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THERAPEUTIC
STRATEGIES
DRUG DISCOVERY
TODAY
Affective symptoms in schizophreniaDebbi A. Morrissette1,3, Stephen M. Stahl1,2,*1The Neuroscience Education Institute, 1930 Palomar Point Way, Carlsbad, CA 92008, United States2The University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093, United States3California State University, San Marcos, 333 South Twin Oaks Valley Road, San Marcos, CA 92069, United States
In addition to positive, negative, aggressive and cogni-tive symptoms, patients with schizophrenia often exhi-
bit affective disorders, including depression and
anxiety. Affective symptoms in schizophrenia can be
particularly disturbing for patients with schizophrenia,
increasing the risk of suicide and diminishing quality of
life. The following review examines the prevalence,
etiology and treatment of affective symptoms, parti-
cularly depression, in patients with schizophrenia.
Section editors:Diana Kristensen Department of Psychiatry, HvidovreUniversity Hospital, Brndby, Copenhagen, DenmarkMikkel Myatt Psykiatrisk Center Glostrup, CopenhagenUniversity, Glostrup, Copenhagen, Denmark
IntroductionSchizophrenia is a chronic psychiatric disorder that encom-
passes several different symptom domains: positive, negative,
affective, aggressive and cognitive. Positive symptoms
include hallucinations and delusions and are often the most
responsive to treatment. Negative symptoms include apathy,
anhedonia and flat affect whereas cognitive symptoms
include attentional deficits and impaired executive function.
There is substantial overlap among these different symptom
domains and it can be particularly difficult to distinguish
negative symptoms from affective symptoms (including
depression and anxiety) [14] (Fig. 1A). The comorbidity of
affective symptoms, especially depression, can have dire
consequences for the quality of life and life span of those
with schizophrenia; thus it is important that affective symp-
toms are properly diagnosed and treated optimally.
Affective symptoms in schizophrenia: incidence,
prevalence and consequences
Affective symptoms are common in schizophrenia; depressive
symptoms are reported in as many as 80% of patients with
schizophrenia while symptoms of mania are reported in as
manyas20%of individuals with schizophrenia [5]. Inaddition
to thosewhomeet criteria formajordepression, there arealso a
significant number ofpatients with schizophrenia whoexperi-
ence subsyndromal depressive symptoms [6]. Depressive
symptoms
in
patients
with
schizophrenia
can have
devastat-ing consequences including increased risk of psychotic relapse
and hospitalization, worse social functioning and poorer qual-
ity of life compared with patients with schizophrenia who do
not have prominent affective symptoms [69]. Depressive
symptoms significantly increase the risk of suicide; the major-
ity (64%) of patients with schizophrenia who commit suicide
do so while experiencing depressive symptoms [9,10]. Simi-
larly, suicide attempts are even more common in individuals
with schizoaffective disorder compared to those with either
schizophrenia or a mood disorder [11]. Interestingly, suicide
risk has not been associated with either positive or negative
symptom
domains
[10].Depressive symptoms in schizophrenia can present as
schizoaffective disorder, comorbid depression or as subsyn-
dromal depression in which depressive symptoms do not
meet criteria for major depression [12]. Schizoaffective dis-
order is described as schizophrenia in which the patient also
meets criteria for a mood disorder (major depressive episode,
manic episode or mixed episode). The diagnostic criteria for
schizoaffective disorder also require that psychotic symptoms
are present without prominent mood symptoms for at least
2 weeks.
Drug Discovery Today: Therapeutic Strategies Vol. 8, No. 12 2011
Editors-in-Chief
Raymond Baker formerly University of Southampton, UK and Merck Sharp & Dohme, UK
Eliot Ohlstein GlaxoSmithKline, USA
Treatment of schizophrenia
*Corresponding author.: S.M. Stahl (sstahl@NEIglobal.com)
1740-6773/$ 2011 Elsevier Ltd. All rights reserved. DOI: 10.1016/j.ddstr.2011.10.005 3
http://dx.doi.org/10.1016/j.ddstr.2011.10.005http://dx.doi.org/10.1016/j.ddstr.2011.10.005mailto:sstahl@NEIglobal.comhttp://dx.doi.org/10.1016/j.ddstr.2011.10.005http://dx.doi.org/10.1016/j.ddstr.2011.10.005mailto:sstahl@NEIglobal.comhttp://dx.doi.org/10.1016/j.ddstr.2011.10.005http://dx.doi.org/10.1016/j.ddstr.2011.10.0057/28/2019 1-s2.0-S1740677311000453-main
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Comorbid and subsyndromal depression can occur before,
during or after a psychotic episode. In fact, depressive symp-
toms
can
be
a
sign
of
imminent
psychotic
relapse
in
manypatients. Affective symptoms are among the most prevalent
prodromal signs with as many as 83% of patients suffering a
depressed mood in the weeks leading up to a first hospitaliza-
tion for psychosis [1,5,13]. In patients at risk for developing
schizophrenia, symptoms of depression and anxiety may
predict higher risk for subsequent development of psychosis
and higher severity of first-episode psychosis [13,14]. In this
context, symptoms of depression and anxiety may serve as
vulnerability markers in individuals at risk for developing
schizophrenia. Depressive symptoms that occur during a
psychotic episode are often amenable to treatment. Post-
psychotic depression, occurring after a psychotic episode,may persist and worsen in some individuals and often is
associated with a poor prognosis [12].
In addition to these apparent temporal relationships
between psychotic and depressive episodes, depression
may also occur as a side effect of antipsychotic treatment
(particularly conventional, first generation antipsychotics;
FGAs), as a result of substance abuse or in response to
psychological stress [13]. Increased cognitive insight in schi-
zophrenia has also been associated with elevated depressive
symptoms [15].
Mood disorders and schizophrenia: separate entities
or parts of a continuous spectrum?
Although
depressive
symptoms
are
common
in
schizophre-nia, only 1030% of patients with schizophrenia spectrum
disorders meet criteria for schizoaffective disorder [12]. There
is an ongoing debate about the validity of schizoaffective
disorder as a distinct diagnosis and it has been suggested that
schizoaffective disorder may actually be comorbidity of schi-
zophrenia and a mood disorder or an intermediate presenta-
tion along the spectrum between schizophrenia and mood
disorders [11,1619] (Fig. 1B). Support for the idea of a
spectrum that spans the realms of mood disorders and schi-
zophrenia comes from genetic findings that symptom profile,
rather than categorical diagnosis, correlates more strongly
with allelic variants. Genetic studies have shown thatpatients with schizophrenia can be sub-grouped based on
the presence or absence of mood symptom types; the same
has not been shown for psychotic symptoms types. In parti-
cular, an association between the glycoprotein M6A gene and
patients with schizophrenia and prominent depressive symp-
toms was found in a recent study [20]. Further evidence for an
overlap between schizophrenia and mood disorders comes
from neuroimaging studies. Rimol et al. [21] have shown that
patterns of subcortical and cortical abnormalities are similar
between schizophrenia and mood disorders. Additionally,
Drug Discovery Today: Therapeutic Strategies | Treatment of schizophrenia Vol. 8, No. 12 2011
DelusionsHallucinations
AssaultiveVerbally abusive
Reduced speech and range of emotionsLoss of interest
Loss of social desire
Loss of motivation
Poor attentionImpaired executive
function
AnxietySuicidality
Depression
(a)
(b)
Schizophrenia
Schizoaffective
disorder
Mood
Disorders
Psychosis
with depressive
symptoms
Depression
with psychotic
features
Drug Discovery Today: Therapeutic Strategies
Figure 1. Overlapping symptom domains. (a) Schizophrenia encompasses positive, negative, aggressive, affective and cognitive symptom domains. Thesesymptom domains often overlap and can be difficult to distinguish. (b) The common overlap in symptom presentation and comorbidity betweenschizophrenia and mood disorders supports the idea that these two disorders are parts of a continuous spectrum rather than separate categorical entities.
According to this model, schizoaffective disorder is found near the midpoint of the spectrum, representing an equal presentation of both psychotic and
mood disorder feature.
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Kaur et al. [22] found similar reductions in event-related
potentials in both first-episode schizophrenia patients and
first-episode affective spectrum patients (Fig. 2).
The neurobiology of affective symptoms in
schizophrenia
Ultimately, the expression of symptoms is largely due to
dysfunctioning of neurotransmitter systems [1] (Fig. 2). Itmay be that the disruption of one system (e.g. dopamine)
underlying schizophrenia hasdownstream effects that lead to
misregulation of other neurotransmitter systems (e.g. sero-
tonin) that underlie the expression of affective symptom.
Alternatively, there may be a common genetically predispos-
ing factor (e.g. catechol-o-methyltransferase; COMT [23]) or
process (e.g. energy metabolism [24]) that leads to dysfunc-
tion of multiple systems simultaneously.
Treatment with medications that block dopamine D2
receptors (i.e. antipsychotics) may induce affective and
negative symptoms by exacerbating a hypodopaminergic
status in the ventromedial prefrontal cortex (VMPFC). Addi-
tional blockade of serotonin 5HT2A receptors by atypical,
second-generation antipsychotics (SGAs) is hypothesized to
mitigate affective, negative and cognitive symptoms caused
by excessive D2 antagonism in the cortex [4] (Fig. 3).
Treating
affective
symptoms
in
schizophreniaThere are no consistent recommendations as to how schi-
zoaffective disorder or depressive symptoms in schizophrenia
are most effectively treated [25]. Despite this fact, antidepres-
sants and/or mood stabilizers are often used in conjunction
with antipsychotics for the treatment of schizophrenia
[12,26,27]. The 1999 Expert Consensus Guidelines recom-
mend treatment of schizophrenia and comorbid depression
first with optimal doses of SGAs, followed by augmentation
with an SSRI, followed by the serotonin and norepinephrine
reuptake inhibitor (SNRI) venlafaxine, and finally, bupropion
Vol. 8, No. 12 2011 Drug Discovery Today: Therapeutic Strategies | Treatment of schizophrenia
normal
(a) The Mesolimbic Dopamine Hypothesis of PositiveSymptoms of Schizophrenia
(b) Mesocortical Pathway to DLPFC and VMPFC
(c) Monoamine Hypothesis of Depression
LowVMPFC
negativesymptoms
negativesymptoms
DLPFC
(SIGH)
(SIGH)
cognitivesymptoms
affectivesymptoms
positive symptoms
overactivationnormalbaselinehypoactivation
mesolimbic overactivity
NE
DA
5HT
Drug Discovery Today: Therapeutic Strategies
Figure 2. Disrupted circuits in schizophrenia and depression. Dysfunction in various neurotransmitter systems are hypothesized to underlie thesymptoms of schizophrenia. (a) The dopamine hypothesis of schizophrenia proposes that hyperdopaminergia in the limbic system underlies the positivesymptoms of schizophrenia. (b) Negative and cognitive symptoms in schizophrenia are believed to be due to hypodopaminergia in the dorsolateral
prefrontal
cortex
(DLPFC)
whereas
hypodopaminergia
in
the
ventromedial
prefrontal
cortex
may
contribute
to
the
negative
and
affective
symptoms
ofschizophrenia. (c) The monoamine hypothesis of depression proposes that depressive symptoms may be due to a deficiency of norepinephrine (NE),
dopamine (DA), and/or serotonin (5HT) neurotransmission in the prefrontal cortex.
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[28].More recent guidelines have indicated that there are not
enough data on which to base a recommendation for the
treatment of depressive symptoms in schizophrenia [29,30].
Antipsychotics
Although FGAs may exacerbate affective symptoms in schi-
zophrenia by causing hypodopaminergia in the cortex (Fig.
3c), all SGAs, via antagonism at serotonin 5HT2A receptors,
and many SGAs via antagonism at 5HT2C receptors, may
reduce negative, affective, and cognitive symptoms (Fig. 3d)
by increasing dopamine activity in the same brain region.Additional binding properties of some SGAs that lead to
increased dopamine, norepinephrine, and serotonin activity
in the cortex, such as norepinephrine reuptake blockade,
alpha 2 adrenergic antagonism, 5HT1A partial agonism,
5HT7 antagonism and other properties, may also lend these
agents antidepressant properties [4]. The affinities of available
SGAs for various receptors that may modulate affective symp-
toms are listed in Fig. 4.
It has been hypothesized that, in depression, dopamine
neurotransmission is reduced, resulting in deficient tonic
activity at dopamine D3 receptors and deficient phasic activ-
ity at dopamine D2 receptors. Partial agonism of D2/D3
receptors may reset the tonic and phasic dopamine neuro-
transmission, resulting in antidepressant effects [4]. Aripipra-
zole, an SGA with D2/D3 partial agonist activity, has been
shown to improve depression [31]. Additionally, the actions
of D2/D3 partial agonists may have antipsychotic and anti-
manic effects due to net antagonist activity at overstimulated
D2/D3 receptors [4].
Enhancement of noradrenergic neurotransmission in the
PFC,
via
norepinephrine
reuptake
inhibition
(NRI)
is
anotherproposed mechanism for antidepressant activities of antipsy-
chotics. Both ziprasidone and quetiapine (via its active meta-
bolite norquetiapine) may exert antidepressant effects in part
through this mechanism of enhanced norepinephrine neu-
rotransmission [4,32,33]. Ziprasidone has the additional
property of serotonin reuptake inhibition (SRI) which may
also contribute antidepressant effects by increasing seroto-
nergic neurotransmission [33].
Antagonism at serotonin 5HT2C receptors, a property
shared by many SGAs, may also have an antidepressant effect
Drug Discovery Today: Therapeutic Strategies | Treatment of schizophrenia Vol. 8, No. 12 2011
DA
DA neuron
5HT2Areceptor
5HT2A
(a) (b)
(c) (d)
D2 receptor
postsynapticneuron
DA neuron
DA neuronDA neuron
no DA release
5HT neuron5HT neuron
5HT neuron 5HT neuron
stimulate5HT2A
receptor
postsynapticneuron
affectivesymptoms
negativesymptoms
cognitivesymptoms
affectivesymptoms
negativesymptoms
cognitivesymptoms
D2
Drug Discovery Today: Therapeutic Strategies
Figure 3. Antipsychotics and affective symptoms. (a) Unlike conventional antipsychotics which bind primarily to dopamine D2 receptors, atypicalantipsychotics also bind to serotonin 5HT2A receptors. (b) In the mesocortical pathway, binding of serotonin to 5HT2A receptors causes a state of
hypodopamine. (c) Conventional antipsychotics exacerbate hypodopaminergia in the cortex and may cause secondary affective, negative and cognitivesymptoms. (d) Additional antagonism of serotonin 5HT2A receptors by atypical antipsychotics may help ameliorate some of the symptoms caused by
hypodopaminergia in the cortex.
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through disinhibition of dopamine and norepinephrine
release in the prefrontal cortex (PFC). Interestingly, two SGAs
with 5HT2C antagonistic activities have proved useful in the
treatment of bipolar mood disorders: olanzapine, in combi-
nation with the SSRI fluoxetine, improves depressive symp-
toms
of
bipolar
depression
and
ziprasidone
has
shownefficacy in the treatment of dysphoric mania [34,35]. Nor-
quetiapine also has binding affinity for 5HT2C which, in
combination with its 5HT1A partial agonism and NRI activ-
ities, may contribute to the antidepressant properties of
quetiapine [33].
Similar to antagonism of 5HT2C receptors, agonism of
serotonin 5HT1A receptors leads to disinhibition of noradre-
nergic and dopaminergic neurons in the PFC and 5HT1A
agonism has been shown to increase serotonin, dopamine,
and norepinephrine neurotransmission [4,36]. There are
many SGAs that bind to 5HT1A receptors and may therefore
have
some
antidepressant
capacity
[33].Blockade of serotonin 5HT7 receptors may have antide-
pressant effectsby increasing serotonergic neurotransmission
in the PFC; antagonism of 5HT7 receptors in the raphe nuclei
leads to disinhibition of serotonergic neurons. Several SGAs
have binding affinity for 5HT7 receptors, most notably two of
the newly approved SGAs, lurasidone and asenapine. One
recent study reported no benefits from asenapine on depres-
sive symptoms in bipolar disorder [37]; however, more data
are needed before any conclusions can be made as to the
efficacy of both asenapine and lurasidone in the treatment of
depressive symptoms in schizophrenia [38]. Aripiprazole also
has 5HT7 antagonistic properties, as well binding affinity for
5HT1A, 5HT2A, 5HT2C, and D2/D3 receptors and was
recently demonstrated to have antidepressant effects [36].
Adrenergic alpha-2 receptors are found on cell bodies of
noradrenergic
neurons.
Antagonism
of
alpha-2
receptors
ispostulated to have antidepressant effects by increasing nor-
epinephrine neurotransmission [36]. There are several SGAs
that may have antidepressant properties due to antagonism
of alpha-2 receptors, including asenapine, paliperidone and
risperidone [33].
Suicide is of great concern for patients with schizophrenia,
especially those in whom affective symptoms are present.
Clozapine has been found to reduce risk of suicide and is now
recommended for patients exhibiting suicidal tendencies or
ideation [30,39]. However, caution should be exercised when
using clozapine due to increased risk for serious side effects,
including
agranulocytosis.Paliperidone was recently approved for the treatment of
schizoaffective disorder [40]. Paliperidone may derive its
mood stabilizing effects from serotonin 5HT2A, 5HT2C, or
5HT7 antagonism, adrenergic alpha-2 antagonism, and/or
binding affinity for dopamine D3 receptors.
Antidepressants
Antidepressants are prescribed in addition to antipsychotics
for as many as 43% of patients with schizophrenia [26]. The
selective serotonin reuptake inhibitor (SSRI) citalopram has
Vol. 8, No. 12 2011 Drug Discovery Today: Therapeutic Strategies | Treatment of schizophrenia
Drug D2 Antag D2 PA D3 5HT1A PA 5HT2A Antag 5HT2C 5HT7 1 2 NRI SRI
Aripiprazole +++ +++ +++ +++ ++ +++
Asenapine +++ +++ ++ ++++ ++++ ++++ +++ +++
Clozapine ++ + + ++ ++ ++ ++ ++
Iloperidone ++ ++ ++ ++++ ++ + ++++ ++
Lurasidone +++ ? +++ +++ ++++ ++
Olanzapine ++ ++ +++ ++ + ++
Paliperidone +++ +++ + ++++ ++ +++ +++ ++
Quetiapine ++ + + + +* + +++ + ++*
Risperidone +++ +++ + ++++ ++ +++ +++ ++
Ziprasidone +++ ++ ++ ++++ ++++ +++ +++ ++ +
Binding affinities based on data from the National Institutes of Mental Health Psychoactive Drug Screening Program online Ki database.+Ki100nM; ++Ki10nM; +++ Ki1nM; ++++ Ki
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been shown to improve depressive symptoms in schizophre-
nia and reduce suicidal ideation in patients with schizophre-
nia [9,27]. Adjunctive treatment with an antidepressant in
patients with schizophrenia may also be useful for amelior-
ating more than just affective symptoms in schizophrenia;
augmentation of antipsychotic treatment with the antide-
pressant mirtazapine has been shown to improve both nega-
tive and cognitive symptoms of schizophrenia [4144]. These
results are postulated to be due to mirtazapines antagonism
of serotonin 5HT2A and 5HT2C as well as noradrenergic
alpha-2 receptors along with agonism of serotonin 5HT1A
receptors. Similarly, addition of the SSRI fluvoxamine to
antipsychotic treatment has also been shown to be beneficial
for treatment-resistant negative symptoms, possibly due in
part to its upregulation of 5HT2A receptor expression [45].
The norepinephrine and dopamine reuptake inhibitor bupro-
pion has also been evidenced to decrease both affective and
negative symptoms in schizophrenia although there are con-
cerns that the prodopaminergic actions of bupropion may
exacerbate psychosis. However, not all studies have shown
this [46]. However, the risk of exacerbating psychosis in
patients with schizophrenia does seem to be high with
adjunctive tricyclic antidepressant (TCA) use [47].
Mood stabilizers
Although mood stabilizers, including lithium, valproate, and
lamotrigine, are commonly prescribed as adjuncts to anti-
psychotic medication in schizophrenia, there is little evi-
dence or regulatory approval for their use [4851].
However, on an individual patient basis, these mood stabi-
lizers
may
provide
some
benefit
for
affective
symptoms.
Someof themechanisms of actionofmood stabilizers hypothesized
to benefit patients with schizophrenia include alteration of
GABAergic, glutamatergic and dopaminergic neurotransmis-
sion in the PFC [50,52,53].
Conclusion
Affective symptoms are common in schizophrenia and can
greatly impair quality of life for patients. Although there is
some debate as to the relationship between psychosis and
mood, there is consensus as to the urgency for addressing
depressive symptoms in schizophrenia. Both antidepressants
and SGAs may have receptor binding profiles that give theseagents antidepressive qualities and may be useful in treating
patients with schizophrenia who have prominent mood
symptoms.
Acknowledgements
Ki determinations and receptor binding profiles were gener-
ously provided by the National Institute of Mental Healths
Psychoactive Drug Screening Program, Contract # HHSN-
271-2008-00025-C (NIMH PDSP). The NIMH PDSP is directed
byBryanL. Roth MD, PhD at theUniversityof NorthCarolina
at Chapel Hill and Project Officer Jamie Driscol at NIMH,
Bethesda MD, USA. For experimental details please refer to
the PDSP web site http://pdsp.med.unc.edu/.
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