ABT-436

Accumulating evidence shows that certain populations of depressed patients have impaired hypothalamus-pituitary-adrenal (HPA) axis function. Arginine-vasopressin (AVP) is one of the primary factors in HPA axis regulation under stress situations, and AVP and its receptor subtype (V1B receptor) play a pivotal role in HPA axis abnormalities observed in depression. Based on this hypothesis, several non-peptide V1B receptor antagonists have been synthesized, and the efficacies of some V1B receptor antagonists have been investigated in both animals and humans. V1B receptor antagonists exert antidepressant-like effects in several animal models at doses that attenuate the hyperactivity of the HPA axis, and some of their detailed mechanisms have been delineated. These results obtained in animal models were, at least partly, reproduced in clinical trials. At least 2 V1B receptor antagonists (TS-121 and ABT-436) showed tendencies to reduce the depression scores of patients with major depressive disorder at doses that attenuate HPA axis hyperactivity or block the pituitary V1B receptor. Importantly, TS-121 showed a clearer efficacy for patients with higher basal cortisol levels than for those with lower basal cortisol levels, which was consistent with the hypothesis that V1B receptor antagonists may be more effective for patients with HPA axis hyperactivity. Therefore, V1B receptor antagonists are promising approaches for the treatment of depression involving HPA axis impairment such as depression.

In this review, the author focused on anticraving therapy for alcohol use disorder (AUD) defined by DMS‐5. A comprehensive review was carried out on the available published papers on anticraving drugs for treating AUD patients.

The author described all drugs with anticraving benefits for treating AUD patients approved by the Food and Drug Administration of the United States (US FDA) and European Medicines Agency of the European Union. Then, the commonly prescribed anticraving drugs and those under development were also described.

The US FDA‐approved anticraving drugs included acamprosate and naltrexone, and those approved by European Medicines Agency were gamma‐hydroxybutyrate and nalmefene. The author also highlighted topiramate, gabapentin, ondansetron, LY196044, ifenprodil, varenicline, ABT‐436, mifepristone, citicoline, and baclofen. The putative mechanisms of action of and the use in clinical practice of those anticraving drugs were also described.

Although slowly developing, the field of anticraving drugs is getting into shape as a promising entity of a pharmaceutical class of drugs. Then, the author addressed on the underused issues of those recommended, and suggested anticraving drugs by the practice guideline of the American Psychiatric Association. The author urges that clinicians should be more “adventurous” in prescribing those promising drugs because benefits of those anticraving drugs are far‐outweighing the possible side effects of anticraving drugs, or the harms of untreated AUD itself.