Ronald A. Weller, MD

Are anticonvulsants safe and effective mood stabilizers for children and adolescents with bipolar disorder? The answer is unclear because most bipolar disorder treatment trials have included adults only, and clinicians are desperate for data.¹

To help you care for young patients, we report what is known about the potential benefits and risks of using mood stabilizers and anticonvulsants in bipolar youth. We base our dosing, target serum level, and monitoring recommendations on clinical experience and the limited published evidence.

AGENTS OF CHOICE?

Bipolar disorder’s “atypical” presentation in children—often more irritability and explosiveness than euphoria—can complicate diagnosis. Bipolar children and adolescents often have comorbid attention-deficit/hyperactivity disorder (ADHD), other disruptive behavior disorders, or anxiety disorders. Thus, comorbidities and presenting symptoms often dictate medication choice.

An expert consensus guideline acknowledges that more evidence on pediatric bipolar disorder is needed. In the meantime, the guideline suggests trying valproate or lithium first to treat nonpsychotic mania in pediatric bipolar patients.¹ It also recommends three atypical antipsychotics— olanzapine, quetiapine, and risperidone—as potential first-line treatments. Valproate and lithium may be preferred because of atypicals’ risk of weight gain and metabolic syndrome.

Trying other anticonvulsants may be justified for bipolar youths who are not functioning well with first-line agents. Lamotrigine, for example, has antidepressant and antimanic effects.² When you try anticonvulsants that lack double-blind, placebo-controlled trials, we recommend that you:

• obtain consent from the parents and child
  
• monitor carefully for side effects.
  

LITHIUM: STRONGEST EVIDENCE

Lithium is one of the most well-studied medications for pediatric bipolar disorder and the only mood stabilizer FDA-approved for children and adolescents (Table 1).³ Although approved for ages 12 and older, lithium has been used in younger children in practice and in clinical trials.

Table 1

FDA-approval status of medications used to treat bipolar disorder

Medication	Indications for adults	Indications for children
Carbamazepine	Acute manic episode and acute mixed episode	Not approved
Lamotrigine	Maintenance therapy	Not approved
Lithium	Acute manic episode and maintenance therapy	Age ≥ 12 years
Oxcarbazepine	Not approved	Not approved
Topiramate	Not approved	Not approved
Valproate	Acute manic episode	Not approved
Source: Reference 3

Efficacy. In an open-label study of 100 adolescents with type I bipolar disorder,⁴ 63% met response criteria after 4 weeks of lithium and 26% showed manic symptom remission. Symptoms worsened in both groups, however, when 40 responders were randomly assigned to continue or discontinue lithium for 2 weeks.⁵ The authors speculated that these conflicting results might indicate that mood stabilization requires longer treatment. Contrary to earlier reports,⁶ manic adolescents with comorbid ADHD did not show poor response to lithium.

In the only double-blind, placebo-controlled trial of lithium in adolescents with bipolar disorder, some subjects had secondary substance dependency disorders.⁷ For 6 weeks, 25 outpatient adolescents received lithium (13 patients) or placebo (12 patients). Lithium was effective in treating bipolar and substance dependency symptoms, with significantly improved clinical global assessment scores and decreased positive urine assays for drugs. Little difference was seen in mood item scores on the Schedule for Affective Disorders and Schizophrenia, child version (KSADS-1986), whether patients were taking lithium or placebo.

Pediatric dosing. For bipolar patients ages 6 to 12, use the child’s weight to determine lithium dosage (Table 2).⁸ Maintain serum levels between 0.8 and 1.2 mEq/L,⁹ and check them frequently when starting therapy.¹⁰ After mood stabilization, check levels every 1 to 3 months or when you suspect noncompliance. Obtain renal and thyroid function values at baseline and every 4 to 6 months.

Table 2

Guide to dosing lithium for prepubertal school-aged children*

	Doses (mg)
Child’s weight (kg)	8 AM	12 PM	6 PM	Total daily
	150	150	300	600
25 to 40	300	300	300	900
40 to 50	300	300	600	1,200
50 to 60	600	300	600	1,500
* Maintain specified dose at least 5 days, drawing serum levels 12 hrs after the last lithium dose until two consecutive levels appear in the therapeutic range (0.6 to 1.2 mEq/L). Dose may then be adjusted based on serum level, side effects, or clinical response. Do not exceed 1.4 mEq/L.
Source: Reference 8

Safety. Common side effects reported in adolescents include weight gain (55%), polydipsia (33%), polyuria (25%), headache (23%), tremor (20%), and GI complaints (up to 18%).⁴ Neurologic side effects are associated with higher serum lithium levels (0.91 to 1.36 mEq/L)¹⁰ and occur more often in younger than in older children.¹¹ The cardiac defect Ebstein’s anomaly occurs in approximately 0.05 to 0.1% of children exposed to lithium in utero (Box).^12-16

Box

 

VALPROATE: OPEN-LABEL TRIALS ONLY

Efficacy. No double-blind, placebo-controlled study has shown valproate to be effective in treating bipolar disorder in children and adolescents. When used as monotherapy in open-label studies, valproate has produced response rates of:

• 53% in a 6-week, randomized, open-label trial in which 42 outpatients (mean age 11.4 years) with bipolar disorder type I or II received lithium, divalproex sodium, or carbamazepine⁹
  
• 61% in an open-label study of 40 patients ages 7 to 19 with a manic, hypomanic, or mixed episode who received divalproex for 2 to 8 weeks¹⁷
  
• 80% in an 8-week open-label trial of 40 patients ages 6 to 17 with bipolar disorder type I (77.5%) or type II (22.5%) and a Young Mania Rating Scale (YMRS)score ≥ 14.¹⁸
  

In a prospective trial, 90 patients ages 5 to 17 with bipolar disorder type I or II were treated with lithium plus divalproex sodium. After up to 20 weeks, 47% met criteria for depressive and manic symptom remission.¹⁹ A chart review has showed valproate’s efficacy in treating aggression and irritability in adolescent mania.²⁰

Safety: Black-box warnings. Valproate therapy carries risks of hepatic failure, pancreatitis, and birth defects. Monitor blood counts and hepatic enzymes throughout therapy (Table 3).³ Rare yet potentially fatal hepatic toxicity appears to occur most often in children age 21 Other studies suggest:

• an association with congenital malformations, including spina bifida and pulmonary atresia, in children exposed to valproate in utero⁶
  
• a link between valproate and hyperammonemic encephalopathy, especially in patients with urea cycle disorders²²
  
• potential for benign thrombocytopenia²³
  
• increased incidence of polycystic ovary syndrome—ovarian cysts, hyperandrogenism, chronic anovulation—in peripubertal mentally retarded women treated with valproate for seizure disorders.²⁴
  

Because of these risks, use caution when prescribing valproate to bipolar adolescent girls. Monitor menstrual cycle regularity, and collaborate with a gynecologist to watch for potentially dangerous effects.

Table 3

Mood stabilizers’ side effects and recommended monitoring

Medication	Major side effects	Monitoring
Carbamazepine	Allergic skin rash, drowsiness, blood dyscrasias, diplopia	CBC with reticulocytes, iron, LFTs, urinalysis, BUN, TFTs, sodium, serum carbamazepine levels
Lamotrigine	Stevens-Johnson syndrome, headache, dizziness, ataxia, somnolence, nausea, diplopia, blurred vision, rhinitis	No serum monitoring recommended
Lithium	Polyuria, polydipsia, nausea, diarrhea, tininecleatremor, enuresis, fatigue, ataxia, leukocytosis, malaise, cardiac arrhythmias, weight gain	BUN/creatinine, crearance, TFTs, calcium/phosphorus, ECG, serum lithium levels every 1 to 3 months once stabilized
Oxcarbazepine	Dizziness, somnolence/fatigue, ataxia/gait disturbance, vertigo, headache, tremor, rash, hyponatremia, hypersensitivity reaction, GI symptoms, diplopia	Sodium levels (particularly ifirst 3 months)
Topiramate	Hyperchloremic metabolic acidosis, oligohydrosis and hyperthermia, acute myopia, somnolence/fatigue, nausea, anorexia/weight loss, paresthesia, tremor, difficulty concentrating	BUN/creatinine, sodium bicarbonate
Valproate	Irritability/restlessness, ataxia, headache, weight gain, hyperammonemic encephalopathy, alopecia, GI upset, pancreatitis,sedation, thrombocytopenia, liver failure, polycystic ovaries/hyperandrogenism, teratogenic effects,rash	Ammonia, LFTs, bilirubin, CBC with platelets, serum valproate levels
BUN: blood urea nitrogen; CBC: complete blood count; ECG: electrocardiography; LFT: liver function tests; TFTs: thyroid function tests
Note: Bolded items included in black-box warnings
Source: Reference 3

Body weight. Valproate has been associated with weight gain. In a study of 372 bipolar adults, 21% reported a 5% weight-gain during 52 weeks of maintenance therapy, compared with 13% of patients on lithium and 7% on placebo.²⁵ Shortterm studies of adjunctive valproate in pediatric bipolar patients raise similar concerns.²⁶ Thus, monitor for weight gain and serum lipid changes in youths starting valproate therapy.

CARBAMAZEPINE: DRUG INTERACTION RISK

Carbamazepine is used less often than lithium or divalproex for bipolar disorder. It tends to be used adjunctively when lithium alone is ineffective.

Efficacy. In an open-label study,⁹ 42 patients ages 8 to 18 with bipolar disorder type I or II were randomly assigned to lithium, divalproex sodium, or carbamazepine monotherapy for 6 weeks. Response rates—measured as a ≥ 50% change from baseline in YMRS scores—were 53% with divalproex, 38% with lithium, and 38% with carbamazepine.

A retrospective review of 44 hospitalized bipolar patients ages 5 to 12 treated for at least 7 days with lithium, valproate, or carbamazepine reported higher (ie, worse) Clinical Global Impression of Improvement scores with carbamazepine.²⁷ Small sample sizes, particularly in the carbamazepine group, limited this naturalistic study.

Safety: Black-box warnings. Carbamazepine’s hematologic “black box” warns of increased risk of aplastic anemia, agranulocytosis, leukopenia, and thrombocytopenia. Risks associated with carbamazepine have been estimated at:

• aplastic anemia: 5.1/million patient years
  
• agranulocytosis: 1.4/million patient years.²⁸
  

Leukopenia is relatively more common and occurs in approximately 20% of children receiving carbamazepine.²⁹ Consider stopping carbamazepine when the white cell count falls below 3,000/mm³ (or the neutrophil count drops to 3).²⁹ Advise children and parents to watch for leukopenia’s signs and symptoms, including fever, infections, sore throat, and mouth ulcers.³

Body weight. Carbamazepine is not associated with significant weight gain, which could be clinically important for some patients.

 

Drug interactions. Carbamazepine activates the cytochrome P-450 liver enzyme system, increasing the metabolism of many medications and decreasing their blood levels. Consider monitoring serum levels when using carbamazepine with valproate, imipramine, corticosteroids, warfarin, oral contraceptives, and some antibiotics. Because carbamazepine induces its own metabolism, you might need to increase its dosage if its effects appear to be waning.³

Carbamazepine and tricyclic antidepressants may show cross-sensitivity because of structural similarity. Do not use monoamine oxidase inhibitors with carbamazepine; discontinue them at least 14 days before starting carbamazepine.³

OXCARBAZEPINE: FEWER INTERACTIONS

Oxcarbazepine has similar efficacy to carbamazepine but less side effect risk and does not require plasma level monitoring. A weaker inducer of CYP-450, it causes fewer clinically important drug-drug interactions and may be useful for patients who respond to carbamazepine but cannot tolerate its side effects.³⁰

Efficacy. Case studies^31,32 have been encouraging, but no published, double-blind, placebo-controlled studies support using oxcarbazepine in bipolar children and adolescents.

Safety. Oxcarbazepine appears to be generally well-tolerated but can cause potentially serious reactions—including hyponatremia.³³ Somnolence, emesis, and ataxia are the most common side effects in pediatric patients.³

Hyponatremia —plasma sodium 125 mEq/L—occurs in 2.5% of adults taking oxcarbazepine³ and has been reported in a similar percentage of children.³⁴ This potentially severe reaction—characterized by nausea, lethargy, malaise, headache, confusion, decreased seizure threshold, or simply decreased serum sodium³⁵—is usually noted within the first 12 weeks of therapy. The risk increases with concomitant use of other sodium-altering drugs, such as antidepressants or antipsychotics.³⁶

Evaluate serum sodium when starting oxcarbazepine, periodically in the first 3 months, and if symptoms occur.^34,36 For sodium levels of 125 to 130 mEq/L, obtain repeat measurements to confirm that hyponatremia is not worsening. Intervention is often required when levels fall below 125 mEq/L.³⁶

Other serious adverse reactions include Stevens-Johnson syndrome, toxic epidermal necrolysis, and hypersensitivity reactions; 25% to 30% of patients with hypersensitivity to carbamazepine also will react to oxcarbazepine.³³

Contraceptive concerns. Oxcarbazepine may reduce contraceptive efficacy by altering estrogen and progesterone plasma concentrations.³⁷ Consider other birth control methods for sexuallyactive bipolar adolescent girls.

LAMOTRIGINE

Neurologists often use lamotrigine for children with atypical seizure disorders, but no controlled data exist on the drug’s efficacy and safety in youths with bipolar disorder.

Efficacy. In a prospective, open-label study,³⁸ 13 adolescents with type I bipolar disorder received lamotrigine, 200 to 400 mg/d. After 12 weeks (mean dosage 241 mg/d), their symptoms had improved as shown by these mean scores:

• Montgomery-Asberg Depression Rating Scale: from 21 at baseline to 4 at endpoint
  
• Clinical Global Impressions–Severity of Illness scale: from 4 to 1
  
• Children’s Depression Rating Scale (CDRS-R): from 74 to 40
  
• YMRS: from 20 to 6.
  

In another open-label study,³⁹ 16 of 18 youths (88%) with bipolar depression or mixed mania improved with lamotrigine alone or as adjunctive therapy, as shown by Clinical Global Impression of Change scores. CDRS-R scores also decreased by ≥50% in 11 of 17 who finished the study.

Safety: Severe rash. An age-related association with Stevens-Johnson syndrome may limit pediatric use of lamotrigine. Severe and potentially life-threatening rashes have been reported in 0.8% of children treated with lamotrigine.⁴⁰ Discontinue lamotrigine if a rash develops, unless it clearly is not drug-related. Three factors that increase rash risk include:

• co-administering lamotrigine with valproate
  
• higher-than-recommended initial dosages
  
• rapid dose titration.⁴¹
  

Most rashes appear in the first 8 weeks,⁴¹ though cases can occur after prolonged treatment.

Pediatric dosing. We find no published studies of efficacious dosages and plasma levels of lamotrigine in pediatric bipolar disorder (Table 4).^3,9,17 Based on our clinical experience, we recommend starting lamotrigine at 1 to 5 mg/kg/day (1 to 3 mg/kg/day if given with valproate) divided into two daily doses. Watch for rash or skin disorders. Do not exceed the recommended daily dosage by 200 mg in children age

Table 4

Using anticonvulsants in pediatric bipolar disorder patients

Drug	Recommended dosage	Target serum level
Carbamazepine	Age 6 to 12: 20 to 30 mg/kg/d	≥ 7.0 μg/L
	Age >12: 400 to 1,200 mg/d
Lamotrigine*	Unknown	Unknown
Oxcarbazepine	11 to 16 mg/kg/d (as adjunct)	Unknown
Topiramate*	Unknown	Unknown
Valproate	15 to 20 mg/kg/d	45 to 125 μg/mL (trough)
		85 to 110 μg/mL (target)
* No published studies found for efficacious dosage and plasma levels in pediatric bipolar disorder.
Dosage supported by case reports only; no studies found examining efficacious plasma levels.
Source: References 3,9, and 17.

TOPIRAMATE: LIMITED INFORMATION

Efficacy. Little is known about using topiramate in children and adolescents. A retrospective chart review⁴² of 26 patients with bipolar disorder type I (n=23) or II (n=3) showed adjunctive topiramate to be effective, with response rates of 73% for mania and 62% overall. Topiramate was well tolerated, and no serious events were reported.

 

A randomized, controlled trial of topiramate for acute mania in youths with type I bipolar disorder⁴³ was recently halted because of lack of efficacy in adul trials. Preliminary data from 56 of the pediatric patients—analyzed before the study was halted—showed improved YMRS scores. Although results were not statistically significant, the authors suggest topiramate might be effective in treating children and adolescents with bipolar disorder.

Safety: FDA warning. Decreased sodium bicarbonate leading to hyperchloremic metabolic acidosis has been reported in youths treated with topiramate for seizure disorder,⁴⁴ leading to an FDA warning to prescribers.³ Although no monitoring guidelines exist, we recommend baseline and periodic serum bicarbonate measurements and acidbase evaluations during topiramate treatment, especially when adding other antiepileptics.⁴⁴

Other rare but serious reactions include:

• impaired sweat production and resultant hyperthermia⁴⁵
  
• ophthalmologic symptoms characterized by secondary acute angle closure glaucoma and acute myacute myopia (usually within 1 month of starting treatment)⁴⁶
  
• sedation and cognitive difficulties.⁴⁷
  

Body weight. Body weight declined an average 5.8 kg across 8 weeks among 36 bipolar adults using topiramate (mean 176 mg/d).⁴⁷ We find that bipolar teens like topiramate because of weight loss, compared with weight gain with divalproex or lithium, but any pediatric weight loss requires monitoring.

Cognitive effects? Reports of “word finding difficulties” with topiramate⁴⁷ may suggest cognitive effects. Thus, be very cautious about using this medication in children and adolescents.

Related resources

• Kowatch R, Fristad M, Birmaher B, et al. Treatment guidelines for children and adolescents with bipolar disorder. J Am Acad Child Adolesc Psychiatry. 2005;44(3):213-35.
  
• Yonkers K, Wisner K, Stowe Z, et al. Management of bipolar disorder during pregnancy and the postpartum period. Am J Psychiatry 2004;161(4):608-20.
  
• American Academy of Child and Adolescent Psychiatry. Treatment guidelines for childhood psychiatric disorders. www.aacap.org
  

Disclosures

Dr. Kloos, Dr. Hitchcock, and Dr. Ronald Weller report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Dr. Elizabeth Weller has been a consultant to or received research grants from GlaxoSmithKline, Johnson & Johnson, Novartis Pharmaceuticals Corp., Abbott Laboratories, and Shire Pharmaceuticals.

Drug brand names

• Carbamazepine • Tegretol
  
• Divalproex • Depakote
  
• Lamotrigine • Lamictal
  
• Lithium • Eskalith, Lithobid, others
  
• Oxcarbazepine • Trileptal
  
• Topiramate • Topamax
  

Are anticonvulsants safe and effective mood stabilizers for children and adolescents with bipolar disorder? The answer is unclear because most bipolar disorder treatment trials have included adults only, and clinicians are desperate for data.¹

To help you care for young patients, we report what is known about the potential benefits and risks of using mood stabilizers and anticonvulsants in bipolar youth. We base our dosing, target serum level, and monitoring recommendations on clinical experience and the limited published evidence.

AGENTS OF CHOICE?

Bipolar disorder’s “atypical” presentation in children—often more irritability and explosiveness than euphoria—can complicate diagnosis. Bipolar children and adolescents often have comorbid attention-deficit/hyperactivity disorder (ADHD), other disruptive behavior disorders, or anxiety disorders. Thus, comorbidities and presenting symptoms often dictate medication choice.

An expert consensus guideline acknowledges that more evidence on pediatric bipolar disorder is needed. In the meantime, the guideline suggests trying valproate or lithium first to treat nonpsychotic mania in pediatric bipolar patients.¹ It also recommends three atypical antipsychotics— olanzapine, quetiapine, and risperidone—as potential first-line treatments. Valproate and lithium may be preferred because of atypicals’ risk of weight gain and metabolic syndrome.

Trying other anticonvulsants may be justified for bipolar youths who are not functioning well with first-line agents. Lamotrigine, for example, has antidepressant and antimanic effects.² When you try anticonvulsants that lack double-blind, placebo-controlled trials, we recommend that you:

• obtain consent from the parents and child
  
• monitor carefully for side effects.
  

LITHIUM: STRONGEST EVIDENCE

Lithium is one of the most well-studied medications for pediatric bipolar disorder and the only mood stabilizer FDA-approved for children and adolescents (Table 1).³ Although approved for ages 12 and older, lithium has been used in younger children in practice and in clinical trials.

Table 1

FDA-approval status of medications used to treat bipolar disorder

Medication	Indications for adults	Indications for children
Carbamazepine	Acute manic episode and acute mixed episode	Not approved
Lamotrigine	Maintenance therapy	Not approved
Lithium	Acute manic episode and maintenance therapy	Age ≥ 12 years
Oxcarbazepine	Not approved	Not approved
Topiramate	Not approved	Not approved
Valproate	Acute manic episode	Not approved
Source: Reference 3

Efficacy. In an open-label study of 100 adolescents with type I bipolar disorder,⁴ 63% met response criteria after 4 weeks of lithium and 26% showed manic symptom remission. Symptoms worsened in both groups, however, when 40 responders were randomly assigned to continue or discontinue lithium for 2 weeks.⁵ The authors speculated that these conflicting results might indicate that mood stabilization requires longer treatment. Contrary to earlier reports,⁶ manic adolescents with comorbid ADHD did not show poor response to lithium.

In the only double-blind, placebo-controlled trial of lithium in adolescents with bipolar disorder, some subjects had secondary substance dependency disorders.⁷ For 6 weeks, 25 outpatient adolescents received lithium (13 patients) or placebo (12 patients). Lithium was effective in treating bipolar and substance dependency symptoms, with significantly improved clinical global assessment scores and decreased positive urine assays for drugs. Little difference was seen in mood item scores on the Schedule for Affective Disorders and Schizophrenia, child version (KSADS-1986), whether patients were taking lithium or placebo.

Pediatric dosing. For bipolar patients ages 6 to 12, use the child’s weight to determine lithium dosage (Table 2).⁸ Maintain serum levels between 0.8 and 1.2 mEq/L,⁹ and check them frequently when starting therapy.¹⁰ After mood stabilization, check levels every 1 to 3 months or when you suspect noncompliance. Obtain renal and thyroid function values at baseline and every 4 to 6 months.

Table 2

Guide to dosing lithium for prepubertal school-aged children*

	Doses (mg)
Child’s weight (kg)	8 AM	12 PM	6 PM	Total daily
	150	150	300	600
25 to 40	300	300	300	900
40 to 50	300	300	600	1,200
50 to 60	600	300	600	1,500
* Maintain specified dose at least 5 days, drawing serum levels 12 hrs after the last lithium dose until two consecutive levels appear in the therapeutic range (0.6 to 1.2 mEq/L). Dose may then be adjusted based on serum level, side effects, or clinical response. Do not exceed 1.4 mEq/L.
Source: Reference 8

Safety. Common side effects reported in adolescents include weight gain (55%), polydipsia (33%), polyuria (25%), headache (23%), tremor (20%), and GI complaints (up to 18%).⁴ Neurologic side effects are associated with higher serum lithium levels (0.91 to 1.36 mEq/L)¹⁰ and occur more often in younger than in older children.¹¹ The cardiac defect Ebstein’s anomaly occurs in approximately 0.05 to 0.1% of children exposed to lithium in utero (Box).^12-16

Box

 

VALPROATE: OPEN-LABEL TRIALS ONLY

Efficacy. No double-blind, placebo-controlled study has shown valproate to be effective in treating bipolar disorder in children and adolescents. When used as monotherapy in open-label studies, valproate has produced response rates of:

• 53% in a 6-week, randomized, open-label trial in which 42 outpatients (mean age 11.4 years) with bipolar disorder type I or II received lithium, divalproex sodium, or carbamazepine⁹
  
• 61% in an open-label study of 40 patients ages 7 to 19 with a manic, hypomanic, or mixed episode who received divalproex for 2 to 8 weeks¹⁷
  
• 80% in an 8-week open-label trial of 40 patients ages 6 to 17 with bipolar disorder type I (77.5%) or type II (22.5%) and a Young Mania Rating Scale (YMRS)score ≥ 14.¹⁸
  

In a prospective trial, 90 patients ages 5 to 17 with bipolar disorder type I or II were treated with lithium plus divalproex sodium. After up to 20 weeks, 47% met criteria for depressive and manic symptom remission.¹⁹ A chart review has showed valproate’s efficacy in treating aggression and irritability in adolescent mania.²⁰

Safety: Black-box warnings. Valproate therapy carries risks of hepatic failure, pancreatitis, and birth defects. Monitor blood counts and hepatic enzymes throughout therapy (Table 3).³ Rare yet potentially fatal hepatic toxicity appears to occur most often in children age 21 Other studies suggest:

• an association with congenital malformations, including spina bifida and pulmonary atresia, in children exposed to valproate in utero⁶
  
• a link between valproate and hyperammonemic encephalopathy, especially in patients with urea cycle disorders²²
  
• potential for benign thrombocytopenia²³
  
• increased incidence of polycystic ovary syndrome—ovarian cysts, hyperandrogenism, chronic anovulation—in peripubertal mentally retarded women treated with valproate for seizure disorders.²⁴
  

Because of these risks, use caution when prescribing valproate to bipolar adolescent girls. Monitor menstrual cycle regularity, and collaborate with a gynecologist to watch for potentially dangerous effects.

Table 3

Mood stabilizers’ side effects and recommended monitoring

Medication	Major side effects	Monitoring
Carbamazepine	Allergic skin rash, drowsiness, blood dyscrasias, diplopia	CBC with reticulocytes, iron, LFTs, urinalysis, BUN, TFTs, sodium, serum carbamazepine levels
Lamotrigine	Stevens-Johnson syndrome, headache, dizziness, ataxia, somnolence, nausea, diplopia, blurred vision, rhinitis	No serum monitoring recommended
Lithium	Polyuria, polydipsia, nausea, diarrhea, tininecleatremor, enuresis, fatigue, ataxia, leukocytosis, malaise, cardiac arrhythmias, weight gain	BUN/creatinine, crearance, TFTs, calcium/phosphorus, ECG, serum lithium levels every 1 to 3 months once stabilized
Oxcarbazepine	Dizziness, somnolence/fatigue, ataxia/gait disturbance, vertigo, headache, tremor, rash, hyponatremia, hypersensitivity reaction, GI symptoms, diplopia	Sodium levels (particularly ifirst 3 months)
Topiramate	Hyperchloremic metabolic acidosis, oligohydrosis and hyperthermia, acute myopia, somnolence/fatigue, nausea, anorexia/weight loss, paresthesia, tremor, difficulty concentrating	BUN/creatinine, sodium bicarbonate
Valproate	Irritability/restlessness, ataxia, headache, weight gain, hyperammonemic encephalopathy, alopecia, GI upset, pancreatitis,sedation, thrombocytopenia, liver failure, polycystic ovaries/hyperandrogenism, teratogenic effects,rash	Ammonia, LFTs, bilirubin, CBC with platelets, serum valproate levels
BUN: blood urea nitrogen; CBC: complete blood count; ECG: electrocardiography; LFT: liver function tests; TFTs: thyroid function tests
Note: Bolded items included in black-box warnings
Source: Reference 3

Body weight. Valproate has been associated with weight gain. In a study of 372 bipolar adults, 21% reported a 5% weight-gain during 52 weeks of maintenance therapy, compared with 13% of patients on lithium and 7% on placebo.²⁵ Shortterm studies of adjunctive valproate in pediatric bipolar patients raise similar concerns.²⁶ Thus, monitor for weight gain and serum lipid changes in youths starting valproate therapy.

CARBAMAZEPINE: DRUG INTERACTION RISK

Carbamazepine is used less often than lithium or divalproex for bipolar disorder. It tends to be used adjunctively when lithium alone is ineffective.

Efficacy. In an open-label study,⁹ 42 patients ages 8 to 18 with bipolar disorder type I or II were randomly assigned to lithium, divalproex sodium, or carbamazepine monotherapy for 6 weeks. Response rates—measured as a ≥ 50% change from baseline in YMRS scores—were 53% with divalproex, 38% with lithium, and 38% with carbamazepine.

A retrospective review of 44 hospitalized bipolar patients ages 5 to 12 treated for at least 7 days with lithium, valproate, or carbamazepine reported higher (ie, worse) Clinical Global Impression of Improvement scores with carbamazepine.²⁷ Small sample sizes, particularly in the carbamazepine group, limited this naturalistic study.

Safety: Black-box warnings. Carbamazepine’s hematologic “black box” warns of increased risk of aplastic anemia, agranulocytosis, leukopenia, and thrombocytopenia. Risks associated with carbamazepine have been estimated at:

• aplastic anemia: 5.1/million patient years
  
• agranulocytosis: 1.4/million patient years.²⁸
  

Leukopenia is relatively more common and occurs in approximately 20% of children receiving carbamazepine.²⁹ Consider stopping carbamazepine when the white cell count falls below 3,000/mm³ (or the neutrophil count drops to 3).²⁹ Advise children and parents to watch for leukopenia’s signs and symptoms, including fever, infections, sore throat, and mouth ulcers.³

Body weight. Carbamazepine is not associated with significant weight gain, which could be clinically important for some patients.

 

Drug interactions. Carbamazepine activates the cytochrome P-450 liver enzyme system, increasing the metabolism of many medications and decreasing their blood levels. Consider monitoring serum levels when using carbamazepine with valproate, imipramine, corticosteroids, warfarin, oral contraceptives, and some antibiotics. Because carbamazepine induces its own metabolism, you might need to increase its dosage if its effects appear to be waning.³

Carbamazepine and tricyclic antidepressants may show cross-sensitivity because of structural similarity. Do not use monoamine oxidase inhibitors with carbamazepine; discontinue them at least 14 days before starting carbamazepine.³

OXCARBAZEPINE: FEWER INTERACTIONS

Oxcarbazepine has similar efficacy to carbamazepine but less side effect risk and does not require plasma level monitoring. A weaker inducer of CYP-450, it causes fewer clinically important drug-drug interactions and may be useful for patients who respond to carbamazepine but cannot tolerate its side effects.³⁰

Efficacy. Case studies^31,32 have been encouraging, but no published, double-blind, placebo-controlled studies support using oxcarbazepine in bipolar children and adolescents.

Safety. Oxcarbazepine appears to be generally well-tolerated but can cause potentially serious reactions—including hyponatremia.³³ Somnolence, emesis, and ataxia are the most common side effects in pediatric patients.³

Hyponatremia —plasma sodium 125 mEq/L—occurs in 2.5% of adults taking oxcarbazepine³ and has been reported in a similar percentage of children.³⁴ This potentially severe reaction—characterized by nausea, lethargy, malaise, headache, confusion, decreased seizure threshold, or simply decreased serum sodium³⁵—is usually noted within the first 12 weeks of therapy. The risk increases with concomitant use of other sodium-altering drugs, such as antidepressants or antipsychotics.³⁶

Evaluate serum sodium when starting oxcarbazepine, periodically in the first 3 months, and if symptoms occur.^34,36 For sodium levels of 125 to 130 mEq/L, obtain repeat measurements to confirm that hyponatremia is not worsening. Intervention is often required when levels fall below 125 mEq/L.³⁶

Other serious adverse reactions include Stevens-Johnson syndrome, toxic epidermal necrolysis, and hypersensitivity reactions; 25% to 30% of patients with hypersensitivity to carbamazepine also will react to oxcarbazepine.³³

Contraceptive concerns. Oxcarbazepine may reduce contraceptive efficacy by altering estrogen and progesterone plasma concentrations.³⁷ Consider other birth control methods for sexuallyactive bipolar adolescent girls.

LAMOTRIGINE

Neurologists often use lamotrigine for children with atypical seizure disorders, but no controlled data exist on the drug’s efficacy and safety in youths with bipolar disorder.

Efficacy. In a prospective, open-label study,³⁸ 13 adolescents with type I bipolar disorder received lamotrigine, 200 to 400 mg/d. After 12 weeks (mean dosage 241 mg/d), their symptoms had improved as shown by these mean scores:

• Montgomery-Asberg Depression Rating Scale: from 21 at baseline to 4 at endpoint
  
• Clinical Global Impressions–Severity of Illness scale: from 4 to 1
  
• Children’s Depression Rating Scale (CDRS-R): from 74 to 40
  
• YMRS: from 20 to 6.
  

In another open-label study,³⁹ 16 of 18 youths (88%) with bipolar depression or mixed mania improved with lamotrigine alone or as adjunctive therapy, as shown by Clinical Global Impression of Change scores. CDRS-R scores also decreased by ≥50% in 11 of 17 who finished the study.

Safety: Severe rash. An age-related association with Stevens-Johnson syndrome may limit pediatric use of lamotrigine. Severe and potentially life-threatening rashes have been reported in 0.8% of children treated with lamotrigine.⁴⁰ Discontinue lamotrigine if a rash develops, unless it clearly is not drug-related. Three factors that increase rash risk include:

• co-administering lamotrigine with valproate
  
• higher-than-recommended initial dosages
  
• rapid dose titration.⁴¹
  

Most rashes appear in the first 8 weeks,⁴¹ though cases can occur after prolonged treatment.

Pediatric dosing. We find no published studies of efficacious dosages and plasma levels of lamotrigine in pediatric bipolar disorder (Table 4).^3,9,17 Based on our clinical experience, we recommend starting lamotrigine at 1 to 5 mg/kg/day (1 to 3 mg/kg/day if given with valproate) divided into two daily doses. Watch for rash or skin disorders. Do not exceed the recommended daily dosage by 200 mg in children age

Table 4

Using anticonvulsants in pediatric bipolar disorder patients

Drug	Recommended dosage	Target serum level
Carbamazepine	Age 6 to 12: 20 to 30 mg/kg/d	≥ 7.0 μg/L
	Age >12: 400 to 1,200 mg/d
Lamotrigine*	Unknown	Unknown
Oxcarbazepine	11 to 16 mg/kg/d (as adjunct)	Unknown
Topiramate*	Unknown	Unknown
Valproate	15 to 20 mg/kg/d	45 to 125 μg/mL (trough)
		85 to 110 μg/mL (target)
* No published studies found for efficacious dosage and plasma levels in pediatric bipolar disorder.
Dosage supported by case reports only; no studies found examining efficacious plasma levels.
Source: References 3,9, and 17.

TOPIRAMATE: LIMITED INFORMATION

Efficacy. Little is known about using topiramate in children and adolescents. A retrospective chart review⁴² of 26 patients with bipolar disorder type I (n=23) or II (n=3) showed adjunctive topiramate to be effective, with response rates of 73% for mania and 62% overall. Topiramate was well tolerated, and no serious events were reported.

 

A randomized, controlled trial of topiramate for acute mania in youths with type I bipolar disorder⁴³ was recently halted because of lack of efficacy in adul trials. Preliminary data from 56 of the pediatric patients—analyzed before the study was halted—showed improved YMRS scores. Although results were not statistically significant, the authors suggest topiramate might be effective in treating children and adolescents with bipolar disorder.

Safety: FDA warning. Decreased sodium bicarbonate leading to hyperchloremic metabolic acidosis has been reported in youths treated with topiramate for seizure disorder,⁴⁴ leading to an FDA warning to prescribers.³ Although no monitoring guidelines exist, we recommend baseline and periodic serum bicarbonate measurements and acidbase evaluations during topiramate treatment, especially when adding other antiepileptics.⁴⁴

Other rare but serious reactions include:

• impaired sweat production and resultant hyperthermia⁴⁵
  
• ophthalmologic symptoms characterized by secondary acute angle closure glaucoma and acute myacute myopia (usually within 1 month of starting treatment)⁴⁶
  
• sedation and cognitive difficulties.⁴⁷
  

Body weight. Body weight declined an average 5.8 kg across 8 weeks among 36 bipolar adults using topiramate (mean 176 mg/d).⁴⁷ We find that bipolar teens like topiramate because of weight loss, compared with weight gain with divalproex or lithium, but any pediatric weight loss requires monitoring.

Cognitive effects? Reports of “word finding difficulties” with topiramate⁴⁷ may suggest cognitive effects. Thus, be very cautious about using this medication in children and adolescents.

Related resources

• Kowatch R, Fristad M, Birmaher B, et al. Treatment guidelines for children and adolescents with bipolar disorder. J Am Acad Child Adolesc Psychiatry. 2005;44(3):213-35.
  
• Yonkers K, Wisner K, Stowe Z, et al. Management of bipolar disorder during pregnancy and the postpartum period. Am J Psychiatry 2004;161(4):608-20.
  
• American Academy of Child and Adolescent Psychiatry. Treatment guidelines for childhood psychiatric disorders. www.aacap.org
  

Disclosures

Dr. Kloos, Dr. Hitchcock, and Dr. Ronald Weller report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Dr. Elizabeth Weller has been a consultant to or received research grants from GlaxoSmithKline, Johnson & Johnson, Novartis Pharmaceuticals Corp., Abbott Laboratories, and Shire Pharmaceuticals.

Drug brand names

• Carbamazepine • Tegretol
  
• Divalproex • Depakote
  
• Lamotrigine • Lamictal
  
• Lithium • Eskalith, Lithobid, others
  
• Oxcarbazepine • Trileptal
  
• Topiramate • Topamax
  

Are anticonvulsants safe and effective mood stabilizers for children and adolescents with bipolar disorder? The answer is unclear because most bipolar disorder treatment trials have included adults only, and clinicians are desperate for data.¹

To help you care for young patients, we report what is known about the potential benefits and risks of using mood stabilizers and anticonvulsants in bipolar youth. We base our dosing, target serum level, and monitoring recommendations on clinical experience and the limited published evidence.

AGENTS OF CHOICE?

Bipolar disorder’s “atypical” presentation in children—often more irritability and explosiveness than euphoria—can complicate diagnosis. Bipolar children and adolescents often have comorbid attention-deficit/hyperactivity disorder (ADHD), other disruptive behavior disorders, or anxiety disorders. Thus, comorbidities and presenting symptoms often dictate medication choice.

An expert consensus guideline acknowledges that more evidence on pediatric bipolar disorder is needed. In the meantime, the guideline suggests trying valproate or lithium first to treat nonpsychotic mania in pediatric bipolar patients.¹ It also recommends three atypical antipsychotics— olanzapine, quetiapine, and risperidone—as potential first-line treatments. Valproate and lithium may be preferred because of atypicals’ risk of weight gain and metabolic syndrome.

Trying other anticonvulsants may be justified for bipolar youths who are not functioning well with first-line agents. Lamotrigine, for example, has antidepressant and antimanic effects.² When you try anticonvulsants that lack double-blind, placebo-controlled trials, we recommend that you:

• obtain consent from the parents and child
  
• monitor carefully for side effects.
  

LITHIUM: STRONGEST EVIDENCE

Lithium is one of the most well-studied medications for pediatric bipolar disorder and the only mood stabilizer FDA-approved for children and adolescents (Table 1).³ Although approved for ages 12 and older, lithium has been used in younger children in practice and in clinical trials.

Table 1

FDA-approval status of medications used to treat bipolar disorder

Medication	Indications for adults	Indications for children
Carbamazepine	Acute manic episode and acute mixed episode	Not approved
Lamotrigine	Maintenance therapy	Not approved
Lithium	Acute manic episode and maintenance therapy	Age ≥ 12 years
Oxcarbazepine	Not approved	Not approved
Topiramate	Not approved	Not approved
Valproate	Acute manic episode	Not approved
Source: Reference 3

Efficacy. In an open-label study of 100 adolescents with type I bipolar disorder,⁴ 63% met response criteria after 4 weeks of lithium and 26% showed manic symptom remission. Symptoms worsened in both groups, however, when 40 responders were randomly assigned to continue or discontinue lithium for 2 weeks.⁵ The authors speculated that these conflicting results might indicate that mood stabilization requires longer treatment. Contrary to earlier reports,⁶ manic adolescents with comorbid ADHD did not show poor response to lithium.

In the only double-blind, placebo-controlled trial of lithium in adolescents with bipolar disorder, some subjects had secondary substance dependency disorders.⁷ For 6 weeks, 25 outpatient adolescents received lithium (13 patients) or placebo (12 patients). Lithium was effective in treating bipolar and substance dependency symptoms, with significantly improved clinical global assessment scores and decreased positive urine assays for drugs. Little difference was seen in mood item scores on the Schedule for Affective Disorders and Schizophrenia, child version (KSADS-1986), whether patients were taking lithium or placebo.

Pediatric dosing. For bipolar patients ages 6 to 12, use the child’s weight to determine lithium dosage (Table 2).⁸ Maintain serum levels between 0.8 and 1.2 mEq/L,⁹ and check them frequently when starting therapy.¹⁰ After mood stabilization, check levels every 1 to 3 months or when you suspect noncompliance. Obtain renal and thyroid function values at baseline and every 4 to 6 months.

Table 2

Guide to dosing lithium for prepubertal school-aged children*

	Doses (mg)
Child’s weight (kg)	8 AM	12 PM	6 PM	Total daily
	150	150	300	600
25 to 40	300	300	300	900
40 to 50	300	300	600	1,200
50 to 60	600	300	600	1,500
* Maintain specified dose at least 5 days, drawing serum levels 12 hrs after the last lithium dose until two consecutive levels appear in the therapeutic range (0.6 to 1.2 mEq/L). Dose may then be adjusted based on serum level, side effects, or clinical response. Do not exceed 1.4 mEq/L.
Source: Reference 8

Safety. Common side effects reported in adolescents include weight gain (55%), polydipsia (33%), polyuria (25%), headache (23%), tremor (20%), and GI complaints (up to 18%).⁴ Neurologic side effects are associated with higher serum lithium levels (0.91 to 1.36 mEq/L)¹⁰ and occur more often in younger than in older children.¹¹ The cardiac defect Ebstein’s anomaly occurs in approximately 0.05 to 0.1% of children exposed to lithium in utero (Box).^12-16

Box

 

VALPROATE: OPEN-LABEL TRIALS ONLY

Efficacy. No double-blind, placebo-controlled study has shown valproate to be effective in treating bipolar disorder in children and adolescents. When used as monotherapy in open-label studies, valproate has produced response rates of:

• 53% in a 6-week, randomized, open-label trial in which 42 outpatients (mean age 11.4 years) with bipolar disorder type I or II received lithium, divalproex sodium, or carbamazepine⁹
  
• 61% in an open-label study of 40 patients ages 7 to 19 with a manic, hypomanic, or mixed episode who received divalproex for 2 to 8 weeks¹⁷
  
• 80% in an 8-week open-label trial of 40 patients ages 6 to 17 with bipolar disorder type I (77.5%) or type II (22.5%) and a Young Mania Rating Scale (YMRS)score ≥ 14.¹⁸
  

In a prospective trial, 90 patients ages 5 to 17 with bipolar disorder type I or II were treated with lithium plus divalproex sodium. After up to 20 weeks, 47% met criteria for depressive and manic symptom remission.¹⁹ A chart review has showed valproate’s efficacy in treating aggression and irritability in adolescent mania.²⁰

Safety: Black-box warnings. Valproate therapy carries risks of hepatic failure, pancreatitis, and birth defects. Monitor blood counts and hepatic enzymes throughout therapy (Table 3).³ Rare yet potentially fatal hepatic toxicity appears to occur most often in children age 21 Other studies suggest:

• an association with congenital malformations, including spina bifida and pulmonary atresia, in children exposed to valproate in utero⁶
  
• a link between valproate and hyperammonemic encephalopathy, especially in patients with urea cycle disorders²²
  
• potential for benign thrombocytopenia²³
  
• increased incidence of polycystic ovary syndrome—ovarian cysts, hyperandrogenism, chronic anovulation—in peripubertal mentally retarded women treated with valproate for seizure disorders.²⁴
  

Because of these risks, use caution when prescribing valproate to bipolar adolescent girls. Monitor menstrual cycle regularity, and collaborate with a gynecologist to watch for potentially dangerous effects.

Table 3

Mood stabilizers’ side effects and recommended monitoring

Medication	Major side effects	Monitoring
Carbamazepine	Allergic skin rash, drowsiness, blood dyscrasias, diplopia	CBC with reticulocytes, iron, LFTs, urinalysis, BUN, TFTs, sodium, serum carbamazepine levels
Lamotrigine	Stevens-Johnson syndrome, headache, dizziness, ataxia, somnolence, nausea, diplopia, blurred vision, rhinitis	No serum monitoring recommended
Lithium	Polyuria, polydipsia, nausea, diarrhea, tininecleatremor, enuresis, fatigue, ataxia, leukocytosis, malaise, cardiac arrhythmias, weight gain	BUN/creatinine, crearance, TFTs, calcium/phosphorus, ECG, serum lithium levels every 1 to 3 months once stabilized
Oxcarbazepine	Dizziness, somnolence/fatigue, ataxia/gait disturbance, vertigo, headache, tremor, rash, hyponatremia, hypersensitivity reaction, GI symptoms, diplopia	Sodium levels (particularly ifirst 3 months)
Topiramate	Hyperchloremic metabolic acidosis, oligohydrosis and hyperthermia, acute myopia, somnolence/fatigue, nausea, anorexia/weight loss, paresthesia, tremor, difficulty concentrating	BUN/creatinine, sodium bicarbonate
Valproate	Irritability/restlessness, ataxia, headache, weight gain, hyperammonemic encephalopathy, alopecia, GI upset, pancreatitis,sedation, thrombocytopenia, liver failure, polycystic ovaries/hyperandrogenism, teratogenic effects,rash	Ammonia, LFTs, bilirubin, CBC with platelets, serum valproate levels
BUN: blood urea nitrogen; CBC: complete blood count; ECG: electrocardiography; LFT: liver function tests; TFTs: thyroid function tests
Note: Bolded items included in black-box warnings
Source: Reference 3

Body weight. Valproate has been associated with weight gain. In a study of 372 bipolar adults, 21% reported a 5% weight-gain during 52 weeks of maintenance therapy, compared with 13% of patients on lithium and 7% on placebo.²⁵ Shortterm studies of adjunctive valproate in pediatric bipolar patients raise similar concerns.²⁶ Thus, monitor for weight gain and serum lipid changes in youths starting valproate therapy.

CARBAMAZEPINE: DRUG INTERACTION RISK

Carbamazepine is used less often than lithium or divalproex for bipolar disorder. It tends to be used adjunctively when lithium alone is ineffective.

Efficacy. In an open-label study,⁹ 42 patients ages 8 to 18 with bipolar disorder type I or II were randomly assigned to lithium, divalproex sodium, or carbamazepine monotherapy for 6 weeks. Response rates—measured as a ≥ 50% change from baseline in YMRS scores—were 53% with divalproex, 38% with lithium, and 38% with carbamazepine.

A retrospective review of 44 hospitalized bipolar patients ages 5 to 12 treated for at least 7 days with lithium, valproate, or carbamazepine reported higher (ie, worse) Clinical Global Impression of Improvement scores with carbamazepine.²⁷ Small sample sizes, particularly in the carbamazepine group, limited this naturalistic study.

Safety: Black-box warnings. Carbamazepine’s hematologic “black box” warns of increased risk of aplastic anemia, agranulocytosis, leukopenia, and thrombocytopenia. Risks associated with carbamazepine have been estimated at:

• aplastic anemia: 5.1/million patient years
  
• agranulocytosis: 1.4/million patient years.²⁸
  

Leukopenia is relatively more common and occurs in approximately 20% of children receiving carbamazepine.²⁹ Consider stopping carbamazepine when the white cell count falls below 3,000/mm³ (or the neutrophil count drops to 3).²⁹ Advise children and parents to watch for leukopenia’s signs and symptoms, including fever, infections, sore throat, and mouth ulcers.³

Body weight. Carbamazepine is not associated with significant weight gain, which could be clinically important for some patients.

 

Drug interactions. Carbamazepine activates the cytochrome P-450 liver enzyme system, increasing the metabolism of many medications and decreasing their blood levels. Consider monitoring serum levels when using carbamazepine with valproate, imipramine, corticosteroids, warfarin, oral contraceptives, and some antibiotics. Because carbamazepine induces its own metabolism, you might need to increase its dosage if its effects appear to be waning.³

Carbamazepine and tricyclic antidepressants may show cross-sensitivity because of structural similarity. Do not use monoamine oxidase inhibitors with carbamazepine; discontinue them at least 14 days before starting carbamazepine.³

OXCARBAZEPINE: FEWER INTERACTIONS

Oxcarbazepine has similar efficacy to carbamazepine but less side effect risk and does not require plasma level monitoring. A weaker inducer of CYP-450, it causes fewer clinically important drug-drug interactions and may be useful for patients who respond to carbamazepine but cannot tolerate its side effects.³⁰

Efficacy. Case studies^31,32 have been encouraging, but no published, double-blind, placebo-controlled studies support using oxcarbazepine in bipolar children and adolescents.

Safety. Oxcarbazepine appears to be generally well-tolerated but can cause potentially serious reactions—including hyponatremia.³³ Somnolence, emesis, and ataxia are the most common side effects in pediatric patients.³

Hyponatremia —plasma sodium 125 mEq/L—occurs in 2.5% of adults taking oxcarbazepine³ and has been reported in a similar percentage of children.³⁴ This potentially severe reaction—characterized by nausea, lethargy, malaise, headache, confusion, decreased seizure threshold, or simply decreased serum sodium³⁵—is usually noted within the first 12 weeks of therapy. The risk increases with concomitant use of other sodium-altering drugs, such as antidepressants or antipsychotics.³⁶

Evaluate serum sodium when starting oxcarbazepine, periodically in the first 3 months, and if symptoms occur.^34,36 For sodium levels of 125 to 130 mEq/L, obtain repeat measurements to confirm that hyponatremia is not worsening. Intervention is often required when levels fall below 125 mEq/L.³⁶

Other serious adverse reactions include Stevens-Johnson syndrome, toxic epidermal necrolysis, and hypersensitivity reactions; 25% to 30% of patients with hypersensitivity to carbamazepine also will react to oxcarbazepine.³³

Contraceptive concerns. Oxcarbazepine may reduce contraceptive efficacy by altering estrogen and progesterone plasma concentrations.³⁷ Consider other birth control methods for sexuallyactive bipolar adolescent girls.

LAMOTRIGINE

Neurologists often use lamotrigine for children with atypical seizure disorders, but no controlled data exist on the drug’s efficacy and safety in youths with bipolar disorder.

Efficacy. In a prospective, open-label study,³⁸ 13 adolescents with type I bipolar disorder received lamotrigine, 200 to 400 mg/d. After 12 weeks (mean dosage 241 mg/d), their symptoms had improved as shown by these mean scores:

• Montgomery-Asberg Depression Rating Scale: from 21 at baseline to 4 at endpoint
  
• Clinical Global Impressions–Severity of Illness scale: from 4 to 1
  
• Children’s Depression Rating Scale (CDRS-R): from 74 to 40
  
• YMRS: from 20 to 6.
  

In another open-label study,³⁹ 16 of 18 youths (88%) with bipolar depression or mixed mania improved with lamotrigine alone or as adjunctive therapy, as shown by Clinical Global Impression of Change scores. CDRS-R scores also decreased by ≥50% in 11 of 17 who finished the study.

Safety: Severe rash. An age-related association with Stevens-Johnson syndrome may limit pediatric use of lamotrigine. Severe and potentially life-threatening rashes have been reported in 0.8% of children treated with lamotrigine.⁴⁰ Discontinue lamotrigine if a rash develops, unless it clearly is not drug-related. Three factors that increase rash risk include:

• co-administering lamotrigine with valproate
  
• higher-than-recommended initial dosages
  
• rapid dose titration.⁴¹
  

Most rashes appear in the first 8 weeks,⁴¹ though cases can occur after prolonged treatment.

Pediatric dosing. We find no published studies of efficacious dosages and plasma levels of lamotrigine in pediatric bipolar disorder (Table 4).^3,9,17 Based on our clinical experience, we recommend starting lamotrigine at 1 to 5 mg/kg/day (1 to 3 mg/kg/day if given with valproate) divided into two daily doses. Watch for rash or skin disorders. Do not exceed the recommended daily dosage by 200 mg in children age

Table 4

Using anticonvulsants in pediatric bipolar disorder patients

Drug	Recommended dosage	Target serum level
Carbamazepine	Age 6 to 12: 20 to 30 mg/kg/d	≥ 7.0 μg/L
	Age >12: 400 to 1,200 mg/d
Lamotrigine*	Unknown	Unknown
Oxcarbazepine	11 to 16 mg/kg/d (as adjunct)	Unknown
Topiramate*	Unknown	Unknown
Valproate	15 to 20 mg/kg/d	45 to 125 μg/mL (trough)
		85 to 110 μg/mL (target)
* No published studies found for efficacious dosage and plasma levels in pediatric bipolar disorder.
Dosage supported by case reports only; no studies found examining efficacious plasma levels.
Source: References 3,9, and 17.

TOPIRAMATE: LIMITED INFORMATION

Efficacy. Little is known about using topiramate in children and adolescents. A retrospective chart review⁴² of 26 patients with bipolar disorder type I (n=23) or II (n=3) showed adjunctive topiramate to be effective, with response rates of 73% for mania and 62% overall. Topiramate was well tolerated, and no serious events were reported.

 

A randomized, controlled trial of topiramate for acute mania in youths with type I bipolar disorder⁴³ was recently halted because of lack of efficacy in adul trials. Preliminary data from 56 of the pediatric patients—analyzed before the study was halted—showed improved YMRS scores. Although results were not statistically significant, the authors suggest topiramate might be effective in treating children and adolescents with bipolar disorder.

Safety: FDA warning. Decreased sodium bicarbonate leading to hyperchloremic metabolic acidosis has been reported in youths treated with topiramate for seizure disorder,⁴⁴ leading to an FDA warning to prescribers.³ Although no monitoring guidelines exist, we recommend baseline and periodic serum bicarbonate measurements and acidbase evaluations during topiramate treatment, especially when adding other antiepileptics.⁴⁴

Other rare but serious reactions include:

• impaired sweat production and resultant hyperthermia⁴⁵
  
• ophthalmologic symptoms characterized by secondary acute angle closure glaucoma and acute myacute myopia (usually within 1 month of starting treatment)⁴⁶
  
• sedation and cognitive difficulties.⁴⁷
  

Body weight. Body weight declined an average 5.8 kg across 8 weeks among 36 bipolar adults using topiramate (mean 176 mg/d).⁴⁷ We find that bipolar teens like topiramate because of weight loss, compared with weight gain with divalproex or lithium, but any pediatric weight loss requires monitoring.

Cognitive effects? Reports of “word finding difficulties” with topiramate⁴⁷ may suggest cognitive effects. Thus, be very cautious about using this medication in children and adolescents.

Related resources

• Kowatch R, Fristad M, Birmaher B, et al. Treatment guidelines for children and adolescents with bipolar disorder. J Am Acad Child Adolesc Psychiatry. 2005;44(3):213-35.
  
• Yonkers K, Wisner K, Stowe Z, et al. Management of bipolar disorder during pregnancy and the postpartum period. Am J Psychiatry 2004;161(4):608-20.
  
• American Academy of Child and Adolescent Psychiatry. Treatment guidelines for childhood psychiatric disorders. www.aacap.org
  

Disclosures

Dr. Kloos, Dr. Hitchcock, and Dr. Ronald Weller report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Dr. Elizabeth Weller has been a consultant to or received research grants from GlaxoSmithKline, Johnson & Johnson, Novartis Pharmaceuticals Corp., Abbott Laboratories, and Shire Pharmaceuticals.

Drug brand names

• Carbamazepine • Tegretol
  
• Divalproex • Depakote
  
• Lamotrigine • Lamictal
  
• Lithium • Eskalith, Lithobid, others
  
• Oxcarbazepine • Trileptal
  
• Topiramate • Topamax
  

With “black box” warnings expected, prescribing antidepressants to children and adolescents is changing. In the past year, information from previously unpublished studies has shown the drugs’ risks to be greater and benefits less in pediatric patients than doctors had believed.

As this article went to press, the FDA said it would adopt tougher labeling for antidepressants, as recommended by its Psychopharmacologic Drugs and Pediatric advisory committees. The advisors voted 15 to 8 at a Sept. 14 hearing in favor of a “black box” for all antidepressants, warning of increased risk of suicidality in pediatric patients.

We reported on the FDA’s Feb. 2 public hearing on increased risk of suicidality with antidepressants (CURRENT PSYCHIATRY, March 2004).¹ This commentary provides a follow-up perspective on:

• the Columbia group’s report on classifying suicidality in SSRI clinical trial data
• how undisclosed clinical trial data tipped the SSRI risk-benefit balance in pediatric patients
• new data on using SSRIs plus psychotherapy for depressed adolescents.

WHAT THE COLUMBIA GROUP FOUND

In March, the FDA requested a warning label on SSRIs and related antidepressants that all patients be “monitored closely for worsening depression or the emergence of suicidality.” The advisory’s text and supporting information is available on the FDA’s Web site.²

The FDA also contracted with Columbia University to classify SSRI clinical trial events—first analyzed by FDA senior epidemiologist Dr. Andrew D. Mosholder—that might represent suicidality. Dr. Mosholder had reviewed pharmaceutical industry data from 22 placebo-controlled trials involving 4,250 pediatric patients and found that youths given antidepressants were nearly twice as likely to become suicidal as those given placebo (Box 1). Suicidality has historically been attributed to depressive illness rather than antidepressant use. Therefore, FDA officials cancelled Dr. Mosholder’s scheduled testimony at the Feb. 2 hearing—a decision that triggered congressional investigations—to allow for further analysis.

Box 1

As of Aug. 21, the Columbia group had analyzed data from 25 studies and reviewed 423 adverse events that occurred during the trials’ randomized double-blind phase and/or within 30 days of the last dose of randomized treatment.³ These events included intentional self-injury, suicidal ideation, suicide attempts, accidental injuries, and accidental overdose.

The preliminary evidence suggests that young antidepressant users were 1.8 times more likely to have suicidal thoughts or behaviors compared with patients given placebo⁴—the same conclusion Dr. Mosholder reached nearly 1 year earlier.

RISK VERSUS BENEFIT

Are SSRIs safe in children? In the United Kingdom, a review by the Medicines and Healthcare Products Regulatory Agency (MHRA) of data submitted by paroxetine’s manufacturer revealed an unfavorable risk-to-benefit ratio in children and adolescents. Review of other data on other antidepressants soon followed.

Last December, the MHRA’s Committee on Safety of Medicines and its Expert Working Group on SSRIs advised that the risks and benefits of treating major depressive disorder in patients younger than age 18 were unfavorable for sertraline, citalopram, paroxetine, and escitalopram, and could not be assessed for fluvoxamine.⁵ The MHRA warned British physicians against prescribing paroxetine to depressed patients younger than age 18 and ordered labeling changes for paroxetine contraindicating its use in pediatric major depression.

Fluoxetine is the only SSRI for which the committee considers the risk-benefit balance to be favorable. It cautions British physicians, however, that fluoxetine may benefit only an estimated 1 in 10 pediatric patients.⁵

 

Are SSRIs effective in children? To be labeled for treating depression in children and adolescents, an SSRI must have proven efficacy (statistically and clinically significant improvement) in two independently conducted, double-blind, placebo-controlled trials. Five trials have met this standard—fluoxetine (2),^6,7 sertraline (1),⁸ paroxetine (1-adolescents only),⁹ and citalopram (1)¹⁰—and three trials have not—paroxetine (2) and citalopram (1).¹¹ Thus, only fluoxetine is FDA-approved for treating depressed children and adolescents.

However, lacking two positive trials does not necessarily indicate that a medication is not effective, especially when only two trials were conducted.¹² Also, unpublished data now becoming available show inconsistencies with the published data.¹³

PUBLISHED VS. UNPUBLISHED DATA

In a meta-analysis by Whittington et al,¹³ data from five published, randomized, controlled trials of SSRIs (fluoxetine, paroxetine, sertraline and venlafaxine) were compared with data from unpublished reports found in the United Kingdom’s Committee on Safety of Medicines’ review. In the unpublished data, for example, paroxetine had a significantly lower response rate and more-pronounced placebo effect than the published data indicated.

As a result, these investigators concluded that the favorable risk-benefit profiles of paroxetine, sertraline, and venlafaxine for children and adolescents should be switched to unfavorable. They recommended against using these three antidepressants in youth because of possible increased risk of suicidal ideation and serious adverse events—findings that corresponded to the MHRA’s 2003 decisions.

Tipping the balance? Discrepancies between published and unpublished data raise alarms about nonreporting of negative trials. Except for one paroxetine trial, one early fluoxetine trial, and one more-recent fluoxetine trial funded by the National Institute of Mental Health (NIMH),¹⁴ the FDA’s “pediatric rule” of 1997 has produced all emerging data on SSRIs in children and adolescents. This rule gives pharmaceutical companies an additional 6 months of patent protection (which translates to millions of dollars) for conducting minimal research to collect data on medications’ safety in pediatric populations.

The subsequent Pediatric Research Equity Act of 2003 (PREA) requires pharmaceutical companies to conduct pediatric studies as part of nearly every new drug application filed since Jan. 1, 1999. Unfortunately, PREA does not regulate the quality of that research nor require that negative studies be disclosed.

TADS: FLUOXETINE PLUS CBT

The recently reported Treatment for Adolescents with Depression Study (TADS)¹⁴—funded by the NIMH—showed the benefit of combining fluoxetine with cognitive-behavioral therapy (CBT) for depressed children and adolescents. In the 12-week, multi-site, double-blind, placebo-controlled trial, 439 adolescents ages 12 to 17 diagnosed with major depressive disorder received fluoxetine, 10 to 40 mg/d; CBT alone; CBT with fluoxetine, 10 to 40 mg/d; or placebo. Response rates were:

• fluoxetine alone, 61% (95% confidence interval [CI], 51-70%)
• CBT alone, 43% (95% CI, 34-52%)
• fluoxetine with CBT, 71% (95% CI, 62- 80%)
• placebo, 34.8% (95% CI, 26-44%).

The two treatments containing fluoxetine were statistically more effective than CBT alone or placebo, as measured by the Clinical Global Impression scale. Clinically significant suicidal thinking—in 29% of the adolescents at baseline—improved significantly in all treatment groups, with fluoxetine plus CBT showing the greatest reduction (P = 0.02). Seven of 439 patients (1.6%) attempted suicide; there were no completed suicides.

Box 2

WHAT ARE CLINICIANS TO DO?

Depression is a known risk factor for suicidal ideation or behavior, and subjects with serious suicidal ideation or suicide attempts are always excluded from clinical trials of antidepressant therapy. Suicide is also relatively rare. Thus, a strong association between SSRI treatment and suicide is difficult to demonstrate. Dozens of controlled trials with thousands of pediatric subjects would be required to show definitively that suicide is associated with antidepressant use.

 

Recently, a panel of psychiatrists and primary care physicians discussed the FDA’s earlier advisory and its effect on depression treatment.¹⁵ Overall, the FDA findings seemed not to have convinced these clinicians of a link between suicide and SSRIs. They commented that:

• the FDA has not established a “firm causal connection” between suicide and SSRIs but uses the term “activation syndrome” (Box 2)^15-18
• “activation” may give some depressed patients “the energy to carry out things they have been somewhat inhibited from doing”
• “antidepressant jitteriness syndrome” has been observed more frequently in patients diagnosed with panic disorder or somatizing anxiety than with major depressive disorder, and very little evidence exists to link this syndrome with suicide risk.

Recommendations. As this dialogue continues, how should clinicians care for pediatric patients with major depressive disorder? We suggest the following approach:

• For patients taking antidepressants, recommend that they not stop the medication abruptly, as this may result in severe withdrawal syndrome and increase the risk of depressive relapse. If you discontinue SSRI therapy, taper the dosage over 1 to 2 weeks while monitoring for risky and suicidal behavior.
• For patients newly diagnosed with severe depression, fluoxetine remains an option to use with caution. This includes making an accurate diagnosis, monitoring for suicidality, minimizing side effects, and preventing drug interactions.¹

Box 3

Because treating bipolar depression with antidepressants can cause switching to mania, rule out bipolar depression and mixed episodes before prescribing antidepressants. Bipolar illness may be characterized by marked irritability—also seen in depressed children and adolescents (Box 3).^19,21

Informed consent. Inform the patient and parents of antidepressants’ labeling and side effects. Discuss the possibility of disinhibition and impulsivity during initial therapy, which may increase the risk of suicidal ideation or suicide attempts.

Dosing. Although SSRIs do not show a clear dose-response relationship, their side effects are considered dose-dependent.²² Therefore, start children on lower dosages than are used in adolescents and adults, and monitor very closely.

Nondrug intervention. CBT and other psychotherapies have shown short-term benefits for depressed children.²³ Therefore, to improve SSRIs’ risk-benefit ratio, you may wish to reserve antidepressants for youths:

• with moderate to severe depression, recurrent depression, or a three-generation family history of depression
• who are unlikely to respond to psychotherapy alone, behavioral or environmental change, or general emotional support.

CONCLUSION

Deciding to start, continue, or discontinue SSRIs and other antidepressants in depressed children and adolescents is difficult for clinicians, patients, and their families. Despite data showing increased suicidal behavior in some pediatric patients, SSRIs—when used with caution—remain an important depression treatment in this population.

Related resources

Drug brand names

• Bupropion • Wellbutrin
• Citalopram • Celexa
• Fluoxetine • Prozac
• Fluvoxamine • Luvox
• Mirtazapine • Remeron
• Nefazodone • Serzone
• Paroxetine • Paxil
• Sertraline • Zoloft
• Venlafaxine • Effexor

Disclosure

Dr. Elizabeth Weller receives research/grant support from Forest Pharmaceuticals, Organon, and Wyeth Pharmaceuticals and is a consultant to Johnson & Johnson, Novartis Pharmaceuticals Corp., AstraZeneca Pharmaceuticals, and Otsuka Pharmaceutical.

Joon Kang reports no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Dr. Ronald Weller receives research/grant support from Wyeth Pharmaceuticals, Organon, and Forest Pharmaceuticals.

With “black box” warnings expected, prescribing antidepressants to children and adolescents is changing. In the past year, information from previously unpublished studies has shown the drugs’ risks to be greater and benefits less in pediatric patients than doctors had believed.

As this article went to press, the FDA said it would adopt tougher labeling for antidepressants, as recommended by its Psychopharmacologic Drugs and Pediatric advisory committees. The advisors voted 15 to 8 at a Sept. 14 hearing in favor of a “black box” for all antidepressants, warning of increased risk of suicidality in pediatric patients.

We reported on the FDA’s Feb. 2 public hearing on increased risk of suicidality with antidepressants (CURRENT PSYCHIATRY, March 2004).¹ This commentary provides a follow-up perspective on:

• the Columbia group’s report on classifying suicidality in SSRI clinical trial data
• how undisclosed clinical trial data tipped the SSRI risk-benefit balance in pediatric patients
• new data on using SSRIs plus psychotherapy for depressed adolescents.

WHAT THE COLUMBIA GROUP FOUND

In March, the FDA requested a warning label on SSRIs and related antidepressants that all patients be “monitored closely for worsening depression or the emergence of suicidality.” The advisory’s text and supporting information is available on the FDA’s Web site.²

The FDA also contracted with Columbia University to classify SSRI clinical trial events—first analyzed by FDA senior epidemiologist Dr. Andrew D. Mosholder—that might represent suicidality. Dr. Mosholder had reviewed pharmaceutical industry data from 22 placebo-controlled trials involving 4,250 pediatric patients and found that youths given antidepressants were nearly twice as likely to become suicidal as those given placebo (Box 1). Suicidality has historically been attributed to depressive illness rather than antidepressant use. Therefore, FDA officials cancelled Dr. Mosholder’s scheduled testimony at the Feb. 2 hearing—a decision that triggered congressional investigations—to allow for further analysis.

Box 1

As of Aug. 21, the Columbia group had analyzed data from 25 studies and reviewed 423 adverse events that occurred during the trials’ randomized double-blind phase and/or within 30 days of the last dose of randomized treatment.³ These events included intentional self-injury, suicidal ideation, suicide attempts, accidental injuries, and accidental overdose.

The preliminary evidence suggests that young antidepressant users were 1.8 times more likely to have suicidal thoughts or behaviors compared with patients given placebo⁴—the same conclusion Dr. Mosholder reached nearly 1 year earlier.

RISK VERSUS BENEFIT

Are SSRIs safe in children? In the United Kingdom, a review by the Medicines and Healthcare Products Regulatory Agency (MHRA) of data submitted by paroxetine’s manufacturer revealed an unfavorable risk-to-benefit ratio in children and adolescents. Review of other data on other antidepressants soon followed.

Last December, the MHRA’s Committee on Safety of Medicines and its Expert Working Group on SSRIs advised that the risks and benefits of treating major depressive disorder in patients younger than age 18 were unfavorable for sertraline, citalopram, paroxetine, and escitalopram, and could not be assessed for fluvoxamine.⁵ The MHRA warned British physicians against prescribing paroxetine to depressed patients younger than age 18 and ordered labeling changes for paroxetine contraindicating its use in pediatric major depression.

Fluoxetine is the only SSRI for which the committee considers the risk-benefit balance to be favorable. It cautions British physicians, however, that fluoxetine may benefit only an estimated 1 in 10 pediatric patients.⁵

 

Are SSRIs effective in children? To be labeled for treating depression in children and adolescents, an SSRI must have proven efficacy (statistically and clinically significant improvement) in two independently conducted, double-blind, placebo-controlled trials. Five trials have met this standard—fluoxetine (2),^6,7 sertraline (1),⁸ paroxetine (1-adolescents only),⁹ and citalopram (1)¹⁰—and three trials have not—paroxetine (2) and citalopram (1).¹¹ Thus, only fluoxetine is FDA-approved for treating depressed children and adolescents.

However, lacking two positive trials does not necessarily indicate that a medication is not effective, especially when only two trials were conducted.¹² Also, unpublished data now becoming available show inconsistencies with the published data.¹³

PUBLISHED VS. UNPUBLISHED DATA

In a meta-analysis by Whittington et al,¹³ data from five published, randomized, controlled trials of SSRIs (fluoxetine, paroxetine, sertraline and venlafaxine) were compared with data from unpublished reports found in the United Kingdom’s Committee on Safety of Medicines’ review. In the unpublished data, for example, paroxetine had a significantly lower response rate and more-pronounced placebo effect than the published data indicated.

As a result, these investigators concluded that the favorable risk-benefit profiles of paroxetine, sertraline, and venlafaxine for children and adolescents should be switched to unfavorable. They recommended against using these three antidepressants in youth because of possible increased risk of suicidal ideation and serious adverse events—findings that corresponded to the MHRA’s 2003 decisions.

Tipping the balance? Discrepancies between published and unpublished data raise alarms about nonreporting of negative trials. Except for one paroxetine trial, one early fluoxetine trial, and one more-recent fluoxetine trial funded by the National Institute of Mental Health (NIMH),¹⁴ the FDA’s “pediatric rule” of 1997 has produced all emerging data on SSRIs in children and adolescents. This rule gives pharmaceutical companies an additional 6 months of patent protection (which translates to millions of dollars) for conducting minimal research to collect data on medications’ safety in pediatric populations.

The subsequent Pediatric Research Equity Act of 2003 (PREA) requires pharmaceutical companies to conduct pediatric studies as part of nearly every new drug application filed since Jan. 1, 1999. Unfortunately, PREA does not regulate the quality of that research nor require that negative studies be disclosed.

TADS: FLUOXETINE PLUS CBT

The recently reported Treatment for Adolescents with Depression Study (TADS)¹⁴—funded by the NIMH—showed the benefit of combining fluoxetine with cognitive-behavioral therapy (CBT) for depressed children and adolescents. In the 12-week, multi-site, double-blind, placebo-controlled trial, 439 adolescents ages 12 to 17 diagnosed with major depressive disorder received fluoxetine, 10 to 40 mg/d; CBT alone; CBT with fluoxetine, 10 to 40 mg/d; or placebo. Response rates were:

• fluoxetine alone, 61% (95% confidence interval [CI], 51-70%)
• CBT alone, 43% (95% CI, 34-52%)
• fluoxetine with CBT, 71% (95% CI, 62- 80%)
• placebo, 34.8% (95% CI, 26-44%).

The two treatments containing fluoxetine were statistically more effective than CBT alone or placebo, as measured by the Clinical Global Impression scale. Clinically significant suicidal thinking—in 29% of the adolescents at baseline—improved significantly in all treatment groups, with fluoxetine plus CBT showing the greatest reduction (P = 0.02). Seven of 439 patients (1.6%) attempted suicide; there were no completed suicides.

Box 2

WHAT ARE CLINICIANS TO DO?

Depression is a known risk factor for suicidal ideation or behavior, and subjects with serious suicidal ideation or suicide attempts are always excluded from clinical trials of antidepressant therapy. Suicide is also relatively rare. Thus, a strong association between SSRI treatment and suicide is difficult to demonstrate. Dozens of controlled trials with thousands of pediatric subjects would be required to show definitively that suicide is associated with antidepressant use.

 

Recently, a panel of psychiatrists and primary care physicians discussed the FDA’s earlier advisory and its effect on depression treatment.¹⁵ Overall, the FDA findings seemed not to have convinced these clinicians of a link between suicide and SSRIs. They commented that:

• the FDA has not established a “firm causal connection” between suicide and SSRIs but uses the term “activation syndrome” (Box 2)^15-18
• “activation” may give some depressed patients “the energy to carry out things they have been somewhat inhibited from doing”
• “antidepressant jitteriness syndrome” has been observed more frequently in patients diagnosed with panic disorder or somatizing anxiety than with major depressive disorder, and very little evidence exists to link this syndrome with suicide risk.

Recommendations. As this dialogue continues, how should clinicians care for pediatric patients with major depressive disorder? We suggest the following approach:

• For patients taking antidepressants, recommend that they not stop the medication abruptly, as this may result in severe withdrawal syndrome and increase the risk of depressive relapse. If you discontinue SSRI therapy, taper the dosage over 1 to 2 weeks while monitoring for risky and suicidal behavior.
• For patients newly diagnosed with severe depression, fluoxetine remains an option to use with caution. This includes making an accurate diagnosis, monitoring for suicidality, minimizing side effects, and preventing drug interactions.¹

Box 3

Because treating bipolar depression with antidepressants can cause switching to mania, rule out bipolar depression and mixed episodes before prescribing antidepressants. Bipolar illness may be characterized by marked irritability—also seen in depressed children and adolescents (Box 3).^19,21

Informed consent. Inform the patient and parents of antidepressants’ labeling and side effects. Discuss the possibility of disinhibition and impulsivity during initial therapy, which may increase the risk of suicidal ideation or suicide attempts.

Dosing. Although SSRIs do not show a clear dose-response relationship, their side effects are considered dose-dependent.²² Therefore, start children on lower dosages than are used in adolescents and adults, and monitor very closely.

Nondrug intervention. CBT and other psychotherapies have shown short-term benefits for depressed children.²³ Therefore, to improve SSRIs’ risk-benefit ratio, you may wish to reserve antidepressants for youths:

• with moderate to severe depression, recurrent depression, or a three-generation family history of depression
• who are unlikely to respond to psychotherapy alone, behavioral or environmental change, or general emotional support.

CONCLUSION

Deciding to start, continue, or discontinue SSRIs and other antidepressants in depressed children and adolescents is difficult for clinicians, patients, and their families. Despite data showing increased suicidal behavior in some pediatric patients, SSRIs—when used with caution—remain an important depression treatment in this population.

Related resources

Drug brand names

• Bupropion • Wellbutrin
• Citalopram • Celexa
• Fluoxetine • Prozac
• Fluvoxamine • Luvox
• Mirtazapine • Remeron
• Nefazodone • Serzone
• Paroxetine • Paxil
• Sertraline • Zoloft
• Venlafaxine • Effexor

Disclosure

Dr. Elizabeth Weller receives research/grant support from Forest Pharmaceuticals, Organon, and Wyeth Pharmaceuticals and is a consultant to Johnson & Johnson, Novartis Pharmaceuticals Corp., AstraZeneca Pharmaceuticals, and Otsuka Pharmaceutical.

Joon Kang reports no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Dr. Ronald Weller receives research/grant support from Wyeth Pharmaceuticals, Organon, and Forest Pharmaceuticals.

With “black box” warnings expected, prescribing antidepressants to children and adolescents is changing. In the past year, information from previously unpublished studies has shown the drugs’ risks to be greater and benefits less in pediatric patients than doctors had believed.

As this article went to press, the FDA said it would adopt tougher labeling for antidepressants, as recommended by its Psychopharmacologic Drugs and Pediatric advisory committees. The advisors voted 15 to 8 at a Sept. 14 hearing in favor of a “black box” for all antidepressants, warning of increased risk of suicidality in pediatric patients.

We reported on the FDA’s Feb. 2 public hearing on increased risk of suicidality with antidepressants (CURRENT PSYCHIATRY, March 2004).¹ This commentary provides a follow-up perspective on:

• the Columbia group’s report on classifying suicidality in SSRI clinical trial data
• how undisclosed clinical trial data tipped the SSRI risk-benefit balance in pediatric patients
• new data on using SSRIs plus psychotherapy for depressed adolescents.

WHAT THE COLUMBIA GROUP FOUND

In March, the FDA requested a warning label on SSRIs and related antidepressants that all patients be “monitored closely for worsening depression or the emergence of suicidality.” The advisory’s text and supporting information is available on the FDA’s Web site.²

The FDA also contracted with Columbia University to classify SSRI clinical trial events—first analyzed by FDA senior epidemiologist Dr. Andrew D. Mosholder—that might represent suicidality. Dr. Mosholder had reviewed pharmaceutical industry data from 22 placebo-controlled trials involving 4,250 pediatric patients and found that youths given antidepressants were nearly twice as likely to become suicidal as those given placebo (Box 1). Suicidality has historically been attributed to depressive illness rather than antidepressant use. Therefore, FDA officials cancelled Dr. Mosholder’s scheduled testimony at the Feb. 2 hearing—a decision that triggered congressional investigations—to allow for further analysis.

Box 1

As of Aug. 21, the Columbia group had analyzed data from 25 studies and reviewed 423 adverse events that occurred during the trials’ randomized double-blind phase and/or within 30 days of the last dose of randomized treatment.³ These events included intentional self-injury, suicidal ideation, suicide attempts, accidental injuries, and accidental overdose.

The preliminary evidence suggests that young antidepressant users were 1.8 times more likely to have suicidal thoughts or behaviors compared with patients given placebo⁴—the same conclusion Dr. Mosholder reached nearly 1 year earlier.

RISK VERSUS BENEFIT

Are SSRIs safe in children? In the United Kingdom, a review by the Medicines and Healthcare Products Regulatory Agency (MHRA) of data submitted by paroxetine’s manufacturer revealed an unfavorable risk-to-benefit ratio in children and adolescents. Review of other data on other antidepressants soon followed.

Last December, the MHRA’s Committee on Safety of Medicines and its Expert Working Group on SSRIs advised that the risks and benefits of treating major depressive disorder in patients younger than age 18 were unfavorable for sertraline, citalopram, paroxetine, and escitalopram, and could not be assessed for fluvoxamine.⁵ The MHRA warned British physicians against prescribing paroxetine to depressed patients younger than age 18 and ordered labeling changes for paroxetine contraindicating its use in pediatric major depression.

Fluoxetine is the only SSRI for which the committee considers the risk-benefit balance to be favorable. It cautions British physicians, however, that fluoxetine may benefit only an estimated 1 in 10 pediatric patients.⁵

 

Are SSRIs effective in children? To be labeled for treating depression in children and adolescents, an SSRI must have proven efficacy (statistically and clinically significant improvement) in two independently conducted, double-blind, placebo-controlled trials. Five trials have met this standard—fluoxetine (2),^6,7 sertraline (1),⁸ paroxetine (1-adolescents only),⁹ and citalopram (1)¹⁰—and three trials have not—paroxetine (2) and citalopram (1).¹¹ Thus, only fluoxetine is FDA-approved for treating depressed children and adolescents.

However, lacking two positive trials does not necessarily indicate that a medication is not effective, especially when only two trials were conducted.¹² Also, unpublished data now becoming available show inconsistencies with the published data.¹³

PUBLISHED VS. UNPUBLISHED DATA

In a meta-analysis by Whittington et al,¹³ data from five published, randomized, controlled trials of SSRIs (fluoxetine, paroxetine, sertraline and venlafaxine) were compared with data from unpublished reports found in the United Kingdom’s Committee on Safety of Medicines’ review. In the unpublished data, for example, paroxetine had a significantly lower response rate and more-pronounced placebo effect than the published data indicated.

As a result, these investigators concluded that the favorable risk-benefit profiles of paroxetine, sertraline, and venlafaxine for children and adolescents should be switched to unfavorable. They recommended against using these three antidepressants in youth because of possible increased risk of suicidal ideation and serious adverse events—findings that corresponded to the MHRA’s 2003 decisions.

Tipping the balance? Discrepancies between published and unpublished data raise alarms about nonreporting of negative trials. Except for one paroxetine trial, one early fluoxetine trial, and one more-recent fluoxetine trial funded by the National Institute of Mental Health (NIMH),¹⁴ the FDA’s “pediatric rule” of 1997 has produced all emerging data on SSRIs in children and adolescents. This rule gives pharmaceutical companies an additional 6 months of patent protection (which translates to millions of dollars) for conducting minimal research to collect data on medications’ safety in pediatric populations.

The subsequent Pediatric Research Equity Act of 2003 (PREA) requires pharmaceutical companies to conduct pediatric studies as part of nearly every new drug application filed since Jan. 1, 1999. Unfortunately, PREA does not regulate the quality of that research nor require that negative studies be disclosed.

TADS: FLUOXETINE PLUS CBT

The recently reported Treatment for Adolescents with Depression Study (TADS)¹⁴—funded by the NIMH—showed the benefit of combining fluoxetine with cognitive-behavioral therapy (CBT) for depressed children and adolescents. In the 12-week, multi-site, double-blind, placebo-controlled trial, 439 adolescents ages 12 to 17 diagnosed with major depressive disorder received fluoxetine, 10 to 40 mg/d; CBT alone; CBT with fluoxetine, 10 to 40 mg/d; or placebo. Response rates were:

• fluoxetine alone, 61% (95% confidence interval [CI], 51-70%)
• CBT alone, 43% (95% CI, 34-52%)
• fluoxetine with CBT, 71% (95% CI, 62- 80%)
• placebo, 34.8% (95% CI, 26-44%).

The two treatments containing fluoxetine were statistically more effective than CBT alone or placebo, as measured by the Clinical Global Impression scale. Clinically significant suicidal thinking—in 29% of the adolescents at baseline—improved significantly in all treatment groups, with fluoxetine plus CBT showing the greatest reduction (P = 0.02). Seven of 439 patients (1.6%) attempted suicide; there were no completed suicides.

Box 2

WHAT ARE CLINICIANS TO DO?

Depression is a known risk factor for suicidal ideation or behavior, and subjects with serious suicidal ideation or suicide attempts are always excluded from clinical trials of antidepressant therapy. Suicide is also relatively rare. Thus, a strong association between SSRI treatment and suicide is difficult to demonstrate. Dozens of controlled trials with thousands of pediatric subjects would be required to show definitively that suicide is associated with antidepressant use.

 

Recently, a panel of psychiatrists and primary care physicians discussed the FDA’s earlier advisory and its effect on depression treatment.¹⁵ Overall, the FDA findings seemed not to have convinced these clinicians of a link between suicide and SSRIs. They commented that:

• the FDA has not established a “firm causal connection” between suicide and SSRIs but uses the term “activation syndrome” (Box 2)^15-18
• “activation” may give some depressed patients “the energy to carry out things they have been somewhat inhibited from doing”
• “antidepressant jitteriness syndrome” has been observed more frequently in patients diagnosed with panic disorder or somatizing anxiety than with major depressive disorder, and very little evidence exists to link this syndrome with suicide risk.

Recommendations. As this dialogue continues, how should clinicians care for pediatric patients with major depressive disorder? We suggest the following approach:

• For patients taking antidepressants, recommend that they not stop the medication abruptly, as this may result in severe withdrawal syndrome and increase the risk of depressive relapse. If you discontinue SSRI therapy, taper the dosage over 1 to 2 weeks while monitoring for risky and suicidal behavior.
• For patients newly diagnosed with severe depression, fluoxetine remains an option to use with caution. This includes making an accurate diagnosis, monitoring for suicidality, minimizing side effects, and preventing drug interactions.¹

Box 3

Because treating bipolar depression with antidepressants can cause switching to mania, rule out bipolar depression and mixed episodes before prescribing antidepressants. Bipolar illness may be characterized by marked irritability—also seen in depressed children and adolescents (Box 3).^19,21

Informed consent. Inform the patient and parents of antidepressants’ labeling and side effects. Discuss the possibility of disinhibition and impulsivity during initial therapy, which may increase the risk of suicidal ideation or suicide attempts.

Dosing. Although SSRIs do not show a clear dose-response relationship, their side effects are considered dose-dependent.²² Therefore, start children on lower dosages than are used in adolescents and adults, and monitor very closely.

Nondrug intervention. CBT and other psychotherapies have shown short-term benefits for depressed children.²³ Therefore, to improve SSRIs’ risk-benefit ratio, you may wish to reserve antidepressants for youths:

• with moderate to severe depression, recurrent depression, or a three-generation family history of depression
• who are unlikely to respond to psychotherapy alone, behavioral or environmental change, or general emotional support.

CONCLUSION

Deciding to start, continue, or discontinue SSRIs and other antidepressants in depressed children and adolescents is difficult for clinicians, patients, and their families. Despite data showing increased suicidal behavior in some pediatric patients, SSRIs—when used with caution—remain an important depression treatment in this population.

Related resources

Drug brand names

• Bupropion • Wellbutrin
• Citalopram • Celexa
• Fluoxetine • Prozac
• Fluvoxamine • Luvox
• Mirtazapine • Remeron
• Nefazodone • Serzone
• Paroxetine • Paxil
• Sertraline • Zoloft
• Venlafaxine • Effexor

Disclosure

Dr. Elizabeth Weller receives research/grant support from Forest Pharmaceuticals, Organon, and Wyeth Pharmaceuticals and is a consultant to Johnson & Johnson, Novartis Pharmaceuticals Corp., AstraZeneca Pharmaceuticals, and Otsuka Pharmaceutical.

Joon Kang reports no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Dr. Ronald Weller receives research/grant support from Wyeth Pharmaceuticals, Organon, and Forest Pharmaceuticals.