Hypothalamic-pituitary-adrenal system, neurotrophic factors and clozapine response: association with FKBP5 and NTRK2 genes.

Clozapine is an atypical antipsychotic drug known as being more effective compared with traditional antipsychotics for patients with poor response or resistance to treatment. It has been demonstrated that clozapine modulates hypothalamic-pituitary-adrenal activity and affects central brain-derived neurotrophic factor levels, which could explain part of its therapeutic efficacy. In this study, we investigated the role of genes related to the hypothalamic-pituitary-adrenal axis (FKBP5 and NR3C1) and neurotrophic factors (BDNF and NTRK2) in clinical response to clozapine in 591 schizophrenia patients. We found significant allelic and genotype associations between FKBP5-rs1360780, NTRK2-rs1778929 and NTRK2-rs10465180 polymorphisms and clozapine response. The haplotypes composed of rs1360780-rs3777747-rs17542466-rs2766533 (FKBP5) and rs1619120-rs1778929-rs10465180 (NTRK2) were also nominally significant. Our results suggest that genetic variability in FKBP5 and NTRK2 genes may partially explain clinical response to clozapine. Further studies are needed to clarify the involvement of these genes in clinical response to atypical antipsychotics.

Factors associated with severe impact of lipodystrophy on the quality of life of patients infected with HIV-1.

A standardized questionnaire was used to assess the impact of lipodystrophy (LD) on quality of life (QoL). Eighty-four consecutive asymptomatic human immunodeficiency virus type 1 (HIV-1)-infected outpatients with clinical LD completed a modified version of the Dermatology Life Quality Index (DLQI) survey to measure the impact of body fat changes on their QoL. Body changes influenced dressing for 55 patients (65%), produced feelings of shame for 41 (49%), and disrupted sexual life for 23 (27%). There was a greater impact on the DLQI due to body changes among women, injection drug users, patients with abdominal or breast lipoaccumulation, and patients with a high number of non-LD side effects. Multivariate proportional odds model analysis showed that the severity of non-LD-associated side effects and the presence of breast lipoaccumulation were associated with impaired psychosocial functioning. Specific characteristics of patients, antiretroviral-based side effects, and breast lipoaccumulation exert a greater impact on QoL in HIV-1-infected patients with LD.

Parahippocampal gray matter density in panic disorder: a voxel-based morphometric study.

OBJECTIVE: The authors examined possible cerebral gray matter abnormalities in patients with panic disorder. METHOD: Gray matter concentration in 18 panic disorder outpatients and 18 healthy subjects was compared by using a voxel-based morphometry approach. RESULTS: Gray matter density of the left parahippocampal gyrus was significantly lower in patients with panic disorder compared with healthy subjects. CONCLUSIONS: This result provides further support for the involvement of the parahippocampal area in the pathophysiology of panic disorder.

Frontal cerebral perfusion after antidepressant drug treatment versus ECT in elderly patients with major depression: a 12-month follow-up control study.

BACKGROUND: Little is known about the evolution of brain perfusion alterations in patients with major depression, and still less about the changes in functional neuroimage produced by different antidepressant biological treatments. METHOD: Between January 2001 and December 2003, long-term follow-up frontal brain perfusion was compared in 2 subgroups of elderly patients (>or= 60 years) treated for severe unipolar major depression (DSM-IV): one subgroup of 16 patients administered electroconvulsive therapy, and another of 26 patients receiving pharmacologic treatment. All patients were remitters. A medication-free brain single photon emission computed tomography was performed in baseline conditions and after a minimum period of 12 months of euthymia. Twenty-eight age- and sex-matched healthy controls were also assessed. RESULTS: No significant differences were found between the 2 subgroups in frontal uptake ratios after a 12-month follow-up period of euthymia. During the acute episode, patients presented significant anterior hypofrontality; 12 months later the hypofrontality had disappeared. CONCLUSION: The long-term evolution of frontal perfusion in elderly major depressives who respond to antidepressant biological treatment is essentially the same in those who receive electroconvulsive therapy and in those who receive medication.

Brain effects of cognitive remediation therapy in schizophrenia: a structural and functional neuroimaging study.

BACKGROUND: Cognitive remediation therapy positively affects cognition and daily functioning in patients with schizophrenia. However, studies on the underlying neurobiological mechanisms of this treatment are scarce. The aim of the current study was to investigate functional and structural connectivity brain changes in schizophrenia patients after cognitive remediation therapy using a whole-brain approach that combined functional magnetic resonance imaging and diffusion tensor imaging. METHODS: A randomized controlled trial with 30 schizophrenia outpatients and 15 healthy volunteers. A strategy-learning-based treatment was used as a cognitive remediation therapy. A social skills training that provides useful information about illness management was used as an active control. We investigated changes in the pattern of functional connectivity assessed during an n-back task by tensorial independent component analysis as implemented in the multivariate exploratory linear decomposition into independent components and in the fractional anisotropy index of white matter integrity using tract-based spatial statistics. RESULTS: Brain networks activation pattern significantly changed in patients exposed to the cognitive treatment in the sense of normalizing toward the patterns observed in healthy control subjects. Additionally, in white matter, they showed an increase in fractional anisotropy index in the anterior part of the genu of the corpus callosum. Cognitive improvement, functional, and also structural changes showed statistically significant correlations. CONCLUSIONS: Improvement in brain functioning detected after cognitive remediation therapy in schizophrenia patients might be based on an increase of the interhemispheric information transfer between the bilateral prefrontal cortexes via the corpus callosum.

Volume changes in gray matter in first-episode neuroleptic-naive schizophrenic patients treated with risperidone.

Structural neuroimaging techniques have consistently shown that treatment of schizophrenic patients with conventional antipsychotics causes an increase in basal ganglia volume. However, findings in schizophrenic patients treated with the newer atypical antipsychotic drugs are less consistently reported. To explore this issue, the authors used a whole-brain, unbiased, and automated technique for comparing brain structural features across scans in schizophrenic patients before and after a treatment with the atypical antipsychotic risperidone. T1-weighted images from 11 first-episode neuroleptic-naive schizophrenic patients were processed and analyzed for regions of interest (basal ganglia) by using optimized voxel-based morphometry. Scans were repeated after 3 months of continuous treatment with risperidone. Region of interest-based voxel-based morphometry analyses revealed increases in gray matter volume for the right and left caudate nuclei and for the left accumbens after the treatment with risperidone. Hence, in our sample of schizophrenic patients, treatment with risperidone was associated, in contrast to the findings for other atypical antipsychotics, with an increase in basal ganglia volume. Such discrepancy could be related to the pharmacodynamics of risperidone (the atypical antipsychotic showing the higher affinity for D2 receptors) and the rather high mean doses used in our study (ie, 6.05 mg/d).

Reduced levels of creatine in the right medial temporal lobe region of panic disorder patients detected with (1)H magnetic resonance spectroscopy.

In vivo proton magnetic resonance spectroscopy ((1)H MRS) was used to study possible neurochemical abnormalities in drug-free, symptomatic panic disorder patients at rest. (1)H MRS was performed in 11 panic disorder patients and 11 healthy age- and sex-matched comparison subjects. Levels of brain metabolites were determined in the right medial temporal lobe region (encompassing the whole amygdala and part of the hippocampus) and in the medial prefrontal cortex on the basis of previous work with both structural and functional neuroimaging techniques. The concentration of creatine and phosphocreatine, metabolites involved in energy-dependent systems in brain, was significantly lower in the right medial temporal lobe region of panic disorder patients compared to healthy subjects. No significant differences between the two groups were observed in the medial prefrontal cortex. These results provide neurochemical evidence suggesting the involvement of the amygdalohippocampal region in the pathogenesis of panic disorder.

Amygdalar atrophy in panic disorder patients detected by volumetric magnetic resonance imaging.

It has been suggested that the pathophysiology of panic disorder (PD) may involve abnormalities in several brain structures, including the amygdala. To date, however, no study has used quantitative structural neuroimaging techniques to examine amygdalar anatomy in this disorder. Volumetric magnetic resonance imaging (MRI) studies of the amygdalas, hippocampi, and temporal lobes were conducted in 12 drug-free, symptomatic PD patients (six females and six males), and 12 case-matched healthy comparison subjects. Volumetric MRI data were normalized for brain size. PD patients were found to have smaller left-sided and right-sided amygdalar volumes than controls. No differences were found in either hippocampi or temporal lobes. These findings provide new evidence of changes in amygdalar structure in PD and warrant further anatomical and MRI brain studies of patients with this disorder.