Treatment Failure

INTRODUCTION

Appropriate antidepressant therapy on average results in symptomatic improvement in up to 70 percent of compliant patients. In a considerable portion of initial non-responders, a variety of strategies will eventually lead to resolution of symptoms as well.

These strategies include:

1. Optimization of initial drug therapy
2. Augmentation of one anti-depressant drug with a second, non-antidepressant agent
3. Substitution of one antidepressant drug with another anti-depressant drug
4. The combination of two antidepressant drugs

Each of these strategies has a place in the treatment of depression which does not respond to an appropriate antidepressant regimen. By systematically considering each of the various strategies for individual patients, general practitioners should be better able to match individual patients with the best alternative, and improve the likelihood of a successful therapeutic outcome.

OPTIMIZATION

Optimization of antidepressant drug therapy is not a trivial strategy as it requires an understanding of the antidepressant being used, as well as individual patient response. The definition of adequate dosage depends on which antidepressant drug is chosen. Moreover, if an effort to optimize therapy is not made, treatment is not likely to be successful. In essence, there are four aspects to optimization. The first is to make sure that patients are given adequate doses of the selected antidepressant agent.

The second is that treatment must continue for a long enough period of time to achieve a complete antidepressant effect.

However, in general, it is important to keep in mind that some patients may not tolerate recommended dosages, at least initially. For these individuals - unfortunately not yet identifiable - it may be necessary to introduce the agent more slowly, and escalate the dose gradually over a period of several weeks to improve both intolerance and compliance.

Lower than recommended dosing is particularly important in the elderly, in whom approximately 50 percent of the recommended starting dose is reasonable on initiation of therapy. Although attempts should be made to increase to standard doses, some patients may also remain on lower than recommended dosage for the remainder of the treatment regimen.

Lower than recommended initial doses should also be used when introducing antidepressant therapy in young patients; patients with concurrent medical problems, especially when hepatic, cardiac or neurologic in nature, and those on concomitant medication such as digoxin and coumadin. Clinicians may safely begin to titrate starting doses up to, if necessary, the maximum recommended dosage for that particular antidepressant agent after an appropriate interlude, depending on the half-life of the drug.

In terms of an adequate therapeutic trial, literature reports confirm that patients require a minimum of five to eight weeks of treatment before any antidepressant agent achieves an appreciable therapeutic effect. This is independent of the half-life of the agent used; at present, there is no evidence that antidepressants with a longer half-life take longer to have an antidepressant effect than those with a shorter half-life, although clearly a longer half-life permits less frequent dosing.

It is, of course, a truism that clinicians can't expect patients to improve if they fail to take their medication. Importantly, studies of compliance in different patient populations suggest that as many as one-third of patients receiving antidepressant medication are not going to take enough of the medication to have any appreciable therapeutic effect; another third will be "hit and miss" with their dosing, with only one-third of the treatment population taking the regimen more or less as prescribed.

Third, to ensure better patient compliance, optimization thus should also include monitoring of blood levels where possible. Currently, blood levels are available for the tricyclic (plasma/tricyclic level) antidepressants (TCAs) such that clinicians may verify that a patient has achieved therapeutic blood levels. (This is particularly useful for nortriptyline which has a narrow "therapeutic window", above which response rates decline).

In certain research settings, blood levels are also available for the SSRIs; however, they are not useful in helping assess the therapeutic effects of an SSRI. Similarly, while percentage inhibition is associated with response in the setting of the MAOIs, it is a complicated equation, and blood levels do not directly reflect the therapeutic response to a MAOI either. If patients still do not respond adequately to medication and remain symptomatic after an adequate therapeutic trial of 6 to 8 weeks, consideration should be given to one of the remaining strategies for improved antidepressant response, namely, substitution, augmentation or combination antidepressant therapy.

In contrast to somewhat outdated notions, agitated and retarded depression do not require different antidepressant drugs: each respond equally well to the same antidepressant therapy, regardless of the specific symptom complex. Likewise, no difference has been shown in treatment response in patients whose depression is associated with a precipitant versus depression without an associated precipitant. Finally, atypical depression, defined by less frequent constellation of increased appetite and weight, along with increased sleep, responds better to the MAOIs and the SSRIs than to TCAs.

Summary of Optimization

Optimization is the first strategy to be used when patients do not achieve a satisfactory antidepressant response to initial treatment. This consists of:

1. Ensuring the dose used is adequate (either adequately high or adequately low)
2. Ensuring the treatment course has been long enough for the antidepressant to take effect
3. Ensuring patients achieve therapeutic blood levels, where appropriate
4. Ensuring the antidepressant chosen is as specific as possible for the type of depression being treated

If all four elements have been adequately addressed, and response is still unsatisfactory, other strategies should be initiated until such time as patients do achieve a therapeutic response.

continue : antidepressant augmentation

This paper was developed and written by Dr. Russell Joffe, Dr. Anthony Levitt, Dr. Stephen Sokolov, and Dr. L. Trevor Young while they were on staff at the Mood Disorders Program, Department of Psychiatry and Behavioural Neurosciences, McMaster University.The paper was supported by an educational grant from Eli Lilly Canada Inc.

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Reviewed: 02/2006