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P.L. Delgado
Primary Psychiatry. 2009;16:5 (Suppl 4):8-15
Neurobiology of Serotonin Norepinephrine
Reuptake Inhibitors
Pedro L. Delgado, MD
ABSTRACT
FOCUS POINTS
Major depressive disorder (MDD) is a complex condition resulting from
• The serotonin (5-HT) and norepinephrine (NE) pathways project
in a partially overlapping fashion to limbic and cognitive areas
involved in functions disrupted in major depressive disorder
(MDD), including mood, emotion, attention, cognition, and
certain aspects of sensory perception.
• Drugs that increase 5-HT, NE, or both are capable of directly
influencing the function of these important brain areas, and
most or all drugs currently approved by the United States
Food and Drug Administration for treatment of MDD directly
or indirectly increase the synaptic availability of 5-HT and/or
NE, although there may be important differences in the pharmacologic properties of the drugs.
• Most antidepressants increase monoamine levels within
hours, but the downstream effects of increasing 5-HT and/or
NE on receptors, intracellular signaling systems, and neural
plasticity are more likely to reflect the underpinnings of shared
therapeutic effects in MDD patients.
• MDD is a genetically complex disorder: one possible explanation for the relatively small magnitude of the clinical
efficacy findings in MDD is the likely heterogeneity of the
patients treated, as genetic variation among patients will
affect treatment response and tolerability through multiple
independent and interacting pathways.
numerous genetic and physiologic factors. This article reviews the neurochemical mechanisms underlying MDD, summarizes recent genetic
findings, and examines the efficacy of various treatments. The norepinephrine (NE) and serotonin (5-HT) pathways affect several areas of the
nervous system that are disrupted in MDD, and agents that increase
levels of either NE (NE reuptake inhibitors [NRIs]) or 5-HT (selective serotonin reuptake inhibitors [SSRIs]) are known to be effective in alleviating
MDD symptoms. The dual-action hypothesis suggests that drugs affecting both neurotransmitters simultaneously (serotonin norepinephrine
reuptake inhibitors [SNRIs]) may have a greater therapeutic effect in
some patients than either NRIs or SSRIs alone. Literature shows that this
hypothesis is valid, but the magnitude of the effect is smaller than might
be predicted, possibly because of genetic heterogeneity among patients
or differences in selectivity among the various SNRIs, and because
modulation of 5-HT and NE activity does not entirely explain the pathophysiology of MDD. Until it is possible to select patients who are more
likely to respond to specific classes of drugs based on certain genes or
sible hypotheses have been proposed but subsequently found
lacking. Much early work investigated the possible causal roles for
abnormalities of the brain serotonin (5-HT) and/or norepinephrine (NE) pathways,1-6 largely driven by the marked therapeutic
success of 5-HT and NE reuptake inhibitors in the treatment of
MDD.2,7,8 However, incremental progress in the neurosciences
and clinical investigation along with the rapid development of
methods for genetic research has led to a set of more complex
causal hypotheses. For example, research suggests that MDD is
what geneticists define as a “complex” disease, where illness results
from the summation of numerous genetic and environmental
biomarkers, data suggest that dual-acting antidepressants are slightly
more effective than those that are selective for a single neurotransmitter
in the treatment of patients with MDD.
INTRODUCTION
In the past 50 years, there has been an exponential increase
in research aiming to elucidate the neurochemical mechanisms
responsible for major depressive disorder (MDD). Many plau-
Dr. Delgado is chairman of and professor in the Department of Psychiatry at the University of Texas Health Science Center in San Antonio.
Disclosure: Dr. Delgado is a consultant to and on the advisory boards of Eli Lilly, Lundbeck, Neuronetics, Takeda, and Wyeth; and has received honoraria from GlaxoSmithKline. Dr. Delgado discusses unapproved/investigational uses of milnacipran for the treatment of major depressive disorder.
Acknowledgment: The author would like to thank Kathleen Dorries, PhD, and Jennifer Hutcheson, BA, of Advogent for assisting in the writing and editing of this article.
Please direct all correspondence to: Pedro L. Delgado, MD, Department of Psychiatry, School of Medicine, University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, Mail
Code 7782, San Antonio, Texas 78229-3900; Tel: 210-567-5391; Fax: 210-567-6941; E-mail: [email protected].
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Neurobiology of Serotonin Norepinephrine Reuptake Inhibitors
factors, each of which have small effects and result in illness
only when their combined effects surpass a certain threshold.9 If
true, then biochemical and genetic causes of MDD may differ
markedly among patients, similar to how genetic and physiologic underpinnings of hypertension or diabetes differ among
patients.10 This concept may explain the sometimes inconsistent
results in research studies investigating specific biochemical
abnormalities in MDD and the outcome of studies testing specific treatments for MDD. The shift to conceptualizing MDD as
a complex disorder has also resulted in the current movement to
identify more homogeneous subgroups of patients with MDD
or endophenotypes.11,12 Finally, if there is great variability in
the underlying biochemistry and genetics among patients with
MDD, then it may be expected that when studying a large group
of people, medications with a broader pharmacologic profile
should demonstrate a broader efficacy profile.
Although research suggests various causes for MDD, the
opposite finding can be applied for how antidepressants function. Most or all drugs currently approved by the United States
Food and Drug Administration for MDD treatment directly
or indirectly increase the synaptic availability of 5-HT and/or
NE.10 The observation that only ~33% of patients achieve
remission with currently available antidepressants13 suggests
that modulating 5-HT and NE neurotransmission is not
sufficient to resolve MDD for all patients or to fully explain
MDD pathophysiology; treatments based on different mechanisms merit further investigation. Nevertheless, agents that
increase the availability of NE (norepinephrine reuptake inhibitors [NRIs]), 5-HT (selective serotonin reuptake inhibitors
[SSRIs]), or both neurotransmitters (serotonin norepinephrine
reuptake inhibitors [SNRIs]) can alleviate MDD symptoms.2,7,8
The NE and 5-HT pathways are both involved in nervous
system functions that are disrupted in MDD, including mood
(limbic areas and frontal cortex); emotion and anxiety (limbic
areas); attention and cognition (prefrontal cortex); appetite, sex
drive, sleep, and pleasure (hypothalamus and brainstem); and
somatic symptoms (limbic areas and spinal cord).14-16 Therefore,
the possibility that antidepressants whose effects involve both
5-HT and NE pathways may have a qualitatively different or
quantitatively greater therapeutic effect is the essence of the
dual-action hypothesis.14 This article reviews basic science and
human research on the neurobiology of antidepressants relevant
to the dual-action hypothesis of antidepressant action.
that the original concept of the limbic system as emotion
circuits separate and distinct from cognition circuits was not
complete—these circuits are now believed to significantly
overlap and interact with each other.18,19 The emotion and
cognition circuits most relevant to mood disorders predominantly comprise local circuits within and along hierarchical
circuits between specific regions of the brain, (eg, prefrontal
cortex, cingulate gyrus, amygdala, hippocampus, insula, ventral striatum, thalamus).20 Mood disorders most likely result
from dysfunction of either the neurons that comprise these
emotion and cognition circuits or the neurochemical systems
that modulate their function. Regardless of circuit malfunction
cause, it is important to remember that these brain structures
and circuits are the most likely proximal mediators of the
alterations in emotions, cognitions, and behaviors that define
mood disorders.17,18,20 Although other neurochemical mediators (eg, glutamate, γ-aminobutyric acid) play an equal or
greater role in the firing of these circuits, the role of 5-HT and
NE systems in modulating emotion has attracted the interest
of researchers in part because they are almost exclusively organized as large systems of single-source divergent neurons able
to simultaneously coordinate neural activity across many parts
of the brain, particularly limbic and cognition circuits. In addition, the unique organizational structure of the 5-HT and NE
systems is ideally suited for modulating emotion, attention,
cognition, and certain aspects of sensory perception.
The NE neurons in the central nervous system originate
from several distinct nuclei in the brainstem and project rostrally to almost all areas of the mid- and forebrain, dorsoventrally to the cerebellum, and caudally to the lumbar segments
of the spinal cord.21 Approximately 50% of all central nervous
system NE cell bodies originate from the locus coeruleus (LC)
in the dorsal pons,22 which is acutely sensitive to novel stimuli
and activated by a variety of stressful and aversive conditions.23
The LC influences arousal and is involved in the process of
using working memory to regulate behavior and attention24
and shifting attention.25 NE projections to the amygdala are
thought to play an important role in the acquisition of new
memories, especially those that are emotionally arousing,26,27
while NE projections to the thalamus and spinal cord are
important in the modulation of both central and peripheral
nervous system aspects of pain and pain perception.28
The 5-HT system is the largest cohesive neurotransmitter
system in the brain, and 5-HT neurons innervate all areas of
the brain.29 There are two major subdivisions: the ascending
and the descending arms. The descending arm projects to the
spinal cord and is involved in pain perception. Limbic brain
regions (hippocampus, amygdala, and temporal lobes) and
areas involved in sensory transmission and pain (thalamus) are
heavily innervated by the ascending arm, while motor areas
of the frontal cortex receive much lower levels of innervation.
The 5-HT-containing neurons terminate in both classical syn-
NEUROBIOLOGICAL UNDERPINNINGS
OF THE DUAL-ACTION CONCEPT
The brain’s emotion and cognition circuits play a central role
in mediating the symptoms that define mood disorders. The
relevant areas and circuits comprise the structures historically
referred to as the limbic system,17 although it is now believed
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P.L. Delgado
aptic connections and nonsynaptic terminals, such that some
5-HT release may be independent of cell firing, accounting
for some of the discrepancies between measures of 5-HT levels and changes in firing rate of 5-HT neurons after stress.30,31
Preclinical studies in laboratory animals demonstrate that
altering the function of the 5-HT system alters many of the
behaviors and somatic functions that form the core symptoms
of MDD, including appetite, sleep, sexual function, pain sensitivity, body temperature, and circadian rhythms.32
Although the NE and 5-HT systems have overlapping projections, major differences in the physiologic function and regulation of these systems exist, and this has implications for how
they differentially modulate behavior. In some target brain areas,
such as the frontal cortex, NE decreases spontaneous neuronal
activity while augmenting activity evoked by afferent stimulation, increasing the “signal:noise” ratio.33 In contrast, 5-HT
neurons fire similar to a pacemaker, with no change in firing
rate in response to novelty.34 For example, if a freely moving cat
is exposed to an environmental stressor (eg, pain), the firing rate
of 5-HT neurons does not change, while, in contrast, the rate of
firing of NE neurons increases. However, physical activity, and
more specifically, repetitive motor activity (eg, grooming behaviors) markedly increases the firing rate of 5-HT neurons.34
Additionally, there are significant differences in the physical
structure of NE and 5-HT neurons and the timing of their
maturation during development. There are two distinct types
of 5-HT nerve terminals. Nerve fibers from the dorsal raphe
have a fine morphology with small granular varicosities and
respond more to drugs that stimulate 5-HT1A receptors, while
fibers from the median raphe are coarse with large spheric
varicosities and have a lower response to drugs that stimulate 5HT1A receptors.31,35,36 The LC neurons demonstrate ≥4 distinct
cell types.37 The NE neurons mature later in development than
5-HT neurons, and aging produces a loss of ~30% to 40% of
NE neurons, whereas 5-HT neurons are less changed.38,39
SSRIs were the first cohort of designer antidepressants that
selectively bound to and blocked the 5-HT transporter.41 Several
NE selective drugs were also developed (eg, atomoxetine, reboxetine); however, clinical trials of atomoxetine failed to demonstrate antidepressant benefits, and results of reboxetine clinical
studies showed only modest benefits. Therefore, neither drug is
currently FDA-approved as an antidepressant.42 Subsequently,
monoamine selective “dual-action” drugs, which potently block
both 5-HT and NE reuptake (eg, venlafaxine, duloxetine, and
milnacipran), were developed and found to be effective.43 All current SSRIs and SNRIs bind selectively to the 5-HT and/or NE
transporters, with low or minimal affinities for other receptors
and transporters (eg, muscarinic, histamine, adrenergic, dopamine [D], opiate, and γ-aminobutyric acid).44-47 For example,
venlafaxine exhibited no significant affinity for muscarinic;
cholinergic; α1-, α2-, and β-adrenergic; histamine (H)1; 5-HT1;
5-HT2; D2; or opiate receptor binding sites.46 Duloxetine also
inhibited 5-HT and NE uptake but was a weak inhibitor of D
uptake in rat brain synaptosomes,47 and it exhibited a lack of
affinity for muscarinic acetylcholine; H1; α1-, α2-, and β-adrenergic subtypes of 5-HT1 (A,B, C, and D), 5-HT2, D2; and opiate receptors.47 Milnacipran inhibited 5-HT and noradrenaline
uptake in rat brain tissue48 and showed no affinity for α1-, α2-,
β-adrenergic; D2; serotonergic (5-HT1 or 5-HT2); muscarinic;
H1; or benzodiazepine receptors.45 The recently FDA-approved
drug desvenlafaxine also demonstrated selective inhibitory activity of 5-HT and NE neurotransmitter uptake44; no significant
affinity to 96 targets, including receptors, transporters, enzymes,
and channels; and no significant affinity besides 5-HT and NE
monoamine transporters.44
There may be important differences and similarities in the
pharmacologic properties of SSRIs and SNRIs. For example,
the SSRI sertraline shows high affinity for the D transporter,
suggesting that, at higher doses, D reuptake blockade may occur
in some patients. Similarly, data suggest that paroxetine may
have sufficiently high affinity for the NE transporter for it to be
a factor in some patients taking higher doses.49 Additionally, the
selectivity ratios for 5-HT and NE transporter binding differ
among the various SNRIs (Table).44,48,50-52 Venlafaxine exhibits
a Ki ratio of 1:30 as demonstrated by its inhibition of specific
radioligand binding to human NE and 5-HT transporters with
Ki values of 2480 and 82 nM, respectively.51 Duloxetine shows
a Ki ratio of 1:9 based on its inhibition of specific radioligand
binding to NE and 5-HT human transporters with Ki values
of 7.5 and 0.8 nM, respectively.51 Desvenlafaxine has a Ki ratio
of 1:14 as determined by its inhibition of specific radioligand
binding to NE and 5-HT human transporters with Ki values
of 558 and 40 nM, respectively.44 Although milnacipran is
largely regarded as a noradrenergic drug, it inhibits binding of
NE and 5-HT nearly equipotently (1:2 ratio).53 It is important
to note that the findings of such preclinical studies can vary
considerably, likely as the result of the different methodologies
ANTIDEPRESSANT EFFICACY OF
SELECTIVELY INCREASING BRAIN
SEROTONIN AND/OR NOREPINEPHRINE
The most compelling evidence for the role of 5-HT and NE
in antidepressant effects is that medications designed to selectively increase one or both of these neurotransmitters are effective in treating MDD.2,7,8 To date, the same cannot be said for
any other pharmacologic property. The first antidepressants (tricyclic antidepressants [TCAs] and monoamine oxidase inhibitors [MAOIs]) possess a plethora of pharmacologic effects, but
newer antidepressants were specifically designed to have a much
narrower profile. These drugs did not share any of the adrenergic, histaminergic, or cholinergic receptor antagonist properties
of TCAs but retained the monoamine reuptake inhibition.40
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Neurobiology of Serotonin Norepinephrine Reuptake Inhibitors
employed to evaluate reuptake inhibition. Further, uncertainty
exists about the exact relationship between in vitro binding
affinity and the magnitude of inhibition achieved in vivo and
even more so, how that relates to clinical effects. However, the
ratio of 5-HT and NE reuptake inhibition could lead to differences in effects on central and peripheral targets. For example,
venlafaxine appears to affect 5-HT and NE uptake inhibition
sequentially over its dose range such that, at both low and high
doses, platelet 5-HT uptake is inhibited, whereas the pressor effect to tyramine is less blunted at low versus high doses
of the SNRI.54 Duloxetine, with a relatively more balanced
NE:5-HT ratio, was found to affect functional consequences
of reuptake inhibition, such as decreased whole blood 5-HT
levels, increased sympathetic tone, and decreased whole body
NE turnover in studies of healthy volunteers.55,56
Another approach to measuring the effects of antidepressants on brain monoamines is to use microdialysis. Studies in
living animals with implanted microdialysis probes show that
antidepressants generally increase monoamine levels in various
brain regions within minutes of peripheral administration.
SSRIs tend to selectively increase 5-HT,57 while NRIs tend
to selectively increase both NE and D.58 SNRIs increase the
concentration of 5-HT and NE in central nervous system
areas within 30–60 minutes of administration.44,53,57,59-61 For
example, administration of venlafaxine 3–30 mg/kg subcutaneous led to a dose-dependent increase in extracellular NE in
the rat frontal cortex with an increase over preinjection levels
of 403% at the 30 mg/kg dose.57 In contrast, desvenlafaxine 10
and 30 mg/kg treatment led to a 96% (P=.0221) and 118%
(P=.0034) increase above baseline, respectively, in rat hypothalamic extracellular NE concentrations in the hypothalamus.44
One interesting aspect of microdialysis data is that levels of
5-HT are generally lower after acute dosing compared with
much higher levels found after chronic administration.62 This
phenomenon is thought to be due to an initial reduction in
firing rate of 5-HT neurons via stimulation of 5-HT1A receptors that desensitize over time.63 The NE release after chronic
administration of NRIs and SNRIs tends to change less over
time, although blocking feedback inhibition of neuronal firing
with α2-adrenergic receptor antagonists will markedly increase
NE release in the presence of the reuptake inhibitor.64-66
therapeutic responses to and maintained on serotonergic antidepressants. The relapse is qualitatively similar to before treatment MDD and correlates with the time course of monoamine
depletion, and patients improve rapidly as monoamine content
returns to baseline levels. Although similar results have been
demonstrated with NE depletion in responders to noradrenergic antidepressants, it is important to note that similar studies
have not yet been conducted with SNRI antidepressants.
Depletion studies suggest that the 5-HT and NE effects of
antidepressants may be independent of each other. For example,
depleting 5-HT causes a rapid MDD return in depressed
patients who have responded to fluoxetine, fluvoxamine,
MAOIs, and imipramine but not in those who have responded
to desipramine, nortriptyline, or bupropion.4,69,70 Depleting NE
and D causes a rapid MDD return in those depressed patients
who have improved on desipramine and mazindol but not on
fluoxetine.68,71 The selectivity seen in neurotransmitter depletion
studies argue against a single monoamine as being responsible
for the therapeutic actions of antidepressants.68,71 Noteworthy in
these studies, symptoms of MDD appeared within ~5–24 hours
after depletion; furthermore, patients recovered rapidly (within
48 hours) after testing was concluded.4,68,69,71 Neither 5-HT nor
NE depletion resulted in MDD symptoms in nondepressed
volunteers.72,73 In a randomized, double-blind, crossover trial,
Shansis and colleagues72 examined the effect of tryptophan on
mood, memory, attention, and induced anxiety in 12 healthy
male volunteers. None of these parameters was affected by 5HT depletion. Likewise, NE depletion in eight healthy volunteers failed to provoke symptoms of depression.73 Additionally,
patients who were experiencing an MDD episode did not experience worsened symptoms with 5-HT or NE depletion.74
TABLE
PHARMACOLOGIC CHARACTERISTICS OF THE SNRIS44,48,50-52
5-HT OR NE DEPLETION REVERSES
CLINICAL ANTIDEPRESSANT RESPONSES
While “downstream” changes in neuroplasticity may be the
final changes mediating antidepressant efficacy, neurotransmitter depletion studies in humans suggest that the initial effects
on NE and 5-HT may be necessary for the therapeutic effects
of many current drugs.4,67,68 Selective depletion of 5-HT4,68
causes a rapid MDD relapse in depressed patients having had
Primary Psychiatry 16:5 (Suppl 4)
Clinical
Indication(s)
Metabolic
Pathway(s)
Desvenlafaxine44 1:14
MDD
Conjugation
CYP 3A4 (minor)
Duloxetine51
1:9
MDD
GAD
DPNP
Fibromyalgia
CYP 1A2
CYP 2D6
Milnacipran48,52
3:1
MDD
Fibromyalgia
Conjugation
Venlafaxine51
1:30
MDD
GAD
SAD
Panic disorder
CYP 2D6
SNRI
5-HT:NE
Selectivity Ratio
SNRIs=serotonin norepinephrine reuptake inhibitors; 5-HT=serotonin; NE=norepinephrine;
MDD=major depressive disorder; CYP=cytochrome P450; GAD=generalized anxiety disorder; DPNP=diabetic peripheral neuropathic pain; SAD=social anxiety disorder.
Delgado PL. Primary Psychiatry. Vol 16, No 5. 2009.
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P.L. Delgado
Data gleaned from monoamine depletion studies suggests that
a simple deficiency of 5-HT or NE is not likely to be the sole
cause of MDD.75 It is hypothesized that MDD is linked to dysfunction of brain areas, such as the frontal cortex, hippocampus/
amygdala, and basal ganglia, known to be modulated by monoamine systems.74 Increased monoamines after treatment with
SSRIs and NRIs may serve to partially restore neuronal function
in these affected brain areas.10 The acute reappearance of MDD
symptoms on monoamine depletion in MDD patients in remission may underscore the fragility of these neuronal networks.10
showed significantly smaller hippocampal white matter (P<.008)
as well as significant left-right asymmetry versus healthy male and
female subjects (P=.001).90 In a separate study of 38 female outpatients with recurrent MDD in remission, mean left, right, and
total hippocampal gray matter was significantly smaller than that
of healthy subjects (P=.005).91 In the MDD patient population,
those patients who experienced longer durations during which
MDD episodes went untreated showed a significant reduction in
left (P=.0005) and right (P=.003) hippocampal volume.91
Chronic treatment with antidepressants increases the proliferation and survival of new neurons in the hippocampus. Malberg
and colleagues92 showed that chronic antidepressant treatment
significantly increases the number of dividing cells in the dentate
gyrus and hilus of the hippocampus. Two-week treatment with
fluoxetine increased pyramidal cell dendritic spine formation in
the hippocampal CA3 field, suggestive of hippocampal remodeling. Behaviorally, in rats exposed to inescapable stress associated
with decreased cell proliferation of the hippocampus, this could be
reversed by fluoxetine treatment.93 In addition, X-ray irradiation of
hippocampal regions of the mouse brain (which prevents neurogenesis) blocked the behavioral and neurogenic effects of chronic
antidepressant treatment with fluoxetine or imipramine.94 Recent
work using X-ray irradiation to block neurogenesis, and therefore
determine whether it was necessary for various stress and antidepressant-mediated behaviors, extends these findings. The adverse
behavioral effects of unpredictable chronic, mild stress were not
blocked by X-ray treatment, suggesting that reduced neurogenesis
was not the cause of the stress-related behaviors.95 However, as
in prior studies, the ability of either fluoxetine or imipramine to
reverse the behavioral effects of unpredictable chronic, mild stress
was blocked.95 These data suggest that, at least in certain animal
models of MDD, neurogenesis was required for the antidepressant
response. Also, existing data show little quantitative differences in
amount of neurogenesis among NRIs, SSRIs, and SNRIs.92-94,96-98
DOWNSTREAM EFFECTS, INTRACELLULAR
SIGNALING, AND NEURAL PLASTICITY
Because most antidepressants increase monoamine levels
within hours but clinical response can take weeks, investigators
have searched for the adaptive changes in various brain areas that
temporally correspond with the clinical data. A chronic increase
in the synaptic concentration of NE and 5-HT with antidepressants is associated with changes in β-adrenergic and 5-HT receptor density and/or sensitivity.6,76-80 These changes are common
to most antidepressants, irrespective of whether they are NRIs,
SSRIs, or SNRIs, and therefore are more likely to reflect the
underpinnings of shared therapeutic81-83 or side effect profiles.
The ability of chronic antidepressant treatment to downregulate monoamine receptors appears to be associated with changes
in neuronal function. This has been observed in experiments
whereby chronic administration of antidepressants led to inhibition of microiontophoretically administered NE or 5-HT
depression of cortical neuron firing.84-87 Again, investigators have
focused on finding a single common characteristic unifying antidepressants, thereby focusing on the characteristics most likely
shared across various antidepressant families rather than those
that may distinguish one drug or category of drug from another.
Neural plasticity, involving changes in intracellular signal
transduction pathways, gene expression, neuronal morphology,
and cell survival, may play an important role in the etiology and
treatment of MDD.88 Areas of the brain shown to be altered
with MDD and stress include the hippocampus and prefrontal
cortex. In the hippocampus, these changes include a decreased
number and size of rodent CA3 neurons, decreased neurogenesis of rodent granule cells, and an overall decrease in hippocampal volume. Changes in the prefrontal cortex include a decrease
in the number and size of neurons, decreased number of glia,
and decreased volume of the subgenual prefrontal cortex.88
Hippocampal volume has been shown to be reduced in patients
with mood or anxiety disorders, including post-traumatic stress
disorder and MDD.89 In a study of 30 inpatients with MDD,
men with a first episode of MDD exhibited significantly smaller
left gray matter hippocampal volume than that of healthy male
subjects (P<.02).90 In addition, both male and female patients
Primary Psychiatry 16:5 (Suppl 4)
MDD AS A GENETICALLY COMPLEX DISORDER
New research has led to important questions about the very
nature of the construct of MDD.99 The modern construct of
MDD evolved from an attempt to improve the reliability of clinical diagnosis and communication among clinicians and researchers.100 To that end, it has been effective, and considerable research
supports the clinical validity of MDD. However, as for many
other disorders in medicine, overinclusive definitions increase the
likelihood of greater heterogeneity of environmental and genetic
causal pathways. Some suggest that some or all of the difficulty in
identifying the genetic or neurobiological basis for MDD is related
to how broadly this condition is defined.99 If the definition of a
condition is overly broad, it may include a large group of underlying conditions that happen to share some of the symptoms used
to define the index condition but have different neurobiological
origins. Such a situation would make it unlikely that any given
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Neurobiology of Serotonin Norepinephrine Reuptake Inhibitors
CONCLUSION
study investigating underlying causal factors would identify a
single biological abnormality or set of genes. Additionally, heterogeneity will likely influence qualitative and quantitative aspects of
treatment response as well as the tolerability of treatments.
The possibility that MDD includes a large number of etiologically narrower subtypes that share some but not all the biological
characteristics is not new. The bipolar-unipolar distinction101 and
the subtypes of melancholic,102 seasonal,103 atypical,104 psychotic,105
brief recurrent,106 postpartum,107 childhood onset,108 early and late
adult onset,109-111 and double112 are some prominent examples of
attempts to define narrower subsets that may be more homogeneous. More research is needed to determine if some of these proposed subtypes are sufficiently distinct to warrant being formally
designated as a separate condition or a causally-distinct subtype.
New methods for measuring genetic differences between people
have fueled much research into individual genetic differences that
contribute to risk of major mental disorders, as well as treatment
response and safety. This exponentially growing body of research
suggests that individual differences in genetically determined biological factors may underlie differences among people in therapeutic drug responsiveness and treatment-related adverse events. Much
of the current work in this regard has focused on small variations
in the genetic sequence for genes, such as single nucleotide polymorphisms and restriction fragment length polymorphisms,113,114
but new research suggests that larger structural variation may be
more common among people.115 Complicating this research,
many polymorphisms do not modify gene function while genetic
variation in distant sites or rare variants can sometimes alter the
expression of gene products, justifying the measurement of gene
expression using microarrays.116 The number of highly idiosyncratic variables that could modify gene expression, or subsequent
protein synthesis as well as the possible interactions between different genetic variants in different people, markedly raises the level of
complexity and suggests that investigators and clinicians will need
to be patient as this research continues to unfold and mature. Its
full implications extend beyond psychiatry and are generally discussed under the rubric of “personalized medicine.”117,118 The lack
of methods and/or resources to simultaneously consider all of the
polymorphisms and structural genomic variations among people
is most likely responsible for the high degree of variability in prior
study outcomes of the effect of single genetic polymorphisms and
antidepressant treatment response. However, it is worth noting
that some studies (although other studies have not confirmed
these findings) have found significant associations between antidepressant treatment response and genetic polymorphisms of the
NE119,120 and D transporters,121 the 5-HT transporter promoter
5-HTT,119,122-124 catecol-O-methyltransferase,125-127 and MAO-B128
enzymes, corticotropin-releasing hormone signaling systems,129,130
glucocorticoid receptor,131 and the propeptide region of the brainderived neurotrophic factor gene.132 Antidepressant side effects
have been associated with polymorphisms of the 5-HTT123,133 and
the cytochrome P450 isozymes.134,135
Primary Psychiatry 16:5 (Suppl 4)
The literature reviewed strongly suggests that increasing brain
NE and/or 5-HT is a pharmacologic characteristic that contributes
substantially to the efficacy of currently available antidepressants.
This most likely includes a temporal sequence with increased
monoamine levels causing alterations in presynaptic autoreceptor
density and sensitivity, which allow further increases in synaptic
levels of the monoamines, culminating in postsynaptic receptor
adaptations and changes in neuronal plasticity and neurogenesis.
The postsynaptic areas affected by these processes notably include
most of the brain areas involved in emotion regulation.
Given that the projections and function of the NE and 5-HT
systems are not identical, it would be anticipated that SSRIs,
NRIs, and SNRIs should have marked differences in the quality
of antidepressant response and tolerability, as well as the overall
proportion of patients that respond. SNRIs should be effective
in a larger number of patients, and patients should have a more
complete response to treatment with SNRIs. However, while
greater efficacy of SNRIs in MDD has been reported, the magnitude of this effect is significantly smaller than one may have predicted based on the neurobiological data. The more robust magnitude of the relative benefit of SNRIs versus SSRIs for treatment
of neuropathic pain136 is closer to what one would have expected
for MDD and is likely explained by the dual modulation of pain
centers in the brain and spinal cord by NE and 5-HT.
The SNRIs as an antidepressant class exhibit affinity toward both
5-HT and NE transporter molecules, but their selectivity differs
among members of the class, possibly leading to differences in their
effects on central and peripheral targets. Recent advances in pharmacogenomics demonstrate that polymorphisms of gene loci involved
in monoamine signaling pathways are associated with changes in the
efficacy, safety, and tolerability of SNRIs.119,120,122-124,133 As this area of
investigation matures, it may be possible to select patients who will
be more likely to respond to specific classes of drugs based on the
presence of certain genes or biomarkers. Until such time, data suggest that there are theoretical reasons why medications with a broader
profile of effects on monoamine systems may have a slight advantage
over the more neurotransmitter-selective compounds. PP
REFERENCES
1. Delgado PL. Common pathways of depression and pain. J Clin Psychiatry. 2004;65(suppl 12):16-19.
2. Blier P. Norepinephrine and selective norepinephrine reuptake inhibitors in depression and mood disorders: their
pivotal roles. J Psychiatry Neurosci. 2001;26(suppl):S1-S2.
3. Blier P, Abbott FV. Putative mechanisms of action of antidepressant drugs in affective and anxiety disorders and
pain. J Psychiatry Neurosci. 2001;26(1):37-43.
4. Delgado PL, Charney DS, Price LH, Aghajanian GK, Landis H, Heninger GR. Serotonin function and the mechanism
of antidepressant action. Reversal of antidepressant-induced remission by rapid depletion of plasma tryptophan.
Arch Gen Psychiatry. 1990;47(5):411-418.
5. Charney DS, Heninger GR, Sternberg DE, et al. Presynaptic adrenergic receptor sensitivity in depression. The effect
of long-term desipramine treatment. Arch Gen Psychiatry. 1981;38(12):1334-1340.
6. Peroutka SJ, Snyder SH. Long-term antidepressant treatment decreases spiroperidol-labeled serotonin receptor
binding. Science. 1980;210(4465):88-90.
7. Brunello N, Mendlewicz J, Kasper S, et al. The role of noradrenaline and selective noradrenaline reuptake inhibition
in depression. Eur Neuropsychopharmacol. 2002;12(5):461-475.
8. Thase ME, Haight BR, Richard N, et al. Remission rates following antidepressant therapy with bupropion or
selective serotonin reuptake inhibitors: a meta-analysis of original data from 7 randomized controlled trials. J Clin
Psychiatry. 2005;66(8):974-981.
13
© MBL Communications Inc.
May 2009
P.L. Delgado
9. Fava M, Kendler KS. Major depressive disorder. Neuron. 2000;28(2):335-341.
10. Delgado PL. How antidepressants help depression: mechanisms of action and clinical response. J Clin Psychiatry.
2004;65(suppl 4):25-30.
11. Phillips ML. The emerging role of neuroimaging in psychiatry: characterizing treatment-relevant endophenotypes.
Am J Psychiatry. 2007;164(5):697-699.
12. Berrettini WH. Genetic bases for endophenotypes in psychiatric disorders. Dialogues Clin Neurosci. 2005;7(2):95-101.
13. Trivedi MH, Rush AJ, Wisniewski SR, et al. Evaluation of outcomes with citalopram for depression using measurement-based care in STAR*D: implications for clinical practice. Am J Psychiatry. 2006;163(1):28-40.
14. Shelton RC. The dual-action hypothesis: does pharmacology matter? J Clin Psychiatry. 2004;65(suppl 17):5-10.
15. Stahl SM. The psychopharmacology of painful physical symptoms in depression. J Clin Psychiatry. 2002;63(5):382-383.
16. Stahl S, Briley M. Understanding pain in depression. Hum Psychopharmacol. 2004;19(suppl 1):S9-S13.
17. MacLean PD. Psychosomatic disease and the visceral brain; recent developments bearing on the Papez theory of
emotion. Psychosom Med. 1949;11(6):338-353.
18. LeDoux JE. Emotion circuits in the brain. Annu Rev Neurosci. 2000;23:155-184.
19. Taylor SF, Liberzon I. Neural correlates of emotion regulation in psychopathology. Trends Cogn Sci. 2007;11(10):413-418.
20. Phillips ML, Drevets WC, Rauch SL, Lane R. Neurobiology of emotion perception I: The neural basis of normal emotion perception. Biol Psychiatry. 2003;54(5):504-514.
21. Ungerstedt U. Stereotaxic mapping of the monoamine pathways in the rat brain. Acta Physiol Scand Suppl.
1971;367:1-48.
22. Grant SJ, Redmond DE Jr. The neuroanatomy and pharmacology of the nucleus locus coeruleus. Prog Clin Biol Res.
1981;71:5-27.
23. Valentino RJ, Foote SL, Page ME. The locus coeruleus as a site for integrating corticotropin-releasing factor and
noradrenergic mediation of stress responses. Ann N Y Acad Sci. 1993;697:173-188.
24. Carli M, Robbins TW, Evenden JL, Everitt BJ. Effects of lesions to ascending noradrenergic neurones on performance
of a 5-choice serial reaction task in rats; implications for theories of dorsal noradrenergic bundle function based on
selective attention and arousal. Behav Brain Res. 1983;9(3):361-380.
25. Devauges V, Sara SJ. Activation of the noradrenergic system facilitates an attentional shift in the rat. Behav Brain
Res. 1990;39(1):19-28.
26. Cahill L, Prins B, Weber M, McGaugh JL. Beta-adrenergic activation and memory for emotional events. Nature.
1994;371(6499):702-704.
27. McGaugh JL, Cahill L, Roozendaal B. Involvement of the amygdala in memory storage: interaction with other brain
systems. Proc Natl Acad Sci U S A. 1996;93(24):13508-13514.
28. Wilson HD, Uhelski ML, Fuchs PN. Examining the role of the medial thalamus in modulating the affective dimension
of pain. Brain Res. 2008;1229:90-99.
29. Azmitia EC, Gannon PJ. The primate serotonergic system: a review of human and animal studies and a report on
Macaca fascicularis. Adv Neurol. 1986;43:407-468.
30. Adell A, Casanovas JM, Artigas F. Comparative study in the rat of the actions of different types of stress on the
release of 5-HT in raphe nuclei and forebrain areas. Neuropharmacology. 1997;36(4-5):735-741.
31. Jacobs BL, Azmitia EC. Structure and function of the brain serotonin system. Physiol Rev. 1992;72(1):165-229.
32. Maes M, Meltzer HY. The serotonin hypothesis of major depression. In: Bloom FE, Kupfer DJ, Bunney BS, et
al, eds. Psychopharmacology: the Fourth Generation of Progress. 4th ed. New York, NY: Lippincott Williams
& Wilkins; 1995:933-944.
33. Aston-Jones G, Rajkowski J, Cohen J. Role of locus coeruleus in attention and behavioral flexibility. Biol Psychiatry.
1999;46(9):1309-1320.
34. Jacobs BL, Fornal CA. Activity of serotonergic neurons in behaving animals. Neuropsychopharmacology.
1999;21(suppl 2):9S-15S.
35. Kosofsky BE, Molliver ME. The serotoninergic innervation of cerebral cortex: different classes of axon terminals arise
from dorsal and median raphe nuclei. Synapse. 1987;1(2):153-168.
36. Blier P, Serrano A, Scatton B. Differential responsiveness of the rat dorsal and median raphe 5-HT systems to 5-HT1
receptor agonists and p-chloroamphetamine. Synapse. 1990;5(2):120-133.
37. Chan-Palay V, Asan E. Quantitation of catecholamine neurons in the locus coeruleus in human brains of normal
young and older adults and in depression. J Comp Neurol. 1989;287(3):357-372.
38. Robinson DS. Changes in monoamine oxidase and monoamines with human development and aging. Fed Proc.
1975;34(1):103-107.
39. Goldman-Rakic PS, Brown RM. Postnatal development of monoamine content and synthesis in the cerebral cortex
of rhesus monkeys. Brain Res. 1982;256(3):339-349.
40. Burrows GD, McIntyre IM, Judd FK, Norman TR. Clinical effects of serotonin reuptake inhibitors in the treatment of
depressive illness. J Clin Psychiatry. 1988;49(suppl):18-22.
41. Owens MJ. Selectivity of antidepressants: from the monoamine hypothesis of depression to the SSRI revolution and
beyond. J Clin Psychiatry. 2004;65(suppl 4):5-10.
42. Messer T, Schmauss M, Lambert-Baumann J. Efficacy and tolerability of reboxetine in depressive patients treated
in routine clinical practice. CNS Drugs. 2005;19(1):43-54.
43. Delgado PL, Zarkowski P. Treatment of mood disorders. In: Panksepp J, ed. Textbook of Biological Psychiatry.
Hoboken, NJ: Wiley-Liss; 2004:231-259.
44. Deecher DC, Beyer CE, Johnston G et al. Desvenlafaxine succinate: A new serotonin and norepinephrine reuptake
inhibitor. J Pharmacol Exp Ther. 2006;318(2):657-665.
45. Moret C, Charveron M, Finberg JP, Couzinier JP, Briley M. Biochemical profile of midalcipran (F 2207), 1-phenyl-1diethyl-aminocarbonyl-2-aminomethyl-cyclopropane (Z) hydrochloride, a potential fourth generation antidepressant drug. Neuropharmacology. 1985;24(12):1211-1219.
46. Muth EA, Haskins JT, Moyer JA, Husbands GE, Nielsen ST, Sigg EB. Antidepressant biochemical profile of the novel
bicyclic compound Wy-45,030, an ethyl cyclohexanol derivative. Biochem Pharmacol. 1986;35(24):4493-4497.
47. Wong DT, Bymaster FP, Mayle DA, Reid LR, Krushinski JH, Robertson DW. LY248686, a new inhibitor of serotonin and
norepinephrine uptake. Neuropsychopharmacology. 1993;8(1):23-33.
48. Moret C, Briley M. Effects of milnacipran and pindolol on extracellular noradrenaline and serotonin levels in guinea
pig hypothalamus. J Neurochem. 1997;69(2):815-822.
49. Owens MJ, Krulewicz S, Simon JS, et al. estimates of serotonin and norepinephrine transporter inhibition in
depressed patients treated with paroxetine or venlafaxine. Neuropsychopharmacology. 2008;33(13)3201-3212.
50. Owens MJ, Morgan WN, Plott SJ, Nemeroff CB. Neurotransmitter receptor and transporter binding profile of antidepressants and their metabolites. J Pharmacol Exp Ther. 1997;283(3):1305-1322.
51. Bymaster FP, Dreshfield-Ahmad LJ, Threlkeld PG, et al. Comparative affinity of duloxetine and venlafaxine for serotonin and norepinephrine transporters in vitro and in vivo, human serotonin receptor subtypes, and other neuronal
receptors. Neuropsychopharmacology. 2001;25(6):871-880.
52. Briley M, Prost JF, Moret C. Preclinical pharmacology of milnacipran. Int Clin Psychopharmacol. 1996;11(suppl 4):9-14.
Primary Psychiatry 16:5 (Suppl 4)
53. Koch S, Hemrick-Luecke SK, Thompson LK, et al. Comparison of effects of dual transporter inhibitors on monoamine
transporters and extracellular levels in rats. Neuropharmacology. 2003;45(7):935-944.
54. Harvey AT, Rudolph RL, Preskorn SH. Evidence of the dual mechanisms of action of venlafaxine. Arch Gen Psychiatry.
2000;57(5):503-509.
55. Chalon SA, Granier LA, Vandenhende FR, et al. Duloxetine increases serotonin and norepinephrine availability in
healthy subjects: a double-blind, controlled study. Neuropsychopharmacology. 2003;28(9):1685-1693.
56. Turcotte JE, Debonnel G, de Montigny C, Hébert C, Blier P. Assessment of the serotonin and norepinephrine reuptake
blocking properties of duloxetine in healthy subjects. Neuropsychopharmacology. 2001;24(5):511-521.
57. Beyer CE, Boikess S, Luo B, Dawson LA. Comparison of the effects of antidepressants on norepinephrine and serotonin
concentrations in the rat frontal cortex: an in-vivo microdialysis study. J Psychopharmacol. 2002;16(4):297-304.
58. Page ME, Lucki I. Effects of acute and chronic reboxetine treatment on stress-induced monoamine efflux in the rat
frontal cortex. Neuropsychopharmacology. 2002;27(2):237-247.
59. Felton TM, Kang TB, Hjorth S, Auerbach SB. Effects of selective serotonin and serotonin/noradrenaline reuptake
inhibitors on extracellular serotonin in rat diencephalon and frontal cortex. Naunyn Schmiedebergs Arch Pharmacol.
2003;367(3):297-305.
60. Engleman EA, Perry KW, Mayle DA, Wong DT. Simultaneous increases of extracellular monoamines in microdialysates from hypothalamus of conscious rats by duloxetine, a dual serotonin and norepinephrine uptake inhibitor.
Neuropsychopharmacology. 1995;12(4):287-295.
61. Mochizuki D, Tsujita R, Yamada S, et al. Neurochemical and behavioural characterization of milnacipran, a serotonin and noradrenaline reuptake inhibitor in rats. Psychopharmacology (Berl). 2002;162(3):323-332.
62. Blier P, de Montigny C, Chaput Y. A role for the serotonin system in the mechanism of action of antidepressant
treatments: preclinical evidence. J Clin Psychiatry. 1990;51(suppl):14-20.
63. Blier P, de Montigny C. Electrophysiological studies on the heterogeneity of 5-HT1A receptors: psychopharmacological implications. Clin Neuropharmacol. 1992;15(suppl 1 Pt A):137A-138A.
64. Tachibana K, Matsumoto M, Koseki H, et al. Electrophysiological and neurochemical characterization of the effect
of repeated treatment with milnacipran on the rat serotonergic and noradrenergic systems. J Psychopharmacol.
2006;20(4):562-569.
65. Weikop P, Kehr J, Scheel-Kruger J. The role of alpha1- and alpha2-adrenoreceptors on venlafaxine-induced elevation of extracellular serotonin, noradrenaline and dopamine levels in the rat prefrontal cortex and hippocampus. J
Psychopharmacol. 2004;18(3):395-403.
66. Invernizzi RW, Garattini S. Role of presynaptic alpha2-adrenoceptors in antidepressant action: recent findings from
microdialysis studies. Prog Neuropsychopharmacol Biol Psychiatry. 2004;28(5):819-827.
67. Delgado PL, Price LH, Miller HL, et al. Rapid serotonin depletion as a provocative challenge test for patients with
major depression: relevance to antidepressant action and the neurobiology of depression. Psychopharmacol Bull.
1991;27(3):321-330.
68. Delgado PL, Miller HL, Salomon RM, et al. Monoamines and the mechanism of antidepressant action: effects of catecholamine depletion on mood of patients treated with antidepressants. Psychopharmacol Bull. 1993;29(3):389-396.
69. Delgado PL, Miller HL, Salomon RM, et al. Tryptophan-depletion challenge in depressed patients treated with
desipramine or fluoxetine: implications for the role of serotonin in the mechanism of antidepressant action. Biol
Psychiatry. 1999;46(2):212-220.
70. Jans LA, Riedel WJ, Markus CR, Blokland A. Serotonergic vulnerability and depression: assumptions, experimental
evidence and implications. Mol Psychiatry. 2007;12(6):522-543.
71. Miller HL, Delgado PL, Salomon RM, et al. Clinical and biochemical effects of catecholamine depletion on antidepressant-induced remission of depression. Arch Gen Psychiatry. 1996;53(2):117-128.
72. Shansis FM, Busnello JV, Quevedo J, et al. Behavioural effects of acute tryptophan depletion in healthy male
volunteers. J Psychopharmacol. 2000;14(2):157-163.
73. Salomon RM, Miller HL, Krystal JH, Heninger GR, Charney DS. Lack of behavioral effects of monoamine depletion in
healthy subjects. Biol Psychiatry. 1997;41(1):58-64.
74. Delgado PL, Moreno FA. Role of norepinephrine in depression. J Clin Psychiatry. 2000;61(suppl 1):5-12.
75. Ruhé HG, Mason NS, Schene AH. Mood is indirectly related to serotonin, norepinephrine and dopamine levels in
humans: a meta-analysis of monoamine depletion studies. Mol Psychiatry. 2007;12(4):331-359.
76. Sarai K, Frazer A, Brunswick D, Mendels J. Desmethylimipramine-induced decrease in beta-adrenergic receptor
binding in rat cerebral cortex. Biochem Pharmacol. 1978;27(17):2179-2181.
77. Wolfe BB, Harden TK, Sporn JR, Molinoff PB. Presynaptic modulation of beta adrenergic receptors in rat cerebral
cortex after treatment with antidepressants. J Pharmacol Exp Ther. 1978;207(2):446-457.
78. McDonald D, Stancel GM, Enna SJ. Binding and function of serotonin 2 receptors following chronic administration
of imipramine. Neuropharmacology. 1984;23(11):1265-1269.
79. Chaput Y, de Montigny C, Blier P. Effects of a selective 5-HT reuptake blocker, citalopram, on the sensitivity of 5-HT autoreceptors: electrophysiological studies in the rat brain. Naunyn Schmiedebergs Arch Pharmacol. 1986;333(4):342-348.
80. Lafaille F, Welner SA, Suranyi-Cadotte BE. Regulation of serotonin type 2 (5-HT2) and beta-adrenergic receptors in rat
cerebral cortex following novel and classical antidepressant treatment. J Psychiatry Neurosci. 1991;16(4):209-214.
81. Siever LJ, Cohen RM, Murphy DL. Antidepressants and alpha 2-adrenergic autoreceptor desensitization. Am J
Psychiatry. 1981;138(5):681-682.
82. de Montigny C, Blier P. Effects of antidepressant treatments on 5-HT neurotransmission: electrophysiological and
clinical studies. Adv Biochem Psychopharmacol. 1984;39:223-239.
83. Sulser F. Regulation and function of noradrenaline receptor systems in brain. Psychopharmacological aspects.
Neuropharmacology. 1984;23(2B):255-261.
84. Olpe HR, Schellenberg A. Reduced sensitivity of neurons to noradrenaline after chronic treatment with antidepressant drugs. Eur J Pharmacol. 1980;63(1):7-13.
85. Olpe HR, Schellenberg A. The sensitivity of cortical neurons to serotonin: effect of chronic treatment with antidepressants, serotonin-uptake inhibitors and monoamine-oxidase-blocking drugs. J Neural Transm. 1981;51(3-4):233-244.
86. Olpe HR. Differential effects of clomipramine and clorgyline on the sensitivity of cortical neurons to serotonin: effect
of chronic treatment. Eur J Pharmacol. 1981;69(3):375-377.
87. Olpe HR, Schellenberg A, Steinmann MW. Differential actions of mianserin and iprindole on the sensitivity of cortical
neurons to noradrenaline: effect of chronic treatment. Eur J Pharmacol. 1981;72(4):381-385.
88. Duman RS, Malberg J, Nakagawa S, D’Sa C. Neuronal plasticity and survival in mood disorders. Biol Psychiatry.
2000;48(8):732-739.
89. Sheline YI. Neuroimaging studies of mood disorder effects on the brain. Biol Psychiatry. 2003;54(3):338-352.
90. Frodl T, Meisenzahl EM, Zetzsche T, et al. Hippocampal changes in patients with a first episode of major depression.
Am J Psychiatry. 2002;159(7):1112-8.
91. Sheline YI, Gado MH, Kraemer HC. Untreated depression and hippocampal volume loss. Am J Psychiatry.
2003;160(8):1516-1518.
92. Malberg JE, Eisch AJ, Nestler EJ, Duman RS. Chronic antidepressant treatment increases neurogenesis in adult rat
hippocampus. J Neurosci. 2000;20(24):9104-9110.
14
© MBL Communications Inc.
May 2009
Neurobiology of Serotonin Norepinephrine Reuptake Inhibitors
93. Malberg JE, Duman RS. Cell proliferation in adult hippocampus is decreased by inescapable stress: reversal by
fluoxetine treatment. Neuropsychopharmacology. 2003;28(9):1562-1571.
94. Santarelli L, Saxe M, Gross C, et al. Requirement of hippocampal neurogenesis for the behavioral effects of antidepressants. Science. 2003;301(5634):805-809.
95. Surget A, Saxe M, Leman S, et al. Drug-dependent requirement of hippocampal neurogenesis in a model of depression and of antidepressant reversal. Biol Psychiatry. 2008;64(4):293-301.
96. Duman RS, Malberg J, Thome J. Neural plasticity to stress and antidepressant treatment. Biol Psychiatry.
1999;46(9):1181-1191.
97. Beauquis J, Roig P, Homo-Delarche F, De Nicola A, Saravia F. Reduced hippocampal neurogenesis and number of
hilar neurones in streptozotocin-induced diabetic mice: reversion by antidepressant treatment. Eur J Neurosci.
2006;23(6):1539-1546.
98. Schmidt HD, Duman RS. The role of neurotrophic factors in adult hippocampal neurogenesis, antidepressant treatments and animal models of depressive-like behavior. Behav Pharmacol. 2007;18(5-6):391-418.
99. Merikangas KR, Chakravarti A, Moldin SO, et al. Future of genetics of mood disorders research. Biol Psychiatry.
2002;52(6):457-477.
100. First MB, Pincus HA. The DSM-IV Text Revision: rationale and potential impact on clinical practice. Psychiatr Serv.
2002;53(3):288-292.
101. Kraepelin E. One Hundred Years of Psychiatry. Oxford, England: Philosophicol Library; 1962.
102. Nelson JC, Mazure C, Quinlan DM, Jatlow PI. Drug-responsive symptoms in melancholia. Arch Gen Psychiatry.
1984;41(7):663-668.
103. Wicki W, Angst J, Merikangas KR. The Zurich Study. XIV. Epidemiology of seasonal depression. Eur Arch Psychiatry
Clin Neurosci. 1992;241(5):301-306.
104. Davidson JR, Miller RD, Turnbull CD, Sullivan JL. Atypical depression. Arch Gen Psychiatry. 1982;39(5):527-534.
105. Bunney WE Jr, Davis JM, Weil-Malherbe H, Smith ER. Biochemical changes in psychotic depression. High norepinephrine levels in psychotic vs neurotic depression. Arch Gen Psychiatry. 1967;16(4):448-460.
106. Angst J, Merikangas K, Scheidegger P, Wicki W. Recurrent brief depression: a new subtype of affective disorder. J
Affect Disord. 1990;19(2):87-98.
107. Forty L, Jones L, Macgregor S, et al. Familiality of postpartum depression in unipolar disorder: results of a family
study. Am J Psychiatry. 2006;163(9):1549-1553.
108. Weissman MM. Juvenile-onset major depression includes childhood- and adolescent-onset depression and may
be heterogeneous. Arch Gen Psychiatry. 2002;59(3):223-224.
109. Price RA, Kidd KK, Weissman MM. Early onset (under age 30 years) and panic disorder as markers for etiologic
homogeneity in major depression. Arch Gen Psychiatry. 1987;44(5):434-440.
110. Nelson JC, Conwell Y, Kim K, Mazure C. Age at onset in late-life delusional depression. Am J Psychiatry.
1989;146(6):785-786.
111. Krishnan KR. Organic bases of depression in the elderly. Annu Rev Med. 1991;42:261-266.
112. Keller MB, Hanks DL. The natural history and heterogeneity of depressive disorders: implications for rational
antidepressant therapy. J Clin Psychiatry. 1994;55(suppl A):25-31.
113. Gershon ES, Merril CR, Goldin LR, DeLisi LE, Berrettini WH, Nurnberger JI Jr. The role of molecular genetics in
psychiatry. Biol Psychiatry. 1987;22(11):1388-1405.
114. Gelernter J, Pakstis AJ, Kidd KK. Linkage mapping of serotonin transporter protein gene SLC6A4 on chromosome
17. Hum Genet. 1995;95(6):677-680.
115. Korbel JO, Urban AE, Affourtit JP, et al. Paired-end mapping reveals extensive structural variation in the human
genome. Science. 2007;318(5849):420-426.
116. van’t Veer LJ, Bernards R. Enabling personalized cancer medicine through analysis of gene-expression patterns.
Nature. 2008;452(7187):564-570.
Primary Psychiatry 16:5 (Suppl 4)
117. Stahl SM. Personalized medicine, pharmacogenomics, and the practice of psychiatry: on the threshold of predictive therapeutics in psychopharmacology? CNS Spectr. 2008;13(2):115-118.
118. Lee C, Morton CC. Structural genomic variation and personalized medicine. N Engl J Med. 2008;358(7):740-741.
119. Kim H, Lim SW, Kim S, et al. Monoamine transporter gene polymorphisms and antidepressant response in Koreans
with late-life depression. JAMA. 2006;296(13):1609-1618.
120. Yoshida K, Takahashi H, Higuchi H, et al. Prediction of antidepressant response to milnacipran by norepinephrine
transporter gene polymorphisms. Am J Psychiatry. 2004;161(9):1575-1580.
121. Kirchheiner J, Nickchen K, Sasse J, Bauer M, Roots I, Brockmoller J. A 40-basepair VNTR polymorphism in the
dopamine transporter (DAT1) gene and the rapid response to antidepressant treatment. Pharmacogenomics J.
2007;7(1):48-55.
122. Kang RH, Wong ML, Choi MJ, Paik JW, Lee MS. Association study of the serotonin transporter promoter polymorphism and mirtazapine antidepressant response in major depressive disorder. Prog Neuropsychopharmacol Biol
Psychiatry. 2007;31(6):1317-1321.
123. Popp J, Leucht S, Heres S, Steimer W. Serotonin transporter polymorphisms and side effects in antidepressant
therapy--a pilot study. Pharmacogenomics. 2006;7(2):159-166.
124. Serretti A, Kato M, De Ronchi D, Kinoshita T. Meta-analysis of serotonin transporter gene promoter polymorphism
(5-HTTLPR) association with selective serotonin reuptake inhibitor efficacy in depressed patients. Mol Psychiatry.
2007;12(3):247-257.
125. Arias B, Serretti A, Lorenzi C, Gasto C, Catalan R, Fananas L. Analysis of COMT gene (Val 158 Met polymorphism)
in the clinical response to SSRIs in depressive patients of European origin. J Affect Disord. 2006;90(2-3):251-256.
126. Szegedi A, Rujescu D, Tadic A et al. The catechol-O-methyltransferase Val108/158Met polymorphism affects
short-term treatment response to mirtazapine, but not to paroxetine in major depression. Pharmacogenomics J.
2005;5(1):49-53.
127. Yoshida K, Higuchi H, Takahashi H et al. Influence of the tyrosine hydroxylase val81met polymorphism and
catechol-O-methyltransferase val158met polymorphism on the antidepressant effect of milnacipran. Hum
Psychopharmacol. 2008;23(2):121-128.
128. Tadic A, Rujescu D, Muller MJ et al. A monoamine oxidase B gene variant and short-term antidepressant treatment
response. Prog Neuropsychopharmacol Biol Psychiatry. 2007;31(7):1370-1377.
129. Papiol S, Arias B, Gasto C, Gutierrez B, Catalan R, Fananas L. Genetic variability at HPA axis in major depression
and clinical response to antidepressant treatment. J Affect Disord. 2007;104(1-3):83-90.
130. Liu Z, Zhu F, Wang G, et al. Association study of corticotropin-releasing hormone receptor1 gene polymorphisms
and antidepressant response in major depressive disorders. Neurosci Lett. 2007;414(2):155-158.
131. Brouwer JP, Appelhof BC, van Rossum EF, et al. Prediction of treatment response by HPA-axis and glucocorticoid
receptor polymorphisms in major depression. Psychoneuroendocrinology. 2006;31(10):1154-1163.
132. Yoshida K, Higuchi H, Kamata M, et al. The G196A polymorphism of the brain-derived neurotrophic factor gene
and the antidepressant effect of milnacipran and fluvoxamine. J Psychopharmacol. 2007;21(6):650-656.
133. Hu XZ, Rush AJ, Charney D, et al. Association between a functional serotonin transporter promoter polymorphism
and citalopram treatment in adult outpatients with major depression. Arch Gen Psychiatry. 2007;64(7):783-792.
134. Grasmader K, Verwohlt PL, Rietschel M, et al. Impact of polymorphisms of cytochrome-P450 isoenzymes 2C9,
2C19 and 2D6 on plasma concentrations and clinical effects of antidepressants in a naturalistic clinical setting.
Eur J Clin Pharmacol. 2004;60(5):329-336.
135. Shams ME, Arneth B, Hiemke C, et al. CYP2D6 polymorphism and clinical effect of the antidepressant venlafaxine.
J Clin Pharm Ther. 2006;31(5):493-502.
136. Sindrup SH, Otto M, Finnerup NB, Jensen TS. Antidepressants in the treatment of neuropathic pain. Basic Clin
Pharmacol Toxicol. 2005;96(6):399-409.
15
© MBL Communications Inc.
May 2009