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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. Brief history
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. Mechanism of action
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 is 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 serotonin significantly more than 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 are at least 10-fold more selective for serotonin reuptake inhibition than for norepinephrine reuptake. However, most SSRIs bind to a large number of other receptors and enzymes in some degree. Each SSRI has a unique profile of these multiple pharmacologic actions, which may explain the differences in their efficacy and tolerability 20.
Approved indications and uses
The SSRIs are all licensed for use in depressive disorders but differ in their licensed indications for other disorders (which differ between countries). 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:
Efficacy and effectiveness
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). However, some differences in the SSRIs efficacy exist. Escitalopram may be superior in efficacy compared with other SSRs in the treatment of major depressive disorder 2. Also escitalopram has better efficacy in the treatment of severe depression than citalopram 4. Paroxetine, fluoxetine, and sertraline are similar in effectiveness for major depression and depression with high levels of anxiety 3, 5. Paroxetine is the only SSRI indicated for all five anxiety disorders in addition to major depressive disorder. Fluoxetine has a slower onset of antidepressants effect than other SSRIs 4. Also, fluoxetine appears to be somewhat less effective, than other SSRIs 24, 25. Sertraline may have a slightly higher rate of response than fluoxetine and paroxetine 26. Sertraline has advantages over paroxetine in the treatment of panic disorder 27. Interesting and important fact is that SSRI antidepressants are not interchangeable. Persons who discontinue one SSRI for lack of tolerability or response can be effectively treated with another 19. 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, this means that patients 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:
Comparison of the adverse effects of SSRIs
All SSRIs are classified as FDA Pregnancy Category C. Pharmacology
Selective serotonin reuptake inhibitors differ in their potency and selectivity in inhibiting serotonin reuptake and there may be important effects on other transporters and receptors, indicating that they are not as selective as their manufacturers suggest. It has been proposed, for example, that fluoxetine's effects on 5-HT2C receptors may underlie a propensity to cause agitation; paroxetine's affinity for muscarinic receptors causes its increased tendency to produce discontinuation effects; sertraline's affinity for the dopamine transporter results in a greater efficacy in severe depression; and sertraline's and fluvoxamine's affinity for sigma1 opioid receptors is responsible for their efficacy in psychotic depression (Goodnick & Goldstein, 1998a). However, at our current state of knowledge pharmacodynamic differences between the SSRIs are of minor practical importance in determining choice. They are used to try to explain observed or suggested clinical effects that have varying degrees of evidential support 14. 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. The possible slower onset of antidepressant action of fluoxetine may be owing to a longer time taken to achieve therapeutic plasma concentrations. In situations where the speed of onset of therapeutic effect is particularly important, such as in severe depression, fluoxetine may not be the SSRI of choice. Patients in whom the long half-life may have advantages (and therefore for whom fluoxetine should be considered) include those who are poorly compliant and those in whom administration less frequent than daily is contemplated. 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
Marked differences exist between the SSRIs with regard to effects on specific CYP enzymes and, thus, the likelihood of clinically important pharmacokinetic drug-drug interactions. The potency of the SSRIs as inhibitors of the metabolism of the P450-P2-D6 varies and is reported in descending order of potency as paroxetine, fluoxetine, sertraline, citalopram, and fluvoxamine. 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). 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. Sertraline, citalopram and escitalopram have the lowest potential for drug interactions among the SSRIs, and are to be preferred in patients on other drugs for general medical conditions or if consideration is given to adding an SSRI to other psychotropic medication. Brief SSRIs comparison table
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