An international team of scientists has found that the brain’s response to rewards is temporarily suppressed after the first dose of citalopram, an antidepressant, but gradually returns with continued use, PsyPost reports.

The findings, published in the Journal of Pharmacological Sciences, shed light on the neurobiological mechanisms behind the delayed effects of selective serotonin reuptake inhibitors (SSRIs), a commonly prescribed class of antidepressants.

Depression is a debilitating mental health disorder characterized by persistent sadness, loss of interest in daily activities, and an inability to experience pleasure. It affects hundreds of millions worldwide and remains one of the leading causes of disability. Despite the widespread use of antidepressants, at least 30% of patients fail to respond to treatment, highlighting the urgent need for a deeper understanding of how these medications work.

SSRIs, including fluoxetine (Prozac) and citalopram (Celexa), function by increasing serotonin levels in the brain, which is thought to enhance mood and restore normal emotional processing. However, their effects do not take hold immediately—most patients experience a delay of several weeks before noticeable improvements occur. Scientists have long speculated that this lag is due to complex neural adaptations, but the precise mechanisms remain unclear.

To explore this phenomenon, Masashi Koda and colleagues conducted a study on mice, focusing on serotonin-producing neurons in the dorsal raphe nucleus (DRN), a brain region involved in mood regulation and reward processing. Their goal was to determine how citalopram affects neural responses to pleasurable stimuli (such as sugar) after a single dose versus after prolonged treatment. By using fiber photometry, an advanced technique that measures brain activity in real time, they sought to uncover why antidepressants take time to become effective and whether their effects could be accelerated.

Results showed that, after a single dose of citalopram, neural response in the dorsal raphe nucleus to sugar (i.e., reward) was decreased. In other words, instead of becoming more sensitive to rewarding experiences (due to increased serotonin levels), mice became less sensitive. It turned out that the first dose of citalopram increases the amount of serotonin in the brain. However, it also triggers an autoinhibitory reaction that initially suppresses the antidepressant effects. With continued intake of citalopram, the brain adapts, and the autoinhibition effect gradually decreases, allowing the antidepressant effects of citalopram to become more visible.

Further investigation showed that this initial suppression of neural activity is achieved through 5-HT1A receptors (a type of serotonin receptor). When the study authors injected mice with (S)-WAY100135, a drug that blocks 5-HT1A receptors, the suppression of neural activity caused by the first dose of citalopram disappeared.

“By using the fiber photometry technique in free-moving animals, this study demonstrated that acute SSRI treatment reduces sucrose licking-induced activation of DRN [dorsal raphe nucleus] serotonin neurons via 5-HT1A autoreceptors, and co-treatment with SSRIs and 5-HT1AR antagonists partly mimic the effects of chronic SSRI treatment within a shorter timeframe,” the study authors concluded.

The study sheds light on the biochemical mechanisms of citalopram’s antidepressant effects.