Evidence-Based Reviews

Triple reuptake inhibitors: What to expect from ‘mega-antidepressants’

Current Psychiatry. 2007 March;6(3):31-42

References

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¹¹ that simultaneously block serotonin, norepinephrine, and dopamine transporters.^6,12-15 These broad-spectrum, “triple reuptake inhibitors” are thought to have a more-rapid onset of action and greater efficacy than single or dual reuptake inhibitors.^15,16

Triple-action rationale. Some trials have shown antidepressants that act on multiple transporters or receptors to be more effective in treating depressed patients and to have a more-rapid onset of action, compared with single-action drugs such as selective serotonin reuptake inhibitors (SSRIs).⁷ Adding dopaminergic drugs to serotonergic and/or noradrenergic antidepressants also has been shown to boost the response of patients who were treatment-resistant or partial responders.¹⁷

Co-administering dopamine receptor agonists such as bromocriptine, pergolide, or pramipexole (D₃ receptor-preferring) with traditional antidepressants has improved clinical symptoms in depressed patients.¹³ In a retrospective chart review, Clinical Global Impressions (CGI)-Improvement Scale scores were shown to improve with adjunctive pramipexole in 6 of 12 patients with bipolar depression and 8 of 20 patients with unipolar depression.¹⁸ Other studies have shown that bromocriptine¹⁹ and pergolide²⁰ can improve refractory depression in patients receiving concurrent traditional antidepressants.

Similarly, pramipexole monotherapy has been shown to improve depressive symptoms—including anhedonia—in patients with Parkinson’s disease.^21,22 In a 14-week, randomized open-label trial of depressed Parkinson’s patients without motor complications, pramipexole was compared with sertraline for improvement of depressive symptoms. Hamilton Depression Rating Scale (HAM-D) scores decreased in both treatment groups, but the proportion of recovered patients (defined as HAM-D ≤8) was significantly greater in the pramipexole-treated group.²¹

Dopamine agonists such as pergolide have been associated with valvular heart disease in Parkinson’s patients, which may limit these agents’ usefulness in depression treatment.²³

Rank order of potency. To provide the most effective depression treatment, would a compound with equal affinity for all 3 transporters be preferable to a drug with greater affinity for 1 or 2 of the transporters compared with the third? The answer is unknown, as the optimum rank order of potency for inhibiting serotonin, norepinephrine, and dopamine transporters is not yet clear.

Having choices of agents with differing transport inhibition profiles (Table 2)^6,13-15 might allow clinicians greater treatment flexibility, however. This could be an advantage when individualizing regimens to target specific symptoms of depression or other psychiatric disorders, such as attention-deficit/hyperactivity disorder.¹⁴

Table 2

Neurotransmitter uptake inhibition: Differences in transporter binding expected to broaden therapeutic options

	Transporter binding affinity*
Compound	Serotonin	Norepinephrine	Dopamine
Investigational triple reuptake inhibitors
PRC025	6	19	100
PRC050	6	0.4	120
DOV 21,947	99	262	213
DOV 102,677	740	1,030	222
DOV 216,303^†	14	20	78
Reference antidepressants
Paroxetine	0.13	40	490
Imipramine	1.4	37	8,500
Setraline	0.29	420	25
Bupropion	9,100	52,000	520
Venlafaxine	9	1,060	9,300
* Affinity of each compound for binding to serotonin, norepinephrine, and dopamine transporters, as expressed by equilibrium dissociation constants (Kd) in nM.
^† Data reflect inhibition of neurotransmitter reuptake.
Source: References 6,13-15

Dopamine and Depression

What can we expect of a “mega-antidepressant” that inhibits serotonin, norepinephrine, and dopamine reuptake? The answer lies in understanding dopamine’s role in depression and antidepressant treatment.

Dopamine plays a part in the underlying pathophysiology of depression and in the action of antidepressant treatments—regardless of their acute mechanism—according to the literature.^24,25

Depression pathophysiology. Mesocorticolimbic dopaminergic circuits originating in the ventral tegmental area and projecting to cortical and sub-cortical structures (such as the prefrontal cortex and nucleus accumbens) are important in mediating reward and incentive behavior, attention, addiction, and emotions.²⁶ Deficits in this pathway can contribute to depressive symptoms, particularly anhedonia.^3,4

Alterations in dopamine pathways also appear to contribute to depression’s pathophysiology. Compared with nondepressed persons, depressed and/or suicidal patients have been shown to have:

lower levels of dopamine and its metabolite homovanillic acid^25,27-29
increased dopamine D₂/D₃ receptor binding^30,31 and reduced dopamine transporter activity.^31,32

Effects of treating depression. Chronic antidepressant treatment—with pharmacotherapies, electro-convulsive therapy, and REM sleep deprivation—has been shown to:

alter dopaminergic neurotransmission²⁴
potentiate dopamine signaling (in preclinical studies) by increasing postsynaptic mesolimbic dopamine receptor sensitivity.^13,24

Therefore, adding dopamine reuptake blockade to serotonin and norepinephrine reuptake blockade would likely produce an effective medication that could be used as first-line antidepressant therapy.

Potential Clinical Effects

Clinical evidence. To date, one triple reuptake inhibitor has been studied clinically and reported in the literature. This investigational compound—identified as DOV 216,303—has been found to be safe and well-tolerated when tested in small samples of normal volunteers and depressed individuals.

Healthy male volunteers were given DOV 216,303 in single doses from 5 to 150 mg or multiple doses of 50, 75, or 100 mg for 10 days. Some participants reported gastrointestinal side effects, although only at the highest doses tested.

In a multicenter comparison trial, 67 depressed patients received DOV 216,303 (50 mg bid; 36 patients) or citalopram (20 mg bid; 31 patients) for 2 weeks. After 1 week, both treatments produced comparable reductions in the primary outcome measure (HAM-D scores). Improvements also were seen in secondary measures (CGI scale and Beck Depression Inventory).¹⁴ The authors noted that the starting citalopram dosage was higher than typically is given.