SSRIs mechanisms

Recent evidence indicates that the 5-HT transporter is subject to post-translational regulatory changes in much the same way as neurotransmitter receptors (Blakeley et al. 1998). Protein kinase A and protein kinase C (PKC), at least, are known to be involved in this process. Phosphorylation of the transporter by PKC reduces the Fmax for 5-HT uptake and leads to sequestration of the transporter into the cell, suggesting that this enzyme has a key role in its intracellular trafficking. Since this phosphorylation is reduced when substrates that are themselves transported across the membrane bind to the transporter (e.g. 5-HT and fi -amphetamine), it seems that the transport of 5-HT is itself linked with the phosphorylation process. Possibly, this process serves as a homeostatic mechanism which ensures that the supply of functional transporters matches the demand for transmitter uptake. By contrast, ligands that are not transported (e.g. cocaine and the selective serotonin reuptake inhibitors (SSRIs)) prevent the inhibition of phosphorylation by transported ligands. Thus, such inhibitors would reduce 5-HT uptake both by their direct inhibition of the transporter and by disinhibition of its phosphorylation (Ramamoorthy and Blakely 1999). 

Davis, LL, Yonkers, KA, Trivedi, M, Kramwer, GL and Petty, F (1999) The mechanism of action of SSRIs, a new hypothesis. In Selective Serotonin Reuptake Inhibitors (SSRIs) Past, Present and Future (Ed. Stanford, SC), RG Landes Co., Austen, TX, pp. 171-185. 

Each antidepressant has a response rate of approximately 60% to 80%, and no antidepressant medication or class has been reliably shown to be more efficacious than another 22 MAOIs may be the most effective therapy for atypical depression, but MAOI use continues to wane because of problematic adverse effects, dietary restrictions, and possibility of fatal drug interactions.22,28 There is some evidence that dual-action antidepressants, such as TCAs and SNRIs, may be more effective for inpatients with severe depression than are the single-action drugs such as SSRIs,22,28 but the more general assertion that multiple mechanisms of action confer efficacy advantages is quite controversial.33... 

After more than a decade of use, bupropion (24) is considered a safe and effective antidepressant, suitable for use as first-line treatment. In addition, it is approved for smoking cessation and seasonal affective disorder. It is also prescribed off-label to treat the sexual dysfunction induced by SSRIs. Bupropion is often referred to as an atypical antidepressant and has much lower affinity for the monoamine transporters compared with other monoamine reuptake inhibitors. The mechanism of action of bupropion is still uncertain but may be related to inhibition of dopamine and norepinephrine reuptake transporters as a result of active metabolites [71,72]. In a recently reported clinical trial, bupropion extended release (XL) had a sexual tolerability profile significantly better than that of escitalopram with similar re-... 

A recent study further supported the involvement of dopamine in the mechanism of antidepressants [82]. In this study, the antidepressant-like effect of citalo-pram, paroxetine, desipramine and imipramine in the mouse forced swim test (FST) was compared with and without dopamine depletion. It was found that lesioning with 6-OHDA did not affect the response of mice to desipramine and imipramine, whereas dopamine depletion abolished the antidepressant-like effect of citalopram and paroxetine. These results suggest that the antidepressant-like effect of SSRIs in the FST requires the activation of dopaminergic pathways. 

A breakthrough in the treatment of major depression was the discovery of fluoxetine, marketed as Prozac. Fluoxetine has a mechanism of action similar to that of imipramine with an important exception. It is a selective serotonin reuptake inhibitor, an SSRI. This strongly suggests that, in some sense, the symptoms of major depression result from a deficit in serotonin specifically. By inhibiting its reuptake from the synapse, the activity of serotonin is enhanced. Two other important drugs for major depression, sertraline (Zoloft) and paroxetine (Paxil), among several others,... 

Bruxism mainly occurs in stage 2 sleep and REM sleep (Bader et ah, 1977). A relationship to stress and anxiety has been suggested, but the disorder can be chronic without apparent association with stress (Faulkner, 1990 Pierce et ah, 1995). It has been suggested that the central dopaminergic system may be involved in the modulation of sleep bruxism (Lobbezoo et al., 1997). Case reports indicate that bruxism can be induced by the SSRI paroxetine (Romanelli et al., 1996). The mechanism remains unclear possibilities include sleep disturbance, serotonergic-mediated inhibition of dopamine manifesting as akathisia, and SSRI-induced anxiety. SSRI-induced bruxism may respond to therapy with buspirone (Ellison et al., 1993). 

In the wake of the SSRI revolution, the 1990s saw the emergence of a number of antidepressant drugs with diverse mechanisms of action. Again, the common thread behind the different approaches was an increase of synaptic monoamine levels (Table 14.1). 

Tramadol is a central-acting analgesic, effective for mild to moderate acute and chronic pain. It impairs nociception by a unique mechanism that is not completely understood. In animal models, it binds to the /u. opioid receptor and is a weak inhibitor of serotonin and norepinephrine reuptake, actions similar to those ascribed to the SSRIs and TCAs. Seizures have been reported in patients taking tramadol. Abuse potential is low, but does exist. 

SSRIs have been approved for the treatment of the majority of anxiety disorders, except agoraphobia and specific phobia. The mechanisms of action responsible for SSRIs anxiolytic activity remain to be fully delineated. Understanding of pre- and postsynaptic receptor regulation with chronic treatment and cross-system effects are critical in furthering our imderstanding of these drugs. Increasing specificity may improve clinical efficacy. 

SERTPR variants may also not be specifically associated with response to SSRIs but confer a more general predisposition to respond to any kind of antidepressant treatment targeting the serotonin system. The 1 allele of SERTP R has not only associated been associated with a better response to SSRIs but also a good response to total sleep deprivation (Benedetti et al. 1999). An enhancement of serotonergic transmission has been proposed as one possible mechanism of action of sleep deprivation (Gardner et al. 1997). 

The low side effect profile, ease of use, and powerful clinical effect of the selective serotonin reuptake inhibitors (SSRIs) revolutionized the treatment of depression and anxiety in the 1990s. The success of the SSRIs shifted the focus from noradrenergic to serotonergic mechanisms in these common disorders. 

For patients who do not respond to a specific antidepressant medication or who do not tolerate its side effects, other antidepressants of the same class or different classes (e.g., venlafaxine for a patient treated with a SSRI) can be tried. The few adult studies published thus far suggest that it is more efficacious to switch antidepressant classes than to stay within the same class, because of the probable heterogeneity in underlying depression mechanisms. Also, it has been suggested that severe depressions appear to respond better to antidepressants with both serotonergic and adrenergic properties (e.g., venlafaxine) (Poirier and Boyer, 1999). 

One explanation for this delay is that the brain adjusts to the presence of SSRIs, and this adjustment is the mechanism by which the drug works. The brain may change the number of serotonin transporters, receptors, or other molecules, a process that would require time as the proteins are made and inserted in the correct positions. 

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