Fourth generation antidepressants, which act specifically on certain neurotransmitters to prevent adverse reactions as much as possible, are being increasingly prescribed. However, they are still not as popular as the SSRIs, which dominate the field of drug therapy for depression.

In this article we will analyse the efficacy of selective noradrenaline reuptake inhibitors , which are part of this group of novel drugs. We will focus primarily on reboxetine, the only ISRN that has been studied in some depth, and on its comparison with other types of antidepressants.

Fourth generation antidepressants

In 1952 the first antidepressant drug in history was discovered: iproniazid, which had been developed to treat tuberculosis but proved effective in improving mood. Iproniazid belonged to the pharmacological class of monoamine oxidase inhibitors (MAOIs), which are very potent and dangerous to general health.

Subsequently, tricyclic antidepressants such as imipramine , clomipramine and nortriptyline appeared. In this case the origin was research on the medical treatment of psychoses. These were in turn displaced by selective serotonin reuptake inhibitors, better known by the abbreviation “SSRIs”.

In recent years, a number of medications for depression have emerged that have been attributed greater safety than SSRIs; these are the fourth-generation antidepressants, which include selective noradrenaline reuptake inhibitors (SNRIs) and dual serotonin-noradrenaline reuptake inhibitors (SNRIs).

Unlike tricyclics and MAOIs, fourth generation antidepressants have a high selectivity index ; this means that they exert their action specifically on one or several neurotransmitters, which should theoretically reduce the risk of side effects. In this sense the new antidepressants resemble SSRIs.

Selective Noradrenaline Reuptake Inhibitors (ISRN)

ISRNs are a class of psychopharmaceuticals with antidepressant effects that act specifically on one of the fundamental neurotransmitters of the nervous system: noradrenaline. This chemical is involved in a wide range of physiological and cognitive responses related to activation.

Thus, noradrenaline influences stress responses (both physiological and cognitive), mood, motivation, maintenance of awareness and alertness, blood circulation, management of attention resources, aggressive behaviour, sexual pleasure and orgasm.

As the name suggests, ISRNs work by inhibiting the reuptake of noradrenaline . This means that, when taking one of these drugs, presynaptic neurons have greater difficulty in absorbing noradrenaline from the synaptic space, increasing the amount that is available for neurotransmission.

Selective noradrenaline reuptake inhibitors are also simply called by the abbreviation “IRN”; in this case the term “selective” is obviated. The best known of these drugs is reboxetine , which is marketed under the names “Irenor”, “Norebox”, “Prolift”, “Edronax” and “Vestra”, among others.

There are, however, other medications that can be categorized within this drug class. These include atomoxetine, talopram, talsupram, nisoxetine, viloxazine, amedaline, lortalamine, tandamine, daledaline, edivoxetine, or esreboxetine.

The effectiveness of reboxetine

Currently, and partly as a result of their recent emergence, there is relatively little research available on selective noradrenaline reuptake inhibitors. This is why the degree of effectiveness of this type of drug is not entirely clear , and we also find very contradictory findings.

The meta-analysis by the Eyding team (2010) evaluated the efficacy of reboxetine for the treatment of major depression using 13 studies with more than 4,000 patients as a starting point. These authors found no significant difference between placebo and reboxetine in remission of symptoms and concluded that SSRIs are more effective than NRTIs .

In contrast, the UK government’s Medicines and Healthcare products Regulatory Agency (MHRA) analysed 11 studies on the efficacy of reboxetine and found it to be effective in severe cases of depression. They also denied that it had a greater potential to cause side effects than placebo, as proposed by the Eyding team.

The data currently available suggest that NRTIs may have a somewhat less severe side effect profile than SSRIs, the most widely used antidepressants; however, their potency is likely to be lower. Both classes of drug appear to be more effective in severe cases than in mild or moderate cases . In any case, more research is needed.

Bibliographic references:

  • Eyding, D., Lelgemann, M., Grouven, U., Härter, M., Kromp, M., Kaiser, T., Kerekes, M. F., Gerken, M. & Wieseler, B. (2010). Reboxetine for acute treatment of major depression: systematic review and meta-analysis of published and unpublished placebo and selective serotonin reuptake inhibitor controlled trials. BMJ, 341: c4737
  • The Medicines and Healthcare products Regulatory Agency (MHRA) (2011). MHRA UK Public Assessment Report: Reboxetine: a review of the benefits and risks.