Meet the editor

Berend Olivier obtained a PhD in Neurobiology from Groningen University, Netherlands. He worked for 22 years at Solvay Pharmaceuticals performing research and development on psychoactive drugs, including antidepressants, antipsychotics, anxiolytics and serenics, specifically aiming for reduction of pathological aggression. He was involved in research and development around fluvoxamine, an SSRI antidepressant, anxiolytic

and anti-OCD medicine. In 1999–2001 he worked in New York to set up a biotech company, PsychoGenics Inc., developing animal psychiatric and neurological (genetic) models to find new psychoactive molecules. From 1992 to 2014 he was professor of CNS-Pharmacology at Utrecht University, Netherlands, performing fundamental research on animal models, brain mechanisms and pharmacology of psychiatric disorders. Dr. Olivier has published more than 600 scientific articles and book chapters.

Contents

**Section 1**

**Section 2**

**Section 3**

Translational Aspects *by Berend Olivier*

Resistant Depression *by Jose Alfonso Ontiveros*

**Preface III**

Introduction **1**

**Chapter 1 3**

Clinical Studies **15**

**Chapter 2 17**

**Chapter 3 37**

Preclinical and Translational Studies **65**

**Chapter 4 67**

**Chapter 5 85**

Influences of Maternal Vulnerability and Antidepressant Treatment during

Orexin 2 Receptor Antagonists from Prefrontal Cortical Circuitry to

*by Gerard J. Marek, Stephen Chaney and Mark J. Benvenga*

Rethinking the Use of Antidepressants to Treat Alcohol Use Disorders and

Introductory Chapter: Antidepressants - Preclinical, Clinical and

Depression Comorbidity: The Role of Neurogenesis

*Raquel Gómez de Heras and Laura Orio*

Pregnancy on the Developing Offspring *by Laura Staal and Jocelien DA Olivier*

Rodent Behavioral Screens

*by Antonio Ballesta, Francisco Alén, Fernando Rodríguez de Fonseca,* 

## Contents


#### **Chapter 6 103**

The BDNF Loop 4 Dipeptide Mimetic Bis(*N*-monosuccinyl-L-seryl-L-lysine) hexamethylenediamide Is Active in a Depression Model in Mice after Acute Oral Administration

*by Polina Povarnina, Yulia N. Firsova, Anna V. Tallerova, Аrmen G. Mezhlumyan, Sergey V. Kruglov, Tatiana A. Antipova, Tatiana A. Gudasheva and Sergey B. Seredenin*

Preface

Major depression is a prevalent and severe brain disorder with a high disability burden, as measured by the Disability-Adjusted Life Years (DALY) metric. Antidepressants were discovered and developed starting in the 1950s and 1960s, however, all 'early' antidepressants were discovered by chance. Based on these early medications, intense research into new and better antidepressants was undertaken, leading to the development of selective serotonin reuptake inhibitors (SSRIs). SSRIs are a class of antidepressants popular in the late 1980s and 1990s that are still being used today. Although many new antidepressants with various mechanisms have been found and introduced, we still have not seen 'real' antidepressants, defined as drugs that 'repair' or 'improve' the depression-causing mechanism in the brains of depressed patients. Another worrying aspect is the limited efficacy of antidepressants; only around 50% of depressed patients respond to existing antidepressants and a considerable number does not respond at all (i.e., treatment-resistant depressed people). Another feature of present antidepressants is their slow onset of action. It takes weeks to moths before a depressed patient experiences improvement of symptoms (if a patient is a 'responder'). All antidepressants have side effects that may lead to cessation of treatment in an early phase before remission of depressive symptoms can occur. Although initially developed as therapy for depression, antidepressants are often also therapeutically active in other psychiatric disorders,

like anxiety and obsessive-compulsive disorders or alcohol use disorders.

faster onset of action and activity against treatment-resistant depression.

abstinence.

severe depression.

All these aspects of antidepressants are reflected in the various sections and chapters of this book. In Section 1, Berend Olivier (Chapter 1) gives an introductory sketch of preclinical, clinical and translational aspects of various antidepressants, including the development of potential new antidepressants with less side effects or

In Section 2 (Clinical Studies), Dr. Laura Orio et al. (Chapter 2) give an extensive overview of the use of antidepressants in alcohol use disorders and these disorders' comorbidity with depression. They particularly focus on the role of neurogenesis in the therapeutic effects of antidepressants by increasing hippocampal plasticity. They also discuss the possibility of implementing treatment during alcohol

Dr. Ontiveros (Chapter 3) gives a thoughtful overview of treatment-resistant depression (TRD), a condition with serious medical and psychosocial complications. An exact definition of TRD is still subject of debate and much research still has to be done to find solutions. The chapter delves into this debate as well as discusses the many strategies that have been applied to help patients recover from

In Section 3 (Preclinical and Translational Studies), Laura Staal and Jocelien Olivier (Chapter 4) discuss the problems associated with antidepressant treatment during pregnancy. Unfortunately, approximately 20% of pregnant women suffer from affective disorders. Treatment is beneficial for these women, but the long-term consequences of in utero treatment for their offspring is unclear. Untreated depression
