The pharmacological management of treatment-resistant depression: what does the future hold?

KEYWORDS:

• Antidepressants
• major depressive disorder
• psychopharmacology
• suicide

1. Introduction

These are exciting times for antidepressants. We are probably at a turning point similar to the discovery of the first generation of antidepressants some 70 years ago. This is not an exaggeration, as there are a number of new compounds that have just entered the market or are in advanced development that overcome most of the limitations of current treatments. However, they are not all completely without limitations.

The limitations of current pharmacological (and non-pharmacological) treatments for depression are highlighted by the existence of the definition of treatment-resistant depression. It is well known in fact among psychiatrists that two-thirds of patients with depression do not fully benefit from antidepressants, half of which do not respond at all. This leads to a long process of trial and error to find the one drug (or combination) that improves the depression. Tolerability is also a common problem with antidepressant treatment, with side effects ranging from mild but bothersome to severe, which in any case reduces compliance. Last but not least, there is the limitation of the speed of action, which is in the order of weeks at best. These limitations apply to varying degrees to all of the more than 40 antidepressants currently available.

New compounds promise to greatly improve these limitations, including speed of action.

2. Ketamine and esketamine

The ketamine (and esketamine) wave started slowly, about 15 years ago, with the first reports of significant efficacy in depression within a few hours of administration. Since then, there have been thousands of studies involving hundreds of clinical trials. At present, intranasal esketamine, which is more convenient than intravenous ketamine, is marketed in many countries and is currently used in thousands of depressed patients. It also proved very effective in suicidal emergency situations [1]. This is an important point given that suicidal behaviors are a serious issue also during antidepressant treatment [2]. However, there are still some limitations regarding the duration of the antidepressant effect, tolerability and potential for abuse [3]. In any case, ketamine and its derivatives proved for the first time that it was possible to achieve a very rapid antidepressant effect, without waiting the usual 2 to 4 weeks. In addition, and most importantly, after decades of antidepressants based on monoamine modulation, a new mechanism of action has been discovered. A completely new mechanism modulating the glutamatergic system and possibly inducing plasticity, while all the antidepressants produced in the previous decades used a monoaminergic mechanism of action that was little changed from the original discovery in the 1950s. These aspects have stimulated a wave of research that is still ongoing and is likely to lead to newer and better antidepressants.

3. Psilocybin

The results with ketamine suggested a focus on similar psychoactive compounds. In recent years there has been a strong interest in serotonergic psychedelics, especially psilocybin. Hundreds of studies have been reported in the last five years, including some clinical trials in depression [4]. Again, the antidepressant effect is surprisingly rapid. Psilocybin is usually combined with psychotherapy, probably because of a synergistic effect on the brain and to mitigate possible dissociative effects. In fact, it has been suggested that psilocybin’s mechanism of action is a relevant rewiring of brain connectivity [5], and this may explain the long-lasting effect of a single dose, even over several months. However, despite the enthusiasm, there are still some aspects that need further research. To date, psilocybin is still a controlled substance and there is potential for recreational abuse, so more research is needed. A similar and promising compound is ayahuasca, which has a slightly different mechanism of action, including monoamine oxidase inhibitor activity. It has shown a rapid antidepressant effect, but tolerability is probably more of an issue compared to psilocybin, partly due to frequent gastrointestinal effects [6].

4. Neurosteroids

But those are not the only innovations that we have seen in the last few years, as neurosteroids have also recently been brought to market [7]. This class of antidepressants also shares with ketamine a rapid onset of action, in this case on the order of days rather than hours, but it is still a significant improvement on traditional antidepressants. Again, a new mechanism of action in the GABAergic system has been discovered and new compounds are being developed. For example, the recently Food and Drug Administration approved zuranolone improves on brexanolone by using an oral rather than an intravenous route, while maintaining efficacy [8–12]. However, there is still a lot of research to be done on neurosteroids. Are they useful only in postpartum depression or also in more common depression? In what psychiatric disorders other than depression are they effective? Should they be used in combination or as monotherapy? A number of trials are ongoing, and results will be available soon.

5. Other drugs

Another novel and promising antidepressant mechanism of action is antagonism of the orexin receptors, which is thought to modulate sleep and mood. Suvorexant was the first to be approved by the Food and Drug Administration, but not in Europe, while Daridorexant has been recently approved also in Europe, and it results well tolerated and with less tolerance when compared to benzodiazepines [13]. More recently, phase one and two trials showed positive effects of seltorexant, which has a greater selectivity for type 2 receptors. However, not all trials showed a significant effect. More studies are needed, but it is likely that those drugs will be very useful, at least in combination with traditional antidepressants, when partial efficacy is observed and when sleep disturbances are present.

Finally, there are a number of other drugs at various stages of development that promise to be of potential benefit [14]. One recently approved by the Food and Drug Administration is the combination of dextromethorphan and bupropion. This is an interesting example of a new use of drugs that were already on the market, but when used in combination they offer a number of mutual benefits, resulting in a much faster, more robust and broader effect than bupropion alone, due to pharmacokinetic and pharmacodynamic interactions [15,16]. Other interesting compounds include esmethadone, a dextro-isomer of racemic methadone, which has received fast-track designation from the Food and Drug Administration as an adjunctive treatment for depression, and a neuroactive steroid belonging to the group of ‘pherines’ (Ph-10) with intranasal administration and promising antidepressant activity [14,17–20].

6. Future perspectives

There are moreover many other encouraging potential developments for the future of antidepressant treatment: microbiota manipulation, monoclonal antibodies, immunomodulation, drug repurposing based on genetic data and a range of possible genetic manipulations [21–25]. The increased power of recent genetic studies through multicentre efforts has produced consistent results for the first time in decades. The identification of gene variants that modulate depression liability may now suggest new drug targets. With more than 5,000 drugs currently on the market, cross-target analysis may suggest drug repurposing, i.e. using a drug for a new indication. This strategy has already proved useful in several diseases. The final step will be to target genes or gene products to treat the physiopathological basis of depression. We are still a long way from this goal, but it is likely that with the convergent development of genetic, bioinformatic and molecular biology tools, we will eventually be able to treat depression, and hopefully all psychiatric disorders, with gene therapy, similar to how we currently treat some blood disorders.

7. Expert opinion

After many decades of frustrating use of traditional antidepressants with issues of efficacy, tolerability and speed of action, we are now facing a wave of new compounds that are likely to revolutionize our daily clinical practice. New compounds will offer improved efficacy, improved tolerability and, most importantly, an antidepressant effect within hours or days rather than weeks. Clinicians should carefully consider the profile and tolerability of new medicines before using them, and tailor each new medicine to specific clinical needs. In the more distant future, genetics will further improve treatment, perhaps offering a long-lasting benefit rather than continuous maintenance treatment. However, there is still much to be done in terms of research and refinement.

Declaration of interest

A Serretti is or has been a consultant to or has received honoraria or grants unrelated to the present work from: Abbott, AbbVie, Angelini, Astra Zeneca, Clinical Data, Boehringer, Bristol Myers Squibb, Eli Lilly, GlaxoSmithKline, Innovapharma, Italfarmaco, Janssen, Lundbeck, Naurex, Pfizer, Polifarma, Sanofi, Servier, Taliaz. The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.