there is no definition of treatment - resistant bipolar depression in the literature . the international society for bipolar disorders ( isbd ) task force published their consensus definition of treatment response in bipolar depression1 and proposed a nomenclature for relapse , remission , and recurrence , but did not define treatment resistance . treatment response is defined as > 50% improvement in the core dsm ( diagnostic and statistical manual of mental disorders ) criteria for depression . treatment - resistant bipolar patients remain symptomatic despite the best available care . here , we propose that treatment resistance in bipolar depression be defined as failure of pharmacotherapy associated with failure of neuromodulation , such as electroconvulsive therapy and repetitive transcranial magnetic stimulation ( rtms ) . the antidepressant effects of psychostimulant drugs have been underappreciated because of conflicting data concerning efficacy , tolerance , and dependence . orr and taylor2 reported that methylphenidate reduced tiredness and enhanced attention and arousal , and recommended its use for treating depressive episodes . candy et al3 reported that the main advantage of methylphenidate over antidepressants might be its rapid onset of action within one day , and highlighted that , unlike conventional antidepressants , methylphenidate reduces fatigue . stoll et al4 and metz and shader5 showed that the combination of methylphenidate and a selective serotonin reuptake inhibitor antidepressant was effective . in a cochrane meta - analysis,3 candy et al reported that psychostimulants ( excluding modafinil ) significantly reduced symptoms of depression in comparison with placebo . emphasizing the role of psychostimulants in increasing dopamine production , stahl6 and nierenberg et al7 support the view that psychostimulants are preferable for the more  biological  depressive disorders ( melancholic and bipolar depression ) but not for the wider spectrum of depressive conditions ( especially nonmelancholic disorders ) . reconsideration of the overall psychostimulant class is likely to be encouraged by the recent introduction of modafinil , a novel psychostimulant that has been studied in both unipolar and bipolar disorders.8 psychiatrists should always remember the potential usefulness of psychostimulants in the treatment of depression based on available evidence . this paper reports the antidepressant effects of methylphenidate , suggesting that this agent might be highly effective and safe , even after neuromodulation had failed , with no withdrawal syndrome when stopped . thus , methylphenidate might be of some considerable utility in managing patients with treatment - resistant depression . we present a case of bipolar depression in which the patient responded significantly to methylphenidate augmentation , without any side effects , after failure of adjunctive rtms and electroconvulsive therapy . mr u , a 56-year - old man with bipolar i disorder according to dsm - fifth edition criteria,9 experienced his first melancholic depression in 1976 , which was followed by five melancholic episodes and four manic episodes . he did not show any comorbid psychiatric condition and had no history of drug or alcohol abuse . his sixth melancholic depressive episode began in march 2008 , just after a prison guard workmate had committed suicide . he showed a depressed and anxious mood , negative and obsessive thinking , loss of interest in activities , impairment in activities of daily living , psychomotor retardation , self - blaming behavior , guilty and suicidal thoughts , insomnia , reduced appetite , and a 5 kg loss of body weight . his laboratory examinations included a full blood count , blood biochemistry and urinalysis , electrocardiography , electroencephalography , and structural cerebral magnetic resonance imaging . his initial 21-item hamilton depression rating scale10 score was 37 and his clinical global impression - severity11 score was 6 . from april 1 , 2008 until june 10 , 2010 , he received various antidepressant ( venlafaxine extended- release , clomipramine or duloxetine , combined with either paroxetine or mirtazapine ) and mood stabilizer ( olanzapine , aripiprazole , or sodium valproate ) combinations with no significant clinical improvement . each medication was prescribed at an optimum and stable dosage for the minimum recommended duration , with no significant clinical improvement . on february 6 , 2009 , we assessed the patient s whole - brain voxel - based regional cerebral blood flow with tc - ethyl cysteinate dimer single photon emission computed tomography , and hypoperfusion was shown in the bilateral anterior cingulate cortices , the right inferior parietal cortex , and the left dorsolateral and bilateral orbital prefrontal cortices . twenty treatment sessions were administered over a 4-week period ( five sessions per week ) . in mid march , after these sessions were completed , mr u showed no significant clinical improvement . rtms was initiated again , with 20 treatment sessions being administered over a 4-week period until april 15 , 2009 . his physicians initiated electroconvulsive therapy three times a week on april 18 , 2009 for 2 months until june 19 , 2009 . mr u showed no significant clinical improvement after 24 sessions of electroconvulsive therapy . at that time , he was treated with a combination of fluoxetine 80 mg / day , duloxetine 360 mg / day , mirtazapine 60 mg / day , and sodium valproate 1,000 mg / day . on june 29 , 2009 , we added methylphenidate at a dose of 10 mg / day for one week . two days after introduction of methylphenidate , mr u reported some mood improvement after a single early morning dose . the second week after its initiation , the dose of methylphenidate was increased to 20 mg / day for one week using an extended - release tablet formulation , with significant improvement . two weeks later , mr u achieved significant and lasting clinical improvement , with hamilton depression rating scale and clinical global impression - severity scores of 8 and 3 , respectively . he remains well on sodium valproate monotherapy and is regularly followed up at our bipolar department . this case report suggests that methylphenidate may be an effective and safe medication for treating treatment - resistant bipolar depression . methylphenidate was well tolerated with no drug - related switching to hypomania or mania . during the treatment period , improvements in the clinical global impression - severity and hamilton depression rating scale scores indicated clinically significant improvement . our patient s melancholic depression was not improved satisfactorily by the combination of duloxetine , mirtazapine , clomipramine / fluoxetine , and olanzapine / valproate after adjunctive rtms or electroconvulsive therapy . it was not until the patient received methylphenidate 20 mg / day that his severe depression improved substantially and durably , suggesting that adjunctive methylphenidate may have had an additional therapeutic effect in this difficult - to - treat patient . unfortunately , whole - brain regional cerebral blood flow with single photon emission computed tomography was not performed at that time . theoretical use of methylphenidate has been discussed by stahl,12 who suggests that the dopamine - releasing stimulant properties of methylphenidate allow this agent to be used in combination with other antidepressants . stahl suggests that methylphenidate may be particularly useful in patients with retarded or melancholic depression or those who require an antidepressant concomitantly with a mood stabilizer for bipolar depression . while a number of authors24,6 have reported that methylphenidate is effective for treating treatment - resistant bipolar depression , patkar et al13 did not demonstrate any statistically significant benefit from augmentation with methylphenidate in treatment - resistant depression in a randomized , double - blind , placebo - controlled trial . theoretical and clinical use of methylphenydate is broadly consistent with our observations in our bipolar department over recent years , ie , that methylphenidate is useful ( as monotherapy or augmentation ) in patients with melancholic or bipolar depression , including many patients who do not respond to conventional antidepressant drugs or neuromodulation techniques . our case suggests that methylphenidate can be used as an adjunctive agent for some patients with treatment - resistant bipolar depression or melancholia who do not adequately respond to combination antidepressant therapy , a mood stabilizer , and rtms or electroconvulsive therapy . clearly , placebo - controlled studies are warranted within these diagnostic subgroups to test our clinical impressions . such augmentation studies would be advanced by measuring serum levels of the relevant antidepressants to determine whether psychostimulants act by increasing these levels and/or if they have independent antidepressant activity .