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Major Depressive Disorder and Bipolar Disorder: Differentiating Features and Contemporary Treatment Approaches


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Principal mood disorders which include major depressive disorder and bipolar disorder are prevalent conditions with high rates of morbidity and mortality. Individuals of both sexes are affected usually in early adulthood, and the disorders follow a relapsing and remitting course throughout life. These are conceptualized as multisystem disorders with a progressive course, such that earlier stages are less virulent and easier to manage than later stages which are characterized by treatment refractoriness, cognitive deficits, and functional decline. Major depressive disorder and bipolar disorder are distinct conditions with differences in clinical presentation and treatment modalities. These distinctions arise from etiopathologic differences, and the current manuscript succinctly describes the latest research findings in this regard. A review of the most pertinent literature reveals that the bipolar diathesis is a much more severe condition and is difficult to diagnose as it tends to masquerade in myriad forms. Since current treatments are palliative rather than curative in nature, there is an urgent need to foster a better understanding of the underpinning pathogenic mechanisms and discover novel therapies so that the suffering of innumerable people afflicted by these ailments can be decreased.
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Chapter Title Major Depressive Disorder and Bipolar Disorder: Differentiating
Features and Contemporary Treatment Approaches
Copyright Year 2018
Copyright Holder Springer Nature Singapore Pte Ltd.
Corresponding Author Family Name Muneer
Given Name Ather
Organization Islamic International Medical College,
Riphah International University
Address Rawalpindi, Pakistan
Abstract Principal mood disorders which include major depressive disorder and
bipolar disorder are prevalent conditions with high rates of morbidity
and mortality. Individuals of both sexes are affected usually in early
adulthood, and the disorders follow a relapsing and remitting course
throughout life. These are conceptualized as multisystem disorders
with a progressive course, such that earlier stages are less virulent
and easier to manage than later stages which are characterized by
treatment refractoriness, cognitive deficits, and functional decline. Major
depressive disorder and bipolar disorder are distinct conditions with
differences in clinical presentation and treatment modalities. These
distinctions arise from etiopathologic differences, and the current
manuscript succinctly describes the latest research findings in this regard.
A review of the most pertinent literature reveals that the bipolar diathesis
is a much more severe condition and is difficult to diagnose as it tends
to masquerade in myriad forms. Since current treatments are palliative
rather than curative in nature, there is an urgent need to foster a better
understanding of the underpinning pathogenic mechanisms and discover
novel therapies so that the suffering of innumerable people afflicted by
these ailments can be decreased.
(separated by “-”)
Bipolar disorder - Major depressive disorder - Gene x environment
disorders - Gene sets - Sterile inflammation - Atypical
© Springer Nature Singapore Pte Ltd. 2018
Y.-K. Kim (ed.), Understanding Depression,
Major Depressive Disorder
and Bipolar Disorder:
Differentiating Features
and Contemporary Treatment
Ather Muneer
2.1 Introduction
Primary mood disorders, including major depres-
sive disorder (MDD) and bipolar disorder (BD),
are among the most prevalent psychiatric condi-
tions. In a relatively recent international survey
of 18 countries, the average lifetime prevalence
of major depressive episodes (MDE) was 14.6%
in 10 high-income countries and 11.1% in 8 low-
to middle-income nations (Bromet et al. 2011).
The population studied was not stratified accord-
ing to the type of affective disorder, so that it can
be assumed that the patients comprised of both
MDD and BD as long as they fulfilled DSM-IV
criteria for a major depressive episode. The cur-
rent nosological classifications do not differenti-
ate between these disorders as far as the diagnostic
features of MDE are concerned, but prevailing
viewpoint dictates that MDD and BD have funda-
mental neurobiological distinctions with thera-
peutic and prognostic implications. In this vein it
must be appreciated that these disorders are dis-
crete conditions, with differences that encompass
genetic and pathophysiologic aspects impacting
on illness trajectory and longitudinal course
(Duman and Monteggia 2006). Such emerging
insights are reflected in the Diagnostic and
Statistical Manual’s 5th edition in which a neces-
sary shift has been implemented by segregating
the two conditions into separate chapters, whereas
previously these were described under the com-
mon rubric of “mood disorders.”
Affective disorders are complex gene x envi-
ronment diseases and are heterogeneous in phe-
notypic expression. Current knowledge assumes
that these disorders lie on a spectrum with depres-
sion and mania being opposite poles of a distur-
bance that has myriad presentations confounded
by such factors as personality characteristics,
neuropsychiatric comorbidities, and psychosocial
incumbencies (Becker and Grilo 2015). In the
early phase of the illness, stress factors are identi-
fied as precipitating events, but with advance-
ment of the diathesis, mood episodes recur
spontaneously. Further, asymptomatic periods
become progressively shorter and an unrelenting
disease state ensues with impairments in cogni-
tive and functional domains (Moylan et al. 2013).
These phenomena are epitomized by such nega-
tive attributes as rapid cycling, residual affective
states and subthreshold symptoms. The overall
consequence of this process which has been aptly
termed as “neuroprogression” is a decline in
autonomy, impairment in role functioning, and
loss of personal independence. In this regard the
later stages of mood disorders are typified by
severe psychosocial and biological disturbances,
with incremental damage to all body systems
because of the derangement of the homeostatic
balance caused by increased “allostatic load”
A. Muneer
Islamic International Medical College, Riphah
International University, Rawalpindi, Pakistan
(McEwen 2003). Figure 2.1 gives a schematic
representation of the pernicious nature of mood
disorders with ensuing profound negative conse-
quences for all bodily systems (Fig. 2.1).
The burden imposed by these ailments in the
biopsychosocial realm is immense, as subjects of
both sexes are initially afflicted in youth or early
adulthood and suffer from relapses and recur-
rences throughout their lifetimes. Modern per-
spective states that these are in essence
multisystem disorders, affecting essentially all
parts of the body and leading to increased mor-
bidity and mortality from such conditions as dia-
betes mellitus, cardiovascular diseases, and
immunological disorders (Mansur et al. 2015).
Further, the neurobiology of mood disorders is
incompletely understood, and presently available
treatments are of palliative rather than curative
value. Despite continued research efforts, gaps in
knowledge are significant which translate into
less than optimal therapeutic measures with
adverse consequences for the sufferers, their fam-
ilies, and the society as a whole (Muneer 2016a,
b, c). In this scenario it is crucial to inculcate a
better understanding of these ailments so that the
patients are managed more effectively and their
disease burden is reduced. With this preamble,
the manuscript is dedicated to discussing the
most relevant issues in the etiology, pathogene-
sis, and treatment of mood disorders. However,
first clinical features are mentioned followed by a
description of the genetic aspects and pathophys-
iologic implications; lastly, therapeutic measures
are considered.
2.2 Clinical Considerations
The sine qua non of BD is a manic episode, but
in actual practice depression is its most frequent
clinical presentation (Muneer 2016a, b, c).
Longitudinal naturalistic studies show that bipolar
patients spend the majority of their time in the
depressed state, rather than being manic or hypo-
manic (De Dios et al. 2012). The former can mani-
fest as major depressive episodes or as subthreshold
symptoms. Additionally, depressive manifesta-
tions can intermingle with manic or hypomanic
symptoms and give rise to mixed states, which are
more severe and lead to adverse psychosocial
sequelae (Valenti et al. 2015). Whereas in MDD,
depressive episodes occur in the mid-20s onward,
bipolar depression has a much earlier onset in
early teenage years, is often the index episode, and
usually has melancholic features (Muneer 2016a,
b, c). BD is notorious in masquerading in myriad
forms, and the presenting illness can be in the way
of anxiety spectrum disorders, conduct disorders,
and substance use disorders. Because of these rea-
sons, the condition is misidentified, and the lag
period in diagnosis is of the magnitude of several
years (Nasrallah 2015).
Psychosocial Impaired role
Loss of
Biological Neuroprogression/
systemic ailments
and mortality
Fig. 2.1 The pernicious nature of mood disorders. Mood
disorders, whether MDD or BD, are conceptualized as
very serious conditions with profound consequences in
the biopsychosocial realm. Repeated affective episodes
increase “wear and tear” in the body with increased allo-
static load. The resulting homeostatic imbalance has a
pervasive negative effect with such consequences as cog-
nitive impairment, physical comorbidities, persistent
affective symptoms, and role impairment leading to even-
tual loss of autonomy
A. Muneer
The major depressive episodes in MDD can be
single or recurrent but tend to be discrete, with
well-characterized periods of remission. In the
case of BD, patients are symptomatic for longer
periods; they may have full blown severe mood
episodes or subsyndromal symptoms in the inter-
episode which has a pervasive negative effect on
the overall prognosis. Rapid cycling is a phenom-
enon in which bipolar patients have four or more
affective episodes in a 12-month period. This is
regarded as an extreme form of the disorder with
harmful consequences in the functional and psy-
chological domains (Carvalho et al. 2014). With
repeated mood episodes, there is deterioration in
all aspects of living and neuroprogression, which
in essence implies the persistence of a deficit
state with eventual loss of autonomy (da Costa
et al. 2016). The suicide rate is very high in BD,
and this may be attributable to many factors,
chief among which are greater number and sever-
ity of episodes, existence of mixed states, and
presence of such comorbidities as anxiety spec-
trum and substance use disorders (Rajewska-
Rager et al. 2015).
In this situation, a primary question for the
treating psychiatrist is the correct identification
of the mood disorder when a patient presents
with a major depressive episode. Although there
are no validated criteria for such a distinction,
certain features should alert the clinician in this
regard. This is important because treatment of
bipolar disorder is primarily with mood stabiliz-
ers, whereas unipolar depression is best managed
with standard antidepressant medications
(Karanti et al. 2016). Administration of antide-
pressants without adjunctive mood stabilizers to
bipolar subjects can result in manic/hypomanic
switch, induction of mixed states, and rapid
cycling (Muneer 2015).
When a patient first presents with an MDE,
the presence of family history of bipolar disorder
is a cautionary sign. Age of onset is also signifi-
cant, with the index episode occurring in adoles-
cence or teenage years in BD, while in the case
of major depression, this is usually in the mid-
20s. Furthermore, bipolar subjects tend to suffer
from recurrent episodes which are of greater
severity, so that there may be a history of psychi-
atric hospitalizations (Shapiro et al. 2014). Of
note, major depression which is treatment resis-
tant to two or more first-line antidepressant
medications should raise the suspicion of a mas-
querading bipolar diathesis. Unipolar patients
who shift to mania or hypomania when treated
with antidepressants, ECT, or chronobiological
measures are considered to lie on the bipolar
spectrum. In this regard seasonal variation may
be marked in BD, with patients experiencing
repeated depressive episodes during fall and win-
ter months (Akhter et al. 2013).
With respect to clinical presentation, patients
with bipolar depression often experience mixed
features such as racing thoughts, irritability,
grandiose ideation, and increased energy.
Moreover, they are prone to having recurrent sui-
cidal ideation, and a history of repeated self-
injurious behavior in unipolar depression should
raise the specter of underlying bipolar illness
(Musliner et al. 2016). Neuropsychiatric and
physical comorbidities are frequently associated
with BD including panic disorder, posttraumatic
stress disorder, alcohol and other substance use
disorders, borderline personality disorder, and
eating disorders (Simhandl et al. 2016).
Neurological conditions found more often in
bipolar patients comprise of migraine, idiopathic
neuropathic pain, vertigo, and restless legs syn-
drome (Fornaro and Stubbs 2015). An important
caveat with respect to the bipolar diathesis is its
association with the metabolic syndrome, obe-
sity, and diabetes mellitus so that cardiovascular
diseases are considered as the foremost cause of
premature mortality in this group of subjects
(Grover et al. 2014). In conclusion, it can be con-
strued that among mood disorders BD is a much
more severe condition than MDD and is chal-
lenging to manage because of the facts men-
tioned above. Table 2.1 gives a summary of
clinical features that should alert clinicians for
the possible presence of bipolar spectrum disor-
ders in patients presenting with major depressive
episodes (Table 2.1).
2 Major Depressive Disorder and Bipolar Disorder
2.3 Etiology of Mood Disorders
2.3.1 Genetic Aspects
Depression is a prevalent mental illness that is
projected to be among the most common causes
of morbidity by 2020. Research efforts have
shown that the share of genetic factors in the cau-
sation of depression is 30–40%, and there is a
growing literature that is linking this vulnerabil-
ity to biological substrates (Lohoff 2010). The
methodology adopted for research purposes is
greatly varied, ranging from candidate gene
approaches to genome-wide association studies.
In this regard, the serotonergic system is a princi-
pal target due to its involvement in the regulation
of mood and anxiety. Of particular significance is
the serotonin transporter protein responsible for
5HT synaptic reuptake, which is also the key tar-
get of monoaminergic antidepressants. The gene
coding for this protein is SLC6A4, and in humans
the s (short) allele of the 5-HTTLPR polymor-
phism of the serotonin transporter gene is incrim-
inated in anxiety related attributes and neuroticism
(Daniele et al. 2011). This variation conveys
increased attention and sensitivity to environ-
mental stressors, and carriers of the genotype
have a tendency to experience neutral stimuli as
negative and threatening. Accompanied by less
efficient coping strategies in the face of stress,
these individuals are more liable to developing
depressive disorders (Kuzelova et al. 2010). In
human studies, an immense range of method-
ologically diverse approaches including the
exploration of different stressors, self-report
questionnaires, imaging techniques, investigation
of the HPA axis, and postmortem brain examina-
tion have given credence to an association
between the s allele and stress-induced reactivity
(Hildebrandt et al. 2016).
s allele carriers are discovered to exhibit
increased and rapid activation in the amygdala, a
structure implicated in regulating homeostatic
and behavioral responses to outside stressors and
fearful stimuli. Further, alterations in the func-
tional and microstructural connectivity of the
amygdala and the medial prefrontal cortex are
also described in s allele carriers (Savitz and
Drevets 2009). The gene for the serotonin trans-
porter protein, 5-HTTLPR, is involved in other
possible mood disorder antecedents such as sub-
threshold depression and affective temperaments.
In an important prospective study, Caspi et al.
showed the effect of s allele of the 5-HTTLPR
polymorphism on the development of depressive
symptoms in the presence of stressful events
(Caspi et al. 2003). This finding was afterward
substantiated by a very large meta-analysis,
which included 54 studies on overall 41,000 sub-
jects. In some of the earlier studies, conflicting
findings regarding the link between different
types of stressors, 5-HTTLPR genotype, and
depression were related to distinctions concern-
ing the definition, evaluation, inclusion of and
delineation between diverse stressors, and life
events. However, the said meta-analysis clarified
these issues and further demonstrated that child-
hood and adolescent maltreatment, proximal life
events, and serious medical conditions were all
liable to cause depression in those carrying the s
allele or the ss genotype of the 5HT transporter
gene (Karg et al. 2011). In a European study
comprising of a large population sample, compa-
rable and statistically significant associations
were observed in subjects carrying the ss geno-
type and a moderately significant association in
sl cases when they were investigated for a rela-
tionship between threatening life events and
mood symptoms as assessed by the Zung Self-
Rating Depression Scale. Whereas extreme
Table 2.1 Likely indicators of bipolarity in patients pre-
senting with major depressive episodes
Onset in adolescence or early teenage years
1. Family history of bipolar disorder
2. Comorbid anxiety, substance use or conduct
3. Major depressive episode with melancholic features
4. Psychotic depression
5. Repeated mood episodes
6. Increased severity of episodes, with history of
7. Treatment-resistant depression
8. Mixed states
9. Seasonal affective disorder
10. Suicidal behavior/repeated attempts at self-harm
11. Switching on antidepressants
A. Muneer
stressors individually explained 2.4% of the vari-
ance in affective manifestations, this proportion
increased approximately twofold to 4.2% upon
including the intermediary effect of 5-HTTLPR
genotype and climbed to 5.9% when genotype
data of other polymorphisms of the serotonin
transporter gene were incorporated in the model
(Lazary et al. 2008). These statistics clearly show
that genetic variability and environmental influ-
ences act together in regulating mood.
2.3.2 New Understanding
of Depression
In the case of depression, the interaction between
the environment and genetic factors is complex.
Previous models posit that in the existence of
inherited predisposition, adversities experienced
during childhood or adolescence contribute to
enhanced susceptibility to depressive illnesses in
adult life in the face of stressful life events. In this
regard carriers of the s allele are at a greater risk
of affective illnesses when encountering severe
stressors; however, recent research underscores
the importance of other DNA regions in this gene
x environment model. For example, one study
showed no association between seasonal affec-
tive disorder and 5-HTTLPR s allele (Molnar
et al. 2010), while in another paper specific link-
age between rumination, a trait-like cognitive
style, and depression was mapped to CREB1 and
BDNF genes (Juhasz et al. 2011). These instances
allude to the fact that everyday stressors are
diverse including among others childhood mal-
treatment, losses, health problems, hormonal
changes, and seasonal variations and each person
has a discrete liability profile toward adverse and
protective events and occurrences. Therefore, dif-
ferent genes may have distinct contributory or
ameliorative effects in the development of a com-
plex phenotype, namely, depression.
In an emerging synthesis of the depression
model, several other genes besides 5HT trans-
porter play a role in the causation of the diathesis.
These include genes involved in serotonergic neu-
rotransmission (HTR1A, HTR2A, TPH1), dopa-
minergic neurotransmission (DRD2, DRD4),
monoamine metabolism (MAOA, COMT), neu-
rotrophins (BDNF), endocannabinoids (CNR1),
transport, and other proteins (SLC1A1, SLC6A2,
CREB1, KCNJ6, CACNA1, GLUR7). In many
studies CNR1, the gene of the cannabinoid CB1
receptor has been strongly implicated in depres-
sion besides the SERT gene and has been further
associated with trait anxiety and neuroticism. An
SNP (rs2180619) in the CNR1 gene interacts with
ss 5-HTTLPR genotype to increase trait anxiety
manifold (Lazary et al. 2009). The substrate of
this interaction is purportedly a sustained high
5HT concentration following activation of the
serotonergic neurons in response to stress, result-
ing from a low expression of the inhibitory CB1
receptors and high synaptic serotonin concentra-
tion because of low SERT levels. Comparable
observation was reported in fMRI studies where
heightened amygdala activation was seen in ss
carriers and this correlated with increased neuroti-
cism scores. These findings suggest that SERT
and CB1 receptor genes are the most strongly
implicated among the candidate genes and further
point out that depressed mood manifests on the
basis of diverse DNA regions mediating the
effects of varied environmental influences.
Additionally, the depressive phenotype arises
from an interaction of these genes at the substrate
level (Bagdy et al. 2012).
The genes incriminated in depression can be
classified into seven groups or sets, some of
which confer resiliency while others induce vul-
nerability. Varied gene sets have a role in the
development of personality, mediation of the
effects of environmental influences, and interplay
of diverse aspects of temperament with external
factors. Environmental dynamics comprise of
internal and external factors; several of the early
influences directly affect the formation of person-
ality traits and temperaments. While some of the
genes, for example, tryptophan hydroxylase 2,
are included in one set, others (5-HTTLPR and
CB1) are constituents of several groups.
Intriguingly, even without one gene set, discrete
genes may have separate roles, and not all genes
are engaged in every function. As an example,
5-HTTLPR has a profound influence in mediat-
ing the effects of particular aggravating life
2 Major Depressive Disorder and Bipolar Disorder
events, but has no significant role in seasonal
depression (Mushtaq et al. 2016). Table 2.2 delin-
eates candidate genes grouped in sets and identified
in large-scale population studies, conferring resil-
iency or predisposing to mood disorders in the wake
of environmental stressors (Table 2.2). Figure 2.2 is
an illustrative rendition of a new model of depres-
sion that emphasizes the interaction between gene
sets, personality, and environment in the develop-
ment of mood disturbance (Fig. 2.2).
The s allele of 5-HTTLPR has a significant but
weak association with depression provoking
effects of stress so that it cannot be utilized for
direct screening of the susceptibility to this dis-
ease. Further, in the absence of multiple severe
stressors, s allele carriers may not show more
depressive symptomatology than those carrying
other genotypes. Nonetheless, in the presence of
extreme and manifold life stresses, s allele carri-
ers are more prone to dysthymic mood, poor
coping, and full-blown depressive illness. Addi-
tionally, these subjects show worse therapeutic
response to SSRIs, the most commonly used anti-
depressants. They show slower onset of action,
lower rates of response, poor tolerability, and fre-
quent side effects with this group of medications,
while drugs with different pharmacodynamics
(e.g., norepinephrine-selective agents) are more
effective in s allele carriers. When vulnerability
and resiliency factors are viewed together, it can
be surmised that screening for 5-HTTLPR geno-
type can be part of a working assumption in bet-
ter understanding the evolving etiopathology of
depression. Further, this could be instrumental in
identifying those individuals who are at increased
risk for mood disorders and be of assistance in
choosing appropriate treatment for the patients
(Fabbri et al. 2013).
2.3.3 Epigenetic Influences
In the case of neuropsychiatric disorders, the
contribution of hereditary factors is estimated to
exceed 30%, but even with state of the art meth-
ods, only a fraction of this variance can be
mapped to specific genes and DNA base sequence
alterations. In this scenario, epigenetic effects
have become the focus of attention as these play
a role in regulating protein synthesis, are only
partially heritable, but subject to modification by
environmental influences. Two chief epigenetic
mechanisms can adapt the function of genes:
1. Acetylation or methylation of histones that
direct the availability of DNA for biological
2. Methylation of the DNA itself, which inhibits
the transcriptional activity of the CpG-rich
regions of the genome
Since these alterations are allele specific,
genetic polymorphisms are linked to different
probability and type of epigenetic changes upon
environmental exposure, and consequently con-
siderable variance occurs in sensitivity to such
Table 2.2 Gene sets responsible for heritable traits that interact with environmental factors in the causation of mood
Factors linked to mood disorders Gene products (proteins) Involved genes
Neuroticism, trait anxiety SERT, CB1 SLC6A4, CNR1
Stress/negative life events SERT, CB1 SLC6A4, CNR1
Depressogenic/anxiogenic effect of medications SERT, CB1 SLC6A4, CNR1
Stress coping (resiliency versus vulnerability) 5-HT1A, 5-HT1B HTR1A, HTR1B
Hopelessness TPH2 TPH2
Impulsiveness 5-HT1A, COMT HTR1A, COMT
Seasonal variations 5-HT2A HTR2A
BDNF brain-derived neurotrophic factor, CB1 endocannabinoid receptor 1, COMT catechol-O-methyltransferase,
CREB cyclic AMP response element-binding protein, GIRK G protein-coupled inwardly rectifying potassium channel,
SERT serotonin transporter protein, TPH tyrosine hydroxylase, 5-HT serotonin
A. Muneer
factors. A pertinent example is the catechol-O-
methyltransferase gene in which the existence of
Val 158 allele in the rs4680 SNP creates a CpG site
for methylation, the repressive effect of which can
compensate for the enhanced dopamine elimina-
tion in the prefrontal cortex in the high- activity
Val allele carriers. However, life stressors dimin-
ish the methylation of this area of the gene,
leading to increased activity of COMT with resul-
tant impaired working memory due to decreased
dopamine availability in this key brain region
(Ursini et al. 2011). In a study investigating the
effect of COMT gene on depressed mood, it was
discovered that variations in the said gene were
associated with depressive symptom scores in
those who had not been depressed previously in
contrast to those who had already suffered from
depression, probably because epigenetic modifi-
cations altered the gene function in patients (Pap
et al. 2012). This mechanism might clarify why
childhood abuse amplifies the risk for later depres-
sive disorders. In a rodent study, maternal mal-
treatment evoked long-lasting methylation of the
BDNF gene in the prefrontal cortex, and these
animals showed impaired rearing behavior toward
their offspring (Roth et al. 2009). In line with this
observation, the BDNF gene in a human popula-
tion study was associated with increased risk of
depression exceptionally in the presence of child-
hood trauma (Juhasz et al. 2011). In this vein it
must be understood that the salient attribute of
epigenetic imprint is its tissue and cell specificity,
so that different parts of the brain show discrete
methylation and acetylation patterns, severely
Fig. 2.2 New gene x environment model of depression.
Candidate genes comprising gene sets: 5-HTTLPR, CB1,
Personality/temperamental factors (predisposing): neu-
roticism, rumination, stress vulnerability, impulsivity,
negative cognitive style. Personality/temperamental fac-
tors (protective): openness, trust, acceptance, stress cop-
ing. External factors: early life events, provoking life
events, seasonal changes, social support. Internal factors:
hormones, biological rhythm generators, comorbid disor-
ders. The new gene x environment model of depression is
based on diverse gene sets that acting through personality,
internal and external factors lead to the development of
depression. Some genes are part of more than one set, for
example 5-HTTLPR and CB1, while others like HTR2A
belong to only one set. These gene sets act with interme-
diaries like temperamental traits or environmental factors,
for example seasonal variation to cause the depressive
2 Major Depressive Disorder and Bipolar Disorder
hampering the ability to investigate this in vivo
human brain. There is no method yet to study epi-
genetic changes in the living brain, but gathering
in-depth knowledge concerning genetic base
sequence and its interaction with environmental
factors is crucial to understanding the pathophysi-
ology of mood disorders, as well as predicting
medication beneficial and adverse effects.
2.4 Pathogenesis of Mood
Mood disorders afflict innumerable people every
year and cause a great deal of morbidity and mor-
tality, but their neurobiology is only partially elu-
cidated. In this situation, a growing body of
evidence points to the involvement of the
immune-inflammatory system in their inception
and progression. During acute affective episodes,
patients have elevated levels of inflammatory
proteins, i.e., cytokines and chemokines in the
peripheral circulation (Rosenblat et al. 2014). It
is now known that repeated and severe stressors,
in the absence of pathogenic disease, can induce
an inflammatory response and this has been aptly
called “sterile inflammation.” Recently, in the
last decade or so, it has become clear that psycho-
logical stress, in the nonexistence of overt tissue
damage, can trigger systemic and CNS sterile
inflammation with homeostatic imbalance that
can have profound effects and damage all organ
systems in the body (Fleshner 2013). This has
been substantiated in laboratory experiments on
animals with such paradigms as social conflict,
threat, isolation, and rejection which cause
increase in C-reactive protein, proinflammatory
cytokines (IL-6, IL-1β, TNF-α), and elevated
expression of NF-ĸB (Aschbacher et al. 2012).
The behavioral effect of this raised inflammatory
status is manifested as an overt expression of the
depressive phenotype in the research animals.
In human subjects parallel findings have been
described, for example, a study reported that the
death of a spouse increased IL-1β and IL-6 activ-
ity in older adults (Schultz-Florey et al. 2012).
Intriguingly, increases in inflammatory indicators
following exposure to an acute traumatic event
are linked to the development, symptom severity,
and duration of affective disturbances like depres-
sion, anxiety, and posttraumatic stress disorder
(Mills et al. 2013). Severe and persistent stress
can by itself induce a low-grade inflammatory
state which can precipitate mood perturbation
reminiscent of major depressive disorder. The
inflammatory receptor-ligand interaction invoked
in this process has been termed danger-associated
molecular patterns (DAMPs), mediated by
inflammasome-dependent signaling which
appears to play an overarching role in the patho-
genesis of mood disorders (Iwata et al. 2013).
2.4.1 Inflammatory Molecular
The main effectors of the inflammatory response
are the innate immune cells, while adaptive
immune cells are important partners. The former
are found throughout the body and CNS and
respond to pathogenic challenges, cellular stress,
and tissue damage. Receptor-ligand recognition
schema is a notable and fundamental differenti-
ating attribute between innate and adaptive
immune cells. The former use germline-encoded
receptors intended to identify conserved molecu-
lar patterns and have been named pattern recog-
nition receptors (PRRs). A huge number of
ligands are capable of binding PRRs and include
both pathogenic and commensal microbes,
termed microbe- associated molecular patterns or
MAMPs, whereas typically pathogenic patterns
are labeled pathogen-associated molecular pat-
terns or PAMPs (Sirisinha 2011). Examples of
MAMPs and PAMPs include lipopolysaccharide
(LPS), a membrane incorporated component of
many gram-negative pathogenic bacteria or CpG
DNA, a common viral motif. Of note, a strong
inflammatory reaction is the result of PRR-
PAMP binding. In contrast to these prototypes,
DAMPs are endogenous molecules which are
increased after cellular stress and tissue damage,
and PRR- DAMP binding leads to sterile inflam-
mation (Ibrahim et al. 2013). Newly recognized
DAMPs are increasingly being reported and
include extracellular heat shock proteins (Hsp),
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adenosine triphosphate (ATP), high mobility
group box 1 (HMGB1), etc. (Frank et al. 2015).
There is extensive overlap in a broad array of
inflammatory proteins that are mediated after
either LPS (PAMP) or stressor exposure
(DAMP). These are detectable in the blood and
peripheral tissues and include cytokines, chemo-
kines, and mRNA transcripts. In this vein, it
needs to be recognized that brain tissue and
microglia also respond to PAMPs and DAMPs
by increasing the secretion of inflammatory
mediators (Frank et al. 2016).
2.4.2 Sterile Inflammation
and the Inflammasome
It has been recently reported that acute and
intense psychological stress in the lack of obvi-
ous tissue damage can provoke a demonstrable
local and systemic sterile inflammatory response,
with DAMPs playing an inciting role. In this
respect, tail shock in rodents increases tissue and
blood concentration of many cytokines and che-
mokines, and both MAMP (derived from the
gut bacteria) and DAMP signals are involved in
the inflammatory response. Significantly, in the
said experiments, this was attributed to the
inflammasome, more specifically the NLRP3
inflammasome known as nucleotide-binding
oligomerization domain, leucine-rich repeat, and
pyrin domain protein 3 (Maslanik et al. 2013).
Inflammasomes are intracellular multiprotein
complexes that act as sensors of DAMPs and
PAMPs, causing activation of catalytic caspases
and the cleavage and release of proinflammatory
For cytokines that are inflammasome indepen-
dent, the process begins with NF-ĸB activation
after MAMPs or DAMPs binding to toll-like
receptor-4 (TLR-4), CD14, and other potential
PRRs. The subsequent signaling cascade com-
prises of inflammatory gene transcription, trans-
lation, protein synthesis, and release. In
contradistinction, inflammasome-dependent cyto-
kine synthesis and release is a two-step process
that is started after ligation of TLRs and other
PRRs leading to NLRP3 gene transcription,
translation, and protein production. Once primed
in this way, a second activation signal is required
for mature caspase-1 to cleave pro-IL1β into
functional IL-1β (Kang et al. 2014). The NLRP3
inflammasome appears to react to a wide array of
signals (ATP, K+ efflux, β-amyloid, reactive oxy-
gen species, etc.) to get activated and binds to
these stimuli as it expresses several PRRs includ-
ing TLRs, RAGE, and CD91. As such it has been
incriminated in a wide range of sterile inflamma-
tory diseases including ischemia-reperfusion
injury, autoimmune disorders, DM II, obesity,
atherosclerosis, and Alzheimer’s disease, condi-
tions which have high comorbidity rates with
mood disorders (Li et al. 2014). More specifi-
cally, patients with depression had increased
expression of NLRP3 and caspase-1 in peripheral
blood mononuclear cells, suggesting that sterile
inflammation mediated by DAMPs and the
inflammasome and induced by exposure to psy-
chological stress is implicated in the pathogenesis
of MDD and other psychopathologies (Alcocer-
Gomez et al. 2014).
2.4.3 Neuroinflammation and Mood
Peripheral inflammatory processes are liable to
incite neuroinflammatory changes through well-
described humoral and neural pathways of
immune-to-brain signaling. For instance, the
humoral pathway may involve blood-borne cyto-
kines provoking neuroinflammatory processes
through active transport across the blood-brain
barrier, entry into the brain at the circum-
ventricular organs, or binding of cognate recep-
tors on brain endothelial cells with transduction
of cytokine signaling into the CNS. In addition,
cytokines as well as PAMPs (e.g., LPS) are capa-
ble of stimulating afferent vagal fibers in the
periphery, which cause activation of neural path-
ways in brain regions involved in motivation and
mood regulation (Marquette et al. 2003). Once a
peripheral inflammatory signal reaches the brain,
microglia the chief innate immune cells of the
CNS play a pivotal role in mediating the neuroin-
flammatory response.
2 Major Depressive Disorder and Bipolar Disorder
Microglia perform several crucial functions in
the brain including immunosurveillance for
pathogens, cellular debris, apoptotic cells, and
neuronal phenotypic alterations. Upon activation
microglia enter a primed position and when stim-
ulated in this state secrete increased amounts of
inflammatory mediators, including IL-1β
(Nakagawa and Chiba 2015). As these special-
ized macrophages express pattern recognition
receptors including TLR2 and TLR4, TLR liga-
tion by danger-associated molecular patterns
(ATP, Hsp, HMGB1, etc.) strongly triggers
microglia (Weber et al. 2015). Furthermore, sev-
eral inflammasomes have been described in the
microglia including NLRP1, NLRP3, and
NLRC4. The NLRP3 inflammasome has been
most widely studied in the CNS and is also the
focus of the preponderance of studies in animal
models of depression. Recent investigations also
suggest that NLRP3 may be exquisitely sensitive
to the homeostatic perturbations induced by psy-
chobiological stress, with a mechanistic role for
the inflammasome-mediated processing and mat-
uration of IL-1β in the generation of mood disor-
ders (Li et al. 2016). While space limitation does
not allow a detailed outline of animal studies
highlighting the link between stress, DAMPs,
and the inflammasome in the instigation of neu-
roinflammation and its behavioral sequel, the
induction of the depressive phenotype, it is clear
that CNS inflammation is caused by acute or
chronic stress in the absence of infection or
pathogen exposure (Zhang et al. 2015).
2.4.4 Purported Model
of Depression
In the light of above considerations, a proposed
model of depression is presented as following
(Fleshner et al. 2017):
1. Exposure to stressors results in the release of
DAMPs within the brain, presumably from
damaged or dying neurons.
2. These neuron-derived DAMPs then target
their cognate receptors on microglia leading
to NLRP3 inflammasome activation and the
synthesis and release of inflammatory media-
tors, including IL-1β.
3. The secreted form of this cytokine may drive
the induction of indoleamine 2,3-dioxygenase
4. IDO-mediated catabolism of tryptophan feeds
into kynurenine pathway, thereby diverting
the pool of this essential amino acid from 5HT
synthesis to potentially neurotoxic metabo-
lites and reducing the availability of the
5. Decreased availability of serotonin provokes a
depressive phenotype with attendant psycho-
logical, neurovegetative, and somatic
As a summarizing note, it must be appreciated
that understanding the processes involving sterile
inflammation, DAMP/MAMP/PAMP signaling in
the periphery and CNS and inflammasome activa-
tion are critical for efficacious therapeutics of
affective disorders. While notable advances are
made in this respect in neurological disorders such
as stroke, novel agents have not yet been tested in
psychiatric patients. New therapeutic modalities
emerging from enhanced knowledge can pave the
way for curative treatments for otherwise recalci-
trant conditions (Alcocer-Gomez and Cordero
2014). Figure 2.3 gives a schematic representation
of this supposed model of depression and depicts
the key role of NLRP3 inflammasome and IL-1β in
the expression of depressive phenotype (Fig. 2.3).
2.5 Treatment of Mood
Disorders: The Current
Mood disorders are lifelong, recurring, and dev-
astating psychiatric conditions that are a leading
cause of suffering and have grave personal and
societal consequences. Major depressive disorder
and bipolar disorder are difficult to manage ail-
ments because of heterogeneity in presentation,
neuropsychiatric and physical comorbidities, and
refractoriness to currently available psychophar-
macological agents (Fountoulakis and Vieta
2008). At different points in the illness, patients
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require complex medication regimens to treat the
varied manifestations, and compliance is very
low due to a whole host of adverse effects caused
by the psychotherapeutic agents. In this event,
there is an immediate unmet need for more effec-
tive and tolerable drugs that are actually curative
rather than palliative in nature. With this pream-
ble, in the present section of the manuscript,
focus will be directed to promising therapeutic
options, and a concise overview will be presented
of the recent trends in mood disorder
Fig. 2.3 Stress-induced sterile inflammation and expres-
sion of the depressive phenotype. In a supposed model of
depression, psychological stressors cause damage to neu-
rons with efflux of a broad range of signals or damage-
associated molecular patterns (DAMPs). These bind to
pattern recognition receptors like toll-like receptors (TLR
2/4) and purinergic receptors (P2X7R) on microglia and
cause the formation of NLRP3 inflammasomes via tran-
scription, translation, and protein synthesis. Primed
microglia release mature IL-1β via activated inflamma-
somes, and further this proinflammatory cytokine induces
the enzyme indoleamine 2,3-dioxygenase (IDO). The
later catabolizes tryptophan, an essential amino acid
required in the synthesis of serotonin. Diversion of trypto-
phan metabolism toward the kynurenine pathway leads to
a deficiency of serotonin, as well as the formation of
potentially neurotoxic metabolites like quinolinic acid. As
a final step, reduction of this key neurotransmitter at the
synapse leads to the provocation of sickness behavior and
depressive symptoms
2 Major Depressive Disorder and Bipolar Disorder
2.5.1 The Emerging Role of Atypical
These medications comprise of second- and
third-generation antipsychotics, and although the
first prototype, clozapine, was discovered in the
1970s, vast strides have been made, and several
new agents have been introduced into clinical
practice. Amazingly, there has been a steady
increase in their licensed and off-label prescrib-
ing in a wide range of neuropsychiatric condi-
tions (Maher and Theodore 2012). Initially
indicated for schizophrenia, these medications
have become first-line agents for the treatment of
manic, mixed, and depressive episodes of BD
and more recently have established a niche as an
augmentation strategy along with standard anti-
depressants in MDD. In the present paper atypi-
cal antipsychotics will be discussed with
reference to the treatment of MDD to highlight
their importance in the current psychopharmaco-
logical landscape (Pompili et al. 2016).
In spite of the availability of several classes of
antidepressants, most MDD patients do not
achieve an adequate response or remission with
such treatment. This issue is underscored by the
STAR*D trial in which a 12-week treatment
with SSRI monotherapy (citalopram) only
resulted in 30% remission rate in unipolar
depression cases (Rush et al. 2009). Further, a
large meta-analysis including 182 antidepressant
RCTs (n = 36,385) revealed that the response
rates were around 54 and 37%, for drug and pla-
cebo, respectively (Papakostas and Fava 2009).
In this situation, most guidelines recommend
augmentation strategies for MDD partial or non-
responders which mainly comprise of atypical
antipsychotics, mood stabilizers (lithium and
various anticonvulsants), and thyroid hormones
(Patkar and Pae 2013). Among these steps, the
addition of second- and third-generation anti-
psychotics to existing antidepressant regimens
has received approval by licensing authorities
such as the United States Food and Drug
Administration (FDA). In this regard, based on
evidence from randomized, placebo-controlled
trials, the FDA first approved aripiprazole in
2007, followed by quetiapine XR and olanzap-
ine/fluoxetine in 2009 and most recently brex-
piprazole in 2015 (Greig 2015).
2.5.2 Pharmacodynamic
In the case of new-generation antipsychotics, the
exact mechanism responsible for therapeutic
effect in MDD has not been clarified, but based
on current understanding of the etiopathogenesis
of mood disorders, their pharmacodynamic
actions can be as following (Rahola 2012):
1. Modulation of key neurotransmitter receptors
and transporters, namely, dopamine, sero-
tonin, and norepinephrine
2. Effects on the circadian machinery and
manipulation of the sleep-wake cycle
3. Exploitation of the steroid hormone homeo-
stasis, particularly the hypothalamic-pituitary-
adrenal axis involved in the management of
stressful stimuli
4. Modification of the immune system with alter-
ations in pro- and anti-inflammatory proteins
5. Balancing out the antioxidant process with net
decrease in pro-oxidant radicals
6. Increase in trophic support to the neurons,
principally through brain-derived neuro-
trophic factor
Specifically, the chief pharmacological mech-
anism of atypical antipsychotics as antidepres-
sant augmentation agents could be explained by
their effects on monoamine neurotransmission.
Third-generation antipsychotics, namely, aripip-
razole, brexpiprazole, and cariprazine, act as par-
tial agonists at D2 and/or D3 receptors and may
increase dopamine neurotransmission in the pre-
frontal cortex. These agents also act as 5-HT1A
receptor partial agonists, and this property may
further enhance dopamine neurotransmission in
the prefrontal cortex through an indirect mecha-
nism (Stahl 2016). The characteristic of 5-HT2A
receptor antagonism is shared by all atypical
antipsychotics, and this attribute may also medi-
ate their antidepressant boosting effect in MDD
nonresponders. Furthermore, the antagonism of
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5-HT2C receptors is incriminated in enhanced
dopamine and norepinephrine transmission in
corticolimbic regions of the brain (Stahl 2014).
While both 5-HT6 receptor agonists and antago-
nists exert antidepressant-like effect in rodent
models of depression, this phenomenon is marked
when standard antidepressants are augmented
with 5-HT6 antagonists (Liu et al. 2015). With
respect to 5-HT7 receptors, preclinical models
consistently show their relevance in different
experimental paradigms such that new- generation
antipsychotics exhibiting antagonism at this site
may have potential therapeutic role in MDD
(Bawa and Scarff 2015). Some atypical antipsy-
chotics have high affinity for α2-adrenergic recep-
tors which enhances the release of norepinephrine
from the presynaptic neuron. Unlike any other
new-generation antipsychotic, ziprasidone has
been reported in vitro to block the synaptic reup-
take of monoamines via inhibition of their trans-
porters. Ionotropic and metabotropic glutamate
receptors are being increasingly incriminated in
the pathophysiology of treatment-resistant
depression so that modulation of these sites by
newer antipsychotics could lead to normalization
of glutamate neurotransmission, decrease in
excitotoxicity, and enhanced neuronal viability
(Bjorkholm et al. 2015). Table 2.3 gives an over-
view of atypical antipsychotics in the treatment
of MDE in major mood disorders (Table 2.3).
Table 2.3 Atypical antipsychotics in the treatment of major depressive episodes in MDD and BD
Medication FDA indication Mechanism of action
Dose range
(mg/day) Evidence
Aripiprazole Augmentation
to AD
5-HT1A/2C partial agonism,
5-HT2A/2B antagonism, weak 5-HT7
antagonism, D2/3 partial agonism,
enhancement of neuroplasticity
5–15 RCT (adjunctive to AD
in MDD). Negative
RCT in bipolar I
Brexpiprazole Augmentation
to AD
5-HT1A and D2 partial agonism,
5-HT2A antagonism
1–3 RCT (adjunctive to AD)
Quetiapine XR Augmentation
to AD
α-2 Receptor antagonism,
norepinephrine transporter inhibition
in PFC (metabolite norquetiapine),
5-HT7 antagonism
50–300 RCT (monotherapy as
well as adjunctive to
5-HT2A/2C antagonism, 5-HT7
5–20 Positive RCT in
MDD. Positive RCT in
bipolar I depression
Cariprazine None for
D2/3 partial agonism, 5-HT1A partial
agonism, 5-HT2A/5-HT7 antagonism
1.5–3 Positive RCT in bipolar
I depression
Lurasidone Indicated for
bipolar I
5-HT7 antagonism, 5-HT1A partial
agonism, weak 5-HT2C antagonism,
weak α-2 antagonism
60–120 Positive RCT in bipolar
I depression
Ziprasidone None for
5-HT2A/2C antagonism, 5HT1A
agonism, 5-HT, NE, DA transporter
40–160 RCT (adjunctive to AD)
Risperidone None for
5-HT2A antagonism, α-2 receptor
antagonism, 5-HT7 antagonism
0.5–3 RCT (adjunctive to AD)
Paliperidone None for
5-HT2A antagonism, α-2 receptor
antagonism, 5-HT7 antagonism
3 Anecdotal reports or
expert opinion
Asenapine None for
5-HT2A/2B/2C antagonism, 5-HT6/7
antagonism, 5HT1A partial agonism,
α-2 antagonism
10–20 Anecdotal reports or
expert opinion
Iloperidone None for
5HT-2A antagonism, 5-HT6/7
Anecdotal reports or
expert opinion
AD antidepressants, BD bipolar disorder, DA dopamine, NE norepinephrine, MDD major depressive disorder, PFC
prefrontal cortex, RCT randomized controlled trial, 5-HT serotonin
2 Major Depressive Disorder and Bipolar Disorder
2.5.3 Individual Medications Brexpiprazole
This is a serotonin-dopamine activity modulator
and structurally related to aripiprazole. In July
2015 it received FDA approval for schizophre-
nia and augmentation therapy of MDD. It shows
partial agonism at the D2 receptor and possibly
functional selectivity at this site. Compared to
aripiprazole, brexpiprazole has lower intrinsic
activity at the D2R, but exhibits tenfold higher
affinity at the 5-HT1A receptor where it acts as
a partial agonist. Two recently published phase
III trials investigated the potential of brexpipra-
zole as an augmentation agent in treatment-
resistant MDD. The two identically designed
studies included subjects who had inadequate
response to one to three standard antidepres-
sants for their current depressive episode. All
patients entered a prospective 8-week phase of
open-label antidepressant therapy, and those
who failed to sufficiently respond were random-
ized to AD + brexpiprazole or AD + placebo
and followed in a double-blind fashion for a
total of 6 weeks. The primary outcome measure
was change in Montgomery-Asberg Depression
Rating Scale (MADRS) from baseline to week
6. In the first study, brexpiprazole 3 mg/day was
superior to placebo on MADRS total score
(8.29 versus 6.33; p = 0.0079), but brexpip-
razole 1 mg/day failed to separate from placebo
(7.64 versus 6.33; p = 0.0737). In the second
study, brexpiprazole 2 mg/day showed superior
efficacy over placebo in changes from baseline
to week 6 on MADRS total scores (8.36 ver-
sus 5.15; p = 0.0002). Further, the active agent
was also better than placebo on the Sheehan
Disability Scale (1.35 versus 0.89;
p = 0.0349). The most common treatment-
related adverse events were weight gain (brex-
piprazole, 8%; placebo, 3.1%) and akathisia
(7.4% versus 1.0%). Taken as a whole, brexpip-
razole addition to standard antidepressants was
safe and well tolerated in the two phase III
RCTs (Thase et al. 2015a, b). Aripiprazole
This third-generation antipsychotic, first intro-
duced in 2002 for schizophrenia, is well studied
as an adjunctive therapy in MDD. With regard to
controlled studies, three matching RCTs showed
that aripiprazole augmentation of traditional anti-
depressants was statistically superior to placebo
in MDD patients who were nonresponders to one
to three adequate antidepressant trials. A post hoc
analysis of the abovementioned three RCTs
divided patients into two categories—in one
group were minimal improvers on antidepressant
monotherapy after 6–8 weeks of administration
and in the second batch were non-improvers as
defined by Clinical Global Impression scale
(CGI-I). After 6 weeks of adjunctive aripiprazole
or placebo, the remission rates were higher for
the active drug in both groups (minimal improv-
ers, 38.8% versus 26.6%, p ˂ 0.05; non- improvers,
24.0% versus 10.3%, p ˂ 0.05). The most com-
mon adverse events with add-on aripiprazole
were akathisia, restlessness, and insomnia (Casey
et al. 2014). Another pooled analysis of the same
RCTs stratified patients according to baseline
MADRS scores as follows: mild 24; moderate
25–30; and severe 31. The results showed that
aripiprazole produced greater improvement than
placebo in the MADRS scores regardless of
MDD severity at baseline (Stewart et al. 2014). A
third post hoc analysis investigated the efficacy
of adjunctive aripiprazole in MDD patients
whose symptoms worsened with antidepressant
monotherapy. In the prospective, open-label
phase, 106 subjects out of 1065 antidepressant
monotherapy non-responders actually deterio-
rated as assessed by MADRS. Those cases, who
worsened, showed higher response and remission
rates with aripiprazole compared to placebo dur-
ing the 6-week double-blind part of the studies
(36.6% versus 22.5% and 25.4% versus 12.4%,
respectively). Similarly, aripiprazole was supe-
rior to placebo for the 905 subjects who did not
show deterioration on antidepressant monother-
apy (Nelson et al. 2014). Lastly, a subgroup post
hoc analysis of a more recently conducted RCT
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in an Asian population (the ADMIRE study)
revealed that the efficacy was consistently greater
with aripiprazole than placebo and was not
related to any clinical factors such as gender, age,
onset of MDD, number of previous episodes,
duration of current episode, length of illness,
MDD specifiers, and type of SSRI/SNRI used in
the prospective phase (Ozaki et al. 2015). Quetiapine
This second-generation antipsychotic has been
well studied in MDD, both as monotherapy and
adjunctively to first-line antidepressants. In this
context the first RCT was published in 2007, in
which quetiapine augmentation of SSRI/venla-
faxine was compared to placebo in a small group
of MDD patients (N = 58) with comorbid anxiety
(HAM-A 14) and residual depressive symp-
toms (CGI-S 4). The mean change in HAM-D
and HAM-A total scores from baseline to study
endpoint (week 8) was significantly greater with
quetiapine (average dose 182 mg/day) than pla-
cebo: 11.2 versus 5.5, p = 0.008, and 12.5
versus 5.9, p = 0.002, respectively. The onset of
quetiapine efficacy (HAM-D/ HAM-A/CGI-S)
was rapid by week 1 and continued through to
week 8. Response, defined as 50% decrease in
baseline HAM-D scores, was numerically but not
significantly higher for quetiapine than placebo.
Similarly remission rate (HAM-D total scores
7) was also higher for the active agent (31%
versus 17%), but this difference did not reach sta-
tistical significance. Adverse events for quetiap-
ine were in line with its known side effect profile,
and sedation and somnolence were most fre-
quently reported. In conclusion, quetiapine was
shown to be effective as augmentation of SSRI/
venlafaxine therapy in patients with major
depression, comorbid anxiety, and residual
depressive symptoms, with no unexpected toler-
ability issues (McIntyre et al. 2007). The efficacy
of quetiapine XR augmentation was shown in
two similarly designed (150, 300 mg/day and
placebo) 6 week RCTs (N = 936). In both trials,
the primary endpoint was mean changes in
MADRS total score from baseline. In these stud-
ies quetiapine XR was statistically superior to
placebo on the primary efficacy measure, and this
change was evident from week 1 (Bauer et al.
2009; El-khalili et al. 2010). In a revealing study,
quetiapine was added to the antidepressant regi-
men of unipolar depressed patients who were
treatment refractory and had failed to respond to
3 weeks of lithium augmentation. They were
assigned to flexible dose adjunctive quetiapine +
CBT or placebo + CBT and followed for
12 weeks. The former group of subjects had sta-
tistically significant improvement on the two effi-
cacy measures of HAM-D and MADRS. Although
the total number of patients was small (N = 22),
this pilot study showed that in refractory MDD
patients, flexible dose quetiapine (12.5–200 mg/
day) was a valid option in conjunction with stan-
dard antidepressants and CBT (Chaput et al.
2008). Finally, quetiapine in combination with an
SNRI (venlafaxine) was studied under controlled
conditions for the treatment of MDD with psy-
chotic features. Subjects (N = 122) were random-
ized to 7 weeks imipramine (plasma levels
200–300 μg/L), venlafaxine (375 mg/day), or
venlafaxine + quetiapine (375 + 600 mg/day).
Primary outcome was response on HAM-D-17,
while secondary outcomes were response on CGI
and remission on HAM-D-17. On the primary
measure, quetiapine + venlafaxine was superior
to venlafaxine monotherapy and equivalent to
imipramine, while secondary outcome measures
also showed similar results. It was revealed that
for the treatment of unipolar psychotic depres-
sion, quetiapine in combination with an SNRI
was superior to the latter alone, but similar con-
clusion could not be drawn with regard to the
TCA, imipramine (Wijkstra et al. 2010).
Quetiapine XR monotherapy has been studied
in several short-term RCTs in MDD, both in
fixed or flexible dose designs. In the majority of
these trials, the active drug showed superiority
over placebo on such validated efficacy measures
as the MADRS. The dose of quetiapine XR was
up to a maximum of 300 mg/day and trial dura-
tions varied from 6 to 8 weeks; the active agent
separated from placebo as early as week 1 and
2 Major Depressive Disorder and Bipolar Disorder
this superiority was maintained until the end of
the study period. The most common adverse
events associated with quetiapine XR were dry
mouth, sedation, and somnolence, EPS were dis-
tinctly uncommon, but metabolic changes like
increased serum glucose and lipids were more
often observed (Brotnick et al. 2011). The fol-
lowing conclusions can be drawn from the extant
1. Quetiapine alone or adjunctively to standard
antidepressants has valid efficacy in the treat-
ment of nonpsychotic MDD.
2. In patients suffering from major depressive
disorder with psychotic features, quetiapine in
conjunction with first line antidepressants is
superior to antidepressant monotherapy.
3. Quetiapine augmentation is a convincing
option in treatment-resistant depression.
4. It has shown therapeutic worth in both adults
as well as the elderly with MDD.
5. It has value in unipolar depressive patients
with comorbid conditions such as anxiety and
6. It is effective despite such demographic vari-
ables as age, gender, and race.
7. The medication has valid efficacy in MDD
regardless of such illness factors as severity,
duration, and number of depressive episodes.
8. The effective dose in MDD is from 100 to
300 mg/day which is less than the maximum
recommended dose of 600 mg/day in
9. While an approved therapy in MDD, it should
be used with the caveat that it has the potential
to cause metabolic abnormalities and careful
monitoring is warranted in this regard. Olanzapine/Fluoxetine
Treatment-resistant depression can be conceptu-
alized as an illness that has failed to respond to
at least two different antidepressant monother-
apy trials of adequate duration and dose. An
enlightening meta-analysis of RCTs revealed
that the antidepressant response rate was 53%
compared to 36% for placebo (p ˂ 0.05), so that
clinicians must employ other strategies to over-
come this underperformance (Papakostas and
Fava 2009). On such approach is augmentation
with atypical antipsychotics, which has become
an important second step as emphasized in cur-
rent guidelines. In this regard, adjunctive olan-
zapine has been studied in at least four RCTs
and specifically olanzapine/fluoxetine combina-
tion (OFC) has been compared to both placebo
and active comparators. A pooled analysis of
these studies showed that OFC had clearly dem-
onstrated significantly greater improvements in
MADRS (primary efficacy measure) total score
than fluoxetine or olanzapine alone and also
resulted in higher remission rates. The short-
term efficacy of OFC for treatment-resistant
depression was supported by these trials (Trivedi
et al. 2009). In a more recently published long-
term trial of up to 27 weeks, relapse rates were
compared for fluoxetine monotherapy and OFC
in stabilized patients on the combination treat-
ment (Brunner et al. 2014). Time to relapse was
significantly longer in the OFC group than in
the fluoxetine monotherapy group (p ˂ 0.001).
Additionally, with regard to safety no signifi-
cant differences emerged between treatment
groups in terms of adverse events (p = 0.621).
However, the rate of patients who experienced
clinically significant (˃7%) weight gain was
greater for OFC than fluoxetine (OFC: 11.8%,
fluoxetine: 2.3%; p ˂ 0.001). At the endpoint, the
mean differences were significant for weight
gain (OFC: +1.14 kg, fluoxetine: 2.78 kg;
p ˂ 0.001). Finally, it must be mentioned that
OFC is not only FDA approved in treatment-
resistant unipolar depression; it also has this
endorsement for major depressive episodes in
bipolar I disorder.
In this paper an endeavor has been made to
outline the most pertinent aspects of major
mood disorders. The current nosological
classifications do not differentiate between
MDD and BD as far as the diagnostic criteria
for a major depressive episode are concerned.
However, these are discrete disorders with
etiopathologic differences and distinct man-
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agement protocols, dissimilar illness trajec-
tories, and disparate prognostic implications.
It is imperative for the practitioner to be alert
for masquerading bipolarity when treating a
patient with a major depressive episode and
in the absence of validated biomarkers, clini-
cal judgment is essentially empirical. In the
management of an MDE, standard antide-
pressants are the first-line option, but when
there are features suggestive of bipolar spec-
trum disorders, the clinician must use evi-
dence-based strategies to treat mood
disturbances which pose therapeutic chal-
lenge. In this regard second- and third-gener-
ation antipsychotics have emerged as
compelling treatment options and have
received FDA approval for licensed use in
mood disorders. Moreover, there is a grow-
ing literature on the utility of newer antipsy-
chotics as add on treatment or monotherapy
in refractory MDD and bipolar depression.
Since no curative treatments are available for
the most prevalent affective disorders, i.e.,
MDD and BD, physicians must use clinical
judgment in managing their patients on a
day-to-day basis and employ the biopsycho-
social model to achieve the best results.
Conflict of Interest I, Dr. Ather Muneer state that I am
the sole author of this manuscript. I received no funding
for this work and have no conflict of interest to report.
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... Mood disorders, including major depressive disorder (MDD) and bipolar disorder (BD), are among the most prevalent mental illnesses and impose substantial social and economic burdens on patients, their families, and societies (Simon, 2003). MDD and BD are considered distinct conditions with differences in treatment modalities (Muneer, 2018), making accurate diagnosis crucial for early and appropriate intervention. However, as patients with BD suffer from symptoms of depression for the majority of their symptomatic lives (Hirschfeld, 2014), patients who have not developed their manic or hypomanic episodes are often misdiagnosed as MDD, according to the current classification systems. ...
Emerging high-throughput proteomic technologies have recently been considered as a powerful means of identifying substrates involved in mood disorders. We performed proteomic profiling using liquid chromatography–tandem mass spectrometry to identify dysregulated proteins in plasma samples of 42 and 45 patients with major depressive disorder (MDD) and bipolar disorder (BD), respectively, in comparison to 51 healthy controls (HCs). Fourteen and six proteins in MDD and BD patients, respectively, were differentially expressed compared to HCs, among which coagulation factor XIII A chain (F13A1), platelet basic protein (PPBP), platelet facor 4 (PF4), glyceraldehyde-3-phosphate dehydrogenase (GAPDH), and thymosin beta-4 (TMSB4X) were altered in both disorders. For proteins dysregulated in both, except F13A1, higher fold changes were observed in MDD than in BD patients. These findings may help identify candidate biomarkers of mood disorders and elucidate their underlying pathophysiology and biochemical abnormalities.
Full-text available
Modern antipsychotic drugs are employed increasingly in the treatment of mood disorders as well as psychoses, stimulating interest in their possible contributions to altering suicidal risk. Clozapine remains the only treatment with an FDA-recognized indication for reducing suicidal risk (in schizophrenia). We carried out a systematic, computerized search for reports of studies involving antipsychotic drug treatment and suicidal behaviors. A total of 19 reports provide data with preliminary support for potential suicide risk-reducing effects of olanzapine, quetiapine, ziprasidone, aripiprazole, and asenapine in addition to clozapine, and provide some support for antipsychotic drug treatment in general. These preliminary findings encourage further testing of antipsychotics for effects on suicidal behavior, making use of explicit, pre-planned assessments of suicidal behavior.
Full-text available
Background: The progress that man has made in all domains of life, during all these years of reign over the earth, is utterly remarkable. However, it always came at a price. Each epoch of progress has seen human beings inflicted with trauma and cynical consequences. During the last two decades, Kashmiri (Indian) people have experienced continuous violence, a reign of terror, and political turmoil. Each of these disastrous events has contributed to the increase in psychiatric disorders in this part of the world, especially major depressive disorders. We can observe that besides the environmental influences, gene polymorphism also plays a crucial role in the development of depressive disorders. The role of Tryptophan Hydroxylase 1 (TPH1) gene is implicated in various psychiatric disorders, including depression. However, no study has investigated TPH1 A779C gene polymorphism in depressive disorders in a distressed society like Kashmir (India). Aims: To study TPH1 A779C single nucleotide polymorphism in depressive disorders in Kashmiri (Indian) population. Materials and methods: Two hundred and forty patients diagnosed with depressive disorder, and 160 unrelated healthy volunteers (control), were studied in a case-control study design. Polymorphism was determined using polymerase chain reaction (PCR) and agarose gel electrophoresis, after digestion with HAP II enzyme. Genotypes and allele frequencies were compared using Chi-square tests, Fisher's exact test, odds ratio, 95% confidence interval (C.I.) and a p-value of <0.05 was considered to be statistically significant. Results: The mean age ± standard deviation (SD) of depression and control group was 32.02±10.99 and 31.75±9.93, respectively (p= 0.512). It was found that the patients from depression group had AA genotype (51.7%) in comparison to control group (17.5%) and these results were statistically significant (p≤0.0001). Calculation of allelic frequency revealed a stronger association of A allele with depression group (70.83%) than with the control group (41.25%), and it was also found to be statistically significant (p≤0.0001) with C.I. of 3.459 (1.909-6.266). Conclusion: TPH1 A779C A gene was found to be associated with a major depressive disorder (MDD) in Kashmiri (Indian) population. There were high HAM-A as well as HAM-D scores in depressive patients of Kashmir (India).
Full-text available
In the majority of cases of bipolar disorder, manic episodes are usually brief and typically responsive to currently available psychopharmacological agents. In contrast, depressive manifestations are more prevalent and persistent, and can present as major depressive/mixed episodes or residual interepisode symptoms. The depressive phase is often associated with other neuropsychiatric conditions, such as anxiety spectrum disorders, substance use disorders, stressor-related disorders, and eating disorders. It is viewed as a systemic disease with associated ailments such as metabolic syndrome, diabetes mellitus, and cardiovascular disease. There is an increased rate of mortality not only from suicide, but also from concomitant physical illness. This scenario is made worse by the fact that depressive symptoms, which represent the main disease burden, are often refractory to existing psychotropic drugs. As such, there is a pressing need for novel agents that are efficacious in acute depressive exacerbations, and also have applicable value in preventing recurrent episodes. The rationale of the present review is to delineate the pharmacotherapy of the depressive phase of bipolar disorder with medications for which there is evidence in the form of observational, open-label, or double-blind randomized controlled studies. In the treatment of acute bipolar depression in adults, a comprehensive appraisal of the extant literature reveals that among mood stabilizers, the most robust proof of efficacy exists for divalproex sodium; while atypical antipsychotics, which include olanzapine, quetiapine, lurasidone, and cariprazine, are also effective, as demonstrated in controlled trials.
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Bipolar disorder is manifested as severe dysregulation of mood with recurrent manic and major depressive episodes. It is associated with psychiatric and medical comorbidities, inadequate response to currently available pharmacological agents and a progressively deteriorating course in many patients. The index episode is often depressive in nature, while the first manic or hypomanic episode may occur several years later in the course of the disorder causing delay in diagnosis and use of inappropriate treatment strategies. Staging has been used to great advantage in other branches of medicine like cardiology and oncology. There is growing realization that major mental disorders are fundamentally progressive, with simpler treatment requirements and better prognosis during initial stages of the illness. Defining these conditions into clinically applicable stages not only helps in better understanding the trajectory of a particular disorder, but also assists in management. Patients with a chronic, recalcitrant condition like bipolar disorder are likely to greatly benefit from this approach. If the illness is correctly identified early in its course, proper treatment can be instigated arresting progression to latter phases which are associated with myriad complications in the biopsychosocial realm. With these considerations, a search of the MEDLINE data base was conducted to seek out literature pertaining to staging models in bipolar disorder. A thorough scrutiny of the existing research work revealed that a number of investigators have endeavored to stage define bipolar disorder. This paper outlines staging proposals for bipolar disorder which have the greatest supporting evidence in the literature.
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Bipolar disorder is a heterogeneous condition with myriad clinical manifestations and many comorbidities leading to severe disabilities in the biopsychosocial realm. The objective of this review article was to underline recent advances in knowledge regarding the neurobiology of bipolar disorder. A further aim was to draw attention to new therapeutic targets in the treatment of bipolar disorder. To accomplish these goals, an electronic search was undertaken of the PubMed database in August 2015 of literature published during the last 10 years on the pathophysiology of bipolar disorder. A wide-ranging evaluation of the existing work was done with search terms such as "mood disorders and biology," "bipolar disorder and HPA axis," "bipolar disorder and cytokines," "mood disorders and circadian rhythm," "bipolar disorder and oxidative stress," etc. This endeavor showed that bipolar disorder is a diverse condition sharing neurobiological mechanisms with major depressive disorder and psychotic spectrum disorders. There is convincing evidence of crosstalk between different biological systems that act in a deleterious manner causing expression of the disease in genetically predisposed individuals. Inflammatory mediators act in concert with oxidative stress to dysregulate hormonal, metabolic, and circadian homeostasis in precipitating and perpetuating the illness. Stress, whether biologically or psychologically mediated, is responsible for the initiation and progression of the diathesis. Bipolar spectrum disorders have a strong genetic component; severe life stresses acting through various paths cause the illness phenotype.
Major Depressive Disorder (MDD) and other mood disorders remain difficult to effectively treat, and innovative interventions and therapeutic targets are needed. Psychological stressors and inappropriate inflammation increase the risk and severity of mood disorders; however, only recently have the importance of sterile inflammatory processes in this effect been revealed. This review will introduce the reader to pathogen versus sterile inflammation, inflammatory receptor-ligand interactions, microbial associated molecular patterns (MAMPs), pathogen-associated molecular patterns (PAMPs), danger associated molecular patterns (DAMPs), and the more recent discovery of the role of the inflammasome in peripheral and CNS cytokine/chemokine inflammatory responses. The review will focus on current pre-clinical and clinical evidence that sterile inflammation and inflammasome-dependent signaling may contribute to mood disorders. By understanding these inflammatory signaling processes, new approaches for quieting chronic or inappropriate inflammatory states may be revealed and this could serve as novel pharmacological targets for the treatment of mood disorders.Neuropsychopharmacology accepted article preview online, 14 July 2016. doi:10.1038/npp.2016.125.
Face cognition, including face identity and facial expression processing, is a crucial component of socio-emotional abilities, characterizing humans as highest developed social beings. However, for these trait domains molecular genetic studies investigating gene-behavior associations based on well-founded phenotype definitions are still rare. We examined the relationship between 5-HTTLPR/rs25531 polymorphisms - related to serotonin-reuptake - and the ability to perceive and recognize faces and emotional expressions in human faces. For this aim we conducted structural equation modeling on data from 230 young adults, obtained by using a comprehensive, multivariate task battery with maximal effort tasks. By additionally modeling fluid intelligence and immediate and delayed memory factors, we aimed to address the discriminant relationships of the 5-HTTLPR/rs25531 polymorphisms with socio-emotional abilities. We found a robust association between the 5-HTTLPR/rs25531 polymorphism and facial emotion perception. Carriers of two long (L) alleles outperformed carriers of one or two S alleles. Weaker associations were present for face identity perception and memory for emotional facial expressions. There was no association between the 5-HTTLPR/rs25531 polymorphism and non-social abilities, demonstrating discriminant validity of the relationships. We discuss the implications and possible neural mechanisms underlying these novel findings.
Importance Evidence suggests that long-term trajectories of major depressive disorder (MDD) are heterogeneous. The Danish Psychiatric Central Research Register (DPCRR) provides a rare opportunity to examine patterns and correlates of long-term trajectories in a large sample of patients with moderate to severe MDD.Objective To characterize patterns and correlates of 10-year course trajectories of MDD in the DPCRR.Design, Setting, and Participants A cohort containing 11 640 individuals born in Denmark in 1955 or later with their first recorded MDD diagnosis in the DPCRR between 1995 and 2002 was established. Patients were followed for 10 years from the date of their initial MDD diagnosis. Data were obtained from Danish civil and psychiatric national registers in June 2013 and were analyzed from April 4, 2014, to December 17, 2015. Correlates of trajectory class membership were sex, characteristics of the first recorded MDD episode (ie, age, severity, inpatient treatment, and record of suicide attempt or self-harm), and psychiatric diagnoses in parents (ie, depression, bipolar disorder, schizophrenia-spectrum disorders, substance abuse, and anxiety or somatoform disorders).Main Outcomes and Measures The outcome variable was past-year contact at a psychiatric hospital with a main diagnosis of MDD during each of the 10 years following the initial MDD diagnosis. Trajectories were modeled using latent class growth analysis.Results The sample included 11 640 individuals (7493 [64.4%] women) aged 18 to 48 years (mean [SD], 31.4 [7.3]) at their first recorded MDD diagnosis. Four trajectory classes were identified: brief contact (77.0%) (characterized by probability of contact after 2 years); prolonged initial contact (12.8%) (characterized by high decreasing probability of contact during the first 5 years); later reentry (7.1%) (characterized by moderate probability of contact during the second 5 years); and persistent contact (3.1%) (characterized by high or moderate probability of contact throughout). Female sex (odds ratio [OR] range, 1.82-2.22), inpatient treatment (OR range, 1.40-1.50), and severity at first recorded MDD episode (OR range: moderate, 1.61-1.84; severe, 1.93-2.23; and psychotic, 2.73-3.07) were associated with more severe trajectories. Parental anxiety (OR, 1.34 [95% CI, 1.10-1.63]) and depression (OR, 1.63 [95% CI, 1.28-2.09]) were associated with the prolonged initial contact and later reentry classes, respectively. Parental schizophrenia was associated with the persistent contact class (OR range, 2.55-3.04).Conclusions and Relevance Most people treated for moderate to severe MDD in Danish psychiatric hospitals do not receive additional MDD treatment after 2 years; however, a minority receive specialty treatment for up to a decade. Observable heterogeneity in the course may be indicative of underlying etiologic differences.
Brexpiprazole is a new therapeutic agent that was recently approved for the treatment of schizophrenia and for the adjunctive treatment of major depressive disorder. Brexpiprazole has features that both overlap and contrast with a related molecule, aripiprazole, and these features are discussed here. How to Cite This Article Link to This Abstract Blog This Article Copy and paste this link Highlight all Citation is provided in standard text and BibTeX formats below. Highlight all BibTeX Format @article{CNS:10195664,author = {Stahl,Stephen M.},title = {Mechanism of action of brexpiprazole: comparison with aripiprazole},journal = {CNS Spectrums},volume = {21},issue = {01},month = {2},year = {2016},issn = {2165-6509},pages = {1--6},numpages = {6},doi = {10.1017/S1092852915000954},URL = {},} Click here for full citation export options. Blog This Article Copy and paste this code to insert a reference to this article in your blog or online community profile: Highlight all Mechanism of action of brexpiprazole: comparison with aripiprazole Stephen M. Stahl (2016). CNS Spectrums , Volume 21 , Issue01 , February 2016 pp 1-6 The code will display like this Mechanism of action of brexpiprazole: comparison with aripiprazole Stephen M. Stahl (2016) CNS Spectrums, , Volume 21, Issue01, February 2016 pp 1-6 Stephen M. Stahl (2016). Mechanism of action of brexpiprazole: comparison with aripiprazole. CNS Spectrums, 21, pp 1-6 doi:10.1017/S1092852915000954 Metrics Related Content Articles with Keywords in Common