Approach to a Patient with ‘Treatment Refractory’ Depression in The Medical Setting: Part 2

May 29, 2008

bellevue.jpgCommentary 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.

Part II

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:

Menza, Matthew
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

2 comments on “Approach to a Patient with ‘Treatment Refractory’ Depression in The Medical Setting: Part 2

  • Avatar of Dan
    Dan on

    Current Depression Medications: Do The Benefits Outweigh the Harm?

    Presently, for the treatment of depression and other what some claim are mental disorders, as they are questionable, selective serotonin reuptake inhibitors are the drugs of choice by most prescribers. Such meds, meds that affect the mind, are called psychotropic medications. SSRIs also include a few meds in this class with the addition of a norepinephrine uptake inhibitor added to the SSRI, and these are referred to SNRI medications. Examples of SNRIs are Cymbalta and Effexor. Some consider these classes of meds a next generation after benzodiazepines, as there are similarities regarding their intake by others, yet the mechanisms of action are clearly different, but not their continued use and popularity by others.
    Some Definitions:
    Serotonin is a neurotransmitter thought to be associated with mood. The hypothesis was first suggested in the mid 1960s that this neurotransmitter may play a role in moods and emotions in humans. Yet to this day, the serotonin correlation with such behavioral and mental conditions is only theoretical. In fact, the psychiatrist’s bible, which is the DSM, states that the definite etiology of depression remains a mystery and is unknown. So a chemical imbalance in the brain is not proven to be the cause of mood disorders, it is only suspected with limited scientific evidence. In fact, diagnosing diseases such as depression is based on subjective assessment only, as interpreted by the prescriber, so one could question the accuracy of such diagnoses.
    Norepinephrine is a stress hormone, which many believe help those who have such mood disorders as depression. Basically, with the theory that by adding this hormone, the SSRI will be more efficacious for a patient prescribed such a med.
    And depression is only one of those mood disorders that may exist, yet possibly the most devastating one. An accurate diagnosis of these mood conditions lack complete accuracy, as they can only be defined conceptually, so the diagnosis is dependent on subjective criteria, such as questionnaires. There is no objective diagnostic testing for depression. Yet the diagnosis of depression in patients has increased quite a bit over the decades. Also, few would argue that depression does not exist in other people. Yet, one may contemplate, actually how many other people are really depressed?
    Several decades ago, less than 1 percent of the U.S. populations were thought to have depression. Today, it is believed that about 10 percent of the populations have depression at some time in their lives. Why this great increase in the growth of this condition remains unknown and is subject to speculation. What is known is that the psychiatry specialty is the one specialty most paid to by certain pharmaceutical companies for ultimately and eventual support of their psychotropic meds, as this industry clearly desires market growth of these products. Regardless, SSRIs and SRNIs are the preferred treatment methods if depression or other mood disorders are suspected by a health care provider. Yet these meds discussed clearly are not the only treatments, medicinally or otherwise, for depression and other related disease states.
    Over 30 million scripts of these types of meds are written annually, and the franchise is around 20 billion dollars a year, with some of the meds costing over 3 dollars per tablet. There are about ten different SSRI/SRNI meds available, many of which are now generic, yet essentially, they appear to be similar in regards to their efficacy and adverse events. The newest one, a SNRI called Pristiq, was approved in 2008, and is believed to being promoted for treatment for menopause. The first one of these SSRI meds was Prozac, which was available in 1988, and the drug was greatly praised for its ability to transform the lives of those who consumed this medication in the years that followed. Some termed Prozac, ‘the happy pill’. In addition, as the years went by and more drugs in this class became available, Prozac was the one of preference for many doctors for children. A favorable book was published specifically regarding this medication soon after it became so popular with others.
    Furthermore, these meds have received additional indications besides depression for some really questionable conditions, such as social phobia and premenstrual syndrome. With the latter, I find it hard to believe that a natural female experience can be considered a treatable disease. Social phobia is a personality trait, in my opinion, which has been called shyness or perhaps a term coined by Dr. Carl Jung, which is introversion, so this probably should not be labeled a treatable disease as well. There are other indications for certain behavioral manifestations as well with the different SSRIs or SRNIs. So the market continues to grow with these meds. Yet, it is believed that these meds are effective in only about half of those who take them, so they are not going to be beneficial for those suspected of having certain medical illnesses treated by such meds. The makers of such meds seemed to have created such conditions besides depression for additional utilization of these types of medications, and are active and have been active in forming symbiotic relationships with related disease- specific support groups, such as providing financial support for screenings for the indicated conditions of their meds- screening of children and adolescents in particular, I understand, and as a layperson, I consider such activities dangerous and inappropriate for several reasons.
    Danger and concerns by others primarily involves the adverse effects associated with these types of meds, which include suicidal thoughts and actions, violence, including acts of homicide, and aggression, among others, and the makers of such drugs are suspected to have known about these effects and did not share them with the public in a timely and critical manner. While most SSRIs and SNRIs are approved for use in adults only, prescribing these meds to children and adolescents has drawn the most attention and debate with others, such as those in the medical profession as well as citizen watchdog groups. The reasons for this attention are due to the potential off-label use of these meds in this population, yet what may be most shocking is the fact that some of the makers of these meds did not release clinical study information about the risks of suicide as well as the other adverse events related to such populations, including the decreased efficacy of SSRIs in general, which is believed to be less than 10 percent more effective than a placebo. Paxil caught the attention of the government regarding this issue of data suppression some time ago, this hiding such important information- Elliot Spitzer specifically, as I recall.
    And there are very serious questions about the use of SSRIs in children and adolescents regarding the effects of these meds on them. For example, do the SSRIs correct or create brain states considered not within normal limits, which in effect could cause harm rather than benefit? Are adolescents really depressed, or just experiencing what was once considered normal teenage angst? Do SSRIs have an effect on the brain development and their identity of such young people? Do adolescents in particular become dangerous or bizarre due to SSRIs interfering with the myelination occurring in their still developing brains? No one seems to know the correct answer to such questions, yet the danger associated with the use of SSRIs does in fact exist. It is observed in some who take such meds, but not all who take these meds. Yet health care providers possibly should be much more aware of these possibilities
    Finally, if SSRIs are discontinued, immediately in particular instead of a gradual discontinuation, withdrawals are believed to be quite brutal, and may be a catalyst for suicide in itself, as not only are these meds habit forming, but discontinuing these meds, I understand, leaves the brain in a state of neurochemical instability, as the neurons are recalibrating upon discontinuation of the SSRI that altered the brain of the consumer of this type of med. This occurs to some degree with any psychotropic med, yet the withdrawals can reach a state of danger for the victim in some classes of meds such as SSRIs, it is believed.
    SSRIs and SRNIs have been claimed by doctors and patients to be extremely beneficial for the patient’s well -being regarding the patient’s mental issues where these types of meds are used, yet the risk factors associated with this class of medications may outweigh any perceived benefit for the patient taking such a drug. Considering the lack of efficacy that has been demonstrated objectively, along with the deadly adverse events with these meds only recently brought to the attention of others, other treatment options should probably be considered, but that is up to the discretion of the prescriber.
    “I use to care, but now I take a pill for that.” — Author unknown
    Dan Abshear

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