Mitochondrial dysfunction and alterations of brain HMPAO SPECT in depressive disorder : perspectives on origins of 'somatization'

A range of somatic symptoms are more common in patients with major depression than in the general population. Similar somatic symptoms and depression have been described in mitochondrial disorders, in which decreased production of adenosine triphosphate (ATP) is found. The aim of the present thesis was to investigate mitochondrial functions, regional distribution of the radiotracer HMPAO at brain SPECT with 3-dimensional interpretation, and results of Karolinska Scales of Personality (KSP) in patients with chronic depression and somatic symptoms. Relationships between measures were explored.

The thesis is based on six papers: I. ATP production and other investigations including mitochondrial DNA (mtDNA) studies in muscle were analyzed in 28 patients, of whom 21 patients filled in the KSP. II. Case history and in situ -hybridization of muscle mtDNA in one patient from study 1. III. Case history and results of muscle biopsy, KSP and HMPAO SPECT in another patient from study I. IV. KSP was filled in by 84 patients. A follow-up rating after 3.5 years was obtained in 65 patients. Comparisons were performed with depressed patients in primary care. V. Comparisons of HMPAO SPECT results between depressed patients, 27 with and 18 without tinnitus. VI. Relationships between the activity of succinate-cytochrome c reductase (SCR, enzyme complex II + III in the mitochondrial respiratory chain) in muscle and the HMPAO distribution at SPECT in 20 unmedicated patients with chronic psychiatric disorders, 16 with depression and four with schizophrenia.

Significantly lower ATP production and respiratory chain enzyme ratios, and increased prevalence of deleted mtDNA, were found in a group of depressed patients with somatic symptoms in comparisons with healthy controls. Low ATP production correlated with high KSP scores for somatic symptoms. Psychiatric symptoms were the first overt disease presentation in two patients also presented individually. Deleted mtDNA correlated with phenotypic expression in one patient with mtDNA rearrangements in blood and muscle. Stable and significantly increased KSP scores were found for somatic symptoms in a large patient group compared with depressed patients in primary care. Significant differences at HMPAO distribution at SPECT were found between depressed tinnitus and non-tinnitus patients in some brain regions previously found to be involved in tinnitus perception. Significant relationships between SCR and HMPAO distribution in associative sensory regions in patients with psychiatric disorders indicate that mitochondrial functions may contribute to SPECT alterations in these disorders.

Biological alterations could be demonstrated in patients with chronic depression and somatic symptoms using novel investigatory methods. Relationships were found between biological alterations and symptom presentation. Various origins of somatic symptoms in depression have been proposed including 'somatization' reflecting a psychological mechanism rather than biological abnormality. The results of the thesis indicate that chronic depression, at least when associated with somatic symptoms, is a systemic disorder with a disturbance at the level of a cell organelle, and entail a different perspective on the etiology of 'somatization'.

List of scientific papers

I. Gardner A, Johansson A, Wibom R, Nennesmo I, von Dobeln U, Hagenfeldt L, Hallstrom T (2003). Alterations of mitochondrial function and correlations with personality traits in selected major depressive disorder patients. J Affect Disord. 76(1-3): 55-68.
https://pubmed.ncbi.nlm.nih.gov/12943934

II. Houshmand M, Gardner A, Hallstrom T, Muntzing K, Oldfors A, Holme E (2004). 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. Neuromuscul Disord. 14(3): 195-201.
https://pubmed.ncbi.nlm.nih.gov/15036329

III. Gardner A, Pagani M, Wibom R, Nennesmo I, Jacobsson H, Hallstrom T (2003). Alterations of rCBF and mitochondrial dysfunction in major depressive disorder: a case report. Acta Psychiatr Scand. 107(3): 233-9.
https://pubmed.ncbi.nlm.nih.gov/12580831

IV. Gardner A, Hallstrom T (2004). High somatic distress with high long-term stability in selected patients with chronic depression: a 3-year follow-up of ratings with Karolinska Scales of Personality (KSP). Nord J Psychiatry. [Accepted]

V. Gardner A, Pagani M, Jacobsson H, Lindberg G, Larsson SA, Wagner A, Hallstrom T (2002). Differences in resting state regional cerebral blood flow assessed with 99mTc-HMPAO SPECT and brain atlas matching between depressed patients with and without tinnitus. Nucl Med Commun. 23(5): 429-39.
https://pubmed.ncbi.nlm.nih.gov/11973483

VI. Gardner A, Pagani M, Beier H, Jacobsson H, Larsson SA, Hallstrom T (2004). 99mTc-HMPAO distribution at SPECT is associated with succinate-cytochrome c reductase (SCR) activity in subjects with psychiatric disorders. Nucl Med Biol. 31(2): 277-82.
https://pubmed.ncbi.nlm.nih.gov/15013494