Evidence-Based Reviews

Stimulants for adult bipolar disorder?

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

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Drug-drug interactions

Polypharmacy is the rule in treating bipolar disorder, and stimulants can interact with many other psychotropics (Table 3).

Antidepressants. Never use traditional stimulants with monoamine oxidase inhibitors, as this combination may precipitate a hypertensive crisis. Coadministered stimulants also may decrease the metabolism of serotonergic agents—such as selective serotonin reuptake inhibitors (SSRIs) or serotonin-norepinephrine reuptake inhibitors (SNRIs)—and cause side effects associated with increased serotonin neurotransmission, including serotonin syndrome.

Combining traditional stimulants with TCAs may increase TCA concentrations. When coadministered with bupropion, stimulants can increase the risk of seizures.

Clinical Point

Modafinil or lisdexamfetamine may have a lower abuse potential compared with immediate-release psychostimulants

Carbamazepine, others. Certain psychotropics can affect stimulants’ efficacy. For example, carbamazepine can decrease stimulant serum concentrations, possibly decreasing their therapeutic effect. Conversely, abruptly discontinuing carbamazepine may increase stimulants’ plasma concentration and predispose patients to associated adverse effects. Antipsychotics and lithium may inhibit stimulants’ stimulatory effects, although this balance may be necessary to maintain mood stability and stimulant effects.

Modafinil is both an inducer and inhibitor of cytochrome P450 isoenzymes. Because it induces CYP3A4 and inhibits CYP2C19 and CYP2C9, modafinil interacts with many other psychopharmacologic agents:

Its induction of CYP3A4 may increase the metabolism of commonly used medications such as carbamazepine, aripiprazole, and triazolam.
Its inhibition of CYP2C19 may decrease the metabolism of many SSRIs, TCAs, diazepam, and clozapine, increasing these drugs’ effects and adverse events.

Table 3

Possible stimulant interactions with other psychotropics

Stimulant class	Psychotropic medication	Possible adverse effects
Traditional (amphetamine mixtures, dexmethylphenidate, dextroamphetamine, lisdexamfetamine methylphenidate)*	MAOIs	Hypertensive crisis
	CBZ	Reduced methylphenidate levels; abruptly stopping CBZ increases methylphenidate’s effect
	TCAs	Increased TCA concentration
	SSRIs, SNRIs	Possible decreased metabolism of antidepressants; potential for serotonin syndrome or NMS-like syndrome
	Typical and atypical antipsychotics	Each may interfere with the other’s therapeutic action
Novel (modafinil)	CBZ	Decreased modafinil efficacy; decreased CBZ levels
	Triazolam	Decreased triazolam efficacy; increased effects of triazolam with modafinil discontinuation
	Fluoxetine, fluvoxamine	Decreased modafinil clearance
	Citalopram, escitalopram, sertraline	Prolonged elimination and increased levels of antidepressant
	MAOIs	Hypertensive crisis(?); not recommended
	Diazepam	Prolonged elimination and increased levels of diazepam
	TCAs	Prolonged elimination and increased levels of TCAs
	Clozapine	Increased clozapine concentration (case report)
	Aripiprazole	Decreased levels of aripiprazole
* 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)
CBZ: carbamazepine; MAOIs: monoamine oxidase inhibitors; NMS: neuroleptic malignant syndrome; SNRIs: serotonin-norepinephrine reuptake inhibitors; SSRIs: selective serotonin reuptake inhibitors; TCAs: tricyclic antidepressants

Treatment considerations

Without evidence to support stimulants’ safety and efficacy in patients with bipolar disorder, we cannot make specific recommendations. We would, however, like to offer some general recommendations if you decide to use stimulants when treating patients with bipolar disorder (Table 4).

Clinical Point

Before adding a stimulant, optimize medications, assess the diagnosis, identify substance abuse, and treat medical comorbidity

Before adding a stimulant, optimize the patient’s treatment regimen and carefully assess the side-effect profiles of his or her medications. Nearly every medication used to treat bipolar illness—including divalproex sodium, lithium, quetiapine, olanzapine, and clozapine—may cause marked sedation, somnolence, and subjective feelings of decreased energy. Try switching to a medication with a lower incidence of these iatrogenic effects.

Carefully assess and—in many cases—reassess the patient’s symptoms to clarify the diagnosis. As mentioned, ADHD and bipolar disorder share many symptoms, particularly in the manic phase of bipolar illness. Overlapping symptoms include decreased ability to concentrate and focus, distractibility, hyperactivity and psychomotor agitation, racing thoughts, and impulsivity.

Substance abuse can negatively impact bipolar illness and present as clinical scenarios in which stimulants are used (such as treatment-resistant depression, impulsivity, somnolence, or fatigue).

Treat medical conditions such as thyroid disease, diabetes, and sleep apnea, which may worsen depression, cause somnolence and sedation, and present with symptoms similar to those of ADHD.

When possible, use lifestyle techniques to help patients manage the course of bipolar illness. Encourage good sleep hygiene, exercise, stable social rhythms, and limited use of alcohol and caffeine (both of which can impair sleep quality, which affects illness stability).

The next step. When you have explored all medication options and ruled out all other causes for the patient’s symptoms, stimulant treatment may be an appropriate next step. In these cases:

Clinical Point

When starting stimulants, use the minimum available dose of whatever stimulant you select and titrate slowly

Engage the patient in decision-making. Carefully review target symptoms to be addressed by stimulant treatment, dosing, possible side effects and drug interactions, as well as safety concerns.

Encourage patients to participate in treatment, particularly in monitoring mood changes (as with life charts), symptoms associated with mood episodes, and emergence of side effects. When possible, involve family members in monitoring for adverse events.