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David Baxter

Mar 26, 2004
Augmentation Strategies in the Management of Treatment-Refractory Depression
by Michael E. Thase, MD

Augmentation strategies for treatment-refractory depression should be pursued when initial choice of treatment has not been effective, it appears that that treatment has been given for a sufficient duration at the maximum tolerated and usually effective dose, and a change is needed.

Generally, a choice is made between a switching strategy and an augmentation strategy, with patients who've shown some benefit on the initial treatment more likely to be augmented, and those who either could not tolerate, or who got little, if no benefit from the initial treatment, often switched. In general we are looking at augmentation strategies for people who have demonstrated some benefit and good tolerability to a mainstream antidepressant.

Another distinction of importance is whether the designation 'augmentation' only refers to medications with secondary effects, or whether the use of an additional antidepressant qualifies as augmentation as well. The field has fair consensus that the term 'combination therapy' should apply only to the use of 2 antidepressants with known active effects, while the term 'augmentation therapy' implies the use of another medication not established as a primary antidepressant to enhance the effects of the first medication.

I favor augmentation strategies that have the best evidence or seem the most useful for particular residual symptoms. Among the various augmentation strategies, augmenting an antidepressant with lithium has the surest evidence of effectiveness, and controlled studies have demonstrated this beyond the shadow of a doubt. Now, who is this strategy best for? Most likely lithium augmentation is best for patients whose depression is within the bipolar spectrum, as well as patients with relatively more severe depression. The drawbacks of lithium augmentation include the need for blood work, as well as the potential for long-term side effects if treatment turns out to be effective. Also, in the short-term, things such as unpleasant taste, excessive urination, tremor, and other lithium side effects may occur. In terms of more recent augmentation strategies, there is evidence that the alerting medication modafinil is useful in patients with persistent fatigue and sleepiness. We participated in several double-blind studies that demonstrated this finding, so when the patient has responded but has significant residual sedation, sleepiness, fatigue, and hypersomnolence, I believe this to be a very reasonable strategy.

On the other hand, for patients who have fairly severe persistent symptoms, the best studied newer treatment strategy is to augment with an atypical antipsychotic. Again, the severity and intensity of the illness need to be such to justify the use of this major class of medications. We will talk a bit more later about the potential for side effects with this strategy.

Some of the other time-tested augmentation strategies include the anti-anxiety medications, including buspirone, which has had the advantage of not having any potential for dependence or abuse. Various kinds of thyroid hormone are also used, with most of the work having been done with triiodothyronine (T3), partly because T3 is the active form of thyroid hormone in the brain. I prefer the thyroid hormone augmentation strategy for patients who show some indication of impaired thyroid function, for example, a borderline elevated thyroid-stimulating hormone level. I prefer buspirone or other anxiolytic medications for patients who have significant persistent anxiety, and if significant insomnia is an issue, a sedative hypnotic medication can be used as a type of augmentation therapy.

Returning to atypical antipsychotics, these agents are by and large still all patent-protected medications, and as treatments for depression go, they are relatively expensive. In addition to simply the cost of buying the medicine, these treatments can be costly in terms of side effect burden. They are not treatments to be used lightly. Nevertheless, depression is not a condition to be taken lightly, and nonresponse to standard antidepressant medications really does serve as a potential warning that a patient may show continued impairment and difficulties in their day to day life. In this case, I believe that augmentation with an atypical antipsychotic is a reasonable treatment strategy. I select within the atypical family, or the second-generation antipsychotic family, partly based on my perception of the match with the patient's persistent symptoms. If the patient has more insomnia, more agitation, or decreased appetite, I'm more likely to pick olanzapine or quetiapine. If the patient has more difficulty with fatigue or psychomotor retardation, I'm more likely to pick aripriprizole. There is evidence that any of these 3 agents, when added to an antidepressant, are likely to improve the chances that the patient will respond by between 10% and 30%, which in difficult-to-treat depression is a significant response.

Importantly, depression is a biopsychosocial phenomenon and people with depression experience difficulties in their intimate lives, with their children, and in the workplace. Antidepressant medications, although they may be useful for energy, other somatic symptoms, or even for the ambient tone of the individual's mood, don't necessarily help people specifically solve the problems in their life. Medication treatments also may take 4, 6, 8, or even 10 weeks to work, and during that time, the patient must struggle with persistent symptoms, low morale, and possibly even contemplation that life is not worth living.

So I do favor a combined treatment approach using psychotherapy as well as pharmacotherapy for patients with the most difficult-to-treat depression. In the Star*D study, we selected one psychotherapy, cognitive behavior therapy, because it had the strongest evidence base. It was found that cognitive therapy, when used instead of medications, worked about as well as alternate major antidepressant medications such as sertraline, bupropion, venlafaxine. Also, when added to ongoing citalopram therapy, cognitive therapy had ultimately about the same chance of helping people as combining citalopram with bupropion. As an augmentation strategy, psychotherapy was slower in its action in Star*D. I think importantly I am recommending thinking about psychotherapy not as a competitor treatment to alternate medications, but a targeted additive treatment like other targeted augmentation strategies.

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