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Triple Reuptake Inhibitors

Last updated on November 21st, 2021


A novel mechanism for the treatment of depression that has attracted much attention is triple reuptake inhibition. Given their additional mechanism of action on dopamine, the triple reuptake inhibitors pose a potential threat to the clinical use and commercial fortunes of selective serotonin reuptake inhibitors and serotonin/norepinephrine reuptake inhibitors. Agents of this type are being developed by Merck, whose DOV-216303 is in Phase II development and DOV-21947 in Phase Italy; by Sepracor, whose R-DDMS is set to enter Phase III trials pending resumption of development activity; and by GlaxoSmithKline (GSK) in collaboration with Neurosearch, whose NS-2359 is in Phase II development.

The dopamine-reuptake inhibition of these agents has a stimulatory effect that is beneficial in the treatment of major depression but that can also be addictive — a serious drawback to their commercial potential, because the marketed drugs might require scheduled labeling as controlled substances depending upon their dopaminergic action. Such labeling would deter most PCPs from choosing this class of antidepressants. It is possible — but unlikely — that DOV’s triple reuptake inhibitors will carry an addiction potential and labeling as a controlled substance.

Dexmethylphenidate, methylphenidate (Novartis’s Focalin and Ritalin), and bupropion (GSK’s Wellbutrin) are examples of dopamine-reuptake inhibitors (that also may trigger dopamine release) that have been successfully marketed. The stimulants dexmethylphenidate and methylphenidate carry abuse potential, but the antidepressant bupropion does not. A dopamine uptake inhibitor that was marketed for the treatment of depression and then later pulled from the European market in 2003 because of abuse risk is amineptine (Servier’s Survector).

It is assumed that drug developers who discover that a serotonergic/noradrenergic/ dopaminergic antidepressant has addiction potential would not bother to commercialize the drug, given the difficulties of marketing an addictive substance to PCPs in the competitive antidepressant market. More likely, developers would attempt to tailor the drug’s pharmacology to reduce the addiction potential — i.e., reduce the drug’s potency at dopaminergic receptors.


Mechanism Of Action

The triple reuptake inhibitors in development are similar to the serotonin/norepinephrine reuptake inhibitors in that they inhibit the reuptake of both serotonin and norepinephrine. In addition, they prevent the reuptake of dopamine. Agents that work by blocking the reuptake of the monoamines serotonin, noradrenaline, and dopamine by presynaptic cells may have an advantage over single- and dual-mechanism antidepressants because these three monoamines are most closely linked to depression (see the “Etiology and Pathophysiology” section for detailed discussion of the monoamine hypothesis).

Researchers theorize that symptoms of depression result from the poor uptake of monoamines by postsynaptic transporters. The leftover monoamines are reabsorbed by the presynaptic cell; consequently, the presynaptic cell releases fewer monoamines into the synaptic cleft. The net result is a monoamine deficit in the synaptic cleft. If these agents are more dopaminergic than serotonergic, they may be able to help alleviate the sexual side effects, sedation, and weight gain associated with serotonergic drugs without compromising antidepressant activity.


Merck is attempting to enter the antidepressant market by licensing from DOV Pharmaceutical the rights to develop and market two triple reuptake inhibitors. In August 2004, Merck licensed DOV-216303 for the treatment of depression, anxiety, and drug addiction; DOV retained the rights for other indications. Also included in the licensing agreement between DOV and Merck were full development rights to DOV-21947, another triple reuptake inhibitor in early Phase Italy trials for depression and other psychiatric indications. DOV Pharmaceutical has the option to copromote DOV-21947 to psychiatrists in the United States. The discussion here focuses on DOV-216303 because it is the furthest along in development: it is in Phase II in the United States and in Germany and France for major depression.

DOV-216303 is the parent compound of the enantiomeric pair DOV-21947 and DOV-102677. DOV-102677 is a selective dopamine uptake inhibitor to which DOV Pharmaceutical has retained the rights. DOV is developing the drug for the treatment of attention-deficit/hyperactivity disorder, restless leg syndrome, and Parkinson’s disease.

In addition to inhibiting the serotonin-reuptake transporter and the norepinephrine-reuptake transporter, like the serotonin/norepinephrine reuptake inhibitors, DOV-216303 inhibits the dopamine-reuptake transporter. DOV-216303′s inhibition of dopamine reuptake is expected to have an important clinical advantage over the selective serotonin reuptake inhibitors and serotonin/norepinephrine reuptake inhibitors. Assuming the compound is more dopaminergic than serotonergic, it will likely offer antidepressant efficacy comparable to that of available drugs but without the associated sexual side effects, sedation, and weight gain.

In early studies for major depression reported in DOV press releases, DOV-216303 appeared to be well tolerated. The company has not published extensive data; information has only been released via company presentations and press releases. In Phase Italy trials, DOV-216303 was studied at six dose levels, ranging from 5 to 150 mg; in these trials, no serious adverse events were reported. The highest dose caused nausea in some patients. In subsequent, small Phase Italy trials (n = 7-10), DOV-216303 was studied using three dosing groups of 25 mg bid, 25 mg tid, and 50 mg bid; DOV reported no serious adverse events in this trial, and few patients experienced any adverse effects. DOV-216303 is now in a multicenter Phase II trial in Germany involving patients with major depression; in this trial, 50 mg bid of DOV-216,303 is being compared with 20 mg bid of citalopram. By May 2004, the ongoing trial had enrolled 60 patients.

Although DOV announced during a company presentation in September 2003 that the composition patent for DOV-216303 had expired, the company believes the agent will be eligible for the five-year exclusivity provisions of the Hatch-Waxman Act. In April 2002, a composition-of-matter patent was issued for DOV-21947 in the United States. There are no publicly available data covering the clinical trials of DOV-21947.

Because DOV-216303 has already lost patent protection, Merck may bring the compound to the U.Spain. market simply to gain a foothold and then quickly replace it with DOV-21947. DOV-216303 will be brought to market in the United States only, after which it will enjoy five years’ new compound exclusivity from the FDA — time enough for Merck and DOV to follow up with launches of DOV-21947 in the United States and Europe.

The use of combined serotonergic, noradrenergic, and dopaminergic agents to treat major depression is already in practice — e.g., augmenting the selective serotonin reuptake inhibitors and serotonin/norepinephrine reuptake inhibitors with bupropion or stimulants such as methylphenidate. DOV has not released data on its triple reuptake inhibitors’ abuse potential specifically, so this concern remains; however, given that the company continues to pursue development of the agents, the drugs’ risk of addiction potential and labeling as such is likely low.


GSK, in collaboration with Neurosearch, is developing the triple reuptake inhibitor NS-2359, which is in Phase II development for attention-deficit/hyperactivity disorder, cocaine addiction, and major depression.

NS-2359 inhibits the reuptake of serotonin, norepinephrine, and dopamine. The additional inhibition of dopamine reuptake is expected to have an important clinical advantage over the selective serotonin reuptake inhibitors and serotonin/norepinephrine reuptake inhibitors because NS-2359 will be able to offer antidepressant efficacy comparable to that of available drugs without the associated sexual side effects, sedation, and weight gain.

The emerging class of triple reuptake inhibitors is expected to garner a substantial share of the antidepressant market. GSK, having significant experience in the depression market, will most likely develop a marketing campaign for major depression that will help boost off-label sales of NS-2359 in minor depression. GSK and Merck will be competing to have their triple reuptake inhibitor debut as the first of its class to market. Because Merck’s triple reuptake inhibitors are further along in development, these drugs will likely be first to market. However, GSK’s successful experience bringing an antidepressant to market makes the race to market tight.

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