Determinants of brain SPECT perfusion and connectivity in treatment-resistant depression.

This study aims to characterize and compare functional brain single photon emission tomography (SPECT) perfusion and connectivity in treatment-resistant depression (TRD) according to distinct demographic or clinical profiles (male vs. female; old vs. young; unipolar vs. bipolar) and to study their relationship to the severity and the duration of episode/illness. We retrospectively included 127 consecutive patients who met DSM-IV criteria for a nonpsychotic major TRD episode. All patients were studied using (99m)Tc-ethyl cysteinate dimer SPECT. Whole-brain, voxel-based, between-groups analyses were performed according to demographic and clinical data and in comparison to 37 healthy subjects. Voxel-wise interregional correlation was also performed to compare functional SPECT connectivity. Finally, relationships were searched for regarding severity and duration of episode/illness. The whole group of patients exhibited significant hypoperfusion within bilateral fronto-temporal, insular, and anterior cingulate cortices, as well as within the left caudate. Functional connectivity between left frontal and left cerebellar regions was higher in patients than in healthy subjects. Gender, age, and type of mood disorder did not influence these SPECT patterns. A significant relationship was found between brain SPECT perfusion and either duration or global severity of illness in particular frontal areas. Our data support the hypothesis of a shared SPECT pattern, whatever the profile of TRD, involving fronto-temporal regions and the cerebellum.

Left temporopolar impairment in a case of posttraumatic hypersomnia.

OBJECTIVE: We report a focal morphofunctional brain impairment within the left temporopolar cortex in a patient with a posttraumatic hypersomnia. This case may contribute to better understanding the possible pathophysiological mechanism for posttraumatic hypersomnia.

Predictive value of brain perfusion SPECT for rTMS response in pharmacoresistant depression.

PURPOSE: The aim of this study was to determine the predictive value of whole-brain voxel-based regional cerebral blood flow (rCBF) for repetitive transcranial magnetic stimulation (rTMS) response in patients with pharmacoresistant depression. METHODS: Thirty-three right-handed patients who met DSM-IV criteria for major depressive disorder (unipolar or bipolar depression) were included before rTMS. rTMS response was defined as at least 50% reduction in the baseline Beck Depression Inventory scores. The predictive value of (99m)Tc-ethyl cysteinate dimer (ECD) single photon emission computed tomography (SPECT) for rTMS response was studied before treatment by comparing rTMS responders to non-responders at voxel level using Statistical Parametric Mapping (SPM) (p < 0.001, uncorrected). RESULTS: Of the patients, 18 (54.5%) were responders to rTMS and 15 were non-responders (45.5%). There were no statistically significant differences in demographic and clinical characteristics (p > 0.10). In comparison to responders, non-responders showed significant hypoperfusions (p < 0.001, uncorrected) in the left medial and bilateral superior frontal cortices (BA10), the left uncus/parahippocampal cortex (BA20/BA35) and the right thalamus. The area under the curve for the combination of SPECT clusters to predict rTMS response was 0.89 (p < 0.001). Sensitivity, specificity, positive predictive value and negative predictive value for the combination of clusters were: 94, 73, 81 and 92%, respectively. CONCLUSION: This study shows that, in pharmacoresistant depression, pretreatment rCBF of specific brain regions is a strong predictor for response to rTMS in patients with homogeneous demographic/clinical features.

Comparison of escitalopram and citalopram in outpatients with severe major depressive disorder: a prospective, naturalistic, 8-week study.

Objective. Escitalopram is a new selective serotonin reuptake inhibitor indicated for the treatment of major depressive disorder (MDD). The objective of this study is to examine its efficacy in the treatment of severe MDD compared with that of citalopram in daily practice. Method. A prospective, naturalistic, 8-week study was conducted involving 127 patients fulfilling DSM-IV criteria for severe MDD and having a baseline Montgomery-Åsberg Depression Rating Scale (MADRS) score of at least 30. A full non-parsimonious logistic model, called the propensity score, was first defined to reduce bias associated with non-randomization. The primary efficacy analysis was the mean change from baseline to week 8 in MADRS score between the escitalopram and citalopram groups, after stratification on the propensity score. Other efficacy measurements consisted of the Clinical Global Impression of Severity and Improvement scales (CGI-S and CGI-I, respectively), response (defined as a reduction of at least 50% on MADRS from baseline to week 8) and remission rates (defined as MADRS ≤ 12 at week 8), after adjustment on propensity score for escitalopram use. Results. A total of 67 escitalopram-treated patients and 60 citalopram-treated patients were enrolled in this study. Escitalopram reduced mean MADRS total score at week 8 compared with citalopram (-23.5 vs. -17.5; P<0.001). The effect of escitalopram was consistently greater than that of citalopram on the CGI scales. Escitalopram-treated patients were also more likely to respond to treatment (79.4 vs. 44.0%; P<0.001), and remission rates were also in favour of escitalopram (56.9 vs. 11.2%, P<0.001). Analysis of safety data showed better tolerability of escitalopram than that of citalopram. Conclusion. Using adequate methodology to reduce biases due to non-randomization, this study indicates better efficacy and tolerability of escitalopram versus citalopram in severe MDD outpatients.

Effectiveness of clozapine in neuroleptic-resistant schizophrenia: clinical response and plasma concentrations.

OBJECTIVE: To assess the relation between plasma concentrations of clozapine and its 2 main metabolites desmethyl clozapine and clozapine N-oxide, and clinical change in a sample of inpatients with schizophrenia who were resistant to conventional neuroleptics. METHOD: Thirty-seven patients (27 men and 10 women, mean age 34.8 yr) with treatment-resistant schizophrenia were treated with clozapine for 18 weeks; dosage was adjusted according to clinical response, and plasma concentrations of clozapine and of its metabolites were measured weekly by high-performance liquid chromatography. Clinical status was also assessed weekly with the Positive and Negative Syndrome Scale (PANSS). Patients were considered "responsive" if they showed at least a 20% improvement over their baseline PANSS ratings. RESULTS: The mean endpoint clozapine dosage was 486.5 mg/day. There was a significant correlation between the daily dosage of clozapine and the plasma levels of clozapine and of its metabolites (p < 0.05). There was no correlation between the clozapine plasma level and the percent improvement on the PANSS. Clozapine plasma levels were not significantly different between those who responded to clozapine (n = 19) and those who did not (n = 18) and were not significantly different between patients who smoked (n = 28) and those who did not (n = 9). Receiver operating characteristic (ROC) curve analysis determined the plasma level threshold (above which a better clinical response was obtained) to be 550 ng/mL. Using the total of plasma levels of clozapine and its metabolites did not lead to a better sensitivity and specificity. CONCLUSIONS: Our calculated plasma clozapine threshold was higher than that reported by others, but this may be related to the severity of symptoms of our patient sample. Monitoring plasma rates remains a useful tool, together with clinical evaluation, to establish the clozapine dosage for an optimum benefit-risk ratio.