Patient-rated Clinical Global Impression Research Articles

Durability of the Clinical Benefit of Droxidopa for Neurogenic Orthostatic Hypotension During 12 Weeks of Open-Label Treatment.

IntroductionDroxidopa is approved to treat neurogenic orthostatic hypotension (nOH) symptoms in patients with autonomic failure based on short-term clinical trial data. Additional data on the long-term efficacy of droxidopa are needed. We have evaluated the 12-week efficacy and tolerability of droxidopa in patients with nOH in an open-label period of an ongoing phase 4 study .MethodsPatients received 12 weeks of open-label treatment with an individually optimized droxidopa dose (100–600 mg, 3 times daily) as identified during a preceding titration period. Patient-reported outcomes included the Orthostatic Hypotension Symptom Assessment (OHSA), Orthostatic Hypotension Daily Activity Scale (OHDAS), and clinician- and patient-rated Clinical Global Impression–Severity (CGI-S) scales. Supine blood pressure (BP) and adverse events (AEs) were recorded.ResultsData from 114 patients enrolled into the 12-week open-label period were available for analyses. After 12 weeks of droxidopa treatment, patients reported significant (P < 0.0001) improvements from baseline in OHSA and OHDAS composite and individual item scores and on clinician and patient CGI-S scores. Mean ± SD supine systolic and diastolic BP at week 12 increased by 15.5 ± 22.9 and 7.8 ± 11.7 mmHg from baseline, respectively (P < 0.0001 for both). The most frequently reported AEs were falls (17%), headache (13%), and dizziness (9%); one (0.9%) patient reported an AE of supine hypertension.ConclusionDuring 12 weeks of open-label treatment, droxidopa was associated with significant improvement from baseline in nOH symptoms and activities of daily living. No clinically important changes in supine hypertension or AEs of concern were observed. These results support the efficacy of droxidopa beyond 2 weeks of treatment. Trial RegistrationNCT02586623.Supplementary InformationThe online version contains supplementary material available at 10.1007/s40120-021-00317-5.

Does ultrasound-guidance improve the outcome of botulinum toxin injections in cervical dystonia?

PurposeUltrasound-guided injections of botulinum neurotoxin in cervical dystonia have a number of theoretical advantages. However, their action has never been compared to that of non-guided injections. The objectives of the study were to compare the outcome of botulinum neurotoxin type A treatment in patients with idiopathic, focal cervical dystonia, according to two methods: inspection and palpation of anatomical landmarks (non-guided group) or ultrasound guidance (ultrasound-guided group). MethodsWe included consecutive patients in this single-center, prospective, real-life, non-randomized study. The outcomes were evaluated one month after the injections: Cervical Dystonia Impact Profile 58 (main outcome), Toronto Western Spasmodic Torticollis Rating Scale-2 (pain and disability subscores), Toronto Western Spasmodic Torticollis Rating Scale-PSYCH, patient-rated Clinical Global Impression - Improvement and adverse events. We used propensity score methods for statistical analysis; ten predefined confounding factors were used to build the propensity score. ResultsSixty-three patients were included in the non-guided group, and 60 other patients in the ultrasound-guided group. We found no difference in main and secondary outcomes between the two study groups. ConclusionThis is the first direct comparison between ultrasound-guided and non-guided botulinum neurotoxin type A injections in patients with cervical dystonia. We hypothesize that ultrasound guidance made it possible to obtain the same results in the most severe (or the most demanding) patients as in the best responders. Further studies are still needed to assess the impact of botulinum neurotoxin injections into deep cervical muscles.

An Internally Validated Nomogram for Predicting the Likelihood of Improvement of Clinical Global Impression in Patients With Lifelong Premature Ejaculation Treated With Dapoxetine

BackgroundAlthough the introduction of dapoxetine has ushered in a new era in the treatment of premature ejaculation, many patients with lifelong premature ejaculation (LPE) exhibit an unimproved clinical global impression even after treatment with dapoxetine. AimTo investigate independent predictors of the improvement of Clinical Global Impression (iCGI) in patients with LPE treated with dapoxetine and develop a nomogram to predict a patient's likelihood of achieving iCGI. MethodsData of 243 patients with LPE diagnosed at Xijing Hospital (Xi'an, China) and Northwest Women's and Children's Hospital (Xi'an, China) from January 2019 to May 2020 were analyzed. Independent predictors of iCGI were identified, and a nomogram was developed using R software based on a multivariate logistic regression model. The predictive accuracy of the nomogram was measured using the area under the receiver operating characteristic curve. The nomogram was calibrated by comparing predictions with observations. Main Outcome MeasuresThe primary outcome was the patient-rated Clinical Global Impression of Change scale score after a 4-week course of dapoxetine treatment, which was collected via an online questionnaire. A Clinical Global Impression of Change score of ≥1 was defined as iCGI in this study. ResultsPatients with LPE with at least a bachelor's degree, a self-reported intravaginal ejaculation latency time of >1 minute, and an International Index of Erectile Function question 5 score of ≥3 were independent factors associated with achieving iCGI, whereas a Premature Ejaculation Diagnostic Tool question 1 score of ≥2 was an independent factor negatively associated with achieving iCGI. The predictive accuracy of the nomogram, which was developed by integrating all variables with independent predictive significance, was 0.710 (95% confidence interval: 0.702–0.718). In addition, the calibration plot demonstrated excellent agreement between predictions and observations. Clinical ImplicationsIf the predictive performance of our nomogram is further proven in multiple external validations, it can be used to select suitable patients for dapoxetine treatment, thereby reducing the number of patients discontinuing treatment. Strengths & LimitationsThis study developed the first nomogram for predicting the likelihood of achieving iCGI in patients with LPE treated with dapoxetine. However, our nomogram was not externally validated using independent cohorts from other institutions. ConclusionThis study identified several independent predictors of iCGI in patients with LPE treated with dapoxetine. An effective nomogram was developed to predict their likelihood of achieving iCGI. External validations using data of Western patients with LPE are required to test the broader applicability of this Chinese patient-based tool.Hou G, Gao M, Zhang L, et al. An Internally Validated Nomogram for Predicting the Likelihood of Improvement of Clinical Global Impression in Patients With Lifelong Premature Ejaculation Treated With Dapoxetine. J Sex Med 2020;17:2341–2350.

Motor Retraining (MoRe) for Functional Movement Disorders: Outcomes From a 1-Week Multidisciplinary Rehabilitation Program

BackgroundFunctional movement disorders (FMDs) are conditions of abnormal motor control thought to be caused by psychological factors. These disorders are commonly seen in neurologic practice, and prognosis is often poor. No consensus treatment guidelines have been established; however, the role of physical therapy in addition to psychotherapy has increasingly been recognized. This study reports patient outcomes from a multidisciplinary FMD treatment program using motor retraining (MoRe) strategies. ObjectiveTo assess outcomes of FMD patients undergoing a multidisciplinary treatment program and determine factors predictive of treatment success. DesignRetrospective chart review. SettingUniversity-affiliated rehabilitation institute. PatientsThirty-two consecutive FMD patients admitted to the MoRe program from July 2014–July 2016. InterventionPatients participated in a 1-week, multidisciplinary inpatient treatment program with daily physical, occupational, speech therapy, and psychotherapy interventions. Main Outcome MeasurementsPrimary outcome measures were changes in the patient-rated Clinical Global Impression Scale (CGI) and the physician-rated Psychogenic Movement Disorder Rating Scale (PMDRS) based on review of standardized patient videos. Measurements were taken as part of the clinical evaluation of the program. ResultsTwenty-four of the 32 patients were female with a mean age of 49.1 (±14.2) years and mean symptom duration of 7.4 (±10.8) years. Most common movement phenomenologies were abnormal gait (31.2%), hyperkinetic movements (31.2%), and dystonia (31.2%). At discharge, 86.7% of patients reported symptom improvement on the CGI, and self-reported improvement was maintained in 69.2% at the 6-month follow-up. PMDRS scores improved by 59.1% from baseline to discharge. Longer duration of symptoms, history of abuse, and comorbid psychiatric disorders were not significant predictors of treatment outcomes. ConclusionsThe majority of FMD patients experienced improvement from a 1-week multidisciplinary inpatient rehabilitation program. Treatment outcomes were not negatively correlated with longer disease duration or psychiatric comorbidities. The results from our study are encouraging, although further long-term prospective randomized studies are needed. Level of EvidenceIII

Tango for treatment of motor and non-motor manifestations in Parkinson's disease: A randomized control study

To determine effects of Argentine tango on motor and non-motor manifestations of Parkinson's disease. Randomized control trial. Forty patients with idiopathic Parkinson's disease. Movement disorder clinic and dance studio. Two randomized groups: group (N=18) with 24 partnered tango classes, and control self-directed exercise group (N=15). The primary outcome was overall motor severity. Secondary outcomes included other motor measures, balance, cognition, fatigue, apathy, depression and quality of life. On the primary intention-to-treat analysis there was no difference in motor severity between groups MDS-UPDRS-3 (1.6 vs.1.2-point reduction, p=0.85). Patient-rated clinical global impression of change did not differ (p=0.33), however examiner rating improved in favor of tango (p=0.02). Mini-BESTest improved in the tango group compared to controls (0.7±2.2 vs. -2.7±5.9, p=0.032). Among individual items, tango improved in both simple TUG time (-1.3±1.6s vs. 0.1±2.3, p=0.042) and TUG Dual Task score (0.4±0.9 vs. -0.2±0.4, p=0.012), with borderline improvement in walk with pivot turns (0.2±0.5 vs. -0.1±0.5, p=0.066). MoCa (0.4±1.6 vs. -0.6±1.5, p=0.080) and FSS (-3.6±10.5 vs. 2.5±6.2, p=0.057) showed a non-significant trend toward improvement in the tango group. Tango participants found the activity more enjoyable (p<0.001) and felt more "overall" treatment satisfaction (p<0.001). We found no significant differences in other outcomes or adverse events. Argentine tango can improve balance, and functional mobility, and may have modest benefits upon cognition and fatigue in Parkinson's disease. These findings must be confirmed in longer-term trials explicitly powered for cognition and fatigue.

Population Pharmacokinetics and Pharmacodynamics of Gabapentin After Administration of Gabapentin Enacarbil

Gabapentin enacarbil (GEn) is an actively transported prodrug of gabapentin that provides sustained dose-proportional exposure to gabapentin and predictable bioavailability. Gabapentin enacarbil is approved by the US Food and Drug Administration for the treatment of moderate-to-severe primary restless legs syndrome (RLS) in adults. Using plasma gabapentin concentration data obtained after administration of GEn in 12 phase 1 to 3 GEn studies in healthy adults or patients with RLS (dose range, 300-2400 mg/d), a population pharmacokinetic (PK) model was developed by nonlinear mixed-effect modeling using NONMEM. Data were similar in subjects with and without RLS. Population PK-pharmacodynamic (PD) models were evaluated using gabapentin exposure and change from baseline in investigator- or patient-rated Clinical Global Impression of Improvement (CGI-I) or International Restless Legs Scale (IRLS) total score. Potential PK-PD models for sleep outcomes and safety parameters were also explored. The CGI-I response increased with increasing GEn dose, whereas the IRLS total score was similar at all exposures tested. Early adverse events of dizziness or somnolence/sedation were more frequent for GEn 600 mg than higher doses; however, this is confounded by the fact that all subjects received the 600-mg dose for 3 days prior to titration to higher dosages.

Long-term efficacy and safety of gabapentin enacarbil in Japanese restless legs syndrome patients

Several short- and long-term studies conducted in Europe/North America have demonstrated good efficacy and tolerability of 600-1800 mg gabapentin enacarbil (GEn). However, no studies have evaluated the efficacy of long-term treatment with GEn in Asian patients. Therefore, the objective of this study was to evaluate the efficacy and safety of long-term treatment with GEn in Japanese patients with restless legs syndrome (RLS) in a multicenter open-label study. RLS patients aged 20-80 years were allocated to receive oral GEn 1200 mg/day for a treatment period of 52 weeks. International Restless Legs Syndrome Scale (IRLS) score, investigator- and patient-rated Clinical Global Impression (CGI) scores, Pittsburgh Sleep Quality Index (PSQI) total scores and subscores, and short form (SF)-36 subscores were assessed, and adverse events (AEs) were monitored. In 181 patients (mean age, 54.9±12.2 years; BMI, 23.0±2.6 kg/m²) IRLS score decreased from 24.4±0.4 at baseline to 6.3±0.6 at week 52, with a reduction of -18.0±0.6. The IRLS responder rate was 80.3% at week 52. ICGI and PCGI responder rates were 87.1% and 87.1%, respectively. PSQI and SF-36 also showed significant improvements. AEs were reported in 96.2% of patients but remained mild-to-moderate in nearly all the cases. Serious AEs occurred in 1.6%. Dizziness and somnolence were noted in 46.2% and 41.2% of patients, respectively, and mostly occurred during the first 4 weeks. No episodes of augmentation were reported. In conclusion, long-term treatment with GEn improved RLS symptoms as well as investigator- and patient-reported outcomes in Japanese patients with moderate-to-severe RLS, with an acceptable safety profile. Randomized, double-blind, placebo/active-controlled trials are desirable to confirm these preliminary results.

Long-Term Follow-Up Study of Patients With Refractory Obsessive-Compulsive Disorder

Long-Term Follow-Up Study of Patients With Refractory Obsessive-Compulsive Disorder

Other: Cyclobenzaprine (Flexeril®) 5 mg: Symptom response and concomitant analgesic use in patients with acute painful muscle spasm

The aim was to describe symptom response and concomitant analgesic use in patients treated with cyclobenzaprine (Flexeril®) 5 mg for acute painful muscle spasm. Prospective, open-label, multi-center, 7-day study of cyclobenzaprine 5 mg tid (CYC5) in patients with acute painful muscle spasm of the back or neck (N=468). Median duration of pain prior to entering the study was 7 days. Patient-rated clinical global impression of change (PCGI) was assessed after 7 days of CYC5 therapy using a 5-point scale from 0-4, with 0=worse and 4=marked improvement. Symptom response was defined as the percentage of patients reporting mild, moderate, or marked improvement on the PCGI. Patients used diary cards to record their concomitant therapies. Mean age of patients was 40 years and 54% were female. Symptom response with CYC5 was 90% among patients who completed a 7 day course of therapy (n=410). Sixty-three percent of patients (n=449) took concomitant therapies. Among these patients, 158 (35%) took analgesics for ≥1 day(s). Most common concomitant analgesics were ibuprofen and acetaminophen. In this prospective study, CYC5 was associated with a high response rate in patients with acute painful muscle spasm. Ibuprofen and acetaminophen were the most common concomitant analgesics.

Efficacy of a low-dose regimen of cyclobenzaprine hydrochloride in acute skeletal muscle spasm: Results of two placebo-controlled trials

Background: Cyclobenzaprine hydrochloride is a muscle relaxant that is effective in improving muscle spasm, reducing local pain and tenderness, and increasing range of motion in acute, painful musculoskeletal conditions. Sedation is the most common adverse event associated with its use at the usual dosage of 10 mg TID. Studies in healthy adults sugges that a lower dose may produce less sedation. Because cyclobenzaprine's duration of action is 4 to 6 hours, reducing the dosing frequency to 10 mg BID would create a potentially painful untreated interval between doses. The alternative is administration of a lower dose (eg, 5 or 2.5 mg) TID.Objective: These studies were designed to assess the efficacy and tolerability of cyclobenzaprine 2.5, 5, and 10 mg TID compared with placebo in patients with acute musculoskeletal spasm.Methods: In 2 randomized, double-blind, placebo-controlled, parallel-group trials conducted at primary care centers in the United States, adult patients with acute painful muscle spasm of the lumbar or cervical region were randomly assigned to receive treatment with 2.5, 5, or 10 mg cyclobenzaprine TID or placebo for 7 days (study 1: cyclobenzaprine 5 or 10 mg TID or placebo; study 2: cyclobenzaprine 2.5 or 5 mg TID or placebo). The primary efficacy measures were patient-rated clinical global impression of change, medication helpfulness, and relief from starting backache. Neither study included a nonsteroidal anti-inflammatory drug (NSAID) as an active control. Although physicians frequently prescribe an analgesic or NSAID in addition to cyclobenzaprine, these studies were not designed to assess whether adding cyclobenzaprine provides a benefit over that of an analgesic.Results: One thousand four hundred five patients (737 study 1; 668 study 2), two thirds with low back pain and one third with neck pain, were randomized to treatment. Their mean age was 42 years, and ∼89% were white. In both studies, patients receiving cyclobenzaprine 5 or 10 mg had significantly higher mean scores on the primary efficacy measures compared with those receiving placebo (study 1—P≤0.001 cyclobenzaprine 5 and 10 mg vs placebo, all measures at visits 2 and 3; study 2—P≤0.03 cyclobenzaprine 2.5 mg vs placebo, relief from starting backache on day 3 only; cyclobenzaprine 5 mg vs placebo, patient-rated clinical global impression of change, medication helpfulness, and relief from starting backache at visit 3 or day 7 only). On day 7, significantly more patients receiving cyclobenzaprine 5 or 10 mg reported relief compared with placebo recipients (P < 0.05 all cyclobenzaprine groups vs placebo). Onset of relief was apparent within 3 or 4 doses of the 5-mg regimen. In the subanalysis of the proportion of responders in the pooled 5-mg groups who did and did not report somnolence, a meaningful treatment effect was observed on all primary efficacy variables in patients who did not report somnolence, suggesting that efficacy was indendependent of sedation. Cyclobenzaprine was well tolerated. Somnolence and dry mouth, the most common adverse effects, were mild and dose related. Overall, ≥ 1 adverse event was reported in 54.1%, 61.8%, and 35.4% of patients receiving cyclobenzaprine 5 or 10 mg or placebo, respectively, in study 1 and by 43.9%, 55.9%, and 35.4% of patients receiving cyclobenzaprine 2.5 or 5 mg or placebo, respectively, in study 2. Adverse events were the primary reason for discontinuation of treatment in the cyclobenzaprine 5- and 10-mg groups in both studies. In study 2, ineffectiveness of therapy was the main reason for discontinuation of therapy in the group receiving cyclobenzaprine 2.5 mg.Conclusions: Cyclobenzaprine 2.5 mg TID was not significantly more effective than placebo. The cyclobenzaprine 5- and 10-mg TID regimens were associated with significantly higher mean efficacy scores compared with placebo. Cyclobenzaprine 5 mg TID was as effective as 10 mg TID, and was associated with a lower incidence of sedation.

An open naltrexone treatment study in pathological gambling disorder.

The present study was designed to test the short-term efficacy and safety of naltrexone in the treatment of pathological gambling disorder. Seventeen subjects (seven men, 10 women) who fulfilled DSM-IV criteria for pathological gambling disorder, and were free from other Axis I diagnoses by Structured Clinical Interview for DSM-III-R screening, participated in a 6-week open naltrexone flexible dose trial. Gambling symptom change was assessed with the patient-rated Clinical Global Impression (CGI) Scale, the clinician-rated CGI and the Gambling Symptom Assessment Scale. Side-effects were monitored weekly and liver function tests biweekly. Naltrexone reduced urges to gamble and gambling behaviour. The mean change in gambling frequency per week was 1.40 +/- 0.28 episodes per week; the mean change in dollars lost per week was $66.95 +/- 13.77; and the mean change in clinician-rated CGI Improvement was 0.40 +/- 0.04. Of those who responded to the medication, the majority had done so by the end of the fourth week. Men responded to naltrexone as well as women. The average naltrexone dose required for effective symptom control was 157 mg/day. Nausea was common during the first week (47%). The present findings provide evidence that naltrexone may be effective in the treatment of pathological gambling disorder. The present report is preliminary and controlled trials are needed to confirm these findings.

Double-blind naltrexone and placebo comparison study in the treatment of pathological gambling

Background: The authors’ goal was to assess the efficacy and tolerability of naltrexone in the treatment of pathologic gambling disorder. Methods: Eighty-three subjects who met criteria for DSM-IV pathologic gambling disorder were enrolled in a 1-week single-blind placebo lead-in followed by an 11-week double-blind naltrexone or placebo trial. Naltrexone was started at 25 mg/day and titrated upward until maximum symptom improvement or 250 mg/day was achieved. Gambling symptom change was assessed with the patient-rated Clinical Global Impression (PG-CGI-PT), clinician-rated CGI (PG-CGI-MD), and the Gambling Symptom Rating Scale (G-SAS). Side effects were monitored weekly and liver function tests biweekly. Results: Data from 45 patients were analyzed. Using random regression analysis, significant improvement was noted in all three gambling symptom measures: patient-rated Clinical Global Impression, p < .001; clinician-rated CGI, p < .001; Gambling Symptom Rating Scale, p < .019. At study end, 75% of subjects taking naltrexone were much or very much improved on both the PE-CEI PT and the PG-CGI-MD, compared with only 24% of those on placebo. Elevated liver enzymes occurred in four subjects who were taking analgesics concurrently. Nausea was common during the first week of treatment. Conclusions: Results suggest that naltrexone is effective in reducing the symptoms of pathologic gambling. Until further studies corroborate the present findings, our report should be interpreted cautiously.

Assessing the efficacy of treatments for panic disorder and agoraphobia. I. Methodological problems.

An assessment of the efficacy of treatments in panic disorder and agoraphobia (PDA) is complicated by methodological problems resulting from the complexity of these disorders. In this paper, commonly used anxiety scales are discussed with regard to their relevance in the assessment of PDA. Although there are already many scales for assessing anxiety and agoraphobia, a qualified instrument for measuring the severity of PDA is still lacking. A survey of the instruments used in recent treatment studies of PDA shows that rather inhomogeneous efficacy criteria were applied. Most often, panic attack frequency was taken as a severity criterion, although this measure showed little power to differentiate between treatments. To deal with the special features of PDA, a battery of different scales was usually employed and non-standardized scales were sometimes used additionally. A new rating scale designed to overcome the methodological problems associated with the assessment of severity in PDA was introduced. The use of the psychiatrist-rated Panic and Agoraphobia (P&A) scale in patients with DSM-III-R panic disorder and/or agoraphobia (n = 235) shows that this scale has the highest correlation with the psychiatrists' clinical global impression of PDA patients (r = 0.79, p < 0.0001), compared with other commonly used observer-rated anxiety scales. The self-rating version of the P&A again had the highest correlation with a patient-rated clinical global impression (r = 0.82, p < 0.0001), whereas the other patient-rated anxiety questionnaires correlated only moderately or poorly. By means of logistic regression, it was shown that the five subscores of the scale contribute independently and almost equally to the prediction of PDA severity.