¹University of Ottawa Institute of Mental Health Research at The Royal, Psychiatry, Ottawa, Canada

Background: A selective serotonin (5-HT) reuptake inhibitors (SSRI) discontinuation syndrome has been well documented following their abrupt cessation, especially with medications that have a shorter half-life than fluoxetine [Rosenbaum et al, 1998]. These symptoms may include worsened mood, irritability, agitation, dizziness, confusion headaches, nervousness, and sensation of electrical shocks. Prolonged administration of SSRIs decrease in a sustained fashion the firing rate of norepinephrine (NE) neurons in the rat locus coeruleus (LC) by about 50%, whereas that of 5-HT neurons in the dorsal raphe (DR) recovers from an initial suppression [El Mansari et al, 2020]. In patients with major depressive disorder, there is a corresponding 50% decrease of the main metabolite of NE, MHPG, in their cerebrospinal fluid following a 6 to 8 week treatment with SSRIs [Sheline et al, 1997].

Aims & Objectives: It was postulated that the SSRI discontinuation syndrome could be due, at least in part, to the rapid release of the 5-HT inhibitory tone on NE neurons and an enhanced excitatory NE tone on 5-HT neurons.

Method: Experiments were performed in male Sprague-Dawley rats anesthetized with chloral hydrate. In vivo electrophysiological recordings of NE and 5-HT neuronal activity were carried out in the LC and DR, respectively, in rats implanted with an osmotic minipump delivering either saline or the SSRI escitalopram (10 mg/kg/day, subcutaneously) for 14 days and recordings were carried out with the minipump delivering the drug or 48 hours after its removal to allow drug elimination. Escitalopram and the alpha₂-adrenergic autoreceptors agonist clonidine were injected intravenously (0.1 and 0.01 mg/kg, respectively) after the washout. Neuronal firing was analyzed for changes in spike frequency.

Results: ₂The NE mean firing rates differed significantly among groups (control: 1.8 ± 0.1 Hz, n=169; escitalopram: 1.0 ± 0.1 Hz, n=68; washout: 2.5 ± 0.2 Hz, n=129). The rebound activity was reversed by the injection of escitalopram (0.7 ± 0.1 Hz, n=89) and clonidine (1.2 ± 0.1 Hz, n=126).The 5-HT mean firing rates differed significantly in the washout group (control: 1.2 ± 0.1 Hz, n=215; escitalopram: 1.1 ± 0.2 Hz, n=72; washout: 2.2 ± 0.2 Hz, n=12). The rebound activity was reversed by the injection of escitalopram (0.7 ± 0.1 Hz, n=89) and clonidine (1.2 ± 0.1 Hz, n=126).

Discussion & Conclusions: Strikingly, the firing rate of NE neurons following the elimination of the SSRI was double that observed in rats still receiving the drug. Suppressing this rebound activity by the re-introduction of the SSRI confirmed the attenuated inhibitory role of 5-HT on NE neurons after a washout. The firing rate of 5-HT neurons being doubled after the washout period was likely driven by enhanced NE release on 5-HT neurons because of clonidine, activating inhibitory alpha₂-adrenergic autoreceptors, restored NE firing to normal. It is first concluded that an abrupt lifting of the inhibitory influence of 5-HT on NE neurons and an enhanced excitatory influence of NE on 5-HT neurons could account for the SSRI discontinuation symptoms. Second, since clonidine reversed rebound firing activities these results suggest a potential therapeutic benefit of this drug for SSRI discontinuation symptoms, as is the case for opiate withdrawal therapy [Rasmussen et al, 1990].