Stress in schizophrenia: an integrative view

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<ul><li><p> .European Journal of Pharmacology 405 2000 375384www.elsevier.nlrlocaterejphar</p><p>Stress in schizophrenia: an integrative viewChristine C. Gispen-de Wied)</p><p>( )Rudolf Magnus Institute for Neuroscience, Department of Psychiatry A01.126 , Uniersity Medical Center, PO Box 85500, 3508 GA Utrecht, NetherlandsAccepted 28 June 2000</p><p>Abstract</p><p> .Stress and the development of a schizophrenic psychosis are inextricably related. The process by which stress actually affectspsychosis is far less clear. The hypothalamicpituitaryadrenal system, and in particular the release of corticosteroids, has been attributedan essential role. However, schizophrenia is a disorder in which many functions are distorted. Dysfunctions can be found in behavior,cognition, coping, physiology, pituitaryadrenal and immune functioning. In this short paper, these functions are discussed as to how theycontribute to the way stress is appraised and processed. Schizophrenic patients are impaired in their biological response to stress byshowing a blunted cortisol response to psychosocial stress. It is hypothesized that this reflects rather cognitive dysfunction, based onbiological dysfunctions in those brain structures that are responsible for these processes, i.e. the prefrontal cortex and the limbic system.Considering the blunted cortisol response as a maladaptive stress response, its consequences are commented on with an emphasis on theimmune system. Finally, the role of neuroleptics, and in particular the atypical ones, is discussed for their beneficial effect, beyond theirfear-and anxiety-reducing properties, in restoring some of the cognitive dysfunctions schizophrenic patients display. By doing so, theymay improve perception of the environment, enhance adjustment and thus a proper stress response. Integration of these processes in stressresearch described, may provide new vistas of the stress concept in schizophrenia. q 2000 Elsevier Science B.V. All rights reserved.</p><p>Keywords: Schizophrenia; Stress; Cognition; Coping; Hypothalamicpituitaryadrenal system; Immune system</p><p>Aif stress is learning, learning is stressBDavid de Wied, personal communication</p><p>Athen this is what I learned from him, writing thispaperB</p><p>1. Introduction</p><p>The involvement of stress in the development of psychi-atric disorders, such as depression, post-traumatic stress</p><p> .disorder PTSD and schizophrenia, is generally acceptedNemeroff, 1998; Heim et al., 2000; Walker and Difioro,</p><p>.1997 . However, the mechanism by which stress actuallyaffects these disorders is far less clear. Moreover, thedefinition of stress that is being used in the literature israther diverse and ranges from describing the stress stimu-</p><p>) Tel.: q31-30-2508459; fax: q31-30-2505443.E-mail address: c.gispendewied@psych.azu.nl C.C. Gispen-de</p><p>.Wied .</p><p>lus, the feelings of discomfort that may arise from it or thebehavioral, physiological, endocrine or immune responses</p><p> .that are elicited by it. Cannon 1929 was the first tointroduce the terms Afight, fright or flightB and Ahomeosta-sisB to indicate that the stress response comprises a cas-cade of events, i.e. actiation and adaptation. The adrenalswere already attributed an essential role in this process forproviding both the catecholamines to activate the organismto actively address the stressor and the corticosteroids tocounteract the primary stress reactions and let the organ-</p><p> .ism return to homeostasis Cannon, 1929, 1935 . Seley .1936 then described the general adaptation syndromeand extended the view on the role of the adrenal steroids,stating that the adaptive stress response was a nonspecificeffect of any demand upon the body. Later, this conceptwas modified in the sense that he made clear that the typeof stress imposed was able to determine the type of</p><p> .response that it would elicit Seley, 1956 . Until now,these concepts still hold in stress research, although a moredynamic approach to the term homeostasis, i.e. allostasis,</p><p> .has been proposed by McEwen 1998 to emphasize the</p><p>0014-2999r00r$ - see front matter q 2000 Elsevier Science B.V. All rights reserved. .PII: S0014-2999 00 00567-7</p></li><li><p>( )C.C. Gispen-de WiedrEuropean Journal of Pharmacology 405 2000 375384376</p><p>plasticity of the endocrine adaptive system throughout lifeand its consequences for developing disease. However, inthe recent literature, stress is predominantly described interms of changes in hypothalamicpituitaryadrenal func-tion, whereas both the psychological aspects of stressprocessing and the involvement of the autonomic nervous</p><p> .system ANS are often neglected or studied separately.Therefore, the role of cortisol, as the sole stress hormone,</p><p>may have been somewhat overestimated for review, see.Heim et al., 2000 .</p><p>In general, when a stimulus is appraised as stressful bythe individual, a process that is predominantly determinedby the novelty and controllability of the stimulus itself .Huether, 1996 , the ability to adequately cope with thestressor will determine, whether, and to what extent, abiological stress response will occur. An example of thestress response to a psychosocial stressor, i.e. a publicspeaking task, is given in Fig. 1. Coping is regarded as thepsychological component in this process and comprisesbehavioral, cognitive and emotional responses in order tomaster a threatening situation and to reduce the impact of</p><p> .the stressor Folkman and Lazarus, 1985 . The higherbrain areas that are involved in interpretation of the stres-sor and activation of the biological stress response arethought to be predominantly the prefrontal cortex and thelimbic system, i.e. the amygdalahippocampus complex.Through the prefrontal cortex, the limbic system is acti-vated to arouse the stress-induced emotions of fear andanxiety. Probably the release of corticotropin releasing</p><p> .hormone CRH directs both the activation of the ANS aswell as the hypothalamicpituitaryadrenal axis Huether,</p><p>.1996 . If a stress stimulus is not adequately responded to,for instance when the hypothalamicpituitaryadrenal sys-tem is hyper- or hyporesponsive or not able to habituate,</p><p> .stress may enhance disease susceptibility McEwen, 1998 .This may be reflected in the hypercortisolemia that can be</p><p>Fig. 1. The net effect of public speaking as psychosocial stress on heart .rate and salivary cortisol secretion in healthy adult subjects 22?r29Y .</p><p>Delta values are calculated by subtracting control day values from testday values, expressed as mean"SE.</p><p>found in chronic depression or the hypocortisolemia thatcan be found in PTSD. In schizophrenia, such dysfunctionsin the hypothalamicpituitaryadrenal system are less ob-vious.</p><p>Schizophrenia is a disorder in which many functions aredistorted. Dysfunctions can be found in behavior, cogni-tion, coping capability, physiology, hypothalamicpitui-taryadrenal and immune functioning. Typical antipsy-chotics, beyond their fear-and anxiety-reducing properties,restore most of the psychotic symptoms, such as delusionsand hallucinations, but usually leave the negative symp-toms, such as lack of drive or emotional withdrawal,</p><p> .unaffected Wolkowitz end Pickar, 1991 . The advantageof the atypical antipsychotics may be considered theirbeneficial effect just on these negative symptoms. Pharma-cologically, the advantage of atypical antipsychotics hasbeen ascribed to the fact that they not only interfere withdopamine, but have strong serotonin-blocking properties aswell. With respect to stress, little attention has been givento the beneficial effect of antipsychotics on the differentfunctional systems that contribute to the stress response.The present article, therefore, tries to highlight the variousfunctional systems that underlie the mechanism of stressprocessing in schizophrenia and to discuss the beneficialeffect of antipsychotic treatment upon them in order toobtain a more integrated view on stress and adaptation inschizophrenia.</p><p>2. Stress in schizophrenia</p><p>In schizophrenia, stress has been predominately de-scribed in terms of the impact of Alife eventsB and ex-</p><p> .pressed emotions EE . In several studies, the impact ofstressful Alife-eventsB on psychotic decompensation and</p><p>relapse frequency has been well established Birley and.Brown, 1970; Nuechterlein et al., 1994 . Furthermore, the</p><p>degree of EE within a family has been described to worsenor ameliorate decompensation in schizophrenic patients,</p><p>respectively, once the disease has developed Nuechterlein.et al., 1992 . Even more important may be the observation</p><p>that in contrast to major life events, relative minor stresses,or the so-called Adaily hasslesB, seem to determine bylarge the subjectively experienced stress in schizophrenicpatients, and, to some extent, the amount of positivesymptoms that are expressed. These relative minor stresses</p><p>may even be predictive of relapse susceptibility Norman.and Malla, 1994 . The assumption that stress is involved in</p><p>the actual onset of a schizophrenic illness is far less clearand usually only reported in a minority of patients Gruen</p><p>.and Baron, 1984 . Nevertheless, stress reduction throughearly intervention, social skill training andror family edu-cation has been proven valuable in the management of</p><p>psychosis Falloon et al., 1985; Falloon, 1992; Liberman et.al., 1986 . This may hold even more so for the use of</p></li><li><p>( )C.C. Gispen-de WiedrEuropean Journal of Pharmacology 405 2000 375384 377</p><p>antipsychotics and anxiolytics in the treatment of psy- .chosis Wolkowitz and Pickar, 1991 . However, even when</p><p>patients are adequately treated with antipsychotic medica-tion and social support, they are only partially protected</p><p> .and still susceptible to stress Barrelet et al., 1990 . Thissuggests that schizophrenic patients may have an alteredsensitivity to stress. This sensitivity to stress in schizo-phrenic patients has been conceptualized in the vulnerabil-ity-stress model with respect to etiology and pathogenesis</p><p>of schizophrenia Zubin and Spring, 1977; Walker and.Difioro, 1997 . In this model, schizophrenia is described as</p><p>the result of a complex interaction between biological andpsychosocial factors, the former being genetically deter-mined, the latter being predominantly developed duringlife, which both contribute to the individuals vulnerabilityto develop a psychosis under stressful circumstances .Nuechterlein et al., 1994 . Schizophrenic patients arehampered both in the effective use of coping strategies andin their cognitive performance. They also display abnor-malities in ANS and hypothalamicpituitaryadrenal func-tion, particularly in their response to stress. It may there-fore be concluded that patients with schizophrenia sufferfrom stress because they are maladapted to their environ-ment, based on the aforementioned principles. Whetherthis is genetically determined or acquired during life orthrough disease remains difficult to discern. Support for atleast some genetic involvement of maladaptation inschizophrenia may be derived from adoptive studies. Stressmore easily triggers a psychosis in adoptees with a geneticload for schizophrenia as compared to those that have no</p><p> .such genetic background Tienari, 1991 . It has thereforebeen suggested that schizophrenic patients may alreadyhave a genetically altered sensitivity to their environment .Kendler and Eaves, 1986 . From this point of view, it isnecessary to get insight in, for instance, how the hypotha-lamicpituitaryadrenal system develops during life andwhat factors determine how it is able to adapt to a con-stantly changing environment.</p><p>2.1. Coping</p><p>Coping is defined as the ability of an individual to usedifferent coping strategies, i.e. behavioral, cognitive andemotional responses, in different stressful situations inorder to be able to master this situation and reduce the</p><p>impact of the stress that comes from it Folkman and.Lazarus, 1985 . In order to cope successfully, one should</p><p>rather be able to apply different strategies in varioussettings than rigidly apply the same strategies in different</p><p> .situations Lester et al., 1994 . In general, one can discrim-inate passive and active coping styles. Patients withschizophrenia tend to use passive and avoiding copingstrategies in stressful situations. They seem less goal-di-rected. This may on one hand be helpful in avoiding stressin daily life, but may also be a limitation to their adaptive</p><p> .capabilities Van den Bosch et al., 1992 . Furthermore, thistype of coping style has been described to be associated</p><p>with poor cognitive functioning Van den Bosch and Rom-.bouts, 1997 . Coping abilities seem best preserved in those</p><p>patients who suffer the least from negative symptoms andhave a high level of illness awareness Middelboe and</p><p>.Mortensen, 1997 . Although the trend in most studies isdirected towards this kind of coping behavior inschizophrenic patients, the actual way coping is usuallyassessed differs in most. Many studies use their owncoping questionnaire, which makes it difficult to makecomparisons. Moreover, most studies only measure gener-alized coping behavior and hardly address coping in rela-tion to an actual event. When exposed to the stress of apublic speaking task, the preference for a passive copingstyle can be found in schizophrenic patients, which ap-peared to be negatively correlated to the magnitude of the</p><p> .cortisol response Jansen et al., 2000a . This may beregarded as a first attempt to find biological correlates forcoping behavior. Coping, however, is such a complexbehavior that it will remain difficult to unravel its biologi-cal underpinnings.</p><p>2.2. Cognition</p><p>The cognitive deficits in schizophrenia have been exten-sively described over years and actually show thatschizophrenic patients are recognized by having a generaldeficit that is already present early in the course of thedisease process and remains relatively unaltered over timeSharma and Mockler, 1998; Hoff et al., 1999; Purdon et</p><p>.al., 2000 . Deficits have been described in many cognitivedomains among which attention, executive functions, ver-bal and visual memory recall, working memory, visiospa-</p><p>tial abilities and fine motor skills Flor-Henry and Yeudall,1979; Kolb and Whishaw, 1983; Palmer et al., 1997;</p><p>.Aleman et al., 1999 . The main brain areas that are in-volved in these cognitive processes are the medio-temporaland prefrontal cortical regions, the motor cortex and the</p><p> .basal ganglia Frith, 1995 . They all contribute to thedifferent cognitive dysfunctions described, indicating thatcognitive impairment in schizophrenia reflects rather dif-fuse brain dysfunctioning, than a single structure defect .Saykin et al., 1994 . Cognitive deficits haven been re-</p><p>ported to be associated with poor social functioning Brekke.et al., 1997 and to be independent of psychotic symptoms</p><p> .Laws and McKenna, 1997 . The fact that cognitive im-pairments are a core feature of the schizophrenic syndromeand already present at an early stage may suggest thatschizophrenic patients are, innate, less well adapted totheir environment. In favor of this hypothesis is the notionthat mild cognitive dysf...</p></li></ul>