanding [3]. In addition, education involves the families as partners of the treatment team and helps them understand the symptoms, causes, and treatment of depression; identify and manage dysphoria in the patient; address psychosocial deficits; and learn the importance of adherence with treatment. The clinical features and diagnosis of depression are discussed separately. (See "Pediatric unipolar depression: Epidemiology, clinical features, assessment, and diagnosis".)

Discussion about the safety of antidepressants should include the US Food and Drug Administration (FDA) boxed warning in medication package inserts regarding suicidal ideation and behavior (table 6) [6,10]. The warning requires clinicians to discuss its content before prescribing the medication and recommends monitoring for clinical worsening, such as increased suicidal ideation and behavior, or unusual changes after onset of treatment and dose changes. (See "Effect of antidepressants on suicide risk in children and adolescents", section on 'FDA black box warning'.)

Patients and families should also be educated about the high risk of morbidity and mortality from untreated depression [3,8]. Following the advent of boxed warnings about antidepressants and suicidal ideation and behavior, studies of antidepressants in pediatric patients have concluded that the benefits of antidepressants under ordinary clinical circumstances outweigh the potential risk of suicidal ideation and behavior [11]. The adverse effects of untreated depression include the risk of suicide. (See "Suicidal behavior in children and adolescents: Epidemiology and risk factors".)

Patient and family education about aspects of depression that are not specifically related to pharmacotherapy are discussed elsewhere in other topics. (See 'Information for patients' below and "Overview of prevention and treatment for pediatric depression", section on 'Education and resources'.)

Pretreatment evaluation — The initial assessment of depressed pediatric patients who are candidates for pharmacotherapy includes the following elements [3]:

History of present illness

Symptoms of depression, irritability, anxiety (particularly panic attacks), restlessness, agitation, and impulsivity

Suicidal ideation and behavior

Homicidal symptoms

Psychotic features (eg, delusions or hallucinations)

Comorbid psychiatric disorders, including:

-Anxiety disorders

-Attention deficit hyperactivity disorder

-Substance related and addictive disorders

Treatment

Past psychiatric history (especially bipolar disorder)

Psychosocial functioning

Family history (especially parental history of depression and/or bipolar disorder)

Social history, including family environment and ongoing negative life events (eg, family conflicts and abuse)

General medical history

Mental status examination

Using school years, birthdays, and holidays as anchor points, timelines can be established to help assess the onset and course of mood disorders.

If an underlying general medical condition (eg, hypothyroidism) is suspected, a physical examination and/or focused laboratory tests should be pursued in collaboration with the patient’s primary care clinician [3].

Confirming the diagnosis of unipolar depressive disorders includes ruling out bipolar disorder by checking for a past history of mania (table 7) and hypomania (table 8). Episodes of major depression usually precede the first lifetime onset of manic and hypomanic episodes in bipolar disorder; thus, youth who initially present with a depressive syndrome may ultimately warrant a diagnosis of bipolar disorder. Patients with known bipolar disorder should first receive treatment with an antimanic drug prior to using an antidepressant and should not receive antidepressant monotherapy. (See "Pediatric bipolar disorder: Clinical manifestations and course of illness", section on 'Major depression' and "Pediatric bipolar disorder: Assessment and diagnosis", section on 'Diagnosis'.)

In some cases, psychometric testing can be useful for children with learning problems or suspected intellectual disability. (See "Specific learning disorders in children: Evaluation", section on 'Psychometric tests'.)

Further assessment depends upon the choice of antidepressant:

Selective serotonin reuptake inhibitor (SSRI), selective-norepinephrine reuptake inhibitor (SNRI), atypical antidepressant, or serotonin modulator – Generally, no pretreatment laboratory evaluation is necessary, other than a urine pregnancy test in postpubertal females who are not using reliable contraception. The potential risks of these antidepressants in pregnancy are discussed separately. (See "Antenatal use of antidepressants and the potential risk of teratogenicity and adverse pregnancy outcomes: Selective serotonin reuptake inhibitors" and "Antenatal use of antidepressants and risks of teratogenicity and adverse pregnancy outcomes: Drugs other than selective serotonin reuptake inhibitors".)

Tricyclics – Tricyclics are rarely used to treat pediatric depression due to their general lack of efficacy in pediatric depression, unfavorable side effect profile (table 4), required monitoring, and their lethality in overdose [10]. (See "Pediatric unipolar depression and pharmacotherapy: Choosing a medication", section on 'Choice of medication for acute treatment'.)

Before administering tricyclics to children and adolescents, clinicians should obtain the patient’s cardiac history and that of the family (first-degree relatives) [3,10]. The history includes symptoms associated with syncope, including dizziness, lightheadedness, or palpitations. For patients with a personal history of cardiac disease or a family history of premature (<40 years of age) cardiac problems, a pediatric cardiology consult is warranted before starting tricyclics.

In youth who are candidates for tricyclics, the pretreatment physical examination and laboratory tests include blood pressure, pulse, weight, and a baseline electrocardiogram (ECG) [3,10]. Tricyclics should not be initiated unless these parameters are within the normal limits for the child's age, sex, and height. Additional baseline tests include a pregnancy test for postpubertal females who are not using reliable contraception.

Additional information about the baseline cardiac evaluation that is performed prior to initiating tricyclics and the effects of tricyclics in pregnancy are discussed separately. (See "Tricyclic and tetracyclic drugs: Pharmacology, administration, and side effects", section on 'Cardiac evaluation' and "Antenatal use of antidepressants and risks of teratogenicity and adverse pregnancy outcomes: Drugs other than selective serotonin reuptake inhibitors", section on 'Tricyclic antidepressants'.)

Dose — For children and adolescents, SSRIs are generally started at approximately one-half the usual adult dose (table 9) for the first week of treatment. To minimize the chance of adverse events, we generally start with the minimum therapeutic dose [6,12-14]. After one week, the dose is increased within the lower therapeutic range. Doses are then titrated incrementally every two to four weeks, depending upon response and tolerability:

Fluoxetine – For adolescents, fluoxetine is started at 5 to 10 mg per day for one week and then increased to a target dose of 20 mg per day. After three weeks, if response is insufficient and the drug is tolerated, the dose is increased to 40 mg per day for the remainder of the drug trial. However, if a partial response occurs within four weeks of prescribing 40 mg per day, the dose is increased to 60 mg per day.

For children, we start at 5 mg per day for one week and then titrate up to a target dose of 10 mg per day. After three weeks, if response is inadequate, we increase the dose to 20 mg per day for the remainder of the drug trial.

CitalopramCitalopram is started at 10 mg per day for one week and then increased to a target dose of 20 mg per day. After three weeks, if response is insufficient and the drug is tolerated, the dose is increased to 30 mg per day for the remainder of the drug trial. However, if a partial response occurs within four weeks of prescribing 30 mg per day, we increase the dose to 40 mg per day.

For patients who do not satisfactorily respond to 40 mg per day after four weeks, we discuss with the patient and family both the possibility of raising the dose further, as well as concerns that doses above 40 mg per day can cause QT interval prolongation. If they wish to continue citalopram, we obtain an ECG at 40 mg per day, prior to increasing the dose, and if the ECG is normal, we increase the dose to 50 mg per day and one week later, obtain another ECG.

For patients who do not satisfactorily respond to 50 mg per day after four weeks, we discuss with the patient and family both the possibility of raising the dose to a maximum of 60 mg per day. If they wish to continue citalopram, we obtain an ECG at 50 mg per day, prior to increasing the dose, and if the ECG is normal, we increase the dose to 60 mg per day and one week later, obtain another ECG.

Dose dependent QT interval prolongation with citalopram is discussed separately. (See "Selective serotonin reuptake inhibitors: Pharmacology, administration, and side effects", section on 'Cardiac'.)

EscitalopramEscitalopram is started at 5 mg per day for one week and then increased to a target dose of 10 mg per day. After three weeks, if response is insufficient and the drug is tolerated, the dose is increased to 20 mg per day for the remainder of the drug trial. However, if a partial response occurs within four weeks of prescribing 20 mg per day, we increase the dose to 30 mg per day.

SertralineSertraline is started at 25 mg per day for one week and then increased to a target dose of 50 mg per day. After three weeks, if response is insufficient and the drug is tolerated, the dose is increased to 75 to 100 mg per day for the remainder of the drug trial. However, if a partial response occurs within four weeks of prescribing 75 to 100 mg per day, the dose may be increased by 25 to 50 mg per day every several (eg, three) weeks to a maximum dose of 200 mg per day.

We typically do not use paroxetine for pediatric depression because of its lack of demonstrated efficacy [6,15,16]. (See "Pediatric unipolar depression and pharmacotherapy: Choosing a medication", section on 'Other specific SSRIs'.)

Symptoms typically begin to improve within two to four weeks after the target dose is achieved [17].

Although a meta-analysis of 13 randomized trials compared SSRIs with placebo in youth with unipolar major depression (n >3000), and found no advantage for the maximum dose of the SSRI that was used, none of the studies were fixed-dose trials, which is the preferred method for studying dose effects [17]. In addition, studies in treatment-resistant pediatric depression suggest that higher doses of SSRIs may be superior to continued low doses [18,19].

Duration of an adequate trial — An adequate antidepressant trial in children and adolescents generally lasts 6 to 12 weeks. This includes the time to administer the starting dose for one week and to titrate the dose to the lower end of the therapeutic range for the next two to four weeks. If response is insufficient, and adherence is confirmed and the medication is tolerated, then the dose is increased to the middle of the therapeutic range [11,20,21]. However, if response remains insufficient over the next four weeks, the dose is increased to the upper end of the therapeutic range, provided it is tolerated. In some situations (eg, the drug is poorly tolerated), switching the medication is indicated and the duration of the trial is truncated [12,13,22].

Evidence supporting this approach includes a meta-analysis of 13 randomized trials lasting 8 to 12 weeks, which compared SSRIs (citalopram, escitalopram, fluoxetine, paroxetine, and sertraline) with placebo in children and adolescents with unipolar major depression (n >3000) [17]. Nearly 70 percent of the improvement with SSRIs occurred within the first two weeks of treatment, and minimal treatment gains were observed after four weeks of treatment.

Monitoring — Clinicians prescribing pharmacotherapy for depressed pediatric patients, as well as families, should regularly assess symptoms, functioning, side effects (table 4 and table 5), adherence, and satisfaction with treatment [3,7]. The family should be educated about possible indicators of worsening depression, activation, and suicidality, and should notify clinicians if these symptoms occur because it may be necessary to further evaluate the patient and adjust the dose or switch to a different medication.

In particular, patients are monitored for the following adverse responses during the initial few months of therapy and when doses are increased or decreased [13,23-25]:

Worsening depressive symptoms (eg, suicidal ideation and behavior, anxiety, and insomnia)

Agitation

Irritability or hostility

Impulsivity and disinhibition

Akathisia (ie, restlessness and inability to sit down)

Hypomania (table 8) or mania (table 7)

In addition, behavioral activation may occur with higher antidepressant concentrations or their rapid titration, and usually resolves when the antidepressant dose is decreased or stopped [26,27]. Serotonin syndrome can also occur when multiple serotonergic medications interact (table 10), and usually requires hospitalization. (See "Pediatric unipolar depression and pharmacotherapy: Choosing a medication", section on 'Adverse effects' and "Serotonin syndrome (serotonin toxicity)".)

We encourage clinicians to provide measurement based care, that is, monitor progress by serially measuring the severity of symptoms with a standardized scale [6]:

Patient Health Questionnaire – Nine Item (PHQ-9): Modified for Teens – The most widely used and studied depression scale among adults is the self-report PHQ-9. It can be used in adolescents [28]; however, there is a modified form of the PHQ-9 specifically for adolescents (PHQ-9: Modified for Teens) (table 11) [29,30].

Mood and Feelings Questionnaire – The Mood and Feelings Questionnaire is validated for both children and adolescents, and has a separate form that is completed by the patient and by the parent or caregiver about their offspring [31-34]. The patient and parent questionnaires are each available in a short version (13 items) and a long version (33 items for the patient, 34 for the parent); the short version lacks a question about suicidal ideation.

Quick Inventory of Depressive Symptomatology, Adolescent Version – The self-report, 17-item Quick Inventory of Depressive Symptomatology, Adolescent Version is another option for monitoring response to treatment [35].

Each of these measures is in the public domain [36-38].

Additional information about measurement based care is discussed separately in the context of adults. (See "Using scales to monitor symptoms and treat depression (measurement based care)".)

Patients treated with tricyclics require monitoring that includes blood pressure and pulse [10]. In addition, an ECG should be repeated in one week after the therapeutic dose is achieved, when the dose is changed, if the patient receives medications that can interact with tricyclics, if clinicians think the tricyclic serum concentration has changed, or following discontinuation of tricyclics. (Tricyclics can interfere with cardiac conduction and cause dose-dependent QTc prolongation.) If cardiac parameters are outside the normal limits for age, sex, and height, particularly in patients who are hypotensive or tachycardic, the dose should be decreased, and the ECG repeated. Consultation with a cardiologist is generally warranted in patients who respond to tricyclics, but manifest persistent ECG abnormalities. Specific interactions of tricyclics with other medications may be determined using the drug interactions tool included in UpToDate.

Frequency — For outpatients who are treated with antidepressants, we typically interview patients and families weekly for the first four weeks at the onset of pharmacotherapy and when medications are switched [8]. Interviews can be conducted in person, or by videoconferencing or phone, but should include several in-person appointments within the first eight weeks of starting medication and as clinically necessary.

The frequency of follow-up at other times is individualized and can range from once every two weeks to once every three months. The schedule is based upon the severity of the depressive syndrome, level of social support, and the presence of comorbidity, adverse effects, and stressors (eg, break-up with girlfriend, death of a close relative, or poor school performance).

Treatment-emergent suicidality — Patients treated with antidepressants who experience severe suicidal ideation or suicidal behavior should be referred for emergency assessment to determine whether hospitalization is required. Once stabilized, patients are evaluated to determine the factors that led to the increased suicidality. Clinicians can then decide whether to adjust the antidepressant dose or switch to a different antidepressant from the same or a different class. The general consensus is that the benefits of antidepressants far outweigh the risk of suicidal events [3,8]. (See "Effect of antidepressants on suicide risk in children and adolescents".)

DISCONTINUING PHARMACOTHERAPY — Pharmacotherapy for pediatric depression generally lasts for at least 6 to 12 months after remission. (See "Pediatric unipolar depression and pharmacotherapy: Choosing a medication", section on 'Continuation and maintenance treatment'.)

For patients who decide to stop antidepressants, prescribing clinicians should supervise discontinuation of treatment [3]. It is preferable to stop pharmacotherapy when psychosocial stress is reduced and the consequences of recurrences are reduced (eg, summer vacation).

Antidepressants should generally be tapered before discontinuation. A taper of approximately 25 to 50 percent per week provides a gradual decrease that allows the body time to adjust to the lower dose. As an example, sertraline 200 mg per day can be decreased to 150 mg per day for week one, 100 mg per day for week two, 50 mg per day for week three, and 25 mg per day for week four, after which the medication is stopped.

Abrupt discontinuation of selective serotonin reuptake inhibitors can cause a discontinuation (withdrawal) syndrome marked by:

Anxiety

Chills

Dizziness

Fatigue

Myalgias

Nausea

Discontinuation symptoms may occur after just six to eight weeks of therapy. However, it is acceptable to abruptly stop fluoxetine because its elimination half-life is long (4 to 16 days) [39-41].

Discontinuation of antidepressants is discussed further in the context of adults. (See "Discontinuing antidepressant medications in adults".)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Depressive disorders".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

Basics topics (see "Patient education: Depression in children and teens (The Basics)" and "Patient education: Coping with high drug prices (The Basics)")

Beyond the Basics topics (see "Patient education: Depression in children and adolescents (Beyond the Basics)" and "Patient education: Depression treatment options for children and adolescents (Beyond the Basics)" and "Patient education: Coping with high prescription drug prices in the United States (Beyond the Basics)")

Additional sources of information about unipolar major depression and treatment that is intended for patients and families is discussed separately. (See "Overview of prevention and treatment for pediatric depression", section on 'Education and resources'.)

SUMMARY

Choosing treatment – Multiple treatment options, including pharmacotherapy and psychotherapy, are available for treating pediatric unipolar depression. (See "Overview of prevention and treatment for pediatric depression".)

General principles of prescribing pharmacotherapy

Indications – Pharmacotherapy is indicated for children and adolescents diagnosed with moderate to severe major depression (table 1), persistent depressive disorder (dysthymia) (table 2), or depressive symptoms with functional impairment, as well as nonresponse to psychotherapy. (See 'Indications' above.)

Approach to the patient – Help patients and families understand and accept pharmacotherapy by explaining the benefits and risks of antidepressants, as well as the risks of no treatment, and soliciting their preferences regarding different options. Allow enough time for patients and families to review the information about antidepressants to make informed decisions. (See 'Approach to the patient' above.)

Education – Prior to starting antidepressants, clinicians should educate patients and families about depression, including its symptoms and available treatments. Clinicians should also discuss the benefits and side effects of pharmacotherapy (table 4 and table 5), the lag in onset of therapeutic effects, and the US Food and Drug Administration (FDA) boxed warning about suicidal ideation and behavior (table 6). (See 'Education' above and "Effect of antidepressants on suicide risk in children and adolescents".)

Pretreatment evaluation – The initial assessment of depressed pediatric patients who are candidates for pharmacotherapy includes the history of present illness, past psychiatric history, family history, social history, general medical history, and mental status examination. If an underlying general medical condition is suspected, a physical examination and/or focused laboratory tests should be pursued in collaboration with the patient’s primary care clinician. (See 'Pretreatment evaluation' above.)

Dose – For children and adolescents, selective serotonin reuptake inhibitors (SSRIs) are generally started at approximately one-half the usual adult dose (table 9) for the first week of treatment. This dose is increased after one week within the low therapeutic range. (See 'Dose' above.)

Duration of an adequate trial – An adequate antidepressant trial in children and adolescents lasts 6 to 12 weeks. (See 'Duration of an adequate trial' above.)

Monitoring – Clinicians and families should monitor patients who are treated with pharmacotherapy by assessing symptoms, including suicidal ideation and behavior, anxiety and panic attacks, agitation, irritability or hostility, impulsivity, and insomnia. Patients should also be monitored for hypomania (table 8) or mania (table 7), as well as medication side effects (table 4) and adherence, psychosocial functioning, and satisfaction with treatment. (See 'Monitoring' above.)

Treatment-emergent suicidality – If patients treated with antidepressants experience suicidal behavior or sudden or severe suicidal ideation, they should be evaluated to determine if a higher level of care is necessary. Once stabilized, patients are assessed to determine what if any changes should be made regarding the antidepressant. (See 'Treatment-emergent suicidality' above.)

Discontinuation – Before discontinuing antidepressants, the dose is generally tapered by 25 to 50 percent per week to avoid discontinuation symptoms. However, it is reasonable to discontinue fluoxetine abruptly. (See 'Discontinuing pharmacotherapy' above.)

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Topic 88735 Version 17.0

References

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