Abstract
Major Depressive Disorder (MDD) is a common clinical condition encountered in primary care practices. Left untreated or, more commonly, undertreated, MDD typically results in significant distress and dysfunction. Successful treatment of MDD, usually defined as achieving sustained remission, is an attainable goal. As such, sustained remission should be the goal sought by physicians and patients. A number of variables have an impact on the likelihood of achieving and sustaining remission including the length of the depressive episode, the completeness of the response to treatment, and whether remission is achieved relatively early in treatment. The selection of pharmacotherapeutic agents and the relative probability of achieving remission has only recently been investigated in outpatient populations, though this issue has been explored in inpatient studies for more than a decade.
This article reviews these variables and presents strategies with the goal of achieving remission for patients with MDD. The importance of both pharmacotherapy, where indicated, as well as psychotherapy is discussed. Finally, remission is presented as a necessary first step to ensure an optimal long-term outcome, rather than as the final goal of treatment.
Major depressive disorder (MDD) is a common clinical entity in primary care practices, and nonpsychiatric physicians write most antidepressant prescriptions in the United States. Despite the widespread nature of MDD, results of studies continue to suggest that most individuals with this disorder do not receive adequate treatment. This article focuses on key points that represent the intersection between clinical practice and clinical research. For the purposes of this article, these points have been distilled to four key perspectives that are listed in
Figure 1.
The following observations will strike the seasoned practitioner as clinically intuitive, but it is worthwhile to examine the data that support these observations. The first, as presented in
Figure 1, that remission is a superior outcome compared with response, has been explored from different perspectives. Before this article examines studies that use traditional outcome measures for MDD (eg, Hamilton Depression Rating Scale,
1 Montgomery–Asberg Depression Rating Scale
2), it may be useful to consider a measure that more closely reflects the desired outcome from the patient's perspective, that is, quality of life.
Remission as the Goal
The Social Adjustment Scale measures quality of life and is constructed such that a lower score equates to a better quality-of-life measure. Miller et al
3 reported on the quality of life attained by patients with MDD as a result of treatment with antidepressants. The Social Adjustment Scale scores of those who achieved a response (n=122) did not differ from those who were classified as nonresponders (n=299).
Compared with the scores of responders and nonresponders, participants who achieved remission (n=202) had a significantly greater improvement in their Social Adjustment Scale scores and had scores that did not differ significantly from a healthy control group (n=482). Quality of life from the patient's perspective often encompasses more complex behavioral symptoms than those typically measured in traditional rating scales and includes perceptions of enthusiasm, interpersonal relatedness, and job and school performance.
The Question of Relapse
Another area of concern among patients with MDD at the onset of treatment is whether the treatment will continue to be effective. In an observational study, Paykel et al
4 demonstrated that an outcome of remission leads to a markedly lower relapse rate than does an outcome of response. In this study, patients with MDD received either antidepressants or the combination of antidepressants and psychotherapy. The study's endpoint was 15 months or relapse of the depressive episode.
Participants who achieved response had an approximate 75% relapse rate, compared with an approximate 25% relapse rate among participants who achieved remission. Further, of the participants in the response group who relapsed, more than half did so within the first 6 months of the study. This finding suggests that treating to remission, rather than settling for response can be a major variable in the long-term success of treatment.
Early Remission and Relapse
The second observation presented in
Figure 1 is that early remission predicts long-term success in treatment. Simon et al
5 followed up patients with treated MDD. The researchers calculated the risk of subsequent relapse or recurrence during the following 24 months based on outcome at 3 months. The group that achieved a response to treatment by the third month was nearly three times more likely to have a relapse or recurrence than the group that was treated to remission by the third month. Although data in the study by Paykel et al and the study by Simon et al differ, each data set demonstrates the common ratio of a near tripling of the risk for the next depressive episode in patients who did not reach remission.
Duration of Episode a Factor in Outcome
Clinicians would likely agree that patients with shorter episodes of MDD are easier to treat than patients with longer episodes; a patient who has a 3-month duration of untreated MDD is usually easier to treat than a patient with a 3-year history of untreated MDD. Data suggest that response rates are higher in patients with MDD whose depressive episodes are of shorter duration. Significantly fewer data are available regarding the more clinically relevant outcome of remission.
Kelsey and Entsuah
6 explored this question in a large database of comparative antidepressant studies. Patients were categorized into groups in which either the duration of the current depressive episode was equal to or less than 52 weeks or the duration of the current depressive episode was greater than 1 year.
In an analysis using last observation carried forward, researchers calculated remission rates after 8 weeks of treatment with placebo, selective serotonin reuptake inhibitors (SSRIs) (eg, fluoxetine hydrochloride, fluvoxamine maleate, paroxetine hydrochloride) or serotoninnorepinephrine reuptake inhibitors (SNRI) (eg, venlafaxine hydrochloride, venlafaxine hydrochloride extended release).
6
The first of the two most clinically relevant observations from this study is that independent of treatment, longer episodes of depression are associated with lower remission rates. The second relevant obsrvation is that independent of the duration of the depressive episode, antidepressants that target more than one neurotransmitter are associated with higher remission rates.
6
Pharmacologic Approaches
Observations from the current study,
6 as well as those from studies that examine the consequences of untreated MDD,
7,8 suggest that longer episodes of depression are more challenging to treat. Further, longer episodes result in exposing patients to more negative consequences. How then might physicians translate these observations into clinical practice?
There appear to be at least two approaches to the treatment of patients with MDD (
Figure 2). The first approach is one that could be labeled
risk averse, though, in fact, this label would be an inaccurate characterization. This approach requires waiting for an appropriate therapeutic response and therefore confers greater risk to the patient by implementing a potentially subtherapeutic treatment algorithm. The goals of this approach, however, seem to minimize
adverse effects.
The alternative approach is to recognize MDD for the serious illness that it is and to be appropriately vigorous in treating the patient for MDD and related adverse effects. Part of the difficulty of this approach is determining the appropriate risk-benefit analysis in regard to adverse effects. The analysis should not be based on a comparison of the adverse effects of treatment with an absence of adverse effects when no treatment is administered. Rather, the analysis should be based on a comparison of the treatment-associated adverse effects with the consequences of the untreated or partially treated disease state.
Pharmacotherapy for Achieving Goal of Remission
One of the challenges in treating patients with MDD is to keep the ultimate goal of treatment in mind. The goal of treatment is neither to reduce symptoms, nor is it to increase productivity in the workplace. The goal is to return the patient to a state of euthymia, achieving remission rather than response. From a patient's perspective, this would be described as getting well, rather than settling for getting better.
Complicating the task of treating patients with MDD to remission is that no laboratory assay currently is available that will identify which neurochemical intervention is most likely to be successful. This lack has been exacerbated by the fact that during the past 5 decades, antidepressants with differing mechanisms of action have been introduced.
In the early history of modern pharmacotherapy for MDD, monoamine oxidase inhibitors (MAOIs) effectively served (and continue to serve) as a classic example of a broad-spectrum antidepressant. The MAOIs involve the noradrenergic, serotonergic, and dopaminergic systems. The MAOIs, however, are not without potential complications (eg, risk of tyramine-containing foods producing a hypertensive crisis, potential drug-drug interactions).
Tricyclic antidepressants (TCAs), tending to be more noradrenergic (except for clomipramine), were introduced at approximately the same time as MAOIs. Although the safety and tolerability profile of TCAs was better than that of MAOIs, TCAs were not the easiest medications to prescribe; therefore, the introduction of fluoxetine in the late 1980s was a revolution in the pharmacotherapeutic treatment of patients with MDD.
Although SSRIs do not have greater efficacy than MAOIs or TCAs, the safety and adverse effect profiles of SSRIs are a major improvement over those two earlier classes of antidepressants. Other antidepressants include bupropion hydrochloride, which is believed to be both noradrenergic and dopaminergic in its mechanism of action; mirtazapine, a dual-acting agent via receptor antagonism; and venlafaxine, an SNRI. Finally, duloxetine hydrochloride, another SNRI, has recently received approval by the US Food and Drug Administration for the treatment of patients with depression.
Essentially then, treatment of patients for MDD has come full circle in that contemporary pharmacotherapy began with the introduction of broad-spectrum antidepressants (eg, MAOIs, clomipramine hydrochloride), moved to selective drugs (eg, TCAs, SSRIs), and is now returning to broad-spectrum medications (eg, mirtazapine, venlafaxine, duloxetine). The introduction of peptidergic-acting drugs (ie, corticotropin-receptor antagonists) is still several years in the future.
Given the current trend toward increased use of broad-spectrum antidepressants, one might reasonably ask whether data exist to support their use. To a certain extent, the answer depends on where in the literature one poses this question. Outpatient studies that have response as their endpoint, do not, in general, differentiate between antidepressant treatment modalities. However, dual-acting agents seem to convey advantages over selective-acting agents in inpatient studies.
9
Finally, in inpatient studies that use the more clinically relevant measure of remission as outcome, dual-acting agents seem to confer an advantage. Examples of two studies that compared an SSRI and a dual-acting TCA were conducted by the Danish University Antidepressant Group in Copenhagen.
10,11 In the first, researchers compared clomipramine (a dual-acting TCA) with paroxetine (an SSRI) in inpatients with MDD.
10 The group treated with clomipramine had a higher rate of remission than the group treated with the SSRI. Researchers in the second study compared an SNRI (clomipramine) with an SSRI (citalopram) in a population of inpatients with MDD.
11 There were equal numbers of nonresponders in both groups, more responders (termed partial remission in the study) were observed in the SSRI-treated group, and a higher percentage of patients treated with the SNRI achieved remission, compared with the SSRI-treated group.
Although these Danish studies were individual trials, developing a pooled analysis of data is often of great benefit. Two such pooled analyses compared SNRIs with SSRIs. The smaller analysis (six studies) compared patients with MDD treated with duloxetine with patients with MDD treated with placebo, fluoxetine, and paroxetine.
12 When patients with a Hamilton Depression Scale score of greater than or equal to 19 (n=approximately 960) were included in the post hoc analysis, the SNRI-treated group had a higher remission rate after 8 weeks of treatment than the SSRI-treated group. The SSRI-treated group, however, had a higher remission rate than that of participants who received placebo.
A second larger pooled analysis included 32 studies (n=7549) that compared venlafaxine or venlafaxine extended release to either citalopram, fluoxetine, fluvoxamine, paroxetine, sertraline, or placebo.
12 This pooled analysis found that higher remission rates were achieved with SNRI treatment than with SSRI treatment. Also rates of remission were higher after 8 weeks of therapy achieved with SSRI treatment, compared with placebo.
The results of these pooled analyses support and extend earlier observations based on single trials of clomipramine compared with SSRIs.
10,11 The advantage to using pooled analyses is that sample sizes become large enough to minimize the chance of incorrectly identifying no difference between two effective treatment approaches.
Dual Activation
Evidence suggests that the simultaneous activation of more than one neurotransmitter system may offer an advantage in treating patients with MDD.
Figure 3 shows different ways to achieve dual activation. Monotherapy strategies include the use of MAOIs, TCAs that have appreciable serotonin reuptake inhibition, mirtazapine, venlafaxine, and duloxetine. Combination therapy is also commonly used, primarily by adding bupropion, TCAs, stimulants, or mirtazapine to an SSRI or an SNRI. One must be aware of the potential for drugdrug interactions between many of the SSRIs, bupropion, and TCAs via inhibition of the cytochrome P450 isoenzyme system, specifically the 2D6 isoenzyme. Elevations in TCA serum levels can be considerable, having the potential for associated adverse effects and cardiac toxicity. A prudent approach is to obtain a baseline electrocardiogram before the initiation of TCA therapy, and when such therapy is given as part of a combination strategy, monitor serum TCA levels.
The decision between the use of monotherapy versus combination therapy is based on a number of factors as outlined in the
Table. Quite often, the history and degree of success that previous modes of therapy have achieved will play an important role in this process. In general, the simpler the approach, the greater the degree of patient adherence with the prescribed therapy.
Table
Potential Benefits of Monotherapy and Combination Therapy in the Treatment of Patients With Major Depressive Disorder
| Monotherapy | Combination Therapy |
|---|
| Simpler | Sometimes more effective |
| Less expensive | Greater spectrum of neurotransmitter activation |
| Fewer drug-drug interactions | Addresses comorbid illnesses |
| Fewer adverse effects | |
| Potential to address | |
| comorbid illness | |
Table
Potential Benefits of Monotherapy and Combination Therapy in the Treatment of Patients With Major Depressive Disorder
| Monotherapy | Combination Therapy |
|---|
| Simpler | Sometimes more effective |
| Less expensive | Greater spectrum of neurotransmitter activation |
| Fewer drug-drug interactions | Addresses comorbid illnesses |
| Fewer adverse effects | |
| Potential to address | |
| comorbid illness | |
×
Considerations in Planning Treatment
The integration of the foregoing information into a treatment plan can be relatively straightforward.
Figure 4 outlines one approach that is similar to the approach used in most disease states. The first step is to decide the diagnosis to ensure that physicians know what they are treating. For patients with MDD, physicians need to distinguish the condition from an episode of bipolar affective disorder, a comorbid anxiety disorder, or a substance abuse disorder. A medical basis for the depression (eg, hypothyroidism) nust also be ruled out. Once the diagnosis is established, treatment can be initiated.
In selecting an appropriate first-choice antidepressant, physicians should consider the following questions: Is there a history of remission with antidepressant treatment? Have biologic relatives responded to a particular mode of treatment? What is the mechanism of action and long-term tolerability of the antidepressant? What is the probability of achieving remission with a given antidepressant based on clinical trials and clinical experience? What is the potential for drug-drug interactions?
After treatment is begun, physicians must assess outcome at the appropriate time (typically between 4 and 8 weeks). The goal is to obtain remission. If treatment is successful in obtaining remission, then it should continue as indicated.
When remission is not obtained, physicians should consider adjusting the dose, switching to a different antidepressant (from a different class), or adding a second agent. Decisions about treatment at this juncture depend on degree of improvement, number of treatment trials attempted, and patient preference. When these adjustments are not successful, it may be more productive to focus on neurotransmitter interventions that have proved to be successful in treating patients with depression (ie, norepinephrine, serotonin, dopamine).
Psychotherapy remains an effective treatment modality for some patients. The combination of psychotherapy with pharmacotherapy may be more effective than either modality alone for those with chronic depression (duration > 2 years). For patients with MDD who are difficult to treat, a final tool is a diagnostic reevaluation to ensure that something is not being overlooked.
Comment
To summarize, major depressive disorder is a treatable illness that must be looked for and treated vigorously. Treatment should proceed in an orderly fashion, but physicians and patients must not lose sight of the goal of treatment: To return patients to a state of euthymia by achieving and sustaining remission.
When treatment is not proceeding as anticipated, it is helpful to focus on the theorized pathophysiology of the disease, consider the neurotransmitter systems acted on by current medications (eg, norepinephrine, serotonin, dopamine); consider psychotherapy as a treatment strategy; and finally, reevaluate to confirm the diagnosis for which patients are being treated.
This article was developed from a lecture presented by Dr Kelsey at a symposium sponsored by Wyeth Pharamaceuticals at the 108th Annual AOA Convention and Scientific Seminars in New Orleans, La, on October 15, 2003.
Dr Kelsey is a member of the speakers bureaus of Abbott Laboratories; Bristol-Myers Squibb; Forest Pharmaceuticals, Inc; Glaxo SmithKline, Pfizer Inc; Pharmacia & Upjohn; Solvay Pharmaceuticals, Inc; and Wyeth Pharmaceuticals. He has also received research support from those companies as well as from Cyberonics; Eli Lilly and Company; Merck & Co, Inc; Mitsubishi Pharma Corporation; Organon; and Sanofi-Synthelabo Inc. In addition, he is a consultant for Bristol-Myers Squibb; Eli Lilly and Company; Janssen Pharmaceutica Products, LP; Skila, Inc; and Wyeth Pharmaceuticals.
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