Is the Mechanism of Prefrontal Hypofunction in Depression the Same as in Schizophrenia?

Berman, Karen F.; Doran, Allen R.; Pickar, David; Weinberger, Daniel R.

doi:10.1192/bjp.162.2.183

Cited by 116 publications

(42 citation statements)

References 41 publications

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“…Decreased levels of expression of subunits of the mitochondrial electron transport chain have been reported for both patients with BD and schizophrenia. 4 Since cell loss and morphological alterations are found in the PFC in patients with BD and schizophrenia, [50][51][52][53][54] cellular dysfunction produced by protein oxidation may contribute to these alterations. This may lead to a decline in the proper functioning of the PFC.…”

Section: Discussionmentioning

confidence: 99%

Oxidation and nitration in dopaminergic areas of the prefrontal cortex from patients with bipolar disorder and schizophrenia

Kim

Andreazza

Yeung

et al. 2014

J Psychiatry Neurosci

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IntroductionBipolar disorder (BD) is characterized by recurrent episodes of mania/hypomania and depression, affects 1.5% of the population, and is associated with high morbidity and mortality. 1 The pathophysiology of BD is linked to a number of factors, including neurotransmitter imbalance, oxidative stress and genetic causes.2 Increased oxidative stress, which could result in oxidative and nitrosative damage to biomolecules, 3 is a consistent finding in patients with BD. For example, mitochondrial dysfunction and decreased expression of genes of the electron transport chain, particularly that of complex I, are reported in patients with BD. 4,5 Decreased efficiency of the electron transport chain could result in increased production of reactive oxygen species (ROS).3 Moreover, increased levels of carbonyl groups, 3-nitrotyrosine (3NT) and decreased levels of antioxidants, such as glutathione, are all reported in patients with BD. [6][7][8][9] It is widely held that dysregulation of the dopamine (DA) system is important in BD, where high levels of DA are thought to underlie mania, a defining feature of the disorder.10 Increasing synaptic DA levels with amphetamine and Levodopa (L-dopa) produces mania-like behaviour, 10,11 and antipsychotics, which act in part by blocking DA receptors, Background: Increased oxidative stress is strongly implicated in bipolar disorder (BD), where protein oxidation, lipid peroxidation and oxidative damage to DNA have been consistently reported. High levels of dopamine (DA) in mania are also well-recognized in patients with BD, and DA produces reactive oxygen species and electron-deficient quinones that can oxidize proteins when it is metabolized. Methods: Using immunohistochemistry and acceptor photobleaching Förster resonance energy transfer (FRET), we examined oxidation and nitration of areas immunoreactive for the DA transporter (DAT) and tyrosine hydroxylase (TH) in the postmortem prefrontal cortex from patients with BD, schizophrenia and major depression as well as nonpsychiatric controls. Results: We found increased oxidation of DAT-immunoreactive regions in patients with BD (F 3,48 = 6.76, p = 0.001; Dunnett post hoc test p = 0.001) and decreased nitration of THimmunoreactive regions in both patients with BD (F 3,45 = 3.10, p = 0.036; Dunnett post hoc test p = 0.011) and schizophrenia (p = 0.027). On the other hand, we found increased global levels of oxidation in patients with BD (F 3,44 = 6.74, p = 0.001; Dunnett post hoc test p = 0.001) and schizophrenia (p = 0.020), although nitration levels did not differ between the groups (F 3,46 = 1.75; p = 0.17). Limitations: Limitations of this study include the use of postmortem brain sections, which may have been affected by factors such as postmortem inter val and antemortem agonal states, although demographic factors and postmortem interval were accounted for in our statistical analysis. Conclusion: These findings suggest alterations in levels of protein oxidation and nitration in DA-rich regions of the prefrontal cortex in pati...

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Section: Discussionmentioning

confidence: 99%

Oxidation and nitration in dopaminergic areas of the prefrontal cortex from patients with bipolar disorder and schizophrenia

Kim

Andreazza

Yeung

et al. 2014

J Psychiatry Neurosci

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“…These impairments are not specific for depression, although the pathophysiological mechanisms underlying these features of depression may differ from those in other psychiatric disorders (Berman et al, 1993;Barch et al, 2003). Specifically, abnormal reduction of CBF and metabolism in the dorsolateral prefrontal cortex and dorsal anterior cingulate cortex (ACC) might explain diminished ability to attend and concentrate in MDD (Drevets and Raichle, 1998), thus providing some evidence for the biological plausibility of this putative endophenotype for MDD.…”

Section: Impaired Learning and Memorymentioning

confidence: 99%

Discovering Endophenotypes for Major Depression

Hasler

Drevets

Manji

et al. 2004

Neuropsychopharmacol

1,023

739

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The limited success of genetic studies of major depression has raised questions concerning the definition of genetically relevant phenotypes. This paper presents strategies to improve the phenotypic definition of major depression by proposing endophenotypes at two levels: First, dissecting the depressive phenotype into key components results in narrow definitions of putative psychopathological endophenotypes: mood bias toward negative emotions, impaired reward function, impaired learning and memory, neurovegetative signs, impaired diurnal variation, impaired executive cognitive function, psychomotor change, and increased stress sensitivity. A review of the recent literature on neurobiological and genetic findings associated with these components is given. Second, the most consistent heritable biological markers of major depression are proposed as biological endophenotypes for genetic studies: REM sleep abnormalities, functional and structural brain abnormalities, dysfunctions in serotonergic, catecholaminergic, hypothalamic-pituitary-adrenocortical axis, and CRH systems, and intracellular signal transduction endophenotypes. The associations among the psychopathological and biological endophenotypes are discussed with respect to specificity, temporal stability, heritability, familiality, and clinical and biological plausibility. Finally, the case is made for the development of a new classification system in order to reduce the heterogeneity of depression representing a major impediment to elucidating the genetic and neurobiological basis of this common, severe, and often life-threatening illness.

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“…Although those few studies implicated a cingulate, prefrontal and striatal dysfunction associated with impaired task performance in depression, the results were not consistent [9][10][11][12].…”

Section: Introductionmentioning

confidence: 99%

Attenuated Left Prefrontal Activation during a Verbal Fluency Task in Patients with Depression

et al. 2003

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Functional neuroimaging studies on patients with depression have found abnormal activity in the left prefrontal and anterior cingulate cortex compared with healthy controls. Other studies have shown that these regions become active in healthy subjects during verbal fluency tasks, while patients with depression show impaired performance on such tasks. We used functional magnetic resonance imaging to investigate changes in cerebral blood oxygenation associated with a verbal fluency task in depressed patients and healthy volunteers. In contrast to 10 age- and sex-matched healthy control subjects who activated the left prefrontal cortex and the anterior cingulate cortex during word generation, 10 depressed subjects showed attenuated activation in the left prefrontal cortex and did not show significant activation in the anterior cingulate cortex. These findings suggest that impaired performance during verbal fluency task in depressed patients is associated with abnormal neural responses within these regions.

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Is the Mechanism of Prefrontal Hypofunction in Depression the Same as in Schizophrenia?

Cited by 116 publications

References 41 publications

Oxidation and nitration in dopaminergic areas of the prefrontal cortex from patients with bipolar disorder and schizophrenia

Oxidation and nitration in dopaminergic areas of the prefrontal cortex from patients with bipolar disorder and schizophrenia

Discovering Endophenotypes for Major Depression

Attenuated Left Prefrontal Activation during a Verbal Fluency Task in Patients with Depression

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