Psychometric evaluation of a Patient-Rated Most Troubling Symptom Scale for Depression: findings from a secondary analysis of a clinical trial.

The objective of this study was to assess the reliability and validity of the presence and severity of eight symptoms rated on the Patient-Rated Troubling Symptoms for Depression (PaRTS-D) instrument used in a risperidone augmentation trial. PaRTS-D total score (sum of four most severe symptoms) and global total score (sum of all eight symptoms) were determined weekly. Clinician-rated and patient-rated instruments were completed at selected time points. Statistical tests of reliability and validity were performed. The frequency of symptoms rated as one of the four most troubling were sadness, 73.5%; trouble concentrating, 70.9%; reduced involvement, 61.9%; tense/uptight, 56.0%; reduced sleep, 52.2%; negative thoughts, 42.9%; inability to feel emotion, 26.5%; and reduced appetite, 13.1%. Evidence of two factors (somatic-related and depression-related) was observed in the exploratory factor analysis. Baseline PaRTS-D total score correlated with the Quality of Life Enjoyment and Satisfaction Questionnaire and the Sheehan Disability Scale. PaRTS-D global total score showed high internal consistency reliability. PaRTS-D total score and global total score distinguished between patients with high and low-Hamilton Rating Scale for Depression Scores and were responsive to Patient Global Improvement Scale changes. The PaRTS-D total score minimal important difference was 4-5 points. In conclusion, PaRTS-D may be useful in symptom presence and severity assessments from the patient's perspective and as an adjunctive to other instruments in major depressive disorder diagnosis and response to treatment.

A randomized, double-blind, placebo-controlled study of maintenance treatment with adjunctive risperidone long-acting therapy in patients with bipolar I disorder who relapse frequently.

OBJECTIVE: No large controlled trials have evaluated adjunctive maintenance treatment with long-acting injectable antipsychotics in patients with bipolar disorder. This study assessed whether adjunctive maintenance treatment with risperidone long-acting therapy (RLAT), added to treatment-as-usual (TAU) medications for bipolar disorder, delays relapse in patients with bipolar disorder type I. METHODS: This study included patients with bipolar disorder type I with > or = four mood episodes in the 12 months prior to study entry. Following a 16-week, open-label stabilization phase with RLAT plus TAU, remitted patients entered a 52-week, double-blind, placebo-controlled, relapse-prevention phase. Randomized patients continued treatment with adjunctive RLAT (25-50 mg every two weeks) plus TAU (n = 65) or switched to adjunctive placebo injection plus TAU (n = 59). The primary outcome measure was time to relapse to any mood episode. RESULTS: Of 240 enrolled patients, 124 entered double-blind treatment. Time to relapse was longer in patients receiving adjunctive RLAT (p = 0.010). Relapse rates were 23.1% (n = 15) with adjunctive RLAT versus 45.8% (n = 27) with adjunctive placebo; relative relapse risk was 2.3-fold higher with adjunctive placebo (p = 0.011). Completion rates were: adjunctive RLAT, 60.0% (n = 39) and adjunctive placebo, 42.4% (n = 25; p = 0.050). Adverse event (AE)-related discontinuations were 4.6% (n = 3) and 1.7% (n = 1), respectively. Common AEs (adjunctive RLAT versus adjunctive placebo) were: tremor (24.6% versus 10.2%), insomnia (20.0% versus 18.6%), muscle rigidity (12.3% versus 5.1%), weight increased (6.2% versus 1.7%), and hypokinesia (7.7% versus 0.0%). CONCLUSIONS: Adjunctive RLAT significantly delayed time to relapse in patients with bipolar disorder type I who relapse frequently. Safety and tolerability of RLAT were generally consistent with that previously observed.

A New Psychosocial Tool for Gaining Patient Understanding and Acceptance of Long-acting Injectable Antipsychotic Therapy.

Nonadherence to antipsychotic medications in serious, persistent mental illness remains a significant clinical challenge. Long-acting therapy was developed to help improve adherence to schizophrenia therapy and provide an effective means for ameliorating symptoms and preventing relapse. The Agency for Health Care Policy and Research/National Institute of Mental Health Schizophrenia Patient Outcomes Research Team recommends that antipsychotic long-acting therapy be strongly considered for patients who have difficulty adhering to an oral medication regimen or who prefer long-acting therapy. Depot conventional formulations have long been available; for clinicians and patients who would rather use an atypical antipsychotic, studies with risperidone long-acting therapy suggest that it is efficacious and well tolerated. A common concern of clinicians who elect to initiate long-acting therapy is how to introduce the possibility of changing from the current oral antipsychotic to an long-acting therapy injection. As with other aspects of patient care, having an established therapeutic relationship with the patient is advantageous for recommending changes in care, but the way in which the idea is approached may improve the likelihood of its acceptance. To help clinicians broach a recommendation of long-acting therapy with their patients, the GAIN approach was designed as a standard interview process for presenting this option. It encompasses (and is an acronym for) goal setting, action planning, initiating treatment, and nurturing motivation. This novel clinical tool is based on the principles of motivational enhancement therapy, a patient-centered approach that seeks to evoke the patient's own motivation for change, to consolidate the decision to change, and to plan for change. This tool is also based on the Listen-Empathize-Agree-Partner, or LEAP, communication strategy. Motivational enhancement therapy, which is typically brief, has been found effective in several chronic illnesses in both outpatient and inpatient settings. GAIN may be a practical tool for aligning clinician-patient expectations and enhancing long-term maintenance of therapy.

Patient-rated troubling symptoms of depression instrument results correlate with traditional clinician- and patient-rated measures: a secondary analysis of a randomized, double-blind, placebo-controlled trial.

BACKGROUND: The Patient-Rated Troubling Symptoms of Depression (PaRTS-D) instrument assesses the presence and troublesomeness of 8 commonly reported depression-related symptoms from the patient's perspective. A post hoc analysis of a double-blind, randomized risperidone augmentation to antidepressant therapy trial in patients with major depressive disorder explored the relationship between the PaRTS-D instrument and other clinician- and patient-rating scales. METHODS: Patients completed the PaRTS-D; the Patient Global Improvement Scale (PGIS), Quality of Life Enjoyment and Satisfaction Questionnaire (Q-LES-Q), and the Sheehan Disability Scale (SDS), while clinicians completed the Hamilton Rating Scale for Depression (HRSD-17), and the Clinical Global Impressions of Severity (CGI-S) at baseline and at pre-determined study weeks. RESULTS: In the PaRTS-D instrument, the four most frequently reported and troublesome symptoms were sadness (73.5%, severity 6.8), trouble concentrating (70.9%, 7.3), reduced involvement in pleasurable activities (61.9%, 7.3), and being tense or uptight (56.0%, 6.7). The improvement in PaRTS-D total score was significantly greater in risperidone-augmented compared with placebo-augmented patients at week 4 (p=0.034) and week 6 (p=0.007). Pearson correlations between the PaRTS-D scores and the measures of HRSD-17, CGI-S, PGIS, Q-LES-Q, and SDS were significant at both baseline and at week 6 LOCF (p<0.001 for each comparison). LIMITATIONS: Results are from a post hoc analysis. CONCLUSIONS: Significant correlations were observed between the PaRTS-D and other clinician- and patient-rated measures, with PaRTS-D being sensitive to the effects of treatment. These findings suggest that the PaRTS-D instrument is a reliable scale to assess antidepressant activity as experienced by the patients.

Dimensions of psychosis in patients with bipolar mania as measured by the positive and negative syndrome scale.

BACKGROUND: Psychosis is present in 50% or more of patients with bipolar mania and is commonly evaluated in clinical research by means of the Positive and Negative Syndrome Scale (PANSS). The aim of the present analysis was to investigate the psychotic dimensions of bipolar disorder and its contributing symptoms based on a factor analysis of baseline PANSS scores and to compare them with those identified in studies of patients with schizophrenia and bipolar disorder. SAMPLING AND METHODS: Baseline data were analyzed from two 3-week, double-blind, placebo-controlled studies of risperidone monotherapy for acute mania associated with bipolar I disorder (n = 535). Inclusion criteria were a DSM-IV diagnosis of bipolar I disorder with manic features, with or without psychotic features, age > or =18 years, and mean baseline Young Mania Rating Scale scores > or =20. A principal component analysis of the 30 PANSS item scores of the 535 patients with a diagnosis of a manic episode at baseline was conducted. RESULTS: Five factors were extracted by the analysis: anxiety (13.4% of the variance), negative symptoms (12.3%), depression (10.5%), excitement (10.3%), and positive symptoms (8.7%). Similar factors, in particular the negative, excitement, and positive factors, have been identified in patients with schizophrenia. There was an absence of a cognitive factor supporting the notion that bipolar patients may present fewer cognitive symptoms. CONCLUSION: The results of the present analysis and those of other studies indicate similarities in psychotic symptom domains, as measured by the PANSS, in patients with bipolar mania and schizophrenia. Future analyses will address the effects of treatment on the identified factors.

The impact of insight on functioning in patients with schizophrenia or schizoaffective disorder receiving risperidone long-acting injectable.

This post hoc analysis explored the role of insight as a mediator of functioning in a 52-week, double-blind, international trial of 323 patients with schizophrenia or schizoaffective disorder receiving risperidone long-acting injectable. Measures included the Positive and Negative Syndrome Scale (PANSS) insight item, PANSS factors, Clinical Global Impressions-Severity (CGI-S), Strauss-Carpenter Levels of Functioning (LOF), Personal and Social Performance (PSP) scale, and a cognitive test battery. Correlation/regression analyses examined associations between demographic and clinical characteristics, including insight, and functional measures. Insight scores correlated significantly with CGI-S, PANSS subscales, PSP, LOF, and several cognitive measures. Regression models demonstrated that changes in insight, changes in negative symptoms, and study duration were significantly associated with PSP and LOF total change scores. Findings identified important variables to consider for intervention to improve functioning in schizophrenia.

Risperidone for treatment-refractory major depressive disorder: a randomized trial.

BACKGROUND: Major depressive disorder has high prevalence, morbidity, and mortality. Inadequate results with antidepressants have prompts addition of a nonstandard treatment (augmentation therapy). OBJECTIVE: To assess whether augmentation therapy with risperidone reduces symptoms and increases response to antidepressant therapy and remission of depression in adults. DESIGN: Multicenter, double-blind, placebo-controlled, randomized trial conducted from 19 October 2004 to 17 November 2005. SETTING: 75 primary care and psychiatric centers. PATIENTS: 274 outpatient adults with major depressive disorder that was suboptimally responsive to antidepressant therapy. INTERVENTION: After a 4-week run-in period to ensure insufficient response to standard antidepressants, patients were randomly assigned to receive risperidone, 1 mg/d, or placebo for 6 weeks. After 4 weeks, the dosage of risperidone was increased to 2 mg/d in some cases. MEASUREMENTS: Symptoms were measured by using the 17-item Hamilton Rating Scale for Depression (HRSD-17). Other outcomes were response to therapy, remission of depression, and various clinician- and patient-rated assessments. RESULTS: Of the intention-to-treat population (268 patients), 81% (111 of 137) who received risperidone and 87.8% (115 of 131) who received placebo completed 6 weeks of double-blind treatment. Mean (+/-SE) HRSD-17 scores improved more in the risperidone augmentation group than in the placebo group (13.4 +/- 0.54 vs. 16.2 +/- 0.53; difference, -2.8 +/- 0.72 [95% CI, -4.2 to -1.4]; P <0.001). More risperidone recipients than placebo recipients experienced remission of depression (24.5% [26 of 106] vs. 10.7% [12 of 112]; P = 0.004) and had a response (46.2% [49 of 106] vs. 29.5% [33 of 112]; P = 0.004). Headache (8.8% of risperidone recipients vs. 14.5% of placebo recipients), somnolence (5.1% vs. 1.5%), and dry mouth (5.1% vs. 0.8%) were the most frequently reported adverse events. LIMITATIONS: Patients were receiving many different antidepressants, and the duration of augmentation therapy was limited. CONCLUSION: Risperidone augmentation produced a statistically significant mean reduction in depression symptoms, substantially increased remission and response, and improved other patient- and clinician-rated measures. ClinicalTrials.gov registration number: NCT00095134.

Adjunctive risperidone in the treatment of generalized anxiety disorder: a double-blind, prospective, placebo-controlled, randomized trial.

BACKGROUND: Residual symptoms despite treatment are common in generalized anxiety disorders (GAD). The Patient-Rated Troubling Symptoms for Anxiety (PaRTS-A) is a newly created and validated instrument that measures the symptoms most troublesome to each individual patient and was used to test the hypothesis that adjunctive risperidone improves residual GAD symptoms. METHODS: Primary care and psychiatry clinicians enrolled adults (n = 417) with GAD and a Clinical Global Impressions of Severity rating ≥ 4 despite ≥ 8 weeks of anxiolytic treatment. Subjects were randomized to adjunctive risperidone or placebo. The primary endpoint was change from baseline to week 4 endpoint in PaRTS-A. RESULTS: Improvement from baseline to week 4 endpoint in PaRTS-A total score (mean +/-SE) was similar between treatment groups (-8.54 [0.63] and -7.61 [0.64] for adjunctive risperidone and placebo, respectively; P = .265). Patients in each treatment group exhibited significant improvements from baseline in nearly all patient- and clinician-rated measures. A post-hoc analysis of PaRTS-A symptoms of moderate to severe severity at baseline suggested greater improvement with risperidone than placebo (P = .04). Headache, weight increase, and increased appetite were the most frequently reported adverse events in both groups. CONCLUSIONS: Residual GAD symptoms assessed by the PaRTS-A improved with either adjunctive risperidone or placebo. Alternative analyses or scoring approaches may improve the ability of the PaRTS-A to provide clinically meaningful information on patient-rated symptoms. Further exploration of the benefits of risperidone in patients with more severe GAD may be indicated.

Evaluation of a treatment manual for risperidone long-acting injectable.

We evaluated the usefulness of a treatment manual to facilitate the use of long-acting injectable risperidone in community mental health centers (CMHCs) during an open-label observational study. Perceived clinical utility and clinician adherence to the manual were evaluated. Patient adherence to treatment satisfaction, Clinical Global Impression of Severity (CGI-S) and the Schizophrenia Quality-of-Life Scale (SQLS) were assessed. Mean score for overall utility of the guidebook was 4.2 +/- .6 (scale ratings ranged from 1 = not at all to 5 = extremely). Most clinicians (89-100%) found the guidebook useful, and were adherent to key aspects of appropriate treatment use including concomitant oral risperidone use and injection and dosing parameters for long-acting risperidone. Most patients were adherent to treatment (86.7%), preferred long-acting risperidone over oral risperidone (72.6%) or other oral antipsychotics (78.4%) and were satisfied with long-acting risperidone (90.1%). The open-label observational design limits interpretation of these data. However, in this study manual-supported use of long-acting risperidone was associated with successful implementation of this pharmacologic treatment in the CMHC setting.

Maintenance therapy with once-monthly administration of long-acting injectable risperidone in patients with schizophrenia or schizoaffective disorder: a pilot study of an extended dosing interval.

BACKGROUND: Several clinical studies have established the efficacy, safety, and tolerability of long-acting risperidone administered once every 2 weeks in patients with schizophrenia or schizoaffective disorder. This report evaluates preliminary efficacy, safety, tolerability, and pharmacokinetic data for a novel (once-monthly) administration of long-acting injectable risperidone 50 mg in patients with schizophrenia or schizoaffective disorder. METHODS: Clinically stable patients participated in a 1-year, open-label, single-arm, multicenter pilot study. During the 4-week lead-in phase, patients received long-acting risperidone 50 mg injections every 2 weeks, with 2 weeks of oral risperidone supplementation. Injections of long-acting risperidone 50 mg every 4 weeks followed for up to 48 weeks, without oral supplementation. The primary endpoint was relapse; other assessments included PANSS, CGI-S, adverse event reports, and determination of risperidone and 9-hydroxyrisperidone plasma concentrations. RESULTS: Twelve patients in the intent-to-treat population (n = 67) met relapse criteria (17.9%). Relapse risk at 1 year was estimated as 22.4%. Non-statistically significant improvements in symptoms (PANSS) and clinical status (CGI-S) at endpoint were observed. The most common adverse events included schizophrenia aggravated not otherwise specified (19.5%), anxiety (16.1%), insomnia (16.1%), and headache (11.5%). There were no unexpected safety and tolerability findings. Mean plasma concentrations for risperidone and 9-hydroxyrisperidone were generally stable during the study. CONCLUSION: Once-monthly dosing of long-acting risperidone was well tolerated, associated with a relatively low relapse rate (similar to that reported with other antipsychotics), and maintained the clinically stable baseline status of most patients. Although the results suggest that some symptomatically stable patients with schizophrenia or schizoaffective disorder might be safely managed with long-acting risperidone 50 mg once monthly, these findings alone do not identify which patients will have a sufficient therapeutic benefit nor do they quantify comparative effects of standard and altered dosing. Study limitations (the open-label pilot study design, small sample size, and lack of a concurrent biweekly treatment arm) prevent broad interpretations and extrapolations of results. Controlled studies would be required to support a recommendation for alternative dosing regimens.

A 1-year double-blind study of 2 doses of long-acting risperidone in stable patients with schizophrenia or schizoaffective disorder.

OBJECTIVE: This study examined the effects of 2 doses of long-acting risperidone injection in patients with schizophrenia or schizoaffective disorder. METHOD: This 52-week, prospective, randomized, double-blind, multicenter, international study included clinically stable outpatients with schizophrenia or schizoaffective disorder (DSM-IV criteria). Settings included physicians' offices and clinics. Patients received a fixed dose of long-acting risperidone (25 or 50 mg) every 2 weeks. Primary outcome was time to relapse, defined as either re-hospitalization or other exacerbation criteria. Other assessments included the Positive and Negative Syndrome Scale, Clinical Global Impressions-Severity of Illness scale, and functional and quality-of-life measures. Safety was assessed via treatment-emergent adverse events, laboratory tests, and movement disorder rating scales. Data were collected from December 2002 to September 2004. RESULTS: A total of 324 patients were randomized to 25 mg (N = 163) or 50 mg (N = 161) of long-acting risperidone. Time to relapse was comparable (p = .131) for both groups. Projected median time to relapse was 161.8 weeks (95% CI = 103.0 to 254.2) with 25 mg and 259.0 weeks (95% CI = 153.6 to 436.8) with 50 mg. One-year incidences of relapse were 21.6% (N = 35) and 14.9% (N = 24), respectively (p = .059). Psychiatric hospitalization was the reason for relapse for 16 (10%) in the 25-mg group and 10 (6%) in the 50-mg group. Patients experienced statistically significant but modest improvements at endpoint in most measures (i.e., psychotic symptoms, functioning, movement disorder severity) with both doses, with no significant between-group differences. CONCLUSION: In this 1-year study, long-acting risperidone was associated with low relapse and rehospitalization rates, indicating that doses of 25 to 50 mg are appropriate for long-term treatment in schizophrenia.

Validation of the Investigator's Assessment Questionnaire, a new clinical tool for relative assessment of response to antipsychotics in patients with schizophrenia and schizoaffective disorder.

The success of long-term therapy in schizophrenia is contingent upon real-world effectiveness or improvements in several domains, including efficacy, safety and tolerability. This report describes the Investigator's Assessment Questionnaire (IAQ), a new 10-item instrument designed to assess relative effectiveness (efficacy, safety and tolerability) of antipsychotic medications in patients with schizophrenia or schizoaffective disorder. To measure content validity, 300 psychiatrists rated the importance of the IAQ items. Efficacy (i.e., positive and negative symptoms) was considered most important, but importance scores relative to the mean ranged only from 0.87 to 1.18, suggesting similar importance of the items. Cronbach's coefficient alpha values showed that the items were internally consistent. Factor analyses indicated that all IAQ items belong to a single domain. Data from the US Broad Effectiveness Trial of Aripiprazole were used for construct validation. Total IAQ score correlated significantly with time to treatment discontinuation (r=-0.50), Clinical Global Impressions-Improvement (CGI-I) score (r=0.76) and medication preference of patients (r=0.71) or caregivers (r=0.70). A one-unit decrease in IAQ score corresponded to an additional 1.35 days in the study and a decrease in CGI-I of 0.21 units. These results provide initial validation of the IAQ as a tool for evaluating antipsychotic response in patients with schizophrenia or schizoaffective disorder.

Aripiprazole, an antipsychotic with a novel mechanism of action, and risperidone vs placebo in patients with schizophrenia and schizoaffective disorder.

BACKGROUND: Aripiprazole is a dopamine D2 receptor partial agonist with partial agonist activity at serotonin 5HT1A receptors and antagonist activity at 5HT2A receptors. This multicenter trial examined the efficacy, safety, and tolerability of aripiprazole in patients with acute exacerbation of schizophrenia or schizoaffective disorder. METHODS: In this 4-week double-blind study, 404 patients were randomized to 20 mg/d (n = 101) or 30 mg/d (n = 101) of aripiprazole, placebo (n = 103), or 6 mg/d of risperidone (n = 99). Efficacy assessments included Positive and Negative Syndrome Scale (PANSS) scores and Clinical Global Impression scores. Safety and tolerability evaluations included extrapyramidal symptoms and effects on weight, prolactin, and corrected QT (QTc) interval. RESULTS: Aripiprazole (20 and 30 mg/d) and risperidone (6 mg/d) were significantly better than placebo on all efficacy measures. Separation from placebo occurred at week 1 for PANSS total and positive scores with aripiprazole and risperidone and for PANSS negative scores with aripiprazole. There were no significant differences between aripiprazole and placebo in mean change from baseline in the extrapyramidal symptom rating scales. Mean prolactin levels decreased with aripiprazole but significantly increased 5-fold with risperidone. Mean change in QTc interval did not differ significantly from placebo with any active treatment group. Aripiprazole and risperidone groups showed a similar low incidence of clinically significant weight gain. CONCLUSIONS: Aripiprazole is effective, safe, and well tolerated for the positive and negative symptoms in schizophrenia and schizoaffective disorder. It is the first non-D2 receptor antagonist with clear antipsychotic effects and represents a novel treatment development for psychotic disorders.