Cytochrome P450 2C19 Poor Metabolizer Phenotype in Treatment Resistant Depression: Treatment and Diagnostic Implications

Background: Pharmacogenomic testing, specifically for pharmacokinetic (PK) and pharmacodynamic (PD) genetic variation, may contribute to a better understanding of baseline genetic differences in patients seeking treatment for depression, which may further impact clinical antidepressant treatment recommendations. This study evaluated PK and PD genetic variation and the clinical use of such testing in treatment seeking patients with bipolar disorder (BP) and major depressive disorder (MDD) and history of multiple drug failures/treatment resistance.Methods: Consecutive depressed patients evaluated at the Mayo Clinic Depression Center over a 10-year study time frame (2003–2013) were included in this retrospective analysis. Diagnoses of BP or MDD were confirmed using a semi-structured diagnostic interview. Clinical rating scales included the Hamilton Rating Scale for Depression (HRSD24), Generalized Anxiety Disorder 7-item scale (GAD-7), Patient Health Questionnaire-9 (PHQ-9), and Adverse Childhood Experiences (ACE) Questionnaire. Clinically selected patients underwent genotyping of cytochrome P450 CYP2D6/CYP2C19 and the serotonin transporter SLC6A4. PK and PD differences and whether clinicians incorporated test results in providing recommendations were compared between the two patient groups.Results: Of the 1795 patients, 167/523 (31.9%) with BP and 446/1272 (35.1%) with MDD were genotyped. Genotyped patients had significantly higher self-report measures of depression and anxiety compared to non-genotyped patients. There were significantly more CYP2C19 poor metabolizer (PM) phenotypes in BP (9.3%) vs. MDD patients (1.7%, p = 0.003); among participants with an S-allele, the rate of CYP2C19 PM phenotype was even higher in the BP (9.8%) vs. MDD (0.6%, p = 0.003). There was a significant difference in the distribution of SLC6A4 genotypes between BP (l/l = 28.1%, s/l = 59.3%, s/s = 12.6%) and MDD (l/l = 31.4%, s/l = 46.1%, s/s = 22.7%) patients (p < 0.01).Conclusion: There may be underlying pharmacogenomic differences in treatment seeking depressed patients that potentially have impact on serum levels of CYP2C19 metabolized antidepressants (i.e., citalopram / escitalopram) contributing to rates of efficacy vs. side effect burden with additional potential risk of antidepressant response vs. induced mania. The evidence for utilizing pharmacogenomics-guided therapy in MDD and BP is still developing with a much needed focus on drug safety, side effect burden, and treatment adherence

Applauding with Closed Hands: Neural Signature of Action-Sentence Compatibility Effects

BACKGROUND: Behavioral studies have provided evidence for an action-sentence compatibility effect (ACE) that suggests a coupling of motor mechanisms and action-sentence comprehension. When both processes are concurrent, the action sentence primes the actual movement, and simultaneously, the action affects comprehension. The aim of the present study was to investigate brain markers of bidirectional impact of language comprehension and motor processes. METHODOLOGY/PRINCIPAL FINDINGS: Participants listened to sentences describing an action that involved an open hand, a closed hand, or no manual action. Each participant was asked to press a button to indicate his/her understanding of the sentence. Each participant was assigned a hand-shape, either closed or open, which had to be used to activate the button. There were two groups (depending on the assigned hand-shape) and three categories (compatible, incompatible and neutral) defined according to the compatibility between the response and the sentence. ACEs were found in both groups. Brain markers of semantic processing exhibited an N400-like component around the Cz electrode position. This component distinguishes between compatible and incompatible, with a greater negative deflection for incompatible. Motor response elicited a motor potential (MP) and a re-afferent potential (RAP), which are both enhanced in the compatible condition. CONCLUSIONS/SIGNIFICANCE: The present findings provide the first ACE cortical measurements of semantic processing and the motor response. N400-like effects suggest that incompatibility with motor processes interferes in sentence comprehension in a semantic fashion. Modulation of motor potentials (MP and RAP) revealed a multimodal semantic facilitation of the motor response. Both results provide neural evidence of an action-sentence bidirectional relationship. Our results suggest that ACE is not an epiphenomenal post-sentence comprehension process. In contrast, motor-language integration occurring during the verb onset supports a genuine and ongoing brain motor-language interaction

Prime esperienze di anestesia caudale in chirurgia ortopedica

edito in:"LA SEDAZIONE IN TERAPIA INTENSIVA, ANESTESIA IN OSTETRICIA", LA GARANGOLA, PADOVA

Role of 3D MRI with proset technique in the evaluation of lumbar radiculopathy.

The aim of this study is to demonstrate the effectiveness of 3-Dimensional Magnetic Resonance Imaging (3D MRI) using the ProSet technique in the diagnosis of lumbar radiculopathy and to compare morphological findings with clinical and neurophysiological data. 40 patients suffering from L5 or S1 mono-radiculopathy caused by a disc herniation were evaluated through preliminary clinical assessment and electromyography (EMG) technique. Both conventional spin-echo sequences and 3D coronal FFE with selective water excitation (ProSet imaging) were acquired. Indentation, swelling and tilt angle of the nerve root were assessed by means of a 3D MR radiculography. 3D ProSet multiplanar reconstructions (MPR) were used for quantitative measurements of L5 and S1 nerve root widths. Widths of the symptomatic nerve root were compared with those of the contralateral nerve. Data were processed using Epi Info 3.3 software (CDC, Atlanta, GA, USA) and were compared through a paired t-Student test. We observed an abnormal tilt angle in 22 patients (57,2 percent, P less than 0.05). Morphologic alterations such as monolateral swelling or indentation of the involved roots were found in 36 patients (90 percent, P less than0.01) using 3D MR radiculography. In 10 patients, EMG revealed more nerve roots involved, while 3D FFE with ProSet technique shows a single root involved. In 2 patients, alterations were demonstrated only through EMG technique. We suggest that 3D MR radiculography can provide more information than other techniques about symptomatic disc herniation, supporting the detection of morphological changes of all nerve segments. 3D FFE with ProSet technique demonstrates high sensibility to exactly identify the level of the root involved and can provide an extremely useful tool to lead a surgical planning