Norepinephrine reuptake inhibitor
A norepinephrine reuptake inhibitor (NRI, NERI) or adrenergic reuptake inhibitor (ARI), is a type of drug that acts as a reuptake inhibitor for the neurotransmitters norepinephrine (noradrenaline) and epinephrine (adrenaline) by blocking the action of the norepinephrine transporter (NET). This in turn leads to increased extracellular concentrations of norepinephrine and epinephrine and therefore an increase in adrenergic neurotransmission.
NRIs are commonly used in the treatment of conditions like ADHD and narcolepsy due to their psychostimulant effects and in obesity due to their appetite suppressant effects. They are also frequently used as antidepressants for the treatment of major depressive disorder, anxiety and panic disorder . Additionally, many drugs of abuse such as cocaine and methylphenidate possess NRI activity, though it is important to mention that NRIs without combined dopamine reuptake inhibitor (DRI) properties are not significantly rewarding and hence are considered to have a negligible abuse potential. However, norepinephrine has been implicated as acting synergistically with dopamine when actions on the two neurotransmitters are combined (e.g., in the case of NDRIs) to produce rewarding effects in psychostimulant drugs of abuse.
For the past decade, the role of norepinephrine in depression has been somewhat neglected in favor of serotonin. This is largely because of the advent of the selective serotonin reuptake inhibitors, which have facilitated clinical and experimental observation of the roles of serotonin. Until now, no such tools have been available to study the noradrenergic system. However, the recent development of reboxetine, the first selective norepinephrine reuptake inhibitor, has allowed clinical investigation of the role of the noradrenergic system in different aspects of depressive disorders. In clinical trials, the use of reboxetine has shown that selective norepinephrine reuptake inhibition is an effective approach to alleviating depression. It is more effective than placebo and at least as effective as desipramine, imipramine and fluoxetine in the short term. In addition, its efficacy is maintained in patients with severe depression and in those receiving long-term maintenance treatment. Reboxetine is very well tolerated, as predicted from its pharmacological profile, having fewer anticholinergic side-effects than imipramine or desipramine. Compared with fluoxetine, patients treated with reboxetine experienced less nausea and sexual dysfunction, adverse events that are common among those taking selective serotonin reuptake inhibitors. Adverse events predicted by the neuroanatomy of the noradrenergic system, such as tremor and cardiovascular effects, occurred less frequently than expected. Clinical experience with reboxetine challenges our current knowledge of the role of norepinephrine in depression and questions existing evidence based on studies with noradrenergic tricyclic antidepressants. Selective norepinephrine reuptake inhibition, as exemplified by reboxetine, therefore offers a significant improvement in antidepressant pharmacotherapy.
But Ben Goldacre, writing in The Guardian, said that reboxetine was an example of a drug company selectively disclosing favorable studies while not publishing unfavorable studies.
Seven trials had been conducted comparing reboxetine against a placebo. Only one, conducted in 254 patients, had a neat, positive result, and that one was published in an academic journal, for doctors and researchers to read. But six more trials were conducted, in almost 10 times as many patients. All of them showed that reboxetine was no better than a dummy sugar pill. None of these trials was published.
The trials comparing reboxetine against other drugs showed exactly the same picture: three small studies, 507 patients in total, showed that reboxetine was just as good as any other drug. They were all published. But 1,657 patients' worth of data was left unpublished, and this unpublished data showed that patients on reboxetine did worse than those on other drugs.
A considerable proportion of patients fail to respond adequately to selective serotonin reuptake inhibitors (SSRIs). Analysis of the unresolved symptoms suggests that a specific set of symptoms related to decreased positive affect respond poorly to serotonergic antidepressants, namely loss of pleasure, loss of interest, fatigue, and loss of energy. There is evidence to suggest that antidepressants that enhance norepinephrine offer a therapeutic advantage over serotonergic antidepressants in the treatment of symptoms associated with reduced positive affect.
List of NRIs
Many NRIs exist, including the following:
- Selective norepinephrine reuptake inhibitors
- Atomoxetine (Strattera)
- Reboxetine (Edronax, Vestra)
- Edivoxetine (LY-2216684)
- Viloxazine (Vivalan)
- Maprotiline (Deprilept, Ludiomil, Psymion)
- Nisoxetine (LY-94,939)
- Lortalamine (LM-1404)
- Amedalin (UK-3540-1)
- Daledalin (UK-3557-15)
- Talopram (Lu 3-010)
- Talsupram (Lu 5-005)
- Tandamine (AY-23,946)
- NRIs with lesser activity at other sites
Note: Only NRIs selective for the NET greater than the other two monoamine transporters (MATs) are listed here. For a list of NRIs that act at multiple MATs, see the other monoamine reuptake inhibitor pages such as NDRI, SNRI, and SNDRI.
- Wee S, Woolverton WL (September 2004). "Evaluation of the reinforcing effects of atomoxetine in monkeys: comparison to methylphenidate and desipramine". Drug and Alcohol Dependence 75 (3): 271–6. doi:10.1016/j.drugalcdep.2004.03.010. PMID 15283948.
- Gasior M, Bergman J, Kallman MJ, Paronis CA (April 2005). "Evaluation of the reinforcing effects of monoamine reuptake inhibitors under a concurrent schedule of food and i.v. drug delivery in rhesus monkeys". Neuropsychopharmacology : Official Publication of the American College of Neuropsychopharmacology 30 (4): 758–64. doi:10.1038/sj.npp.1300593. PMID 15526000.
- Rothman RB, Baumann MH, Dersch CM, et al. (January 2001). "Amphetamine-type central nervous system stimulants release norepinephrine more potently than they release dopamine and serotonin". Synapse 39 (1): 32–41. doi:10.1002/1098-2396(20010101)39:1<32::AID-SYN5>3.0.CO;2-3. PMID 11071707.
- Moret, C; Briley, M (2011). "The importance of norepinephrine in depression". Neuropsychiatric Disease and Treatment 7 (Suppl 1): 9–13. doi:10.2147/NDT.S19619. PMC 3131098. PMID 21750623.
- Fehske CJ, Leuner K, Müller WE (July 2009). "Ginkgo biloba extract (EGb761) influences monoaminergic neurotransmission via inhibition of NE uptake, but not MAO activity after chronic treatment". Pharmacological Research : the Official Journal of the Italian Pharmacological Society 60 (1): 68–73. doi:10.1016/j.phrs.2009.02.012. PMID 19427589.