Ann Gardner

(Neuro)inflammation and neuroprogression as new pathways and drug targets in depression: from antioxidants to kinase inhibitors.

In 1993 the first review on the inflammatory findings in depression was published (Maes, 1993). The second review on this topic (Maes, 1995) appeared in this journal that now publishes a special state-of-the art issueon the inflammatorypathways indepression. The initial so-called “monocyte-T lymphocyte”, “cytokine” or “inflammatory” hypothesis was based on findings on increased levels of proinflammatory cytokines produced bymonocytic cells/macrophages, e.g. interleukin-1β (IL-1β), IL6, and tumor necrosis factor-α (TNFα); and T lymphocytes, e.g. interferon-γ (IFNγ) and IL-2, in depression, and entailed 6 statements (Maes, 1995, 1997; Maes et al., 1995):

Somatomedins in aging and dementia disorders of the Alzheimer type

Serum levels of somatomedins were determined in apparently healthy aged individuals and dementia patients primarily with clinically suspected Alzheimer type disorder. Serum somatomedin values, determined by radioreceptorassay and radioimmunoassay, fell with advancing age in normal subjects. A significant elevation in serum somatomedins was observed in dementia patients. CSF somatomedin levels were also increased in the only two patients with suspected Alzheimer type disease examined. Since somatomedins are believed to act as anabolic hormones, it was suggested that the elevated levels represent a compensatory mechanism to overcome receptor insensitivity in patients with dementia disorders of the Alzheimer type.

Mitochondrial energy depletion in depression with somatization.

Multiple somatic symptoms are reported worldwide in more than half of patients with major depression and were suggested to be a core component of the depressive syndrome [1] . The somatic symptoms, including headache, muscle pain and fatigue, are often attributed to ‘somatization’ [2] , a concept that has replaced the previous terms of ‘hysteria’ and ‘Briquet’s syndrome’ as a diagnostic label for multiple ‘medically unexplained’ somatic symptoms in psychiatric classification systems [3] . The same somatic, as well as mood, symptoms are common in disorders of mitochondrial energy [adenosine triphosphate (ATP)] production [4, 5] , a process involving the expression of about 1,000 proteins encoded on the chromosomes as well as the asexual, maternally inherited mitochondrial DNA (mtDNA). The tissues most affected in mitochondrial disorders are those with the highest energy demands, especially brain and muscle. A several-fold increased likelihood of developing depression and somatic symptoms can be maternally inherited along with the mtDNA [5, 6] , which strongly argues that mitochondrial dysfunction can precede and predispose to depression. Thus, we hypothesized that decreased ATP production rates are often present in depressed patients with very high levels of somatic symptoms (somatization). The investigated patients, 10 males and 11 females with a mean age of 49 8 9 years, were recruited from an earlier report [7] and have chronic depression that fulfilled the DSM-IV criteria for major depressive disorder. All subjects also have tinnitus and/or hearing loss, which are common conditions in depression. As correlates of the degree of somatic symptomatology, 3 self-reported scales, Somatic Anxiety, Muscular Tension and Psychasthenia, from the Karolinska Scales of Personality were used. Each scale contains 10 items with a 4-point response format [8] and is considered to measure symptoms of dysautonomia, muscle discomfort and fatigue, respectively. Loadings on various factor solutions applied to find underlying traits (‘latent variables’) usually group the 3 scales together [9] . A cutoff score for each scale at the second standard deviation (SD) above the mean (corresponding to the 98th percentile) from 400 individuals sampled from the general Swedish population [8] was applied to indicate very high and lesser degrees of somatic symptoms. Statistics were performed by 2 or Fisher exact test, as appropriate. ATP production rates using the substrate -ketoglutarate were assessed in isolated muscle mitochondria in the patients and 10 healthy sedentary controls recruited from hospital staff, 3 males and 7 females with a mean age of 46 8 8 years. -Ketoglutarate supports the highest rate of ATP production of any single substrate tested [10] . Respiration through complex I of the respiratory chain is stimulated by -ketoglutarate. Previous data showed deficient respiration at complex I, while normal results were obtained for respiration through complex IV [7] . All 8 very high scorers on Somatic Anxiety also scored very high on the other 2 Karolinska Scales of Personality, indicating that those subjects self-report very high levels ( 6 2 SD) of a broad range of somatic symptomatology (somatization). Figure 1 depicts the results for Somatic Anxiety, which suggests a threshold effect for clinical symptomatology once mitochondrial energy production drops to a certain level (p = 0.015 for very high vs. lesser scoring depressed subjects above and below the lower limit of our control range: 3.9 mmol ATP min –1 kg –1 muscle). In mitochondrial disease, it is well established that cellular dysfunction and clinical symptomatology often appear abruptly once mitochondrial function decreases below a critical level (a ‘threshold model’) [11] . Very similar results were found for Muscular Tension (p = 0.031) and Psychasthenia (p = 0.003). On each of the 3 Karolinska Scales of Personality, virtually every patient with very high levels of somatic symptomatology demonstrated muscle ATP production rates below the control range. The findings are not a function of any potential confounding variables that we could identify. Mitochondrial ATP production rates decline with a sedentary lifestyle [10] and with advancing age [12] . In this study, no significance differences or trends were found between ATP production rates and subject activity level or age. In addition, no significance differences or trends were noted between ATP production rates with gender or past or present medication usage. Our results demonstrate that mitochondrial function correlates very strongly with self-reported data related to somatic symptoms. That the mitochondrial function was measured in muscle indicates a systemic and more fundamental cellular abnormality than if measured in the brain, whereas it could be argued to be a result of neuronal activity or ‘psychic processes’. As the brain has a high ATP requirement in order to maintain the transmembrane potential and neurotransmitter signaling, there are many potential mechanisms as to how energy deficiency might predispose towards somatic and mood symptoms. Of par-

Differences in resting state regional cerebral blood flow assessed with 99mtc-hmpao Spect and brain atlas matching between depressed patients with and without tinnitus

An increased occurrence of major depressive disorder has been reported in tinnitus patients, and of tinnitus in depressive patients. Involvement of several Brodmann areas (BAs) has been reported in tinnitus perception. The aim of this study was to assess the regional cerebral blood flow (rCBF) changes in depressed patients with and without tinnitus. The rCBF distribution at rest was compared among 45 patients with a lifetime prevalence of major depressive disorder, of whom 27 had severe tinnitus, and 26 normal healthy subjects. 99mTc-hexamethylenepropylene amine oxime (99mTc-HMPAO) single photon emission computed tomography (SPECT), using a three-headed gamma camera, was performed and the uptake in 34 functional sub-volumes of the brain bilaterally was assessed by a computerized brain atlas. Decreased rCBF in right frontal lobe BA 45 (P<0.05), the left parietal lobe BA 39 (P<0.00) and the left visual association cortex BA 18 (P<0.05) was found in tinnitus patients compared with non-tinnitus patients. The proportion of tinnitus patients with pronounced rCBF alterations in one or more of the temporal lobe BAs 41+21+22 was increased compared to gender matched controls (P<0.00) and patients without tinnitus (P<0.05). Positive correlations were found between trait anxiety scales from the Karolinska Scales of Personality and rCBF in tinnitus patients only in three limbic BAs (P<0.01), and inverse correlations in non-tinnitus patients only in five BAs subserving auditory perception and processing (P<0.05). rCBF differences between healthy controls and depressed patients with and without tinnitus were found in this study. The rCBF alterations were distributed in the cortex and were particularly specific in the auditory cortex. These findings suggest that taking audiological symptoms into account may yield more consistent results between rCBF studies of depression.

Alterations of rCBF and mitochondrial dysfunction in major depressive disorder: a case report

Objective:  A mitochondrial disease might be considered when depressive disorder is associated with diabetes mellitus or other symptoms commonly found in mitochondrial disease. Scattered regional cerebral blood flow (rCBF) decreases and increases have been reported in depressive and mitochondrial disorders. A 61‐year‐old male patient with early adult onset of depressive disorder and a slowly developing multiorgan syndrome including diabetes mellitus was investigated.

Mitochondrial Function Is Related to Alterations at Brain SPECT in Depressed Patients

INTRODUCTION 99mTc-d,l-hexamethylpropylene amine oxime (99mTc-HMPAO) retention in brain is proportional to cerebral blood flow and related to both the local hemodynamic state and to the cellular content of reduced glutathione. Alterations of the regional distribution of 99mTc-HMPAO retention, with discrepant results, have been reported at functional brain imaging of unipolar depression. Since mitochondrial involvement has been reported in depressed patients, the aim of the study was to explore whether the 99mTc-HMPAO retention at single-photon emission computed tomography in depressed patients may relate to different levels of mitochondrial function. METHODS All patients had audiological and muscular symptoms, somatic symptoms that are common in depression. Citrate synthase (CS) activity assessed in muscle mitochondria correlated strongly with the activities of three mitochondrial respiratory chain enzymes and was used as a marker of mitochondrial function. K-means clustering performed on CS grouped eight patients with low and 11 patients with normal CS. Voxel-based analysis was performed on the two groups by statistical parametric mapping. RESULTS Voxel-based analysis showed significantly higher 99mTc-HMPAO retention in the patients with low CS compared with the patients with normal CS in the posterior and inferior frontal cortex, the superior and posterior temporal cortex, the somato-sensory cortex, and the associative parietal cortex. CONCLUSION Low muscle CS in depressed patients is related to higher regional 99mTc-HMPAO retention that may reflect cerebrovascular adaptation to impaired intracellular metabolism and/or intracellular enzymatic changes, as previously reported in mitochondrial disorder. Mitochondrial dysfunction in varying proportions of the subjects may explain some of the discrepant results for 99mTc-HMPAO retention in depression.

Different tissue distribution of a mitochondrial DNA duplication and the corresponding deletion in a patient with a mild mitochondrial encephalomyopathy: deletion in muscle, duplication in blood

Large-scale heteroplasmic mtDNA rearrangements were identified in a 57-year-old woman with chronic depressive disorder, hearing-loss, diabetes mellitus and a slowly progressive encephalomyopathy. A high percentage of a 24.2 kb duplicated molecule was found in lymphocytes whereas the corresponding deletion dimer dominated in muscle. PCR and Southern blot analyses were used to identify a 7658 bp duplication/deletion fragment. The duplicated mtDNA disrupted the cytochrome oxidase subunit I and cytochrome b genes at a position where there were no direct repeats. Duplicated mtDNA was not observed in the mother and brother of the patient. Histochemical analysis of skeletal muscle demonstrated pathological accumulation of mitochondria in cytochrome c oxidase negative fibers. In situ hybridization demonstrated only deleted mtDNA in cytochrome c oxidase negative fibres. We conclude that occurrence of deleted mtDNA correlates with phenotypic expression and that the duplicated mtDNA might serve as a generator of deletions, but is not directly pathogenic.

Endocrine disruptors, the increase of autism spectrum disorder and its comorbidity with gender identity disorder--a hypothetical association.

Endocrine disruptors, the increase of autism spectrum disorder and its comorbidity with gender identity disorder : a hypothetical association

Imaging the neurobiological substrate of atypical depression by SPECT

PurposeNeurobiological abnormalities underlying atypical depression have previously been suggested. The purpose of this study was to explore differences at functional brain imaging between depressed patients with and without atypical features and healthy controls.MethodsTwenty-three out-patients with chronic depressive disorder recruited from a service for patients with audiological symptoms were investigated. Eleven fulfilled the DSM-IV criteria for atypical depression (mood reactivity and at least two of the following: weight gain, hypersomnia, leaden paralysis and interpersonal rejection sensitivity). Twenty-three healthy subjects served as controls. Voxel-based analysis was applied to explore differences in 99mTc-HMPAO uptake between groups.ResultsPatients in the atypical group had a higher prevalence of bilateral hearing impairment and higher depression and somatic distress ratings at the time of SPECT. Significantly higher tracer uptake was found bilaterally in the atypical group as compared with the non-atypicals in the sensorimotor (Brodmann areas, BA1–3) and premotor cortex in the superior frontal gyri (BA6), in the middle frontal cortex (BA8), in the parietal associative cortex (BA5, BA7) and in the inferior parietal lobule (BA40). Significantly lower tracer distribution was found in the right hemisphere in the non-atypicals compared with the controls in BA6, BA8, BA44, BA45 and BA46 in the frontal cortex, in the orbito-frontal cortex (BA11, BA47), in the postcentral parietal cortex (BA2) and in the multimodal association parietal cortex (BA40).ConclusionThe differences found between atypical and non-atypical depressed patients suggest different neurobiological substrates in these patient groups. The putative links with the clinical features of atypical depression are discussed. These findings encourage the use of functional neuroimaging in psychiatric disorders.

Principal component and volume of interest analyses in depressed patients imaged by 99m Tc-HMPAO SPET: a methodological comparison

Previous regional cerebral blood flow (rCBF) studies on patients with unipolar major depressive disorder (MDD) have analysed clusters of voxels or single regions and yielded conflicting results, showing either higher or lower rCBF in MDD as compared to normal controls (CTR). The aim of this study was to assess rCBF distribution changes in 68 MDD patients, investigating the data set with both volume of interest (VOI) analysis and principal component analysis (PCA). The rCBF distribution in 68 MDD and 66 CTR, at rest, was compared. Technetium-99m d,l-hexamethylpropylene amine oxime single-photon emission tomography was performed and the uptake in 27 VOIs, bilaterally, was assessed using a standardising brain atlas. Data were then grouped into factors by means of PCA performed on rCBF of all 134 subjects and based on all 54 VOIs. VOI analysis showed a significant group × VOI × hemisphere interaction (P<0.001). rCBF in eight VOIs (in the prefrontal, temporal, occipital and central structures) differed significantly between groups at the P<0.05 level. PCA identified 11 anatomo-functional regions that interacted with groups (P<0.001). As compared to CTR, MDD rCBF was relatively higher in right associative temporo-parietal-occipital cortex (P<0.01) and bilaterally in prefrontal (P<0.005) and frontal cortex (P<0.025), anterior temporal cortex and central structures (P<0.05 and P<0.001 respectively). Higher rCBF in a selected group of MDD as compared to CTR at rest was found using PCA in five clusters of regions sharing close anatomical and functional relationships. At the single VOI level, all eight regions showing group differences were included in such clusters. PCA is a data-driven method for recasting VOIs to be used for group evaluation and comparison. The appearance of significant differences absent at the VOI level emphasises the value of analysing the relationships among brain regions for the investigation of psychiatric disease.