Betydelsen av inflammation och reninangiotensin- aldosteron-systemet vid ångest och depression

Sammanfattning: A number of biological systems have been studied in the past in an attempt to find the underlying cause of anxiety and depression. The main aim of the work described in this thesis was to investigate the importance of inflammation and the renin-angiotensin-aldosterone system (RAAS) in relation to anxiety and depression. The methods used ranged from studying patients to preclinical animal experiments. In Study I the RAAS was investigated in depressed patients who had recently attempted suicide, in depressed patients without a history of attempted suicide, and in healthy controls. Psychiatric symptoms were evaluated with the Comprehensive Psychopathological Rating Scale (CPRS). Study II investigated the change in plasma cytokines in depressed patients and healthy controls during an exercise test. In Study III, the behavioural changes of rats treated with the systemic inflammation inducer lipopolysaccharide (LPS) in combination with aldosterone were investigated. Cytokine and cytokine mRNA concentrations were measured in blood, cerebrospinal fluid (CSF) and the prefrontal cortex. Depressive-like behaviour in the animals was assessed using the forced swim test. Study IV investigated depression and anxiety disorders, using the Mini International Neuropsychiatric Interview (M.I.N.I.), in patients with suspected renal artery stenosis (RAS) in which the RAAS is overactive. The main findings of this work were: Depressed patients who had recently attempted suicide had significantly lower levels of aldosterone than depressed patients without a history of suicide attempts and healthy controls. In the depressed patients who had recently attempted suicide, a significant, negative correlation was found between aldosterone level and the reported CPRS score. The baseline levels of cytokines did not differ significantly between the depressed patients and the healthy controls. The cytokines IL-6, IL-8 and TNF-α increased during the exercise test in both the depressed patients and the healthy controls. The initial decrease in IL-6 was significantly smaller in the depressed patients than in the healthy controls. The treatment of rats with LPS increased the level of mRNA for IL-1β in the prefrontal cortex. Both treatment with aldosterone and LPS increased the concentration of IL-1β in CSF. Aldosterone treatment also increased the concentration of IL-6 in serum, and depressive-like behaviour. A positive correlation was found between depressive-like behaviour and IL-1β, TNF-α and CINC-1 levels in CSF. Eighteen of the 59 patients invited to participate in the research study at the vascular centre agreed to undergo a psychiatric examination. Fifty-six per cent of the examined patients met the DSM-IV criteria for a current anxiety disorder, 11 % met the DSM-IV criteria for current episode of depression, and 16.6 % had attempted suicide at least once in the past. Conclusions: The findings presented in this thesis support the hypotheses that dysregulation of the RAAS may be involved in the underlying cause of depression and possible also anxiety. Furthermore, it appears that RAAS induces inflammation which, in itself, appears to induce symptoms of depression.