Somatic treatment for depressive illnesses in children and adolescents

Somatic treatment for depressive illnesses in

children and adolescents

Robert L. Findling, MD*, Norah C. Feeny, PhD,Robert J. Stansbrey, MD, Denise DelPorto-Bedoya, MA,

Christine Demeter, BADepartment of Psychiatry, University Hospitals of Cleveland, Case Western Reserve University,

11100 Euclid Avenue Cleveland, OH 44106–5080, USA

An ever-increasing body of evidence has demonstrated that depressive ill-

nesses are chronic conditions associated with significant human suffering,

psychosocial morbidity, and the risk of suicide in children and adolescents.

[1,2] As the malignant outcome of pediatric depression has become better

understood, the need for identifying safe and effective interventions for these

vulnerable young people has also become clearer.

Somatic interventions are commonly considered for adults suffering from

major depression or dysthymia. These treatments include pharmacotherapy,

electroconvulsive therapy, light therapy, and alternative therapies. Unfortunately,

much less is known about these interventions in children and adolescents than in

adults with depressive illnesses.

This article briefly reviews what is known about the use of somatic inter-

ventions for the treatment of children and adolescents with major depression,

dysthymia, and related conditions. Particular emphasis is placed on interpreting

the available scientific data so that they may be rationally applied to current

clinical practice.

Tricyclic antidepressants

For decades, tricyclic antidepressants were the benchmarks for pharmacother-

apy. Several of these compounds, such as amitriptyline, desipramine, imipramine,

1056-4993/02/$ – see front matter D 2002, Elsevier Science (USA). All rights reserved.

PII: S1056 -4993 (02 )00010 -X

This work was supported, in part, by a Clinical Research Center grant from the Stan-

ley Foundation.

* Corresponding author.

E-mail address: [email protected] (R.L. Findling).

Child Adolesc Psychiatric Clin N Am

11 (2002) 555–578

and nortriptyline, were shown to be effective in treating depressed adults. Initial

uncontrolled studies in children and adolescents suggested that some tricyclic

antidepressants might have beneficial effects when prescribed for depressed

youths. Randomized controlled trials, however, have failed to demonstrate that

these agents are superior to placebo in ameliorating symptoms of depression in

children and adolescents [3–5].

Birmaher and colleagues found that treatment with amitriptyline at an average

dose of 173 mg/day was not associated with greater symptom amelioration than

placebo in 27 treatment-resistant adolescent patients [6]. The patients treated with

amitriptyline experienced more tachycardia and complained more frequently of

dry mouth than the patients taking placebo. Another study published within the

past few years similarly failed to demonstrate that desipramine at an average

daily dose of 214.1 mg/day was superior to placebo in 45 adolescents between

the ages of 13 and 18 years who were treated in a double-blind, controlled

6-week study [7].

Most recently, Keller and colleagues treated 182 depressed adolescents from

12 to 18 years of age with imipramine or placebo in a double-blind study over

an 8-week period [8]. As discussed later, this study also included a third

treatment arm in which 93 teenagers were treated with paroxetine. The patients

treated with imipramine received between 200 and 300 mg of medication per

day. The authors found no significant differences in changes in depressive

symptomatology in the 95 adolescents treated with imipramine at a mean dose

of 205.8 mg/day and the 87 teenagers who received placebo. Moreover, the

authors found that 31.5% of the patients treated with imipramine but only 9.7%

of the patients treated with paroxetine withdrew from the treatment study

because of side effects. Perhaps of even greater importance, 14% of the patients

treated with imipramine had cardiovascular side effects that led to discontinua-

tion of the study.

There is some evidence that intravenous pulse treatment with the tricyclic

antidepressant clomipramine may be superior to placebo when administered to

depressed teenagers. In one study, treatment with a single intravenous 200-mg

dose of clomipramine was found to be safe and superior to intravenously admin-

istered placebo in 16 depressed adolescents, 8 of whom received active treatment

[9]. These data may not be applicable to oral treatment with clomipramine. The

authors hypothesized that the therapeutic effects of the intravenous clomipramine

may have resulted from pharmacodynamic changes that occur specifically with

pulse intravenous therapy.

In short, numerous agents from this class of compounds have failed to show

superiority to placebo in randomized, clinical trials. Tricyclic antidepressants

have the potential for causing significant and potentially life-threatening cardi-

ovascular side effects. Other problematic drug-related side effects (such as

anticholinergia and sedation) may also significantly interfere with the use of

tricyclic antidepressants in treating pediatric depression [3]. For these reasons,

tricyclic antidepressants should generally not be considered as first-line treat-

ments for depressed young people.

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Monoamine oxidase inhibitors

Historically, the monoamine oxidase inhibitors (MAOIs) were the second most

commonly prescribed class of drugs administered for the treatment of depression

in adults. These compounds are effective in the treatment of depressed adults.

Older compounds that are nonselective inhibitors of both MAO-A and MAO-B

(eg, isocarboxazid, phenelzine, and tranylcypromine) require significant dietary

restrictions of tyramine-rich foods to avoid the risk of a hypertensive crisis [10].

In the first randomized, controlled trial to examine the efficacy of antide-

pressant agents in depressed children, the effects of phenelzine and chlordiaze-

poxide were compared with those of phenobarbitone plus placebo in a cross-over

study [11]. The author noted that most patients treated with phenelzine and

chlordiazepoxide for the 2-week study period had some clinical benefit from

treatment. The diagnostic heterogeneity of this patient cohort, the small sample

size (n = 32), the lack of a placebo arm, and the brief duration of treatment

significantly impair the definitive interpretation of these results.

A chart review of 23 teenagers between the ages of 11 and 18 years who were

unresponsive to tricyclic antidepressant therapy and were subsequently treated

with an MAOI suggested that treatment with tranylcypromine or phenelzine

alone or adjunctively with the previously prescribed tricyclic antidepressant

might be associated with a good or fair response to MAOI treatment in some

patients [12]. Approximately 30% percent of the youths, however, failed to

comply with the necessary dietary restrictions.

The authors generally do not recommend the routine use of nonselective

MAOIs for the treatment of depressed children or teenagers for several reasons.

The first relates to the paucity of data from controlled, clinical trials. The second

arises from the dietary restrictions that are necessary for these drugs to be ad-

ministered safely and that may be difficult for most teenagers to comply with.

Both phenelzine (Nardil; Parke-Davis Morris, Plains, NJ) and tranylcypromine

(Parnate; Glaxo Smith Kline Research, Triangle Park, NC) are still marketed for

adults in the United States. Because there is one case report that phenelzine may

be useful in treatment-resistant cases of adolescent depression [13], the use of

MAOIs that are nonselective inhibitors of MAO-A and MAO-B might be a

reasonable consideration for patients with treatment-resistant depression.

Other MAOIs are not associated with the same degree of risk of tyramine-

associated hypertensive crises. There is substantial evidence from randomized,

clinical trials that moclobemide (a reversible inhibitor of MAO-A) is safe and

effective for the treatment of depression in adults [14,15]. Dietary restrictions do

not seem to be necessary when adults are treated with moclobemide at the

generally recommended doses [14]. Evidence also suggests that open-label

treatment with moclobemide might be safe and of benefit to children with attention

deficit hyperactivity disorder (ADHD) [16,17]. Whether or not moclobemide may

be useful in treating pediatric depression has yet to be adequately considered.

Similarly, some evidence suggests that selegiline (L-deprenyl), a compound

that at low doses selectively inhibits MAO-B, might be useful for the treatment of

R.L. Findling et al / Child Adolesc Psychiatric Clin N Am 11 (2002) 555–578 557

children with ADHD and tic disorders [18,19]. In adults, there is evidence

suggesting that selegiline is an effective antidepressant when given at higher oral

doses, at which its MAO-B selectivity may be lost. This consideration is

important because it is selegiline’s MAO-B selectivity at low doses that mediates

its modest risk for tyramine-associated hypertensive events. Whether selegiline is

an effective antidepressant at the lower doses at which it retains its MAO-B

selectivity has yet to be definitively established [20]. At present there are no data

regarding the use of selegiline in depressed children or adolescents.

Pirlindole, befloxatone, and toloxatone are other reversible MAO-A inhibitors

that are marketed outside the United States or are currently under clinical devel-

opment in adults [15,20]. Whether these agents can eventually be used to treat

depressed young people is not yet known.

Trazodone

Trazodone is a triazolopyridine derivative that was initially marketed in the

United States in 1981 for the treatment of depression in adults [21,22]. Its phar-

macodynamics seems to result from its action as a serotonin receptor antagonist

[23,24]. There is only limited information about the use of this compound in

depressed children or adolescents, most probably because of concerns about the

possibility of drug-induced priapism [25,26]. Also, sedation seems to be a dose-

limiting side effect with this agent.

Some clinicians, however, have taken advantage of trazodone’s sedating

properties in their treatment of adults with depression. Trazodone, at doses lower

than typically given for the treatment of depression, has been reported to be an

effective adjunct to antidepressant pharmacotherapy with other agents in adults

with depression- or antidepressant-related sleep disturbances [27]. In contrast, a

retrospective chart review found that little benefit from the addition of trazodone

to fluoxetine pharmacotherapy in adolescent inpatients [28].

Because of the limited data about the use of trazodone in pediatric depression

and concerns about priapism and sedation, the authors generally do not prescribe

this compound to depressed children or teenagers.

Bupropion

Bupropion is an aminoketone antidepressant that was initially marketed in the

United States in 1988. Bupropion seems to act by modulating the reuptake of

norepinephrine and dopamine in the CNS [29]. Bupropion has historically been

marketed in the United States as Wellbutrin (Glaxo Smith Kline Research,

Triangle Park, NC). Recommended daily dosing for Wellbutrin was administra-

tion in three divided doses. Of major concern is Wellbutrin’s association with a

0.40% seizure rate in adults [30].


A sustained-release formulation, Wellbutrin SR (Glaxo Smith Kline Research,

Triangle Park, NC), was approved for use in this country in 1996 and has

subsequently been marketed here. Wellbutrin SR is effective in treating adults

with depression and allows twice-daily dosing. Of perhaps greater importance,

Wellbutrin SR seems to have has a reduced seizure risk than the originally

available immediate-release preparation [31–33]. The active ingredient in Zyban

(Glaxo Smith Kline Research, Triangle Park, NC), a product marketed as an aid

to smoking cessation, is the sustained-release formulation of bupropion [34].

Although evidence from several studies suggests that bupropion may be safe

and effective in the treatment of pediatric ADHD [35–38], there is a paucity of

data regarding the use of this compound in either formulation in depressed youths.

This lack of information probably arises from concerns about the risk of seizures

in adults that has been reported with Wellbutrin, particularly at higher doses [30].

In one open-label study, Wellbutrin SR, at doses of approximately 6 mg/kg/day,

was found to be safe and associated with amelioration in depressive symptomato-

logy in a cohort of 16 adolescents with ADHD and either major depression or

dysthymia [39].

Unfortunately, data about the use of bupropion in depressed children or

adolescents are limited. Because Wellbutrin SR seems to have some advantages

over Wellbutrin in adults, the safety and efficacy of Wellbutrin SR in children and

adolescents with depression should be a topic of future study.

Serotonin-selective reuptake inhibitors

Five serotonin-selective reuptake inhibitors (SSRIs) are currently marketed

in the United States. All SSRIs have been shown to be effective in treating

depression in adults [40]. Although these agents have different effects on neural

transmission, they all seem to act primarily by selectively inhibiting serotonin

reuptake [41].

Fluoxetine (Eli Lilly and Company, Indianapolis, IN) was the first SSRI re-

leased in the United States. It is currently marketed under the name Prozac for use

in adults with depression, obsessive-compulsive disorder, and bulimia nervosa.

Fluoxetine is also marketed under the name Sarafem as a treatment for

premenstrual dysphoric disorder. At present, fluoxetine is not approved for use

in children or adolescents. The second SSRI available in the United States was

sertraline (Zoloft; Pfizar Inc., New York, NY). Sertraline is currently approved

for use in the treatment of obsessive-compulsive disorder in adults and children

and in treating adults with depression, panic disorder, or posttraumatic stress

disorder. Paroxetine (Paxil; Glaxo Smith Kline Research, Triangle Park, NC) the

next SSRI released in the United States, is indicated for use in adults with

depression, obsessive-compulsive disorder, panic disorder, and social anxiety

disorder. Presently, paroxetine is not approved for use in children or adolescents.

Fluvoxamine (Luvox; Solvey Pharmaceuticals Inc., Maritta, GA) is currently

approved for use in the treatment of adults and children with obsessive-


Table 1

Selected studies of fluoxetine in pediatric depressive disorders

Lead author (Year) Diagnosis Study design N Age (years) Dosing (mg/d) Comments

Simeon (1990) MDD RPC 40 13–18 60 Two thirds of placebo- and fluoxetine-treated patients

had marked or moderate response. No statistically

significant differences noted between treatment arms.

Boulos (1992) MDD OLP 15 16–24 5–40 Most patients benefited from therapy despite being

unresponsive to TCAs. Starting doses of

5–10 mg recommended.

Jain (1992) MDD, BP-Dep RCR 31 (27 MDD) 9–18 20–60 Fifty-four percent were much or very much improved;

20% showed minimal improvement.

Gammon (1993) MDD, DYS,

Others

OLP 32 (6 MDD,

25 DYS)

9–17 2.5–20 Adjunctive treatment with fluoxetine at doses at 20 mg/d

or lower were found to be effective for patients with

ADHD and comorbid depressive disorders who were

partially responsive to methylphenidate.

Colle (1994) MDD OLP 9 15–18 10–40 Treatment with fluoxetine for up to 1 year was reported

to be generally safe and effective.

Ghaziuddin (1995) MDD OLP 6 15–18 20–60 Fluoxetine was associated with reductions in depressive

symptoms for patients unresponsive to TCA therapy.

Emslie (1997) MDD RPC 106 7–17 20 Fluoxetine was found to be safe and superior to placebo in

reducing symptoms of depression during an 8-week trial.

Riggs (1997) MDD, CD,

SUD

OLP 8 14–18 20 Fluoxetine was found to be effective in reducing symptoms

of depression in depressed teenagers with comorbid CD

and histories of SUD while in residential treatment.

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Strober (1999) MDD OLP 52 13–17 20–40 Fluoxetine was associated with reductions in depressive

symptoms in hospitalized teenagers. When compared with

28 historical controls that had been treated with imipramine,

fluoxetine seemed to be associated with greater salutary

effects over a 6-week trial.

Waslick (1999) DYS ± MDD OLP 19 12–18 20 Fluoxetine seemed to be safe and effective for patients with

DYS ± MDD who do not respond to psychotherapy.

Dittman (2000) MDD, Others RCR 213 11–23 - Naturalistic use of fluoxetine seems to be generally

safe and effective.

Emslie (2000) MDD RPC 219 8–17 20 Fluoxetine was found to be safe and superior to placebo

in reducing symptoms of depression over an

8-week controlled study.

Emslie (2001) MDD RPC 40 8–17 20–60 Patients who responded to 15 weeks of fluoxetine treatment

were randomly assigned to receive either continued

fluoxetine or placebo. Fluoxetine was found to be superior

to placebo in preventing depressive relapses.

Hoog (2001) MDD RCT 29 9–17 20–60 Patients unresponsive to 9 weeks of fluoxetine treatment

at 20 mg/d were either maintained at their current dose or

could have their dose increased to 40–60 mg/d.

Clinical response to the increased dose was robust,

but statistical between-group significance was not seen,

probably because of small sample size.

RPC, randomized, placebo-controlled; MDD, major depressive disorder, BP-Dep, bipolar depression; OLP, open-label prospective; TCA, tricyclic antidepressant; RCR,

retrospective clinical review; DYS, dysthymia; ADHD, attention-deficit/hyperactivity disorder; CD, conduct disorder; SUD, substance use disorders; -, data not available;

RCT, randomized, controlled trial.

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compulsive disorder. Citalopram (Celexa; Forest Pharmaceuticals Inc., St. Louis,

MO), the SSRI most recently released in the United States, is approved for the

treatment of depression in adults.

Fluoxetine

More is known about fluoxetine than about any of the newer antidepressants

(Table 1). Results of open-label studies suggest that fluoxetine is a generally

effective treatment in pediatric major depression or dysthymia for patients with

and without comorbid psychiatric diagnoses. These reports also suggest that more

than 90% of young patients treated with fluoxetine tolerate it well. When

considered as a group, these open studies also suggest that fluoxetine is likely

to be effective for major depression and dysthymia at doses lower than those

typically prescribed for adults [42–50].

The first study that compared the antidepressant efficacy of fluoxetine with

placebo failed to demonstrate any difference between the two treatments [51].

The results of this study were difficult to interpret, however, because of the small

sample size, high placebo-response rate, and forced titration to 60 mg/day, a

higher dose than is generally prescribed.

The two other randomized, double-blind, placebo-controlled studies that have

been conducted found that fluoxetine, at a dose of 20 mg/day, was superior to

placebo in the acute treatment of depressed children and teenagers [52,53].

There is also evidence that, for patients who do not respond to fluoxetine

therapy at the 20-mg/day dose level, increasing the doses of fluoxetine to 40 or

60 mg/day may be of benefit [54]. Finally, evidence suggests that fluoxetine

may also be an effective maintenance therapy for the treatment of pediatric

depression [55].

In short, more data support the use of fluoxetine in pediatric depressive

illnesses than any other compound. In practice, the authors generally initiate

treatment at 10 mg/day and increase doses in 10-mg increments every 3 to

4 weeks. Although the data from randomized, controlled studies have shown that

higher starting doses and larger dosing increments are generally well tolerated,

the open-label literature and the authors’ clinical experience suggest the use of

smaller dosing increments as a reasonable treatment approach.

Sertraline

Several studies have examined the safety and effectiveness of sertraline in

children and adolescents (Table 2).The pharmacokinetics of sertraline was studied

in 61 children and adolescents, 44 of whom were depressed [56]. Results of that

study found that the pharmacokinetics of sertraline is similar in children,

adolescents, and adults. Those findings have clinical relevance because they

support the once-daily administration of sertraline.

Although data from double blind studies have demonstrated that sertraline is

safe and effective in treating pediatric obsessive-compulsive disorder [57], data


from double-blind, placebo-controlled studies in depressed children and teen-

agers are not available. The data that exist suggest that when a flexible dose

strategy is used during open-label treatment, sertraline therapy is generally well

tolerated and is associated with high rates of depressive symptom amelioration

[56,58–61].

The results of the available studies indicate that sertraline is a promising treat-

ment for children and adolescents with depressive disorders. Data from double-

blind, placebo-controlled studies are needed, however.

Paroxetine

Open-label studies of the effectiveness of paroxetine as a treatment for

pediatric depressive disorders have reported that this drug may be a safe and

well-tolerated agent in a variety of distinct patient cohorts (see Table 2). The

results of these open studies also suggest that paroxetine may be an effective

antidepressant in children at smaller doses than usually prescribed for adults

[62–65]. Although the biotransformation of paroxetine seems to be more rapid

in children and adolescents than adults, the available data support once-daily

dosing of paroxetine [62].

Published data available from a large, randomized, placebo-controlled clinical

trial describe the acute efficacy of paroxetine in adolescents with depression (see

Table 2). The authors of that study found that paroxetine was superior to placebo

in reducing several measures of depressive symptomatology, whereas imipramine

was not [8].

In summary, the evidence suggests that paroxetine is a safe and effective

treatment for pediatric depressive-spectrum illnesses. Doses of paroxetine lower

than those generally administered to adult patients may be effective for treating

depressed children. For this reason the authors initiate treatment with paroxetine

at a dose of 10 mg/day and use 10-mg dose increments as needed. More data

from randomized, placebo-controlled trials are necessary to confirm or to refute

these impressions.

Fluvoxamine

Data from double-blind studies have demonstrated that fluvoxamine is safe

and effective in treating pediatric obsessive-compulsive disorder [66]. There are

few published data about the use of fluvoxamine in children and adolescents with

depressive spectrum disorders (see Table 2). The existing data suggest that

fluvoxamine is effective in adolescents with depressive illnesses [67,68,84].

More data about the use of fluvoxamine in this population are needed.

Citalopram

In a recently completed, unpublished study, 178 depressed children and

teenagers between the ages of 7 and 17 years were randomly assigned to receive

either citalopram at a dose of 20 to 40 mg/day or placebo for 8 weeks. The results


Table 2

Selected studies of antidepressants in pediatric depressive disorders

Lead author (year) Diagnosis Study design N Age (years) Dosing (mg/d) Comments

Sertraline

Tierney (1995) MDD RCR 33 8–18 25–200 Most patients (65%) were much or very much improved.

Seven patients developed mania or disinhibition.

McConville (1996) MDD OLP 13 12–18 25–200 Eleven of 13 patients had a greater than 50% reduction

in their Hamilton

Rating Scale for Depression scores.

Alderman (1998) MDD,

OCD

OLP 61 6–17 25–200 Significant improvement in depression severity noted.

Pharmacokinetics found to be similar to those seen in adults.

Sallee (1998) MDD OLP 18 9–17 200 Seventy-two percent were considered responders.

Ambrosini (1999) MDD OLP 53 12–19 50–200 At the end of 10 weeks of treatment, 85% were considered

much or very much improved.

Paroxetine

Masi (1997) MDD, MR OLP 7 14–18 20–40 Reductions in depressive symptoms were noted in this

cohort of subjects with IQs ranging from 53–68.

Rey-Sanchez (1997) MDD OLP 45 Mean = 10.7 Mean = 16.22 With a flexible dose strategy, relatively low doses of

paroxetine were found to be safe and effective.

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All patients were considered symptom-free after an average

of 8.4 months of treatment.

Findling (1999) MDD OLP 30 6–17 10–20 Paroxetine was found to be safe and well tolerated with most

patients responding to the 10–mg/d doses. Pharmacokinetics

of paroxetine are also described.

Nobile (2000) DYS OLP 7 11–18 10–40 Treatment over 3 months was well tolerated with 5/7

subjects being considered responders.

Keller (2001) MDD RPC 275 12–18 20–40 Paroxetine, but not imipramine, was found to be superior to

placebo on some, but not all, measures of depression.

Paroxetine was better tolerated than placebo and was

associated with low discontinuation rates from adverse events.

Fluvoxamine

Apter (1994) MDD OLP 6 13–17 100–300 Significant reductions in depressive symptomatology were noted.

Rabe-Joblanska (2000) DYS OLP 21 Mean = 15.6 150–200 Treatment with fluvoxamine for up to 26 weeks was associated

with symptom amelioration and was generally well tolerated.

RPC, randomized, placebo-controlled; MDD, major depressive disorder; OLP, open-label prospective; RCR, retrospective clinical review; DYS, dysthymia; MR, mental

retardation; OCD, obsessive-compulsive disorder.

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of this study showed that citalopram was well tolerated and was superior to

placebo in ameliorating symptoms of depression when youngsters were assessed

with the Children’s Depression Rating Scale–Revised (Paul J. Tiseo, PhD, per-

sonal communication, 2001).

Doses of citalopram, 70 mg/day, have been reported as being effective in the

treatment of a variety of anxiety disorders in children and adolescents [69]

including posttraumatic stress disorder [70], obsessive-compulsive disorder

[71,72], and panic disorder [73]. The safety and efficacy of citalopram in treating

pediatric depression should be a topic of future study.

Venlafaxine

Venlafaxine is a bicyclic phenylethylamine that was initially marketed in the

United States as Effexor (Wyeth-Ayerst, Philadelphia, PA). More recently, an

extended-release version of this preparation, Effexor XR (Wyeth-Ayerst, Phila-

delphia, PA) has been marketed. Both preparations are safe and effective in the

treatment of adults with depression [74,75]. The extended-release version of the

drug seems to have two key advantages: it allows once-daily dosing and seems to

be associated with less nausea and dizziness seen with the immediate-release

form of the compound [74]. Venlafaxine seems to act by inhibiting the uptake of

serotonin and norepinephrine from the synaptic cleft [76,77].

One published study has examined the efficacy of venlafaxine as an adjunct to

psychotherapy in pediatric depression. In that trial, venlafaxine was not found to

be superior to placebo [78], but the low dose of venlafaxine used and the small

sample employed prevent definitive conclusions from being made concerning the

efficacy of venlafaxine in treating juvenile depression (Table 3). Because some

data suggest that venlafaxine may have salutary effects in ADHD [79,80], it

would be of particular interest to clinicians to have data from randomized, clinical

trials about the safety, efficacy, and dosing of venlafaxine in depressed youths

with and without ADHD.

Nefazodone

Marketed as Serzone (Bristol-Meyers Squibb, Princeton, NJ) in the United

States, nefzadone is a phenylpiperazine antidepressant that blocks postsynaptic

serotonin 5-HT2a receptors and also inhibits the reuptake of serotonin and

norepinephrine. Nefazodone has been shown to be safe and effective in the

treatment of depressed adults [81].

There is a modest amount of data pertaining to the use of nefazodone in the

young (see Table 3). A pharmacokinetic study of nefazodone found the

pharmacokinetics of this drug to be similar in children, adolescents, and adults

[82]. Open-label reports suggest that nefazodone is safe and effective in treating

depressed young people [82–84]. Adolescents generally seem to respond to


doses similar to those used in adults, whereas children seem to benefit from lower

doses of medication. Whether nefazodone is truly safe and effective in pediatric

depressive illnesses should be a topic of future research.

Mirtazapine

Mirtazapine (Remeron Oregon, Inc., West Orange, NJ) is a 6-aza derivative of

the antidepressant mianserin. Mirtazapine potentiates serotonergic and noradre-

nergic neural transmission and has been shown to be safe and effective in the

treatment of depressed adults [85].

Unfortunately, there are no published studies of mirtazapine in depressed

children or teenagers. Of clinical interest is a case report of an 8-year-old girl with

posttraumatic stress disorder successfully treated with 7.5 mg of mirtazapine at

bedtime (half the recommended starting dose of mirtazapine for depressed adults)

[86]. More data are needed about the use of mirtazapine in the young.

Lithium

Lithium has been reported to be effective in preventing relapses of depression

in adults [87]. Data from adult studies also support the use of lithium as an

augmenting agent to antidepressants [88].

There are data from chart reviews and an open clinical trial about the use of

lithium as an antidepressant augmentation strategy in youths (see Table 3). What

information exists suggests that the addition of lithium may be an effective ap-

proach for patients who are not fully responsive to antidepressant pharmacother-

apy [89–91]. Whether lithium truly is effective as an antidepressant-augmenting

agent remains to be rigorously studied in young patients.

Of particular interest are the results of a randomized, clinical trial in which

lithium was compared with placebo in a group of depressed children at risk for

developing bipolar disorder. In that study, lithium and placebo were found to have

equal efficacy [92].

Light therapy

A growing body of evidence indicates that bright light therapy may be helpful

for adult patients who have seasonal patterns to their depressive episodes when

they are seen in mental health settings [93]. Despite its potential as a safe,

effective treatment for depression, a recent study of bright light therapy in adults

did not support its widespread use in a primary care–based population [94]. The

optimal light therapy regimen for the treatment of patients with seasonal affective

disorder remains to be definitively determined [95,96].

Although a seasonal pattern of depression may have a very early age of onset

[97], few studies have carefully looked at the treatment of seasonal depression in


Table 3

Selected studies of other somatic treatments in pediatric depressive disorders

Lead author (year) Diagnosis Study design N Age (years) Dosing (mg/d) Comments

Venlafaxine

Mandoki (1997) MDD RPC 40 8–18 37.5–75 Patients treated with venlafaxine and psychotherapy

had outcomes similar to those treated with

placebo and psychotherapy.

Nefazodone

Wilens (1997) MDD, BP-Dep RCR 7 9–17 200–600 Clinical improvement was often seen for patients

with bipolar depression and unipolar depression.

Findling (2000) MDD OLP 28 7–17 200–600 Pharmacokinetics in adolescents and children were

found to be similar to those seen in adults.

Treatment seemed to be effective and safe.

Goodnick (2000) MDD OLP 10 13–17 400 Treatment was generally well tolerated and

associated with reduction in depressive symptoms.

Lithium

Ryan (1988) MDD RCR 14 14–19 600–1200 Lithium augmentation to TCA therapy was

associated with a good response in 6/14 teenagers

who were not responsive to TCAs alone.

Strober (1992) MDD OLP 24 Mean = 15.4 Variable For 10/24 depressed adolescents unresponsive to IMI,

3 weeks of adjunctive lithium was found to be helpful.

R.L.Findlin

get

al/Child

Adolesc

Psych

iatric

Clin

NAm

11(2002)555–578

568

Geller (1998) MDD RPC 30 6–12 Variable Lithium was not found to be superior to placebo in

the treatment of depressed children with family history

predictors for developing bipolar disorder.

Walter (1998) MDD RCR 2 16 500–1250 Lithium was reported to be a useful adjunct to

venlafaxine in two adolescents partially responsive

to venlafaxine therapy.

Light therapy

Sonis (1987) SAD RCT 19 - 2 hours of bright

light therapy

Light therapy was associated with a greater

reduction of neuro-vegatative symptoms when

compared with relaxation therapy.

Swedo (1997) SAD RPC 28 7–17 2 hours dawn stimulation and

1 hour of bright light therapy

Light therapy was found to be effective

and superior to placebo.

Rosenthal (1986),

Giedd (1998)

SAD RCR 7 13–22 Variable Patients with SAD who were initially responsive

to light therapy were followed up over a 7-year

period and were found to have persistent seasonal

symptomatology. Light therapy generally continued

to ameliorate symptoms in these patients.

Magnusson (1998) SAD OLP 18 18–19 40 minutes of bright

light therapy

Mild benefit was noted.

RPC, randomized, placebo-controlled; MDD, major depressive disorder; BP-Dep, bipolar depression; OLP, open-label prospective; TCA, tricyclic antidepressant; IMI,

imipramine; RCR, retrospective clinical review; SAD, seasonal affective disorder; -, data not available; RCT, randomized clinical trial.

R.L.Findlin

get

al/Child

Adolesc

Psych

iatric

Clin

NAm

11(2002)555–578

569

children and adolescents (see Table 3). Most notably, in a randomized, clinical

trial, 28 participants between the ages of 7 and 17 years with seasonal affective

disorder were found to have greater reductions in depressive symptomatology

after bright light therapy than after placebo treatment [98].

At present, light therapy seems to be a promising treatment for patients with

seasonal affective disorders. More research into the usefulness of this intervention

is needed.

Alternative therapies

Alternative therapies are forms of treatment that are not typically delivered by

health care professionals. They consist of interventions such as herbal therapies,

folk remedies, biofeedback, acupuncture, and homeopathy [99]. These practices

have become commonly used in the United States, and many parents wish to treat

their children with these alternative forms of therapy [100,101]. Unfortunately,

there are relatively few studies of alternative treatments for adult or pediatric

patients with depression.

Electroacupuncture is a form of acupuncture in which electrical stimulation is

applied through acupuncture needles. Some evidence to suggests that electro-

acupuncture may be an effective form of treatment for depressed adults [102].

There are no studies of acupuncture in children or adolescents with depression.

Probably the best-studied alternative therapy for depression is the extract from

St. John’s wort (Hypericum perforatum). Numerous studies of varying methodo-

logic rigor have suggested that St. John’s wort may be a safe and effective

treatment of depression in adults [103–106]. A recently published rigorous,

placebo-controlled trial has brought the efficacy of St. John’s wort for adults with

major depression into question, however [107].

Few data are available about the use of St. John’s wort in depressed youths. In

a case series describing the use of St. John’s wort in five adolescents with

psychiatric illnesses, Walter and Rey described this naturotherapy as well

tolerated and associated with reductions in depressive symptomatology in a

single 17-year old girl with major depression and panic attacks [108].

An 8-week, flexible-dose, open-label trial of St. John’s wort was recently

completed at the University Hospitals of Cleveland/CaseWestern Reserve Uni-

versity. In that study, more than 25 children and adolescents were administered

St. John’s wort at doses of up to 900 mg/day. Observations from this trial suggest

that open-label treatment with St. John’s wort may be safe and effective in this

population (R.L. Findling, unpublished data, 2002). Because this study was not

placebo-controlled, and because the small sample size was relatively small,

definitive conclusions about the safety and efficacy of Saint John’s wort cannot

and should not be made.

Because there are so few data about the use of alternative treatments in

children and adolescents, the authors generally recommend that parents eschew

these forms of treatment. Parents seem to be quite interested in these forms of


therapy, however, so the use of alternative interventions for pediatric depression

should be a topic of further study.

Electroconvulsive therapy

Electroconvulsive therapy (ECT) does not seem to be commonly used to treat

children or adolescents [109]. Although no controlled studies have examined the

use of electroconvulsive therapy in young people, a reasonably extensive body of

evidence that suggests that when electroconvulsive therapy is administered to

youths, high rates of symptom amelioration generally occur [110–113]. The use of

electroconvulsive therapy in young people remains controversial [114,115],

mostly because of concerns about the acute- and long-term safety of this inter-

vention. The data that are available about the safety of electroconvulsive therapy

in the young suggest that, although it is associated with transient cognitive effects,

it is not associated with long-term adverse sequelae [116,117]. The available data

suggest that electroconvulsive therapy is a reasonable consideration for the

treatment of depressed youths who are not responsive to other forms of therapy.

Repetitive transcranial magnetic stimulation

Data suggest that repetitive transcranial magnetic stimulation may be a safe,

effective treatment for adults with major depression [118]. Results of recently

published, double-blind studies have provided further evidence that repetitive

transcranial magnetic stimulation may be effective in the short-term treatment of

major depression [119,120]. The safety and effectiveness of this intervention in

the young have yet to be studied.

Vagus nerve stimulation

Evidence from an open clinical trial indicates that vagus nerve stimulation

may be useful in the treatment of adults with treatment-resistant depression [121].

What role, if any, vagal nerve stimulation will have in the treatment of pediatric

depression has not been determined.

Other clinical considerations with antidepressant medications

A somatic intervention in a young patient with a depressive-spectrum illness

should be initiated only after a careful clinical assessment has been made. In

addition, such treatments should be administered as part of a treatment plan in

which the implementation of other therapeutic modalities has also been considered.

The SSRIs are the antidepressants for which the greatest amount of data is

available to support their use, but several other agents seem promising. Unfortu-

nately, when compared with what is known about the treatment of depression in


adults, only a modest amount of data is available regarding the safety, efficacy,

and optimal dosing of the antidepressants in pediatric depressive disorders.

The adverse event that seems most commonly to interfere significantly with

the use of the newer antidepressants in the young is emergence of disruptive

behaviors or restlessness during pharmacotherapy. If the patient is not abusing

drugs and does not have a general medical condition that could explain these

behaviors, this phenomenon can often be explained by (1) the development of

mania or hypomania, (2) medication-induced disinhibition, or (3) the unmasking

of latent ADHD. When a patient has these difficulties during antidepressant

pharmacotherapy, a careful clinical assessment is needed.

A patient who has developed mania, hypomania, or antidepressant-induced

disinhibition may well respond to a reduction in antidepressant dose. For some

patients the antidepressant must be discontinued. In more severe cases of mania

and hypomania in which euthymia does not return after the discontinuation of

antidepressant pharmacotherapy, treatment with a mood stabilizer may be

indicated. For patients who have latent ADHD that has become more readily

manifest as the patient’s mood has improved, treatment with an adjunctive

psychostimulant may be reasonable [122].

A review of the literature indicates that children may tolerate adult-sized

doses of the newer antidepressants, but data also suggest that young people may

respond to lower doses of antidepressants than adults. Because some antide-

pressant side effects seem to be dose related, it is generally reasonable to adhere

to the rule, ‘‘start low and go slow’’ when starting medication treatment of

pediatric depression.

Future directions

Much remains to be learned about the acute somatic treatment of pediatric

depressive disorders. Unfortunately, even fewer data are available regarding the

long-term treatment of these conditions. Moreover, for many groups of patients

who have historically not been included in research trials, almost no data are

available. These groups include youngsters with substance abuse disorders,

psychosis, family histories of bipolar disorder, and patients with general medical

conditions. There is also little information about how best to combine somatic

treatments with psychosocial interventions.

Many avenues need to be considered in future clinical research studies. Only

such investigations can generate scientifically sound, empirically based evidence

about the treatment of pediatric depressive illnesses.

Acknowledgments

The authors thank Lisa A. Branicky, MA, for her assistance in preparing

this article.


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Somatic treatment for depressive illnesses in children and adolescents

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