Aticaprant

Aticaprant is a highly selective, short-acting kappa opioid receptor (KOR) antagonist, with demonstrated selectivity over mu opioid receptor (MOR) and delta opioid receptor (DOR) which is currently undergoing phase III trials as adjunct treatment for major depressive disorder, primarily with strong anhedonic component. being developed for adjunctive treatment of MDD with ANH+.

At some point, it was also a candidate drug for the treatment of alcoholism, cocaine-related disorders and smoking withdrawal – it was, however discontinued, since the initial test results were considered not satisfactory.

Apart from significant (30-fold) selectivity for the KOR over other opiod receptor types, it has a relatively long half-life of 30-40 hours. From neurophysiological point of view it is highly bioavailable, as it readily crosses the blood-brain barrier and can therefore produce central effects. At clinically-relevant doses, aticaprant is able to occupy 73–94 % of KORs. Clinial trials have demonstrated that aticaprant as adjunctive therapy for MDD is associated with considerable improvement of depressive symptoms, furthermore, it might be particularly clinically benefit measures of anhedonia particularly efficient in depressive patients with evident anhedonic component. The latter is a statement of clinical import in that none of the existing, approved antidepressant medications are known to alleviate the anhedonia; moreover, it can be argued that the emotional blunting that is often observed with prolonged treatment with certain medications is one of the factors that account for the persistent, treatment-resistant nature of the anhedonic component.

Kappa opioid receptors (KORs) are present in the periphery and central nervous system (CNS), including hypothalamus and nucleus accumbens). They serve the role of endogenous receptors for dynorphin A and B and are known to inhibit dopamine release in the striatum of the mesolimbic system, a major and crucial circuit in the brain’s reward system. High KOR activity levels have generally been associated with dysphoria and aversion in humans and depressive symptoms including anhedonia in animal models. KOR antagonists are thus hypothesized to ameliorate the depressive symptoms associated with dopamine insufficiency symptom relief by directly increasing dopamine release or by suppressing the inhibition of dopamine release caused by stress exposure.

Furthermore, navacaprant, with its selectivity for KOR larger by a factor of ten is a candidate drug for MDD monotherapy.

Benefits of taking aticaprant

• reduced anhedonia;
• relief in depressive symptoms;
• possibly helpful in treatment-resistant depression;
• potential aid in drug addiction recovery (i.e., alcoholism, cocaine use);
• may suppress the tendency towards risky reward-seeking behavior;
• possible addiction prevention in ADHD;
• more favorable safety profile compared to other adjunctive treatments to SSRI/SNRI antidepressants.

Side effects

• itching;
• headaches;
• diarrhea;
• nasopharyngitis.

Dosage

Aticaprant is ingested orally once a day, the usual dose being 10 mg.  It is hypothesized that it might be effective in MDD monotherapy at higher doses (up to 60 mg).