Effect of comorbid tics on a clinically meaningful response to 8-week open-label trial of fluoxetine in obsessive compulsive disorder

Currently, there are limited published data evaluating the effects of tics on serotonin reuptake inhibitor (SRI) monotherapy responses in treating obsessive-compulsive disorder (OCD). One retrospective case-controlled analysis of OCD patients treated with SRI monotherapy showed lesser improvement in OCD symptoms in patients with tics than those without. However, more recently there were preliminary reports of OCD subjects treated with SRI monotherapy which did not demonstrate poorer response in subjects with tics or Tourette's Syndrome (TS). The specific aim of this study was to investigate whether the presence of comorbid chronic tics affected "clinically meaningful improvement" [McDougle, C.J., Goodman, W.K., Leckman, J.F., Barr, L.C., Heninger, G.R., Price, L.H., 1993. The efficacy of fluvoxamine in obsessive-compulsive disorder: effects of comorbid chronic tic disorder. Journal of Clinical Psychopharmacology 13, 354-358] of OCD in an 8-week open-label trial of fluoxetine monotherapy. Seventy-four adult subjects (13 patients with comorbid chronic tics and 61 patients without tics) with a primary DSM-IV OCD diagnosis were treated with up to 40mg fluoxetine for 8 weeks and had at least one post-baseline evaluation. The results indicate that there was a significant response by time in both fluoxetine-with-tic subjects and fluoxetine-without-tic subjects. Additionally, there were 3 (23.0%) OCD subjects with tics who had clinically meaningful improvement versus 16 (26.2%) OCD subjects without tics that demonstrated similar levels of improvement. These findings indicate that OCD patients with or without chronic tic disorders did not have a differential response to an 8-week open-label trial of fluoxetine. Limitations include the relatively low number of tic subjects and the open-label nature of the study. Additional data are needed on how comorbid tics may affect SRI treatment response in OCD.     

Accuracy of single-photon emission computed tomography in differentiating frontotemporal dementia from Alzheimer's disease

Background

Alzheimer''s disease (AD) and frontotemporal dementia (FTD) are the commonest causes of presenile dementia. In the absence of a biological marker, diagnosis is reliant on clinical evaluation. Confirmation is often sought from neuroimaging, including single‐photon emission computed tomography (SPECT). Most previous SPECT studies lack pathological validation.

Aim

To examine the accuracy of SPECT in differentiating FTD from AD in patients with subsequent pathological confirmation.

Methods

Technetium‐99‐labelled hexamethyl propylene amine oxime SPECT images obtained at initial evaluation in 25 pathologically confirmed cases of FTD were examined. These images were visually rated by an experienced blinded nuclear medicine consultant and compared with those of 31 patients with AD, also with pathological validation.

Results

A reduction in frontal cerebral blood flow (CBF) was more common in FTD and was of diagnostic value (sensitivity 0.8, specificity 0.65 and likelihood ratio (LR) 2.25; 95% CI 1.35 to 3.77). A pattern of bilateral frontal CBF reduction without the presence of associated bilateral parietal CBF change is diagnostically more accurate (sensitivity 0.80, specificity 0.81 and +LR 4.13, 95% CI 1.96 to 8.71). Diagnostic categorisation (FTD or AD) on the basis of SPECT alone was less accurate than clinical diagnosis (based on neurology and detailed neuropsychological evaluation). One patient with FTD was initially clinically misdiagnosed as AD, owing to the lack of availability of full neuropsychological assessment. However, SPECT correctly diagnosed this patient, providing a diagnostic gain of 4%.

Conclusion

Technetium‐99‐labelled hexamethyl propylene amine oxime SPECT CBF patterns provide valuable information in the diagnosis of FTD and AD. These data can be better used as an adjunct to clinical diagnosis if pathology is to be correctly predicted in life.Frontotemporal dementia (FTD) is a cortical dementia distinct from other dementing illnesses. It typically presents with personality/behavioural change and decline in social conduct with early loss of insight.^1,2 In the absence of biological markers, the pathological detection of characteristic histological changes remains the gold standard of diagnosis. In life, diagnosis is primarily based on patterns of neurological and neuropsychological findings. However, differentiation from other dementias can be difficult and demands an astute qualitative analysis of various behaviours and neuropsychological test performances.³ With a paucity of experienced neuropsychologists, additional and independent diagnostic information is often sought through imaging, be it structural (CT and MRI) and/or functional (single‐photon emission computed tomography (SPECT) and positron emission tomography).SPECT is used to evaluate patients with dementia and can show purported characteristic changes in FTD and in Alzheimer''s disease (AD).^4,5,6,7,8,9 The technique provides a method of evaluating blood flow in various regions of the brain, which reflects areas of poor function by showing reductions in regional cerebral blood flow (CBF). It has been shown that posterior changes in regional CBF are common in AD,^4,5,6,7 whereas in FTD anterior changes are prevalent^7,8,9 and posterior changes rare.⁷However, CBF changes are neither wholly specific nor invariable in various dementing illnesses. Masterman et al¹⁰ looked at the value of bitemporal hypoperfusion in diagnosing AD, and found that, although a sensitive measure for detecting dementia (0.75), it was poorly specific for AD (0.55). Consequently, bitemporal hypoperfusion on SPECT can be a non‐specific finding in various forms of dementia and is not exclusive to AD. Starkstein et al¹¹ reported deficits in CBF in the frontal (especially orbitofrontal) and anterior temporal cortices in FTD. However, they provided neither the measure of the diagnostic accuracy of SPECT in FTD nor of the diagnostic gain it may provide. Most of these studies are also limited by the fact that the dementia groups are defined clinically. The clinical diagnostic accuracy of FTD in life varies hugely between 14–85%.^12,13,14A few studies have looked at the accuracy of clinical and SPECT findings in relation to the final pathological diagnoses.^{15,16,17,18,19} Although these studies found that SPECT findings do correlate with dementia type, they failed to enquire whether SPECT provides any additional diagnostic gain over clinical judgement. These studies are also severely limited by the small numbers of patients in the FTD groups.The aims of this study include evaluation of the diagnostic accuracy of SPECT in differentiating FTD from AD at initial assessment in a group of patients with final pathological confirmation of diagnosis. We also examined the diagnostic gain SPECT may provide over clinical diagnosis of FTD from among this group of patients with FTD and AD.     

The slow afterhyperpolarization modulates high pH-induced changes in the excitability of rat CA1 pyramidal neurons

Extra- and intracellular recordings from the CA1 region of rat hippocampal slices were employed to examine the role of the slow afterhyperpolarization (sAHP) in modulating the increases in neuronal excitability observed on increasing extracellular pH (pHo) from 7.4 to 7.7. In the majority of experiments, an antidromic conditioning stimulus applied in the presence of D(-)-2-amino-5-phosphonopentanoic acid (D-APV), 6-cyano-7-nitroquinoxaline-2,3-dione disodium salt (CNQX) and bicuculline was employed to elicit a sAHP, and an antidromic test stimulus was applied during the sAHP. At pHo 7.4, a single conditioning stimulus elicited an action potential followed by a sAHP, which in turn inhibited the response to the test stimulus compared with the conditioning stimulus. Increasing the number of action potentials in the conditioning stimulus augmented the sAHP and further inhibited the test response, whereas isoproterenol inhibited the sAHP and prevented the relative inhibition of the test response. At pHo 7.7, a single conditioning stimulus elicited a burst of action potentials followed by a large sAHP, which in turn prevented the test stimulus from eliciting a burst of action potentials and, in extracellular recordings, further increased the inhibition of the test response. The latter effect did not solely reflect a high pHo-induced increase in the conditioning response (and, thus, the subsequent sAHP), but rather involved a more direct effect of high pHo to augment the sAHP. The results indicate that increasing pHo increases the excitability of CA1 neurons to an initial stimulus; however, a high pHo-dependent increase in the sAHP evoked by the initial stimulus limits the response to subsequent stimuli.