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however , in a proportion of the patients with major depression , despite the use of adequate antidepressant doses for the adequate duration , clinical remission is not achieved .
although there is no consensus , but in general it is accepted that those patients with major depression who do not respond to 2 - 3 adequate trials of antidepressants are considered to have treatment - resistant depression ( trd ) . some of the authors have suggested staging for trd and based on the level of nonresponse the patient is allocated to different stages of trd .
it is suggested that whenever a patient present 's with trd , a thorough evaluation needs to be done to evaluate the underlying organic and psychosocial causes .
we here , report a case of recurrent depressive disorder , current episode severe depressive episode without psychotic symptoms , who did not respond to adequate trials of antidepressants and showed minimal response to electroconvulsive therapy ( ect ) . in view of the lack of remission , on investigation
she was managed with ketoconazole 400 mg / day along with the continuation of antidepressants with which she achieved remission .
mrs . a , 40-year - old , known case of recurrent depressive disorder , with first episode occurring at the age of 36 years , with two episodes in the past which responded to antidepressant treatment , presented with severe depressive episode without psychotic symptoms of 18 months duration . for the current episode ,
the onset was insidious with the evolution of symptoms over the period of 1-month , without any precipitating event and the course was continuous for the current episode .
her clinical presentation was characterized by persistent sadness of mood with morning worsening , poor interaction , anhedonia , lethargy , psychomotor retardation , sleep disturbance in the form of difficulty in falling asleep with frequent midnight awakenings , reduced appetite associated with weight loss of 3 kg , reduced libido , ideas of guilt , suicidal ideations , suicidal planning with one unsuccessful attempt and off and on anxiety symptoms .
her treatment history revealed that during the current episode she was treated with tablet paroxetine 12.5 - 37.5 mg / day for 4 months , tablet mirtazapine 15 - 30 mg / day for 3 months , tablet imipramine up to 175 mg / day for 5 months , c. venlafaxine up to 300 mg / day for 2 months with no response .
later she was treated with c. venlafaxine 300 mg / day along with thyroxine 75 g / day ( for 2 months ) and c. venlafaxine 300 mg / day and lithium 600 mg / day for a period of 2 months but with minimal improvement .
on mental status examination , she had sadness of mood , psychomotor retardation , ideas of hopelessness , worthlessness , guilt , and suicidal ideas .
investigations in the form of hemogram , liver function test , renal function test , serum electrolytes , thyroid function test , serum vitamin b12 levels were did not reveal any abnormality .
her magnetic resonance imaging ( mri ) scan of the brain did not show any abnormality .
her psychosocial history did not reveal any evidence of chronic stressors and her family was very supportive .
there was no history suggestive of mania , psychotic symptoms , alcohol or drug abuse , seizure , head injury , and cognitive decline .
she was continued on c. venlafaxine 300 mg / day along with tablet lithium carbonate 300 mg / day ( with serum levels in the therapeutic range ) .
in addition , due to lack of response to adequate doses of antidepressants she was treated with 14 sessions of modified ect over the period of 6 weeks with minimal improvement ( hdrs score reduced to 32 ) . in view of the lack of response to ect
, further investigations were done for cushing 's syndrome although her physical examination was not suggestive of the same .
workup for cushing 's syndrome revealed raised plasma cortisol level ( 722.7 nmol / l [ normal range 193 - 634
mri scan of the abdomen revealed small homogenous , well - defined lesion measuring 2 cm in the adrenal cortex with clear margins suggestive of an adrenal adenoma .
as a result , she was started on tablet ketoconazole 200 mg / day and increased to 400 mg / day over next 15 days along with the continuation of c. venlafaxine 300 mg / day .
patient improvement was monitored clinically and using ham - d score . over a period of next 4 weeks
, the patient showed significant improvement in her depressive symptoms with no associated side effects .
she has been maintaining well on tablet ketoconazole 400 mg / day and of c. venlafaxine 225 mg / day for the last 4 years .
her adrenal mass has been monitored with no increase in the size of the tumor .
according to the staging of trd by thase and rush , the index case can be considered as stage-5 trd , that is , patient who has not responded to antidepressants of two different classes , tricyclic antidepressants and ect .
in addition , the patient had also not responded to augmentation with thyroxine and lithium .
it is suggested that whenever a patient presents with trd , first there is a need to evaluate the patient for pseudo - resistance .
the factors that contribute to pseudo - resistance include poor compliance , inadequate dosing , and discontinuation of antidepressant before adequate duration .
the history of the index case did not reveal the same . in view of the stage-5 nonresponse
, she was empirically evaluated for cushing 's syndrome and was found to have positive evidence for the same .
due to the role of stress and involvement of cortisol in understanding the etiopathogenesis of depression , researchers have used antiglucocorticoid drugs such as metyrapone , aminoglutethimide , ketoconazole , and mifepristone in the management of trd . in a review , which included 11 studies
, authors reported that 67 - 77% of the patients show at least a partial antidepressant response and largest two series documenting response rates of 70 - 73% .
our case highlights the fact that while dealing with patients with trd , psychiatrists should look into all possible medical causes for depression .
further , our case suggests that antiglucocorticoid medications can be considered in patients with trd who do not respond to conventional treatments .
treatment resistant depression ( trd ) is a common clinical occurrence among patients treated for major depressive disorder . 
 a significant proportion of patients remain significantly depressed in spite of aggressive pharmacological and psychotherapeutic approaches . 
 management of patient with treatment resistant depression requires thorough evaluation for physical causes . 
 we report a case of recurrent depressive disorder , who presented with severe depressive episode without psychotic symptoms , not responding to multiple adequate trials of antidepressants , who on investigation was found to have cushing 's syndrome and responded well to ketoconazole .