Next Generation Antidepressants

9780521760584

Reviews the future of mood-disorder research, covering identification of new therapeutic targets, preclinical models, and medicinal chemistry opportunities, and increasing understanding of genetic influences. Essential reading for everyone involved in psychopharmacology development, and mental health clinicians seeking a preview of discoveries soon to influence their practice.

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Preface

As the World Health Organization estimates that depression will become the second leading cause of death by the year 2020 – due primarily to complications arising from stress and the cardiovascular system – the need to develop novel and more effective treatment strategies for patients suffering with mood disorders has never been more paramount. Current treatment options for depressed patients include a variety of molecules designed to exclusively elevate central nervous system levels of monoamines such as serotonin (5-HT). These classes include the monoamine oxidase inhibitors and tricyclics and are exemplified by the selective serotonin reuptake inhibitors (SSRIs) and the dual serotonin/norepinephrine reuptake inhibitors (SNRIs). While these medicines are moderately effective in some patient populations, there are still considerable limitations associated with all commercially available antidepressants. These drawbacks include, but are not limited to, delayed onset of efficacy, treatment resistance in many patients, and deleterious side effects such as emesis and sexual dysfunction. The focus of this book is to review the current landscape and state of the field for depression research with an eye towards shedding light on where the future of mood disorders research is headed in terms of novel therapeutic targets, preclinical model development, exploring depression endophenotypes, and medicinal chemistry strategies. Undoubtedly all of these disciplines, as well as others including genetics and translational medicine approaches, will need to successfully collaborate to help build a better understanding of disease etiology, patient stratification, and treatment. As depression research has evolved over the past 50 years, the next decade will be instrumental in facilitating a move beyond our current understanding and pharmacological treatment options, and strive to discover and develop more personalized and effective treatment options for the millions of patients suffering from chronic and debilitating mood disorders.

Chad E. Beyer, PhD, MBA

Department of Pharmacology, University of Colorado School of Medicine, Aurora, CO, USA

Chapter 1	Chapter 5
Current depression landscape: a state of the field today	Defining depression endophenotypes
Chapter 2	Chapter 6
Novel therapeutic targets for treating affective disorders	Genetic and genomic studies of major depressive disorder
Chapter 3	Chapter 7
Developing novel animal models of depression	Medicinal chemistry challenges in the design of next generation antidepressants
Chapter 4	Chapter 8
Translational research in mood disorders: using imaging technologies in biomarker research	Application of pharmacogenomics and personalized medicine for the care of depression

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Chapter 7 Medicinal chemistry challenges in the design of next generation antidepressants

Introduction
Potential multitarget approaches
Triple reuptake inhibitors
Glutamatergic targets
Orphanin FQ/nociceptin receptor agonists
Targets in the hypothalamic–pituitary–adrenal axis
Glucocorticoid receptor antagonists
Vasopressin receptor antagonists
Melanocortin receptor antagonists
Summary and outlook
References

Medicinal chemistry challenges in the design of next generation antidepressants

Abstract

Monoamine-based strategies and targets have provided a useful variety of therapeutic agents with beneficial activity in the treatment of depression. However, this approach has some limitations, including a delayed onset of efficacy and treatment resistance. As a result, there is significant interest in non-monoamine targets and their potential as antidepressants. This search for new treatment modalities has been aided by better understanding of the neurochemical pathways involved in mood. This chapter will review medicinal chemistry advances in a selection of non-monoamine targets of current interest in the field.

Index

5-HT.. See serotonergic system
5-HTT.. See serotonin transporter
5-hydroxy-indole acetic acid (5-HIAA)
levels in CSF of depressed patients,

acetylcholine (ACh) system
target for treatment strategies,
addictive behavior,
adrenalin 2A receptor (ADRA2A) gene,
agomelatine, , ,
α₂-adrenoceptors
antidepressant targets,
amitriptyline, ,
AMPA receptors
antidepressant targets,
anhedonia,
animal models,
definition,
objective laboratory measurement,
anhedonia as a depressive endophenotype, ,
biological plausibility,
clinical plausibility,
cosegregation,
familial association,
future research directions,
heritability,
objective laboratory measurement,
role of anhedonia in depression,
specificity,
state-independence,
animal models of depression
affective and cognitive disturbances,
anhedonia,
barriers to development of novel treatments,
brain abnormalities in depression,
challenges,
chronic antidepressant treatment,
chronic mild stress model,
current models,
forced swim test,
forced swim test modifications,
gender differences,
genetically modified mouse models,
in-vivo brain monitoring,
limitations, ,
modeling depressive symptoms,
Morris water maze test,
need for novel models,
novel animal models,
novelty-induced hypophagia model,
open space swim test,
preclinical models in translational research,
range of approaches,
requirements and aims,
stress response,
tail suspension test,
translational neuroimaging,
withdrawal of drugs of abuse,
anticipation (genetic),
antidepressant metabolism
effects of individual genetic variations,
antidepressant therapeutic targets
effects of genetic variations in,
antidepressant treatment approaches
combination and augmentation strategies,
looking beyond monoamines,
new formulations of old medications,
staging of major depression,
successive monotherapies,
unmet therapeutic needs,
antidepressant treatment strategies,
5-HT1A/1B receptor targets,
5-HT2A/2C receptor targets,
5-HT2C receptor blockers,
5-HT3/5A/7 antagonism,
acetylcholine (ACh) system,
α₂-adrenoceptor targets,
AMPA receptor modulators,
atypical antipsychotics,
DA/NE release stimulator (bupropion),
dual 5-HT/NE reuptake inhibitors,
GABA-related approaches,
glutamate system,
histamine H3 antagonist and SSRI,
HPA axis-related treatment,
neurokinin receptor antagonists,
NMDA receptor antagonists,
non-monoaminergic approaches,
norepinephrine dopamine disinhibitors,
novel agents with new targets,
selective NE reuptake inhibitors,
substance P as target,
triple monoamine reuptake inhibitors,
ultraselective serotonin reuptake inhibitor (escitalopram),
antidepressants
animal models of chronic treatment,
discovery of tricyclic antidepressants (TCAs),
early discoveries,
effectiveness in major depression,
efficacy of interventions,
history of development,
limitations of current medications,
novel drug targets,
proven efficacy in trials,
time lag to take effect, , ,
apolipoprotein E epsilon4 gene,
aprepitant, ,
atypical antipsychotics
treatment of depression,

BDNF (brain-derived neurotrophic factor),
functions,
gene, ,
gene polymorphism,
Beck Depression Inventory (BDI),
benzodiazepines
co-administration with SSRIs,
for patients with depression,
beta 3 agonists,
beta adrenalin receptor (betaARs) gene,
biomarkers
applications for neuroimaging techniques,
cognitive deficits in mood disorders,
cognitive impairment,
disease biomarkers, ,
HPA axis dysfunction under stress,
negative bias,
neuroimaging of negative bias,
patient selection and stratification,
pharmacodynamic,
pharmacogenomics,
pharmacokinetic,
placebo effect,
preclinical animal models,
presymptomatic diagnosis in surrogate populations,
role of inflammation in depression,
role of neurotrophins,
surrogate biomarkers,
target validation biomarkers,
target–compound interaction,
vascular depression,
bipolar disorder
distinction from unipolar depression,
DSM-IV-TR criteria,
functional disorders,
bipolar II disorder,
blood–brain barrier (BBB),
BOLD (blood oxygen level-dependent) imaging,
brain imaging
abnormalities in depression,
brain monitoring
animal models of depression,
brain-derived neurotrophic factor.. See BDNF
bupropion, , ,
catecholamine (DA/NE) release stimulator,
hydrobromide salt formulation,

California Psychological Inventory,
Cambridge Neuropsychological Test Automated Battery (CANTAB),
candidate gene studies
MDD,
catecholamine (DA/NE) release stimulator
bupropion,
catechol-O-methyltransferase (COMT) gene,
cerebrovascular disease
vascular depression,
chronic mild stress model (animals),
citalopram, , , , ,
comparison with escitalopram,
pharmacology,
classification of mood disorders,
endophenotypic approach,
limitations of diagnostic criteria, . See also DSM-IV
clomipramine,
cognitive deficits in mood disorders
neuroimaging biomarkers,
cognitive impairment
biomarkers,
preclinical animal models,
Composite International Diagnostic Interview (CIDI),
copy-number variation (CNV)
MDD risk studies,
corticotropin-releasing factor (CRF),
cortisol
glucocorticoid receptor antagonists,
COX-2 inhibitors,
cytochrome P450 enzymes (CYPs)
effects of individual genetic variations,

depression,
clinical effectiveness of antidepressants,
clinical symptoms,
comorbidity,
etiology,
health consequences,
hypotheses of,
monoamine hypothesis, , ,
morbidity and mortality,
neurotransmitter receptor sensitivity hypothesis,
prevalence, , , ,
psychiatric comorbidity,
staging,
subtypes, . See also bipolar disorder major depressive disorder (MDD) unipolar depression.
depression endophenotypes.. anhedonia endophenotypes
depressive disorders
as a spectrum,
diagnostic challenges,
desimipramine,
desipramine, ,
desvenlafaxine, , ,
dexamethasone suppression test (DST),
diagnosis
difficulties with mood disorders,
distinction between unipolar and bipolar depression,
mood disorders as a spectrum,
DISC1 (Disrupted in Schizophrenia-1) gene,
disease biomarkers, ,
DNA structural variation
MDD risk studies,
dopamine (DA)
DA/NE release stimulator (bupropion),
monoamine hypothesis of depression,
dopamine D2, D3, D4 receptor (DRD2, DRD3, DRD4) genes,
dopamine transporter (DAT) blockade,
dopamine transporter (DAT1) gene,
dorsal raphe nucleus,
drug discovery and development.. See translational neuroimaging
DSM-IV
heterogeneity of clinical phenotypes,
DSM-IV-TR
criteria for mood disorders,
dual 5-HT/NE reuptake inhibitors,
duloxetine, ,
dysphoria,

endophenotypes
anhedonia as a depressive endophenotype, ,
biological plausibility, ,
clinical plausibility, ,
cosegregation, ,
criteria,
definition,
familial association, ,
future research directions,
heritability, ,
in MDD,
limitations of current classification systems,
measurement, ,
neuroticism,
specificity, ,
state-independence, ,
validation,
value in psychiatric research, . See also biomarkers.
endophenotypic approach, ,
environmental stress
effects of,
epigenetics,
epigenomics,
escitalopram, ,
clinical trials in depressed patients,
comparison with citalopram,
comparison with venlafaxine,
pharmacology,
safety,
tolerability,
eszopiclone,
etiology of depression,

familiality studies
MDD,
fatty acid amide hydrolase inhibitors,
fluoxetine, , , , , , , , , , , , ,
fluvoxamine, , , , ,
fMRI (functional MRI),
characterization of mood disorders,
use in drug discovery and development,
use in preclinical animal models,
forced swim test
animal model of depression, ,

galanthamine,
gamma-aminobutyric acid (GABA)
antidepressant target,
gender differences
animal models of depression,
genetic association studies
MDD,
genetic linkage studies
MDD,
genetic variations
enzymes which metabolize ADs,
therapeutic targets of ADs,
genetically modified mice
models of depression,
transgenic models of mood disorders,
genomewide association studies (GWAS), ,
glucocorticoid receptor antagonists,
glutamate system
antidepressant targets,
glutamatergic targets,
glutathione-S-transferase (GST) gene,
G-protein beta3-subunit (Gbeta3) gene,

Hamilton depression rating scale (HAM-D scale),
heritability studies
MDD,
heterogeneity of clinical phenotypes,
heterogeneity within classification criteria,
histamine H3 antagonist and SSRI,
Huntington’s disease (HD)
association with MDD,
hydroxyl bupropion,
hypothalamic–pituitary–adrenal (HPA) axis,
candidate genes for MDD risk,
glucocorticoid receptor antagonists,
melanocortin receptor antagonists,
role in depression,
role in mood disorders,
role in the stress response,
targets for drug development,
treatment target,
vasopressin receptor antagonists,

idazoxane,
imipramine, , , , ,
Implicit Association Test (IAT),
improving treatments.. See antidepressant treatment approaches
individualized medicine.. See pharmacogenomics
inflammation
role in depression,
Investigational New Drug requirements,
iproniazid, ,
isonazid,

ketamine,

l-5-methyl-tetrahydrofolate (MTHF),
lithium, , ,
LSD,
Lu 21004, ,
Lu AA 24530,

major depression,
clinical effectiveness of antidepressants,
depression subtypes,
morbidity and mortality,
prevalence,
psychiatric comorbidity,
staging,
major depressive disorder (MDD)
adoption studies,
association with rare genetic variations,
candidate gene studies,
common gene hypothesis,
copy-number variation (CNV) studies,
disease burden,
DSM-IV-TR criteria,
endophenotypes,
familiality studies,
family studies,
functional disorder,
genetic association studies,
genetic linkage studies,
genomewide association studies (GWAS), ,
heritability studies,
heterogeneity within classification criteria,
identifying depressive subtypes,
lack of response to drug treatment,
multiple phenotypes hypothesis,
prevalence,
rare genetic variants approach,
role of trinucleotide repeats,
studies of inheritance patterns,
twin studies,
median raphe nucleus,
medicinal chemistry
glucocorticoid receptor antagonists,
glutamatergic targets,
melanocortin receptor antagonists,
non-monoamine based targets,
orphanin FQ/nociceptin receptor agonists,
potential multitarget approaches,
SNRIs,
SSRIs,
SSRIs combined with 5-HT1A receptor antagonism,
targets in the HPA axis,
tricyclic antidepressants (TCAs),
triple reuptake inhibitors,
vasopressin receptor antagonists,
melanocortin receptor antagonists,
milnacipran, , ,
Minnesota Multiphasic Personality Inventory,
mirtazapine, ,
monoamine hypothesis of depression, , ,
5-HIAA in CSF of depressed patients,
evidence from post-mortem brain tissue,
evidence from therapeutic interventions,
role of serotonin in depression,
monoamine oxidase (MAO) gene,
monoamine oxidase (MAO) inhibitors,
mood disorders
as a spectrum,
diagnostic challenges,
DSM-IV-TR criteria,
pharmacogenomics,
possible progressive nature,
prevalence,
Morris water maze test,
mouse
genetic models of depression,
transgenic models of mood disorders,
MRI (magnetic resonance imaging),
MRS (magnetic resonance spectroscopy)
PK/PD studies,
multidrug-resistance gene (MDR1),

National Comorbid Study (NCS),
n-back task,
nefazodone,
negative bias
biomarkers,
in depressed patients,
neuroimaging biomarkers,
preclinical animal models,
neuroimaging
biomarker research applications,
brain abnormalities in depression,
role in translational research, . See also translational neuroimaging
neurokinin receptor antagonists, ,
neuropsychological deficits in mood disorders
neuroimaging biomarkers,
neuroticism endophenotype,
neurotransmitter receptor sensitivity hypothesis of depression,
neurotrophic factors,
neurotrophins
role in depression,
NMDA receptors
antidepressant targets,
nomifensine,
non-monoaminergic treatment approaches,
noradrenergic system
and reboxetine,
norepinephrine (NE)
DA/NE release stimulator (bupropion),
monoamine hypothesis of depression,
role in depression,
selective NE reuptake inhibitors,
norepinephrine dopamine disinhibitors,
norepinephrine transporter (NET) blockade,
norepinephrine transporter (NET) gene,
nortriptyline,
novelty-induced hypophagia animal model,

open space swim test
animal model of depression,
orosomucoid 1 and 2 (ORM1 and ORM2) genes,
orphanin FQ/nociceptin receptor agonists,

P38 kinase inhibitors,
Parkinson’s disease,
paroxetine, , , , ,
patient selection and stratification biomarkers,
disease biomarkers,
pharmacogenomics,
PDE inhibitors,
personalized medicine.. See pharmacogenomics
PET (positron emission tomography),
in vivo PK/PD studies,
role in drug discovery and development,
target–compound interaction biomarkers,
use in preclinical animal models,
pharmacodynamic biomarkers,
pharmacodynamics,
genetic basis for individual variations,
pharmacogenetics
genetic basis for individual responses,
pharmacogenomic panels,
pharmacogenomics,
barriers to clinical application,
clinical decision-making process,
clinical testing process,
definition,
genetic basis for individual responses,
mood disorders,
pilot studies of individualized medicine,
potential for individualized medicine,
tools for interpreting results,
translational research applications,
use in patient stratification,
pharmacokinetic biomarkers,
pharmacokinetics
genetic basis for individual variations,
phMRI (pharmacological MRI),
pindolol, ,
placebo effect
neuroimaging,
preclinical animal models.. animal models
presymptomatic diagnosis
neuroimaging in surrogate populations,
progression of mood disorders,
proteomics,
proton [¹H] spectroscopy,
psychosocial stressors
effects of,

quetiapine,

radiolabeling of drugs, ,
reboxetine, , ,
and the 5-HT system,
and the NE system,
in combination with SSRIs,
long-term efficacy,
selective NE reuptake inhibitor,
tolerability,
versus SSRIs,
versus TCAs,
reserpine, ,
risperidone, ,

selective NE reuptake inhibitors,
sense reversal,
Sequenced Treatment Alternatives to Relieve Depression study.. See STAR*D study
serotonergic system
and reboxetine,
and SSRIs,
serotonin
evidence for role in depression,
levels in post-mortem brain tissue,
monoamine hypothesis of depression,
serotonin receptors
1A/1B receptor targets,
2A receptor gene,
2A/2C receptor targets,
2C receptor blockers,
3/5A/7 receptor antagonism,
serotonin transporter
blockade,
effects of genetic polymorphisms,
gene polymorphism,
MDD candidate gene studies,
SERT.. See serotonin transporter
sertraline,
Sigma 1 agonists,
smoking cessation and depression,
Snaith–Hamilton Pleasure scale,
SNRIs (selective norepinephrine reuptake inhibitors),
SNRIs (serotonin/norepinephrine reuptake inhibitors),
SSR/NRI combined approach,
SSRIs (selective serotonin reuptake inhibitors),
and the serotonergic system,
combined with 5-HT1A receptor antagonism,
combined with histamine H₃ antagonist,
combined with reboxetine,
comparative efficacy in major depression,
delayed onset of action,
efficacy compared with TCAs,
fluoxetine,
introduction of,
long-term efficacy,
relapse features,
tolerability,
versus reboxetine,
St. John’s wort,
staging
major depression,
unipolar depression,
STAR*D study, ,
stress
role in depression,
stress response
animal models,
substance P
antidepressant targeting,
suicide and depression, , , ,

tail suspension test
animal model of depression,
target validation biomarkers,
target–compound interaction biomarkers,
TCAs (tricyclic antidepressants), ,
discovery of,
efficacy compared with SSRIs,
versus reboxetine,
Temperament and Character Inventory (TCI),
therapeutic dose range,
therapeutic interventions
evidence for the monoamine hypothesis of depression,
tianeptine,
transgenic animal models, ,
translational neuroimaging,
biomarker research applications,
biomarkers of cognitive deficits, ,
biomarkers of negative bias, ,
disease biomarkers, ,
HPA axis dysfunction under stress,
MRS studies,
patient selection and stratification biomarkers,
pharmacodynamic biomarkers,
pharmacogenomics applications,
pharmacokinetic biomarkers,
placebo effect,
preclinical animal models,
presymptomatic diagnosis in surrogate populations,
radiolabeling of drugs, ,
role of inflammation in depression,
role of neurotrophins,
target validation biomarkers,
target–compound interaction biomarkers,
therapeutic dose range,
transgenic mouse models,
vascular depression,
translational research
aims,
drug discovery and development,
lack of response to drug treatment,
pharmacogenomics applications,
preclinical animal models,
role of neuroimaging techniques,
surrogate biomarkers,
trazodone
new formulation,
tricyclic antidepressants.. See TCAs
triiodothyronine,
trinucleotide repeats
role in MDD,
triple monoamine reuptake inhibitors, , , ,
tryptophan hydroxylase (TPH) gene,
TSNAX (Translin-associated factor X) gene,
twin studies
inheritance of MDD risk,

UDP-glucuronosyltransferases (UGTs) genes,
unipolar depression
distinction from bipolar disorder,
staging,
uridine,

vascular depression,
vasopressin,
vasopressin receptor antagonists,
venlafaxine, , , , , ,
vilazodone,

Wisconsin Card Sorting Test (WCST),
Wisconsin General Testing Apparatus (WGTA),
withdrawal of drugs of abuse
animal models,
depressive symptoms,

Next Generation Antidepressants: List of Contributors

Lisa H. Berghorst, MA

Department of Psychology, Harvard University, Cambridge, MA, USA

Chad E. Beyer, PhD, MBA

Department of Pharmacology, University of Colorado School of Medicine, Aurora, CO, USA

Adam M. Brickman, PhD

The Taub Institute for Research on Alzheimer’s Disease and the Aging Brain, Columbia University, New York, NY, USA

Chun-Yu Chen, MS

Division of Mental Health and Addiction Medicine, National Health Research Institutes (NHRI), Taipei, Taiwan

Thomas I. F. H. Cremers, PhD

Brains On-Line BV, The Netherlands, and Brains On-Line LLC, San Francisco, CA

Mark Day, PhD

Experimental Neuroimaging, Abbott Laboratories, Abbott Park, IL, USA

Eliyahu Dremencov, PhD

Brains On-Line BV, Groningen, The Netherlands

Malgorzata Filip, PhD, DSc

Laboratory of Drug Addiction Pharmacology, Department of Pharmacology, Institute of Pharmacology, Polish Academy of Sciences, Krakow, Poland

Chris D. Griesemer, BS

The Center for Molecular and Genomic Imaging, University of California, Davis, CA, USA

Lotte de Groote, PhD

Solvay Pharmaceuticals Research Laboratories, Weesp, The Netherlands

Keh-Ming Lin, MD, MPH

Center for Advanced Study in the Behavioral Science, Stanford, California, USA, and Division of Mental Health and Addiction Medicine, National Health Research Institutes (NHRI), Taipei, Taiwan

Andrew C. McCreary, PhD

Solvay Pharmaceuticals Research Laboratories, Weesp, The Netherlands

Laurence Mignon, PhD

Neuroscience Education Institute, Carlsbad, CA, USA

Anna Parachikova, PhD

Cognitive Neuroscience, PsychoGenics, Inc, Tarrytown, NY, USA

Roy H. Perlis, MD, MSc

Laboratory of Psychiatric Pharmacogenomics, Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA, USA

Diego A. Pizzagalli, PhD

Department of Psychology, Harvard University, Cambridge, MA, USA

David P. Rotella, PhD

Chemical & Screening Sciences, Wyeth Research, Princeton, NJ, USA

Jul Lea Shamy, PhD

Drug Discovery and Development, PsychoGenics, Inc, Tarrytown, NY, USA

Stephen M. Stahl, MD, PhD

Department of Psychiatry, University of California San Diego and Neuroscience Education Institute, Carlsbad, CA, USA

Yu-Jui Yvonne Wan, PhD

Department of Pharmacology, Toxicology & Therapeutics, University of Kansas Medical Center, Kansas City, Kansas, USA