Mood, blues, and reuptake pathways: Why common interventions are not always effective

According to Harvard Health Blog, about 1 in every 10 Americans takes an antidepressant.  The most commonly prescribed class of antidepressants is Selective Serotonin Reuptake Inhibitors (SSRIs).

Figure 1. Mechanism of action for SSRI medications: serotonin is released from the pre-synaptic neuron to bind receptors on the post-synaptic neuron.  Normally, the serotonin is then reuptaken into the presynaptic neuron and repackaged.  SSRIs block the reuptake channels, keeping the serotonin in the synapse for longer to act on the post-synaptic neuron.

Figure 1. Mechanism of action for SSRI medications: serotonin is released from the pre-synaptic neuron to bind receptors on the post-synaptic neuron. Normally, the serotonin is then reuptaken into the presynaptic neuron and repackaged. SSRIs block the reuptake channels, keeping the serotonin in the synapse for longer to act on the post-synaptic neuron.

SSRIs block the removal of serotonin from the synapse, allowing serotonin to signal longer on the post-synaptic neuron (Figure 1).  The net effect is to allow serotonin signaling to occur following what would otherwise be an insufficient release of serotonin. It has been estimated that, at best, approximately 50% of patients using SSRI medications achieve positive clinical outcomes while some are effective for no more than 5% of patients.

Why don’t SSRIs work more often?

Lack of symptom improvement may be attributed to a number of things including: improper absorption, slow metabolic breakdown, and existing serotonin levels.  SSRIs do not create more serotonin and therefore require a certain circulating levels of serotonin to have its desired clinical effects. This can be observed through 2 common clinical outcomes:

  1. Patients taking SSRIs for depression experience reoccurrence of symptoms over time.
  2. Antidepressant efficacy can be improved when serotonin synthesis is supported.

People suffering from depression often begin with low serotonin stores and it is hypothesized that extended use of SSRI medications will deplete serotonin stores further, regardless of baseline levels.  It is well documented that serotonin support increases serotonin synthesis.  In the handful of published studies, serotonin support along with SSRIs have been shown to be safe, effective, and further highlight the need to manage serotonin stores in depressed patients.

Guest author: Jennifer Farley is a manager of the Clinical Support & Education Department at NeuroScience, Inc. and one of the resident experts in psychiatric disorders.

References:
Delgado, PL., et al. (2000). Role of norepinephrine in depression. J Clin Psychiatry, 1:5-12.
Nelson, JC. (2000).  Augmentation strategies in depression. J Clin Psychiatry, 61:213-219.
vanPraag, HM. (1984). In search of the mode of action of antidepressants: 5-HTP/tyrosine mixtures in depression. Adv Biochem Psychopharmacol, 39:301-314.
vanPraag, HM. (1996). Serotonin precursors in the treatment of depression. Adv Biochem Neuropsychiatry Clin Neurosci, 8(2):168-71.
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One Response to Mood, blues, and reuptake pathways: Why common interventions are not always effective

  1. Eileen Wright, M.D. says:

    It is also important to recognize that genetic variants in 5-HTT (5-HTTLPR and STin2), STin2, HTR1A, HTR2A, TPH1 and BDNF modulate antidepressant response. Also, Variations in CYP2D6 have been associated with people’s ability to metabolize antidepressants. To date, up to 75 different alleles have been reported for CYP2D6 (descriptions available at http://www.imm.ki.se/cypalleles); more than 15 of these encode an inactive isoform or no enzyme, whereas other variations consist of gene duplications. These gene variants are often associated with different rates of metabolizing drugs. Thus, individuals can be classified as poor, intermediate, extensive and ultrarapid metabolizers on the basis of their inherited genetic profiles. The genetic background that differentiates poor metabolizers from intermediate and ultrarapid metabolizers seems to be associated with the number of gene copies: those with the ultrarapid metabolizer phenotype have been found to have multiple copies of CYP2D6 with a direct influence on plasma drug concentration, and 97% of all poor metabolizer phenotypes can be explained by the presence of 4 deficient activity CYP2D6 alleles (3, 4, 5, 6). This information is relevant to choosing candidates for antidepressant therapy, for choosing the drug with the highest potential for success and for dosing drug chosen. This “personalized” approach to treatment reduces side effects and improves outcomes. As an example, ultrarapid metabolizer isoform, named CYP2C19*17 (rs12248560) has been shown to be associated with a reduced concentration of escitalopram to about half, whereas deletion of this gene is associated with an almost 6-fold increase of escitalopram concentration. it has recently been shown that the efficacy and side effects of
    citalopram treatment are influenced by CYP2C19 and that the side effect profile associated with the
    amitriptyline treatment is partially dependent on the combination of a number of alleles coding for CYP2D6 and CYP2C19. Genomind (www.genomind.com), group with whom I have no association, offers a panel of genomic tests relevant to the management of depression, which I have found helpful with patients who have tried multiple therapeutic approaches without success.
    A 2011 review article, “Pharmacogenetics of antidepressant response” in the Journal of Psychiatry Neurosciences, reviews the genetic contributions to anti-depressant response in detail and the full article can be downloaded here: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3044192/pdf/0360087.pdf

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