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Review
. 2021 Feb 23;11(2):155.
doi: 10.3390/jpm11020155.

Treatment-Resistant Depression Revisited: A Glimmer of Hope

Angelos Halaris  1 , Emilie Sohl  1 , Elizabeth A Whitham  1
Affiliations
Review

Treatment-Resistant Depression Revisited: A Glimmer of Hope

Angelos Halaris et al. J Pers Med. .

Abstract

Major Depressive Disorder (MDD) is a highly prevalent psychiatric disorder worldwide. It causes individual suffering, loss of productivity, increased health care costs and high suicide risk. Current pharmacologic interventions fail to produce at least partial response to approximately one third of these patients, and remission is obtained in approximately 30% of patients. This is known as Treatment-Resistant Depression (TRD). The burden of TRD exponentially increases the longer it persists, with a higher risk of impaired functional and social functioning, vast losses in quality of life and significant risk of somatic morbidity and suicidality. Different approaches have been suggested and utilized, but the results have not been encouraging. In this review article, we present new approaches to identify and correct potential causes of TRD, thereby reducing its prevalence and with it the overall burden of this disease entity. We will address potential contributory factors to TRD, most of which can be investigated in many laboratories as routine tests. We discuss endocrinological aberrations, notably, hypothalamic-pituitary-adrenal (HPA) axis dysregulation and thyroid and gonadal dysfunction. We address the role of Vitamin D in contributing to depression. Pharmacogenomic testing is being increasingly used to determine Single Nucleotide Polymorphisms in Cytochrome P450, Serotonin Transporter, COMT, folic acid conversion (MTHFR). As the role of immune system dysregulation is being recognized as potentially a major contributory factor to TRD, the measurement of C-reactive protein (CRP) and select immune biomarkers, where testing is available, can guide combination treatments with anti-inflammatory agents (e.g., selective COX-2 inhibitors) reversing treatment resistance. We focus on established and emerging test procedures, potential biomarkers and non-biologic assessments and interventions to apply personalized medicine to effectively manage treatment resistance in general and TRD specifically.

Keywords: HPA axis; MTHFR; Vitamin D; diabetes; folic acid; major depressive disorder; pharmacogenomics; sex hormones; treatment resistance.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Folic acid pathway and other critical pathways involved in neurotransmitter synthesis.
Figure 2
Figure 2
Downstream effects of MTHFR polymorphism and implications on neurotransmitter synthesis. MTHFR polymorphisms lead to decreased synthesis of L-methylfolate, leading to decreased levels of dopamine, norepinephrine and serotonin.
Figure 3
Figure 3
SLA6A4 Alleles. The SLC6A4 promoter variant is among the best studied polymorphisms in psychiatry. Multiple meta-analyses confirm significantly lower rates of response and remission in S/S and L/S individuals.
Figure 4
Figure 4
Flow chart for assessment of TRD: approach to assessing possible contributing factors to TRD.
See this image and copyright information in PMC

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