The Role of Inflammatory Proteins in Anti-Glucocorticoid Therapy for Treatment-Resistant Depression.

BACKGROUND: Optimising treatments for patients with treatment-resistant depression (TRD) is key to reducing the burden of this severe illness. The anti-glucocorticoid medication metyrapone has mixed evidence supporting a role as a possible augmentation treatment in TRD. The degree of treatment resistance in depression has been associated prospectively and retrospectively with elevated inflammation, and inflammatory activity may influence responses to antidepressant treatments. AIMS: To investigate whether levels of pro-inflammatory cytokines are associated with clinical outcomes to metyrapone or placebo. METHODS: A double-blind RCT randomised patients with TRD to 3 weeks of placebo or metyrapone augmentation to ongoing serotonergic antidepressants. No benefit of metyrapone was reported in the primary analysis. The current study assessed levels of pro-inflammatory proteins interleukin-6 (IL-6), tumour necrosis factor (TNFα), c-reactive protein (CRP) and interleukin-10 (IL-10) before randomisation and after treatment as potential moderators and/or mediators of clinical outcomes. RESULTS: The three pro-inflammatory proteins (but not IL-10) were elevated in this sample of patients with TRD compared to a non-affected control group. High pre-treatment IL-6 levels predicted a poorer response in the trial overall but did not moderate response to metyrapone versus placebo. Changes in IL-6 indirectly mediated depression outcome, with metyrapone increasing IL-6 levels and IL-6 increase associated with a poorer outcome on depression. Other inflammatory proteins did not mediate or moderate treatment outcomes. INTERPRETATION: Metyrapone is hypothesised to have a therapeutic effect in depression on the basis of inhibiting the synthesis of cortisol. In this study, metyrapone did not reduce cortisol, possibly due to glucocorticoid system overcompensation). The mediation effect of IL-6 may support this and perhaps help to indicate why the treatment was not effective.

Neuropsychological study of IQ scores in offspring of parents with bipolar I disorder.

INTRODUCTION: Studies comparing IQ in Offspring of Bipolar Parents (OBP) with Offspring of Healthy Controls (OHC) have reported conflicting findings. They have included OBP with mental health/neurodevelopmental disorders and/or pharmacological treatment which could affect results. This UK study aimed to assess IQ in OBP with no mental health/neurodevelopmental disorder and assess the relationship of sociodemographic variables with IQ. METHODS: IQ data using the Wechsler Abbreviated Scale of Intelligence (WASI) from 24 OBP and 34 OHC from the North East of England was analysed using mixed-effects modelling. RESULTS: All participants had IQ in the average range. OBP differed statistically significantly from OHC on Full Scale IQ (p = .001), Performance IQ (PIQ) (p = .003) and Verbal IQ (VIQ) (p = .001) but not on the PIQ-VIQ split. OBP and OHC groups did not differ on socio-economic status (SES) and gender. SES made a statistically significant contribution to the variance of IQ scores (p = .001). CONCLUSIONS: Using a robust statistical model of analysis, the OBP with no current/past history of mental health/neurodevelopmental disorders had lower IQ scores compared to OHC. This finding should be borne in mind when assessing and recommending interventions for OBP.

Soft neurological signs do not increase with age in euthymic bipolar subjects.

BACKGROUND: Soft neurological signs (SNS) are found to be in excess in bipolar disorder (BD). This paper explores changes in SNS with ageing to ascertain whether BD is associated with a progressive neurological decline or a relatively fixed, persistent deficit. METHODS: 53 euthymic BD subjects and controls, aged 15-55 years, were for examined for the presence of SNS which were rated using a modified Kolakowska battery. RESULTS: In controls, SNS scores increased slowly and significantly with age whereas in BD subjects high scores occurred throughout the age range and were not age dependent. This confirms and extends an earlier, smaller, study which is reanalysed. LIMITATIONS: The study design was cross-sectional whereas a longitudinal study would better reveal changes in soft signs with ageing. CONCLUSIONS: The studies suggest strongly that BD is accompanied by a significant neurobiological deficit which may progress only minimally with increasing age.

Neuropsychological dysfunction, soft neurological signs and social disability in euthymic patients with bipolar disorder.

BACKGROUND: Neurocognitive deficits exist in euthymic patients with bipolar disorder, but relationships between symptoms, psychosocial and neurological factors remain uncertain. AIMS: To measure neurocognitive function in bipolar disorder and explore links to sub-syndromal mood symptoms, soft neurological signs and psychosocial impairment. METHOD: Attention, memory and executive function were tested in 37 euthymic patients with bipolar disorder and 37 controls. Psychosocial functioning, soft neurological signs and residual mood symptoms were assessed. RESULTS: Performances on tests reflecting executive function and verbal memory (but not attention) were significantly poorer in the bipolar disorder group. Sub-syndromal mood symptoms produced small cognitive effects, predominantly on verbal memory. Soft neurological signs, especially frontal signs, were marked; some patients showed marked social disability which correlated strongly with soft neurological signs but weakly with executive dysfunction, which was linked to illness episodes. CONCLUSIONS: Cognitive dysfunction, social dysfunction and soft signs occur in euthymic patients with bipolar disorder and may represent trait deficits.

Effects of adjunctive mifepristone (RU-486) administration on neurocognitive function and symptoms in schizophrenia.

BACKGROUND: It has been suggested that hypercortisolemia may cause or exacerbate both neurocognitive impairment and symptoms in schizophrenia. We hypothesized that antiglucocorticoid treatments, particularly glucocorticoid receptor (GR) antagonists, would improve neurocognitive functioning and clinical symptoms in this disorder. METHOD: Twenty patients with schizophrenia were treated with 600 mg/day of the GR-antagonist mifepristone (RU-486) or placebo for 1 week in a double-blind, crossover design. Neurocognitive function was evaluated at baseline and 2 weeks after each treatment. Neuroendocrine profiling was performed at these times and also immediately after each treatment. Symptoms were evaluated weekly. RESULTS: Mifepristone administration resulted in a temporary two- to threefold increase in plasma cortisol levels (p < .0001). No significant effects were observed on any measure of neurocognitive function, including the primary outcome measures of spatial working memory and declarative memory. Minor changes in symptoms occurred in both arms of the study and were indicative of a general improvement over time, irrespective of treatment. CONCLUSIONS: In contrast to our earlier report of positive effects in bipolar disorder, these data suggest that the GR-antagonist mifepristone has no effect on neurocognitive function or symptoms in this group of patients with schizophrenia. Future studies in schizophrenia should examine patients with demonstrable hypothalmic-pituitary-adrenal axis dysfunction.

Enlargement of the Third Ventricle in affective disorders.

INTRODUCTION: There have been inconsistent reports of dilation of the third ventricle (lll-V) in bipolar disorder. Within the lateral walls of lll-V are hypothalamic nuclei which mediate the neuroendocrine, sleep, appetite and autonomic disturbances which characterise a depressive episode. METHODS: The lll-V width, immediately anterior to the mamillary bodies, was measured in 74 bipolar I or II subjects (m=25, f=49, mean age 36.1(1 l.3yr) and 33 healthy controls (m= 17, f= 16, mean age 35.6( 12.6yr) from MRI coronal inversion recovery scans. RESULTS: Bipolar subjects had significantly (t=2.l6,p=0.03) wider lll-V (0.45(0.15cm) than controls (0.40(0.12cm). Examining data with a General Linear Model with gender and diagnoses as categoric variables and age as a continuous variable, lll-V width depended significantly on gender (p=O.OI6), age (p< 0.00l) and differed significantly (p=0.03) between bipolar subjects and controls. The rate of lll-V dilation was estimated to be 0.0048cm/yr in male bipolar subjects and 0.0040cm/yr in females. COMMENT: Bipolar disorder is associated with increased lll-V width and progressive dilation. It is proposed that dilation may be associated with dysfunction of hypothalamic nuclei in the lll-V lateral walls.

A randomized controlled trial of fluvoxamine in prostatodynia, a male somatoform pain disorder.

BACKGROUND: Prostatodynia is a common and often disabling condition that affects males and has the characteristics of a somatoform pain disorder. It presents with urogenital pain and urinary symptoms. Failure of conventional treatment and a successful uncontrolled pilot study with fluvoxamine in this condition prompted this study. METHOD: In a randomized double-blind trial, 42 patients with prostatodynia were assigned to receive either fluvoxamine (N = 21) or placebo (N = 21) for up to 8 weeks. Doses were adjusted according to therapeutic need. The median dose of fluvoxamine was 150 mg (range, 50-300 mg). Self-rated pain scores, urinary flow rates, and depression and anxiety scores were measured at baseline and several times throughout the study period. RESULTS: The groups were similar at baseline, and the results were examined by intent-to-treat analysis either using the last observation carried forward or, in the case of dichotomous measures, counting treatment dropouts as treatment failures. Fluvoxamine was significantly more likely to reduce pain intensity (p = .01) and normalize urinary flow rates (p = .03) with a clinically significant number needed to treat value of 1.5 (confidence interval = 1.12 to 5.50). This therapeutic effect could not be attributed to change in mood, as the 2 groups did not differ with respect to affective ratings at the end of the study. The fluvoxamine-treated group had significantly lower (p = .02) final scores on the General Health Questionnaire, indicating an overall benefit from pain relief. CONCLUSION: Fluvoxamine is a viable treatment for prostatodynia. Dose-ranging studies and longer trials are needed to evaluate this agent further.