Fluoxetine hydrochloride: an FDA-approved medication

Fluoxetine hydrochloride is an FDA-approved medication that has demonstrated efficacy in treating a spectrum of psychological conditions. These indications include major depressive disorder, obsessive-compulsive disorder, panic disorder, bulimia, binge eating disorder, premenstrual dysphoric disorder, and bipolar depression, including cases of treatment-resistant depression when combined with olanzapine. The mechanism of action involves the inhibition of serotonin reuptake in presynaptic neurons, achieved by blocking the reuptake transporter protein.

Synthesis

A mixture of (R)-N-methyl-3-hydroxy-3-phenylpropylamine (0.33 g, 2 mmol), 4-iodobenzotrifluoride (0.82 g, 3 mmol), cuprous iodide (0.1 g), cesium carbonate (1.3 g, 4 mmol) and butyronitrile (0.5 mL) was stirred under nitrogen at 130-140° C. until reaction completion as determined by 1H NMR (16-24 hours). The reaction mixture was cooled to room temperature, diluted with methyl t-butyl ether (10 mL), filtered, and rinsed with more methyl t-butyl ether. A 20% HCl solution in isopropanol (1 mL) was added and the resulting solution was evaporated to dryness to give a solid residue. The residue was stirred with methyl t-butyl ether (5 mL) for 1 hour at room temperature and the suspension was filtered and washed with more methyl t-butyl ether to give 0.59 g of (R)-N-methyl-3-(4-trifluoromethylphenoxy)-3-phenylpropylamine hydrochloride ((R)-Fluoxetine hydrochloride) as a white solid [α]D23=-16.1° (c 1, CHCl3). 1H NMR (CDCl3) δ 9.73 (br s, 2H), 7.42 (d, J=8.7 Hz, 2H), 7.4-7.2 (m, 5H), 6.91 (d, J=8.7 Hz, 2H), 5.48 (dd, J=8.0, 4.5 Hz, 1H), 3.2-3.0 (m, 2H), 2.63 (at, J=5.4 Hz, 3H), 2.6-2.4 (m, 2H).[1]

Mechanism of Action

Serotonin and norepinephrine, both biological amines, have been shown to play a role in the treatment of depression. Low concentrations of serotonin appear in the cerebrospinal fluid of patients with depression. Additionally, lower numbers of serotonin uptake sites are located on the platelets of patients with depression. Presynaptic serotonin (5-HT1A) receptors are located in the dorsal raphe nucleus, which project to the prefrontal cortex. Fluoxetine hydrochloride exerts its antidepressant effects by blocking the reuptake of serotonin in the presynaptic serotonin neurons by blocking the reuptake transporter protein in the presynaptic terminal. Fluoxetine hydrochloride also has mild activity at the 5-HT2A and 5-HT2C receptors. Fluoxetine hydrochloride has minimal activity on noradrenergic reuptake. Due to the drug's action on the reuptake of serotonin, Fluoxetine hydrochloride produces an activating effect, and due to its long half-life, the initial antidepressant effect emerges within 2 to 4 weeks.[2]

Pharmacokinetics

Absorption: Peak plasma concentrations of Fluoxetine hydrochloride are attained after 6 to 8 hours. This drug is well absorbed with a bioavailability of 70% to 90%. Food does not appear to impact the bioavailability of Fluoxetine hydrochloride, but it may slow its absorption by 1 to 2 hours, which is not clinically significant. Thus, it may be administered with or without food.Distribution: Fluoxetine hydrochloride has plasma protein binding of approximately 94.5%, bound to albumin and alpha-1 glycoprotein. Fluoxetine HCL readily crosses the blood-brain barrier, with a brain-to-plasma ratio of 2.6:1 in humans. The volume of distribution (Vd) of Fluoxetine HCL and its metabolite ranges between 20 to 42 L/kg. Some studies report that it has the maximum volume of distribution (Vd) of any SSRI (between 14 and 100 L/kg). Metabolism: Fluoxetine hydrochloride's active metabolite is norFluoxetine hydrochloride, produced when the cytochrome P450 enzyme (CYP2D6) acts on it. Prescribers must remember that this drug has several drug-drug interactions due to its metabolism through the CYP2D6 isoenzyme. Additionally, norFluoxetine HCL can have an inhibitory effect on CYP3A4. Fluoxetine hydrochloride has a half-life of 2 to 4 days, and its active metabolite norFluoxetine hydrochloride has a half-life of 7 to 9 days. Approximately 7% of individuals definitively exhibit poor metabolism of which due to reduced activity of CYP2D6. Elimination: Fluoxetine HCL and norFluoxetine hydrochloride have long elimination half-lives, leading to the presence of the drug in the body for several weeks, even after stopping its use. 

Adverse Effects

The most common adverse effects reported by adults include insomnia, nausea, diarrhea, anorexia, dry mouth, headache, drowsiness, anxiety, nervousness, yawning, bruising, seizures, bleeding (rarely), hyperhidrosis, induction of mania, rare activation of suicidal ideation and behavior (especially in teenagers), weight gain/loss, decreased orgasm (anorgasmia and ejaculation latency), muscle weakness, tremors, and pharyngitis. The 5-HT2C antagonism is thought to contribute to the anxiety, insomnia, and agitation patients perceive with Fluoxetine hydrochloride. Patients may even have a panic attack with the administration of Fluoxetine hydrochloride. Thus, the clinician's responsibility is to educate patients.[3]

Most adverse effects are immediate and disappear with time. Thus, waiting for the side effects to subside is best before altering treatment. Most adverse effects are dose-dependent and time-dependent. Clinicians must exercise caution against the emergence of agitation or activation, which may indicate a bipolar state and require the addition of a mood stabilizer or an atypical antipsychotic. Fluoxetine hydrochloride can be activating; if insomnia is present, consider dosing early in the morning. Additionally, the dose may be reduced if the side effects are too distressing. The patient should be cautioned about adverse effects; if they persist, switching to a different antidepressant may be indicated after a few weeks. It is best to try another antidepressant before relying on augmentation strategies. This approach can minimize polypharmacy and encourage adherence to psychotropic medications. Trazodone, mirtazapine, or a hypnotic may be options for insomnia. Mirtazapine may also help with agitation or gastrointestinal adverse effects. Benzodiazepines may be used to treat anxiety. Bupropion or a phosphodiesterase inhibitor (such as sildenafil) may address sexual dysfunction. Bupropion may also be an option for potential cognitive slowing or apathy seen with Fluoxetine hydrochloride.

Enhancing Healthcare Team Outcomes

Fluoxetine hydrochloride is a commonly prescribed antidepressant by physicians and advanced practice practitioners, psychiatrists, and internists, but effective therapy requires the effort of an interprofessional team. When treating pregnant women during the third trimester with Fluoxetine hydrochloride, the prescriber should consider the potential benefits and risks of treatment. In addition, clinicians should consider that women who stopped antidepressant medication while pregnant were more likely to experience a relapse of MDD than women who continued to use antidepressant drugs.

Nursing staff and prescribers should monitor children and adolescent patients for suicidal ideation, especially when starting Fluoxetine hydrochloride or increasing doses. Nursing staff, particularly those with specialty training in psychiatric health, can counsel patients on proper dosing and administration. For example, it is crucial to educate patients that they should not combine the drug with alcohol or other antidepressants. The patient should have regular follow-ups regarding depression and suicidal thoughts. The pharmacist should verify dosing, especially check for drug interactions, given Fluoxetine hydrochloride's extensive list of interactions, and report these to the prescriber if present. All interprofessional team members are responsible for monitoring the patient, offering counsel, and noting any patient status changes. If they observe any issues, they should be documented in the patient's health record for all team members to follow, and the new information should be communicated to other team members so changes can be made if necessary. With close monitoring from all team members, Fluoxetine hydrochloride can be an effective drug for numerous psychiatric conditions, including major depression. An interprofessional approach involving open communication between clinicians, specialists, and pharmacists can achieve optimal outcomes related to Fluoxetine hydrochloride therapy while mitigating adverse effects.

References

[1] APOTEX PHARMACHEM INC - US2007/10678, 2007, A1

[2] Sohel AJ, Shutter MC, Patel P, et al. Fluoxetine. [Updated 2024 Feb 28]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2025 Jan-.

[3] Mullen S. Major depressive disorder in children and adolescents. Ment Health Clin. 2018 Nov;8(6):275-283.

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