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What Is Treatment-Resistant Depression?

By Christina Hall
Updated May 17, 2024
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Treatment-resistant depression (TRD) is a term used to describe a case of major depressive disorder that does not seem to respond to conventional depression treatment. Clinical psychiatry coined the term is 1974, when electroconvulsive treatment was used extensively to treat serious depressive disorders that seemed to be immune to cognitive-behavioral therapy (CBT) and early antidepressant medications. With the introduction of more varied antidepressants, the term was amended to describe major depressive illness that does not respond to at least two of the newer antidepressant medications. The treatment of TRD includes some invasive procedures, like vagus nerve stimulation, and also the addition of other psychiatric medications. Some practitioners have also pointed to coexisting physical conditions, like chronic nasobronchial allergies, that could induce chronic depressive symptoms, like restlessness and agitation.

Patients who experience treatment-resistant depression will often feel relief from their depression with conventional antidepressant medication and psychotherapy, but then experience a slow return of depressive symptoms. Some patients do not feel any initial relief from symptoms. The etiology of treatment-resistant depression is controversial, with some researchers thinking it is due to the patient being under unabated emotional stress that has not been addressed thoroughly, while others think most cases stem from medication not being taken correctly, the existence of additional medical or psychiatric illness, or a total misdiagnosis of the condition. The illness thought to be the most commonly-misdiagnosed as TRD is bipolar disorder, where simple treatment with medication does not address the totality of clinical symptoms.

The first line of defense when treating TRD is often the addition of an atypical antipsychotic medication, like aripiprazole. The sedative properties of atypical antipsychotic medication will sometimes reduce agitation in chronically-depressed patients. Depression that presents with agitation will sometimes be later diagnosed as bipolar illness because this symptom can be a sign of mania. Treatment with atypical antipsychotics is detrimental to some patients, however, because the medication can actually worsen depressive symptoms.

Stimulant medications, like methylphenidate and amphetamines, can also be used to augment antidepressant medication and psychotherapy in treatment-resistant depression. The treatment is most effective for patients who do not have a high level of agitation or restlessness. In the absence of these symptoms, stimulation of the central nervous system can help patients who have a significant lack of motivation and desire. Some psychiatrists are reluctant to experiment with stimulant-based therapy, however, because stimulant medications have a high abuse potential. Other mood-stabilizing medications, like lithium, are often tried in cases of TRD as well.

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