Fluoxetine HCl (Prozac, Sarafem) is probably the most well-known antidepressant and the archetypal selective serotonin reuptake inhibitor (SSRI). It is used for the pharmacological treatment of several mental disorders, most notably depression and anxiety, and sometimes neuropathy.
Introduction to Fluoxetine
Fluoxetine is a highly selective inhibitor of the serotonin transporter (SERT,) preventing serotonin in the synapse from being taken back into the presynaptic neuron. This increases the amount of serotonin available to postsynaptic receptors. Fluoxetine is a relatively safe antidepressant with few serious side effects, although combinations with other serotonergic drugs can result in possibly fatal serotonin syndrome. Fluoxetine has by far the longest half-life of all SSRIs. Fluoxetine is a first-line treatment for major depressive disorder and is less likely to cause a discontinuation syndrome than any other SSRI.
Using Fluoxetine
Ways of Administration
Fluoxetine is available in immediate-release capsules and tablets in dosages of 10, 20, and 40 mg, a delayed-release capsule containing 90 mg fluoxetine in enteric-coated pellets (Prozac Weekly,) and an oral solution containing 20 mg fluoxetine/5 ml.[1]Effects of Fluoxetine
As with other antidepressants, fluoxetine may take 2 or more weeks to produce a noticeable effect; single doses have minimal utility. Fluoxetine's psychoactive effects are usually subtle; euphoria and CNS stimulation or depression are estimated to occur in 1/100-1/1000 patients and thus the drug is considered to have minimal recreational potential. Emotional blunting, an inability to feel extreme emotions of any kind, is often reported.
There is controversy regarding the efficacy of fluoxetine and other SSRIs; in some clinical trials there is little to no statistically significant difference between the effects of fluoxetine and a placebo.Combinations with Fluoxetine
Fluoxetine is commercially available in combination with the 2nd-generation antipsychotic olanzapine, as Symbyax, for depressive episodes of bipolar disorder. Symbyax contains either 6 or 12 mg olanzapine with either 25 or 50 mg fluoxetine.Different Uses for Fluoxetine
In the U.S., fluoxetine is approved for major depressive disorder, obsessive-compulsive disorder, bulimia nervosa, and panic disorder alone and with agoraphobia, and premenstrual dysphoric disorder, and sometimes prescribed off-label for selective mutism, post-traumatic stress disorder (PTSD), social anxiety disorder, chronic neuropathic pain, fibromyalgia, and Raynaud's phenomenon.
Pharmacology of Fluoxetine
LD50 (mg/kg) as hydrochloride :
Mice : 248 (orally)
Rat : 452 (orally)
Fluoxetine inhibits serotonin reuptake almost exclusively, having no clinically appreciable effect on adrenergic, dopaminergic, muscarinic, or histaminergic receptors.
It is available as a racemic mixture of R and S enantiomers, which are mostly pharmacologically equivalent. Fluoxetine in plasma is approximately 94.5% bound to proteins, including albumin and alpha-1-glycoprotein.
Fluoxetine is effectively absorbed thorugh oral administration, with bioavailability of at least 60-80%. Time to peak plasma concentrations is between 4-8 hours following oral administration of normal therapeutic preparations and doses.
Fluoxetine is a substrate and inhibitor of cytochrome P450 2D6, and inhibits several other isoforms as well. It is extensively metabolized by the liver to norfluoxetine and several inactive metabolites. S-norfluoxetine is also a potent SSRI.
The half-life of fluoxetine ranges from 1 to 6 days, depending on acute or chronic administration, and norfluoxetine's may be as long as 16 days. Hence weekly dosing is feasible with fluoxetine, missed daily doses are rarely problematic, and SSRI discontinuation syndrome is unlikely.
Chemistry of Fluoxetine
Column 1 Column 2 Systematic(IUPAC) name: N-Methyl-3-phenyl-3-[4-(trifluoromethyl)phenoxy]-1-propanamine Synonyms: Prozac, Sarafem, Fontex, Molecular Formula: C17H18F3NO Molar mass: 309.33 g/mol. CAS Registry Number: 54910-89-3 Melting Point: 179-182 ℃ Boiling Point: 395 ℃ Flash Point: 192.757 °C Solubility: Sparingly soluble in Water and in Dichloromethane (DCM); Freely soluble in Ethanol and in methanol; practically insoluble in Ether
[1]
Column 1 Column 2 Title compound: Fluoxetine Systematic (IUPAC) name: N-Methyl-[gamma]-[4-(trifluoromethyl)phenoxy]benzenepropanamine Synonyms: (±)-N-methyl-3-phenyl-3-[([alpha],[alpha],[alpha]-trifluoro-p-tolyl)oxy]propylamine, dl-N-methyl-3-(p-trifluoromethylphenoxy)-3-phenylpropylamine; LY-110140, Adofen, Fluctin, Fluneurin, Fluoxeren, Fluox-Puren, Flusol, Fluxet, Fontex, Foxetin, Lovan, Prozac, Reconcile, Sarafem (hydrochloride) Molecular Formula: C17H18F3NO Molar mass: 309.33 g/mol, 345.79 g/mol (hydrochloride) CAS Registry Number: 54910-89-3, 59333-67-4 (hydrochloride) Melting Point: 158.4-158.9°C (hydrochloride) Boiling Point: no data Flash Point: no data Solubility: Hydrochloride (mg/mL) : methanol, ethanol > 100; acetone, acetonitrile, chloroform 33-100; dichloromethane 5-10; ethyl acetate 2-2.5; toluene, cyclohexane, hexane 0.5-0.67; maximum solubility in water 14; practically insoluble in ether Additionnal data: none Notes: hydrochloride aspect : white to off white crystalline powder. There is mention of an oxalate salt (mp 179-182°C).
The Dangers of Fluoxetine
Physical Health Risks
Physical Problem 1
Physical Problem 2
Overdose
Fluoxetine has an advantage over tricyclic antidepressants and monoamine oxidase inhibitors in that overdoses are rarely fatal. Seizures, coma, and cardiac arrythmias may result, but most patients survive overdoses without sequelae.Reported Deaths
Mental Health Risks
Fluoxetine's prescribing information includes a black box warning for suicidality in children and adolescents aged under 25, and caregivers are warned to monitor patients taking fluoxetine for changes in mood and behavior. However, meta-analyses of clinical trials suggest this may not be as much of a problem as such a warning implies. The benefits of treating depression appear to outweigh the risks of no treatment.[2][3]Mental Health Risk 1
In patients with bipolar disorder, fluoxetine may trigger mania, but has been successfully used as monotherapy in clinical trials.Mental Health Risk 2
Side Effects
The most common adverse events associated with fluoxetine include nausea/vomiting and diarrhea, due to the effects of 5HT3 receptors in the chemoreceptor trigger zone. Fluoxetine may also cause dry mouth, appetite loss, insomnia or somnolence, bleeding due to inhibited platelet activity, and various sexual problems including lowered libido, difficulty orgasming, and erectile dysfunction.Addiction
Physical Addiction
Mental Addiction
References
- ^Prozac Prescribing Information (2006) Eli Lilly and Company. In Physician's Desk Reference, 61st ed. Thomson PDR, Montvale, NJ.
- ^Beasley CM Jr, Dornseif BE, Bosomworth JC, Sayler ME, Rampey AH Jr, Heiligenstein JH, Thompson VL, Murphy DJ, Masica DN. Fluoxetine and suicide: a meta-analysis of controlled trials of treatment for depression. British Medical Journal. 1991 Sep 21;303(6804):685-92.
- ^Bridge JA, Iyengar S, Salary CB, Barbe RP, Birmaher B, Pincus HA, Ren L, Brent DA. Clinical response and risk for reported suicidal ideation and suicide attempts in pediatric antidepressant treatment: a meta-analysis of randomized controlled trials. Journal of the American Medical Association. 2007 Apr 18; 297(15):1683-96.
[1]Merck Index, fifteenth edition (2013)