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• SSRIs - Selective Serotonin Reuptake Inhibitors
• Brief history
• Mechanism of action
• Indications and uses
• Efficacy
• Adverse reactions, side effects
• Discontinuation symptoms (withdrawal)
• Drug interactions
• Brief SSRIs comparison table
• SSRI's pharmacology
• References

It is difficult to say which antidepressant is the best because each person is different. No one antidepressant is going to be the best answer for every person.

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, 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 controlled substances.

Among the SSRIs, there are more similarities than differences. Although all SSRI drugs have the same 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.

	Citalopram (Celexa)	Escitalopram (Lexapro)	Fluoxetine (Prozac)	Paroxetine (Paxil)	Sertraline (Zoloft)
FDA approval date	July 17, 1998	August 14, 2002	December 29, 1987	December 29, 1992	December 30, 1991
Pharmaceutical Forms	10mg, 20mg, 40mg tablets, oral solution 10 mg/5 mL	5mg, 10mg, 20mg tablets, oral solution 5 mg/5 mL	10mg tablets, 10mg, 20mg, 40mg pulvules, oral solution 20mg/5mL, weekly capsules 90 mg	10mg, 20mg, 30mg, 40mg tablets, oral suspension 10 mg/5 mL	25mg, 50mg, 100mg tablets, oral concentrate 20 mg/mL
Recommended dose (for Major Depressive Disorder)	20-40 mg/day	10–20 mg/day	5-20 mg/day	20 mg/day	50 mg/day
Drug interaction potential	Relatively low	Relatively low	High	Moderate to high	Relatively low
Most common side effects	Nausea Dry mouth Drowsiness Insomnia Increased sweating Diarrhea	Nausea Insomnia Diarrhea Headache	Nausea Headache Insomnia Nervousness Anxiety Drowsiness Anorexia Diarrhea	Nausea Drowsiness Headache Dry mouth Dizziness Weakness Fatigue Sexual dysfunction Increased sweating Diarrhea Insomnia	Nausea Headache Insomnia Diarrhea Dry mouth Sexual dysfunction (ejaculation failure, decreased libido) Drowsiness Dizziness Fatigue
Less common side effects	Tremor Sexual dysfunction (abnormal ejaculation, decreased libido, impotence) Fatigue Anxiety Agitation Anorexia	Sexual dysfunction (abnormal ejaculation, decreased libido, impotence) Dry mouth Drowsiness Fatigue Increased sweating Dizziness Anxiety Anorexia	Dizziness Weakness Dry mouth Anxiety Agitation Tremor Increased sweating Sexual dysfunction	Tremor Constipation Decreased appetite Anxiety Nervousness	Tremor Increased sweating Agitation Anorexia Nervousness Anxiety
Pharmacokinetic Variables
Half-life	35 hours	27–32 hours	2-4 days	20 hours (highly variable)	26 hours
Time to steady-state	7 days	7 days	30 to 60 days	10-14 days	7-14 days
Active Metabolite?			Yes		Yes, but not significant

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 medications 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.

SSRI antidepressants 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 tolerability20.

	Secondary binding properties of SSRIs
Citalopram (Celexa)	most selective serotonin reuptake inhibitior
Escitalopram (Lexapro)	most selective serotonin reuptake inhibitior
Fluoxetine (Prozac)	least selective serotonin reuptake inhibitior norepinephrine reuptake 18 dopamine reuptake 18 serotonin-2C receptors 21 cytochrome P450 2D6 cytochrome P450 3A4
Paroxetine (Paxil)	muscarinic cholinergic receptors (most potent blocker of muscarinic receptors among the SSRIs) histamine H1 receptors nitric oxide synthase cytochrome P450 2D6
Sertraline (Zoloft)	dopamine reuptake (more potent dopamine uptake inhibitor than other SSRIs) 22 norepinephrine reuptake sigma receptors

Relative Potency for Different Sites of Action for the SSRI Class of Antidepressants - Based on data from Hyttel 1993

Figure is taken from De-Spinning In Vitro Data, Sheldon H. Preskorn, M.D.

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:

• depression

Lexapro (Escitalopram) is indicated for the treatment of

• major depressive disorder
• generalized anxiety disorder (GAD)

Paxil (Paroxetine) is indicated for the treatment of

• major depressive disorder
• obsessive compulsive disorder (OCD)
• panic disorder
• social anxiety disorder
• generalized anxiety disorder
• posttraumatic stress disorder (PTSD)

Prozac (Fluoxetine) is indicated for the treatment of:

• major depressive disorder
• obsessive-compulsive disorder
• moderate to severe bulimia nervosa
• panic disorder

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:

• major depressive disorder
• obsessive-compulsive disorder
• panic disorder
• posttraumatic stress disorder
• premenstrual dysphoric disorder (PMDD) in adults (newest indication)
• social anxiety disorder

Clinical trials comparing one SSRI with another indicate that drugs in this class are equally efficacious. Each antidepressant 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 SSRIs in the treatment of major depressive disorder2. Also escitalopram has better efficacy in the treatment of severe depression than citalopram4.

Paroxetine, fluoxetine, and sertraline are similar in effectiveness for major depression and depression with high levels of anxiety3,5.

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 SSRIs4. Also, fluoxetine appears to be somewhat less effective, than other drugs in this class24,25.

Sertraline may have a slightly higher rate of response than fluoxetine and paroxetine26. Sertraline has advantages over paroxetine in the treatment of panic disorder27.

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 another19.

As a group, the SSRIs possess the following adverse effects:

• nausea
• sexual dysfunction, including decreased libido, orgasm difficulties, abnormal ejaculation
• diarrhea
• headache
• nervousness
• insomnia
• agitation
• sweating
• dry mouth
• tachycardia
• anorexia
• increased appetite
• weight gain
• anxiety
• insomnia
• drowsiness

While SSRIs do not appear to differ in overall tolerability, the reported incidences of specific side effects vary. Antidepressants have some different pharmacological characteristics, this means that patients may respond differently to certain SSRIs or experience different side effects with different drugs.

• 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
  The SSRIs as a class produce a variety of sexual side effects, including anorgasmia, decreased libido, and impotence. Analysis of the clinical trials suggests that fluvoxamine and fluoxetine are less likely to produce sexual side effects than paroxetine and sertraline. 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.
  The SSRIs are reported to cause sexual dysfunction in the following descending order of frequency: citalopram 72.7%; paroxetine 70.7%; sertraline 62.9%; fluvoxamine 62.3%; fluoxetine 57.7%28.
  Paroxetine produces more delay of orgasm or ejaculation than fluvoxamine, fluoxetine and sertraline 16.
• Weight gain
  Weight gain is another troubling side effect. The SSRIs vary in their effect on the weight.
  Paroxetine, fluoxetine, citalopram and sertraline have been shown to increase body weight after 6–12 months of administration8.
  Fluoxetine and sertraline have the lowest incidence of weight gain during long-term treatment, paroxetine and citalopram higher17.
  Paroxetine may cause a significant weight increase, sertraline may cause modest but nonsignificant weight increase with long-term treatment15.
  Of the SSRIs, paroxetine may be responsible for the highest amounts of weight gain9.
  Sertraline is generally associated with a small degree of weight loss in the acute phase of treatment.
  Fluoxetine has the most potent appetite suppressing effects and may cause modest but nonsignificant weight decrease15.
• Effects on sleep
  SSRIs interfere with sleep architecture. Fluoxetine, paroxetine, and sertraline delay the onset of REM sleep, and fluoxetine and paroxetine increase awakenings and reduce REM sleep, slow-wave sleep, total sleep time, and sleep efficiency. In contrast, sertraline minimally increases sleep efficiency and reduces nocturnal wakefulness time, which may benefit depressed patients with sleep disturbances29
• 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
• 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. Recently, sertraline has been shown to cause statistically significantly more diarrhea than other SSRIs7.
• Anxiety, agitation, insomnia
  Fluoxetine has been associated with highest rate of anxiety and agitation1. Escitalopram and paroxetine are less likely to cause insomnia than fluoxetine and sertraline. Escitalopram and citalopram have been associated with low rates of insomnia, anxiety, and other activating side effects.
  The possible increased potential for agitation and/or stimulatory side-effects is difficult to put in perspective, as many agitated or anxious patients tolerate fluoxetine without difficulty and, as with other drugs that have alleged stimulant effects, they may even obtain relief from tension and anxiety. However, if SSRI-induced agitation has previously occurred, then fluoxetine may not be the drug of choice.
• 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.

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.

All antidepressants do not have the same type or severity of withdrawal symptoms. 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 symptoms10.

Abrupt interruption of antidepressant therapy for 5-8 days was associated with the emergence of new somatic and psychological symptoms in patients treated with paroxetine and to a lesser degree sertraline, with few symptoms seen with fluoxetine12.

All SSRIs (except paroxetine) are classified as pregnancy Category C, meaning that they may not be safe for use during pregnancy.

Paroxetine (Paxil, Paxil CR) is pregnancy Category D medication. Paroxetine may cause heart defects or serious, life-threatening lung problems in newborn babies whose mothers take the medication during pregnancy.

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.

Initial treatment with fluoxetine or paroxetine may not be preferred for patients in whom a potential for a clinically significant drug-drug interaction exists.

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, 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 support14.

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.

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.

Sertraline exhibits a sex- and age-dependent half-life. In men, the half-life is approximately 30% shorter (22.4 hr) than in females or the elderly (32.1-36.7 hr).

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 non-linear 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.

Fluoxetine, paroxetine and sertraline are highly protein bound. In contrast, the protein binding of citalopram (50%) and fluvoxamine (77%) is considerably less.

Clinically important differences exist between commonly prescribed antidepressants for both efficacy and acceptability in favour of escitalopram and sertraline, according to the recent antidepressant meta-analysis reported in The Lancet30.

Sertraline may be the best choice when starting treatment for moderate to severe major depression because it has the most favourable balance between benefits, side effects, and acquisition cost.

A major consideration with escitalopram is that it is not yet available in lower-cost generic form. The drug is still under patent. In 2006 Forest Laboratories was granted an 828 day (2 years and 3 months) extension on its patent for escitalopram31. This pushed the patent expiry from December 7, 2009 to March 14, 2012.

• Celexa Prescribing Information Celexa.com, Forest Pharmaceuticals, Inc.
• Lexapro Prescribing Information Lexapro.com, Forest Pharmaceuticals, Inc.
• Paxil Prescribing Information - Paxil.com, GlaxoSmithKline
• Prozac Prescribing Information Prozac.com, Eli Lilly and Company
• Zoloft Prescribing Information - Zoloft.com, Pfizer Inc.
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Published: May 05, 2007
Last updated: August, 2009