Drug Discovery Today: Therapeutic Strategies

Editors-in-Chief Raymond Baker formerly University of Southampton, UK and Merck Sharp & Dohme, UK Eliot Ohlstein GlaxoSmithKline, USA
DRUG DISCOVERY

Vol. 8, No. 12 2011

STRATEGIES

TODAY THERAPEUTIC

Treatment of schizophrenia

Affective symptoms in schizophrenia

Debbi A. Morrissette1,3, Stephen M. Stahl1,2,*
1 2

The Neuroscience Education Institute, 1930 Palomar Point Way, Carlsbad, CA 92008, United States The University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093, United States 3 California State University, San Marcos, 333 South Twin Oaks Valley Road, San Marcos, CA 92069, United States

In addition to positive, negative, aggressive and cognitive symptoms, patients with schizophrenia often exhibit 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, particularly depression, in patients with schizophrenia. Introduction
Schizophrenia is a chronic psychiatric disorder that encompasses 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 at affect whereas cognitive symptoms include attentional decits and impaired executive function. There is substantial overlap among these different symptom domains and it can be particularly difcult 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 symptoms are properly diagnosed and treated optimally.

Section editors: Diana Kristensen Department of Psychiatry, Hvidovre University Hospital, Brndby, Copenhagen, Denmark Mikkel Myatt Psykiatrisk Center Glostrup, Copenhagen University, Glostrup, Copenhagen, Denmark
schizophrenia while symptoms of mania are reported in as many as 20% of individuals with schizophrenia [5]. In addition to those who meet criteria for major depression, there are also a signicant number of patients with schizophrenia who experience subsyndromal depressive symptoms [6]. Depressive symptoms in patients with schizophrenia can have devastating consequences including increased risk of psychotic relapse and hospitalization, worse social functioning and poorer quality of life compared with patients with schizophrenia who do not have prominent affective symptoms [69]. Depressive symptoms signicantly increase the risk of suicide; the majority (64%) of patients with schizophrenia who commit suicide do so while experiencing depressive symptoms [9,10]. Similarly, 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 subsyndromal depression in which depressive symptoms do not meet criteria for major depression [12]. Schizoaffective disorder 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.
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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
*Corresponding author.: S.M. Stahl (sstahl@NEIglobal.com) 1740-6773/$ 2011 Elsevier Ltd. All rights reserved. DOI: 10.1016/j.ddstr.2011.10.005

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(a)
Delusions Hallucinations

Assaultive Verbally abusive

Poor attention Impaired executive function

Reduced speech and range of emotions Loss of interest Loss of social desire Loss of motivation

Anxiety Suicidality Depression

(b) Schizophrenia Mood Disorders Psychosis with depressive symptoms Depression with psychotic features
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Schizoaffective disorder

Figure 1. Overlapping symptom domains. (a) Schizophrenia encompasses positive, negative, aggressive, affective and cognitive symptom domains. These symptom domains often overlap and can be difcult to distinguish. (b) The common overlap in symptom presentation and comorbidity between schizophrenia 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.

Comorbid and subsyndromal depression can occur before, during or after a psychotic episode. In fact, depressive symptoms can be a sign of imminent psychotic relapse in many patients. 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 rst hospitalization 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 rst-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. Postpsychotic 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, rst generation antipsychotics; FGAs), as a result of substance abuse or in response to psychological stress [13]. Increased cognitive insight in schizophrenia has also been associated with elevated depressive symptoms [15].
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Mood disorders and schizophrenia: separate entities or parts of a continuous spectrum?

Although depressive symptoms are common in schizophrenia, 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 schizophrenia and a mood disorder or an intermediate presentation 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 schizophrenia comes from genetic ndings that symptom prole, rather than categorical diagnosis, correlates more strongly with allelic variants. Genetic studies have shown that patients 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 particular, an association between the glycoprotein M6A gene and patients with schizophrenia and prominent depressive symptoms 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,

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Drug Discovery Today: Therapeutic Strategies | Treatment of schizophrenia

(a) The Mesolimbic Dopamine Hypothesis of Positive Symptoms of Schizophrenia

overactivation normal baseline hypoactivation

(b)

Mesocortical Pathway to DLPFC and VMPFC

(SIGH)

DLPFC
normal

negative cognitive symptoms symptoms

Low

(SIGH)

VMPFC

negative affective symptoms symptoms

(c)
positive symptoms mesolimbic overactivity

Monoamine Hypothesis of Depression

NE DA 5HT

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Figure 2. Disrupted circuits in schizophrenia and depression. Dysfunction in various neurotransmitter systems are hypothesized to underlie the symptoms of schizophrenia. (a) The dopamine hypothesis of schizophrenia proposes that hyperdopaminergia in the limbic system underlies the positive symptoms 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 of schizophrenia. (c) The monoamine hypothesis of depression proposes that depressive symptoms may be due to a deciency of norepinephrine (NE), dopamine (DA), and/or serotonin (5HT) neurotransmission in the prefrontal cortex.

Kaur et al. [22] found similar reductions in event-related potentials in both rst-episode schizophrenia patients and rst-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). It may be that the disruption of one system (e.g. dopamine) underlying schizophrenia has downstream effects that lead to misregulation of other neurotransmitter systems (e.g. serotonin) that underlie the expression of affective symptom. Alternatively, there may be a common genetically predisposing factor (e.g. catechol-o-methyltransferase; COMT [23]) or process (e.g. energy metabolism [24]) that leads to dysfunction 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). Additional 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 schizophrenia

There are no consistent recommendations as to how schizoaffective disorder or depressive symptoms in schizophrenia are most effectively treated [25]. Despite this fact, antidepressants and/or mood stabilizers are often used in conjunction with antipsychotics for the treatment of schizophrenia [12,26,27]. The 1999 Expert Consensus Guidelines recommend treatment of schizophrenia and comorbid depression rst with optimal doses of SGAs, followed by augmentation with an SSRI, followed by the serotonin and norepinephrine reuptake inhibitor (SNRI) venlafaxine, and nally, bupropion
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(a) 5HT2A

(b)

DA

D2 receptor

no DA release

DA neuron 5HT2A receptor

postsynaptic neuron

DA neuron
stimulate 5HT2A receptor

postsynaptic neuron

D2

5HT neuron

5HT neuron

(c)

(d)

DA neuron

DA neuron

5HT neuron

5HT neuron

affective cognitive negative symptoms symptoms symptoms

affective cognitive negative symptoms symptoms symptoms Drug Discovery Today: Therapeutic Strategies

Figure 3. Antipsychotics and affective symptoms. (a) Unlike conventional antipsychotics which bind primarily to dopamine D2 receptors, atypical antipsychotics 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 cognitive symptoms. (d) Additional antagonism of serotonin 5HT2A receptors by atypical antipsychotics may help ameliorate some of the symptoms caused by hypodopaminergia in the cortex.

[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 schizophrenia 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 afnities of available SGAs for various receptors that may modulate affective symptoms are listed in Fig. 4. It has been hypothesized that, in depression, dopamine neurotransmission is reduced, resulting in decient tonic
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activity at dopamine D3 receptors and decient phasic activity at dopamine D2 receptors. Partial agonism of D2/D3 receptors may reset the tonic and phasic dopamine neurotransmission, resulting in antidepressant effects [4]. Aripiprazole, 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 antimanic 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 another proposed mechanism for antidepressant activities of antipsychotics. Both ziprasidone and quetiapine (via its active metabolite norquetiapine) may exert antidepressant effects in part through this mechanism of enhanced norepinephrine neurotransmission [4,32,33]. Ziprasidone has the additional property of serotonin reuptake inhibition (SRI) which may also contribute antidepressant effects by increasing serotonergic neurotransmission [33]. Antagonism at serotonin 5HT2C receptors, a property shared by many SGAs, may also have an antidepressant effect

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Drug Discovery Today: Therapeutic Strategies | Treatment of schizophrenia

Drug

D2 Antag

D2 PA

D3

5HT1A PA

5HT2A Antag

5HT2C

5HT7

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 <1nM. Note that a higher Ki is indicative of a lower binding affinity. *Represents the binding affinity of norquetiapine, the active metabolite of quetiapine.
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Figure 4. Receptor binding proles of atypical antipsychotics. Binding of atypical antipsychotics to various receptors including dopamine D3, serotonin 5HT1A, 5HT2A, 5HT7, adrenergic alpha 2 may endow some atypical antipsychotics with antidepressive properties. Additionally, both quetiapine and ziprasidone may have antidepressant properties due to their actions as norepinephrine and serotonin reuptake inhibitors (NRI and SRI, respectively).

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 combination with the SSRI uoxetine, improves depressive symptoms of bipolar depression and ziprasidone has shown efcacy in the treatment of dysphoric mania [34,35]. Norquetiapine also has binding afnity for 5HT2C which, in combination with its 5HT1A partial agonism and NRI activities, may contribute to the antidepressant properties of quetiapine [33]. Similar to antagonism of 5HT2C receptors, agonism of serotonin 5HT1A receptors leads to disinhibition of noradrenergic 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 antidepressant effects by increasing serotonergic neurotransmission in the PFC; antagonism of 5HT7 receptors in the raphe nuclei leads to disinhibition of serotonergic neurons. Several SGAs have binding afnity for 5HT7 receptors, most notably two of the newly approved SGAs, lurasidone and asenapine. One recent study reported no benets from asenapine on depressive symptoms in bipolar disorder [37]; however, more data are needed before any conclusions can be made as to the efcacy of both asenapine and lurasidone in the treatment of

depressive symptoms in schizophrenia [38]. Aripiprazole also has 5HT7 antagonistic properties, as well binding afnity 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 is postulated to have antidepressant effects by increasing norepinephrine 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 afnity 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
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been shown to improve depressive symptoms in schizophrenia and reduce suicidal ideation in patients with schizophrenia [9,27]. Adjunctive treatment with an antidepressant in patients with schizophrenia may also be useful for ameliorating more than just affective symptoms in schizophrenia; augmentation of antipsychotic treatment with the antidepressant mirtazapine has been shown to improve both negative 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 uvoxamine to antipsychotic treatment has also been shown to be benecial for treatment-resistant negative symptoms, possibly due in part to its upregulation of 5HT2A receptor expression [45]. The norepinephrine and dopamine reuptake inhibitor bupropion has also been evidenced to decrease both affective and negative symptoms in schizophrenia although there are concerns 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].

at Chapel Hill and Project Ofcer Jamie Driscol at NIMH, Bethesda MD, USA. For experimental details please refer to the PDSP web site http://pdsp.med.unc.edu/.

References
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Mood stabilizers
Although mood stabilizers, including lithium, valproate, and lamotrigine, are commonly prescribed as adjuncts to antipsychotic medication in schizophrenia, there is little evidence or regulatory approval for their use [4851]. However, on an individual patient basis, these mood stabilizers may provide some benet for affective symptoms. Some of the mechanisms of action of mood stabilizers hypothesized to benet patients with schizophrenia include alteration of GABAergic, glutamatergic and dopaminergic neurotransmission 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 proles that give these agents antidepressive qualities and may be useful in treating patients with schizophrenia who have prominent mood symptoms.

Acknowledgements
Ki determinations and receptor binding proles were generously provided by the National Institute of Mental Healths Psychoactive Drug Screening Program, Contract # HHSN271-2008-00025-C (NIMH PDSP). The NIMH PDSP is directed by Bryan L. Roth MD, PhD at the University of North Carolina
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