Original Research

A Review of Psychostimulants for Adults With Depression

Fed Pract. 2015 April;32(suppl 3):30S-37S

References

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modafinil and armodafinil have the most evidence in DBPC trials.

There are relatively few DBPC trials with high power and sufficient duration for dextroamphetamine and methylphenidate preparations. This discovery is surprising, considering the duration that these medications have been available. However, several chart reviews and open-label trials provided some evidence to support their use in patients without a history of substance misuse or cardiac conditions. ⁶² Osmotic controlled- release oral system methylphenidate seems to be ineffective, and the efficacy of atomoxetine for augmentation
is uncertain.

Precautions

Prescribing physicians who offer stimulants should consider potential AEs, such as psychosis, anorexia, anxiety, insomnia, mood changes (eg, anger), misuse, addiction, mania, and cardiovascular problems. Psychostimulants have been implicated in precipitating psychosis. ^63,64 However, in a 12-month study of 250 adults with ADHD, 73 reported AEs, and only 31 discontinued the stimulant. Adverse effects leading to discontinuation included mood instability (n = 7), agitation (n = 6), irritability (n = 4), or decreased appetite (n = 4). ⁶⁵

Although associated with the risks of anorexia and insomnia in patients with ADHD, methylphenidate rapidly improved daytime sleepiness and mood, and—paradoxically—appetite and nighttime sleep in medically ill elderly patients with depression. ⁶⁶ Misuse or abuse of methylphenidate and dextroamphetamine were noted in 23% of patients referred for substance misuse. ⁶⁷ Nonetheless, little evidence exists that these drugs possess significant misuse potential in patients taking them as prescribed. As a prodrug, lisdexamfetamine is hypothesized to have less abuse potential compared with dextroamphetamine and methylphenidate, but it carries the same prescribing and monitoring precautions. ⁶⁸ Risks related to stimulant usage extend to manic symptoms. ⁶⁹ Patients with bipolar disorder should not receive stimulants if they have a history of stimulant-induced mania, rapid cycling, or psychosis. ⁷⁰

Long-term cardiovascular safety data exist for dextroamphetamine and methylphenidate but are limited or unavailable for modafinil, armodafinil, and atomoxetine. A retrospective cohort study found no significant increase in the number of cardiac events in patients receiving dextroamphetamine,
methylphenidate, or atomoxetine for an average of 1 year compared with controls. ⁷¹ Another cohort study of > 44,000 patients found that initiation of
methylphenidate was associated with increased risk of sudden death or arrhythmia, but the risk was attributed to an unmeasured confounding factor, as the authors found a negative correlation between methylphenidate dose and all cardiovascular events. ⁷²

Recent practice guidelines recommend that before prescribing stimulants, clinicians should perform a physical examination (including heart and lung auscultation), obtain vital signs and height and weight, and request an electrocardiogram in case of abnormal findings on a cardiovascular examination or in case of a personal or family history of heart disease. Before offering atomoxetine, clinicians should evaluate the patient for a history of liver disease (and check liver function studies in case of a positive history). Clinicians should also assess risk of self-harm prior to initiating psychostimulant therapy. ⁷³ Throughout treatment, clinicians should evaluate the patient for changes in blood pressure, pulse, weight or mood, as well