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SSRI List: Selective Serotonin Reuptake Inhibitors

SSRIs (Selective Serotonin Reuptake Inhibitors) are specific types of drugs that are most commonly utilized to treat depression and anxiety disorders. The drugs work to increase the amount of the neurotransmitter serotonin by preventing or inhibiting its reuptake. By preventing the reuptake of serotonin in the pre-synaptic neurons, this allows for increased serotonin in the synapse which leads to a higher level of neuronal stimulation.

These drugs were created using a process called “rational drug design” which involved a specific biological target, followed by a molecule designed to affect this target. The drug class was created with the intention of specifically targeting serotonin levels, hence being called “selective serotonin” reuptake inhibitors. SSRIs tend to have less of an effect on other neurotransmitters like norepinephrine and dopamine compared to SNRIs and atypical antidepressants.

In addition to being used for depression and anxiety, other common uses for SSRIs include: OCD (obsessive compulsive disorder), eating disorders, premature ejaculation, and rehabilitation following a stroke. The SSRI class of medications has been documented as inducing neurogenesis or growth of new brain cells.

SSRI List: Selective Serotonin Reuptake Inhibitors

Below is a list of SSRI drugs (in alphabetical order) that have been approved for usage in the United States.

Celexa (Citalopram)

Approved in 1998 to treat major depression, Celexa had quickly become one of the most popular antidepressants to treat depression. In comparison to other antidepressants on the market, it ranked fifth overall in effectiveness and fourth in cost-effectiveness. It is often prescribed off label to treat conditions other than depression including panic disorder and obsessive-compulsive disorder. This drug is sold as a mixture of 50% R-citalopram and 50% S-citalopram.

Researchers quickly discovered that only the S-citalopram enantiomer produces an antidepressant effect and the other half of the drug is relatively useless. Upon making this discovery, now a version of the drug is made with just the active S-citalopram portion under the brand name Lexapro.

Lexapro (Escitalopram)

Approved in 2002 to treat major depression and generalized anxiety disorder, this SSRI is an example of a company improving an existing treatment by making modifications. When researchers discovered that the only active portion of the drug Celexa was the S-enantiomer, they removed the inactive R-enantiomer and marketed the S-enantiomer as a new drug called Lexapro. In other words, this drug is considered to be an improved version of Celexa.

There is some controversy as to whether this drug results in improved therapeutic response compared to Celexa is considered controversial. Other uses for this drug include obsessive compulsive disorder, panic disorder, and social anxiety disorder. Researchers went on to discover that Lexapro was found slightly superior to Celexa in terms of tolerability as well as antidepressant response. Despite these findings, other reports suggest that all current SSRIs are considered equally effective.

Lexapro works by increasing levels of serotonin between synapses in the brain. It blocks the reuptake of serotonin at presynaptic neurons. Compared to other SSRIs, this drug has the most significant effect on the serotonin transporter. Some researchers have suggested that the R-citalopram portion of Celexa was found to inhibit the full effect of the S-citalopram, making Lexapro more potent; this research isn’t fully supported. This drug is still among the most popular SSRIs on the market.

Luvox (Fluvoxamine)

Approved in 1994, Luvox was among the first SSRIs used to treat obsessive compulsive disorder. It is also considered effective for treating major depression and anxiety disorders such as social anxiety, panic attacks, and PTSD. The drug works as a selective serotonin reuptake inhibitor and exhibits a potent effect on the serotonin transporter.

The reason Luvox is thought to work extremely well for OCD has to do with its affinity for the Sigma-1 receptor. At the Sigma-1 receptor, this drug works as an agonist and is considered to affect this receptor more than any other SSRI. Some hypothesize that its agonist effect on the Sigma-1 receptor is what results in anxiolytic effects as well as improving cognition in those with depression.

Paxil (Paroxetine)

Approved in 1992, this SSRI is utilized to treat major depression, OCD, panic disorder, and generalized anxiety disorder. In some cases this drug is used in adults to treat symptoms such as hot flashes and night sweats associated with menopause. Paxil is considered among the most potent as well as most specific SSRIs on the market.

It has a strong affinity for the serotonin transporter site and compared to other SSRIs, it inhibits the reuptake of norepinephrine to a greater extent. It may also affect Sigma-1 receptors which would further increase its anxiolytic effects. Like most SSRIs, this drug is associated with high rates of unwanted weight gain and sexual side effects. Additionally some regard the discontinuation from Paxil as being the toughest of any SSRI due to its potency as well as short half life.

I personally have gone through withdrawal, which you can read about if you want more perspective (Quitting Paxil Cold Turkey). It is the only SSRI drug that has been associated with causing birth defects. Interestingly enough, this drug has proven itself to provide antimicrobial effects. When combined with antibiotics to treat bacteria, Paxil demonstrates some synergy in fighting the bacteria. Research has also shown that it has antifungal properties.

Prozac (Fluoxetine)

Approved in 1987 to treat major depression, it is among the first antidepressants in the SSRI class. Other conditions which Prozac is used for include: OCD, eating disorders, panic disorders, and trichotillomania. In 2010, it was the third most prescribed antidepressant in the United States with over 24.4 million prescriptions filled.

It is on the World Health Organization’s List of Essential Medicines, acknowledging it as being among the most important drugs in a basic health care system. Prozac works as an SSRI by delaying the reuptake of serotonin, which ends up increasing levels of serotonin. At standard doses, it does not affect norepinephrine and dopamine to a significant extent.

However, very high doses, it is thought that it may affect both norepinephrine and dopamine. Compared to other SSRI drugs, this one is considered the “least selective” due to the fact that it has significant differences in binding for its initial and secondary targets. It is thought that Prozac may have some effect as a result of activity on the 5-HT2 receptor as an antagonist and agonist of the Sigma-1 receptor; whether this extra activity is significant is not fully supported.

Of all SSRIs, this is one with the longest half life, which tends to result in an easier time withdrawing and avoiding discontinuation symptoms.

Zoloft (Sertraline)

Approved in 1991 to treat major depression, obsessive-compulsive disorder, and social anxiety disorders. Other conditions that are treated by this medication include: body dysmorphic disorder, PTSD, and premature ejaculation. In 2011, it was prescribed approximately 37 million times, which made it the second-most prescribed antidepressant in the United States.

The drug works as a serotonin reuptake inhibitor and binds primarily with the serotonin transporter. To a lesser extent, it also functions as a dopamine reuptake inhibitor, but this is not a primary binding target. It also has a small effect as an antagonist on the Sigma-1 receptor and an antagonist on the Alpha-1 receptor.

Drug comparison research has suggested Zoloft may be superior to Prozac in regards to sleep, weight disturbance, and cognition among depressed patients. Like Paxil, this drug also has antifungal properties.

Other SSRIs

There have been other SSRI medications on the market that were discontinued. Additionally there remains one SSRI that is used specifically for premature ejaculation, but not for depression.

Priligy (Dapoxetine)

This drug was the first SSRI developed specifically to treat premature ejaculation (PE) in men. It works by inhibiting the serotonin transporter, thereby boosting the amount of serotonin at the presynaptic cleft. As a result, most people who take it end up noticing delayed ejaculation. It was initially devised to be an antidepressant, but it was absorbed and eliminated too quickly from the body.

The fast absorption and elimination made it work very well for premature ejaculation, but not so well as an antidepressant. The exact way which this drug works for premature ejaculation is still not well known, but researchers theorize that it is due to its inhibition of the serotonin transporter. Although this drug has not yet hit the market, it is slated to be released soon.

Upstene (Indalpine)

This is another SSRI drug that was initially discovered in 1977, and was quickly taken off market in 1983 due to the fact that it had been associated with Guillain-Barre syndrome. Creators of this antidepressant were just beginning to understand that serotonin (5-HT) may play an important role in depression.

Initially there were many concerns about SSRI drugs and associations between this drug and severe adverse effects, so the best move at the time was to remove it from the market. The drug worked by inhibiting serotonin transporters.

Zelmid (Zimelidine)

This drug was developed in the late 1970s by Arvid Carlsson. Initially he was searching for drugs that had similar structure to brompheniramine, an antihistamine that also had antidepressant properties and ended up discovering Zelmid. This was considered the very first selective serotonin reuptake inhibitor (SSRI) to be marketed for mainstream usage. It worked by inhibiting reuptake of serotonin from the synaptic cleft without acting upon any postsynaptic receptors.

Zelmid was first sold in 1982 and is regarded as being structurally different from other antidepressants due to its classification as a “pyridylallylamine.” Although Zelmid had a relatively favorable safety profile, there were cases of people developing Guillain-Barre syndrome as a result of this drug. Within a year of its approval, Zelmid ended up getting withdrawn from the market.

SSRI Antidepressants: What do you think?

In the United States, many people have begun to favor SNRI medications over SSRIs because they tend to have less unfavorable side effects such as weight gain and sexual dysfunction.  The two most prescribed antidepressants in the in the United States last year were Cymbalta and Pristiq, both of which are SNRI drugs. (Read more: Most prescribed psychiatric drugs from July 2013 to June 2014).  Despite SNRIs overtaking SSRIs for prescriptions in the U.S., in many other countries SSRIs are still the most commonly utilized antidepressants.

They can be very helpful for people stuck in a state of deep depression. Research has deemed all of these drugs as being statistically significant for treating major depression. Although they are helpful, many people are unable to tolerate the side effects associated with these drugs including: sexual dysfunction and weight gain. Some have made the argument that SSRIs lower testosterone, but this is not supported by clinical research.

The upside of these drugs is that they can work to fight depression for years before their antidepressant effect wears off. The downside associated with these drugs is that a person can eventually become tolerant to their effects and the desired (antidepressant) effects slowly diminish. In this case a person either has to increase the dosage, which could carry even more unwanted side effects or withdraw.

Withdrawal from SSRIs is documented as being very difficult for certain individuals. Prozac is considered the easiest to withdraw from, but most carry very difficult symptoms as a result of discontinuation. Only in recent years did doctors become aware of the difficulty associated with withdrawal and began advising people to gradually taper down from their doses upon discontinuation.

Selective Serotonin Reuptake Inhibitors were certainly an improvement on past drugs. They do have less side effects and utilize a more targeted approach in treating depression than older medications.  SSRIs don’t work for everyone and are an imperfect long-term strategy. They carry significant withdrawal symptoms and unwanted side effects.  Unfortunately for those with major depression, SSRIs are still the most favorable antidepressant class.

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{ 2 comments… add one }
  • Kim August 3, 2015, 12:04 pm

    Prozac used to help, no weight gain, only sleepiness in the afternoon. Now when I tried to get back on it, I feel like my body has been beaten badly, and the tiredness is overwhelming.

  • Raph August 8, 2016, 7:57 am

    Yeah, Prozac really rocks for severe depression, it sucks for anxiety though. First 5 weeks were indeed tough, whole-body flu-like pain, stuttering, and that “crashed” feeling. Even I’m thankful for what it has done, I had to quit because of making my mind foggy-fuddled. And the withdrawal wasn’t easy at all, when compared to Lexapro.

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