Optimal treatment of social phobia: systematic review and meta-analysis

This article proposes a number of recommendations for the treatment of generalized social phobia, based on a systematic literature review and meta-analysis. An optimal treatment regimen would include a combination of medication and psychotherapy, along with an assertive clinical management program. For medications, selective serotonin reuptake inhibitors and dual serotonin-norepinephrine reuptake inhibitors are first-line choices based on their efficacy and tolerability profiles. The nonselective monoamine oxidase inhibitor, phenelzine, may be more potent than these two drug classes, but because of its food and drug interaction liabilities, its use should be restricted to patients not responding to selective serotonin reuptake inhibitors or serotonin-norepinephrine reuptake inhibitors. There are other medication classes with demonstrated efficacy in social phobia (benzodiazepines, antipsychotics, alpha-2-delta ligands), but due to limited published clinical trial data and the potential for dependence and withdrawal issues with benzodiazepines, it is unclear how best to incorporate these drugs into treatment regimens. There are very few clinical trials on the use of combined medications. Cognitive behavior therapy appears to be more effective than other evidence-based psychological techniques, and its effects appear to be more enduring than those of pharmacotherapy. There is some evidence, albeit limited to certain drug classes, that the combination of medication and cognitive behavior therapy may be more effective than either strategy used alone. Generalized social phobia is a chronic disorder, and many patients will require long-term support and treatment

An improved human anxiety process biomarker: Characterization of frequency band, personality and pharmacology

Anxiety disorders are among the most common mental illness in the western world with a major impact on disability. But their diagnosis has lacked objective biomarkers. We previously demonstrated a human anxiety process biomarker, goal-conflict-specific electroencephalography (EEG) rhythmicity (GCSR) in the stop-signal task (SST). Here we have developed and characterized an improved test appropriate for clinical group testing. We modified the SST to produce balanced numbers of trials in clearly separated stop-signal delay groups. As previously, right frontal (F8) GCSR was extracted as the difference in EEG log Fourier power between matching stop and go trials (that is, stop-signal-specific power) of a quadratic contrast of the three delay values (that is, power when stopping and going are in balanced conflict compared with the average of when stopping or going is greater). Separate experiments assessed drug sensitivity (n = 34) and personality relations (n = 59). GCSR in this new SST was reduced by three chemically distinct anxiolytic drugs (administered double-blind): buspirone (10 mg), triazolam (0.25 mg) and pregabalin (75 mg)" had a frequency range (4–12 Hz) consistent with rodent model data" and positively correlated significantly with neuroticism and nonsignificantly with trait anxiety scores. GCSR, measured in our new form of the SST, should be suitable as a biomarker for one specific anxiety process in the testing of clinical groups and novel drugs and in the development of measures suitable for individual diagnosis

Development of the Ketamine Side Effect Tool (KSET)

Background: Currently, no specific, systematic assessment tool for the monitoring and reporting of ketamine-related side effects exists. Our aim was to develop a comprehensive Ketamine Side Effect Tool (KSET) to capture acute and longer-term side effects associated with repeated ketamine treatments. Methods: Informed by systematic review data and clinical research, we drafted a list of the most commonly reported side effects. Face and content validation were obtained via feedback from collaborators with expertise in psychiatry and anaesthetics, clinical trial piloting and a modified Delphi Technique involving ten international experts. Results: The final version consisted of four forms that collect information at time points: screening, baseline, immediately after a single treatment, and longer-term follow-up. Instructions were developed to guide users and promote consistent utilisation. Limitations: Further evaluation of feasibility, construct validity and reliability is required, and is planned across multiple international sites. Conclusions: The structured Ketamine Side Effect Tool (KSET) was developed, with confirmation of content and face validity via a Delphi consensus process. This tool is timely, given the paucity of data regarding ketamine's safety, tolerability and abuse potential over the longer term, and its recent adoption internationally as a clinical treatment for depression. Although based on data from depression studies, the KSET has potential applicability for ketamine (or derivatives) used in other medical disorders, including chronic pain. We recommend its utilisation for both research and clinical scenarios, including data registries

The Ketamine Side Effect Tool (KSET):A comprehensive measurement-based safety tool for ketamine treatment in psychiatry

Objectives: On a background of the rapidly expanding clinical use of ketamine and esketamine for treatment of depression and other conditions, we examined safety monitoring, seeking to identify knowledge gaps relevant to clinical practice. Methods: An international group of psychiatrists discussed the issue of safety of ketamine and esketamine and came to a consensus on key safety gaps. Results: There is no standard safety monitoring for off-label generic ketamine. For intranasal esketamine, each jurisdiction providing regulatory approval may specify monitoring. Treatment is often provided beyond the period for which safety has been demonstrated, with no agreed framework for monitoring of longer term side effects for either generic ketamine or intranasal esketamine. Limitations: The KSET has established face and content validity, however it has not been validated against other measures of safety. Conclusions: We recommend the Ketamine Side Effect Tool (KSET) as a comprehensive safety monitoring tool for acute and longer term side effects

Epileptiform Activity in Alcohol Dependent Patients and Possibilities of Its Indirect Measurement

Background: Alcohol dependence during withdrawal and also in abstinent period in many cases is related to reduced inhibitory functions and kindling that may appear in the form of psychosensory symptoms similar to temporal lobe epilepsy frequently in conditions of normal EEG and without seizures. Because temporal lobe epileptic activity tend to spread between hemispheres, it is possible to suppose that measures reflecting interhemispheric information transfer such as electrodermal activity (EDA) might be related to the psychosensory symptoms. Methods and Findings: We have performed measurement of bilateral EDA, psychosensory symptoms (LSCL-33) and alcohol craving (ACQ) in 34 alcohol dependent patients and 32 healthy controls. The results in alcohol dependent patients show that during rest conditions the psychosensory symptoms (LSCL-33) are related to EDA transinformation (PTI) between left and right EDA records (Spearman r = 0.44, p,0.01). Conclusions: The result may present potentially useful clinical finding suggesting a possibility to indirectly assess epileptiform changes in alcohol dependent patients

Ribavirin-Induced Anemia in Hepatitis C Virus Patients Undergoing Combination Therapy

The current standard of care for hepatitis C virus (HCV) infection – combination therapy with pegylated interferon and ribavirin – elicits sustained responses in only ∼50% of the patients treated. No alternatives exist for patients who do not respond to combination therapy. Addition of ribavirin substantially improves response rates to interferon and lowers relapse rates following the cessation of therapy, suggesting that increasing ribavirin exposure may further improve treatment response. A key limitation, however, is the toxic side-effect of ribavirin, hemolytic anemia, which often necessitates a reduction of ribavirin dosage and compromises treatment response. Maximizing treatment response thus requires striking a balance between the antiviral and hemolytic activities of ribavirin. Current models of viral kinetics describe the enhancement of treatment response due to ribavirin. Ribavirin-induced anemia, however, remains poorly understood and precludes rational optimization of combination therapy. Here, we develop a new mathematical model of the population dynamics of erythrocytes that quantitatively describes ribavirin-induced anemia in HCV patients. Based on the assumption that ribavirin accumulation decreases erythrocyte lifespan in a dose-dependent manner, model predictions capture several independent experimental observations of the accumulation of ribavirin in erythrocytes and the resulting decline of hemoglobin in HCV patients undergoing combination therapy, estimate the reduced erythrocyte lifespan during therapy, and describe inter-patient variations in the severity of ribavirin-induced anemia. Further, model predictions estimate the threshold ribavirin exposure beyond which anemia becomes intolerable and suggest guidelines for the usage of growth hormones, such as erythropoietin, that stimulate erythrocyte production and avert the reduction of ribavirin dosage, thereby improving treatment response. Our model thus facilitates, in conjunction with models of viral kinetics, the rational identification of treatment protocols that maximize treatment response while curtailing side effects

Pharmacokinetic/pharmacodynamic analysis of adjuvant pegylated interferon α-2b in patients with resected high-risk melanoma

PurposeHigh-dose pegylated interferon α-2b (peginterferon α-2b) significantly decreased disease recurrence in patients with resected stage III melanoma in a clinical study. We investigated the pharmacokinetics (PK) and safety of high-dose peginterferon α-2b in patients with high-risk melanoma.MethodsFor PK analysis, 32 patients received peginterferon α-2b 6 μg/(kg week) subcutaneously for 8 weeks (induction) then 3 μg/(kg week) for 4 weeks (maintenance). PK profiles were determined at weeks 1, 8, and 12. Exposure-response relationships between peginterferon α-2b and absolute neutrophil count (ANC) and alanine aminotransferase (ALT) level were also studied.ResultsPeginterferon α-2b was well-absorbed following SC administration, with a median T (max) of 24 h. Mean half-life estimates ranged from 43 to 51 h. The accumulation factor was 1.69 after induction therapy. PK parameters showed moderate interpatient variability. PK profiles were described by a one-compartmental model with first-order absorption and first-order elimination. Toxicity was profiled and was acceptable; observed side effects were similar to those previously described. Dose reduction produced proportional decreases in exposure and predictable effects on ANC in an Imax model; however, a PK/pharmacodynamic (PK/PD) relationship between peginterferon α-2b and ALT could not be established with high precision.ConclusionsPeginterferon α-2b was well-absorbed and sustained exposure to peginterferon α-2b was achieved with the doses tested. These data confirm and extend previous PK observations of peginterferon α-2b in melanoma and solid tumors. Our PK/PD model of exposure and ANC effect provides useful information for prediction of peginterferon α-2b-related hematologic toxicity

Ribavirin restores ESR1 gene expression and tamoxifen sensitivity in ESR1 negative breast cancer cell lines

Tumor growth is estrogen independent in approximately one-third of all breast cancers, which makes these patients unresponsive to hormonal treatment. This unresponsiveness to hormonal treatment may be explained through the absence of the estrogen receptor alpha (ESR1). The ESR1 gene re-expression through epigenetic modulators such as DNA methyltransferase inhibitors and/or histone deacetylase inhibitors restores tamoxifen sensitivity in ESR1 negative breast cancer cell lines and opens new treatment horizons in patients who were previously associated with a poor prognosis

Influence of IL28B Polymorphisms on Response to a Lower-Than-Standard Dose peg-IFN-α 2a for Genotype 3 Chronic Hepatitis C in HIV-Coinfected Patients

Background: Data on which to base definitive recommendations on the doses and duration of therapy for genotype 3 HCV/HIV-coinfected patients are scarce. We evaluated the efficacy of a lower peginterferon-α 2a dose and a shorter duration of therapy than the current standard of care in genotype 3 HCV/HIV-coinfected patients. Methods and Findings: Pilot, open-label, single arm clinical trial which involved 58 Caucasian HCV/HIV-coinfected patients who received weekly 135 μg peginterferon-α 2a plus ribavirin 400 mg twice daily during 20 weeks after attaining undetectable viremia. The relationships between baseline patient-related variables, including IL28B genotype, plasma HCV-RNA, ribavirin dose/kg, peginterferon-α 2a and ribavirin levels with virological responses were analyzed. Only 4 patients showed lack of response and 5 patients dropped out due to adverse events related to the study medication. Overall, sustained virologic response (SVR) rates were 58.3% by intention-to-treat and 71.4% by per protocol analysis, respectively. Among patients with rapid virologic response (RVR), SVR and relapses rates were 92.6% and 7.4%, respectively. No relationships were observed between viral responses and ribavirin dose/kg, peginterferon-α 2a concentrations, ribavirin levels or rs129679860 genotype. Conclusions: Weekly 135 μg pegIFN-α 2a could be as effective as the standard 180 μg dose, with a very low incidence of severe adverse events. A 24-week treatment duration appears to be appropriate in patients achieving RVR, but extending treatment up to just 20 weeks beyond negativization of viremia is associated with a high relapse rate in those patients not achieving RVR. There was no influence of IL28B genotype on the virological responses. © 2012 López-Cortés et al.Funding provided by Fundación Pública Andaluza para la gestión de la Investigación en Salud de Sevilla. Hospitales Universitarios Virgen del Rocío. Seville, Spain. The enzyme-linked immunosorbent assay Hu-INF-α kits for determination of pegIFN-α-2a were financed by Roche Pharma, S.A. (Spain).Peer Reviewe