Prof. Andreas Reif

Andreas Reif is a German Psychiatrist, who received his training at the University Hospital Würzburg, where he also did his residency and later on became Vice Chair of the Department of Psychiatry. In 2014, he took over the position of the Chair of the Department of Psychiatry, Psychosomatic Medicine and Psychotherapy at the University Medical Center Frankfurt, where he is also full professor of psychiatry. AR’s clinical and research interests encompass affective disorders (TRD, bipolar disorder, suicidality), aggression and adult ADHD; his research is translational in nature and revolves around the ideas of precision psychiatry, i.e. identifying the best therapy at the exact time for a given individual patient. He has published more than 675 original papers and reviews, also in the most prestigious journals such a the New England Journal of Medicine, Lancet and Science, and has an h² index of 101. Collaborative research efforts where he has a leading role include the Collaborative Research Center on the Neurobiology of Aggression (TRR SFB 379) and the LOEWE Centre DYNAMIC, the latter focusing on conceptualizing mental disorders as a disturbance of dynamic networks on several levels from neurobiology to psychopathology. He is an internationally renowned speaker and active in several learned societies, especially the German Psychiatric Association (DGPPN), where he is an executive board member since 2017, as well as ECNP, where he is President Elect (Presidency 2025-2028). Also, he is involved in several clinical guidelines and outreach programs.

For several decades, depression appeared to be the death valley of innovation in psychopharmacotherapy. The discovery of tricyclic antidepressants and MAO inhibitors in the fifties triggered the monoamine theory of depression, which further led to the development of SSRI/SNRI in the 1980ies. Since then, no new developments hit the market. This has changed ca. five years ago, when intranasal esketamine was approved for the treatment of therapy-resistant depression (TRD) and psychiatric emergency in the context of depression: it was the first-in-class compound of NMDA antagonists (or rather indirect AMPA agonists, which seems to be the downstream mechanism of action). This triggered the development of other molecules that target the glutamatergic system. Most of those modulate the NMDA receptor itself; this includes the NMDA antagonists dextromethorphan, already on the market in the US as a fixed combination with bupropion (Auvelity®), esmethadone, and laughing gas (nitrous oxide). Beyond direct antagonism, negative allosteric modulators of the NMDA receptor are currently tested for their antidepressant efficacy. Next to the NMDA receptor, other molecules of this signalling cascade are evaluated for being an antidepressant target. AMPA activators (AMPAkines) are most promising in this respect and have already shown efficacy in phase II trials. Besides glutamatergic compounds, “psychedelics” – being characterized by 5HT2a agonism – are the second mechanistic class of novel antidepressants with great promise. Here, the lead compound psilocybin was studied in several phase II trials and is currently tested in a large multicenter phase III trial program. Unlike other trials in depression, most psilocybin trials incorporate an intricate psychotherapy regime which makes it hard to determine whether drug or doc is the main driver of improvement. This strategy has been left in phase II trials of 5-MeO-DMT, which is a highly psychoactive yet short-acting psychedelic, where no psychotherapy was delivered as part of the study. Nevertheless, the effect size was substantial with a ca. 15 point MADRS reduction after just one dose of 5-MeO-DMT in TRD. While glutamatergic and psychedelic drugs are most advanced and also most diverse, there are further different mechanisms of action, currently tested in clinical studies: these include positive allosteric modulators of GABA-A receptors (GABA-PAM, a.k.a. neurosteroids), which are already licensed for post-partum depression (PPD) in the US (lead compound, zuranolone); muscarine M1 receptor antagonists (lead compound, scopolamine); orexin 2 receptor antagonists (lead compound, seltorexant) and immunomodulators.

Notably, the indication for most, if not all of the newly developed antidepressants is not “major depressive disorder”, but rather sub-indications: psychiatric emergency in depression, failure of first line therapy of depression, TRD, PPD, depression with anhedonia, depression with insomnia, to name but a few. While this might be considered a precision psychiatry approach, regulatory and HTA reasons might play an even more important role, as the bar to obtain reimbursement for treatment-naïve, first episode patients is quite high.

To conclude, for the first time since half a century, we have recently seen the introduction of a new mechanism of action in antidepressant treatment and several others are highly promising, with likely market approval of at least one or two psychedelics in the coming years. Also, there is a clear trend to develop drugs for sub-indications of depression, rather than depression as a whole. These developments can be expected to transform the psychiatric treatment landscape in the next ten years, to the benefit of our patients.

• Freudenberg F, Celikel T, Reif A. (2015). The role of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors in depression: central mediators of pathophysiology and antidepressant activity? Neurosci Biobehav Rev. 2015 May;52:193-206. doi: 10.1016/j.neubiorev.2015.03.005
• Reif A, et al. (2023). Esketamine Nasal Spray versus Quetiapine for Treatment-Resistant Depression. N Engl J Med. 2023 Oct 5;389(14):1298-1309. doi: 10.1056/NEJMoa2304145.
• Metaxa AM, Clarke M. (2023). Efficacy of psilocybin for treating symptoms of depression: systematic review and meta-analysis. BMJ. 2024 May 1;385:e078084. doi: 10.1136/bmj-2023-078084.
• Freudenberg F, Reif-Leonhard C, Reif A. (2024). Advancing past ketamine: emerging glutamatergic compounds for the treatment of depression. Eur Arch Psychiatry Clin Neurosci. 2024 Aug 29. doi: 10.1007/s00406-024-01875-z.