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

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 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.
All SSRIs are not controlled substances.
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.
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.
Brief SSRIs comparison table

FDA
date

approval

Pharmaceutical
Forms

Citalopram
(Celexa)

Escitalopram
(Lexapro)

July 17, 1998

August 14, 2002

10mg,
20mg,
40mg
tablets,
oral solution 10
mg/5 mL

5mg,
10mg,
20mg
tablets,
oral solution 5
mg/5 mL

Fluoxetine
(Prozac)
December
29, 1987
10mg tablets,
10mg, 20mg,
40mg
pulvules,
oral solution
20mg/5mL,
weekly
capsules 90
mg

Paroxetine
(Paxil)
December 29,
1992

Sertraline
(Zoloft)
December 30,
1991

10mg, 20mg,
30mg, 40mg
tablets,
oral
suspension 10
mg/5 mL

25mg, 50mg,
100mg tablets,
oral
concentrate 20
mg/mL

50-100 mg/day

Recommended
dose (for Major
20-40 mg/day
Depressive
Disorder)

1020 mg/day

10-20
mg/day

20 mg/day

Drug interaction
Relatively low
potential

Relatively low

High

Moderate
high

to

Relatively low

Nausea
Headache
Insomnia
Diarrhea
Dry
mouth
Sexual
dysfunction
(ejaculation
failure,
decreased
libido)
Drowsiness
Dizziness
Fatigue

Tremor
Increased
sweating
Agitation
Anorexia
Nervousness
Anxiety

Nausea
Dry
mouth
Drowsiness
Most
common
Insomnia
side effects
Increased
sweating
Diarrhea

Nausea
Insomnia
Diarrhea
Headache

Nausea
Drowsiness
Headache
Nausea
Dry
mouth
Headache
Dizziness
Insomnia
Weakness
Nervousness
Fatigue
Anxiety
Sexual
Drowsiness
dysfunction
Anorexia
Increased
Diarrhea
sweating
Diarrhea
Insomnia

Tremor
Sexual
dysfunction
(abnormal
ejaculation,
Less
common decreased
libido,
side effects
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

2732 hours

2-4 days

20
hours
(highly
26 hours
variable)

7 days

30 to 60 days 10-14 days

7-14 days

Yes

Yes, but not

significant

Pharmacokinetic Variables
Half-life

35 hours

Time to steady7 days

state
Active
Metabolite?

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
3

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 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, 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)
Escitalopram
(Lexapro)

most selective serotonin reuptake inhibitor

most selective serotonin reuptake inhibitor

least selective serotonin reuptake inhibitor

norepinephrine reuptake 18
dopamine reuptake 18
Fluoxetine
serotonin-2C receptors 21
(Prozac)
cytochrome P450 2D6
cytochrome P450 3A4
the most potent serotonin reuptake blocker, but has a low selectivity
for the serotonin reuptake
muscarinic cholinergic receptors (most potent blocker of muscarinic
Paroxetine (Paxil) receptors among the SSRIs)
histamine H1 receptors
nitric oxide synthase
cytochrome P450 2D6
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
Sertraline (Zoloft)
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 firstline 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:

depression

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) in adults (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, 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.
7

Paroxetine, fluoxetine, citalopram and sertraline have been shown to increase body weight
after 612 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 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.
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.
Discontinuation symptoms (withdrawal)
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.
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. Fluoxetine and paroxetine are more likely to cause P450 drug interactions
than citalopram and sertraline, particularly in combination with medications metabolized by
9

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.
10

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

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.
11

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 most slow 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.

12

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Last updated: May 01, 2014

May

05,

15

2007