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 .
 adjunctive use of methylphenidate , a central stimulant , has been considered as a potential therapeutic choice for patients with refractory unipolar , geriatric , or bipolar depression , and depression secondary to medical illness . 
 we present a case of bipolar depression in which the patient responded significantly to augmentation with methylphenidate , without any side effects , after failure of adjunctive repetitive transcranial magnetic stimulation and electroconvulsive therapy . 
 mr u , a 56-year - old man with bipolar i disorder , had melancholic symptoms during his sixth episode of bipolar depression . 
 after failure of repetitive transcranial magnetic stimulation and electroconvulsive therapy , he was treated with fluoxetine 80 mg / day , duloxetine 360 mg / day , mirtazapine 60 mg / day , and sodium valproate 1,000 mg / day , with no improvement . 
 we added methylphenidate at a dose of 10 mg / day for one week , which resulted in mild clinical improvement , and then methylphenidate extended - release 20 mg / day for one week , with significant clinical improvement . 
 he tolerated his medications well . 
 his clinical recovery was stable over one year . 
 the patient s antidepressants and methylphenidate were gradually tapered and finally discontinued after one year with no withdrawal syndrome . to date , he remains well on sodium valproate as monotherapy and is being followed up at our bipolar department . 
 this case suggests that methylphenidate augmentation might be a therapeutic option when treating highly treatment - resistant patients with bipolar depression , even if they had not responded to adjunctive neuromodulation . in these clinical situations 
 , physicians might be interested in prescribing methylphenidate because of its efficacy and safety . 
Introduction
Case report
Discussion
Conclusion