Antidepressants, present and future.

Despite more than 50 years of research in the field of antidepressants, little advances have been observed in the last decade in the clinical practice. With the notable exception of agomelatine, we have still to hope on drugs in development to face the well known unmet needs of partial response, delayed response or non response tout court. The basic idea underlying this issue was to face the problem of antidepressant treatment from many perspectives. The use of glutamate modulators in the treatment of depression is one of the most exciting news of the last few years. Given the well known difficulty in treating resistant depressed patients, the possibility to relieve their status in few hours using ketamine suggests that we are close to the long dreamed target of many clinicians. However this is not so simple considering the many problems linked to this strategy, including transient effect, psychotomimetic side effects and reduce efficacy on rechallenge. Probably the mechanism of rapid antidepressant effect differs from the long lasting one. The detailed review of Hashimoto in this issue enlightens this issue with pro and cons of all possible treatments modulating different glutamatergic systems. However the knowledge of its exact impact in depression and antidepressant treatment is far from clear also because of the many interplay with other neurotransmitter systems. However glutamate modulators remain the most interesting and promising compounds for the future antidepressant treatment. Antidepressant efficacy may be better understood when biological bases of their efficacy are identified. Genetics and pharmacogenetics are frequently considered the future. The possibility to tailor antidepressant treatment on the basis of the individual genetic background, or, even better, synthesize new compounds on the basis of the identified genetic abnormalities, would greatly improve our everyday clinical practice. Though still early for a clinical application, some promising results have been achieved. In this issue Laje and McMahon reports the latest findings of the most advanced technology available to date, i.e. whole genome analysis, applied to three large samples but still the picture is far from clear. A complementary investigation is imaging. To know which are the regions morphologically and dynamically involved in depression is crucial. Again we are facing an heterogeneous situation where findings are discrepant. However a strong convergence has been observed regarding prefrontal cortex and some anterior cingulate and medial temporal areas, both for depression and antidepressant mechanism of action. Probably we need a much more detailed information, maybe at molecular level. As an example, magnetic resonance spectroscopy studies are not yet at a sufficiently detailed level to observe rapid, slight and very local modifications. Bellani and collaborators offered an updated view in his review. The focus on cannabinoid system by Gorzaca and Hill and the one on circadian rhythms by Monteleone and collaborators offer other important perspectives on the issue. The latter in particular raised growing interest due to the findings of the very fast effect of circadian manipulation in depressed patients and of the protective effect of circadian regulation in bipolar patients, not to mention the recent results of agomelatine use in depression. Not everyone consider antidepressant as useful, in fact another important issue that has been raised recently is about the usefulness of antidepressants at all or even of their harmfulness. Fava and Offidani in this issue present a detailed review of all evidence toward the possible induction of more resistant forms of depression in the long term use. Even if one can disagree with the author's conclusion, also in partial disagreement with international guidelines, always to be considered by clinicians in the field, it offers an important and alternative point of view. Finally, a common mistake is to consider neurotransmitter pathways as separate entities, in this issue the intriguing contribution by Porcelli and collaborators faces the issues that major theories of depression are intertwined. In particular the monoaminergic, inflammatory, epigenetics, neurotrophin and anti-apoptotic theories are analyzed under their dopamine common control. It is obviously only one perspective and many other complementary ones could be presented, but it has the advantage of showing for the first time as a common factor can explain some contradictory findings, an example that could lead the way to further developments. The neurotropin/neurodevelopmental perspective is then very nicely complemented with the environmental one in the Pringle and collaborators review. This line of research, supported by much independent evidence, posits that antidepressants do not act in a straight fashion, but through changing the emotional attitude. Drugs would therefore decrease negative biases in information processing thus allowing for an improved environment in turn facilitating the biological changes leading to remission. In conclusion, skeptical comments about the neurobiology of depression and antidepressant action are common and point to the contradictory findings, in my opinion there is sufficient evidence that we are getting close to the understanding of those mechanisms, it is just a question of time and of the possibility to perform simultaneous assessment of environmental and biologic factors.