Brain & Health

New Advances in Depression Therapy

Written by

As humans, we experience a very wide range of emotions, happiness being the one we focus on the most. This might be a reason why talking about feeling depressed is still a taboo in many cultures, even though depression is a widely spread mental disorder.

The World Health Organization (WHO) describes a mental disorder as a health condition characterized by “significant disturbance in an individual’s cognition, emotional regulation, or behavior” (WHO, 2022). In 2019, 1 in every 8 people worldwide suffered from a mental disorder, with anxiety and depression being the most common ones (IHME, 2022). Fueled by the COVID-19 pandemic, these numbers have increased dramatically and now depression and anxiety cases have doubled. The prevalence of these conditions in children and adolescents has also increased alarmingly by more than 20% (Racine et al., 2021).

Regardless of the constant need of assertive therapies against depression, the discovery of new treatments is rather stagnant. Compared to other mortal diseases, advances in the treatment of psychological disorders in general have been devastatingly moderate for decades. Reasons for this include the complexity of the diseases, inadequate read-outs, poor clinical study designs and a general lack of neurobiological hypotheses (Blackburn, 2019). For over 50 years, antidepressants like selective serotonin reuptake inhibitors (SSRIs) and the monoamine theory have dominated the field with moderate results against depression (Blackburn, 2019; WHO, 2021). Sadly, a fast-acting well-tolerated antidepressant agent has never been found with the SSRIs approach. In the past decade, new approaches and neurobiological hypotheses have emerged, creating hope for a change in the prospects of treatments against depression.

Depression treatments

Regardless of our scientific advancements and technology development, we are still far from understanding the brain, which poses a critical limit to the development of better treatments for depression.

Serotonin reuptake inhibitors (SSRIs) are currently the most used antidepressant drugs. On the molecular level, these drugs block the reuptake of the neurotransmitter serotonin, which is involved in several physiological functions. Higher serotonin levels have been associated with a positive effect in mood, emotion and sleep (Blackburn, 2019). Be that as it may, the effect of SSRIs is oddly not correlated with the administered dose, meaning a higher dose of SSRIs does not result in a stronger effect. Without going into further detail of the status quo, the available antidepressants nowadays are not sufficient and new approaches to treat psychological disorders are dearly needed.

Nowadays, psychoactive compounds (psychedelics) are slowly entering the  world of psychotherapy through their professionally supervised intake during psychedelic-assisted therapy (PAP) (Schenberg, 2018). Psychedelics are substances that “alter consciousness in a marked and novel way” (Carhart-Harris & Goodwin, 2017) and create temporary changes in mood (Schenberg, 2018). Psilocybin is a naturally occurring psychedelic that produces hallucinations; it is found in hundreds of mushrooms worldwide and was discovered by Albert Hofmann in the mushroom Psilocybe mexicana (Haberman, 2018). Psilocybin is currently a promising antidepressant candidate (Carhart-Harris et al., 2021).

What is the effect of psilocybin in humans?

The effect of psilocybin in humans remained a mystery to science for a long time. Nevertheless, in recent years more and more studies have helped to understand its effects (Carhart-Harris et al., 2012; Brown, 2017; Carhart-Harris et al., 2021.; Studerus et al., 2011), showing that psilocybin induces changes in mood, perception and thought in a dose-dependent way. Such changes are perceived as pleasurable and enriching by the patients (Studerus et al., 2011). An important finding from follow-up studies indicates that psilocybin induced neither a subsequent drug abuse problem in the subjects, nor impairment or persistence of perception disorders (Haberman, 2018; Studerus et al., 2011). Furthermore, results suggest that moderate doses of psilocybin coupled to careful monitoring might be a path worth exploring, as a treatment against mental disorders such as depression. However, due to limited information about potential subjective side effects, the controlled medical use of these compounds has remained controversial (Studerus et al., 2011).

How close are we from using psychoactive compounds as psychiatric medical tools?

Currently, psychoactive compounds for psychiatric medical use are a hot topic in clinical research, producing groundbreaking results for treating mental disorders. MDMA, the nervous system stimulant known as ecstasy, revolutionized post-traumatic stress disorder (PTSD) therapies (Mitchell, 2021) with efficacy results beyond any comparison (Hieronymus et al., 2016). Johnson & Johnson (Janssen group) received FDA approval in August 2020 for their esketamine nasal spray SPRAVATO® to counteract “Major Depressive Disorder with Acute Suicidal Ideation or Behavior”, due to outstanding clinical research results. Rapid-acting antidepressants (RAADs) such as ketamine showed a therapeutic effect within hours of administration, while monoamine-based antidepressants require a minimum of 4 weeks before they exhibit any effect (Riggs & Gould, 2021).

A new age of psychotherapy is emerging, paved by solid evidence. Psilocybin could be the next candidate.

In recent years, funding restrictions started to slowly be lifted for research involving psilocybin or other psychoactive compounds for psychological disorder therapy. The agenda is essentially the same as it was with marijuana: if enough clinical studies prove the medical use of a category 1 drug, it does not further qualify for the category 1 definition, which clearly states that a category 1 drug does not have any medical use. With a transfer into category 2, as it was achieved with marijuana in recent years, prescription of a drug such as psilocybin would be possible, and a new treatment option would emerge for the public. This could be the greatest attempt to address the growing public health crisis of depression in all ages.

Written by Karla Azucena Juárez Núñez; Edited by Jie Shi. Featured Image: NGC/Design.


Blackburn TP. Depressive disorders: Treatment failures and poor prognosis over the last 50 years. Pharmacol Res Perspect. 2019 May 3;7(3):e00472. PMID: 31065377; PMCID: PMC6498411

Brown RT, Nicholas CR, Cozzi NV, Gassman MC, Cooper KM, Muller D, Thomas CD, Hetzel SJ, Henriquez KM, Ribaudo AS, Hutson PR. Pharmacokinetics of Escalating Doses of Oral Psilocybin in Healthy Adults. Clin Pharmacokinet. 2017 Dec;56(12):1543-1554. PMID: 28353056

Carhart-Harris et al. Neural correlates of the psychedelic state as determined by fMRI studies with psilocybin. PNAS. 2012

Carhart-Harris, R. & Goodwin, G. The Therapeutic Potential of Psychedelic Drugs: Past, Present, and Future. Neuropsychopharmacol 42, 2105–2113 (2017)

Carhart-Harris et al. 2021. Trial of Psilocybin versus Escitalopram for Depression. The new england journal of medicine

Haberman Daniel. Clinical potential of psilocybin as a treatment for mental health conditions. Ment Health Clin. 2018 Mar 23;7(1):24-28. PMID: 29955494; PMCID: PMC6007659

Hieronymus et al. A mega-analysis of fixed-dose trials reveals dose-dependency and a rapid onset of action for the antidepressant effect of three selective serotonin reuptake inhibitors. Transl Psychiatry. 2016 Jun 7;6(6):e834. PMID: 27271860; PMCID: PMC4931602

Institute of Health Metrics and Evaluation (IHME). Global Health Data Exchange (GHDx). 2022. Accessed in October 2022

Mitchell et al. MDMA-assisted therapy for severe PTSD: a randomized, double-blind, placebo-controlled phase 3 study. Nat Med 27, 1025–1033 (2021)

Racine et al. Global Prevalence of Depressive and Anxiety Symptoms in Children and Adolescents During COVID-19: A Meta-analysis. JAMA Pediatr. 2021;175(11):1142–1150

Riggs LM & Gould TD. Ketamine and the Future of Rapid-Acting Antidepressants. Annu Rev Clin Psychol. 2021 May 7;17:207-231. Epub 2021 Feb 9. PMID: 33561364; PMCID: PMC8170851

Schenberg EE. Psychedelic-Assisted Psychotherapy: A Paradigm Shift in Psychiatric Research and Development. Front Pharmacol. 2018 Jul 5;9:733. PMID: 30026698; PMCID: PMC6041963

Studerus et al. Acute, subacute and long-term subjective effects of psilocybin in healthy humans: a pooled analysis of experimental studies. J Psychopharmacol. 2011 Nov;25(11):1434-52

World Health Organization (WHO). Mental Disorders. 2022. Accessed in October 2022

Go back