Evidence-Based Reviews

Stimulants for adult bipolar disorder?

Current Psychiatry. 2008 November;7(11):33-45

References

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Modafinil may have some efficacy in treating bipolar depression. In a case series of 7 depressed patients (4 unipolar and 3 bipolar), 5 patients showed a 50% decrease in HAM-D scores with adjunctive modafinil. Dosages ranged from 100 to 200 mg/d, although most patients took 200 mg/d. In this series, modafinil was added to a variety of treatments, including bupropion, nefazodone, paroxetine, venlafaxine, an unspecified tricyclic antidepressant (TCA), divalproex sodium, lamotrigine, lithium, electroconvulsive therapy, olanzapine, and gabapentin.¹⁵

The only randomized, double-blind, placebo-controlled trial of adjunctive modafinil for bipolar depression enrolled 85 patients with moderate or more severe depression. In this 6-week trial by Frye et al,² 41 patients received modafinil, 100 to 200 mg/d (mean dose 174.2 mg/d), and 44 received placebo.

Clinical Point

Prodromal symptoms similar to ADHD may persist in patients with bipolar disorder

Response and remission rates—as measured by the clinician-rated Inventory of Depressive Symptoms—were significantly higher in patients treated with modafinil (44% and 39% respectively), compared with placebo (23% and 18%). Manic or hypomanic symptoms emerged in 6 patients during modafinil treatment and in 5 who received placebo. One patient in each group required hospitalization.

Bipolar disorder plus ADHD

An estimated 10% to 21% of bipolar patients meet criteria for ADHD,^16-19 although at times the line differentiating these 2 disorders is unclear. Co-occurring ADHD worsens the course of bipolar illness,^20-22 and data from the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) trial suggest that only 2% of dual-diagnosis patients are receiving treatment specifically for ADHD symptoms.²³

Theoretically, overlapping symptoms such as talkativeness, distractibility, and physical activity remain relatively constant in ADHD but wax and wane with bipolar disorder’s manic and depressive phases. Recent evidence suggests, however, that many bipolar patients experience prodromal symptoms that may resemble ADHD, including cognitive impairment, distractibility, and increased psychomotor activity.²⁴ In addition, medications used to treat bipolar disorder may impair cognitive function, making ADHD diagnosis difficult in this population.

We are not aware of any clinical trials that examined stimulants’ safety and efficacy in adult bipolar patients with co-occurring ADHD. One of the only studies to examine stimulant treatment of ADHD symptoms in a bipolar population was a retrospective chart review of 34 adolescents hospitalized with bipolar mania. An earlier age of bipolar illness onset was reported in adolescents who had been exposed to stimulants, whether or not they also had ADHD.²⁵

Clinical Point

Using adequate mood-stabilizer treatment may attenuate stimulants’ undesirable effects in patients with bipolar disorder

One randomized trial. In a study by Scheffer et al³ of children with bipolar mania and ADHD, divalproex sodium produced an 80% response rate in manic symptoms but no significant decrease in ADHD symptoms.³ Forty responders then participated in a double-blind, placebo-controlled trial in which mixed amphetamine salts, 5 mg bid, was added for ADHD symptoms. In patients treated with divalproex sodium plus the stimulant, ADHD symptoms decreased significantly compared with the group receiving divalproex sodium plus placebo. Mania developed in 1 of 23 subjects treated with the combination therapy.

Possible adverse events

Some bipolar disorder patients tolerate stimulants well, whereas others experience serious side effects, toxicities, and illness destabilization (Table 2). Because mood-stabilizer treatment may attenuate stimulants’ undesirable effects in bipolar disorder patients,^26,27 be sure to use adequate dosing of a mood stabilizer if you determine a stimulant trial is warranted in your patient.

Destabilization. Stimulants can have a direct negative effect on mood; they can cause restlessness, irritability, anxiety, and mood lability. Some bipolar patients may be more sensitive to these adverse effects than others. Particularly concerning is the possibility of switching to mania or worsening of manic symptoms.^28,29 Other potential destabilizing effects include:

changing cycling patterns, such as inducing rapid cycling
sleep disturbance because stimulants promote wakefulness.

Substance abuse in bipolar disorder has been associated with increased treatment resistance, earlier age at illness onset, and an overall worse course of illness.^30,31 Some reports have estimated substance abuse rates as high as 60% in bipolar populations.³² Particularly concerning is that up to 40% of patients with bipolar disorder may have a history of amphetamine abuse.³³

If you are considering stimulant treatment for a bipolar disorder patient in whom substance abuse is a concern, modafinil or lisdexamfetamine may have a lower abuse potential compared with immediate-release psychostimulants. Lisdexamfetamine is metabolized in the GI tract and does not produce high d-amphetamine blood levels or cause reinforcing effects if injected or snorted.³⁴

Table 2

Possible stimulant side effects, signs of toxicity, and contraindications

Stimulant class	Possible side effects	Signs of toxicity/overdose	Contraindications/cautions
Traditional (amphetamine mixtures, dexmethylphenidate, dextroamphetamine, lisdexamfetamine methylphenidate)*	Restlessness, insomnia, mood lability, anxiety	Agitation, confusion, tremor, tachycardia, hyperreflexia, hypertension, sweating, psychomotor agitation, seizure, arrhythmia, coma, psychosis	Cardiovascular disease, hypertension, hyperthyroidism, glaucoma, Tourette’s syndrome/motor tics, history of seizure disorder, hypersensitivity to medication class
Novel (modafinil)	Restlessness, insomnia, mood lability, anxiety	Agitation, tremor, nausea, diarrhea, confusion	Cardiovascular disease, hepatic impairment, psychosis
* Amphetamines and dextroamphetamine (Adderall, Adderall XR); dexmethylphenidate (Focalin, Focalin XR), dextroamphetamine (Dexedrine, DextroStat); lisdexamfetamine (Vyvanse); methylphenidate (Concerta, Daytrana, Metadate CD, Methylin, Methylin ER, Ritalin, Ritalin LA, Ritalin SR)