Some carefully selected bipolar patients may tolerate ongoing stimulant treatment. For example, in 2 years of open experience with 5 bipolar type I and 3 bipolar type II adults, adding methylphenidate or amphetamine for residual depression or sedation was moderately helpful and did not lead to manic switching or drug misuse.28
On the other hand, affective symptoms worsened in nearly two-thirds of 31 children ages 2 to 5 when treated with stimulants or antidepressants without mood stabilizers. Most of the children also had ADHD, and valproate usually helped.6
In 40 patients, mean age 10, who entered the open-label phase of an 8-week trial of divalproex for manic and ADHD symptoms:
- Young Mania Rating Scale (YMRS) scores declined by≥50% in 32 (80%) by week 8, a greater initial response than usually reported in pediatric bipolar disorder with comorbid ADHD.
- ADHD symptoms, measured by Clinical Global Impressions (CGI) scores, did not change significantly.29
Thirty divalproex responders then received mixed amphetamine salts, 10 mg/d, or placebo plus divalproex, crossing over to the other treatment in a 4-week, double-blind trial. ADHD symptoms improved twice as much with the stimulant as with placebo, as measured by CGI scores, whereas YMRS scores did not differ significantly. Among 23 patients who continued the stimulant and divalproex for 12 more weeks, 45% required an increase in stimulant dosage and 1 relapsed into mania.
In this study, ADHD symptoms did not respond to mania treatment but did improve when a stimulant was added. This suggests either that patients had two disorders or that not all bipolar features remit at the same time. The trial’s low stimulant dosage and short duration provide insufficient evidence to support using stimulants over long periods in bipolar children.
LOng-term stimulant effects
Without long-term observations, some investigators have inferred stimulants’ impact on bipolar disorder. A poll of pediatric psychiatrists in the Netherlands, for example, found bipolar disorder in 39 children ages <13 (0.001%) in the previous year, compared with a prevalence of at least 1% in the United States.3 The authors concluded:
- Bipolar disorder emerges at younger ages in the United States than in the Netherlands.
- One reason may be that U.S. psychiatrists have a lower threshold for treating pediatric depression and hyperactivity with antidepressants and stimulants than Dutch psychiatrists do, evoking more-obvious bipolar symptoms at an earlier age.
Observations of 30 U.S. children with a manic episode and ADHD suggested that stimulants can induce manic symptoms:
- Mean age of ADHD onset was 5.5 years.
- Mean age of starting stimulants was 6.9 years.
- Mean age of hypomanic or manic symptom onset was 7.1 years.30
Similarly, in a survey of 34 adolescent manic inpatients, those who had taken stimulants had earlier mania onset (mean age 10.7) than did those who had not taken stimulants (mean age 13.9). Exposure to two stimulants was associated with earlier onset than exposure to one, but comorbid ADHD alone did not affect age of bipolar disorder onset.31
The same group10 reviewed charts of 80 consecutively hospitalized adolescents with a manic or mixed bipolar episode and found stimulant exposure was associated with relatively worse inpatient course, longer length of stay, more emergency medications, and more seclusion and restraint orders. Comorbid ADHD, mixed versus manic episode, and prior antidepressant exposure did not worsen the inpatient course.
A chart review by El-Mallakh et al32 found bipolar disorder was diagnosed at mean age 10.7 in 49 children exposed to antidepressants or stimulants, compared with mean age 12.7 in 44 unexposed children. The exposed group appeared to have tolerated stimulants longer than antidepressants before mania or hypomania emerged.33
In contrast, a retrospective review by Carlson et al34 of data from a longitudinal study of 75 boys with “hyperkinetic reaction of childhood” found that methylphenidate treatment did not appear more common in boys later diagnosed with bipolar disorder than in those without a bipolar diagnosis. This study had obvious methodologic limitations, lacking a hypothesis and focusing on a population with “minimal brain dysfunction.”
In a reanalysis of data from a 1-month methylphenidate titration trial, Galanter et al35 examined whether some 300 children ages 5 to 12 experienced manic symptoms, using the Diagnostic Interview Schedule for Children or the Child Behavior Checklist. At least during this brief trial, patients with and without manic symptoms showed no differences in response rates or adverse effects with stimulant therapy.
Drug treatment hierarchy
Mood stabilizers. Evidence supports starting all bipolar children with a mood stabilizer such as lithium or valproate (Algorithm). A few patients may tolerate stimulants without mood stabilizers, but the risk is high of inducing mania and precipitating a more complex and treatment-resistant disorder.