Evidence-Based Reviews

Stimulants for adult bipolar disorder?

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Adding a stimulant could improve residual symptoms, but it also might cause serious side effects, toxicities, and destabilization.



Patients with bipolar disorder show an unpredictable range of responses to stimulants, from virtually no ill effects to emerging manic-like symptoms.1 Thus, although stimulants may be beneficial to some bipolar patients, there is a great deal of concern about using stimulants in this population. Even so, stimulants may be a rational adjunct for treating certain aspects of bipolar illness, particularly resistant depression, iatrogenic sedation, and comorbid attention-deficit/hyperactivity disorder (ADHD).

To help you decide if and when your patient might be a candidate for stimulant therapy, this article:

  • reviews the evidence on stimulants’ safety and tolerability for patients with bipolar disorder
  • weighs potential benefits and risks of using stimulants in this population
  • addresses stimulants’ possible adverse effects on illness course and from interactions with other psychotropics
  • discusses treatment options based on the limited evidence and our clinical experience.

Limited support

We are aware that using stimulants to treat patients with bipolar disorder is not an uncommon clinical practice, but supportive evidence is limited (Table 1). In searching the literature, we found only 2 randomized controlled studies—Frye et al2 and Scheffer et al3—that addressed this practice. (One author of this review [TS] participated as a coinvestigator with Frye et al.2) Other evidence that suggests a role for stimulants in bipolar disorder comes from case reports, retrospective case series, and open-label studies.4-11

For this article, we recognize 2 broad stimulant categories:
  • “traditional” stimulants (including amphetamine-based compounds such as dextroamphetamine, methylphenidate, dexmethylphenidate, and lisdexamfetamine) thought to affect the dopamine transporter, resulting in increased dopamine in nerve terminals
  • the “novel” psychostimulant modafinil, thought to affect multiple neurotransmitter systems (dopamine, GABA, serotonin, histamine, and glutamate), although its mechanism of action is unclear.
The traditional stimulants are FDA-approved for ADHD, and some have an additional indication for narcolepsy. Modafinil is indicated for improving wakefulness in patients with excessive sleepiness associated with narcolepsy, obstructive sleep apnea, and shift-work sleep disorder. No stimulant is FDA-approved for adjunctive use in patients with bipolar disorder.

Table 1

Clinical studies of stimulant use in patients with bipolar disorder

Stimulant(s) studiedStudy designPatients studiedClinical outcomes
Traditional stimulants
Adjunctive methylphenidateChart review, naturalistic1216 adults (5 with comorbid ADHD, 11 with bipolar depression)Improvements in depression, overall functioning, and ability to concentrate; sleep disturbance, irritability/agitation reported
Adjunctive methylphenidate or racemic mixture of AMPH saltsChart review of sedation and depressive symptoms138 adults (BD II)Improved clinical impression of bipolar illness; no manic switches, changes in cycling patterns, or substance abuse noted
Adjunctive methylphenidate12-week open study, bipolar depression1412 adults (10 BD I, 2 BD II)Significant clinical improvements in depressive symptoms; no change in manic symptoms; anxiety, agitation, and hypomania reported
Multiple stimulantsChart review, history of stimulants and bipolar illness course2534 hospitalized adolescentsPrior stimulant treatment associated with earlier age of illness onset
Adjunctive mixed amphetamine saltsRandomized, placebo-controlled; comorbid BD and ADHD330 children with ADHD symptoms stabilized on divalproex sodiumDecrease in ADHD symptoms with adjunctive amphetamine treatment but not with divalproex sodium alone; 1 case of mania
Novel stimulant
Adjunctive modafinilCase series15Mixed sample of depressed adults (4 unipolar, 3 bipolar)Significant improvement in depressive symptoms
Adjunctive modafinilRandomized, double-blind, placebo-controlled285 adults with bipolar depressionTreatment group showed greater response and remission of depressive symptoms compared with placebo group; no difference in development of manic symptoms
ADHD: attention-deficit/hyperactivity disorder; AMPH: amphetamine; BD: bipolar disorder; NOS: not otherwise specified

Depression and iatrogenic sedation

Small, uncontrolled trials have reported some benefit and tolerability in bipolar disorder patients when stimulants are used to treat residual depressive symptoms or iatrogenic sedation associated with mood stabilizers.

Traditional stimulants. A retrospective chart review of 16 patients treated with adjunctive methylphenidate noted improved functioning, as measured by the Global Assessment of Functioning scale. Some patients’ depressive symptoms and concentration also appeared to improve, but how these parameters were assessed is not clear. Some patients tolerated stimulants well, whereas others experienced irritability, agitation, and sleep disturbances.12

Another retrospective chart review described 8 patients with iatrogenic sedation or depression who received adjunctive methylphenidate, mean 20 to 40 mg/d, or a racemic mixture of amphetamine salts, mean 20 to 40 mg/d. Overall bipolar symptoms decreased in severity, as measured by Clinical Global Impression (CGI) scores, but the authors did not directly measure sedation or depression. The stimulants were well-tolerated, with no evidence of stimulant-induced mania.13

In a 12-week open-label trial of methylphenidate in 14 patients with bipolar disorder, depressive symptoms improved as measured by the Hamilton Depression Rating Scale (HAM-D). Mean doses were 10 mg/d for the 3 patients who discontinued because of anxiety, agitation, or hypomania and 16.6 mg/d for those who completed the trial.14


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