Brain volume abnormalities and neurocognitive deficits in diabetes mellitus: Points of pathophysiological commonality with mood disorders?

McIntyre, Roger S.; Kenna, Heather A.; Nguyen, Ha Thi Thu; Law, Candy W. Y.; Sultan, Farah; Woldeyohannes, Hanna O.; Alsuwaidan, Mohammad; Soczynska, Joanna K.; Adams, Amanda; Cheng, Jenny S. H.; Lourenço, Maria Helena; Kennedy, Sidney H.; Rasgon, Natalie

doi:10.1007/s12325-010-0011-z

Cited by 73 publications

(56 citation statements)

References 41 publications

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“…These findings show that central and systemic metabolic markers are involved in the pathophysiology of depression and are key factors to be considered for the development of better therapeutics. Our findings also suggest that FSL can be a useful model for comorbidity of depressive and central and systemic metabolic-like phenotypes (11,12) as well as a stress-induced model of treatment resistance.…”

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confidence: 53%

“…Such glutamate overflow is concomitant with central metabolic alterations [e.g., upregulation in Insr, Lepr, Glut-4, Glut-12, and Cartpt, a prohormone involved in the regulation of appetite through NPY signaling (24)]. The occurrence of these central metabolic alterations along with systemic metabolic changes in endogenously depressed FSL indicates that the FSL can be a useful model for future research to study the mechanisms of comorbidity of depression and central and systemic metabolic impairments that is of great interest because of the high incidence of metabolic syndrome in depressed subjects (11,12). Here, the dysregulation in central insulin levels in FSL does not seem to involve the canonical mechanism of insulin resistance linked to Glut-4, which, instead, is up-regulated in the vDG of FSL, thereby suggesting that there may be an upstream mechanism in the insulin resistance associated with the depressive-like phenotype of FSL that could involve other glucose transporters, such as Glut-12.…”

Section: Rapid Impact Of Lac On Central and Systemic Energy Regulatiomentioning

confidence: 99%

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Epigenetics and energetics in ventral hippocampus mediate rapid antidepressant action: Implications for treatment resistance

Bigio

Mathé

Sousa

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Although regulation of energy metabolism has been linked with multiple disorders, its role in depression and responsiveness to antidepressants is less known. We found that an epigenetic and energetic agent, acetyl-L-carnitine (LAC, oral administration), rapidly rescued the depressiveand central and systemic metabolic-like phenotype of LAC-deficient Flinders Sensitive Line rats (FSL). After acute stress during LAC treatment, a subset of FSL continued to respond to LAC (rFSL), whereas the other subset did not (nrFSL). RNA sequencing of the ventral dentate gyrus, a mood-regulatory region, identified metabolic factors as key markers predisposing to depression (insulin receptors Insr, glucose transporters Glut-4 and Glut-12, and the regulator of appetite Cartpt) and to LAC responsiveness (leptin receptors Lepr, metabotropic glutamate receptors-2 mGlu2, neuropeptide-Y NPY, and mineralocorticoid receptors MR). Furthermore, we found that stress-induced treatment resistance in nrFSL shows a new gene profile, including the metabolic regulator factors elongation of long chain fatty acids 7 (Elovl7) and cytochrome B5 reductase 2 (Cyb5r2) and the synaptic regulator NPAS4. Finally, while improving central energy regulation and exerting rapid antidepressant-like effects, LAC corrected a systemic hyperinsulinemia and hyperglicemia in rFSL and failed to do that in nrFSL. These findings establish CNS energy regulation as a factor to be considered for the development of better therapeutics. Agents such as LAC that regulate metabolic factors and reduce glutamate overflow could rapidly ameliorate depression and could also be considered for treatment of insulin resistance in depressed subjects. The approach here serves as a model for identifying markers and underlying mechanisms of predisposition to diseases and treatment responsiveness that may be useful in translation to human behavior and psychopathology. metabolic factors | acetylcarnitine | dentate gyrus | insulin | RNAseq P revious research has shown that agents that influence energy homeostasis, such as the epigenetic molecule acetyl-L-carnitine (LAC), exert rapid antidepressant-like effects by correcting imbalance of the glutamate system in the hippocampus of a genetic rat model of depression, Flinders Sensitive Line rats (FSL), and in a mouse model of stress-induced depressive-like traits (1-3). LAC, which passes through the blood-brain barrier, is a nutritional supplement and is also synthetized in the brain, liver, and kidney (4). Among its beneficial effects on the brain and the body, LAC regulates mitochondrial metabolism by facilitating transfer of fatty acids from the cytosol to the mitochondrial matrix for subsequent β-oxidation (5), needed for energy metabolism, deficits of which have been associated with a variety of diseases, including psychiatric disorders (6). However, the role of energy regulation in depression and in the responsiveness and/or resistance to antidepressants is less known.Because the ventral dentate gyrus (vDG) has a key role in regulating resilie...

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confidence: 53%

Section: Rapid Impact Of Lac On Central and Systemic Energy Regulatiomentioning

confidence: 99%

Epigenetics and energetics in ventral hippocampus mediate rapid antidepressant action: Implications for treatment resistance

Bigio

Mathé

Sousa

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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“…It has been hypothesized that BD and metabolic syndrome share a set of common risk factors and overlapping pathophysiology 782, 783, 784. While medications used to treat BD, particularly atypical antipsychotics, can also lead to metabolic dysfunction and weight problems (Section 8), insufficient access to primary and preventative health care, low socioeconomic status, habitual inactivity, insulin dysfunction, peripheral inflammation and neuroinflammation, oxidative stress, and childhood adversity are also important contributors 785…”

Section: Specific Populationsmentioning

confidence: 99%

Canadian Network for Mood and Anxiety Treatments (CANMAT) and International Society for Bipolar Disorders (ISBD) 2018 guidelines for the management of patients with bipolar disorder

et al. 2018

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The Canadian Network for Mood and Anxiety Treatments (CANMAT) previously published treatment guidelines for bipolar disorder in 2005, along with international commentaries and subsequent updates in 2007, 2009, and 2013. The last two updates were published in collaboration with the International Society for Bipolar Disorders (ISBD). These 2018 CANMAT and ISBD Bipolar Treatment Guidelines represent the significant advances in the field since the last full edition was published in 2005, including updates to diagnosis and management as well as new research into pharmacological and psychological treatments. These advances have been translated into clear and easy to use recommendations for first, second, and third‐ line treatments, with consideration given to levels of evidence for efficacy, clinical support based on experience, and consensus ratings of safety, tolerability, and treatment‐emergent switch risk. New to these guidelines, hierarchical rankings were created for first and second‐ line treatments recommended for acute mania, acute depression, and maintenance treatment in bipolar I disorder. Created by considering the impact of each treatment across all phases of illness, this hierarchy will further assist clinicians in making evidence‐based treatment decisions. Lithium, quetiapine, divalproex, asenapine, aripiprazole, paliperidone, risperidone, and cariprazine alone or in combination are recommended as first‐line treatments for acute mania. First‐line options for bipolar I depression include quetiapine, lurasidone plus lithium or divalproex, lithium, lamotrigine, lurasidone, or adjunctive lamotrigine. While medications that have been shown to be effective for the acute phase should generally be continued for the maintenance phase in bipolar I disorder, there are some exceptions (such as with antidepressants); and available data suggest that lithium, quetiapine, divalproex, lamotrigine, asenapine, and aripiprazole monotherapy or combination treatments should be considered first‐line for those initiating or switching treatment during the maintenance phase. In addition to addressing issues in bipolar I disorder, these guidelines also provide an overview of, and recommendations for, clinical management of bipolar II disorder, as well as advice on specific populations, such as women at various stages of the reproductive cycle, children and adolescents, and older adults. There are also discussions on the impact of specific psychiatric and medical comorbidities such as substance use, anxiety, and metabolic disorders. Finally, an overview of issues related to safety and monitoring is provided. The CANMAT and ISBD groups hope that these guidelines become a valuable tool for practitioners across the globe.

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“…A bi-directional relationship between obesity and cognitive function is suggested by studies reporting that individuals with impairment in executive function are more likely to become overweight or obese, perhaps related to disturbances in impulse control, self-monitoring, and goal-directed behaviour [24]. It is further hypothesized that cognitive abnormalities observed in overweight/obese individuals are the expression of abnormalities in brain structure and function [11,16,36]. It has been amply documented that individuals with BD are differentially associated with overweight/obesity and abdominal obesity, and excess weight adversely effects illness presentation, course and outcome; however, to our knowledge, no published study has primarily examined the association between overweight/obesity and cognitive function in adults with BD [15].…”

Section: Introductionmentioning

confidence: 99%

The effect of overweight/obesity on cognitive function in euthymic individuals with bipolar disorder

et al. 2012

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BackgroundPersistent impairment in cognitive function has been described in euthymic individuals with bipolar disorder. Collective work indicates that obesity is associated with reduced cognitive function in otherwise healthy individuals. This sub-group post-hoc analysis preliminarily explores and examines the association between overweight/obesity and cognitive function in euthymic individuals with bipolar disorder.MethodsEuthymic adults with DSM-IV-TR-defined bipolar I or II disorder were enrolled. Subjects included in this post-hoc analysis (n = 67) were divided into two groups (normal weight, body mass index [BMI] of 18.5–24.9kg/m2; overweight/obese, BMI≥25.0kg/m2). Demographic and clinical information were obtained at screening. At baseline, study participants completed a comprehensive cognitive battery to assess premorbid IQ, verbal learning and memory, attention and psychomotor processing speed, executive function, general intellectual abilities, recollection and habit memory, as well as self-perceptions of cognitive failures.ResultsBMI was negatively correlated with attention and psychomotor processing speed as measured by the Digit Symbol Substitution Test (P<0.01). Overweight and obese bipolar individuals had a significantly lower score on the Verbal Fluency Test when compared to normal weight subjects (P<0.05). For all other measures of cognitive function, non-significant trends suggesting a negative association with BMI were observed, with the exception of measures of executive function (i.e. Trail Making Test B) and recollection memory (i.e. process-dissociation task).ConclusionNotwithstanding the post-hoc methodology and relatively small sample size, the results of this study suggest a possible negative effect of overweight/obesity on cognitive function in euthymic individuals with bipolar disorder. Taken together, these data provide the impetus for more rigorous evaluation of the mediational role of overweight/obesity (and other medical co-morbidity) on cognitive function in psychiatric populations.

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Brain volume abnormalities and neurocognitive deficits in diabetes mellitus: Points of pathophysiological commonality with mood disorders?

Cited by 73 publications

References 41 publications

Epigenetics and energetics in ventral hippocampus mediate rapid antidepressant action: Implications for treatment resistance

Epigenetics and energetics in ventral hippocampus mediate rapid antidepressant action: Implications for treatment resistance

Canadian Network for Mood and Anxiety Treatments (CANMAT) and International Society for Bipolar Disorders (ISBD) 2018 guidelines for the management of patients with bipolar disorder

The effect of overweight/obesity on cognitive function in euthymic individuals with bipolar disorder

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