Fluoxetine in Brief
- Active ingredient: Fluoxetine hydrochloride
- Common brand names: Prozac, Sarafem, Fontex, Foxetin,
Ladose, Fluctin, Prodep, Fludac, Lovan
- Drug class: Antidepressant, Selective serotonin
reuptake inhibitor (SSRI)
- FDA Approved: December 29, 1987
- Patent expiration date: August, 2001
- Chemical Formula: C17H18F3NO
- Pregnancy Category: C
- Habit forming? No
- Originally discovered: 1970s; Eli Lilly, USA
In the early 1970s, evidence of the role of serotonin (5-hydroxytryptamine
or 5-HT) in depression began to emerge and the hypothesis that enhancing
5-HT neurotransmission would be a viable mechanism to mediate antidepressant
response was put forward.
On the basis of this hypothesis, efforts to develop agents that inhibit
the uptake of 5-HT from the synaptic cleft were initiated. These studies
led to the discovery and development of the selective serotonin-reuptake
inhibitor fluoxetine hydrochloride (Prozac; Eli Lilly), which was approved
for the treatment of depression by the US FDA in 1987.
In late 1971 Bryan Molloy in Lilly synthesized a range of new compounds,
a group of phenoxyphenyl-propylamines from diphenhydramine, an antihistamine
found to inhibit reuptake of the neurotransmitter "serotonin". One of
these compounds, Lilly-110140 (later in 1975 called fluoxetine), was
found to be highly selective, affecting only the neurotransmitter serotonin.
As the chemist who synthesized the new series of compounds, Molloy was
in this literal sense Prozac’s creator. Years of development and testing
finally led to approval of fluoxetine hydrochloride for marketing.
In 1976 Eli Lilly begins clinical trials of fluoxetine. In 1983 Lilly
applied to U.S. FDA for approval to sell Prozac for treatment of depression.
Fluoxetine was initially approved for treatment of depression in Belgium
in 1986, and then Eli Lilly's Prozac was approved by the FDA on December
29, 1987 and introduced in the United States at the beginning of 1988.
It was the first of a new class of drugs, called selective serotonin
reuptake inhibitors (SSRIs), to be approved for use in the United States.
FDA approved indications
- Major depressive disorder
- Obsessive-compulsive disorder
- Bulimia nervosa (binge-eating and vomiting behaviors in patients
with moderate to severe bulimia nervosa)
- Panic disorder
- Premenstrual dysphoric disorder.
Off-label & Investigational uses
- Migraine headaches 10, 11
- Chronic daily headache 16
- Fibromyalgia 12
- Alcoholism 14
- Attention-deficit hyperactivity disorder (ADHD/ADD) 15
- Tourette's Syndrome 17
- Premature ejaculation 18
- Discontinuation of other SSRIs and SNRIs
- Smoking cessation 20
- Irritable Bowel Syndrome (IBS) 21
- Chronic pain syndromes 22
- Anxiety disorders in children and adolescents 23
- Hot flashes 24
Fluoxetine for Migraine headaches
Fluoxetine may be useful for patients who cannot use standard
prophylactic agents or if other agents fail. It is also a good choice
for persons with concomitant depression or other illness treatable with
SSRI. Three randomized, double-blind, placebo-controlled studies showed
a decrease in the frequency and severity of migraine headaches with
fluoxetine therapy. Daily dosages of fluoxetine ranged from 20 to 40
mg in these studies 10, 11.
Fluoxetine for Fibromyalgia
Fibromyalgia is the most common rheumatic cause of chronic pain.
In randomized placebo-controlled study women who received fluoxetine
had significant improvement in pain, fatigue and depression compared
with those who received placebo. In this study fluoxetine was generally
Crossover, placebo-controlled trial comparing fluoxetine (20 mg daily)
and amitriptyline (25 mg daily) demonstrated significant improvement
in global well-being, pain, and sleep for each medication alone. Further
improvement in efficacy and in fatigue and feeling refreshed upon awakening
occurred when two medications were used in combination 12.
Fluoxetine has been found to increase the
latent period of intravaginal ejaculation and therefore to be beneficial
in patients who prematurely ejaculate.
Fluoxetine "pros" and "cons"
Fluoxetine may be an appropriate antidepressant choice in
persons with hypersomnia or psychomotor retardation, who are poorly
compliant with medications. Fluoxetine should probably be avoided
in persons with concomitant anxiety, panic, and agitation.
- may have advantages over other SSRIs in patients who are poorly
compliant with treatment 3
(missing dose unlikely to cause problems)
- safety in overdose, relatively mild toxic effects even in children
- mild withdrawal symptoms 8
- low potential for weight gain 9
- the only SSRI approved by FDA for use in children 8 years of age and older
- associated with the lowest risk of suicide 28
- delay in onset of action, not suitable for patients in whom a rapid antidepressant effect is important or for
those who are agitated 3
- less effective than sertraline (Zoloft), mirtazapine (Remeron),
and venlafaxine (Effexor) for depression 4
- activating (insomnia, agitation, tremor and anxiety) and gastrointestinal (nausea, vomiting, diarrhoea) adverse effects
are higher than with other antidepressants 5
- may alter blood glucose control in patients with diabetes
- more likely to interact with other drugs than some of the other SSRI's (sertraline, citalopram, escitalopram)
- long wash out period may be required when switching to another antidepressant
- long half-life and non-linear pharmacokinetics make dose titration more difficult
- decreases sleep quality
- sexual dysfunction, according to the prospective multicenter study
the incidence of fluoxetine-induced SD is about 58% 19
Mechanism of action
The antidepressant, antiobsessional, and antibulimic effects of fluoxetine
are thought to be related to its effects on serotonergic neurotransmission.
It is a potent and selective inhibitor of serotonin (5-HT) uptake,
but not of norepinephrine or dopamine uptake, in the central nervous
system (CNS). In depressed patients who had received 40 to 60 mg per
day of fluoxetine for 6 weeks, the cerebrospinal fluid concentrations
of the metabolites of 5-HT (5-HIAA), dopamine (HVA), and norepinephrine
(HMPG) were reduced by 46%, 14%, and 18%, respectively. Because uptake
inactivates serotonin by removing it from the synaptic cleft, uptake
inhibition by fluoxetine enhances serotonergic function. As a consequence,
the 5-HT 1 receptors are desensitized or downregulated after long-term
fluoxetine administration. Fluoxetine does not interact directly with
postsynaptic serotonin receptors, muscarinic-cholinergic receptors,
histaminergic receptors, or alpha-adrenergic receptors. It does not
appear to cause downregulation of postsynaptic beta-adrenergic receptors
or a decrease in beta-adrenergic–stimulated cyclic adenosine monophosphate
(cAMP) generation as do older antidepressants.
Fluoxetine is an atypical SSRI. Studies have shown that plasma norepinephrine, epinephrine and dopamine levels are
significantly increased after acute and chronic treatment with fluoxetine 7.
Time to clear out of the system
The body eliminates fluoxetine very slowly. The half-life of fluoxetine
after a single dose is 2 days and after multiple dosing 4 days. The
liver then metabolizes fluoxetine into norfluoxetine, a desmethyl metabolite,
which is also a serotonin reuptake inhibitor. Norfluoxetine has an even
longer half-life, i.e. 8.6 and 9.3 days for single and repeated dosage respectively.
Because of the long half-lives of fluoxetine and norfluoxetine, it
may take up to 1 to 2 months for the active substance to disappear
from the body. There are no effective methods known to enhance the elimination of fluoxetine.
Onset of action
Because of the long time it takes for fluoxetine to reach a steady
state (4-5 weeks), full therapeutic effect may be delayed until 4 or
6 weeks of treatment. The lack of onset of response at 4-6 weeks is
associated with about a 73%-88% chance that patient would not have an
onset of response by 8 weeks 27.
Weaning off Fluoxetine (Prozac)
After treatment with fluoxetine, abrupt cessation may produce
discontinuation (withdrawal) reactions. Fluoxetine discontinuation symptoms include:
- dysphoric mood
- sensory disturbances (paresthesias such as electric shock sensations)
- emotional lability
- nausea and vomiting
Fluoxetine (Prozac) and Alcohol
Although fluoxetine has not been shown to alter alcohol metabolism
and does not appear to potentiate cognitive or psychomotor effects of
alcohol in healthy subjects, concomitant use is not recommended.
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Published: November 27, 2008
Last updated: January 18, 2012
- Fluoxetine exists as a racemic mixture, and a single-enantiomer
version, R-fluoxetine, was in development. R-fluoxetine is a potent
inhibitor of the serotonin transporter, but due to cardiotoxicity
resulting from prolongation of QTc intervals, its development was
stopped in favor of continuing use of the racemate.
- Fluoxetine is very activating, which makes it a good
choice for people who have very low energy. However, may be more
likely to increase nervousness, insomnia, and anxiety than other SSRIs, especially at higher dosages.
- Prozac is the best studied of the SSRIs
in pregnancy. While it has not been demonstrated to be entirely
safe, its use during pregnancy may be appropriate under certain conditions.
- Fluoxetine produces antinociceptive effect, which involves
central opioid, muscarinic and the serotoninergic pathways 6.
- It is the only SSRI that is FDA-approved specifically for the
treatment of depression in patients who are 65 years of age or older.