International Union of Basic and Clinical Pharmacology CIV: The Neurobiology of Treatment-resistant Depression: From Antidepressant Classifications to Novel Pharmacological Targets

Abstract

Major depressive disorder is one of the most prevalent and life-threatening forms of mental illnesses and a major cause of morbidity worldwide. Currently available antidepressants are effective for most patients, although around 30% are considered treatment resistant (TRD), a condition that is associated with a significant impairment of cognitive function and poor quality of life. In this respect, the identification of the molecular mechanisms contributing to TRD represents an essential step for the design of novel and more efficacious drugs able to modify the clinical course of this disorder and increase remission rates in clinical practice. New insights into the neurobiology of TRD have shed light on the role of a number of different mechanisms, including the glutamatergic system, immune/inflammatory systems, neurotrophin function, and epigenetics. Advances in drug discovery processes in TRD have also influenced the classification of antidepressant drugs and novel classifications are available, such as the neuroscience-based nomenclature that can incorporate such advances in drug development for TRD. This review aims to provide an up-to-date description of key mechanisms in TRD and describe current therapeutic strategies for TRD before examining novel approaches that may ultimately address important neurobiological mechanisms not targeted by currently available antidepressants. All in all, we suggest that drug targeting different neurobiological systems should be able to restore normal function but must also promote resilience to reduce the long-term vulnerability to recurrent depressive episodes.

The emergence of loss of efficacy during antidepressant drug treatment for major depressive disorder: An integrative review of evidence, mechanisms, and clinical implications

“…A closely related phenomenon seems to be "resistance" to antidepressant treatment. As noted, there are many drivers of treatment resistance in depression [27], with a number of clinical factors identified by the studies GSRD (European Group for the Study of Resistant Depression) [28,29] including, but not limited to, psychiatric and general medicine comorbidities, and a number of clinical-demographic variables affecting the lifetime course and current status of depression, as reviewed by Caraci F. et al, 2018 [30]. In 1984, Lieb and Balter [31] described the emergence of refractoriness in some patients with MDD to drugs for depression that had been previously efficacious.…”

Is cognitive dysfunction involved in difficult-to-treat depression? Characterizing resistance from a cognitive perspective

“…(a) Duration is scored 1-3 corresponding to acute (<1 year), subacute (1 to <2 years), and chronic (>2 years); (b) severity is scored 1-5 corresponding to subsyndromal, mild, moderate, severe without psychosis, and severe with psychosis; and (c) treatment strategies are scored 1-5 with regard to antidepressants (level 1: 1-2 medications; level 2: 3-4 medications; level 3: 5-6 medications; level 4: 7-10 medications; and level 5: >10 medications), plus 0 or 1 with regard to pharmacological augmentation strategy, and plus 0 or 1 with regard to ECT. Study participants were categorized as resistant (7)(8)(9)(10)(11)(12)(13)(14)(15) or nonresistant (3-6) according to their total MSM score.…”

“…Several sociodemographic, clinical, and neurobiological factors have been associated with the presence of treatment resistance in depression. A recent review by Caraci et al [7], which includes the study performed by the European Group for the Study of Resistant Depression, reported several clinical features significantly associated with treatment resistance. These variables were comorbid psychiatric disorders, suicide risk, severity and duration of current episode, number of hospitalizations, depressive recurrences, melancholic and psychotic features, nonresponse to a first antidepressant treatment, occurrence of side effects during treatment, lower age at onset, high occupational level, and family psychiatric history.…”

The impact of whole-body hyperthermia interventions on mood and depression – are we ready for recommendations for clinical application?

“…The S-3 guidelines from the Association of Scientific Medical Societies in Germany (AWMF) [3] recommend pharmacological and behavioral interventions for mild to moderate depression and electroconvulsive therapy (ECT) as the standard treatment for more severe and chronic symptomology. About 20-30% of patients receiving common, pharmacological treatments, do not respond to the intervention or develop side effects [4,5]. Furthermore, a treatment resistant depression has been associated with significant alterations of cognitive functions and even suicidal attempts [5,6].…”

“…About 20-30% of patients receiving common, pharmacological treatments, do not respond to the intervention or develop side effects [4,5]. Furthermore, a treatment resistant depression has been associated with significant alterations of cognitive functions and even suicidal attempts [5,6]. This might reflect a need for effective alternative treatments or interventions to complement common clinical practice.…”