Jeffrey A Lieberman2

1 Duke University School of Medicine and Durham VAMC, Durham, NC 27705, USA -UNC-Chape! Hill School of Medicine, Chapel Hill, NC 27599, USA 3Vanderbilt University School of Medicine, Psychiatric Hospital at Vanderbilt, Suite 313, 1601 23rd Avenue South, Nashville, TN 37218, USA

Abstract: Both preclinical and clinical evidence suggest that atypical antipsychotics may modulate the stress response in a manner that is distinct from conventional agents. For example, atypical antipsychotics have anxiolytic-like actions in a number of animal models. The mechanisms underlying these anxiolytic effects are not clear, but it is possible that antipsychotic-induced alterations in GABAergic neurosteroids play a role. Atypical antipsychotics also demonstrate unique effects in prefrontal cortex stress paradigms focusing on dopamine alterations. Data that mild stress also increases extracellular GABA levels in prefrontal cortex but not striatum, with no concurrent effects on glycine levels is presented. Neurosteroids may be relevant to these prefrontal cortex investigations. The authors review the emerging stress-modulatory profile of atypical antipsychotics and discuss potential ramifications of these findings for the therapeutic efficacy of these compounds. In addition to their well-established roles in the treatment of schizophrenia core symptoms, atypical antipsychotics also have utility in the treatment of depression- and anxiety-spectrum symptoms that frequently accompany the illness. Atypical antipsychotics also appear to have efficacy in the treatment of stresssensitive anxiety disorders such as post-traumatic stress disorder (PTSD) and obsessive-compulsive disorder (OCD), underscoring the possibility that these agents may have stress-modulatory actions that are clinically therapeutic. As the knowledge of the stress-modulatory actions of atypical antipsychotics evolves, it may be possible to target these properties in the development of novel agents in the treatment of schizophrenia and other psychiatric disorders.

Introduction

Increasing preclinical and clinical evidence suggests that atypical antipsychotics may modulate the stress response. Atypical antipsychotics (sometimes also referred to as second generation antipsychotics) approved for use in the United States include clozapine (Clozaril), olanzapine (Zyprexa), risperidone (Risperidal), quetiapine (Seroquel), ziprasidone (Geodon), and aripiprazole (Abilify). A number of rodent studies at the behavioral, cellular, and molecular levels have demonstrated that atypical antipsychotics have effects on biological markers of the stress response that may be specific to these second

»Corresponding author. Tel.: + 1919-843-3794; Fax: + 1919-966-9064; Email: grobinacitmed.unc.edu generation agents and distinguish them from conventional antipsychotics such as haloperidol (also referred to as typical, classical, or first-generation antipsychotics). In addition to these findings in animal models, preliminary evidence suggests that atypical antipsychotics may also modulate stress in a manner that is distinct from conventional agents in clinical populations. We will review this emerging unique stress-modulatory profile of atypical antipsychotics and discuss potential ramifications of recent data for the therapeutic efficacy of these compounds.

In addition to their well-established roles in the treatment of schizophrenia core symptoms, atypical antipsychotics also have utility in the treatment of depression- and anxiety-spectrum symptoms that frequently accompany the illness. Atypical antipsychotics also appear to have efficacy in the treatment of stress-sensitive anxiety disorders, including post-traumatic stress disorder (PTSD), and obsessive-compulsive disorder (OCD). These potential indications for atypical antipsychotics are also reviewed. As the knowledge of the stress-modulatory role of atypical antipsychotics evolves, it may be possible to target these properties in the development of novel agents in the treatment of schizophrenia and other psychiatric disorders.

Atypical antipsychotics and stress: preclinical investigations

Modulation of stress-related behaviors

Atypical antipsychotics appear to have specific modulatory effects on stress-related behaviors. For example, certain atypical antipsychotics have pronounced anxiolytic-like elfects in animal behavioral models, in contrast to conventional antipsychotics (Arnt and Skarsfeldt, 1998). Specifically, both clozapine and olanzapine increase punished responding in a conflict schedule anxiety model, but haloperidol has no significant effects (Wiley et al, 1993; Moore et al, 1994). These atypical antipsychotics also dose-dependently inhibit the acquisition of conditioned freezing (Inoue et al, 1996). Olanzapine increases exploration of the open arms in the elevated plus-maze and decreases the duration of freezing following a shock stimulus (Frye and Seliga, 2003). Clozapine (but not haloperidol) also appears to have anxiolytic-like effects in a separation-induced vocalization model of anxiety in 9-11 day old rat pups (Kehne et al, 2000). The mechanisms underlying these anxiolytic effects are not clear, but initial evidence suggests that antipsychotic-induced neurosteroid elevations may play a role. For example, the GABAergic neurosteroid allopregnanolone may mediate the anxiolytic effects of olanzapine (Frye and Seliga 2003).

Neurosteroids

Neurosteroids are steroids synthesized de novo in the brain from cholesterol or peripheral steroid precursors. Many neurosteroids are also neuroactive and rapidly alter neuronal excitability by acting at membrane-bound ligand-gated ion channel receptors (Paul and Purdy, 1992). The neurosteroid allopregnanolone, for example, is a potent positive allosteric modulator of GABAa receptors (Majewska et al, 1986; Morrow et al, 1987) and demonstrates marked anxiolytic effects (Crawley et al, 1986; Bitran et al, 1991). Both olanzapine (Marx et al, 2000, 2003) and clozapine (Barbaccia et al, 2001; Marx et al, 2003) dose-dependently elevate allopregnanolone in rodent brain, but haloperidol has no effect on this neurosteroid. Neurosteroid induction may therefore contribute to the anxiolytic effects of these atypical antipsychotics and represent a mechanism by which these compounds alter GABAergic neurotransmission in schizophrenia. Converging evidence suggests that the GABA neurotransmitter system is altered in schizophrenia (Akbarian et al, 1995; Lewis 2000; Benes and Berretta 2001), and GABAergic agents such as benzodiazepines (Carpenter et al, 1999) and divalproex (Casey et al, 2003) may be useful therapeutic adjuncts. Atypical antipsychotic-induced alterations in GABAergic neurosteroids such as allopregnanolone may therefore interact with this pathophysiologic component of the disorder and contribute to antipsychotic efficacy. Furthermore, allopregnanolone increases following a number of stressors (Purdy et al, 1991; Barbaccia et al, 1998) and has pronounced effects on the HPA axis. For example, allopregnanolone decreases corticotropin-releasing factor (CRF), adrenocorticotropin hormone (ACTH), and corticosterone release (Patchev et al, 1994, 1996; Guo et al, 1995), and may therefore contribute to a return to homeostasis following a stressful event. Allopregnanolone also ameliorates prenatal stress effects (Zimmerberg and Blaskey, 1998), and the GABAergic neurosteroid THDOC prevents the neuroendocrine and behavioral consequences of maternal deprivation stress (Patchev et al, 1997). Antipsychotic-induced elevations in neurosteroids may therefore be relevant to stress modulation and treatment response in schizophrenia.

A number of other investigations suggest that atypical antipsychotics modulate stress responses. For example, the ability of clozapine to modulate the response to stress has been studied in numerous paradigms and several species. Specifically, clozapine reduces stress-induced gastric mucosal lesions in rodents (Glavin and Hall, 1994). Cardiovascular signs of stress (increased heart rate and blood pressure) are also attenuated in rodents pretreated with clozapine (van den Buuse, 2003). In addition to ameliorating physiological symptoms of stress, clozapine administration reverses stress-induced cognitive deficits in nonhuman primates (Murphy et al, 1997). Acute administration of the atypical antipsychotics clozapine and risperidone reduces cardiovascular stress responses, in contrast to haloperidol (van den Buuse, 2003). The atypical antipsychotic quetiapine also appears to have stress-ameliorating actions. For example, recent efforts have demonstrated that quetiapine attenuates stress-induced decreases in brain-derived neurotophic factor protein levels (Xu et al, 2002).

Ex-vivo studies distinguish atypical from typical antipsychotics

Additional ex-vivo studies of tissue generated by stress paradigms have extended behavioral investigations of atypical antipsychotics and explored potential mechanisms by which atypical antipsychotics are distinct from conventional antipsychotics. Stress-induced activation of limbic forebrain areas serves as a useful model for comparing the pharmacology of typical and atypical antipsychotics (Bubser and Deutch, 1999). Furthermore, because a mild stressor selectively activates frontal cortical regions of brain, measuring the modulation of these stress effects by antipsychotics may be particularly relevant to schizophrenia, since accumulating evidence implicates this brain region in the pathophysiology of the disorder (Bunney and Bunney, 2000; Lewis and Gonzalez-Burgos, 2000; Weinberger et al, 2001). Chronic clozapine (but not haloperidol) alters the stress-induced increase in dopamine turnover in rodent prefrontal cortex (Morrow et al, 1999). The selective effects of clozapine in frontal cortex in this stress paradigm suggests that distinct prefrontal cortical dopamine innervations can be functionally dissociated on the basis of responsiveness to stress (Deutch, 1993). Such functional distinction may be helpful in identifying chemical entities representing candidate "third generation" antipsychotics. Also supporting this possibility, recent evidence suggests that chronic olanzapine administration prevents footshock-induced elevations in prefrontal cortical extracellular dopamine concentrations in rats (Dazzi et al, 2001). This effect may be mediated by olan-zapine-induced allopregnanolone elevations, since intraventricular neurosteroid administration also decreases stress-induced cortical dopamine release (Grobin et al, 1992; Motzo et al, 1996). Evidence that the depletion of cortical allopregnanolone potentiates stress-induced increases in cortical dopamine output supports this hypothesis (Dazzi et al, 2002). Thus, in both ex-vivo and behavioral analyses of the effects of stress, comparing atypical and conventional antipsychotics has advanced the understanding of the mechanism of action and specificity of atypical antipsychotic agents.

Stress increases GABA levels in prefrontal cortex

In prefrontal cortex (PFC), many neurotransmitter systems have been studied with regard to their responses to stress. GABAa receptor modulators are arguably among the most efficacious blockers of stress-induced activation of PFC (Tam and Roth, 1985; Deutch et al, 1991). Given this potent effect, it is possible that GABAergic systems participate in the PFC response to stress. Most attempts to characterize the GABAergic response to stress have focused on understanding changes in the GABAa receptor complex (Biggio et al, 1987; Drugan et al, 1993; Wilson and Biscardi, 1994). Surprisingly, few studies examining stressor-related events have focused directly on GABA. Similar to dopaminergic investigations, however, available GABA studies also demonstrate that the PFC is exquisitely sensitive to stress and selectively activated by mild stress that does not activate the striatum or nucleus accumbens (Acosta et al, 1993; Acosta and Rubio, 1994). Therefore, extracellular GABA levels in the medial PFC of rat during a 20-min exposure to mild footshock stress was measured. Microdialysis experiments were conducted as previously described (Grobin and Deutch, 1998) in accordance with institutional animal care guidelines.

Mild foot shook stress produced a significant and sustained increase in extracellular GABA levels in PFC (see Fig. 1). PFC glycine levels remained unchanged under the same conditions, as did extracellular levels of GABA and glycine in striatum (Fig. la and b). These data indicate that exposure to a mild stressor enhances GABA release in the PFC but not the striatum. The increase in GABA levels does not appear to reflect a nonspecific increase in neuronal metabolism, since glycine levels did not change during or after stress exposure. Furthermore, striatal GABA levels tended to decline following the stressor, indicating that a global change in brain metabolism is not occurring.

Increased extracellular GABA levels in the PFC may be part of the execution of a coping mechanism aimed at reducing or eliminating the effects of stress. This hypothesized adaptive mechanism is consistent with converging data documenting the presence of endogenous anxiolytic systems involving GABAergic neurotransmission that are altered in a specific manner during stress. For example, GABAergic a a>

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Time {mill)

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Time {mill)

Fig. 1. Stress increases extracellular GABA levels in cortex, (a) Extracellular GABA and glycine levels in prefrontal cortex of rat before and after 20min of mild footshook stress. Bar indicates duration of stress. Data are presented as the mean (=t SEM) change from baseline, « = 7-9. *p < 0.05 relative to baseline at time = 0. (b) Extracellular GABA and glycine levels in striatum of rat before and after 20min of mild footshook stress. Bar indicates duration of stress. Data are presented as the mean (± SEM) change from baseline, n = 3-7.

neurosteroids that can be synthesized in brain are markedly increased in brain and plasma following a number of different stressors (Purdy et al., 1991), as described previously. Similarly, stress alters GABA-elicited CI" flux (Havoundjian et al., 1986). The present data offer the first demonstration that extracellular GABA levels are directly increased by stress exposure, and thus suggest that both presynaptic changes from GABA neurons and postsynaptic changes in the GABAa receptor complex may function cooperatively, perhaps as components of an endogenous anxiolytic system.

Neurosteroids may mediate some of the anxiolytic actions of atypical antipsychotics

If the efficacy of atypical antipsychotics is achieved in part by modulating endogenous anxiolytic systems, one might expect atypical antipsychotics to increase GABAergic tone. However, clozapine markedly decreases extracellular GABA levels in rodent PFC and chronic exposure to clozapine and olanzapine reduces cortical GABAa receptor density (Giardino et al., 1991; Bourdelais and Deutch 1994; Farnbach-Pralong et al., 1998). A functional increase in GABAergic tone may be achieved via an increase in endogenous modulators of GABAa receptors, however, such as neurosteroids. Accordingly, the atypical antipsychotics clozapine and olanzapine increase GABAergic neurosteroid levels in rat cortex, as previously discussed (Marx et al., 2000, 2003; Barbaccia et al., 2001). Since stress also increases cortical neurosteroid levels, a stressful event may therefore lead to even further enhancement of brain neurosteroid levels in the presence of certain atypical antipsychotics. Since the neurosteroid allopregnano-lone has a negative effect on the HPA axis, this represents a potential stress-modulatory mechanism by which treatment with atypical antipsychotics may facilitate an adaptive stress response and result in the amelioration of negative stress effects.

Specificity at the cellular or subcellular level may be indirectly achieved if a global decrease in GABA levels and GABAa receptors observed following the administration of atypical antipsychotics is accompanied by a shift in the population of GABAa receptors that are sensitive to neurosteroids.

Stress alters GABAa receptor subunit expression (Orchinik et al, 1995), and subunit composition determines the pharmacological profile of GABAa receptor modulators. For example, neurosteroid activity at GABAa receptors is determined by subunit composition (Vicini et al, 2002). If the anxiolytic actions of GABAergic neurosteroids are integral to an adaptive stress response, atypical anti-psychotic-induced neurosteroid alterations may result in the selective modulation of specific subsets of GABAa receptors that are sensitive to neurosteroids. This area of investigation remains to be explored.

Overall, preclinical investigations into atypical antipsychotic effects on stress responses suggest that these agents have specific stress-modulatory actions that merit further investigation in both animal models and clinical populations.

Atypical antipsychotics and stress: clinical investigations

Overview: schizophrenia and the HP A axis

With regard to the HPA axis in schizophrenia, investigations to date have produced somewhat inconsistent results (Marx and Lieberman, 1998). A number of investigators have demonstrated that Cortisol levels are significantly elevated in patients with schizophrenia at baseline compared to control subjects (Walker and Diforio, 1997; Meltzer et al, 2001; Ryan et al, 2003), although other studies have not reported this finding. Patients with schizophrenia appear to have higher rates of dexamethasone nonsuppression (Marx et al, 1998), and antipsychotic treatment may be associated with normalization of the dexamethasone suppression test (Wik et al, 1986; Tandon et al, 1991). Several researchers have reported blunted Cortisol responses in patients with schizophrenia following a number of different stressors, including lumbar puncture (Breier et al, 1986), surgical stress (Kudoh et al, 1997), and public speaking (Jansen et al, 2000). No blunting of the Cortisol response was found in schizophrenia patients following physical exercise stress (Jansen et al, 2000) or 2-deoxyglucose metabolic stress (Breier and Buchanan, 1992; Elman et al, 1998), however, suggesting that various stressors may elicit unique HPA axis responses in these patients. Cortisol response to the dopamine agonist apomorphine was significantly reduced in patients with schizophrenia compared to control subjects, and this parameter appeared to be relevant to treatment response (Meltzer et al, 2001). In this study, patients who responded to clozapine had significantly higher Cortisol responses to apomorphine compared to nonresponders, suggesting an interaction of the HPA axis with treatment outcome (Meltzer et al, 2001). A recent study also demonstrated that patients with schizophrenia have a blunted response to apomorphine compared to healthy control subjects (Duval et al, 2003). Overall, the above evidence suggests that the HPA axis is altered in patients with schizophrenia, but additional research is required to characterize these alterations and the mechanisms leading to stress dysregulation more definitively.

In some studies, treatment with antipsychotics resulted in lower Cortisol levels in patients with schizophrenia (Wik, 1995), and patients switched from typical antipsychotics to clozapine demonstrated significantly lower Cortisol levels (Hatzimanolis et al, 1998; Markianos et al, 1999). Another study determined that patients treated with clozapine had significantly lower Cortisol levels compared to patients treated with conventional antipsychotics (Meltzer, 1989), but a later study in stable outpatients with schizophrenia found no changes in Cortisol following treatment with clozapine (Breier et al, 1994). The reason for the discrepancy in findings was hypothesized to be secondary to the absence of an antipsychotic washout period in the latter study, which would be expected to result in increased arousal and stress (Breier et al, 1994). Stable outpatients with no drug washout period might, thus, have been less likely to experience stress-reducing clozapine effects (Breier et al, 1994). Clozapine treatment resulted in the attenuation of the Cortisol response to the serotonergic probes d-fenfluramine (Curtis et al, 1995) and m-chlorophenylpiperazine (Owen et al, 1993). Since serotonin-2 (5HT2) antagonism is hypothesized to have antipsychotic activity and 5HT2a/c receptors can modulate prefrontal cortical GABA levels (Abi-Saab et al, 1998), serotonergic effects of atypical antipsychotics may also regulate stress effects via GABA level regulation. Treatment with olanzapine for six weeks also appears to decrease Cortisol levels (Scheepers et al, 2001). It remains to be elucidated if atypical antipsychotic-induced decreases in Cortisol levels following chronic treatment contribute to therapeutic efficacy, but these antipsychotic actions on the HPA axis may represent a stress-modulatory mechanism with clinical relevance.

Atypical antipsychotics and relapse prevention in schizophrenia

Stress is known to exacerbate schizophrenia symptomatology and may lead to clinical decompensation and relapse (Gispen-de Wied, 2000). Atypical antipsychotics appear to decrease relapse risk (to a somewhat greater degree than conventional antipsychotics), raising the possibility that these agents modulate the stress response in a manner that is clinically therapeutic (Leucht et al, 2003). Although many factors are likely to contribute to a relapse in symptoms among patients with schizophrenia, medication noncompliance is among the most common. It is, therefore, possible that atypical antipsychotics have positive modulatory effects on the stress response in schizophrenia, potentially increasing resilience following stress exposure and decreasing vulnerability to relapse during stressful events. This possibility is consistent with a number of studies using animal models of stress discussed previously and will require further investigation.

Atypical antipsychotic effects on anxiety, depression, and suicidality in schizophrenia

Patients with schizophrenia frequently demonstrate significant comborbid depression and anxiety symptoms, and atypical antipsychotics appear to be effective for this group of symptoms (Keck et al, 2000). Clozapine appears to have antidepressant effects, reducing suicidality, depression, and hopelessness (Meltzer and Okayli, 1995; Meltzer et al, 2003; Potkin et al, 2003) and decreasing anxiety-depression symptoms (Breier and Hamilton, 1999; Kane et al, 2001) in patients with schizophrenia. Olanzapine also demonstrates antidepressant effects in patients with schizophrenia (Tollefson et al, 1997, 1998). In addition, olanzapine significantly decreased

Montgomery-Asberg depression rating scale (MADRS) depression scores compared to haloper-idol (Lieberman et al, 2003), decreased the anxiety-depression cluster of the Brief Psychiatric Rating Scale compared to haloperidol (Tollefson and Sanger, 1999), and decreased anxiety scores in a 6-month open label trial (Littrell et al, 2003). Decreases in depressive symptoms have also been observed in psychotic patients following treatment with quetiapine (Sajatovic et al, 2002), and decreases in anxiety-depression (Conley and Mahmoud 2001), and anxiety and hostility (Glick et al, 2001) have been demonstrated following treatment with risperidone. Together these studies suggest that atypical antipsychotics have distinct antidepressant and anxiolytic actions in patients with schizophrenia.

Atypical antipsychotics and stress-sensitive anxiety disorders: PTSD, OCD, and social anxiety disorder

Recent data suggest that atypical antipsychotics may also be helpful in the treatment of stress-sensitive anxiety disorders, including PTSD, OCD, and social anxiety disorder. Since atypical antipsychotics exhibit anxiolytic-like effects in animal models and initial evidence suggests that they also ameliorate anxiety symptoms in patients with schizophrenia, their potential use in anxiety disorders warrants investigation.

Posttraumatic stress disorder (PTSD)

Posttraumatic stress disorder is a chronic disabling anxiety disorder that is caused by one or more traumatic events resulting in symptoms that cause clinically significant distress or impairment in personal, social, and occupational functioning. By definition, PTSD is precipitated by a severe stressor (or stressors), and appears to involve a dysregulation in the stress response resulting in severe symptoms that include reexperiencing, avoidance/numbing, and increased arousal symptom clusters. Increasing evidence suggests that atypical antipsychotics demonstrate efficacy in the treatment of this disorder, underscoring the possibility that these agents may have stress-modulatory actions. In addition, atypical antipsychotics likely have utility in treating psychotic symptoms in PTSD. Psychotic symptoms are surprisingly common in patients with PTSD and are likely underdiagnosed, present in 30-40% of patients with the disorder (David et al, 1999; Hamner et al., 1999, 2000). They correlate with overall PTSD symptom severity, and include auditory and visual hallucinations and delusions that tend to be paranoid in nature (Hamner et al., 1999, 2000). Psychotic symptoms in PTSD may be associated with depressive symptoms (David et al., 1999; Hamner et al., 1999), but do not appear to correlate with reexperiencing symptoms of PTSD or with alcohol history (Hamner et al., 1999), nor with a family history of psychotic disorder (Sautter et al, 2002).

To date, three placebo-controlled double-blind augmentation trials utilizing atypical antipsychotics have reported efficacy in PTSD. Olanzapine augmentation reduced PTSD symptoms, sleep disturbance, and depressive symptoms in combat veterans with chronic illness (Stein et al., 2002). Risperidone improved psychotic symptoms in combat veterans with PTSD (with comorbid psychotic features), as assessed by the PANSS (Hamner et al., 2003). Risperidone was also effective in reducing irritability and intrusive thoughts in combat-related PTSD in another augmentation study (Monnelly et al., 2003). In addition, one open label augmentation trial with quetiapine resulted in improvements in PTSD symptoms, PANSS scores and depressive symptoms (Hamner et al., 2003). Data are more limited with regard to the use of atypical antipsychotics as monotherapy in PTSD. One open label trial demonstrated that olanzapine reduced PTSD, depression, and anxiety symptoms (Petty et al., 2001), but a small double-blind placebo-controlled pilot study of olanzapine in the treatment of PTSD (seven patients treated with olanzapine and four patients treated with placebo completing the study) did not demonstrate greater olanzapine efficacy compared to placebo (Butterfield et al., 2001). Larger placebo-controlled double-blind trials will be required to determine the specific role of atypical antipsychotics in the treatment of PTSD, but overall initial findings are promising.

Patients with PTSD have very high rates of comorbidity with other psychiatic disorders, including depression (Kessler et al., 1995; Brady et al., 2000). Given increasing evidence suggesting that atypical antipsychotics have antidepressant effects, these agents may be particularly helpful in the treatment of PTSD. In addition, the rate of comorbid PTSD in patients with schizophrenia is high, ranging between 29-43% in six studies published to date, with fewer than 5% of identified cases having a diagnosis of PTSD documented in their medical charts (Mueser et al., 2002). Given this high degree of PTSD comorbidity in schizophrenia, atypical antipsychotics that are potentially efficacious in the treatment of PTSD symptoms may function to decrease overall symptom load in a significant number of patients with schizophrenia. Information regarding the course of comorbid PTSD in patients with schizophrenia is currently unavailable and merits further exploration.

Obsessive-compulsive disorder (OCD)

Obsessive-compulsive disorder is an anxiety disorder that appears to have some degree of comorbidity in a subset of patients with schizophrenia (Adler and Strakowski, 2003). Initial evidence suggests that atypical antipsychotics may be efficacious adjuncts in this disorder, especially in patients with OCD symptoms refractory to SSRIs. A double-blind placebo-controlled study of risperidone augmentation in patients with refractory OCD on an SSRI decreased OCD, depressive, and anxiety symptoms in this cohort (McDougle et al., 2000). A single-blind placebo-controlled study of quetiapine augmentation also demonstrated beneficial effects on OCD symptoms (Atmaca et al., 2002). Open label augmentation strategies utilizing quetiapine (Denys et al., 2002; Mohr et al., 2002), olanzapine (Weiss et al., 1999; Bogetto et al., 2000; Koran et al., 2000; Francobandiera 2001; D'Amico et al., 2003), and risperidone (Ravizza et al., 1996; Pfanner et al., 2000) in SSRI-refractory OCD have also yielded positive results. In contrast, a small open label study using clozapine as monotherapy did not demonstrate efficacy in OCD (McDougle et al., 1995). Larger, placebo-controlled, double-blind studies will be necessary to explore the role of atypical antipsychotics in OCD, but available evidence suggests that augmentation with atypical antipsychotics is efficacious, particularly for patients with SSRI-refractory OCD.

Social anxiety disorder

A small study examining the effects of olanzapine in social anxiety disorder demonstrated that olanzapine yielded greater improvements than placebo on primary measures (Barnett et al, 2002). This potential indication for atypical antipsychotics is under further study.

Other possible indications for atypical antipsychotics

A small literature suggests that atypical antipsychotics may have utility for a number of additional indications. Although evidence is currently limited, preliminary studies suggest that atypical antipsychotics may be useful in a number of clinical situations involving anxiety and stress. For example, the atypical antipsychotic ziprasidone appears to have anxiolytic effects that were comparable to diazepam (but without the sedative effects of diazepam) in nonpsychotic subjects who were anxious prior to minor dental surgery (Wilner et al, 2002). Olanzapine also appears to decrease anxiety symptoms in patients with Alzheimer's disease (Mintzer et al, 2001). Risperidone demonstrated efficacy for acute stress symptoms in adult burn patients (Stanovic et al, 2001). Although more extensive studies are needed to clearly delineate a potential role for atypical antipsychotics in these settings, initial findings suggest these agents may be efficacious.

Conclusions and future directions

Investigations of atypical antipsychotics and stress have yielded a number of promising preclinical and clinical findings that may have relevance to stress modulation in schizophrenia and lead to new targets for pharmacological treatment strategies. There appears to be a definite role for atypical antipsychotics in the treatment of depression and anxiety symptom clusters in schizophrenia. Increasing evidence also suggests that atypical antipsychotics may have clinical utility in PTSD and other stress-sensitive anxiety disorders. Together these research areas represent promising future avenues of investigation.

Abbreviations

ACTH adrenocorticotropin hormone

CRF corticotropin-releasing factor

HPA hypothalamic pituitary-adrenal

OCD obsessive-compulsive disorder

MADRS Montgomery-Asberg depression rating scale

PANSS positive and negative symptom scale

PFC prefrontal cortex

PTSD post-traumatic stress disorder

SSRI selective serotonin reuptake inhibitor

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