# Species differences in comorbid alcohol use disorder and major depressive disorder: A narrative review

## TL;DR

This review discusses how animal models of alcohol and depression disorders often fail to match human symptoms, especially in timing and recovery patterns.

## Contribution

The paper highlights translational barriers in preclinical models of AUD and MDD comorbidity due to species differences in symptom timelines and pharmacological responses.

## Key findings

- Human depression symptoms often remit after alcohol abstinence, while animal models show worsening symptoms without recovery.
- Classic antidepressants show preclinical success but fail in clinical trials for AUD and MDD comorbidity.
- High-drinking animal models lack withdrawal and negative affect seen in human patients.

## Abstract

Alcohol use disorder (AUD) and major depressive disorder (MDD) are often comorbid, and it is estimated that between 15 % to 33% of people dependent on alcohol have an MDD diagnosis. Mood‐related symptoms are also common in humans during acute withdrawal, but by most accounts, symptoms abate after 2–4 weeks of alcohol abstinence. Preclinical studies, important for understanding the etiology and finding treatments for this comorbidity, also find depression‐like and anxiety‐like phenotypes in early abstinence along with protracted negative affect detectable past 2 weeks postcessation. In this narrative review, we focus on the translational divergence of AUD and MDD comorbidity with a focus on the time line mismatch between species in concurrent AUD + MDD and MDD following AUD. We also highlight the preclinical success and clinical failure of classic antidepressants for AUD and the relative absence of withdrawal and negative affect in high‐drinking selected lines of mice and rats. We suggest sources of these discrepancies, including discussion of relief/reward‐driven drinking subpopulations and future directions for the field.

In this narrative review, we identify barriers to the translation of preclinical comorbidity models of alcohol use disorder and depressive disorders, including temporal and pharmacological discrepancies. In humans, depression is high during and immediately after the cessation of drinking and usually remits subsequently, while in animals it seems to worsen during abstinence without much evidence for recovery. We suggest probing preclinical models that more closely recapitulate the time course and symptomatology of anhedonia and negative affect seen in these patients.