Mechanism of Serotonin
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SSRIs reduces serotonin reuptake. Image Source:

Serotonin Reuptake Inhibitors (SSRIs) are generally the first line of treatment for major depression, anxiety, and other personality disorders as well. They are a form of antidepressants that act to increase the levels of extracellular serotonin (5-HT) in the synaptic cleft, by inhibiting its reuptake [1]. This process occurs by the conjunction of SSRIs and serotonin transporter (5-HTT or SERT), preventing serotonin from being transported back into the pre-synaptic cleft. In consequence, more serotonin is produced, as the negative feedback mechanism of serotonin-SERT reuptake is withdrawn [1].

In return, the activity of the amygdala is less sensitive towards negative stimuli [2], as well as reduced hyper-stimulation of other brain regions [2].
On the other hand, whether SSRIs are suitable for the elderly age group is debated [11], and its correlation with higher suicide tendencies versus suicide protection is variable [11].
SSRIs help to provide a better neurochemical balance that provides similar learning experiences, relative to healthy subjects [1]. Although similar, the brain system of major depression subjects is not normal like healthy subjects [1].

Beneficial and Shortfall Effects

Beneficial Effects

SSRIs are seen to reverse the effects of major depression, such as the attenuation of the hyperactive amygdala, and promoted hippocampal neurogenesis.

Amygdala Attenuation

The amygdala, area known for emotional processing and fear response is hyperactive in MDD, especially towards negative stimuli [2]. In consequence, its hyperactivity contributes to behavioural reactions dedicated to negative outlook, such as learning inhibitions and punishment sensitivity. Specifically, the left amygdala is more prevalent in this hyper activation. SSRIs are seen to help reverse some of the effects of major depression, by attenuation of this brain area [2]. It has been observed that the serotonin system is more prevalent in this brain region, as the number of serotonin transporters are major compared to dopaminergic and epinephrine transporters [2]. High levels of serotonin activity also contribute to amygdala regulation by higher cognitive processes. Conversely, low or lack of serotonin transporters is correlated with behaviours of anxiety [2].

Hippocampal Neurogenesis

Much in literature supports the process of hippocampal neurogenesis, in which the combination of glucocorticoids and antidepressants support this mechanism. The activation of glucocorticoid receptors by antidepressants mediates a cyclic AMP and protein kinase A signaling cascade, thereby initiating transactivation [3]. Cell proliferation and differentiation is promoted in the neurons of the hippocampus, specifically, the progenitor cells [3]. Studies suggest that this process mainly occurs when antidepressants are present, as the activation of PKA signaling is the one of the determining factors following neuronal maturation. Glucocorticoids alone are unable to cause neurogenesis [3]. In addition to neuron growth promotions, it is also observed that the proliferation period is condensed; neuronal differentiation enhanced. Sertraline was specifically used in this clinical study, along with other types of antidepressants. Findings suggest that many various types of antidepressants are able to activate the same product of neurogenesis, although their mechanisms may differ for the process [3].



However, the efficacy of SSRIs is only as much as placebo in the less depressive, and as much as 50%, experience remission or fail to have these antidepressants as an effective treatment. [4]

Time Lag

Another drawback of antidepressants is its slow transformation on depressed patients. Though work is immediate at the molecular level, effects are not noticeable until after several weeks [5]. Stemming from this notion, there was previous belief that antidepressants can trigger a cascade of ‘adaptive’ neurobiological events [5], occurring over time to improve depressive symptoms and behaviour. As adaptive changes take place with time, the effects of antidepressants may not be required [5]. However, this theory was disproved. Experiments using acute tryptophan depletion (ATD) after adaptation of antidepressant treatment were still able to cause depressive modes [5], which suggests that it is necessary for serotonin levels to potentiate.

Chronic Disadvantage

Future drawbacks reside with chronic use. Despite the increase in extracellular serotonin levels, there is decrease in serotonin tissue. The minimal activity of 5-HTT transporters reduces the feedback system to the cell, thereby reducing monoamine production, and hence reduced tissue levels [6].

This is also demonstrated by phasic and tonic firing in the raphe nucleus and projection areas. SERT blockage in the raphe nucleus stimulates higher extracellular serotonin. But because of the activation serotonin 1A auto-inhibiting receptors in response to excess serotonin, the overall tonic firing of the raphe nucleus is lowered [7]. As less firing is transmitted toward projection areas, the level of serotonin secreted in the terminal projection area is also low [7]. Due to SERT blockage present in the projection areas, serotonin levels are stimulated for production, and the same mechanism occurs. Although high levels of serotonin are achieved with aid of SSRIs, the overall effects result in lowered tonic and baseline phasic firing [7] – beneficial in the short-term, but can be hazardous in the long run.

Genetic-related Factors

Genetic related factors are seen affect an individual’s susceptibility to depression, and their sensitivity to antidepressants. Mutations such as in the TH/TPH enzyme causes lower levels of serotonin synthesis compared to normal. Elderlies who have this mutation (G1463A) also had major depression [6]. The active form of this mutation differs in those with bipolar disorder and attention-deficit disorder, but is seen in those with psychiatric disorders [6]. Although TPH2 mutations are seen to be rare, its contribution to the population cannot be neglected towards the group of mood and personality disorders prevalent.

Tyrosine Hydroxylase (TH) and tryptophan hydroxylase (TPH) are the rate limiting enzymes for production of serotonin [8]. Mutation in the gene for TPH2 enzyme reduces levels of serotonin synthesis, contributing to the susceptibility to mood and personality disorders [6]. A study on mice measured how those with the mutation compared to wild type species fared when given SSRIs. By looking at chronic effects on serotonin brain tissues, treatment of SSRIs along with mutation further depleted serotonin levels, down to approximately 20% of wild types [8]. On a continuation of the same study, co-treatment with 5-hydroxytryptophan (5-HTP), reversed these effects, bringing serotonin back to baseline, at wild type levels [6]. As 5-HTP is the serotonin precursor, it is able to bypass the rate limiting step, and is able to restore and prevent serotonin depletion [8].

Suicide-related Possibilities

A meta-analysis of various studies looked at the effects of antidepressants relative to suicide for all age groups. Findings suggest decreased risks in adults and elderly (~40% and ~50% respectively), while increased the risks in children and adolescents almost two-fold [9]. There are no clear reasons for why this is the case. However, a case analysis study suggests the activation syndrome to be a possible explanation. In the first few weeks of antidepressant administration, clients are more active despite the anhedonia aspects of depression. Because the individual is in transition between depressive effects versus antidepressant effects, the mixed combination contributes to the risk of suicide tendencies to be more dynamic [10]. In addition, suicide tendency rates were highest on the day of prescription, and rates decreased when prescriptions were ceased [10]. Paroxetine and venlafaxine appear to be more hazardous for this probability in various studies [9], while fluoxetine appears to be the safest for children [10].

Impact on Elderly

Compared to other antidepressants, SSRIs are more tolerable for this age group. Double blind experiments comparing SSRIs with other types of antidepressants (such as TCA), selective serotonin reuptake inhibitors demonstrate more agreeable side effect symptoms and minimal interactions with other pharmacological medication [11]. There are mixed responses between toleration and efficacy response in this age category, with citalopram and escitalopram being the best tolerable, but just as efficable as placebo. Similarly, fluvoxamine and sertraline are more efficable, but are relatively least tolerable [11]. The general effect of antidepressants may take longer to have an effect on elderly individuals, as in accordance with biological changes, such as alterations to the serotonergic pathway and reduced sensitivity with age [11]. Accordingly, genetic susceptibility also plays a role in medication sensitivity. Elderly who have very severe MDD are still able to respond quickly to medication [11]. Overall, SSRIs are the most preferred antidepressants for elderly individuals, because of its less reactive chemical composition and its considerably mild side effects, despite the lack of supporting evidence for its efficacy in depression remission. However, they still remain beneficial for reducing depressive symptoms.

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6. Siesser et al. Chronic SSRI treatment exacerbates serotonin deficiency in humanized Tph2 mutant mice. ACS Chem. Neurosci . (2013) 4: 84-88
7. Lanzenberger et al. Prediction of SSRI treatment response in major depression based on serotonin transporter interplay between median raphe nucleus and projection areas. Neuroimage. (2012) 63: 874-881
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11. Topiwala A, et al. Prescribing selective serotonin reuptake inhibitors in older age. Maturitas (2013)

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