Revisiting allostatis and allostatic load in bipolar disorder
Aysegul Ozerdem
Article No: 0   Article Type :  Guest Editorial
Keywords :
Dusunen Adam : The Journal of Psychiatry and Neurological Sciences : 2015;28:183-188
Full Text:

The term “allostasis” defines the process of adaptation and management of changing physiological and emotional demands. The need for a normally functioning system to change bodily parameters in response not only to physiological changes, but also to other environmental challenges such as diseases, noise etc. is called allostasis. Allostasis is normally a protective process. However, the system may face a chronically forced (overactive or inactive) process while coping with the changes. This “wear and tear of the body and brain” is called “allostatic load” (1). Aging and acute and chronically repeating stress are among the most notable processes where “allostatic load” is evident (2). In such events, either it is not possible to shut off the physiological stress response when the stress is over or the stress response is inadequate. In either case, the allostatic load increases and results in pathological conditions (2,3). In follow-up studies, allostatic load, as a cumulative measure of dysregulation across multiple physiological systems, was reported to be an independent predictor of decline in physical and cognitive functionality in the elderly population (4). Also the risk of all-cause mortality and frailty were shown to increase together with each unit increment in the allostatic load (5,6).

A good example of allostasis is the mobilization of energetic pathways through glucocorticoids, the end-effectors of the hypothalamic–pituitary–adrenal (HPA) axis. Both the HPA axis and glucocorticoid hormones are pivotal in the adaptive response to various internal or external stressors (3,7). Overactivation of the HPA axis is known to result in insulin resistance, predisposition to diabetes, obesity, atherosclerosis, and hypertension. This system also exerts a strong effect on the hippocampus, causing changes in its major functions, such as cognition, memory, behavior, and mood (7).

Bipolar disorder (BD) is a chronic, disabling brain disease that follows a relapsing and remitting course (8-10). The terms “kindling” and “episode sensitization” are used to model cycle acceleration and illness progression occurring in the longitudinal course of mood disorders (11). According to this model, the first few mood episodes are mostly triggered by various life events. After multiple recurrences, episodes may appear spontaneously as well. The concept is supported by longitudinal studies where the number of prior episodes was shown to be a strong predictor of the recurring episodes in both unipolar and BD (12), and psychosocial stressors were less likely to be involved in the precipitation of the recurrences after the first few episodes (13,14).

In line with this model, there is evidence that acute mood episodes are associated with significant alterations related to neurochemical components (i.e. catecholamines), neurotrophins, oxidative stress, and inflammation, and that this so called “systemic toxicity”, which involves systems that play a key role in allostasis such as the HPA axis, becomes more evident at later stages of illness (15). Evolving systemic toxicity leads to a system less resilient to stressors and perhaps to accelerated cycling, medical comorbidities, cognitive impairment, and difficulties in treatment response.

For several years, brain derived neurotrophic factor (BDNF) has been one of the most studied neurotrophins in BD (16). Recent studies reported decreased BDNF and increased glia-derived neurotrophic factor (GDNF) levels in both mania and depression (17), increased GDNF/BDNF ratio in mania (18), and increased GDNF levels during manic switch due to ECT (19) confirming the role of the disrupted supportive cellular network in BD. Altered antioxidant enzymes, lipid peroxidation and nitric oxide levels (20-22), as well as increased DNA damage (23-27) in BD and a probable coactivation of oxidative damage and repair mechanisms have been reported, particularly in a depressive state of BD (28). Also various inflammatory markers such as TNF-α, interleukin (IL) 1β, IL-6, IL-10, IL-18, IL-4, interferon-γ, monocyte chemotactic protein-1, fibroblast growth factor β, vascular endothelial growth factor, and hs-CRP were reported to be activated in both manic and depressive states of BD (29,30). HPA axis dysfunction, as determined by enhanced cortisol response to the dex/CRH test, was shown in both remitted and non-remitted patients (31).

The interplay between the abovementioned mediators is hypothesized to be nonlinear, meaning that any alteration in each of these domains may induce further changes in others (15). For example, microglial activation caused by neuro-inflammation results in a cascade of increased oxidative stress, pathologic synaptic pruning, and disturbed neuroplasticity. Occurrence of these events in major brain areas where mood and cognition are regulated results in both core clinical symptoms of mood disorders as well as cognitive dysfunction, which is a part of active episodes and known to be sustained even in euthymia. In addition, immune dysregulation also leads to activation of the HPA axis, which results in hypercortisolemia and metabolic dysfunction. This in return induces further neuronal dysfunction (32). These multisystem alterations defined as “systemic toxicity” take place in systems that are involved in allostasis (33).

Accumulation of such toxicity becomes more evident at later stages of illness (33-38), causing less efficient cellular resilience mechanisms that may be leading to a pathological reorganization between different brain areas (39). This rewiring of the brain within the context of clinical and cognitive deterioration is called “neuroprogression”. Neuroprogression is suggested to be associated with the impaired resilience to stress in patients with BD (39). In sum, it has been proposed that mood episodes generate an extra load on the allostasis that is responsible for the illness progression (15).

Structural alterations and volumetric changes in BD in brain areas that are involved in emotion regulation and executive functions and response inhibition have been repeatedly reported (40-43). There is evidence for time-related gray matter volume increases in bipolar patients that vary by age (44). However, whether these changes result directly from toxic effects of the illness or if they are related to medication use or comorbid conditions has not been fully uncovered.

Despite persisting uncertainties about the origin of structural brain changes, progressive dysfunction is a commonly seen and well established feature of BD. Neurocognitive impairment that is evident across all states of BD (mania, depression and euthymia), subservient to a disturbance in functionality, is another core feature of BD (45). The degree of impairment in working memory in euthymic bipolar patients was shown to be positively correlated with post-dexamethasone cortisol levels, suggesting a role of abnormally functioning glucocorticoid receptors (46). Persistence of cognitive decline during euthymia and its being related to the abnormally functioning HPA axis is consistent with the concept of allostatic load: the continuing stress, through its interaction with the HPA axis, gives way to new mood episodes, each of which in turn causes further disturbance in the system.

Patients with BD are predisposed to increased rates of metabolic syndrome (47) and suffer from frequently occurring general medical conditions such as cardiovascular diseases, various cancers, obesity, and diabetes, all of which individually lead to increased morbidity and mortality during the course of the illness (48-68). Major markers of allostatic load, such as oxidative stress and increased cortisol, are known to be related to increased risk for cardiovascular diseases, through involvement in mechanisms of atherosclerosis. It has been shown that the atherosclerosis process is associated with an inflammatory response, and both phenomena together could contribute to cognitive decline (69). On the other hand, increased rates of obesity, metabolic syndrome, and diabetes independently show a deteriorating effect on the course of BD. Therefore, it has been hypothesized that the cumulative effect of increased oxidative stress in mood episodes and increased allostatic load may partially explain the increased morbidity in BD (2). Cognitive deficits related to obesity and neuropsychiatric diseases in general (70), and BD in particular (71,72), have been reviewed as expression of abnormalities in brain structure and function. In a recent study, BMI was found to be negatively correlated with attention and psychomotor processing speed. In addition, overweight and obese patients with BD scored significantly lower on the Verbal Fluency Test in comparison to normal weight patients (73). In another recent study that included patients with BD and patients with schizophrenia, obesity and worse overall cognitive performance as well as poorer performance on processing speed, reasoning/problem-solving, and sustained attention were found to be associated in BD. A similar association was not found in patients with schizophrenia. Obesity did not correlate with symptom severity in either mental illness (74).

In conclusion, accumulated data support the concept that bipolar disorder is a condition that involves various systems from micro to macro level. The non-linear interaction between systems that are involved in allostasis may help to elucidate the pathophysiology of bipolar disorder, where genetic vulnerability interacting with environmental challenges triggers the illness, which in turn increases the load on allostasis and therefore leads to illness progression in emotional, cognitive and behavioral domains as well as to detrimental metabolic and systemic conditions, causing increased morbidity and mortality in patients. In this review, the treatment effect within the context of allostasis or allostatic role has not been discussed. Scarcity of data on prospectively-designed studies exploring the change in allostatic load in bipolar disorder was evident. There seems to be a need for prospectively-designed studies measuring various allostasis-related parameters with the inclusion of at risk population and/or drug naive first/multiple episode patients before and after treatment to explore the illness toxicity and progression as well as the effect of treatment on the pathogenesis of bipolar disorder. The approach is crucial in order to provide the clinician tools for early detection of illness in genetically vulnerable individuals as well as to researchers for developing new treatment options.

REFERENCES

 

1.McEwen BS. Sex, stress and the hippocampus: allostasis, allostatic load and the aging process, Neurobiol Aging 2002; 23:921-939. [CrossRef]

2.Kapczinski F, Vieta E, Andreazza AC, Frey BN, Gomes FA, Tramontina J, Kauer-Sant’anna M, Grassi-Oliveira R, Post RM. Allostatic load in bipolar disorder: implications for pathophysiology and treatment. Neurosci Biobehav Rev 2008; 32:675-692. [CrossRef]

 

3.Möller-Leimkuhler AM. Higher comorbidity of depression and cardiovascular disease in women: A biopsychosocial perspective. World J Biol Psychiatry 2010; 11:922-933. [CrossRef]

4.Karlamangla AS, Singer BH, McEwen BS, Rowe JW, Seeman TE. Allostatic load as a predictor of functional decline: MacArthur studies of successful aging. J Clin Epidemiol 2002; 55:696-710. [CrossRef]

 

5.Karlamangla AS, Singer BH, Seeman TE. Reduction in allostatic load in older adults is associated with lower all-cause mortality risk: MacArthur studies of successful aging. Psychosom Med 2006; 68:500-507. [CrossRef]

6.Gruenewald TL, Seeman TE, Karlamangla AS, Sarkisian CA. Allostatic load and frailty in older adults. J Am Geriatr Soc 2009; 57:1525-1531. [CrossRef]

7.Kino T. Stress, glucocorticoid hormones, and hippocampal neural progenitor cells: implications to mood disorders. Front Physiol 2015; 6:230. [CrossRef]

8.Belmaker RH. Medical progress: Bipolar disorder. N Engl J Med 2004; 351:476-486. [CrossRef]

9.Murray CJ, Lopez AD. The utility of DALYs for public health policy and research: A reply. Bull World Health Organ 1997; 75:377-381.

10.Ayuso-Mateos JL. Global burden of bipolar disorder in the year 2000. World Health Organization Global Program on Evidence for Health Policy (GPE). Draft 21.06.06.

11.Post RM. Kindling and sensitization as models for affective episode recurrence, cyclicity, and tolerance phenomena. Neurosci Biobehav Rev 2007; 31:858-873. [CrossRef]

12.Kessing LV, Hansen MG, Andersen PK, Angst J. The predictive effect of episodes on the risk of recurrence in depressive and bipolar disorders—a life-long perspective. Acta Psychiatrica Scandinavica 2004; 109:339-344. [CrossRef]

13.Kendler KS, Thornton LM, Gardner CO. Stressful life events and previous episodes in the etiology of major depression in women: an evaluation of the ‘’kindling’’ hypothesis. Am J Psychiatry 2000; 157:1243-1251. [CrossRef]

14.Kendler KS, Thornton LM, Gardner CO. Genetic risk, number of previous depressive episodes, and stressful life events in predicting onset of major depression. Am J Psychiatry 2001; 158:582-586. [CrossRef]

15.Grande I, Magalhães PV, Kunz M, Vieta E, Kapczinski F. Mediators of allostasis and systemic toxicity in bipolar disorder. Physiol Behav 2012; 106:46-50. [CrossRef]

16.Frey BN, Andreazza AC, Houenou J, Jamain S, Goldstein BI, Frye MA, Leboyer M, Berk M, Malhi GS, Lopez-Jaramillo C, Taylor VH, Dodd S, Frangou S, Hall GB, Fernandes BS, Kauer-Sant’Anna M, Yatham LN, Kapczinski F, Young LT. Biomarkers in bipolar disorder: a positional paper from the International Society for Bipolar Disorders Biomarkers Task Force. Aust N Z J Psychiatry 2013; 47:321-332. [CrossRef]

17.Tunca Z, Kivircik Akdede B, Ozerdem A, Alkin T, Polat S, Ceylan D, Bayin M, Cengizcetin Kocuk N, Simsek S, Resmi H, Akan P. Diverse glial cell line-derived neurotrophic factor (GDNF) support between mania and schizophrenia: a comparative study in four major psychiatric disorders. Eur Psychiatry 2015; 30:198-204. [CrossRef]

18.Tunca Z, Ozerdem A, Ceylan D, Yalcin Y, Can G, Resmi H, Akan P, Ergor G, Aydemir O, Cengisiz C, Kerim D. Alterations in BDNF (brain derived neurotrophic factor) and GDNF (glial cell line-derived neurotrophic factor) serum levels in bipolar disorder: The role of lithium. J Affect Disord 2014; 166:193-200. [CrossRef]

19.Tunca Z, Bayn M, Alkn T, Ozerdem A, Resmi H, Akan P. A Preliminary Observation of Increased Glial Cell Line-Derived Neurotrophic Factor in Manic Switch due to Electroconvulsive Treatment in Depressive Patients. J ECT 2015; 31:167-172. [CrossRef]

20.Andreazza AC, Kauer-Sant’anna M, Frey BN, Bond DJ, Kapczinski F, Young LT, Yatham LN. Oxidative stress markers in bipolar disorder: A meta-analysis. J Affect Disord 2008; 111:135-144. [CrossRef]

21.Siwek M, Sowa-Kućma M, Dudek D, Styczeń K, Szewczyk B, Kotarska K, Misztakk P, Pilc A, Wolak M, Nowak G. Oxidative stress markers in affective disorders. Pharmacol Rep 2013; 65:1558-1571. [CrossRef]

22.Bengesser SA, Lackner N, Birner A, Fellendorf FT, Platzer M, Mitteregger A, Unterweger R, Reininghaus B, Mangge H, Wallner-Liebmann SJ, Zelzer S, Fuchs D, McIntyre RS, Kapfhammer HP, Reininghaus EZ. Peripheral markers of oxidative stress and antioxidative defense in euthymia of bipolar disorder-Gender and obesity effects. J Affect Disord 2014; 172:367-374. [CrossRef]

23.Buttner N, Bhattacharyya S, Walsh J, Benes FM. DNA fragmentation is increased in non-GABAergic neurons in bipolar disorder but not in schizophrenia. Schizophr Res 2007; 93: 33-41. [CrossRef]

24.Mustak MS, Hegde ML, Dinesh A, Britton GB, Berrocal R, Subba Rao K, Shamasundar NM, Rao KS, Sathyanarayana Rao TS. Evidence of altered DNA integrity in the brain regions of suicidal victims of bipolar depression. Indian J Psychiatry 2010; 52:220-222. [CrossRef]

25.Andreazza AC, Frey BN, Erdtmann B, Salvador M, Rombaldi F, Santin A, Gonçalves CA, Kapczinski F DNA damage in bipolar disorder. Psychiatry Res 2007; 153:27-32. [CrossRef]

26.Brown NC, Andreazza AC, Young LT. An updated meta-analysis of oxidative stres markers in bipolar disorder. Psychiatry Res 2014; 218:61-68. [CrossRef]

 

27.Black CN, Bot M, Scheffer PG, Cuijpers P, Penninx BW. Is depression associated with increased oxidative stress? A systematic review and meta-analysis. Psychoneuroendocrinology 2015; 51:164-175. [CrossRef]

28.Ceylan D, Tuna G, Kirkali G, Tunca Z, Dizdaroglu M, Can G, Arat HE, Ozerdem A. Base excision repair and oxidative DNA damage in patients with bipolar disorder. European Congress of Neuropsychopharmacology; 09/2014.

29.Fiedorowicz JG, Prossin AR, Johnson CP, Christensen GE, Magnotta VA, Wemmie JA. Peripheral inflammation during abnormal mood states in bipolar I disorder. J Affect Disord 2015; 187:172-178. [CrossRef]

30.Uyanik V, Tuglu C, Gorgulu Y, Kunduracilar H, Uyanik MS. Assessment of cytokine levels and hs-CRP in bipolar I disorder before and after treatment. Psychiatry Res 2015; 228:386-392. [CrossRef]

31.Watson S, Gallagher P, Ritchie JC, Ferrier IN, Young AH. Hypothalamic-pituitary-adrenal axis function in patients with bipolar disorder. Br J Psychiatry 2004; 184:496-502. [CrossRef]

32.Rosenblat JD, Brietzke E, Mansur RB, Maruschak NA, Lee Y, McIntyre RS. Inflammation as a neurobiological substrate of cognitive impairment in bipolar disorder: Evidence, pathophysiology and treatment implications. J Affect Disord 2015; 188:149-159. [CrossRef]

33.Daban C, Vieta E, Mackin P, Young AH. Hypothalamic–pituitary–adrenal axis and bipolar disorder. Psychiatr Clin North Am 2005; 28:469. [CrossRef]

34.Kauer-Sant’Anna M, Kapczinski F, Andreazza AC, Bond DJ, Lam RW, Young LT, Yatham LN. Brain-derived neurotrophic factor and inflammatorymarkers in patientswith early vs. late-stage bipolar disorder. Int J Neuropsychopharmacol 2009; 12:447-458. [CrossRef]

35.Andreazza AC, Kapczinski F, Kauer-Sant’Anna M, Walz JC, Bond DJ, Goncalves CA, Young LT, Yatham LN. 3-Nitrotyrosine and glutathione antioxidant system in patients in the early and late stages of bipolar disorder. J Psychiatry Neurosci 2009; 34:263-271.

36.Lewandowski KE, Cohen BM, Ongur D. Evolution of neuropsychological dysfunction during the course of schizophrenia and bipolar disorder. Psychol Med 2011; 41:225-241. [CrossRef]

37.Cacilhas AA, Magalhaes PVD, Cereser KM, Walz JC, Weyne F, Rosa AR, Vieta E, Kapczinski F. Bipolar disorder and age-related functional impairment. Revista Brasileira De Psiquiatria 2009; 31:354-357. [CrossRef]

 

38.Magalhães PV, Jansen K, Pinheiro RT, Klamt F, Teixeira AL, da Silva RA, Kapczinski F. Systemic toxicity in early-stage mood disorders. J Psychiatr Res 2011; 45:1407-1409. [CrossRef]

39.Fries GR, Pfaffenseller B, Stertz L, Paz AV, Dargél AA, Kunz M, Kapczinski F. Staging and neuroprogression in bipolar disorder. Curr Psychiatry Rep 2012; 14:667-675. [CrossRef]

40.Arnone D, Cavanagh J, Gerber D, Lawrie SM, Ebmeier KP, McIntosh AM. Magnetic resonance imaging studies in bipolar disorder and schizophrenia: meta-analysis. Br J Psychiatry 2009; 195:194-120. [CrossRef]

41.Bora E, Fornito A, Yucel M, Pantelis C. Voxelwise meta-analysis of gray matter abnormalities in bipolar disorder. Biol Psychiatry 2010; 67:1097-1105. [CrossRef]

42.Houenou J, Frommberger J, Carde S, Glasbrenner M, Diener C, Leboyer M, Wessa M. Neuroimaging based markers of bipolar disorder: evidence from two meta-analyses. J Affect Disord 2011; 132:344-355. [CrossRef]

43.Saricicek A, Yalin N, Hidiroglu C, Cavusoglu B, Tas C, Ceylan D, Zorlu N, Ada E, Tunca Z, Ozerdem A. Neuroanatomical correlates of genetic risk for bipolar disorder: A voxel-based morphometry study in bipolar type I patients and healthy first degree relatives. J Affect Disord 2015; 186:110-118. [CrossRef]

44.Lisy ME, Jarvis KB, DelBello MP, Mills NP, Weber WA, Fleck D, Strakowski SM, Adler CM. Progressive neurostructural changes in adolescent and adult patients with bipolar disorder. Bipolar Disord 2011; 13:396-405. [CrossRef]

45.Sole B, Bonnin CM, Torrent C, Martinez-Aran A, Popovic D, Tabare´ s-Seisdedos R, Vieta E. Neurocognitive Impairment Across the Bipolar Spectrum. CNS Neurosci Ther 2012; 18:194-200. [CrossRef]

46.Watson S, Thompson JM, Ritchie JC, Ferrier IN, Young AH. Neuropsychological impairment in bipolar disorder: the relationship with glucocorticoid receptor function. Bipolar Disord 2006; 8:85-90. [CrossRef]

47.Yalin N. Metabolic syndrome rate in patients with bipolar disorder type I and its relationship with treatment. Dissertation for Specialist in Psychiatry; Dokuz Eylul University, Faculty of Medicine, Department of Psychiatry, Izmir, 2014.

48.Kupfer DJ. The increasing medical burden in bipolar disorder. JAMA 2005; 293:2528-2530. [CrossRef]

 

49.Kessing LV, Anderson PK. Does the risk of developing dementia increase with the number of episodes in patients with depressive disorder and in patients with bipolar disorder? J Neurol Neurosurg Psychiatry 2004; 75:1662-1666. [CrossRef]

 

50.McElroy SL. Diagnosing and treating comorbid (complicated) bipolar disorder. J Clin Psychiatry 2004; 65:35-44.

 

51.Sylvia LG, Shelton RC, Kemp DE, Bernstein EE, Friedman ES, Brody BD, McElroy SL, Singh V, Tohen M, Bowden CL, Ketter TA, Deckersbach T, Thase ME, Reilly-Harrington NA, Nierenberg AA, Rabideau DJ, Kinrys G, Kocsis JH, Bobo WV, Kamali M, McInnis MG, Calabrese JR. Medical burden in bipolar disorder: findings from the Clinical and Health Outcomes Initiative in Comparative Effectiveness for Bipolar Disorder study (Bipolar CHOICE). Bipolar Disord 2015; 17:212-223. [CrossRef]

52.BarChana M, Levav I, Lipshitz I, Pugachova I, Kohn R, Weizman A, Grinshpoon A. Enhanced cancer risk among patients with bipolar disorder. J Affect Disord 2008; 108:43-48. [CrossRef]

53.Goldstein BI, Fagiolini A, Houck P, Kupfer DJ. Cardiovascular disease and hypertension among adults with bipolar I disorder in the United States. Bipolar Disord 2009; 11:657-662. [CrossRef]

54.Kemp DE, Gao K, Ganocy SJ, Caldes E, Feldman K, Chan PK, Conroy C, Bilali S, Findling RL, Calabrese JR. Medical and substance use comorbidity in bipolar disorder. J Affect Disord 2009; 116:64-69. [CrossRef]

55.McIntyre RS, Konarski JZ, Soczynska JK, Wilkins K, Panjwani G, Bouffard B, Bottas A, Kennedy SH. Medical comorbidity in bipolar disorder: Implications for functional outcomes and health service utilization. Psychiatr Serv 2006; 57:1140-1144. [CrossRef]

56.Kupka RW, Nolen WA, Post RM, McElroy SL, Altshuler LL, Denicoff KD, Frye MA, Keck PE Jr, Leverich GS, Rush AJ, Suppes T, Pollio C, Drexhage HA. High rate of autoimmune thyroiditis in bipolar disorder: lack of association with lithium exposure. Biol Psychiatry 2002; 51:305-311. [CrossRef]

57.Matthews AM, Huckans MS, Blackwell AD, Hauser P. Hepatitis C testing and infection rates in bipolar patients with and without comorbid substance use disorders. Bipolar Disord 2008; 10:266-270. [CrossRef]

58.van Winkel R, De Hert M, Van Eyck D, Hanssens L, Wampers M, Scheen A, Peuskens J. Prevalence of diabetes and the metabolic syndrome in a sample of patients with bipolar disorder. Bipolar Disord 2008; 10:342-348. [CrossRef]

59.Goldstein BI, Liu SM, Zivkovic N, Schaffer A, Chien LC, Blanco C. The burden of obesity among adults with bipolar disorder in the United States. Bipolar Disord 2011; 13:387-395. [CrossRef]

 

60.McElroy SL, Frye MA, Suppes T, Dhavale D, Keck PE Jr, Leverich GS, Altshuler L, Denicoff KD, Nolen WA, Kupka R, Grunze H, Walden J, Post RM. Correlates of overweight and obesity in 644 patients with bipolar disorder. J Clin Psychiatry 2002; 63:207-213. [CrossRef]

61.Kilbourne AM, Perron BE, Mezuk B, Welsh D, Ilgen M, Bauer MS. Co-occurring conditions and health-related quality of life in patients with bipolar disorder. Psychosom Med 2009; 71:894-900. [CrossRef]

62.Fagiolini A, Goracci A. The effects of undertreated chronic medical illnesses in patients with severe mental disorders. J Clin Psychiatry 2009; 70:22-29. [CrossRef]

63.Kilbourne AM, Rofey DL, McCarthy JF, Post EP, Welsh D, Blow FC. Nutrition and exercise behavior among patients with bipolar disorder. Bipolar Disord 2007; 9:443-452. [CrossRef]

64.Thompson WK, Kupfer DJ, Fagiolini A, Scott JA, Frank E. Prevalence and clinical correlates of medical comorbidities in patients with bipolar I disorder: Analysis of acute-phase data from a randomized controlled trial. J Clin Psychiatry 2006; 67:783-788. [CrossRef]

65.Crump C, Sundquist K, Winkleby MA, Sundquist J. Comorbidities and mortality in bipolar disorder: A Swedish national cohort study. JAMA Psychiatry 2013; 70:931-939. [CrossRef]

66.Hung YN, Yang SY, Huang MC, Lung FW, Lin SK, Chen KY, Kuo CJ, Chen YY. Cancer incidence in people with affective disorder: nationwide cohort study in Taiwan, 1997-2010. Br J Psychiatry 2014; 205:183-188. [CrossRef]

67.McGinty EE, Zhang Y, Guallar E, Ford DE, Steinwachs D, Dixon LB, Keating NL, Daumit GL. Cancer incidence in a sample of Maryland residents with serious mental illness. Psychiatr Serv 2012; 63: 714-717. [CrossRef]

68.Lin GM, Chen YJ, Kuo DJ, Jaiteh LE, Wu YC, Lo TS, Li YH. Cancer incidence in patients with schizophrenia or bipolar disorder: A nationwide population-based study in Taiwan, 1997-2009. Schizophr Bull 2013; 39:407-416. [CrossRef]

69.Yaffe K, Kanaya A, Lindquist K, Simonsick EM, Harris T, Shorr RI, Tylavsky FA, Newman AB. The metabolic syndrome, inflammation, and risk of cognitive decline. JAMA 2004; 292: 2237-2242. [CrossRef]

70.McIntyre RS, Cha DS, Jerrell JM, Soczynska JK, Woldeyohannes HO, Taylor V, Kaidanovich-Beilin O, Alsuwaidan M, Ahmed AT. Obesity and mental illness: implications for cognitive functioning. Adv Ther 2013; 30:577-588. [CrossRef]

71.Bond DJ, Lang DJ, Noronha MM, Kunz M, Torres IJ, Su W, Honer WG, Lam RW, Yatham LN. The association of elevated body mass index with reduced brain volumes in first-episode mania. Biol Psychiatry 2011; 70:381-387. [CrossRef]

72.Kuswanto CN, Sum MY, Yang GL, Nowinski WL, McIntyre RS, Sim K. Increased body mass index makes an impact on brain white-matter integrity in adults with remitted first-episode mania. Psychol Med 2014; 44:533-541. [CrossRef]

73.Yim CY, Soczynska JK, Kennedy SH, Woldeyohannes HO, Brietzke E, McIntyre RS. The effect of overweight/obesity on cognitive function in euthymic individuals with bipolar disorder. Eur Psychiatry 2012; 27:223-228. [CrossRef]

74.Depp CA, Strassnig M, Mausbach BT, Bowie CR, Wolyniec P, Thornquist MH, Luke JR, McGrath JA, Pulver AE, Patterson TL, Harvey PD. Association of obesity and treated hypertension and diabetes with cognitive ability in bipolar disorder and schizophrenia. Bipolar Disord 2014; 16:422-431. [CrossRef]

SUBMIT AN ARTICLE
11th National Alcohol and Substance Abuse Congress
DUSUNEN ADAM BROCHURES
COVER
Creative Commons Lisansı

Dusunen Adam: The Journal of Psychiatry and Neurological Sciences is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.
Düşünen Adam - Psikiyatri ve Nörolojik Bilimler Dergisi
Bakırköy Prof. Dr. Mazhar Osman Ruh Sağlığı ve Sinir Hastalıkları Eğitim ve Araştırma Hastanesi
Yayıncı
Yerküre Tanıtım ve Yayıncılık Hizmetleri A.Ş.