On February 4, 1988, the U.S. Food and Drug Administration (FDA) approved fluoxetine hydrochloride, marketed as Prozac by Eli Lilly and Company, for the treatment of major depressive disorder in adults. Fluoxetine was the first selective serotonin reuptake inhibitor (SSRI) to receive FDA approval, introducing a new mechanism of action and a different side-effect profile compared with the tricyclic and monoamine oxidase inhibitor antidepressants then commonly used. Development and mechanism Fluoxetine was discovered and developed in the 1970s and 1980s by researchers at Eli Lilly. SSRIs act by inhibiting the reuptake of serotonin (5-hydroxytryptamine) into presynaptic nerve terminals, increasing serotonin availability in the synaptic cleft. This pharmacological profile differed from older antidepressant classes, which acted on multiple neurotransmitter systems and often produced anticholinergic, cardiovascular, and sedative adverse effects. Clinical trials and regulatory review The approval followed clinical trials demonstrating fluoxetine’s efficacy in reducing depressive symptoms compared with placebo and its tolerability relative to older agents. Pivotal randomized controlled trials submitted to the FDA showed statistically significant improvements on standard depression rating scales. Safety data indicated that common side effects included insomnia, headache, gastrointestinal symptoms, and sexual dysfunction; serious but less common concerns such as serotonin syndrome and interactions with other serotonergic drugs were noted. Impact on treatment and prescribing Prozac’s approval accelerated the adoption of SSRIs in clinical practice. Many clinicians favored SSRIs because they were generally perceived as safer in overdose and better tolerated than tricyclic antidepressants. Over the following years, fluoxetine and subsequent SSRIs became widely prescribed for major depressive disorder and, as evidence accumulated and regulatory approvals expanded, for conditions such as obsessive-compulsive disorder, panic disorder, bulimia nervosa, and premenstrual dysphoric disorder. Caution, controversy, and evolving guidance As SSRI use grew, clinicians and researchers monitored adverse effects and population-level outcomes. Debates emerged about the balance of benefits and harms in different age groups; in the early 2000s, regulatory agencies issued warnings about increased risk of suicidal thoughts and behaviors in children, adolescents, and young adults treated with some antidepressants, prompting boxed warnings and recommendations for careful monitoring. These later developments do not change the fact of the original 1988 approval but form part of the broader historical context of fluoxetine’s clinical use. Legacy The FDA approval of fluoxetine in 1988 is widely seen as a watershed moment in psychiatric pharmacotherapy. It opened the era of SSRIs, altering prescribing patterns and stimulating both enthusiasm for and scrutiny of pharmacologic approaches to treating depression. Fluoxetine remains approved for multiple indications and continues to be used, though clinical practice now emphasizes individualized treatment selection, monitoring for adverse effects, and integration with psychotherapy and other nonpharmacologic interventions where appropriate. Sources and verification The date of FDA approval—February 4, 1988—and fluoxetine’s status as the first SSRI approved in the United States are documented in FDA archives and contemporaneous scientific literature, as well as in regulatory histories and peer-reviewed reviews of antidepressant development.