Selective serotonin reuptake inhibitors or serotonin-specific reuptake inhibitor ( SSRIs ) are a class of compounds typically used as antidepressants in the treatment of depression, anxiety disorders, and some personality disorders. They are also typically effective and used in treating premature ejaculation problems as well as some cases of insomnia.
SSRIs increase the extracellular level of the neurotransmitter serotonin by inhibiting its reuptake into the presynaptic cell, increasing the level of serotonin available to bind to the postsynaptic receptor. They have varying degrees of selectivity for the other monoamine transporters, with pure SSRIs having only weak affinity for the noradrenaline and dopamine transporter.
The first class of psychotropic drugs to be rationally designed, SSRIs are the most widely prescribed antidepressants in many countries.
List of SSRIs
Drugs in this class include (trade names in parentheses):
- citalopram (Celexa, Cipramil, Cipram, Dalsan, Recital, Emocal, Sepram, Seropram, Citox)
- dapoxetine (no trade name yet; not yet approved by the FDA)
- escitalopram (Lexapro, Cipralex, Esertia)
- fluoxetine (Prozac, Fontex, Seromex, Seronil, Sarafem, Ladose, Fluctin (EUR), Fluox (NZ), Depress (UZB), Lovan (AUS))
- fluvoxamine (Luvox, Fevarin, Faverin, Dumyrox, Favoxil, Movox)
- paroxetine (Paxil, Seroxat, Sereupin, Aropax, Deroxat, Rexetin, Xetanor, Paroxat, Loxamine)
- sertraline (Zoloft, Lustral, Serlain)
- zimelidine (Zelmid, Normud)
Related antidepressants
SSRIs from a subclass of serotonin uptake inhibitors, which includes other non-selective inhibitors as well. Serotonin-norepinephrine reuptake inhibitors, serotonin-norepinephrine-dopamine reuptake inhibitors and selective serotonin reuptake enhancers are also serotonergic antidepressants.
Medical indications
The main indication for SSRIs is clinical depression. SSRIs are frequently prescribed for anxiety disorders, such as social anxiety, panic disorders, obsessive–compulsive disorder (OCD), eating disorders, chronic pain and occasionally, for posttraumatic stress disorder (PTSD). Though not specifically indicated by the manufacturers, they are sometimes prescribed to treat irritable bowel syndrome (IBS), Lichen simplex chronicus and premature ejaculation.
All SSRIs are approved in the U.S. for use with psychiatric disorders as outlined in the Diagnostic and Statistical Manual of Mental Disorders (DSM IV).
The uses for which SSRIs have approval vary by country and are determined by the overseeing branch of government in charge of regulating drugs. In the U.S., the Food and Drug Administration (FDA) approves drugs after trial results have been submitted by the pharmaceutical companies. In Europe, drugs can be approved either by the European Medicines Agency for human consumption throughout the European Union or by the regulatory agencies of individual countries for use within those countries.. In Canada, the drug approval process is carried out by Health Canada.
A general disadvantage of SSRIs in treating premature ejaculation is that they require continuous daily treatment to delay ejaculation significantly. For the occasional "on-demand" treatment, a few hours before coitus, clomipramine gave better results than paroxetine in one study, while in another study both sertraline and clomipramine were indistinguishable from the pause–squeeze technique and inferior to paroxetine. The most recent research, conducted in 2007, suggests that on-demand treatment with sildenafil (Viagra) offers a dramatic improvement in ejaculation delay and sexual satisfaction as compared with daily paroxetine, with on-demand sertraline, paroxetine or clomipramine, and with the pause–squeeze technique.
Contraindications and drug interaction
One major contraindication of SSRIs is the concomitant use of MAOIs (monoamine oxidase inhibitors). This is likely to cause severe serotonin syndrome/toxidrome.
People taking SSRIs should also avoid taking pimozide (an antipsychotic diphenylbutylpiperidine derivative). The atypical opioid analgesic tramadol hydrochloride (or Ultram, Ultracet) can, in rare cases, produce seizures when taken in conjunction with an SSRI or tricyclic antidepressant. Liver impairment is another contraindication for medications of this type.
SSRIs may increase blood levels and risk of toxicities of certain medications:
- highly protein-bound medications like warfarin (coumadin) and digoxin
- antiarrhythmic agents like propafenone (Rythmol) or flecainide (Tambocor)
- beta blockers like metoprolol (Toprol xl) or propranolol (Inderal)
- TCAs like amitriptyline (Elavil, Endep) etc., and triptans like sumatriptan (Imitrex, Imigran) etc. - please see the Tricyclic_antidepressant and Triptan pages for complete lists (increased risk of seratonin syndrome/toxidrome)
- benzodiazepines like alprazolam (Xanax) or diazepam (Valium)
- carbamazepine (Tegretol)
- cisapride (Propulsid)
- clozapine (Clozaril)
- ciclosporin (Neoral)
- haloperidol (Haldol)
- phenytoin (Dilantin)
- pimozide (Orap)
- theophylline (Theo-dur)
Certain drugs may increase toxicities of SSRIs:
- alcohol and other CNS depressants
- diuretics (water pills)
- MAOIs - possibly dangerous
- sympathomimetic drugs like pseudoephedrine (Sudafed)
- lithium
- sibutramine (Meridia)
- MDMA (ecstasy)
- zolpidem (ambien)
- Dextromethorphan
- tramadol (synergistic serotoninergic effect said to increase risk of seizure or seratonin syndrome/toxidrome)
Mode of action
SSRIs are believed to act by inhibiting the reuptake of serotonin after being released in synapses. How much an individual will respond to this, however, also depends on genetics. In addition, several other mechanisms are suggested for the desired effect, e.g. neuroprotection and anti-inflammatory and immunomodulatory factors. Taken together, SSRI has several advantages compared with tricyclic antidepressants (TCA)s and 5-HT-prodrugs. However, the latter might be required in addition to SSRIs in certain situations.
Basic understanding
Further information: Chemical synapseIn the brain, messages are passed between two nerve cells via a chemical synapse, a small gap between the cells. The (presynaptic) cell that sends the information releases neurotransmitters (of which serotonin is one) into that gap. The neurotransmitters are then recognized by receptors on the surface of the recipient (postsynaptic) cell, which upon this stimulation, in turn, relays the signal. About 10% of the neurotransmitters are lost in this process; the other 90% are released from the receptors and taken up again by monoamine transporters into the sending (presynaptic) cell (a process called reuptake ).
To stimulate the recipient cell, SSRIs inhibit the reuptake of serotonin. As a result, the serotonin stays in the synaptic gap longer than it normally would, and may be recognized again (and again) by the receptors of the recipient cell, stimulating it.
Pharmacodynamics
SSRIs inhibit the reuptake of the neurotransmitter serotonin (5-hydroxytryptamine or 5-HT) into the presynaptic cell, increasing levels of 5-HT within the synaptic cleft.
However, there is one counteracting effect: high serotonin levels will not only activate the postsynaptic receptors, but also flood presynaptic autoreceptors, that serve as a feedback sensor for the cell. Activation of the autoreceptors (by agonists like serotonin) triggers a throttling of serotonin production. The resulting serotonin deficiency persists for some time, as the transporter inhibition occurs downstream to the cause of the deficiency and therefore, is not able to counterbalance the serotonin deficiency. The body adapts gradually to this situation by lowering (downregulating) the sensitivity of the autoreceptors.
Another adaptive process provoked by SSRIs has potentially harmful effects: the downregulation of postsynaptic serotonin 5-HT 2A receptors. After the use of an SSRI, since there is more serotonin available, the response is to decrease the number of postsynaptic receptors over time and in the long run, this modifies the serotonin/receptor ratio. The augmented amount of serotonin often does not match up with the rate of receptor neurogenesis and therefore, the increased amount of binding of SSRI ligands to the serotonin receptors has the potential to "wear out" those receptors if the SSRI acts as an agonist. Because of this, prolonged agonist SSRI usage followed by discontinuation can promote deeper depression for some individuals. SSRIs which function as antagonists may have equally negative consequences, as antagonists tend to bind to receptors without activating them, thereby inhibiting the generation of signaling. Because of this, these receptors may essentially become inactive over time due to lack of use.
Most of the serotonin receptors on the surface of the cell are coupled to a G-protein inside it. These proteins activate or inhibit second messengers, which in turn affect transcription factors. Transcription factors are proteins that fit to the beginning of a gene and tell the cell to start using it.
These (slowly proceeding) neuro
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