Fluoxetine (Prozac)

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

History

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 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
• Anorexia nervosa31

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 well tolerated.

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.

Premature ejaculation
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, psychomotor retardation, or low energy, who are poorly compliant with medications.

Fluoxetine has activating properties and should probably be avoided in persons with concomitant anxiety, agitation, and panic. This antidepressant is more likely to increase nervousness, insomnia, and anxiety than other SSRIs, especially at higher dosages.

Advantages:

• Fluoxetine has advantages over other SSRIs in patients who are poorly compliant 3. Fluoxetine has a long half-life, so missing the dose unlikely to cause problems.
• Safety in overdose, relatively mild toxic effects even in children 25, 26
• 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
• Fluoxetine improves peripheral and hepatic insulin action in type 2 diabetes patients 29

Disadvantages:

• Delayed onset of action. Fluoxetine is not suitable for patients in whom a rapid antidepressant effect is important or for those who are agitated 3
• Less effective than sertraline, mirtazapine, and venlafaxine 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.
• Potential for drug interactions -- fluoxetine is a strong inhibitor of CYP 2D6 and a moderate inhibitor of 2C9, 2C19, and 3A4.
• Long wash out period is 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
• irritability
• fatigue
• weakness
• agitation
• dizziness
• sensory disturbances (paresthesias such as electric shock sensations)
• anxiety
• confusion
• headache
• lethargy
• emotional lability
• insomnia
• hypomania
• 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.Further reading

• Fluoxetine (Prozac) vs Paroxetine (Paxil)
• Fluoxetine vs Amitriptyline
• Fluoxetine vs Citalopram
• Fluoxetine (Prozac®) vs Sertraline (Zoloft®)

References

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Published: November 27, 2008
Last updated: January 30, 2017