Treatment-Resistant Depression: Therapeutic Approaches

Richard C. Shelton, MD


Medscape Psychiatry & Mental Health eJournal. 1996;1(6) 

In This Article

Combination Therapy

De Montigny and colleagues[23] postulated that lithium should be effective as an augmenting agent combined with tricyclics because of preclinical evidence that lithium enhances presynaptic release of serotonin. These early clinical observations of the beneficial effect of lithium augmentation of tricyclics[23,24] have been confirmed by subsequent open and placebo-controlled studies.[14] Response rates have ranged between 44% and 83%. De Montigny and coworkers[23,24] described rapid early response in many subjects. However, in another study, Thase and associates[25] showed that while some patients responded within 2 weeks of initiation of lithium augmentation, a second group did not respond until 4 to 6 weeks. Lithium augmentation of tricyclics remains the best tested of all therapeutic approaches to refractory patients. Although lithium has been used in combination with MAOIs clinically, there is little empiric support for this practice.[14]

Although SSRIs are used widely as first-line antidepressants, little research has documented the effectiveness of SSRI plus lithium augmentation. Fava and coworkers[21] treated a group of fluoxetine nonresponders with lithium carbonate (300 to 600mg/day). Although there was minimal response in partial responders to fluoxetine, a good overall effect was achieved in a small subset of nonresponders.

Delgado and associates[17] treated a mixed inpatient and outpatient group of 18 patients with depression (16 with unipolar depression, 2 with bipolar depression) who had failed fluvoxamine open-label treatment. Fifty percent of subjects who had failed fluvoxamine responded to combination fluvoxamine plus lithium treatment. Neither bipolar patient responded, but 9 of 16 patients (56%) with unipolar major depression responded to the combination. These studies indicated that lithium augmentation may be effective with SSRIs. Further study is needed to confirm this effect.

Early published reports indicated that thyroid hormone added to tricyclics could speed the antidepressant response in women, but not in men.[26] A series of open studies seemed to suggest that triiodothyronine (T3) had a beneficial effect in a majority of patients with depression refractory to tricyclic therapy.[27] Controlled trials have produced somewhat mixed results.[27] Overall, however, the results seem reasonably convincing. Joffe and colleagues[28] studied 51 outpatients with unipolar depression who were refractory to desipramine or imipramine pharmacotherapy. Patients were randomly assigned to 3 groups: T3 at a dosage of 37.5mcg per day, lithium carbonate 900mg per day, or placebo. T3 was as effective as lithium (59% and 53%, respectively), and both were more effective than placebo (19%).

In an earlier study, Joffe and Singer[29] contrasted T3 at a dose of 37.5mcg with thyroxine (T4) at a dose of 150mcg for augmentation of tricylics in 38 patients with major unipolar depression who were refractory to desipramine or imipramine. In this study, T3 produced a superior effect (59% response) to that of T4 (19%).

Baron and colleagues[30] reported that the combination of desipramine (a predominantly noradrenergic antidepressant) and fluoxetine (principally serotonergic) produced a more rapid down-regulation of central beta receptors than either drug given alone. This led to a succession of case reports of heterocyclic-SSRI combinations in refractory patients. Weilburg and others[31] reported that 26 of 30 (87%) depressed patients who were refractory to a heterocyclic antidepressant showed a positive response to the addition of fluoxetine. Other investigators have reported similar results.[32,33]

Nelson and colleagues[34] reported on an open series of 14 subjects who were refractory to tricyclic antidepressant drug therapy. Both desipramine and fluoxetine were administered in standard doses to these patients. Seventy percent of the group showed a greater than 75% reduction in HRSD scores. Finally, Zajecka and associates[35] reported on 70 depressed patients who had failed to respond to a presumably adequate trial of a heterocyclic agent. Fluoxetine was substituted for the heterocyclic and titrated to a maximum dosage of 60mg/day. Then, a heterocyclic was added back to the treatment regimen of the 20 subjects who had failed fluoxetine monotherapy. Of this group, 7 (35%) showed a positive effect with the combination. These reports suggest that the combination of a noradrenergic heterocyclic agent (desipramine) and an SSRI may be an effective combination in some refractory patients. However, controlled studies are needed to confirm these results.

Early anecdotal reports and open series have reported a beneficial effect associated with the combination of a tricyclic and an MAOI antidepressant in depressed patients refractory to either agent alone,[14,27,36] but there are no controlled studies of this combination.

A comparison of electroconvulsive therapy (ECT) with a combination of phenelzine and amitriptyline in depressed patients refractory to therapy showed that ECT produced a superior outcome,[37] indicating that a combination of a tricyclic with an MAOI should generally be reserved for patients who have failed prior treatment with ECT.[14]

On the other hand, the combination of MAOIs and tricyclics appears to be reasonably safe when used cautiously.[36] Most investigators recommend either the addition of the MAOI slowly to an established tricyclic dose or the joint titration of both the MAOI and tricyclic in an alternating fashion.[6] The most common combination treatment has been phenelzine with amitriptyline. There are some anecdotal reports of significant toxicities with imipramine or clomipramine cotherapy.[6]

Several case series and open trials have reported beneficial effects associated with a combination of antidepressants and anticonvulsants, especially the anticonvulsant carbamazepine.[14,37] These reports have suggested that between 20% and 40% of patients with refractory unipolar depression may respond to the combination.[14] More recently, Ketter and coworkers[38] reported on the results of combining an MAOI (phenelzine or tranylcypromine) with carbamazepine in 10 inpatients with refractory depression (7 bipolar, 3 unipolar). Four of 10 patients improved significantly to the point of discharge from hospital. Although these preliminary reports suggest a potential benefit of combined antidepressant-anticonvulsant treatment, much more study is needed. In particular, research on the potential benefits of valproate as an augmenting agent is imperative.

The coadministration of psychostimulants such as dextroamphetamine or methylphenidate with tricyclics or MAOIs has been successful in anecdotal reports.[14,27,39] However, controlled trials are nonexistent. The same is true for combinations such as estrogen supplementation in women with refractory depression[40] or buspirone augmentation of tricyclics or SSRIs.[41,42] One particularly intriguing possibility is steroid suppression therapy. Murphy and others[43] reported that monotherapy with steroid-suppressive drugs such as aminoglutethimide, ketoconazole, or metyrapone produced significant remission of depressive symptoms in 6 of 8 patients with refractory depression and partial response in the other 2. These researchers proposed that the results were based on a "readjustment" of the hypothalamic-pituitary-adrenal axis. This and other novel treatments such as sleep manipulations (including phase-advance of the sleep cycle and total sleep deprivation)[44] and phototherapy[45] need further research (Table III).


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