Response to Agomelatine Treatment is Independent of Smoking Status and Dosage: Results From the AGOPSYCH Study.

INTRODUCTION: Cigarette smoking influences response to antidepressant treatment. It accelerates the metabolism of several cytochrome P450 (CYP) subtypes, including CYP1A2, and therefore bears the risk of pharmacokinetic interactions with psychotropic drugs using that pathway. Agomelatine is a substrate of CYP1A2; the association between nicotine use and agomelatine dosage, however, has never been studied before. METHODS: Smoking habits were correlated with agomelatine doses and treatment outcomes in a sample of 27 patients with lifetime diagnoses within the schizophrenia spectrum who received agomelatine treatment in addition to their stable antipsychotic treatment regimen because of depressive symptoms. RESULTS: No interactions were found between smoking status and agomelatine dosage, and treatment outcomes did not differ between smokers and nonsmokers. DISCUSSION: Agomelatine efficacy appears to be independent of dosage and smoking status, pointing toward mechanisms beyond mere dose-response relationships. Further research will be necessary to validate these findings.

Neurocognitive Effects of Agomelatine Treatment in Schizophrenia Patients Suffering From Comorbid Depression: Results From the AGOPSYCH Study.

BACKGROUND: Cognitive impairment in schizophrenia is highly disabling and remains one of the major therapeutic challenges. Agomelatine (AGO), an agonist at melatonergic MT1/MT2 receptors and antagonist at 5-HT2C receptors, increases dopamine and norepinephrine in the prefrontal cortex and may therefore have the potential of improving neurocognition in patients with schizophrenia. METHODS: Twenty-seven patients with schizophrenia and comorbid depression were treated with AGO in addition to stable doses of antipsychotic drugs. Cognitive abilities were assessed with the Measurement and Treatment Research to Improve Cognition in Schizophrenia Consensus Cognitive Battery (MCCB) at study entry and after 12 weeks of AGO treatment after the intention-to-treat principle. RESULTS: We observed statistically significant yet clinically negligible increases of the MCCB composite score and the reasoning/problem solving subscore. Patients with unimpaired sleep at baseline showed greater improvements over time than those with sleep disturbances. Changes on the MCCB were not correlated with other psychometric variables. CONCLUSIONS: Despite statistically significant, cognitive improvements after 12 weeks of AGO treatment were clinically irrelevant. Our findings may be limited by baseline properties of the study sample and the study design. In particular, lacking a control group, it cannot be ruled out that improvements were unrelated to AGO treatment. That is why randomized controlled trials are needed to validate the relevance of AGO as a cognitive enhancer in schizophrenia.

Agomelatine for the Treatment of Major Depressive Episodes in Schizophrenia-Spectrum Disorders: An Open-Prospective Proof-of-Concept Study.

BACKGROUND: Depressive episodes in schizophrenia constitute a major clinical problem, and treatment success is often limited by treatment-emergent side effects. Agomelatine, an agonist at melatonergic MT1/MT2 receptors and 5-HT2C receptor antagonist, is a new antidepressant with a novel mode of action which constitutes a potential therapeutic option for depression in schizophrenia. METHODS: Twenty-seven patients with lifetime diagnoses within the schizophrenia spectrum and comorbid depression were treated with agomelatine in addition to stable doses of antipsychotic agents. Severity of depression and other psychopathological domains (positive/negative symptoms, general psychopathology, psychosocial performance) was assessed regularly by means of standardized rating scales during a 6-week acute treatment phase as well as after a 6-week extension phase. Moreover, safety measures (electrocardiograms, laboratory counts, neurological and non-neurological side effects, sleep quality, sexual functioning) were monitored on a regular basis. RESULTS: Depressive symptoms improved significantly during the 6-week acute treatment phase. In parallel, a significant improvement of negative symptoms, global psychopathology, and psychosocial performance was observed, whereas positive symptoms remained stable. Agomelatine was mostly well tolerated with predominantly mild and self-limiting side effects. However, pharmacokinetic interactions with antipsychotic agents were observed. Interestingly, the quality of sleep did not improve significantly, pointing toward mechanisms that do not depend on resynchronization of circadian rhythms. CONCLUSIONS: Agomelatine appears to be safe and efficacious in treating depressive symptoms in patients with schizophrenia. The risk of pharmacokinetic interactions with antipsychotic agents warrants the need of therapeutic drug monitoring, and regular recording of vital signs seems necessary. Further randomized trials will have to confirm these findings.

Rethinking restimulation: a case report.

The individual time-course of the seizure threshold (ST) in electroconvulsive therapy is mostly unknown. It is assumed that a typical seizure is followed by a short refractory period and that ST increases in the long run. We hypothesize ST to be lowered immediately after the refractory period, particularly after inadequate or abortive seizures where risk for prolonged seizures is generally higher. Ketamine anesthesia does not possess pronounced anticonvulsive properties like propofol, etomidate, thiopental, or methohexital. It is therefore ideal to test such a hypothesis. We report the case of a geriatric patient with a major depressive episode, who received 5 consecutive electroconvulsive therapies with S-ketamine, all with identical right unilateral high-energy stimulation and restimulation. Whereas all primary stimulations were inadequate, all restimulations showed significantly improved seizure parameters such as midictal amplitude, maximal postictal heart rate, and average seizure energy index. In this patient, the refractory period turned out to be longer than 1 minute, and ST was lower in all 5 instances of restimulation. This ST decrease could be clinically useful in one-session restimulations.

Strain-encoded cardiac MRI as an adjunct for dobutamine stress testing: incremental value to conventional wall motion analysis.

BACKGROUND: High-dose dobutamine stress MRI is safe and feasible for the diagnosis of coronary artery disease (CAD) in humans. However, the assessment of cine scans relies on the visual interpretation of regional wall motion, which is subjective. Recently, strain-encoded MRI (SENC) has been proposed for the direct color-coded visualization of myocardial strain. The purpose of our study was to compare the diagnostic value of SENC with that provided by conventional wall motion analysis for the detection of inducible ischemia during dobutamine stress MRI. METHODS AND RESULTS: Stress-induced ischemia was assessed by wall motion analysis and by SENC in 101 patients with suspected or known CAD and in 17 healthy volunteers who underwent dobutamine stress MRI in a clinical 1.5-T scanner. Quantitative coronary angiography deemed as the standard reference for the presence or absence of significant CAD (> or =50% diameter stenosis). On a coronary vessel level, SENC detected inducible ischemia in 86 of 101 versus 71 of 101 diseased coronary vessels (P<0.01 versus cine) and showed normal strain response in 189 of 202 versus 194 of 202 vessels with <50% stenosis (P=NS versus cine). On a patient level, SENC detected inducible ischemia in 63 of 64 versus 55 of 64 patients with CAD (P<0.05 versus cine) and showed normal strain response in 32 of 37 versus 34 of 37 patients without CAD (P=NS versus cine). Quantification analysis demonstrated a significant correlation between strain rate reserve and coronary artery stenosis severity (r(2)=0.56, P<0.001), and a cutoff value of strain rate reserve of 1.64 was deemed as a highly accurate marker for the detection of > or =50% stenosis (area under the curve, 0.96; SE, 0.01; 95% CI, 0.94 to 0.98; P<0.001). CONCLUSIONS: The direct color-coded visualization of strain on MR images is a useful adjunct for dobutamine stress MRI, which provides incremental value for the detection of CAD compared with conventional wall motion readings on cine images.

Strain-encoded (SENC) magnetic resonance imaging to evaluate regional heterogeneity of myocardial strain in healthy volunteers: Comparison with conventional tagging.

PURPOSE: To evaluate the ability of strain-encoded (SENC) magnetic resonance imaging (MRI) for regional systolic and diastolic strain analysis of the myocardium in healthy volunteers. MATERIALS AND METHODS: Circumferential and longitudinal peak systolic strain values of 75 healthy volunteers (35 women and 40 men, mean age 44 +/- 12 years) were measured using SENC at 1.5T. MR tagging was used as the reference standard for measuring regional function. Diastolic function was assessed in the 10 youngest (24 +/- 8 years) and 10 oldest (62 +/- 5 years) subjects. RESULTS: Peak strain values assessed with SENC were comparable to those obtained by MR tagging, showing narrow limits of agreement (limits of agreement -5.6% to 8.1%). Regional heterogeneity was observed between different segments of the left ventricle (LV) by both techniques (P < 0.001). Longitudinal strain obtained by SENC was also heterogenous (P < 0.001). Interestingly, no age- or gender-specific differences in peak systolic strain were observed, whereas the peak rate of relaxation of circumferential strain rate was decreased in the older group. CONCLUSION: SENC is a reliable tool for accurate and objective quantification of regional myocardial systolic as well as diastolic function. In agreement with tagged MRI, SENC detected slightly heterogeneous myocardial strain within LV segments.