Major Depressive Disorder: History
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        Despite the extensive research conducted in the last decades, the molecular mechanisms underlying major depressive disorder (MDD) and relative evidence-based treatments remain unclear. Various hypotheses have been successively proposed, involving different biological systems. This narrative review aims to critically illustrate the main pathogenic hypotheses of MDD, ranging from the historical ones based on the monoaminergic and neurotrophic theories, through the subsequent neurodevelopmental, glutamatergic, GABAergic, inflammatory/immune and endocrine explanations, until the most recent evidence postulating a role for fatty acids and the gut microbiota. Moreover, the molecular effects of established both pharmacological and non-pharmacological approaches for MDD are also reviewed. Overall, the existing literature indicates that the molecular mechanisms described in the context of these different hypotheses, rather than representing alternatives one to each other, are likely to contribute together, often with reciprocal interactions, to the development of MDD and to the effectiveness of treatments, and points at the need for further research efforts in this field. 

  • major depressive disorder
  • antidepressant drugs
  • non-pharmacological treatments
  • electroconvulsive therapy
  • monoamines
  • serotonin
  • neurotrophins
  • brain-derived neurotrophic factor
  • inflammation

1. Symptoms

       Major depressive disorder (MDD) is a disabling psychiatric condition leading to a persistent feeling of sadness and loss of interest, and it is among the top five leading causes of disability and disease burden throughout the world. MDD and other forms of clinical depression are characterized by persistent low mood with associated changes in behaviour, cognition, sleep and appetite, impaired social and occupational functioning, increased risk of self-harm or suicide, and increased mortality due to co-occurring general medical disorders [1].

       The course of MDD is quite variable; indeed, many patients never, or only rarely, reach remission, considered as a period of at least two months without symptoms, and experience relapses. Moreover, although MDD may occur only once during life, people typically have multiple depressive episodes; in this case, the disease is defined as recurrent depression. For the definition of recurrence, there must be an interval of at least two consecutive months between separate episodes in which the criteria for a major depressive episode are not met. Recurrence rates are over 85% within a decade from an index depressive episode, and average approximately 50% or more within six months of apparent clinical remission if the initially effective treatment is not continued [2][3]. In turn, the chronicity of the pathology reduces drastically the probability of a complete resolution of the symptomatology.

2. Therapy

       Several international guidelines for the acute treatment of moderate to severe MDD recommend a first-line treatment with antidepressant drugs (ADs), including selective serotonin (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs), older tricyclic antidepressants (TCAs) and a growing number of other types of drugs. However, although the most widespread therapeutic approach for MDD is represented by drug treatments, these are often ineffective. The most  important pharmacological trials carried out on MDD patients revealed that only about one third of them respond to the first treatment with ADs [4][5]. Most patients with MDD need different pharmacological treatments, often in combination, to achieve remission of symptoms, and a high percentage of them, about 30–40%, is classified as suffering from treatment-resistant depression (TRD) [6][7]. Moreover, acute treatment with antidepressant medications has not been associated with the prevention of recurrence or relapse, but continuing or maintaining antidepressant medication regimens for patients has been associated with forestalling symptom return [8][9].

       The inadequacy of the response to pharmacological therapies encouraged the development and the interest in non-pharmacological treatments, mainly used as adjuvants to drug treatments. Currently, several non-pharmacological treatments for MDD are available, such as electroconvulsive therapy (ECT) and cognitive behavioural therapy (CBT), which are relatively well established as having at least moderate efficacy for the short-term treatment of acute MDD [2][9][10]. A relevant issue concerning non-pharmacological treatments is that this term refers to a myriad of procedures that have in common the non-use of drugs, but which are strongly different one to each other. To date, the non-pharmacological treatments widespread in clinical practice for the treatment of MDD (particularly for severe and recurrent forms) that have demonstrated strong efficacy and have been reported in the National Institute for Health and Care Excellence guidelines update in 2019 are ECT, repetitive transcranial magnetic stimulation (rTMS) and vagus nerve stimulation (VNS) among neuromodulation strategies, and CBT and interpersonal psychotherapy (IPT) among psychotherapies [11][12][13][14].

       Several molecular studies were carried out concerning the pathogenesis of MDD, but the implicated molecular mechanisms remain largely unclear, although various hypotheses have been proposed. Furthermore, studies conducted on biomarkers of MDD treatments did not allow drawing exhaustive conclusions about the mechanisms involved and the possibility to discriminate responders and non-responders; consequently, personalized medicine for MDD is far from being used in daily clinical practice.

This entry is adapted from the peer-reviewed paper 10.3390/genes11091089


  1. Hasin, D.S.; Sarvet, A.L.; Meyers, J.L.; Saha, T.D.; Ruan, W.J.; Stohl, M.; Grant, B.F. Epidemiology of Adult DSM-5 Major Depressive Disorder and Its Specifiers in the United States. JAMA Psychiatry 2018, 75, 336–346, doi:10.1001/jamapsychiatry.2017.4602.
  2. Sim, K.; Lau, W.K.; Sim, J.; Sum, M.Y.; Baldessarini, R.J. Prevention of Relapse and Recurrence in Adults with Major Depressive Disorder: Systematic Review and Meta-Analyses of Controlled Trials. Int. J. Neuropsychopharmacol. 2015, 19, doi:10.1093/ijnp/pyv076.
  3. Baldessarini, R.J.; Lau, W.K.; Sim, J.; Sum, M.Y.; Sim, K. Duration of initial antidepressant treatment and subsequent relapse of major depression. J. Clin. Psychopharmacol. 2015, 35, 75–76, doi:10.1097/JCP.0000000000000263.
  4. Trivedi, M.H.; Rush, A.J.; Wisniewski, S.R.; Nierenberg, A.A.; Warden, D.; Ritz, L.; Norquist, G.; Howland, R.H.; Lebowitz, B.; McGrath, P.J.; et al. Evaluation of outcomes with citalopram for depression using measurement-based care in STAR*D: Implications for clinical practice. Am. J. Psychiatry 2006, 163, 28–40, doi:10.1176/appi.ajp.163.1.28.
  5. Gaynes, B.N.; Rush, A.J.; Trivedi, M.H.; Wisniewski, S.R.; Spencer, D.; Fava, M. The STAR*D study: Treating depression in the real world. Cleve. Clin. J. Med. 2008, 75, 57–66.
  6. Berlim, M.T.; Turecki, G. Definition, assessment, and staging of treatment-resistant refractory major depression: A review of current concepts and methods. Can. J. Psychiatry. 2007, 52, 46–54, doi:10.1177/070674370705200108.
  7. Thomas, L.; Kessler, D.; Campbell, J.; Morrison, J.; Peters, T.J.; Williams, C.; Lewis, G.; Wiles, N. Prevalence of treatment-resistant depression in primary care: Cross-sectional data. Br. J. Gen. Pract. 2013, 63, e852–e858, doi:10.3399/bjgp13X675430.
  8. Glue, P.; Donovan, M.R.; Kolluri, S.; Emir, B. Meta-analysis of relapse prevention antidepressant trials in depressive disorders. Aust. N. Z. J. Psychiatry 2010, 44, 697–705, doi:10.3109/00048671003705441.
  9. DeRubeis, R.J.; Zajecka, J.; Shelton, R.C.; Amsterdam, J.D.; Fawcett, J.; Xu, C.; Young, P.R.; Gallop, R.; Hollon, S.D. Prevention of Recurrence After Recovery From a Major Depressive Episode With Antidepressant Medication Alone or in Combination With Cognitive Behavioral Therapy: A Phase 2 Randomized Clinical Trial. JAMA Psychiatry 2019, doi:10.1001/jamapsychiatry.2019.3900.
  10. Cuijpers, P.; Sijbrandij, M.; Koole, S.L.; Andersson, G.; Beekman, A.T.; Reynolds, C.F. Adding psychotherapy to antidepressant medication in depression and anxiety disorders: A meta-analysis. World Psychiatry 2014, 13, 56–67, doi:10.1002/wps.20089.
  11. Kellner, C.H.; Obbels, J.; Sienaert, P. When to consider electroconvulsive therapy (ECT). Acta Psychiatr. Scand. 2020, 141, 304–315, doi:10.1111/acps.13134.
  12. McClintock, S.M.; Reti, I.M.; Carpenter, L.L.; McDonald, W.M.; Dubin, M.; Taylor, S.F.; Cook, I.A.; O’Reardon, J.; Husain, M.M.; Wall, C.; et al. Consensus Recommendations for the Clinical Application of Repetitive Transcranial Magnetic Stimulation (rTMS) in the Treatment of Depression. J. Clin. Psychiatry 2017, 79, doi:10.4088/JCP.16cs10905.
  13. Bottomley, J.M.; LeReun, C.; Diamantopoulos, A.; Mitchell, S.; Gaynes, B.N. Vagus nerve stimulation (VNS) therapy in patients with treatment resistant depression: A systematic review and meta-analysis. Compr. Psychiatry 2019, 98, 152156, doi:10.1016/j.comppsych.2019.152156.
  14. Whiston, A.; Bockting, C.L.H.; Semkovska, M. Towards personalising treatment: A systematic review and meta-analysis of face-to-face efficacy moderators of cognitive-behavioral therapy and interpersonal psychotherapy for major depressive disorder. Psychol. Med. 2019, 49, 2657–2668, doi:10.1017/S0033291719002812.
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