Commentary by Brian Bronson, MD, Chief of Psychosomatic Medicine, VA New York Harbor, New York Campus
Summary: Symptoms of depression in the medical setting may not respond to usual pharmacologic antidepressant treatment for a number of reasons. These may include an incorrect psychiatric diagnosis; failure to consider underlying medical causes of the symptoms; or insufficient antidepressant medication trial due to poor patient adherence, insufficient dose or length of trial. There is no consensus as to the definition of ‘treatment refractory’ depression. However, when the above steps have not resulted in improved outcome, the clinician may either change to an alterative antidepressant, or add a second medication as adjuvant treatment if the patient had a partial response to the first medication. Failure to modify critically important environmental or psychosocial stressors may also impair a full treatment response. Part I of this discussion focused on making the correct diagnosis. Part II summarizes pharmacologic management concepts for treatment non responders.
Assuming the diagnosis of a major depressive episode or adjustment disorder with depressed mood is correct and is not the manifestation or another underlying disorder, the primary care practitioner has many options to approach the treatment non-responder.
A common cause of patient non-response or partial symptom response to antidepressant treatment is a failure to titrate the antidepressant medication to adequate doses. Starting doses recommended by the drug manufacturer are often not sufficient final doses. In outpatient, non-emergent settings, clinicians should titrate the dose up every 3-4 weeks until the patient demonstrates some symptom improvement, holding the initially effective dose for 6-10 weeks or as long as symptoms continue to improve before titrating up further. The goal of increasing dose titration should be a complete remission of symptoms; ie a return to baseline. Asking patients about missed doses should be a routine part of follow-up, given the high prevalence of partial adherence or complete self-cessation of antidepressant treatment by patients.
Patients with a major depressive episode that do not respond to the maximum approved or tolerated dose of medication after at least 8 weeks should be considered for an alternative or second add on medication. In practice, patients with a partial treatment response to an antidepressant medication are generally continued on that medication at that dose, and a second medication is added to treat residual symptoms. This approach is supported by empiric evidence.
Patients with no response to an antidepressant at an adequate trial are generally tried an on a different antidepressant with an alternative mechanism of action. Patients that tolerate a particular SSRI at a full dose without response may respond to a different SSRI. However after one or two SSRIs have been tried, a trial of an alternative class of antidepressant with a different pharmacologic mechanism is often indicated. Mirtazapine, Buproprion and Venlafaxine each have unique mechanisms of action different from one another and from the SSRIs. No single antidepressant has proven itself more effective than any other for populations. However individual patients respond to and tolerate these medications differently. Patients with a prior response or family member response to a particular antidepressant will often respond again to that medication. Remember to take a history about prior medication trials in both the patient and family members.
While there is limited empiric data on safety, tolerability and efficacy of various antidepressants in combination, clinicians in practice will commonly combine two antidepressants with two different pharmacologic mechanisms. An SSRI and Buproprion, SSRI and Mirtazapine or an SSRI and TCA are common combinations in clinical practice. Additionally, several non-antidepressant medications have empiric evidence of varying quality for their efficacy as add on medications in partially treatment responsive depression. Common examples include psychostimalants such as Modafanil and Methylphenidate, T3, Lithium and more recently ‘second generation’ antipsychotics, such as abilify, risperidone or seroquel, also frequently called ‘atypical’ antipsychotics as a class.
The choice of a second, adjuvant medication should carefully consider both residual symptoms that are present, medical co-morbidities and side effects. For example, patients with residual fatigue or a history of attention deficit disorder may respond to a psycho stimulant or T3, with neuropathic pain a tricylclic antidepressant and with co-morbid psychotic, obsessive compulsive or manic symptoms an atypical antipsychotic. In some cases, a hypnotic may be added for residual insomnia or a benzodiazepine for residual anxiety.
Finally, non pharmacologic considerations that attempt to mitigate precipitating psychosocial stressors should also be incorporated into treatment, particularly so in treatment non-responders. Common precipitators of depression include losses such as of finances, housing, employment, a relationship or health. Referral for brief, time limited psychotherapy and/or concrete social work services to address these problems should be considered. Finally, patients who meet criteria for personality disorders or have personality disorder traits in subsyndromal form, particularly borderline or narcissistic personalities, may suffer from chronic mood instability, anxiety, sadness or feelings of emptiness. Such personality characteristics are generally felt to be less responsive to antidepressant medications than new onset time limited depressive symptoms that occur in a patient with an otherwise baseline stable mood and good coping skills. Furthermore, patients with personality disorders frequently have unstable family or social relationships making referral for adjunctive psychotherapy an important part of their overall treatment.
For further reading, please see:
STAR*D: The Results Begin to Roll in
Am J Psychiatry 2006 163: 1123
A. John Rush
STAR*D: What Have We Learned?
Am J Psychiatry, Feb 2007; 164: 201 – 204.
Image coutesy of Ehrman Medical Library, Bellevue Hospital, A view of the hospital from the East River, in 1879