Treatment-Resistant Depression (TRD): Is the Opioid System Involved?

Abstract

About 30% of major depression disorder patients fail to achieve remission, hence being diagnosed with treatment-resistant major depression (TRD). Opium had been largely used effectively to treat depression for centuries, but when other medications were introduced, its use was discounted due to addiction and other hazards. In a series of previous studies, we evaluated the antinociceptive effects of eight antidepressant medications and their interaction with the opioid system. Mice were tested with a hotplate or tail-flick after being injected with different doses of mianserin, mirtazapine, trazodone, venlafaxine, reboxetine, moclobemide, fluoxetine, or fluvoxamine to determine the effect of each drug in eliciting antinociception. When naloxone inhibited the antinociceptive effect, we further examined the effect of the specific opioid antagonists of each antidepressant drug. Mianserin and mirtazapine (separately) induced dose-dependent antinociception, each one yielding a biphasic dose-response curve, and they were antagonized by naloxone. Trazodone and venlafaxine (separately) induced a dose-dependent antinociceptive effect, antagonized by naloxone. Reboxetine induced a weak antinociceptive effect with no significant opioid involvement, while moclobemide, fluoxetine, and fluvoxamine had no opioid-involved antinociceptive effects. Controlled clinical studies are needed to establish the efficacy of the augmentation of opiate antidepressants in persons with treatment-resistant depression and the optimal dosage of drugs prescribed.

Keywords: antinociception; fluoxetine; fluvoxamine; mianserin; mice; mirtazapine; moclobemide; opioids; reboxetine; trazodone; treatment-resistant depression; venlafaxine.

Figure 1

Dose-response curves indicating the antinociceptive effect of each of the four antidepressants exhibiting opioid interaction; Mianserin, Mirtazapine, Trazodone, and Venlafaxine: Each group of mice received an ip injection and were tested with the analgesia hotplate meter test.

Figure 2

Dose-response curves indicating the antinociceptive effect of each of the four antidepressants without opioid interaction; reboxetine, moclobemide, fluoxetine, and fluvoxamine: each group of mice received an ip injection (except for Reboxetine injected sc) and was tested using the analgesia hotplate meter test (except for moclobemide tested with the mouse-tail flick test).

Figure 3

The effect of opioid antagonists on the antinociceptive effect of four antidepressants exhibiting opioid interaction; mianserin, mirtazapine, trazodone, and venlafaxine. Groups of mice were treated with either antidepressant alone or were challenged in addition to naloxone, β-FNA, naltrindole, or nor-BNI. * p < 0.05; ** p < 0.01.

Figure 4

Effects of opioid antagonists on the antinociceptive effect of four antidepressants without opioid interaction; reboxetine, moclobemide, fluoxetine, and fluvoxamine. The effects of naloxone, β-FNA, naltrindole, or nor-BNI can be seen for reboxetine. moclobemide, fluoxetine, and fluvoxamine are seen challenged with naloxone. * p < 0.05..

Figure 5

The effect of opioid antagonists on the antinociceptive effect of eight antidepressants: Mianserin, mirtazapine, trazodone, venlafaxine, reboxetine, moclobemide, fluoxetine, and fluvoxamine. The table shows the percentage of antinociception when the drug was administered to the mice alone or when challenged in addition to Naloxone, β-FNA, Naltrindole, or nor-BNI (arrows and equal signs indicate the course of opioid interaction: * p < 0.05; ** p < 0.01).