Prefrontal-amygdala connectivity in trait anxiety and generalized anxiety disorder: Testing the boundaries between healthy and pathological worries.

BACKGROUND: Current brain-based theoretical models of generalized anxiety disorder (GAD) suggest a dysfunction of amygdala-ventromedial prefrontal cortex emotional regulatory mechanisms. These alterations might be reflected by an altered resting state functional connectivity between both areas and could extend to vulnerable non-clinical samples such as high worriers without a GAD diagnosis. However, there is a lack of information in this regard. METHODS: We investigated differences in resting state functional connectivity between the basolateral amygdala and the ventromedial prefrontal cortex (amygdala-vmPFC) in 28 unmedicated participants with GAD, 28 high-worriers and 28 low-worriers. We additionally explored selected clinical variables as predictors of amygdala-vmPFC connectivity, including anxiety sensitivity. RESULTS: GAD participants presented higher left amygdala-vmPFC connectivity compared to both groups of non-GAD participants, and there were no differences between the latter two groups. In our exploratory analyses, concerns about the cognitive consequences of anxiety (the cognitive dimension of anxiety sensitivity) were found to be a significant predictor of the left amygdala-vmPFC connectivity. LIMITATIONS: The cross-sectional nature of our study preclude us from assessing if functional connectivity measures and anxiety sensitivity scores entail an increased risk of GAD. CONCLUSIONS: These results suggest a neurobiological qualitative distinction at the level of the amygdala-vmPFC emotional-regulatory system in GAD compared to non-GAD participants, either high- or low-worriers. At this neural level, they question previous hypotheses of continuity between high worries and GAD development. Instead, other anxiety traits such as anxiety sensitivity might confer a greater proneness to the amygdala-vmPFC connectivity alterations observed in GAD.

Haloperidol: therapeutic window in schizophrenia.

Twenty-two schizophrenic inpatients were treated for 3 weeks with three randomly fixed oral doses of haloperidol (10, 20, or 30 mg). Analysis of the results by a nonlinear regression model revealed a curvilinear relationship between haloperidol levels in plasma and clinical response, as assessed on the Brief Psychiatric Rating Scale (pseudo-R2 = 0.85, F = 17.7, p < 0.001, correlation between coefficients ranged from 0.99 to -0.52). This curve defines roughly three drug level ranges (low, < 5.5 ng/ml; optimal, 5.5 to 14.4 ng/ml; and high or toxic, > 14.4 ng/ml), which are significant for clinical practice. Patients with high levels improve to a lesser extent or even worsen in negative symptoms, showing a nonstatistically significant trend to present more extrapyramidal symptoms. Our data thus support the existence of a therapeutic window for haloperidol. Schizophrenic patients with acute exacerbation and drug levels in this range would have a greater probability of global clinical improvement.

Positive versus negative symptoms in schizophrenia: response to haloperidol.

1. Clinical response to treatment with haloperidol was studied in 20 schizophrenic inpatients with acute exacerbation (DSM-IIIR). 2. Patients were assigned to fixed doses of haloperidol (10, 20 or 30 mg/day) for three weeks. Clinical assessment was made using scales SAPS, SANS, BPRS and Simpson-Angus Scale for rating of extrapyramidal side effects. 3. Sixteen patients showed forty per cent or more decrease in positive symptoms assessed by SAPS, being considered the group of responders. Six out of the twenty patients showed improvement in negative symptoms assessed by SANS (improvement above 30%). 4. Clinical predictors of response were only identified for SAPS. The group of responders showed higher basal scores in total scale and formal thought disorder. 5. Negative symptoms responsive to treatment were affective flattening and alogia. Improvement in negative symptoms was independent from that in positive ones. 6. Socio-demographic predictors of clinical response were not found. No differences in clinical response were found in relation to the dose administered. 7. The results of our study suggest that negative symptomatology improves in a scheduled treatment with haloperidol. Assessment of negative symptoms may be useful in the evaluation of treatment of acute schizophrenia.