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

January 2018

In book: Understanding Depression (pp.15-34)

Authors:

Rawal Institute of Health Sciences

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.

.2 Gene sets responsible for heritable traits that interact with environmental factors in the causation of mood disorders

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Chapter Title Major Depressive Disorder and Bipolar Disorder: Differentiating

Features and Contemporary Treatment Approaches

Corresponding Author Family Name Muneer

Particle

Given Name Ather

Suffix

Organization Islamic International Medical College,

Riphah International University

Address Rawalpindi, Pakistan

Email muneerather2@gmail.com

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.

Keywords

(separated by “-”)

Bipolar disorder - Major depressive disorder - Gene x environment

disorders - Gene sets - Sterile inflammation - Atypical

antipsychotics

Y.-K. Kim (ed.), Understanding Depression, https://doi.org/10.1007/978-981-10-6577-4_2

Major Depressive Disorder

and Bipolar Disorder:

Differentiating Features

and Contemporary Treatment

Approaches

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”

AU1

A. Muneer

Islamic International Medical College, Riphah

International University, Rawalpindi, Pakistan

e-mail: muneerather2@gmail.com

(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).

AU2

AU3

Mood

Episodes

↑ Allostatic

load

Homeostatic

disturbance

Psychosocial Impaired role

functioning

Loss of

autonomy

Biological Neuroprogression/

systemic ailments

↑ morbidity

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

AU7

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

disorders

3. Major depressive episode with melancholic features

4. Psychotic depression

5. Repeated mood episodes

6. Increased severity of episodes, with history of

hospitalization

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

processes

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

disorders

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

Rumination CREB1, GIRK, BDNF CREB1, KCNJ6, BDNF

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

GENE SETS

PERSONALITY AND

TEMPERAMENTAL

FACTORS

EXTERNAL

FACTORS

GENE SETS

INTERNAL FACTORS

GENE SETS

D E P R E S S I O N

Fig. 2.2 New gene x environment model of depression.

Candidate genes comprising gene sets: 5-HTTLPR, CB1,

TPH2, CREB1, BDNF, COMT, GIRK, HTR1A, HTR2A.

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

diathesis

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

Disorders

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

Patterns

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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A. Muneer

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

cytokines.

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

Disorders

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

(IDO).

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

neurotransmitter.

5. Decreased availability of serotonin provokes a

depressive phenotype with attendant psycho-

logical, neurovegetative, and somatic

symptoms.

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

Perspective

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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A. Muneer

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

psychopharmacology.

DAMP

MICR

OGLIA SURVEILLANT MICROGLIA PRIMED

IL-1b

STRESS

NEURONAL

APOPTOSIS

EXPRESSION OF DEPRESSIVE PHENOTYPE

KYNURENINE PATHWAY

IDO TRYPTOPHAN Ø 5HT

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

Antipsychotics

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

Considerations

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

A. Muneer

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

depression

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

AD)

Olanzapine/

ﬂuoxetine

combination

Treatment-

resistant

depression

5-HT2A/2C antagonism, 5-HT7

antagonism

5–20 Positive RCT in

MDD. Positive RCT in

bipolar I depression

(monotherapy)

Cariprazine None for

MDD

D2/3 partial agonism, 5-HT1A partial

agonism, 5-HT2A/5-HT7 antagonism

1.5–3 Positive RCT in bipolar

I depression

(monotherapy)

Lurasidone Indicated for

bipolar I

depression

5-HT7 antagonism, 5-HT1A partial

agonism, weak 5-HT2C antagonism,

weak α-2 antagonism

60–120 Positive RCT in bipolar

I depression

(monotherapy)

Ziprasidone None for

MDD

5-HT2A/2C antagonism, 5HT1A

agonism, 5-HT, NE, DA transporter

inhibition

40–160 RCT (adjunctive to AD)

Risperidone None for

MDD

5-HT2A antagonism, α-2 receptor

antagonism, 5-HT7 antagonism

0.5–3 RCT (adjunctive to AD)

Paliperidone None for

MDD

5-HT2A antagonism, α-2 receptor

antagonism, 5-HT7 antagonism

3 Anecdotal reports or

expert opinion

Asenapine None for

MDD

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

MDD

5HT-2A antagonism, 5-HT6/7

antagonism

Not

available

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

2.5.3.1 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).

2.5.3.2 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).

2.5.3.3 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

literature:

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

ﬁbromyalgia.

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

schizophrenia.

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.

2.5.3.4 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.

Conclusion

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-

A. Muneer

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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via neuroinﬂammation. Int J Neuropsychopharmacol.

2015;18(8):pyv006.

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Identification of altered protein expression in major depressive disorder and bipolar disorder patients using liquid chromatography–tandem mass spectrometry

Article

Mar 2021
PSYCHIAT RES

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.

Do Atypical Antipsychotics Have Antisuicidal Effects? A Hypothesis-Generating Overview

Article

Full-text available

Oct 2016
INT J MOL SCI

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.

Is there a link between Depressive Disorders and Tryptophan Hydroxylase 1 (TPH1) Gene Polymorphism? - Study from a Distressed Area, Kashmir (India)

Article

Full-text available

Jul 2016

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).

Pharmacotherapy of Acute Bipolar Depression in Adults: An Evidence Based Approach

Article

Full-text available

May 2016

Ather Muneer

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.

Staging Models in Bipolar Disorder: A Systematic Review of the Literature

Article

Full-text available

May 2016

Ather Muneer

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.

The Neurobiology of Bipolar Disorder: An Integrated Approach

Article

Full-text available

Feb 2016

Ather Muneer

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.

Danger Signals and Inflammasomes: Stress-Evoked Sterile Inflammation in Mood Disorders

Article

Jul 2016

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 and Emotion Expression Processing and the Serotonin Transporter Polymorphism 5-HTTLPR/rs22531: Face Cognition & 5-HTTLPR/rs22531 Polymorphism

Article

Apr 2016

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.

Heterogeneity in 10-Year Course Trajectories of Moderate to Severe Major Depressive Disorder

Article

Mar 2016

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.

Mechanism of action of brexpiprazole: Comparison with aripiprazole

Article

Feb 2016

Stephen Stahl

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 http://dx.doi.org/10.1017/S1092852915000954 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 = {http://journals.cambridge.org/article_S1092852915000954},} 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 http://journals.cambridge.org/action/displayAbstract?aid=10195664 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 http://journals.cambridge.org/abstract_S1092852915000954 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

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