Medical Pharmacology: Drugs Used to Manage Depression

Etiology of depression (continued)

Although the exact cause of major depressive disorder remains to be elucidated, a number of factors have been suggested.²
- These potential contributors include genetic, psychodynamic, socioenvironmental and biochemical factors.²

Genetics (continued)

Perhaps as much as 40% of the risk of developing depression may be hereditary; as an example, adopted children whose biological parents exhibited depression have a greater risk of developing depression then those adopted children whose biological parents were unaffected.²⁶
Furthermore, frequency of depression is increased in relatives of patients, with a prevalence rate between about 15%-25% in first-degree relatives.
Depression risk among first-degree relatives is increased comparing 15% to about 1%-2% general population risk.²⁶
- Considering "twin studies", for unipolar depressive disorder 40% of monozygotic twins and 11% of same-sex dizygotic twins are affected. (The values for bipolar depressive disorder, for comparison, are 72% [monozygotic] and 14% [same-sex dizygotic]).^26,49
- Some texts indicate that the serotonin transporter gene allelic variations (polymorphism) may be responsible for depression susceptibility; however, given conflicting reports in the literature, further studies are needed to clarify possible relationships between serotonin transporter gene polymorphism and depression.
The relative risk ratio (RRB, i.e., ratio of risks to first-degree relatives of individuals exhibiting major depressive disorder compared to the general population) is about 2-3.^50,51
- However, the mode of inheritance remains to be elucidated and significant environmental risk factors include child abuse, neglect, and life stress.^50,52

Genetic mapping study utility is based on determining the relative risk ratio associated with each gene or interaction; furthermore, endogenous depression susceptibility may be due to multigenic mechanisms.⁵⁰

**Genes and Treatment for Depression and Anxiety⁵⁷**

Attribution: Pine D. Genes and Treatment for Depression and Anxiety (8 of 8) http://www.youtube.com/watch?v=mzNdE6kD5tc (11/2019) DNA Learning Center YouTube Channel: https://www.youtube.com/channel/UC8wZzNSXUHzv3QijdOzeELA

The relative risk ratio for both recurrent and early-onset major depression has been estimated to be at least 4-5.⁵⁰
- As an aside, although relatives of bipolar disorder patients are at risk for major depression, the converse is not observed.

Other neuropsychiatric conditions may predict major depressive disorder.⁵⁰

Neuroticism, characterized by anxiety, dysphoria, tension and emotional reactivity, exhibits heritability on the order of 40%-50% and appears to be a prominent predictor of future major depressive disorder onset.^50,53,54,55

Perhaps 55% of genetic risk associated with major depression appear shared with neuroticism.

Genetic factors appear more likely associated with major depressive disorder, neuroticism and generalized anxiety disorder and less likely associated with panic disorder and social phobia.⁵⁰

**Social Anxiety Disorder⁵⁶**

Attribution: Granet D Stein M "What is Social Anxiety Disorder", http://www.youtube.com/watch?v=4truuD_xMP0 . University of California Television (UCTV) YouTube Channel: https://www.youtube.com/channel/UCh6KFtW4a4Ozr81GI1cxaBQ

As described earlier, studies on functional polymorphism, defined as DNA sequence alterations that change expression and/or gene product function, have focused on monoamine related genes and on brain-derived neurotrophic factor neuroprotective proteins.⁵⁰

With respect to monoamine-related genes, the serotonin transporter gene (SLC6A4) has received particular attention.

However, a recent comprehensive study has cast doubt on whether historical candidate genes, including SLC6A4, related to depression is supportable.
- Border R Johnson EC Evans LM Smolen A Berley N Sullivan PF Keller MC No Support for Historical Candidate Gene or Candidate Gene-by-Interaction Hypothesis for Major Depression Across Multiple Large Samples Am J Psychiatry 2019 May 1; 176(5): 376-387. https://www.ncbi.nlm.nih.gov/pubmed/30845820.

**Serotonin reuptake transporters: Mechanism of Action⁶⁴**

"The action of 5-HT at the synapse is terminated by its re-uptake across the pre-synaptic membrane. This is an energy dependent process. Sodium/potassium ATPases use energy from ATP hydrolysis to create a concentration gradient of ions across the pre-synaptic membrane that drives the opening of the transporter and co-transport of sodium and chloride ions and 5-HT from the synaptic cleft. Potassium ions binding to the transporter enable it to return to the outward position. Release of the potassium ions into the synaptic cleft equilibrates the ionic gradient across the pre-synaptic membrane. The 5-HT re-uptake transporter is then available to bind another 5-HT molecule for re-uptake."⁶⁴

Additionally, the serotonin 2A receptor gene the tyrosine hydroxylase gene, tryptophan hydroxylase 2 (TPH2) gene and the catechol-O-methyltransferase (COMT) gene have also been analyzed.

With respect to the serotonin transporter gene, a polymorphic region consisting of 44-base pair insertion/deletion site on the short allele has received special attention.⁵⁰
- Provisional results suggest possible associations with suicidal behavior and alcoholic (as opposed to depressed) individuals; furthermore, modest association with bipolar depression and an association with depression-related trait scores have been reported.
  - These conclusions were derived from meta-analysis.
A recent meta-analysis study considered interaction between serotonin transporter gene, stressful life events and depression risk.⁵⁸
- This analysis considered 26 studies, of which 14 met the authors criteria for the meta-analysis.
  - In this meta-analysis of published research results, the number of stressful life events was associated with depression; however, no association was noted between the serotonin transporter gene genotype and depression.
  - Furthermore, no evidence was found that serotonin transporter gene type interacting with stressful life events was associated with increased depression risk in men alone, women alone, or in both sexes combined.⁵⁸

The tryptophan hydroxylase 2 isoform, has been identified as the principle enzyme form in the brain.⁵⁹
- Serotonin Biosynthesis Pathway⁶⁵
- Tryptophan hydroxylase⁶⁶
- Major depressive disorder may be associated with single nucleotide polymorphisms of the gene associated with this isoform.^60,63
  - A recent study analyzed an association between tryptophan hydroxylase 2 isoform and late-onset depression.⁶¹
    - These investigators genotyped 8 single nucleotide polymorphisms in the TPH2 gene in 84 patients with late onset depression and in 79 individuals who served controls.
      - The study was conducted in the Brazilian population.
      - Association was found between two single nucleotide polymorphisms and late onset depression.⁶¹
  - A related study involving Caucasians (Northern Swedish) reported association between TPH2 haplotypes and major depression.⁶²

Brain-derived neurotrophic factor (BDNF) is a neuroprotective protein that may be linked to major depressive disorder.⁵⁰

**BDNF Structure⁷³**

BDNF is a member of the neurotrophin group of growth factors related to "nerve growth factor."⁷⁴

**Brain-Derived Neurotrophic Factor (BDNF) Pathway⁷²**

Brain-Derived Neurotrophic Factor (BDNF) pathway (© 2009 QIAGEN, all rights reserved)

Brain structural abnormalities may be associated with geriatric depression.⁶⁷
- These structural changes may be reflected in reduced size i.e., volume and prefrontal cortex, anterior cingulate gyrus, amygdala and hippocampus.
  - Some studies focusing on hippocampal volume in geriatric depression have concluded that older depressed patients may have smaller hippocampal volumes⁶⁸, although other studies have not verified this conclusion⁶⁹.
  - Within this framework hippocampal volume may be affected by neurotrophic factors.
    - In particular, brain-derived neurotrophic factor (BDNF) may be associated with human hippocampal structural abnormalities.⁷⁰
  - A single-nucleotide polymorphism in the BDNF gene results in a valine to methionine substitution.⁷¹
    - A recent study considered relationships between BDNF genotype, hippocampal volumes and major depressive disorder in older patients. ⁶⁷
      - Study results provided preliminary evidence that the valine/valine genotype might be neuroprotective and the BDNF valine/methionine polymorphism might be involved in hippocampal structural changes in older patients with major depressive disorder.⁶⁷

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