Augmentation and Combination Pharmacotherapy Trends

INTRODUCTION

Depression is a socially debilitating illness, sometimes lifelong, that afflicts the U.S. population with an estimated lifetime risk of 16%. Unfortunately, only a third of depressed patients are receiving any form of treatment, and among the ones who are, only one half to two thirds ever achieve a full response to therapy.

Treatment-resistant depression, unfortunately, is quite common in clinical practice, and the failure to achieve an adequate response in 50% to 60% of patients after at least one trial of an antidepressant of sufficient dose and duration also seems to be commonplace. In order to improve therapeutic effectiveness of monotherapy with the ultimate aim of achieving and maintaining remission, additional methods are often employed in clinical psychopharmacology, including augmentation and combination therapies.

Monotherapy Approach

Before we discuss these practices, we will summarize the usual monotherapy practices. To date, there are no discrete national guidelines to delineate the stepwise treatment of resistant depression, although many local and regional practices are followed. Available treatment guidelines for depression from various geographical regions and organizations usually assume that a patient is antidepressant-naive and is starting out without prior intervention. We will discuss the usual stepwise approach for depression treatment with this in mind. Actually, many patients do have pre-existing depression and may already be receiving treatment when they are first seen in the office. This scenario may be considered to be an initially treatment-resistant state.

First-Line Therapy

The term “first-line” may have multiple meanings. One definition suggests that an antidepressant agent should be used first because of its clinical efficacy, its safety, or both. Most often, effectiveness is comparable between first-line and second-line drugs, but safety is improved with the first-line agents. In rare instances, a second-line drug may have better efficacy but may be associated with too many adverse effects to warrant a first-line use.

The second definition of a first-line drug, which we do not use in this article, is usually dictated by managed care insurance agencies when they declare an agent to be “first-line.” This definition is often based on a third variable, cost.

Since the 1980s, the selective serotonin reuptake inhibitors (SSRIs), including drug fluoxetine (Prozac canadian, Eli Lilly) generic sertraline (Zoloft tablet, Pfizer), (GlaxoSmithKline), citalopram hydro-bromide (Forest), and oxalate (Forest), have become first-line medications because they are safer than the older tricyclic antidepressants (TCAs). The Food and Drug Administration (FDA) suggests that the TCAs and SSRIs are comparable in efficacy, based on usual approval standards, which evaluate each drug’s ability to lower the severity of depression by 50% or better (a “response”). However, more clinical evidence-based data have suggested that TCAs are more effective in promoting a “remission” of symptoms (more than 70% improvement).

Second-Line Therapy

It has been postulated that either the tricyclic molecule is superior to SSRIs or, more likely, that the TCAs often elevate levels of norepinephrine plus serotonin—which itself may be a polypharmacy approach. If the SSRIs fail to relieve depression, the patient is usually switched to a “second-line” agent. These medications are often the selective serotonin-norepinephrine reuptake inhibitors (SNRIs), such as (canadian Effexor, Wyeth) and duloxetine tablet (medication Cymbalta, Eli Lilly) or a norepinephrine-dopamine reuptake inhibitor (NDRI), such as (Wellbutrin canadian, GlaxoSmithKline).

The idea is to switch from a serotonin-only agent to a new class of drugs that manipulates a different set of neurotransmitters. On the other hand, it may still be common practice to switch from one SSRI to another, because of individual variability in responses to the different SSRIs. It is possible that it is just the added duration of serotonin manipulation that produces efficacy instead of the perceived variability among the SSRIs, all of which have the same mechanism of action.

Third-Line Therapy

“Third-line” antidepressants may include the TCAs, monoamine oxidase inhibitors (MAOIs), or combinations of the aforementioned drugs. Third-line drugs are considered to be associated with an increased risk because of their adverse event profile. In clinical practice, it appears that primary care physicians often use this stepwise approach, and psychiatrists more often start with second-line agents or combine agents more quickly than in the third step noted here. Again, the idea is to manipulate multiple neurotransmitters for better efficacy.

Combination/Augmentation Therapy

Combination/augmentation approaches in major depression often appear to have clinical benefits; however, there are some factors to consider before one takes this step.

First of all, every drug has adverse effects, and the addition of multiple agents may result in even more of a side-effect burden. As the number of drugs taken increases, patient adherence and compliance often decrease. There is evidence that depressed patients who stop their medications too quickly relapse into depression more often. Sometimes augmentation/combination strategies allow a “win-win” situation when the two agents improve efficacy and decrease each other’s side effects. An example might include the addition of bupropion to an SSRI. Bupropion may add effectiveness and symptom relief and, at the same time, may reduce weight gain and sexual dysfunction induced by the original SSRI that was used.

Cost may become important as the number of medications used increases. Polypharmacy generally costs patients and society more money. Drug prices per patient increase, as does the use of health care resources to manage these complex regimens and their potential side effects. Many health care insurance agencies take issue with polypharmacy practices, because there are often almost no randomized trials of significant power to prove that complex regimens work. Even though many clinicians use combination/augmentation approaches in psychiatry and other medical areas, subjective reports and small and lower-powered studies do not usually carry weight in most health plans.

Augmentation of initial monotherapy refers to the addition of a non-FDA-approved (“off-label”) agent with counterdepres-sive qualities, whereas combination therapy consists of the addi tion of a second FDA-approved antidepressant. The use of multiple agents with different variations inherent in individual psychiatric practice has led to combinations and augmentations being the perceived and probable standard of care. The variability among individual psychiatrists in terms of their prescribing habits in managing major depression is still unmeasured; hence, conclusive data regarding the impact on achieving and maintaining remission cannot be adequately determined.

One current trend in the marketplace is a demand for the development of new drugs that can embody “polypharmacy in a single pill.” Preliminary reports and abstracts suggest that the newest wave of antidepressants may be the “triple reuptake inhibitors”—single drugs with the ability to elevate serotonin, norepinephrine, and dopamine levels simultaneously (PR Newswire, June 27, 2005). Currently, a physician would have to combine two or three drugs to achieve this effect in a patient.

Bristol-Myers Squibb gained FDA approval for the selegiline (Emsam) MAOI patch, and at higher doses, all three mono-amines would be simultaneously elevated via MAO inhibition for the treatment of depression.

In order to determine the prevailing strategies in combination/augmentation therapy for Major Depressive Disorder (MDD), given the ambiguity and variability of evidence-based medicine in this area, we surveyed a group of international psychiatrists. We did not study the outcomes of their practices because of the sample of convenience method applied.

Category: Disease

Tags: antidepressants, augmentation, combination, depression