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Evidence-Based Reviews

How to reduce mania risk when prescribing stimulants

Evidence-based hierarchy helps when bipolar and ADHD symptoms overlap.

Vol. 4, No. 10 / October 2005

Stimulants are most effective for childhood attention-deficit/hyperactivity disorder (ADHD),1 but they may induce mania or trigger a treatment-resistant course in children with comorbid bipolar disorder. To help you safely manage these complicated symptoms, this article offers a treatment algorithm and tips to:

  • differentiate bipolar and ADHD symptoms
  • identify patients at risk for stimulantinduced mania
  • choose medications by a hierarchythat may reduce the risk of mood destabilization.

Box 1

Bipolar disorder and ADHD: High comorbidity, greater impairment

Bipolar mood symptoms emerge before age 20 in about 25% of persons with bipolar disorder (BP).3 Early-onset BP may be more severe than the adult-onset form, with more-affected family members and greater comorbidity with other disorders, especially ADHD.4

In one study, 91% of children with BP also met criteria for ADHD, and 19% of patients with ADHD also received a diagnosis of BP.5 Among 31 children ages 2 to 5 with BP, 80% met criteria for concurrent ADHD.6

Of 40 children age <5 presenting consecutively to a mental health clinic, 11 (28%) met criteria for mania, which was usually associated with euphoria.7 These 11 children also met criteria for ADHD.

A comparison study8 of children (mean age 12) found greater impairment, suicidality, irritability, and sadness in 43 with ADHD plus bipolar depression than in:

  • 109 with ADHD plus major depressive disorder
  • 128 without depression or mania.

Family prevalence of bipolar disorder and major depression was highest in the bipolar-ADHD group, which also had the highest rates of comorbid conduct disorder, oppositional defiant disorder, alcohol abuse, and agoraphobia. Average age of bipolar diagnosis was 6.3 years.

Adhd and/or bipolar disorder?

Some 70% to 90% of bipolar children and at least 30% to 40% of bipolar adolescents also have ADHD.2 This high comorbidity (Box 1)3-8 might mean that:

  • one disorder predisposes to the other
  • one is a precursor of the other
  • they share common vulnerabilities or causes
  • their symptoms overlap so much that patients with one disorder appear to meet criteria for the other.

Some experts contend that bipolar disorder and ADHD usually can be differentiated. Bipolar children score higher than those with ADHD on measures of anxiety/depression, aggression, and attention problems on the Child Behavior Checklist.9 Others believe ADHD symptoms that occur with bipolar disorder are a dimension of bipolar illness rather than a separate disorder.10

For every DSM-IV-TR diagnostic criterion for ADHD, a corresponding diagnostic criterion or common feature of bipolar disorder can be identified (Table 1). Mania and hypomania are obviously associated with hyperactivity and impulsivity, and tangential thinking and distractibility interfere with attention in many patients with bipolar disorder.

Though most ADHD symptoms can occur in bipolar patients, some features of bipolar illness are not characteristic of ADHD (Table 2). Children with ADHD can become hyper-focused on video games and television, for example, but they usually do not become engrossed in long, complicated books or preoccupied with other people, as can occur in bipolar disorder.

Table 1

How ADHD, bipolar symptoms overlap in three domains


Bipolar disorder


Fails to pay attention

Racing and tangential thoughts

Difficulty sustaining attention

Attention driven by racing thoughts, affective themes, and psychosis

Does not follow through

Direction of activity shifts with shifting mood

Difficulty organizing tasks

Disorganization, psychosis, excessive energy

Easily distracted



Fidgets or squirms

Increased energy and activity

Runs about or climbs excessively

Hyperactivity, thrill-seeking

Difficulty engaging quietly in leisure activities

Increased energy, boredom

Often on the go

Increased energy, hyperactivity

Talks excessively

Rapid, pressured speech


Blurts out answers

Rapid, pressured, impulsive speech

Difficulty awaiting turn

Hyperactivity, increased energy, impatience, grandiosity

Interrupts or intrudes on others

Grandiosity, impatience, pressured speech, increased mental content

Table 2

Bipolar features not seen in ADHD

  • Depression
  • Elation
  • Suicidal thoughts
  • Murderous rage
  • Psychosis
  • Grandiosity
  • Decreased/increased sleep
  • Hypersexuality
  • Affective family history

A treatment hierarchy

Whether a bipolar patient’s attention problems are features of the primary condition or caused by comorbid ADHD may be unclear, but the treatment implications are important. All antidepressants can induce mania/hypomania and increase the risk of mixed states and mood cycling. Because stimulants have antidepressant properties and because some antidepressants are used to treat ADHD, a systematic approach is necessary when treating inattention in juvenile bipolar disorder.

A treatment hierarchy developed by the American Academy of Child and Adolescent Psychiatry Workgroup on Bipolar Disorder recommends beginning psychosocial approaches, such as training parents in behavior management techniques, and:

  • treating bipolar disorder first in children who clearly have both ADHD and bipolar disorder
  • adding ADHD treatment if ADHD symptoms persist and impair functioning.2

Who’s at risk for mood destabilization?

No data address differences between bipolar patients whose mood disorders deteriorate with stimulant use and those who remain stable. However, risk factors for mood destabilization that have been reported with antidepressants likely also apply to stimulants (Table 3) because stimulants’ adverse effects in bipolar disorder are probably related to their antidepressant properties.

For example, depressed patients who report that an antidepressant worked within hours to days may have bipolar disorder and be at risk for mood destabilization leading to treatment resistance.11 Antidepressant-induced mania also may be more likely:

  • when depression is mixed with hypomanic symptoms such as racing thoughts, excessive talkativeness, aggression, irritability, distractibility, and increased drive12
  • in patients with a history of antidepressant-induced mania, family history of bipolar disorder, or multiple antidepressant trials.13

Similarly, patients who report feeling better immediately after starting a stimulant—especially if they have evidence of elation, increased irritability, more aggression or impulsivity, decreased sleep, or related symptoms—may be developing stimulant-induced hypomania.

Table 3

Risk factors that may increase risk of stimulant-induced mania

  • Family history of bipolar disorder
  • Early onset of the mood disorder
  • Comorbid substance use disorder
  • History of rapid cycling or antidepressantinduced mania
  • Multiple antidepressant trials

Source: Reference 25

Antidepressant-induced mania

Most studies of antidepressant-induced mania have examined outright mania, but hypomania and subsyndromal hypomanic syndromes also may cause significant morbidity and may worsen bipolar disorder’s course. A change in polarity may worsen a patient’s prognosis, but how do we know that antidepressants (or stimulants) caused it?

One suggested criterion is that mania or hypomania develops within 8 weeks of starting an antidepressant for the first time. A chart review of 51 bipolar patients who had extensive life charting found that 82% developed mania while taking an antidepressant—35% of them within 8 weeks.14 The authors attributed 50% of the risk of a first manic episode and/or cycle acceleration to antidepressants and 50% to spontaneous mood swings. They also noted that:

  • an initial manic episode appeared to sensitize patients to subsequent manic episodes and rapid cycling
  • mood stabilizers did not seem to prevent these outcomes.

A meta-analysis of 12 randomized, controlled, 4-to 12-week trials among 1,088 patients found antidepressants no more likely than placebo to induce mania in the short term.15 These trials did not, however, consider less-severe forms of overstimulation and were not designed to determine mania risk in bipolar depressed patients.

Post-mania cycling. Rapid and ultradian cycling and other forms of deterioration are more likely to occur after a manic or hypomanic episode than after a depressive episode.16

A longitudinal study17 indicated that antidepressant use did not predictably predate rapid cycling when depression was controlled. The authors, however, looked at the correlation between taking an antidepressant at study entry and rapid cycling over 1 year but did not examine whether antidepressants were started or stopped during the study.18 Rapid cycling prevalence declined from 19% to 5% during the study, but they did not determine whether withdrawing antidepressants was associated with this change.

In an earlier prospective study, rapid cycling was more severe while patients were taking antidepressants—despite the use of mood stabilizers—and cycling duration decreased when antidepressants were withdrawn.19

TCAs vs. newer agents. Tricyclic antidepressants (TCAs) are perceived as more likely to induce mania than are selective serotonin reuptake inhibitors (SSRIs) or bupropion. Comparing TCAs’ and newer antidepressants’ switch rates is difficult, however. Most antidepressant trials were designed to show efficacy and safety in unipolar, not bipolar, depression. Moreover, as exclusion criteria have improved with greater awareness of bipolar illness’ polymorphic manifestations, recent studies likely have enrolled fewer bipolar patients—who are most at risk to develop a manic switch—than did earlier TCA trials.

Bupropion, which has been used to treat ADHD, has been thought to have a low risk of inducing mania. In open observation, however, >50% of 11 patients with a history of developing mania with other antidepressants also had a manic switch on bupropion, even though they were taking mood stabilizers.20

Analysis of 155 antidepressant trials in 41 depressed patients found mania risk to be similar with bupropion, SSRIs, TCAs, monoamine oxidase inhibitors (MAOIs), and other newer antidepressants.21 Mania risk doubled when patients were not also taking mood stabilizers.

Going without mood stabilizers. Reports have emerged of patients with bipolar depression taking antidepressants such as fluoxetine and venlafaxine without a mood stabilizer for extended periods, without high rates of mania or mood cycling.22-24 These reports suggest that some bipolar depressed patients can tolerate antidepressants without a mood stabilizer, although we have no way to identify such patients in advance.

Cycle acceleration and treatment resistance may follow antidepressant-induced mania.25 In DSM-IV field trials, antidepressants appeared to have triggered rapid cycling in some 20% of bipolar patients.26 Mood stabilizers were not particularly effective in patients with treatment-resistant ultradian cycling, but withdrawing antidepressants improved outcome.27

Stimulant-induced mania

Compared with antidepressants, less information is available about stimulant-induced mania and rapid cycling.

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

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