Would add on stimulants help in bipolar depression?:Int J Neuropsypharm: Jan.2013


Treating bipolar depression is often a clinical challenge. Antidepressants are less effective and may induce mood instability.Mood stabilisers and antipsychotics do not offer much help in many cases. Would stimulants be a helpful as adjunctive agents?

Bernardo Dell’Osso and Terence A. Ketter review the evidence for stimulants as adjunctive treatment in  adult bipolar depression.

Stimulants are a heterogeneous group of medications.Stimulants can promote alertness and wakefulness, reduce fatigue, and can perhaps even improve mood.  Fatigue, somnolence, and cognitive impairments  are often present in bipolar depression.Stimulants can cause manic switch and this limits its use.

The systematic search identified nine studies, one open uncontrolled study of amphetamines, four open uncontrolled studies of methylphenidate, four studies (including three open uncontrolled studies and one RCT (Frye et al2007) of modafinil, and one RCT of armodafinil (Calabrese et al. 2010).Stimulants were used as adjunctive treatment in all studies.


Methyl phenidate: 

El-Mallakh,2000:  12-wk open study of adjunctive methylphenidate in 14  BD-dep. effective, but 3/14 dropped out due to anxiety,hypomania, agitation.

Carlson et al 2004: retrospective series, 8 subjects. methyl phenidate( 10-20mg) improved symptoms over 18 m period. No adverse events.

Lydon and El-Mallakh,2006: retrospective chart review ,16 BD patients,  methylphenidate  (5-40 mg/day): 14 months. Effective. 2/16 discontinued due to side effects.

Parker and Brotchie, 2010:  open case series that included  27 bipolar depression (treatment resistant) subjects, treated with methylphenidate or dextro- amphetamine, either as monotherapy or adjunctive therapy (in most of the patients).Majority had some improvement.  18% had significant side effects including one manic episode. Mean duration 52 weeks.


Menza et al 2000: Retrospective case series , 3 patients. at 100–200 mg/d, all patients achieved full or partial remission, generally within 1–2 wk. No significant side effects.

Fernandes and Petty, 2003: Two patients. Modafinil used to treat drowsiness .Rapid improvement with no side effects.

Nasr, 2004 : Retrospective chart review. Outpatients (only some were bipolar depression) with depression , treated with modafinil,improved sleepiness and fatigue.

RCT: Frye et al 2007: Double-blind, placebo-controlled study in 85 patients with bipolar depression.Patients were randomized to adjunctive placebo (n=44) or modafinil (n=41), two tablets of 100 mg/d for 6 wk. Significant improvement in treatment group, with no difference in hypomania or mania.Headache was the commonest side effect in modafinil group.

RCT: Calabrese et al 2010: 8-wk, multicentre, randomized, double-blind, placebo-controlled study. Patients were randomly assigned to adjunctive armodafinil or placebo. Armodafinil 150 mg/d (n=128) and placebo (n=129) were administered once daily in the morning. Stimulant significantly improved the depression inventory scores but not the MADRS scores. Stimulant did not cause increase in manic switches.

Conclusions: There are only two RCTs to address this question.In patients with bipolar depression where drowsiness and fatigue are prominent and  symptoms are unresponsive to usual treatments, stimulants might be an add on option.However, the over all quality of evidence to support this is limited.


Use of adjunctive stimulants in adult bipolar depression.Dell’osso B, Ketter TA.

Int J Neuropsychopharmacol. 2013 Feb;16(1):55-68.


2 thoughts on “Would add on stimulants help in bipolar depression?:Int J Neuropsypharm: Jan.2013

  1. That is interesting. Did they also attempt to distinguish the ‘mania’ switch between the natural evolution of the illness? One can imagine that the stimulant could act as a secondary factor to induce mania. For instance, by making one feel less tired and thus less prone to not sleeping enough…

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