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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 ([email protected])

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:[email protected]://dx.doi.org/10.1016/j.ddstr.2011.10.005http://dx.doi.org/10.1016/j.ddstr.2011.10.005mailto:[email protected]://dx.doi.org/10.1016/j.ddstr.2011.10.005http://dx.doi.org/10.1016/j.ddstr.2011.10.005

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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


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


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


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.

6


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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


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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