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Editorials   |    
Linkage of Cognitive Impairments With Metabolic Disorders in Schizophrenia
Henry A. Nasrallah, M.D.
Am J Psychiatry 2010;167:1155-1157. doi:10.1176/appi.ajp.2010.10060838
View Author and Article Information

Editorial accepted for publication June 2010

Dr. Nasrallah has received research support from or served in a speaking or consulting capacity for AstraZeneca, Forest, Janssen, Merck, Novartis, Otsuka, Pfizer, Roche, Sanofi, and Shire. Dr. Freedman has reviewed this editorial and found no evidence of influence from these relationships

Address correspondence and reprint requests to Dr. Nasrallah, Department of Psychiatry and Behavioral Neuroscience, 260 Stetson St., Suite 3224, Cincinnati, OH 45219, henry.nasrallah@uc.edu (e-mail).

Accepted June , 2010.

Copyright © American Psychiatric Association

Over the past 20 years, two major challenges have emerged in the treatment of schizophrenia and have become the focus of considerable research. The first is the severe cognitive dysfunction across several domains (1,2), especially short-term memory and executive function, ranging between one and two standard deviations below the general population mean. Cognitive decline is observed over several years prior to the onset of psychotic symptoms, and the cognitive deficits of schizophrenia are now regarded by most researchers as the primary reason for the functional disability that is widely seen even after the successful treatment and abatement of psychotic symptoms. Kraepelin's term "dementia praecox" (3) a century ago for what Bleuler later renamed "schizophrenia" reflects the prominence of cognitive deficits observed in young people who are afflicted with this brain disorder.

The second issue that has come to the forefront for both clinicians and researchers is the metabolic dysregulation associated with schizophrenia (4) before and after pharmacotherapy, including weight gain, hypertension, hyperglycemia, and dyslipidemia. Those disorders cluster together under the term "metabolic syndrome," which has been reported in about 43% of persons with chronic schizophrenia in the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) study (5). Not only do such metabolic disorders significantly increase cardiovascular risk and lead to early mortality (6), but they frequently remain untreated in large proportions of persons with schizophrenia (7). This double jeopardy for persons with schizophrenia is a serious health care disparity that requires urgent attention, especially in the public sector.

The article by Friedman et al. in this issue (8) reports an important association between two metabolic parameters (high body mass index [BMI] and hypertension) and a key cognitive deficit (memory) in schizophrenia. The authors' findings, if replicated, could have important implications for understanding and ameliorating the memory deficits in schizophrenia and perhaps enhancing the outcomes of cognitive and vocational rehabilitation. Previous studies have reported an association between dementia and cardiovascular risk factors, which include obesity and hypertension, but such findings were based on general population investigations, not on schizophrenia samples. Thus, the findings of Friedman et al. imply that the two worst outcomes in schizophrenia—high functional disability (attributed to cognitive impairment) and high cardiovascular mortality (associated with obesity and hypertension)—may be linked.

Researchers are feverishly pursuing pharmacological treatments for cognitive dysfunction in schizophrenia (2). Several mechanisms are being targeted, such as α7 nicotinic receptor agonists, dopamine D1 receptor agonists, AMPA glutamatergic receptor agonists, α2-adrenergic agonists, N-methyl-d-aspartate glutamatergic receptors, γ-aminobutyric acid receptor agonists, and others (9). Most researchers assume that cognitive deficits are part of the genetic etiology of schizophrenia, as evidenced by their presence in first-degree relatives (10). However, nongenetic (secondary) factors in cognitive impairments have been attributed to lifestyle factors (isolation and lack of stimulation), antipsychotic treatment factors (excessive dopamine receptor blockade), and the use of anticholinergic medications to mitigate iatrogenic movement disorders, such as parkinsonism and dyskinesia (11). Similarly, metabolic disorders in schizophrenia have been attributed to genetic factors, which could explain the higher visceral adiposity and glucose dysregulation at the onset of psychosis in drug-naive schizophrenia patients, which may later worsen due to lifestyle factors (sedentary living, high caloric intake) and antipsychotic drug side effects (increased appetite and loss of satiety). The bottom line, however, is that regardless of etiology, interventions to reduce obesity and hypertension (diet, exercise, and cognitive remediation and/or antihypertensive medication) may have a salutary effect on both cognitive deficits and metabolic disorders and may reduce the dual grave outcomes of functional disability and cardiovascular risk.

It is possible to speculate that other preventable health risk factors contribute to other cognitive deficits in schizophrenia, and the study by Friedman et al. should inspire researchers to think outside the traditional box of finding a drug to improve memory dys-function in schizophrenia and instead examine other lifestyle and health factors that may exacerbate other cognitive deficits (such as executive function), the prevention or mitigation of which may lessen the severity of cognitive deficits and their functional impact.

The following are some possible implications of the finding that higher BMI and blood pressure may significantly compromise cognitive performance in schizophrenia:

Freedman  R:  Schizophrenia.  N Engl J Med 2003; 349:1738—1749
[CrossRef] | [PubMed]
 
Green  MF:  Stimulating the development of drug treatments to improve cognition in schizophrenia.  Annu Rev Clin Psychol 2007; 3:159—180
[CrossRef] | [PubMed]
 
Kraepelin  E:  Dementia Praecox and Paraphrenia (1919). Translated by Barclay  RM; edited by Robertson  M.  New York, Robert E Krieger, 1971
 
Meyer  JM;  Nasrallah  HA:  Medical Illness and Schizophrenia.  Washington, DC,  American Psychiatric Publishing, Inc, 2009
 
McEvoy  JP;  Meyer  JM;  Goff  DC;  Nasrallah  HA;  Davis  SM;  Sullivan  L;  Meltzer  HY;  Hsiao  J;  Stroup  TS;  Lieberman  JA:  Prevalence of the metabolic syndrome in patients with schizophrenia: baseline results from the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) schizophrenia trial and comparisons with national estimates from NHANES III.  Schizophr Res 2005; 80:19—32
[CrossRef] | [PubMed]
 
Coulton  CW;  Manderscheid  RW:  Congruencies in increased mortality rates, years of potential life lost, and causes of death among public mental health clients in eight states.  Prev Chronic Dis 2006; 31:1—4
 
Nasrallah  HA;  Meyer  JM;  Goff  DC;  McEvoy  JP;  Davis  SM;  Stroup  TS;  Lieberman  JA:  Low rates of treatment for hypertension, dyslipidemia, and diabetes in schizophrenia: data from the CATIE schizophrenia trial sample at baseline.  Schizophr Res 2006; 86:15—22
[CrossRef] | [PubMed]
 
Friedman  JI;  Wallenstein  S;  Moshier  E;  Parrella  M;  White  L;  Bowler  S;  Gottlieb  S;  Harvey  PD;  McGinn  TG;  Flanagan  L;  Davis  KL:  The effects of hypertension and body mass index on cognition in schizophrenia.  Am J Psychiatry 2010; 167:1232—1239
[CrossRef] | [PubMed]
 
Tamminga  CA:  The neurobiology of cognition in schizophrenia.  J Clin Psychiatry 2006; 67(suppl 9):9—13
[CrossRef] | [PubMed]
 
Sitskoorn  MM;  Aleman  A;  Ebisch  SJ;  Appels  MC;  Kahn  RS:  Cognitive de-cits in relatives of patients with schizophrenia: a meta-analysis.  Schizophr Res 2004; 71:285—295
[CrossRef] | [PubMed]
 
Vinogradov  S;  Fisher  M;  Warm  H;  Holland  C;  Kirshner  MA;  Pollock  BG:  The cognitive cost of anticholinergic burden: decreased response to cognitive training in schizophrenia.  Am J Psychiatry 2009; 166:1055—1062
[CrossRef] | [PubMed]
 
Meyer  JM;  Davis  VG;  Goff  DC;  McEvoy  JP;  Nasrallah  HA;  Davis  SM;  Rosenheck  RA;  Daumit  GL;  Hsiao  J;  Swartz  MS;  Stroup  TS;  Lieberman  JA:  Change in metabolic syndrome with antipsychotic treatment in the CATIE schizophrenia trial: prospective data from phase 1.  Schizophr Res 2008; 101:273—286
[CrossRef] | [PubMed]
 
References Container
+

References

Freedman  R:  Schizophrenia.  N Engl J Med 2003; 349:1738—1749
[CrossRef] | [PubMed]
 
Green  MF:  Stimulating the development of drug treatments to improve cognition in schizophrenia.  Annu Rev Clin Psychol 2007; 3:159—180
[CrossRef] | [PubMed]
 
Kraepelin  E:  Dementia Praecox and Paraphrenia (1919). Translated by Barclay  RM; edited by Robertson  M.  New York, Robert E Krieger, 1971
 
Meyer  JM;  Nasrallah  HA:  Medical Illness and Schizophrenia.  Washington, DC,  American Psychiatric Publishing, Inc, 2009
 
McEvoy  JP;  Meyer  JM;  Goff  DC;  Nasrallah  HA;  Davis  SM;  Sullivan  L;  Meltzer  HY;  Hsiao  J;  Stroup  TS;  Lieberman  JA:  Prevalence of the metabolic syndrome in patients with schizophrenia: baseline results from the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) schizophrenia trial and comparisons with national estimates from NHANES III.  Schizophr Res 2005; 80:19—32
[CrossRef] | [PubMed]
 
Coulton  CW;  Manderscheid  RW:  Congruencies in increased mortality rates, years of potential life lost, and causes of death among public mental health clients in eight states.  Prev Chronic Dis 2006; 31:1—4
 
Nasrallah  HA;  Meyer  JM;  Goff  DC;  McEvoy  JP;  Davis  SM;  Stroup  TS;  Lieberman  JA:  Low rates of treatment for hypertension, dyslipidemia, and diabetes in schizophrenia: data from the CATIE schizophrenia trial sample at baseline.  Schizophr Res 2006; 86:15—22
[CrossRef] | [PubMed]
 
Friedman  JI;  Wallenstein  S;  Moshier  E;  Parrella  M;  White  L;  Bowler  S;  Gottlieb  S;  Harvey  PD;  McGinn  TG;  Flanagan  L;  Davis  KL:  The effects of hypertension and body mass index on cognition in schizophrenia.  Am J Psychiatry 2010; 167:1232—1239
[CrossRef] | [PubMed]
 
Tamminga  CA:  The neurobiology of cognition in schizophrenia.  J Clin Psychiatry 2006; 67(suppl 9):9—13
[CrossRef] | [PubMed]
 
Sitskoorn  MM;  Aleman  A;  Ebisch  SJ;  Appels  MC;  Kahn  RS:  Cognitive de-cits in relatives of patients with schizophrenia: a meta-analysis.  Schizophr Res 2004; 71:285—295
[CrossRef] | [PubMed]
 
Vinogradov  S;  Fisher  M;  Warm  H;  Holland  C;  Kirshner  MA;  Pollock  BG:  The cognitive cost of anticholinergic burden: decreased response to cognitive training in schizophrenia.  Am J Psychiatry 2009; 166:1055—1062
[CrossRef] | [PubMed]
 
Meyer  JM;  Davis  VG;  Goff  DC;  McEvoy  JP;  Nasrallah  HA;  Davis  SM;  Rosenheck  RA;  Daumit  GL;  Hsiao  J;  Swartz  MS;  Stroup  TS;  Lieberman  JA:  Change in metabolic syndrome with antipsychotic treatment in the CATIE schizophrenia trial: prospective data from phase 1.  Schizophr Res 2008; 101:273—286
[CrossRef] | [PubMed]
 
References Container
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