Treatment-resistant depression (TRD) is defined as the failure to achieve remission of symptoms after continuous therapy for six to 12 weeks with an adequate dose of a single antidepressant.1 Individuals receiving antidepressant monotherapy may be partially or totally resistant to treatment in up to 30% of cases.2

Q: What is the etiology of TRD?

A: About 15% of the population will experience some form of depression throughout their life span. Approximately 6% to 8% of outpatients satisfy most of the depression criteria. Depression is almost twice as common in women as in men, and the incidence increases with age in both sexes. The cause of TRD is unknown. 

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The causes of depression are usually related to a neuroendocrine abnormality. The signs and symptoms of depression that these abnormalities stem from include increased secretion of cortisol and corticotropin-releasing hormone, increased adrenal size, decreased inhibitory response of glucocorticoids to dexamethasone, and a blunted response to thyroid-stimulating hormone. TRD has also developed as a result of inappropriate management of patients with clinical depression. These causes are usually iatrogenic and include inadequate dose of antidepressant medication, inadequate duration of treatment, and inadequate evaluation of response to medications. The misuse of antidepressant medications has directly led to the increase in TRD. 

Most cases of depression begin in the early-adult stage of life. The number of past episodes of depression is a good indicator of risk of recurrence. About 50% to 60% of patients with one episode are likely to have at least one or two recurrences in their lifetime.3

Q: What findings in the history and physical examination can be used to diagnose TRD? 

A: Be alert for any signs and symptoms of depression that are refractory to treatment, such as sadness, indifference, apathy, irritation, changes in sleep patterns or appetite, weight loss or weight gain, motor agitation, loss of interest in pleasurable activities, impaired concentration and decision making, feelings of shame or guilt, and thoughts of death or dying. On physical exam, the patient could present with a flat affect, looking at the floor to avoid eye contact. A depressed patient may speak in a monotone or cry when answering questions. A loss of concentration may alter the patient’s comprehension of the questions asked by the clinician. If previous records are available, a change in BP could be noted. Aigns of dementia that may be present are considered pseudodementia, because depression is usually the cause. The Hamilton Depression Rating Scale (HAM-D) is a valuable clinical tool used to evaluate the progress of the disease.3,4 Grading the patient’s responses to a questionnaire designed to measure the severity of depressive symptoms, the scale classifies depression as normal (0-7), mild (8-13), moderate (14-18), severe (19-22), and very severe (>23). 

Q: What tests are available to diagnose TRD?

A: In one study, an electroencephalogram monitor showed cordance of the frontal lobe in patients resistant to treatment with a selective serotonin reuptake inhibitor (SSRI).5 Decreases in prefrontal cordance differentiated treatment responders from nonresponders as well. These findings suggest that cordance biomarkers may be helpful in diagnosing TRD.

Q: What is the standard workup for TRD?

A: Once a patient presents with depression that appears to be refractory, it is important to determine if an adequate trial of antidepressant medication (typically four to six weeks) was used.6 If any improvement was seen, the dosage can be increased and treatment continued for an additional four to six weeks. Anywhere from eight to 10 weeks will give the clinician a clear picture of the effectiveness of the medication, and another treatment may be applied. One study found that a depressed individual who had not improved by the third week of treatment with paroxetine (Paxil, Pexeva) is unlikely to respond to further treatment.7 After an adequate trial of antidepressant therapy has been identified, referral to a mental-health specialist is recommended. The specialist will reassess to make sure the depression was not caused by an undiagnosed illness or prescribed medications. Other diagnoses that must be ruled out before initiating treatment for TRD include somatoform disorder, personality disorders, bipolar disorder, anxiety disorders, anorexia nervosa, multiple sclerosis, Parkinson disease, alcohol or drug abuse, hypothyroidism, and bereavement. 

Q: What treatment options are available for TRD?

A: Most clinicians will begin with a stepwise increase in treatment. Start with one antidepressant medication, and maximize the therapeutic dose and duration. Then reassess the patient to see if the signs and symptom have been alleviated. If not, another antidepressant agent may be added from another class. If combination drug therapy fails to alleviate the depression, electroconvulsive therapy is an option.