On September 30th, 2013, the U.S. Food and Drug Administration (FDA) approved vortioxetine (Brintellix ®; previously Lu AA21004) for the treatment of depressive disorders. Approval from the European Medicines Agency (EMA) was requested in September 2012. Thus, approval in the EU can be expected soon. The substance was also assessed for the treatment of Generalized Anxiety Disorder (GAD). Vortioxetine is marketed by Takeda and Lundbeck.Vortioxetine inhibits the serotonin transporter with high affinity (Ki = 1.6 nM) and with moderate affinity also the norepinephrine transporter (Ki = 113 nM). Pharmacologically, the substance is differentiated from the selective serotonin reuptake inhibitors (SSRIs) by its binding to different serotonin receptors. The substance antagonizes serotonin 5-HT1D, 5-HT3 and 5-HT7 receptors. It acts as a partial agonist at 5-HT1A and 5-HT1B receptors, with being almost a full agonist at the 5-HT1A receptor. The manufacturers therefore characterize their compound as a serotonin modulator and stimulator.
Vortioxetine was tested against placebo, agomelatine, venlafaxine and duloxetine. Several studies in depression and GAD have already been published. These are mainly placebo-controlled studies in which the substance was given in doses between 2.5 mg and 5 mg. In these low doses vortioxetine was generally not superior to placebo. In the press release of the FDA six placebo-controlled trials are mentioned, in which the superiority over placebo was demonstrated. In an additional study, the relapse rate compared to placebo was reduced.
Furthermore, a PET study has already been published. Here, the occupancy of the serotonin transporter (5-HTT) and the 5-HT1A receptor were measured in healthy volunteers. The occupancy of the 5-HTT was on average only 2% at the 2.5 mg dose. It increased to 97% after administration of 60 mg. 80% of the 5-HTT are blocked at doses of about 20 mg. The authors from their results draw the conclusion that daily doses between 20 mg and 30 mg lead to effective occupancy of the 5-HTT. This also explains the inconclusive effectiveness of the low doses. In this PET study, no significant occupancy of the 5-HT1A receptor was measured at vortioxetine doses of up to 30 mg. The extent to which the binding to this receptor contributes to the clinical effects of the drug remains therefore unclear. Since the compound here, however, acts as a partial agonist with very high intrinsic activity, only a few percent receptor occupancy may be sufficient for pharmacodynamic effects. According to the press release of the FDA, Brintellix ® will be available as 5 mg, 10 mg, 15 mg and 20 mg tablet in the U.S.
The prescribing information now recommends starting treatment with a single dose of 10 mg, which can be increased to 20 mg if needed. It also contains a “black box” warning (similar to all other antidepressants in the U.S.) with the note that vortioxetine can lead to or worsen suicidal thoughts and impulses especially among young adults up to the age of 24 years. Most common adverse reactions in clinical studies were nausea, vomiting and constipation.
Bioavailability of vortioxetine is high (75%). Maximum plasma concentrations (Tmax) are measured after 7-11 hours. The protein binding is 98%. With a mean of 66 hours the elimination half-life is very long, steady state is reached after about 14 days. Elimination is primarily via the hepatic cytochrome P450 isoenzyme CYP2D6. If vortioxetin is combined with a CYP2D6 inhibitor (eg, bupropion, fluoxetine, paroxetine), the dose should be reduced. Conversely, when combining with a strong CYP2D6 inducer (eg rifampicin, carbamazepine), a dose increase is necessary. Food has no effect on the pharmacokinetics of vortioxetine. There is no pharmacologically active metabolite.
Vortioxetin must not be combined with MAO inhibitors (MAOI). If an irreversible MAOI is discontinued, one must wait 14 days before treatment with vortioxetin is initiated. After discontinuation of vortioxetine three weeks have to be waited before a MAOI can be used because of vortioxetine’s slow elimination.
In Germany, the success of vortioxetine will crucially depend on whether the manufacturers can demonstrate additional benefit of the drug in comparison to available treatments. In animal models vortioxetine has cognitive enhancing properties (which may be related to its 5-HT7 antagonism). In humans, this has not been proven yet. Such a characteristic would give the substance a unique feature, which would put the manufacturers in a favorable position in price negotiations in the framework of the German Pharmaceutical Market Reorganization Act (AMNOG).
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