Guest NewsItem Posted October 18, 2001 Report Share Posted October 18, 2001 From http://www.thedoctorwillseeyounow.com/article....x.shtml <P ALIGN="center"><B>Schizophrenia and Stress</B></P> Cheryl Corcoran, M.D., and Dolores Malaspina, M.D., M.S.P.H. <I>Dr. Corcoran is Research Fellow, New York State Psychiatric Institute, and Dr. Malaspina is Associate Professor of Psychiatry, Columbia University College of Physicians and Surgeons, New York. Drs. Corcoran and Malaspina report no commercial conflict of interest.</I> The more we learn about stress, the more we understand how great a role it plays in a wide range of diseases and conditions. Not surprisingly, this is especially true of psychiatric problems such as psychosis, affective illness (a category that includes manic-depression and major depression) 1,2,3,4 and alcoholism.5,6 Stress seems to be particularly harmful for those suffering from the psychiatric disorder schizophrenia. For a patient with schizophrenia, the death of a parent or other loved one, a change in therapist, moving from one apartment to another; these events can trigger acute anxiety, depression and psychotic episodes, which may lead to hospitalization. Even seemingly mildly stressful events such as a job interview or a date can have a devastating effect. This increased susceptibility to stress fits the current thinking that schizophrenia is fundamentally related to a combination of difficulty in filtering out what is happening in the outside world and misattribution of internal thoughts and feelings, along with an inability or lessened ability to interpret social cues, all of which make it difficult for individuals with schizophrenia to cope. This is backed up by research showing that patients with schizophrenia are more affected by stress physically as well as emotionally; for instance they show different changes in heart rate under stress and a greater overall risk of cardiovascular disease.7 <B>Schizophrenia is a Group of Disorders</B> Schizophrenia is best understood not as a single disease, but rather as a group of related psychiatric disorders. Each of these is characterized by various combinations of the following symptoms: 1) "positive" or psychotic symptoms such as hallucinations and delusions; 2) "negative" symptoms such as apparent lack of emotion ("flat affect") and motivation (" passivity"); 3) cognitive impairments such as problems with working and short-term memory. Individuals with schizophrenia may sit quietly, make little or no eye contact and speak very little, or conversely may be agitated or suffer from elaborate hallucinations and delusions. The causes of schizophrenia have been shown to be as varied as its symptoms. Genetic abnormalities, environmental factors and interactions of the two have all been implicated. A strong hereditary component for schizophrenia has been confirmed in scores of family, twin and adoption studies, although no particular gene has yet been identified as a cause. The same studies have demonstrated the role of environmental factors; for example, if one identical twin has schizophrenia, the other twin will develop schizophrenia only about half of the time.8 Among the environmental factors that have been implicated as risk factors for schizophrenia are exposure to infection while in the womb, problems during delivery, adversity in childhood and brain injury. These exposures may cause illness directly, but they also appear to interact with some genetic vulnerability. Understanding the environmental risk factors for schizophrenia is key for both prevention and treatment. While little can be done at present to treat purely genetic causes, environmental factors may be modified and individuals may be taught strategies to manage stress. For instance, if stress can cause or worsen schizophrenia, measures can be taken to protect those at risk and to better manage those who are already ill. This would include reducing exposure to stress as well as countering the effects of stress by training in stress management and social skills, fostering positive relationships, increasing social support and encouraging exercise. <B>The "Two-hit" Theory of the Origin of Schizophrenia</B> The leading theory about the origins of schizophrenia is that the disease results, in part, from abnormal early development.9 Evidence for this theory comes from studies showing the existence of structural brain abnormalities long before the appearance of any psychiatric symptoms;10, 11,12,13,14 and an increased incidence of certain minor physical anomalies (for example, high arched palate, multiple hair whorls, abnormal head circumference, asymmetrical ears, curved fifth finger, webbed toes) in people with schizophrenia.15 However, many individuals who have these abnormalities do not go on to develop schizophrenia. This has led to the so-called "two-hit" hypothesis of schizophrenia: that genetic vulnerability or problems in the womb set the stage for schizophrenia, but that a second event in adolescence or early adulthood leads to the development of schizophrenia. This "second hit" may be a major life event or episode of stress. <B>A Diverse Illness</B> Given similar treatments, some patients with schizophrenia recover completely; some are able to work and have families. However, more than half experience some degree of disability throughout their lives, while an additional 25% require lifelong care. It is not clear what accounts for these differences. One answer may be stress. Researchers suspect that stress worsens the course of illness by increasing the body's production of a substance called cortisol, which can damage an area of the brain called the hippocampus. There is a growing body of evidence supporting the idea that stress and schizophrenia are closely linked.16 One groundbreaking study found that 46% of patients who experienced their first bout of schizophrenia underwent some stressful life event in the preceding three months.17,18 <B>The Effects of Stress on the Body and on the Brain</B> Medical scientists have demonstrated that stress can cause physical damage to the brain. Although schizophrenia is not the only illness that is connected to stress, the so-called "stress cascade" appears to play an important role in schizophrenia. The stress cascade begins with the release of certain hormones in the brain. This release, in turn, triggers physiological effects that make your heart work more, shunt blood away from the digestive system and set up the "fight or flight" reaction, a state of high arousal, increased vigilance and excessive levels of cortisol.19 Stress and cortisol have been shown to damage -- and even destroy -- nerve cells in the hippocampus, which plays an important role in memory. These elements of the stress cascade -- excessive cortisol production, damage to the hippocampus and impairment in certain types of memory related to the hippocampus, all occur commonly in patients with schizophrenia. 20,21,22,23,24,25,26,27,28,29,30 Research has shown that patients with schizophrenia have smaller hippocampal volumes than people without the disease. 31,32,33,34,35,36 This is backed up by studies that have found that individuals with schizophrenia suffer from problems in areas of brain functions that are associated with the hippocampus, such as memory and the ability to coordinate and carry out tasks.37 <B>Stress, Cortisol, Memory and the Hippocampus</B> A number of studies in the last several years have confirmed a strong connection between stress, high cortisol levels, damage to the hippocampus and memory. This connection shows up across a wide range of human medical conditions, including post-traumatic stress disorder (PTSD), Cushing's disease, overexposure to steroid drugs, aging and depression. For example, combat veterans with PTSD suffer a loss of hippocampal volume. In fact, there is a direct link between how these veterans perform on standard memory tests and the size of their hippocampus. Adult survivors of childhood abuse also have both smaller hippocampi and impaired memory. Problems regulating cortisol production ("cortisol dysregulation") and small hippocampal size are also common in depression.38 Chronic stress by itself seems to cause wear and tear on the brain. Cortisol levels increase with age and studies have shown shrinkage of the hippocampus and memory impairment even in healthy older people. Cushing's disease is an illness that causes the body to make too much cortisol. Patients with Cushing's have memory problems that can actually be reversed when the disease is successfully treated. Finally, both healthy research subjects who take medications that resemble cortisol, such as prednisone, and patients who take these medications for medical reasons, demonstrate these same reversible memory problems. <B>New Possibilities for the Treatment of Schizophrenia</B> Cognitive deficits such as problems with memory are a major component of schizophrenia.39.40 If these problems are related to the stress cascade, as they seem to be, then the exciting possibility exists that reducing stress may be an effective way of treating the disease.41 Not only may stress management techniques prevent the onset or lessen the severity of schizophrenia, delay relapse in those already ill and reduce overall anxiety, 42, 43,44,45 but studies indicate that cells within a damaged hippocampus can regenerate when stress or cortisol is reduced. There are also several drugs with good safety records that seem to prevent stress-induced damage to the hippocampus. These include tianeptine, 46 an anti-depressant, and phenytoin (sold under the brand name Dilantin?)) which is used to treat seizures (epilepsy). <B>Conclusion</B> Stress has long been suspected as a player in the onset and course of schizophrenia. And, although the precise details of the relationship between the two remains poorly understood, there is extensive and consistent research linking stress, cortisol regulation, the area of the brain called the hippocampus, as well as memory and other brain functions in schizophrenia. Because schizophrenia is a group of varied disorders, not one disease, and because there is unquestionably a genetic component to the disease, stress may well be a more important factor in some cases of schizophrenia than in others. Nevertheless, a better understanding of how stress may affect the onset and course of schizophrenia is likely to lead to the development of newer and better treatments, including more effective drugs, for the devastating and, up to now, relatively untreatable cognitive problems that are one of the chief effects of this terrible disease. June 2001 <B>References</B> 1. Harkness KL, Monroe SM, Simons AD, Thase M. The generation of life events in recurrent and non-recurrent depression. Psychol.Med. 1999; 29:135-144. 2. Frank E, Anderson B, Reynolds CF, III, Ritenour A, Kupfer DJ. Life events and the research diagnostic criteria endogenous subtype. A confirmation of the distinction using the Bedford College methods. Arch.Gen.Psychiatry 1994; 51:519-524. 3. Rosenzweig MR, Bennett E.: Psychobiology of plasticity: effects of training and experience on brain and behavior. Behav Brain Res. 1996;78:57-65. 4. Leverich GS, Post RM, Rosoff AS. Factors associated with relapse during maintenance treatment of affective disorders. Int.Clin.Psychopharmacol. 1990; 5:135-156. 5. Swann AC, Secunda SK, Stokes PE, Croughan J, Davis JM, Koslow SH, Maas JW. Stress, depression, and mania: relationship between perceived role of stressful events and clinical and biochemical characteristics. Acta Psychiatr.Scand. 1990; 81:389-397. 6. Brown SA, Vik PW, McQuaid JR, Patterson TL, Irwin MR, Grant I. Severity of psychosocial stress and outcome of alcoholism treatment. J.Abnorm.Psychol. 1990; 99:344-348. 7. Malaspina D, Bruder G, Dalack GW, Storer S, Van Kammen M, Amador X, Glassman A, Gorman J. Diminished cardiac vagal tone in schizophrenia: associations to brain laterality and age of onset. Biol Psychiatry. 1997;41:612-617. 8. Onstad S, Skre I, Torgersen S, Kringlen E. Twin concordance for DSM-III-R schizophrenia. Acta Psychiatr Scand. 1991;83:395-401. 9. Marenco S, Weinberger DR. The neurodevelopmental hypothesis of schizophrenia: following a trail of evidence from cradle to grave. Dev Psychopathol. 2000;12:501-527. 10. Waddington JL. Schizophrenia: developmental neuroscience and pathobiology. Lancet. 1993;341:531-536. 11. Fish B, Marcus J, Hans SL, Auerbach JG, Perdue S. Infants at risk for schizophrenia: sequelae of a genetic neurointegrative defect. A review and replication analysis of pandysmaturation in the Jerusalem Infant Development Study. Arch Gen Psychiatry. 1992;49:221-235. 12. Davidson M, Weiser M. Early diagnosis of schizophrenia--the first step towards secondary prevention. Acta Psychiatr Scand Suppl. 2000;400:7-10. 13. Jones P, Cannon M. The new epidemiology of schizophrenia. Psychiatr Clin North Am. 1998;21:1-25. 14. Done DJ, Crow TJ, Johnstone EC, Sacker A. Childhood antecedents of schizophrenia and affective illness: social adjustment at ages 7 and 11. BMJ. 1994;309:699-703. 15. Ismail B, Cantor-Graae E, McNeil TF. Minor physical anomalies in schizophrenia: cognitive, neurological and other clinical correlates. J Psychiatr Res. 2000;34:45-56. 16. Brown GW, Birley JL. Crises and life changes and the onset of schizophrenia. J.Health Soc.Behav. 1968; 9:203-214. 17. Norman RM, Malla AK. Stressful life events and schizophrenia. I: A review of the research. Br.J.Psychiatry 1993; 162:161-166. 18. Ventura J, Nuechterlein KH, Lukoff D, Hardesty JP. A prospective study of stressful life events and schizophrenic relapse. J.Abnorm.Psychol. 1989; 98:407-411. 19. McEwen BS, De Kloet ER, Rostene W. Adrenal steroid receptors and actions in the nervous system. Physiol Rev. 1986; 66:1121-1188. 20. Newcomer JW, Craft S, Askins K, Hershey T, Bardgett ME, Csernansky JG, Gagliardi AE, Vogler G. Glucocorticoid interactions with memory function in schizophrenia. Psychoneuroendocrinology. 1998;23:65-72. 21. Walder DJ, Walker EF, Lewine RJ. Cognitive functioning, cortisol release, and symptom severity in patients with schizophrenia. Biol Psychiatry. 2000;48:1121-1132. 22. Yeragani VK. The incidence of abnormal dexamethasone suppression in schizophrenia: a review and a meta-analytic comparison with the incidence in normal controls. Can.J.Psychiatry 1990; 35:128-132. 23. Sharma RP, Pandey GN, Janicak PG, Peterson J, Comaty JE, Davis JM. The effect of diagnosis and age on the DST: a metaanalytic approach. Biol.Psychiatry 1988; 24:555-568. 24. Newcomer JW, Faustman WO, Whiteford HA, Moses JA, Jr., Csernansky JG. Symptomatology and cognitive impairment associate independently with post-dexamethasone cortisol concentrations in unmedicated schizophrenic patients. Biol.Psychiatry 1991; 29:855-864. 25. Tandon R, Mazzara C, DeQuardo J, Craig KA, Meador-Woodruff JH, Goldman R, Greden JF. Dexamethasone suppression test in schizophrenia: relationship to symptomatology, ventricular enlargement, and outcome. Biol.Psychiatry 1991; 29:953-964. 26. Kaneko M, Yokoyama F, Hoshino Y, Takahagi K, Murata S, Watanabe M, Kumashiro H. Hypothalamic-pituitary-adrenal axis function in chronic schizophrenia: association with clinical features. Neuropsychobiology 1992; 25:1-7. 27. Aleem A, Kulkarni A, Yeragani VK. Dexamethasone suppression test, schizophrenia and movement disorder [see comments]. Acta Psychiatr.Scand. 1988; 78:689-694. 28. Sachar EJ, Hellman L, Roffwarg HP, Halpern FS, Fukushima DK, Gallagher TF. Disrupted 24-hour patterns of cortisol secretion in psychotic depression. Arch.Gen.Psychiatry 1973; 28:19-24. 29. Wik G, Wiesel FA, Eneroth P, Sedvall G, Astrom G. Dexamethasone suppression test in schizophrenic patients before and during neuroleptic treatment. Acta Psychiatr.Scand. 1986; 74:161-167. 30. Tandon et al. Op cit. 31. Weinberger DR. Cell biology of the hippocampal formation in schizophrenia. Biol.Psychiatry 1999; 45:395-40. 32. Deicken RF, Pegues M, Amend D. Reduced hippocampal N-acetylaspartate without volume loss in schizophrenia. Schizophr.Res. 1999; 37:217-223. 33. Heckers S, Rauch SL, Goff D, Savage CR, Schacter DL, Fischman AJ, Alpert NM. Impaired recruitment of the hippocampus during conscious recollection in schizophrenia [see comments]. Nat.Neurosci. 1998; 1:318-323. 34. Malaspina D, Perera GM, Lignelli A, Marshall RS, Esser PD, Storer S, Furman V, Wray AD, Coleman E, Gorman JM, Van Heertum RL. SPECT imaging of odor identification in schizophrenia. Psychiatry Res. 1998; 82:53-61. 35. Jonsson SA, Luts A, Guldberg-Kjaer N, Ohman R: Pyramidal neuron size in the hippocampus of schizophrenics correlates with total cell count and degree of cell disarray. Eur.Arch.Psychiatry Clin.Neurosci. 1999; 249:169-173. 36. Dwork A. personal communication. 37. Green MF. What are the functional consequences of neurocognitive deficits in schizophrenia? [see comments]. Am.J.Psychiatry 1996; 153:321-330. 38. Axelson DA, Doraiswamy PM, McDonald WM, Boyko OB, Tupler LA, Patterson LJ, Nemeroff CB, Ellinwood EH, Jr., Krishnan KR. Hypercortisolemia and hippocampal changes in depression. Psychiatry Res. 1993; 47:163-173. 39. Harvey PD, Silverman JM, Mohs RC, Parrella M, White L, Powchik P, Davidson M, Davis KL. Cognitive decline in late-life schizophrenia: a longitudinal study of geriatric chronically hospitalized patients. Biol.Psychiatry 1999; 45:32-40. 40. Davidson M, Harvey P, Welsh KA, Powchik P, Putnam KM, Mohs RC. Cognitive functioning in late-life schizophrenia: a comparison of elderly schizophrenic patients and patients with Alzheimer's disease. Am.J.Psychiatry 1996; 153:1274-1279. 41. Gould E, McEwen BS, Tanapat P, Galea LA, Fuchs E. Neurogenesis in the dentate gyrus of the adult tree shrew is regulated by psychosocial stress and NMDA receptor activation. J.Neurosci. 1997; 17:2492-2498. 42. Van Hassel JH, Bloom LJ, Gonzalez AM. Anxiety management with schizophrenic outpatients. J.Clin.Psychol. 1982; 38:280-285. 43. Falloon IR. Psychotherapy of schizophrenia. Br J Hosp Med. 1992;48:164-170. 44. Linszen D, Lenior M, De Haan L, Dingemans P, Gersons B. Early intervention, untreated psychosis and the course of early schizophrenia. Br J Psychiatry Suppl. 1998;172:84-89. 45. Stein F, Nikolic S. Teaching stress management techniques to a schizophrenic patient. Am.J.Occup.Ther. 1989; 43:162-169. 46. McEwen BS, Conrad CD, Kuroda Y, Frankfurt M, Magarinos AM, McKittrick C. Prevention of stress-induced morphological and cognitive consequences. Eur.Neuropsychopharmacol. 1997; 7 Suppl 3:S323-S328. Quote Link to comment Share on other sites More sharing options...
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