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Comparison of Selective Serotonin Reuptake Inhibitors (SSRIs)
SSRIs - Selective Serotonin Reuptake Inhibitors The most significant class of antidepressants marketed in recent years is the selective serotonin reuptake inhibitors (SSRIs). The six SSRIs available in the United States are citalopram (Celexa), escitalopram (Lexapro), fluoxetine (Prozac), fluvoxamine (Luvox), paroxetine (Paxil), and sertraline (Zoloft). The primary uses for the SSRIs include unipolar and bipolar major depression and all of the anxiety disorders. However, controlled trials also support the use of SSRIs in the treatment of other psychiatric disorders including dysthymia, premenstrual dysphoria, bulimia nervosa, obesity, borderline personality disorder, alcoholism, rheumatic pain, and migraine headache. The SSRIs are the first rationally designed class of psychotropic medications. The strategy behind rational drug development is to design a new drug that is capable of affecting a specific neural site of action (eg, uptake pumps, receptors) while avoiding effects on other site of actions. The goal in such development is to produce agents that are more efficacious, safer and better tolerated than older medications. SSRIs are generally considered to be first-line treatments of depression. They are prescribed more often for elderly patients than any other psychotropic and are the antidepressant of choice for many practitioners. All SSRIs are not a controlled substances. Among the SSRIs, there are more similarities than differences. Although all SSRI drugs have the same the mechanism of action, each SSRI has a slightly different pharmacological and pharmacokinetic characteristics. This leads to differences among the SSRIs in their half-lives, clinical activity, side effects, and drug interactions. There are differences between SSRIs that could be clinically significant. Also, SSRIs have very different molecular structures. The first drug in the SSRI class was Prozac (Fluoxetine), which hit the United States market in 1987. Prozac was FDA approved in December 29, 1987. It is manufactured by Eli Lilly and Company. Zoloft (Sertraline hydrochloride) was the second SSRI to come to market in the United States, and it was approved by the FDA in December 30, 1991. Zoloft is manufactured by Pfizer Inc. Paxil (Paroxetine hydrochloride) was the third SSRI to come to market in the United States and was approved by the FDA in December 29, 1992. Paxil is manufactured by GlaxoSmithKline. Luvox (Fluvoxamine maleate) was the next SSRI FDA approved in December 05, 1994. However, now its marketing status is "Discontinued". Celexa (Citalopram hydrobromide) was approved by the FDA in July 17, 1998. Celexa is manufactured by Forest Pharmaceuticals, Inc. Lexapro (Escitalopram oxalate) is the newest and most selective of the SSRIs approved by the FDA in August 14, 2002. Lexapro is manufactured by Forest Pharmaceuticals, Inc. Lexapro is a cleaner, improved version of Celexa. It is the active isomer of racemic citalopram. The brain communicates with itself through the use of special chemicals called neurotransmitters, such as serotonin and norepinephrine. Neurotransmitters carry signals from one nerve cell to another. Research suggests that abnormalities in neurotransmitter activity can affect mood and behavior. Low levels of serotonin and norepinephrine have not been proven to cause depression but it widely believed that elevation of these chemicals is associated with improvement in mood in depressed people. All SSRIs have the same general mechanism of action. SSRIs seem to relieve symptoms of depression by blocking the reabsorption (reuptake) of serotonin by certain nerve cells in the brain. This leaves more serotonin available, which enhances neurotransmission and improves mood. SSRIs are called selective because they seem to affect only serotonin, not other neurotransmitters. Thus, the SSRIs work by allowing the body to make the best use of the reduced amounts of serotonin that it has at the time. In due course, the levels of natural serotonin will rise again, and in some instances the SSRI can be reduced and withdrawn. SSRIs have been primarily used for the treatment of depression and have been studied for several indications outside of depression. Celexa (Citalopram) is indicated for the treatment of:
Lexapro (Escitalopram) is indicated for the treatment of
Paxil (Paroxetine) is indicated for the treatment of
Prozac (Fluoxetine) is indicated for the treatment of:
In January 2003, Prozac (fluoxetine) was approved by the FDA for the treatment of depression and OCD in children and adolescents who are 7 to 17 years of age. Zoloft (Sertraline) is indicated for the treatment of:
Clinical trials comparing an SSRI with another SSRI indicate that drugs in this class are equally efficacious. Each SSRI produces approximately a 60% overall response rate (ie, at least a 50% reduction in symptoms as a result of treatment). Adverse reactions and side effects While SSRIs do not appear to differ in overall tolerability, the reported incidences of specific adverse effects vary. SSRIs have some different pharmacological characteristics, that means you may respond differently to certain SSRIs or experience different side effects with different SSRIs. Adverse reactions that patients experience are usually mild to moderate and do not require dose reductions or discontinuation. As a group, the SSRIs possess the following adverse effects:
A comparison of the adverse effects of SSRIs: Nausea. The most coomon side effect accociated with use of SSRIs is nausea. Paroxetine and sertraline have been associated with slightly more cases of nausea. Sexual dysfunction. Depression itself may cause sexual dysfunction and all SSRIs have been associated with sexual dysfunction during therapy in men and women. There may be lesser detrimental effect on sexual function by fluoxetine compared to other agents. Paroxetine appears to cause the highest rate of sexual dysfunction. Citalopram has been associated with loss of libido and may be associated with a relatively higher level of sexual dysfunction compared with sertraline. Anticholinergic effects. Paroxetine, like the TCAs desipramine and imipramine, has an in vitro affinity for the muscarinic cholinergic receptor. As a result, paroxetine causes a higher rate of anticholinergic effects, such as dry mouth, constipation, and cognitive disruption, compared with other SSRIs. These effects may be particularly difficult to tolerate for elderly or concomitantly medically ill patients Weight. The SSRIs vary in their effect on the weight. Sertraline is generally associated with a small degree of weight loss in the acute phase of treatment, whereas paroxetine can cause weight gain after long term treatment. Fluoxetine has the most potent appetite suppressing effects in the short term and produces a greater degree of weight loss than paroxetine, sertraline, citalopram, or escitalopram. Diarrhea. Sertraline and fluoxetine are more frequently associated with diarrhea due to their greater specificity for serotonin receptors, while paroxetine has a lower incidence because of its antimuscarinic effects. Anxiety, agitation, insomnia. Fluoxetine has been associated with highest rate of anxiety and agitation. Escitalopram and paroxatine are less likely to cause insomnia than fluoxetine and sertraline. Escitalopram and citalopram have been associated with low rates of activating side effects. Dry mouth. Citalopram and paroxetine are more likely to cause dry mouth than escitalopram and fluoxetine. Drowsiness, fatigue. Paroxetine has been associated with highest rate of drowsiness, somnolence than other SSRIs. Headache. Sertraline and fluoxetine are associated with higher level of headache. Withdrawal symptoms. SSRIs aren't considered addictive. However, stopping treatment abruptly or missing several doses can cause withdrawal-like symptoms, including nausea, headache, dizziness, lethargy and flu-like symptoms. This is sometimes called discontinuation syndrome. This discontinuation syndrome is more common with the SSRIs with shorter half lives and inactive metabolites, such as paroxetine, sertraline, and fluvoxamine. The incidence of discontinuation syndrome is highest with paroxetine followed by fluvoxamine and sertraline. Citalopram and fluoxetine have a lower occurrence of withdrawal symptoms. Fluoxetine may not be the drug of first choice for patients in whom a rapid antidepressant effect is important or for those who are agitated, but it may have advantages over other SSRIs in patients who are poorly compliant with treatment and those who have previously had troublesome discontinuation symptoms. In some cases, antidepressants may be associated with worsening symptoms of depression or suicidal thoughts or behavior, particularly early in treatment or when you change your dosage. Be sure to talk to your doctor about any changes in your symptoms. You may need more careful monitoring at the beginning of treatment or upon a change in treatment, or you may need to stop the medication if your symptoms worsen. All SSRIs are classified as FDA Pregnancy Category C. Some of the key differences among SSRIs are due to differences in their pharmacokinetic properties. The only pharmacokinetic parameters shared by all the SSRIs is that they are relatively slowly, but completely, absorbed from the gut (ie, time to peak plasma concentration is 3 to 8 hours). They differ with regard to their protein binding, metabolism, half-lives, whether they have linear or nonlinear pharmacokinetics, whether they have active metabolites. Half-life The half-life of a drug is the time required to achieve steady-state plasma concentrations (i.e., to metabolize half the dose and lower blood concentrations by 50%). Half-life can be used to estimate how long it will take to clear a drug from the body after treatment is discontinued. Fluoxetine is unique because of its long half-life and the long half-life of its active metabolite norfluoxetine. Fluoxetine has a half-life of 2-4 days and its active metabolite, norfluoxetine, has a half-life of 4-16 days. In comparison, citalopram, escitalopram, paroxetine, and sertraline have shorter half-lives in the range of 20-35 hours, and steady-state concentrations (and therapeutic effect) are reached much more rapidly. The long half-life of fluoxetine may blunt the effects of missed doses or treatment discontinuation and makes it easier to discontinue than any of the other SSRIs. On the other hand, fluoxetine requires a much longer washout period than the other SSRIs (several weeks), particularly when switching to monoamine oxidase inhibitors (MAOIs) or TCA. Antidepressants with relatively short half-lives are desirable for people with multiple comorbidities and complex, multiple-drug regimens because they allow for once-daily dosing. A short half-life enables physicians to switch more rapidly and safely to an alternative antidepressant if treatment fails or if unfavorable drug reactions occur. Paroxetine and fluvoxamine are more quickly cleared from the body than the other SSRIs. Linear and nonlinear pharmacokinetic. One of the important differences to note among the SSRIs is whether their pharmacokinetic properties are linear or nonlinear. Citalopram, escitalopram and sertraline show linear and dose-proportional pharmacokinetics (changes in drug concentration proportional to the change in dose). Plasma concentrations of these drugs are proportional to the daily dose administered and, therefore, predictable. In contrast, fluvoxamine, fluoxetine and paroxetine have nonlinear pharmacokinetics. Higher doses may produce much greater increases in plasma drug concentrations than would otherwise be expected. Thus, increasing the dose of paroxetine or fluoxetine can result in disproportionate and unpredictable increases in plasma levels, half-lives, and ADEs. Titration of fluoxetine and paroxetine doses may therefore be more difficult than with citalopram, escitalopram and sertraline. Protein Binding Fluoxetine, paroxetine and sertraline are highly protein bound. In contrast, the protein binding of citalopram (50%) and fluvoxamine (77%) is considerably less. Drug interactions with clinical consequences usually involve combinations of an SSRI with other psychotropics, especially monoamine oxidase inhibitors (MAOIs) and tricyclic antidepressants, clozapine, lithium, methadone, etc. The interaction between MAOIs and SSRIs is the most important drug interaction limiting SSRI use. This combination may lead to the development of a hyperserotonergic syndrome consisting of excitement, diaphoresis, rigidity, hyperthermia, tachycardia, hypertension, and possibly death. The severity of this interaction necessitates at least 5 week washout when switching a patient from fluoxetine to an MAOI to allow complete elimination of the fluoxetine. At least 14 days should be allowed after stopping citalopram, escitalopram, paroxetine or sertraline before starting an MAOI. This difference in washout time between fluoxetine and citalopram, escitalopram, paroxetine and sertraline when switching from an SSRI to an MAOI is one of the key differences between SSRIs. When in doubt about the risks of drug interactions, citalopram, escitalopram or sertraline should be considered given the lower theoretical risk of interactions. Citalopram drug may be appropriate in patients taking multiple medications because of its low potential for drug interactions and in elderly patients because of its tolerability. Citalopram should be avoided in patients likely to take overdoses. Sertraline would be preferable for cardiac patients taking beta blockers or type IC antiarrhythmic agents. Fluoxetine and paroxetine are more likely to cause P450 drug interactions than citalopram and sertraline, particularly in combination with medications metabolized by or inhibiting the cytochrome P450 2D6 isoenzyme (e.g., certain antidepressants, phenothiazines, antipsychotics, type IC antiarrhythmics). Taking thioridazine with paroxetine or fluoxetine may cause serious heart problems.
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