Prozac was the first selective serotonin reuptake inhibitor (SSRI) approved to treat major depressive disorder (MDD) in 1987. This began the shift away from tricyclic antidepressants and monoamine oxidase inhibitors as Prozac is just as effective with better tolerability with a more favorable side effect profile.
Prozac, like all SSRIs, functions primarily by blocking SERT and increasing serotonin levels. One thing to appreciate about it is it can provide the patient with some activation, which is why it is typically dosed in the morning. The activation is at least partially credited to its downstream effects by partially inhibiting norepinephrine transporters (NETs). While this is not to the same degree as a serotonin-norepinephrine reuptake inhibitor (SNRI) like Effexor (venlafaxine), its activation can be used to target symptoms such as fatigue and low motivation.
Prozac carries FDA approvals for MDD (ages 8 and older), obsessive compulsive disorder (ages 7 and older), panic disorder, bulimia, and premenstrual dysphoric disorder (as Sarafem). Off-label uses include post-traumatic stress disorder (PTSD) and social anxiety disorder.
Sarafem is a brand of fluoxetine that is marketed specifically for PMDD. It is available in 10 mg, 15 mg and 20 mg and can be dosed continuously or intermittently. Intermittent dosing is defined as 20 mg daily 14 days prior to the anticipated onset of menstruation through the first full day of menses and repeated with each cycle. The intermittent dosing model is not something I use frequently, but it does confuse patients given it takes SSRIs 4-8 weeks before the therapeutic benefit is seen. One of the mechanisms for this model is fluoxetine’s action on allopregnanolone. Allopregnanolone is a neuroactive steroid derived from progesterone that promotes anxiolytic effects through GABA-A modulation. Fluoxetine enhances the conversion of progesterone to allopregnanolone, independent of its action on SERT.
Prozac’s lengthy half-life of 4-6 days for fluoxetine and 9 days for its metabolite norfluoxetine make discontinuation effects rare and give clinicians the option of abruptly stopping it without a slow and gradual taper. Typically I will do a 7-day washout period if switching to another SSRI, especially in a patient 65 years or older. A mandatory 5-week washout period is needed if switching to an MAOI.
Prozac is not a medication I start often in adults due to drug interactions. The medication is a potent inhibitor of CYP2C9, 2C19, and 2D6, with the inhibition of 2D6 being the most problematic. A quarter of all drugs prescribed are metabolized by 2D6, with Abilify (aripiprazole) and Strattera (atomoxetine) being two medications as examples commonly used in psychiatry that can have their levels raised with concurrent administration of Prozac. All TCAs are metabolized by 2D6 and while one may think it would be odd to see a TCA with Prozac, remember amitriptyline and doxepin are medications that have indications outside of psychiatry (also keep this in mind if the patient is already on a TCA and you want to add Wellbutrin for more dopaminergic action).
Prozac boasts robust data with its use in children and I would be much more likely to start it in that population, although I do not currently see patients under the age of 18.
Patients will come to me already on Prozac and I will optimize if the patient is doing well on it. I often have to add buspirone if there is comorbid generalized anxiety and Wellbutrin can also be an augmenting agent, but it is important to consider Wellbutrin is also a potent CYP2D6 inhibitor.
Prozac is dosed 10 mg to 50 mg daily for depression, up to 60 mg daily for panic disorder and up to 80 mg daily for OCD. I typically start at 20 mg per day and titrate in 10 mg increments based on effect.
In overdose, Prozac was a common exposure and toxic effects were relatively mild. Typically the patient would present with nausea, vomiting, and irritability and treatment was symptomatic and supportive (antiemetics for n/v, BZDP for agitation, intravenous fluids for hydration, EKG, CMP, CBC, and co-ingestion labs). Because of its lengthy half life, I would encourage observation times longer than 6 hours, usually 8-12 hours, if completely asymptomatic, and overnight observation is not a bad idea, especially if there is evidence to suggest the ingestion was significant. Seizures and serotonin syndrome were rare in single ingestions but I can think of at least three cases where a patient had a seizure following a Prozac overdose.
Seizures from fluoxetine were slightly a contentious topic at the Poison Center, as our director instructed emphasizing them in SSRIs that were not Celexa (citalopram) or Lexapro (escitalopram) was not necessary. Unique to those medications, they have stronger blockade of the hERG potassium channel, which is responsible for prolonging the QT interval and can trigger seizures. Prozac blocks the hERG potassium channel as well but much weaker than Celexa.
Prozac, like all SSRIs, loses its selectivity in overdose, which is true for both fluoxetine and its metabolite norfluoxetine. This loss of selectivity means in addition to SERT, there is even more action on NET and dopamine transporters (DAT). This is what contributes to the sympathetic symptoms such as agitation, tremors, and tachycardia.
Higher concentrations of serotonin can lower a patient’s seizure threshold and obviously there is a risk for serotonin syndrome. As noted, serotonin syndrome is rare, even in an SSRI overdose. I saw it more frequently when multiple serotonergic medications were ingested and it is not something to expect. The best way to diagnose serotonin syndrome is to refer to the Hunter’s criteria, which includes spontaneous clonus, inducible clonus with agitation or diaphoresis, ocular clonus with agitation or diaphoresis, tremor, and hyperreflexia, hypertonia, temperature above 38 degrees C and either ocular or inducible clonus. We would often encourage providers to look for hyperreflexia and clonus of the lower extremities.
The treatment for serotonin syndrome seemed to be controversial between what the Poison Center recommended and what providers wanted to do. Our recommendations were supportive in nature, stopping all serotonergic medications, giving intravenous fluids for hydration, and benzodiazepines for agitation/hyperthermia. Providers frequently wanted to administer Periactin (cyproheptadine), which is something that is taught in schools across the country (I was taught this in my graduate studies as well).
Cyproheptadine is a first-generation antihistamine with strong 5-HT2A receptor antagonism. The anecdotal evidence is that by giving the medication, it blocks the excessive stimulation of 5-HT2A receptors, thus reversing the symptoms of serotonin syndrome. The position of the Poison Center at the time I worked there was it did more harm than good (adding an antihistamine with the potential of making symptoms worse/adding anticholinergic effects to an already agitated and confused patient). I have been argued with so much regarding the administration of cyproheptadine, it has become a drug I loathe (although I absolutely see its value as an appetite stimulant in the pediatric population). I realize there is evidence out there to show its role in the treatment of serotonin syndrome, but do not believe it is necessary or adds value to the supportive steps I mentioned above.
All and all, Prozac was a groundbreaking drug that altered psychiatry for the better and it is still widely used in practice today. I appreciate its role, but am more hesitant in starting it in adults in favor of other options that do not carry the same risk of drug interactions. I also think there are better options for anxious depression, which I will discuss in a future post. Prozac is still considered first-line in children and that is the population where it is most used in 2025.
As a reminder, this post is not meant to be used as medical advice or for treatment recommendations. If you are a provider managing a case or if you have made a medication error, consult your local Poison Center at 1-800-222-1222. The Poison Center is HIPPA compliant and failure to provide patient information impedes quality care and can result in poor patient outcomes.
This post was written by Richard Gray, PMHNP-BC. The above information is for educational/entertainment purposes and is not intended to be treated as medical advice. If you have questions about a medication you are taking, discuss these questions with your medical provider.