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Triple reuptake inhibitors: what to expect from 'mega-antidepressants'; Rapid onset of action could make serotonin-norepinephrine-dopamine reuptake blockers a clinically useful option for patients with depression.

The first triple reuptake inhibitors are at least several years from approval, but this novel antidepressant class represents an intriguing strategy for treating depression. Several pharmaceutical companies are developing these compounds--with at least one in phase-III clinical trials.



Adding a dopamine reuptake component to serotonin and norepinephrine reuptake blockade could result in an antidepressant with a more rapid onset of action, greater efficacy, and fewer side effects. This article updates what is known about triple reuptake inhibitors and suggests their potential role among first-line antidepressants and in treating patients who have not responded adequately to existing agents.


Remission--the absence of depression signs and symptoms--is the optimum goal in treating depression. Patients who do not meet this goal are more likely to relapse and to relapse more rapidly than those whose symptoms are treated to remission. Incomplete response rates and delayed onset of action limit the efficacy of available antidepressants (Box, page 32). (1-6)

Monoamine hypothesis. Although the precise pathophysiology of depression is unclear, dysfunction of monoamine neurotransmission has been a central hypothesis in depression research for decades. This hypothesis is based in part on observations that antidepressants alter monoamine neurotransmission via acute pharmacologic effects at the synapse.

Three major mechanisms account for the acute actions of antidepressants on monoamines:

* inhibition of monoamine oxidase, the enzyme that degrades serotonin, norepinephrine, and dopamine

* blockade of neurotransmitter reuptake by binding to transporters

* antagonism of presynaptic neurotransmitter receptors, resulting in an increase in neurotransmitter release. (4)

Most antidepressants act by increasing the synaptic availability of serotonin (such as fluoxetine and paroxetine); norepinephrine (such as reboxetine); norepinephrine and serotonin (such as duloxetine and venlafaxine); or norepinephrine, serotonin, and dopamine (such as phenelzine). Although controversial, some clinical data suggest that antidepressants that elevate synaptic levels of both norepinephrine and serotonin have greater efficacy and higher remission rates than antidepressants that are selective for norepinephrine or serotonin. (7)

Monoamine oxidase inhibitors (MAOIs)--the only available antidepressants known to elevate synaptic levels of norepinephrine, serotonin, and dopamine--are recommended for use in appropriately selected, treatment-resistant patients. (8) Meta-analysis of clinical trial data suggests that MAOIs such as phenelzine are particularly effective in outpatients with atypical depression features. (9) Even so, the clinical usefulness of MAOIs is limited by their potential for serious drug-drug interactions.

Other mechanisms. Because the synaptic actions of available antidepressants on monoamine neurotransmission occur within hours of administration, the several-week delay in onset of therapeutic action suggests that monoamine dysfunction might not be solely responsible for depression's pathophysiology. Recent investigations suggest that chronic antidepressant use could cause alterations in gene expression, neuronal plasticity, and downstream signaling pathways that underlie the therapeutic effect. (10)

Even so, medications that target serotonin, norepinephrine, and dopamine remain mainstays of depression pharmacotherapy.


Novel antidepressants that do not involve direct action on monoamines are under investigation (Table 1). Several compound classes--such as neurokinin and glucocorticoid receptor antagonists--are reported to be in phase-III clinical trials, with projected approval within 5 years. (11)

Even so, many strategies remain focused on directly targeting monoaminergic circuits because this mechanism of action is compelling and understandable. Among these are agents projected to reach the market by 2010 (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 ([D.sub.3] 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 bromocriptine (19) and pergolide (20) 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 [less than or equal to]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)


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 subcortical 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 [D.sub.2]/[D.sub.3] receptor binding (30,31) and reduced dopamine transporter activity. (31,32)

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

* alter dopaminergic neurotransmission (24)

* 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.


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.

By acutely blocking dopamine reuptake, triple reuptake inhibitors could have immediate effects on dopamine-related depression symptoms such as anhedonia, rather than requiring a lead-in of chronic dosing common to other antidepressant classes. (16) A triple reuptake inhibitor also might:

* address a broader range of depression symptoms, compared with a single or dual reuptake inhibitor

* be useful for treating substance abuse if it can substitute for addictive compounds at the dopamine transporter without possessing reinforcing characteristics.

Because of dopamine transporter blockade, triple reuptake inhibitors may pose their own risks for reinforcing effects and abuse, as seen with cocaine and amphetamine. Imaging studies have shown, however, that the rate of dopamine transporter blockade--rather than the affinity of the drug for the transporter--is relevant to reinforcing effects. (33) Nonetheless, these medications will require evaluation for dependency characteristics that could limit their clinical use.

Side effects observed with SSRIs, such as sexual dysfunction and weight gain, can be related to a continuous, high occupancy of serotonin transporters. This effect might not occur with a triple reuptake inhibitor and the incidence of serotonin-associated side effects might be lower. (14)


1. Holtzheimer PE 3rd, Nemeroff CB. Advances in the treatment of depression. NeuroRx 2006;3(1):42-56.

2. Kennedy N, Paykel ES. Residual symptoms at remission from depression: impact on long-term outcome. J Affect Disord 2004;80(2-3):135-44.

3. Naranjo CA, Tremblay LK, Busto UE. The role of the brain reward system in depression. Prog Neuropsychopharmacol Biol Psychiatry 2001;25(4):781-823.

4. Richelson E. Pharmacology of antidepressants. Mayo Clin Proc 2001;76(5):511-27.

5. Nemeroff CB, Owens MJ. Treatment of mood disorders. Nat Neurosci 2002;5(suppl):1068-70.

6. Popik P, Krawczyk M, Golembiowska K, et al. Pharmacological profile of the "triple" monoamine neurotransmitter uptake inhibitor, DOV 102,677. Cell Mol Neurobiol 2006;26(4-6):855-71.

7. Richelson E. Interactions of antidepressants with neurotransmitter transporters and receptors and their clinical relevance. J Clin Psychiatry 2003;64(suppl 13):5-12.

8. Trivedi MH, Kleiber BA. Using treatment algorithms for the effective management of treatment-resistant depression. J Clin Psychiatry 2001;62(suppl 18):25-9.

9. Thase ME, Trivedi MH, Rush AJ. MAOIs in the contemporary treatment of depression. Neuropsychopharmacology 1995;12(3):185-219.

10. Wong ML, Licinio J. Research and treatment approaches to depression. Nat Rev Neurosci 2001;2(5):343-51.

11. Rosack J. Companies desperately seek antidepressant breakthrough. Psychiatry News 2006;41:22-37.

12. Carlier PR, Lo MM, Lo PC, et al. Synthesis of a potent wide-spectrum serotonin-, norepinephrine-, dopamine-reuptake inhibitor (SNDRI) and a species-selective dopamine-reuptake inhibitor based on the gamma-amino alcohol functional group. Bioorg Med Chem Lett 1998;8(5):487-92.

13. Shaw AM, Boules M, Zhang Y, et al. Antidepressant-like effects of novel triple reuptake inhibitors, PRC025 and PRC050. Eur J Pharmacol 2007;555(1):30-6.

14. Skolnick P, Krieter P, Tizzano J, et al. Preclinical and clinical pharmacology of DOV 216,303, a "triple" reuptake inhibitor. CNS Drug Rev 2006;12(2):123-34.

15. Skolnick P, Popik P, Janowsky A, et al. Antidepressant-like actions of DOV 21,947: a "triple" reuptake inhibitor. Eur J Pharmacol 2003;461(2-3):99-104.

16. Skolnick P, Popik P, Janowsky A, et al. "Broad spectrum" antidepressants: is more better for the treatment of depression? Life Sci 2003;73(25):3175-9.

17. Fava M. Augmentation and combination strategies in treatment-resistant depression. J Clin Psychiatry 2001;62(suppl 18):4-11.

18. Sporn J, Ghaemi SN, Sambur MR, et al. Pramipexole augmentation in the treatment of unipolar and bipolar depression: a retrospective chart review. Ann Clin Psychiatry 2000;12(3):137-40.

19. Inoue T, Tsuchiya K, Miura J, et al. Bromocriptine treatment of tricyclic and heterocyclic antidepressant-resistant depression. Biol Psychiatry 1996;40(2):151-3.

20. Bouckoms A, Mangini L. Pergolide: an antidepressant adjuvant for mood disorders? Psychopharmacol Bull 1993;29(2):207-11.

21. Barone P, Scarzella L, Marconi R, et al. Pramipexole versus sertraline in the treatment of depression in Parkinson's disease: a national multicenter parallel-group randomized study. J Neurol 2006;253(5):601-7.

22. Lemke MR, Brecht HM, Koester J, Reichmann H. Effects of the dopamine agonist pramipexole on depression, anhedonia, and motor functioning in Parkinson's disease. J Neurol Sci 2006;248(1-2):266-70.

23. Zanettini R, Antonini A, Gatto G, et al. Valvular heart disease and the use of dopamine agonists for Parkinson's disease. N Engl J Med 2007;356(1):39-46.

24. D'Aquila PS, Collu M, Gessa GL, Serra G. The role of dopamine in the mechanism of action of antidepressant drugs. Eur J Pharmacol 2000;405(1-3):365-73.

25. Papakostas GI. Dopaminergic-based pharmacotherapies for depression. Eur Neuropsychopharmacol 2006;16(6):391-402.

26. Greene JG. Gene expression profiles of brain dopamine neurons and relevance to neuropsychiatric disease. J Physiol 2006;575(Pt 2):411-6.

27. Engstrom G, Ailing C, Blennow K, et al. Reduced cerebrospinal HVA concentrations and HVA/5-HIAA ratios in suicide attempters. Monoamine metabolites in 120 suicide attempters and 47 controls. Eur Neuropsychopharmacol 1999;9(5):399-405.

28. Hamner MB, Diamond BI. Plasma dopamine and norepinephrine correlations with psychomotor retardation, anxiety, and depression in non-psychotic depressed patients: a pilot study. Psychiatry Res 1996;64(3):209-11.

29. Mitani H, Shirayama Y, Yamada T, Kawahara R. Plasma levels of homovanillic acid, 5-hydroxyindoleacetic acid and cortisol, and serotonin turnover in depressed patients. Prog Neuropsychopharmacol Biol Psychiatry 2006;30(3):531-4.

30. Klimek V, Schenck JE, Han H, et al. Dopaminergic abnormalities in amygdaloid nuclei in major depression: a postmortem study. Biol Psychiatry 2002;52(7):740-8.

31. Shah PJ, Ogilvie AD, Goodwin GM, Ebmeier KP. Clinical and psychometric correlates of dopamine [D.sub.2] binding in depression. Psychol Med 1997;27(6):1247-56.

32. Meyer JH, Kruger S, Wilson AA, et al. Lower dopamine transporter binding potential in striatum during depression. Neuroreport 2001;12(18):4121-5.

33. Volkow ND, Wang GJ, Fowler JS, et al. The slow and long-lasting blockade of dopamine transporters in human brain induced by the new antidepressant drug radafaxine predict poor reinforcing effects. Biol Psychiatry 2005;57(6):640-6.

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Mona Boules, PhD

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Elliott Richelson, MD

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Box Incomplete response, 'therapeutic lag' can limit antidepressants' efficacy

Antidepressant response. An estimated 60% to 70% of depressed patients respond to antidepressants, but only 20% to 40% achieve remission; 15% of depressed patients do not respond to any available antidepressants. (1,2)

Delayed onset of action with most antidepressants means that depression does not improve noticeably for at least 1 week and typically 3 weeks or more. (3,4) Many patients remain greatly impaired during this "therapeutic lag" and can perceive that the medication isn't helping them with signs and symptoms such as:

* persistent sad mood

* decreased interest in pleasurable activities (anhedonia)

* changes in body weight or appetite

* changes in sleep patterns

* difficulty thinking or concentrating

* feelings of worthlessness or guilt

* low energy, fatigue, or increased agitation

* recurrent thoughts of death or suicide

* poor self-esteem.

Newer antidepressants such as selective serotonin reuptake inhibitors, selective norepinephrine reuptake inhibitors, and dual serotonin/norepinephrine reuptake inhibitors generally are better tolerated and easier to use than tricyclics and monoamine oxidase inhibitors. Even the newer antidepressants can cause side effects such as weight gain and sexual dysfunction, however, and might not be more efficacious than older antidepressants. (5,6)

Related resources

*** Nutt DJ. The role of dopamine and norepinephrine in depression and antidepressant treatment. J Clin Psychiatry 2006;67(suppl 6):3-8.

*** American College of Neuropsychopharmacology. Neuropsychopharmacology: the fifth generation of progress.


Bromocriptine * Parlodel

Bupropion * Wellbutrin

Citalopram * Celexa

Duloxetine * Cymbalta

Fluoxetine * Prozac

Imipramine * Tofranil

Paroxetine * Paxil

Pergolide * Permax

Phenelzine * Nardil

Pramipexole * Mirapex

Reboxetine * Edronax

Sertraline * Zoloft

Venlafaxine * Effexor


Dr. Shaw and Dr. Boules report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products. Dr. Richelson is a consultant to Eli Lilly and Company.


By acutely blocking dopamine reuptake, triple reuptake inhibitors could have immediate effects on depression. They also might improve a broader range of symptoms than single or dual reuptake inhibitors, with less risk for sexual side effects or weight gain. Potential adverse effects from dopamine reuptake inhibition, such as dependency characteristics, warrant investigation.
Table 1 Mechanisms of select antidepressants in development

Drug class/target           Proposed mechanism of action

Triple reuptake inhibitors  Block serotonin, norepinephrine, and
                            dopamine reuptake
[CRF.sub.1] antagonists     Block receptors for corticotropin releasing
                            factor; regulate HPA axis
NK receptor antagonists     Block substance P receptor; offer
                            antidepressant/anxiolytic properties
Glutamate acting drugs      Block or modulate NMDA receptor
Anti-glucocorticoid agents  Block glucocorticoid receptors; modulate HPA
                            axis feedback
cAMP signal transduction    Increases cAMP levels; may affect

cAMP: Cyclic adenosine monophosphate
CRF: Corticotropin releasing factor
HPA: Hypothalamic-pituitary-adrenal (axis)
NK: Neurokinin
NMDA: N-methyl-D-aspartate

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 ([dagger])     14          20             78

Reference antidepressants
  Paroxetine                  0.13       40            490
  Imipramine                  1.4        37          8,500
  Sertraline                  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.
([dagger]) Data reflect inhibition of neurotransmitter reuptake.
Source: References 6,13-15
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Author:Shaw, Amanda M.; Boules, Mona; Richelson, Elliott
Publication:Current Psychiatry
Geographic Code:1USA
Date:Mar 1, 2007
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