Christopher B. Kelly

Predictors of therapy resistant asthma: outcome of a systematic evaluation protocol

Background: It has been suggested that asthmatic subjects with persisting symptoms despite adequate maintenance therapy should be systematically evaluated to identify factors contributing to poor control. The aims of this study were to examine the prevalence of these factors in a cohort of sequentially referred poorly controlled asthmatics, and to determine if any factor or combination of factors predicted true therapy resistant asthma (TRA). Methods: Patients were evaluated using a systematic evaluation protocol including induced sputum analysis, psychiatric assessment, ear, nose and throat examination, pulmonary function testing, high resolution CT scan of the thorax, and 24 hour dual probe ambulatory oesophageal pH monitoring; any identified provoking factor was treated. Asthma was managed according to BTS guidelines. Results: Of 73 subjects who completed the assessment, 39 responded to intervention and 34 had TRA. Subjects with TRA had a greater period of instability, a higher dose of inhaled steroids at referral, more rescue steroid use, and a lower best percentage forced expiratory volume in 1 second (FEV1%). Oesophageal reflux, upper airway disease, and psychiatric morbidity were common (57%, 95%, 49%, respectively) but were not more prevalent in either group. Using multivariate logistic regression analysis, inhaled steroid dose >2000 μg BDP, previous assessment by a respiratory specialist, and initial FEV1% of <70% at referral predicted a final diagnosis of TRA. Conclusions: In poorly controlled asthmatics there is a high prevalence of co-morbidity, identified by detailed systematic assessment, but no difference in prevalence between those who respond to intervention and those with TRA. Targeted treatment of identified co-morbidities has minimal impact on asthma related quality of life in those with therapy resistant disease.

The MTHFR C677T polymorphism is associated with depressive episodes in patients from Northern Ireland.

Low plasma folate and its derivatives have been linked with depressive disorders in studies dating back over 30 years. A thermolabile variant (677C>T) of the enzyme 5,10-methylenetetrahydrofolate reductase (MTHFR) is associated with low serum folate. The present study aimed to explore whether the thermolabile variant of MTHFR is associated with a vulnerability to depressive episodes. MTHFR C677T genotype frequencies in a cohort of patients (mean age 48 years) with depressive disorder (n = 100) were compared with those in age- and sex-matched controls. Serum levels of folate, homocysteine and vitamin B12 were also compared between groups. The thermolabile variant of MTHFR was significantly more common in the group with a history of depressive disorder (P= 0.03). Serum levels of folate, homocysteine and vitamin B12 did not differ significantly between groups. A MTHFR C677T genotype is associated with increased risk of depressive episodes in this homogenous patient population.

Gender influences the detection of spatial working memory deficits in bipolar disorder.

OBJECTIVE Despite evidence that gender may influence neurocognitive functioning, few studies have examined its effects in bipolar disorder (BD) a priori. The aim of this study was to examine how gender influences executive-type functions, which are potentially useful as endophenotypes for BD. METHODS The performance of 26 euthymic patients (12 males, 14 females) with DSM-IV BD (20 BD type I and six BD type II) was compared to that of 26 controls (12 males, 14 females) on tests of executive function. Controls were matched to patients on an individual basis for sex, age and premorbid IQ. Tests assessed spatial working memory (SWM), planning, attentional set-shifting and verbal fluency. RESULTS Overall, patients showed deficits in SWM strategy (p < 0.001) and made more SWM errors relative to controls (p < 0.001). These deficits were more apparent in male-only comparisons (both p < 0.001) than in female-only comparisons (both p < 0.05). When examined in isolation, male controls were significantly better at performing the SWM task than female controls (both p < 0.05). This pattern was not observed in the patient cohort: male patients had poorer strategy scores than female patients (p < 0.05), but made a similar number of SWM errors. CONCLUSIONS These findings provide evidence that gender can influence the detection of SWM deficits in the euthymic phase of BD, as the sex-related disequilibrium in SWM identified in healthy controls was disrupted in BD.

Normal levels of prepulse inhibition in the euthymic phase of bipolar disorder

BACKGROUND Deficits in prepulse inhibition (PPI) of the acoustic startle response have been suggested as a potentially useful endophenotype for schizophrenia spectrum disorders and may explain certain symptoms and cognitive deficits observed in the psychoses. PPI deficits have also been found in mania, but it remains to be confirmed whether this dysfunction is present in the euthymic phase of bipolar disorder. METHOD Twenty-three adult patients with DSM-IV bipolar disorder were compared to 20 controls on tests of acoustic startle reactivity and PPI of the startle response. Sociodemographic and treatment variables were recorded and symptom scores assessed using the Hamilton Depression Inventory and the Young Mania Rating Scale. RESULTS Overall, the patient and control groups demonstrated similar levels of startle reactivity and PPI, although there was a trend for the inter-stimulus interval to differentially affect levels of PPI in the two groups. CONCLUSIONS In contrast to bipolar patients experiencing a manic episode, general levels of PPI were normal in this euthymic sample. Further studies are required to confirm this finding and to determine the mechanisms by which this potential disruption/normalization occurs. It is suggested that an examination of PPI in a high-risk group is required to fully discount dysfunctional PPI as a potentially useful endophenotype for bipolar disorder.

Differences and variability in plasma noradrenaline between depressive and anxiety disorders

Plasma noradrenaline (NA) levels were compared between two groups of patients with major depressive disorder (melancholic/psychotic and non-melancholic), patients with general anxiety disorders and healthy controls. The melancholic/psychotic depressed group had the highest plasma NA levels. This only reached statistical significance with respect to the control group. Within the depressed group, there was no association between plasma NA levels and age, weight loss, ratings of depression, anxiety or plasma cortisol levels. Variance of plasma NA was greatest in the melancholic/psychotic depressed group. A review of previous studies shows an association between raised plasma NA, depressive illness and alterations in NA variance. This association may be limited to melancholic/psychotic depressed patients. The above findings support a dysregulated noradrenergic system in depressive illness.

Plasma norepinephrine and prediction of outcome in major depressive disorder.

BACKGROUND Several epidemiologic and clinical factors have been shown to predict long term outcome in major depressive disorder (MDD). The value of biological predictors has not been extensively studied. This study examined whether plasma norepinephrine may be useful in predicting outcome in MDD. METHODS Forty patients were followed up 8 years after an index major depressive episode. Three outcome variables were assessed: time to first recurrence (the primary outcome measure), the Lee and Murray criteria and the Depression Outcome Scale (DOS). The results were examined against plasma norepinephrine value, at the index episode, using survival analysis and linear regression. RESULTS High plasma norepinephrine at the index episode was positively and significantly associated with time to first recurrence for patients with nonpsychotic MDD (n = 31, chi 2 = 8.38, on 1 df, p < .01). Similarly, plasma norepinephrine was significantly associated with good global outcome, both using Lee and Murray criteria (n = 34, adjusted R2 = .24, p < .01) and DOS criteria (n = 31, adjusted R2 = .17, p < .01) for this group of patients. In contrast, plasma norepinephrine was not significantly related to outcome for MDD with psychotic features. CONCLUSIONS Plasma norepinephrine at index episode seems to be a predictor of outcome in MDD.

Plasma norepinephrine response to a cold pressor test in subtypes of depressive illness

Noradrenergic systems have been shown to be disordered in depressive illness. The plasma norepinephrine response to a cold pressor test was used to investigate norepinephrine activity in subtypes of depressive illness. Patients with melancholic or psychotic depression, non-melancholic depression, general anxiety disorder and normal control subjects had a cold pressor test carried out under standard conditions. Blood samples were taken to measure plasma norepinephrine during the test. The plasma norepinephrine response to a cold pressor test was reduced in the melancholic/psychotic depressed patients compared to control subjects. No other intergroup comparisons were statistically significant. These results suggest noradrenergic systems are disturbed and subresponsive to stress in melancholic/psychotic depressed patients. This does not appear related to other clinical or biochemical factors.

Deliberate self-poisoning presenting at a rural hospital in Northern Ireland 1976-1996: relationship to prescribing

PURPOSE This study reports on a project to monitor deliberate self-poisoning in a rural area of Northern Ireland over a 20-year period. Comparison is made with reports from large urban centres. In addition, a local prescribing database allows assessment of any association between psychotropic drug prescription and use for deliberate self-poisoning. MATERIALS AND METHODS Frequency of self-poisoning, demographic details and drugs used were recorded for all episodes of deliberate self-poisoning occurring at Craigavon Area Hospital for the years 1976, 1986, 1991 and 1996. It was possible to compare prescriptions of psychotropic drugs with their use for deliberate self-poisoning between the years 1991 and 1996 in the region served by the hospital, using the Defined Daily Dose (DDD) system. RESULTS In this rural area the pattern of deliberate self-poisoning has changed, as in urban centres, with a rise in frequency and the male/female ratio approaching unity. The pattern of drug use has altered, with paracetamol overtaking benzodiazepines as the most commonly used agent. More recently, antidepressants have become the second most frequently used drug class for this purpose. Psychotropic medications used for self-poisoning altered in proportion to their prescription between the years 1991 and 1996. CONCLUSIONS In the face of a continuing rise in deliberate self-poisoning, which is effecting both urban and rural areas, care should be taken to prescribe the least toxic agent available as this is associated with likely frequency of self-poisoning for most classes of psychotropic drug.

Acute tryptophan depletion does not alter central or plasma brain-derived neurotrophic factor in the rat.

Dietary induced acute tryptophan depletion (ATD) is used to reduce central serotonergic function and to investigate the role of serotonin (5-HT) in psychiatric illness. In healthy volunteers ATD produces working memory deficits and decreases mood in some studies. Brain-derived neurotrophic factor (BDNF) plays a role in both cognition and in the regulation of mood; however, the possible contribution of central BDNF changes to the effects of ATD has not been examined. Therefore, using a rat model we have examined the effect of amino acid mixture-induced ATD on plasma and central BDNF protein levels. ATD significantly reduced free-plasma TRP by 79% and central hippocampal 5-HT by 35% when compared to controls. However, plasma or central BDNF protein levels in the hippocampus and midbrain were not significantly altered by ATD. These results suggest that changes in central BDNF do not contribute to the cognitive or mood effects of ATD.

β2-Adrenoceptor antagonism in anxiety

Abstract The relative role of β1-and β-adrenoceptor andngonism in the management of anxiety symptoms is not clear. We studied the effect of ICI 118,551, a selective β2-antagonist, in 51 patients presenting with acute anxiety symptoms and fulfilling DSM-III criteria for anxiety disorder. All patients received placebo during the first week of treatment followed by thrice daily diazepam (2 mg) or ICI 118,551 (50 mg) or placebo for 4 weeks with double-blind, random allocation. Hamilton anxiety scale scores improved on all treatments but there was no significant difference between treatments. β2-adrenoceptor antagonism does not appeat to be effective in acute anxiety neurosis. Some earlier literature suggests that β1-antagonism may be more important.