Comparison of Selective Serotonin Reuptake Inhibitors (SSRIs)

• SSRIs - Selective Serotonin Reuptake Inhibitors
• Brief history
• Mechanism of action
• Indications and uses
• Efficacy
• Side effects
• Discontinuation symptoms (withdrawal)
• Drug interactions
• Brief SSRIs comparison table

Based on "Essential Psychopharmacology"
written by Stephen M. Stahl, MD, PhD

by eMedExpert staff
Medical references reviewed: August, 2018

Selective Serotonin Reuptake Inhibitors (SSRIs)

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)
• sertraline (Zoloft)

The SSRIs represent 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 (e.g., 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.

All SSRIs are non-controlled prescription-only medications.

Although all SSRI drugs have the same mechanism of action, each SSRI has slightly different pharmacological and pharmacokinetic characteristics. This leads to differences among the SSRIs in their half-lives, clinical activity, side effects, and drug interactions. Certain differences between SSRIs are 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. Chemical structure of Paroxetine differs from other SSRIs by having a piperidine ring.

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.

Brief SSRIs comparison table

	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	10-20 mg/day	20 mg/day	50-100 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
Oral bioavailability	80%	51-93%	70%	50%	20-36%
Time to steady-state	7 days	7 days	30 to 60 days	10-14 days	7-14 days
Active Metabolite?	N-Desmethylcitalopram		O-Desmethyl-fluoxetine, norfluoxetine		N-desmethyl

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 selective serotonin reuptake inhibitors have the same principal 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, SSRIs differ in their potency and selectivity in inhibiting serotonin reuptake and many of them have important effects on other transporters and receptors. Each SSRI has a unique profile of multiple pharmacologic actions, which explains the differences in their efficacy and tolerability20.

	Binding properties of SSRIs
Citalopram (Celexa)	most selective serotonin reuptake inhibitor
Escitalopram (Lexapro)	most selective serotonin reuptake inhibitor
Fluoxetine (Prozac)	least selective serotonin reuptake inhibitor norepinephrine reuptake 18 dopamine reuptake 18 serotonin-2C receptors 21 cytochrome P450 2D6 cytochrome P450 3A4
Paroxetine (Paxil)	the most potent serotonin reuptake blocker, but has a low selectivity for the serotonin reuptake muscarinic cholinergic receptors (most potent blocker of muscarinic receptors among the SSRIs) histamine H1 receptors nitric oxide synthase cytochrome P450 2D6
Sertraline (Zoloft)	the second most potent inhibitor of serotonin reuptake and the second most selective blocker of serotonin over noradrenaline uptake 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.

Approved indications and uses

All the SSRIs are licensed for major depressive disorder and are considered to be the first-line treatments of depression. They are prescribed more often for elderly patients than any other psychotropics and are the antidepressant of choice for many practitioners.

The SSRIs differ in their licensed indications for non-depression disorders (which differ between countries).

Celexa (Citalopram) licensed indications:

• Major depressive disorder

Lexapro (Escitalopram) licensed indications:

• Major depressive disorder
• Generalized anxiety disorder (GAD)

Paxil (Paroxetine) licensed indications:

• Major depressive disorder
• Obsessive compulsive disorder (OCD)
• Panic disorder
• Social anxiety disorder
• Generalized anxiety disorder
• Posttraumatic stress disorder (PTSD)

Prozac (Fluoxetine) licensed indications:

• 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) licensed indications:

• Major depressive disorder
• Obsessive-compulsive disorder
• Panic disorder
• Posttraumatic stress disorder
• Premenstrual dysphoric disorder (PMDD) (newest indication)
• Social anxiety disorder

Efficacy and Effectiveness

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 antidepressant 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 the lack of tolerability or response can be effectively treated with another19.

Comparison of SSRI's side effects

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 common side effect associated 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, impotence, and delayed ejaculation. 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 therapy8.
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 risk of weight gain9.
Sertraline is generally associated with a small degree of weight loss in the acute phase of treatment.

Fluoxetine has potent appetite suppressing effects and may cause modest but nonsignificant weight decrease15.

Predictors for antidepressant-induced weight gain35:

• Family history of obesity (genetic factors)
• Lower levels of educational attainment
• Low body mass index at the beginning of antidepressant therapy

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.

QT interval prolongation
Citalopram has a higher risk of QT interval prolongation than other SSRIs33.

Discontinuation symptoms (withdrawal)

SSRIs aren't considered addictive. However, stopping treatment abruptly or missing several doses can cause discontinuation syndrome accompanied by withdrawal symptoms, including nausea, headache, dizziness, lethargy and flu-like symptoms.

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.

Pregnancy category

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.

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.

Paroxetine is the most potent inhibitor of the cytochrome P450 2D6 enzyme of all antidepressants34. 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.

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.

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).

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 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.

Protein binding

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

What is the best SSRI? Balancing benefits, side effects, cost

Head-to-head comparisons:

• Citalopram vs Fluoxetine
• Escitalopram vs Paroxetine
• Escitalopram vs Citalopram
• Fluoxetine vs Paroxetine
• Sertraline vs Fluoxetine

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

Clinically important differences exist between 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 drawback with escitalopram is a relatively high cost of its generic version. However, European data indicates that escitalopram is the most cost-effective antidepressant compared with other SSRIs31.

The fastest SSRI

Escitalopram has a rapid onset of antidepressant effect and is a good choice when rapid antidepressant response is desirable.

Fluoxetine has the slowest onset of antidepressant action.

The most sedative SSRI
Fluvoxamine and paroxetine are the most sedating of the SSRIs.

The most activating SSRI
Fluoxetine and sertraline are more activating and preferred in depressed patients with apathy, lack of energy, or hypersomnia. And they are least preferred in patients with anxiety and insomnia.

The lowest risk for drug interactions

Sertraline and citalopram have the lowest risk of enzyme inhibition making them the SSRIs of choice in patients at risk for drug interactions.

The best SSRI for anxiety

Escitalopram has potent anxiolytic-like effects32.

The best tolerated SSRI

Escitalopram and sertraline appear to be the best tolerated antidepressants.

For patients with poor compliance with medication or those likely to miss doses or interrupt treatment - fluoxetine is the best SSRI.

References

• Celexa Prescribing Information Forest Pharmaceuticals, Inc.
• Lexapro Prescribing Information PDF
• Paxil Prescribing Information PDF
• Prozac Prescribing Information Eli Lilly and Company
• Zoloft Prescribing Information Pfizer Inc.
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Published: May 05, 2007
Last updated by eMedExpert staff: February 03, 2018