Lawrence Herz

A placebo-controlled pilot study of the ampakine CX516 added to clozapine in schizophrenia

CX516, a positive modulator of the glutamatergic α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptor, improves performance in tasks requiring learning and memory in animals. CX516 was added to clozapine in 4-week, placebo-controlled, dose-finding (N = 6) and fixed-dose (N = 13) trials. CX516 was tolerated well and was associated with moderate to large, between-group effect sizes compared with placebo, representing improvement in measures of attention and memory. These preliminary results suggest that CX516 and other “ampakines” hold promise for the treatment of schizophrenia.

An exploratory haloperidol-controlled dose-finding study of ziprasidone in hospitalized patients with schizophrenia or schizoaffective disorder

Ninety patients with schizophrenia or schizoaffective disorder according to DSM-III-R criteria participated in this double-blind, exploratory, dose-ranging trial. After a single-blind washout period of 4 to 7 days, patients were randomly assigned to receive one of four fixed doses of the new antipsychotic, ziprasidone 4 (N = 19), 10 (N = 17), 40 (N = 17), or 160 (N = 20) mg/day or haloperidol 15 mg/day (N = 17) for 4 weeks. A dose-response relationship among ziprasidone groups was established for improvements in Clinical Global Impression Severity (CGI-S) score (p = 0.002) but not in Brief Psychiatric Rating Scale (BPRS) total score (p = 0.08). The intent-to-treat analysis of mean changes from baseline in the BPRS total, BPRS Psychosis core, and CGI-S scores demonstrated that ziprasidone 160 mg/day was comparable with haloperidol in reducing overall psychopathology and positive symptoms and was superior to ziprasidone 4 mg/day. Despite the small sample size and short duration of the trial, the improvement in CGI-S with both ziprasidone 160 mg/day and haloperidol 15 mg/day was statistically significantly greater than with ziprasidone 4 mg/day (p = 0.001 andp = 0.005, respectively). The percentage of patients classified as responders on both the BPRS total (> or = 30% improvement) and CGI-Improvement (score of 1 or 2) scales in the ziprasidone 160 mg/day group was similar to that in the haloperidol group and nonsignificantly greater than that in the ziprasidone 4 mg/day group. On all assessments of clinical efficacy, the improvements associated with ziprasidone 4 mg/day, 10 mg/day, and 40 mg/day were similar. Concomitant benztropine use at any time during the study was less frequent with ziprasidone 160 mg/day (15%) than with haloperidol (53%). Haloperidol was associated with a sustained hyperprolactinemia, unlike ziprasidone, where only transient elevations in prolactin that returned to normal within the dosing interval were observed. Ziprasidone was well tolerated, and the incidence of adverse events was similar in all groups. The results of this study suggest that ziprasidone 160 mg/day is as effective as haloperidol 15 mg/day in reducing overall psychopathology and positive symptoms of an acute exacerbation of schizophrenia or schizoaffective disorder but has a lower potential to induce extrapyramidal symptoms.

Psychometric profile of posttraumatic stress disorder, anxious, and healthy Vietnam veterans: correlations with psychophysiologic responses.

Three groups of Vietnam combat veterans, posttraumatic stress disorder (PTSD, n = 25), anxious (n = 7), and healthy (n = 18), completed a battery of psychometric tests. Measurement of psychophysiologic responses to imagery of individualized combat experiences followed the psychometrics. The PTSD Ss differed significantly from the healthy Ss on almost all measures but showed fewer differences from the anxious Ss. The typical PTSD S was characterized as anxious, depressed, prone to dissociation, and external in locus of control. Correlations with the physiologic responses supported the validity of psychometric scales specifically designed to measure PTSD but cast doubt on the interpretation of traditional measures of overreporting or dissimulation in this disorder.

Measuring the quality of depression care in a large integrated health system.

Background. Guideline-based depression process measures provide a powerful way to monitor depression care and target areas needing improvement. Objectives. To assess the adequacy of depression care in the Veterans Health Administration (VHA) using guideline-based process measures derived from administrative and centralized pharmacy records, and to identify patient and provider characteristics associated with adequate depression care. Research Design. This is a cohort study of patients from 14 VHA hospitals in the Northeastern United States which relied on existing databases. Subject eligibility criteria: at least one depression diagnosis during 1999, neither schizophrenia nor bipolar disease, and at least one antidepressant prescribed in the VHA during the period of depression care profiling (June 1, 1999 through August 31, 1999). Depression care was evaluated with process measures defined from the 1997 VHA depression guidelines: antidepressant dosage and duration adequacy. We used multivariable regression to identify patient and provider characteristics predicting adequate care. Subjects. There were 12,678 patients eligible for depression care profiling. Results. Adequate dosage was identified in 90%; 45% of patients had adequate duration of antidepressants. Significant patient and provider characteristics predicting inadequate depression care were younger age (<65), black race, and treatment exclusively in primary care. Conclusions. Under-treatment of depression exists in the VHA, despite considerable mental health access and generous pharmacy benefits. Certain patient populations may be at higher risk for inadequate depression care. More work is needed to align current practice with best-practice guidelines and to identify optimal ways of using available data sources to monitor depression care quality.

A six-month, placebo-controlled trial of D-cycloserine co-administered with conventional antipsychotics in schizophrenia patients.

Rationaled-Cycloserine, a partial agonist at the glycine site of the N-methyl-d-aspartate receptor, has demonstrated inconsistent efficacy for negative and cognitive symptoms of schizophrenia. The strongest evidence for efficacy has come from studies using d-cycloserine at a dose of 50 mg/day added to conventional antipsychotics in trials of 8 weeks duration or less.ObjectiveTo assess the efficacy for negative symptoms and cognitive impairment of d-cycloserine augmentation of conventional antipsychotics in a 6-month trial.MethodsFifty-five schizophrenia patients with prominent negative symptoms, treated with conventional antipsychotics, were randomly assigned to treatment with d-cycloserine 50 mg/day or placebo for 6 months in a double-blind, parallel group design.ResultsTwenty-six subjects completed the 6-month trial; drop-out rates did not differ between treatment groups. d-Cycloserine treatment did not differ from placebo treatment on any primary outcome measure at 8 or 24 weeks, including response of negative symptoms and performance on a cognitive battery. Serum d-cycloserine concentrations did not correlate with response of negative symptoms.Conclusiond-Cycloserine did not exhibit therapeutic effects in this trial, possibly reflecting the high drop-out rate, a narrow range of therapeutic serum concentrations, a modest magnitude of therapeutic effect for the selected outcome measures, or loss of efficacy over time. Because d-cycloserine is a partial agonist with relatively low affinity for the glycine site, the magnitude of potential therapeutic effect may be smaller than that achieved by the higher-affinity full agonists, glycine and d-serine.

Development and validation of a psychiatric case-mix system.

Background:Although difficulties in applying risk-adjustment measures to mental health populations are increasingly evident, a model designed specifically for patients with psychiatric disorders has never been developed. Objective:Our objective was to develop and validate a case-mix classification system, the “PsyCMS,” for predicting concurrent and future mental health (MH) and substance abuse (SA) healthcare costs and utilization. Subjects:Subjects included 914,225 veterans who used Veterans Administration (VA) healthcare services during fiscal year 1999 (FY99) with any MH/SA diagnosis (International Classification of Diseases, 9th Revision, Clinical Modification [ICD-9-CM] codes 290.00–312.99, 316.00–316.99). Methods:We derived diagnostic categories from ICD-CM codes using Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition definitions, clinical input, and empiric analyses. Weighted least-squares regression models were developed for concurrent (FY99) and prospective (FY00) MH/SA costs and utilization. We compared the predictive ability of the PsyCMS with several case-mix systems, including adjusted clinical groups, diagnostic cost groups, and the chronic illness and disability payment system. Model performance was evaluated using R-squares and mean absolute prediction errors (MAPEs). Results:Patients with MH/SA diagnoses comprised 29.6% of individuals seen in the VA during FY99. The PsyCMS accounted for a distinct proportion of the variance in concurrent and prospective MH/SA costs (R2 = 0.11 and 0.06, respectively), outpatient MH/SA utilization (R2 = 0.25 and 0.07), and inpatient MH/SA utilization (R2 = 0.13 and 0.05). The PsyCMS performed better than other case-mix systems examined with slightly higher R-squares and lower MAPEs. Conclusions:The PsyCMS has clinically meaningful categories, demonstrates good predictive ability for modeling concurrent and prospective MH/SA costs and utilization, and thus represents a useful method for predicting mental health costs and utilization.

Acupuncture and relaxation response for substance use disorder recovery

Background & Aims: Substance abuse is a major health problem in the US population, particularly among veterans. Current treatments for substance abuse in the form of pharmacologic, behavioural, or psychosocial therapy can be effective in limited instances. We investigated the effect of using two complementary and alternative approaches, acupuncture and the relaxation response, to treat veterans who are recovering from substance use disorders. Methods: We conducted a controlled trial at a US Veterans Administration homeless residential rehabilitation programme. Study participants were randomly assigned to acupuncture, relaxation response or usual care groups. Results: Both acupuncture and the relaxation response interventions were well received by the veterans with high intervention attendance rates (75% and 80%, respectively). The acupuncture group had significantly greater reductions in craving and anxiety levels and greater improvements in the spirituality dimension of quality of life, while the relaxation response group had significantly greater reductions in anxiety level and greater improvements in mental health and spirituality dimensions of quality of life than usual care. The two intervention groups had no significant difference in any outcome measures. Conclusions: This trial provided promising pilot data for larger studies to validate the effects of acupuncture and the relaxation response for relapse prevention.

Treatment persistence: a comparison among patients with schizophrenia who were initiated on atypical antipsychotic agents

Background:  Although clinical trials have demonstrated the efficacy of atypical antipsychotic agents in reducing symptoms of schizophrenia, the likelihood of sustaining control of schizophrenic symptoms may depend on treatment persistence.

Documenting pathways to dementia care: Relative validity of questionnaire, interview, and medical record formats

One of the shortcomings of the pathways-to-care literature is the lack of empirical support for the validity of the data collection methods. This study uses three common formats to collect retrospective pathways-to-care data for adults who have been diagnosed with possible or probable Alzheimers disease (AD) and compares indicators to evaluate their relative validity. Forty family caregivers of adults diagnosed with possible or probable AD were recruited from the caregiver registry of the Boston University Alzheimers Disease Core Center (BU ADCC). In each of three formats (questionnaire, structured interview, and medical record review), data were collected regarding four key events in the pathway to dementia care: first appearance of symptoms, first verbalized recognition of symptoms, first effort to seek professional help, and first diagnosis by a professional. In addition to the dates of these events, researchers attempted to determine: the first verbalized concern about the symptoms, who first sought professional help, what professional was first approached, and what professional made the first diagnosis. In a consensus meeting, data collected in all three formats were reviewed, and a consensus on the most likely answers to all questions was recorded and compared to data collected in each format. The results suggest that the three formats are not equivalent in terms of concurrent validity. While substantial agreement is found among data collection methods, the validity of the structured interview format and the medical record review is most consistently supported by the data in this study. Questionnaire data resulted in underestimates of delays and correlated poorly with other data sources, including the consensus judgment.

Measurement of Treatment Adherence with Antipsychotic Agents in Patients with Schizophrenia

The importance of medication adherence in sustaining control of schizophrenic symptoms has generated a great deal of interest in comparing levels of treatment adherence with different antipsychotic agents. However, the bulk of the research has yielded results that are often inconsistent. In this prospective, observational study, we assessed the measurement properties of 3 commonly used, pharmacy-based measures of treatment adherence with antipsychotic agents in schizophrenia using data from the Veterans Health Administration during 2000 to 2005. Patients were selected if they were on antipsychotics and diagnosed with schizophrenia (N = 18,425). A gap of ≥30 days (with no filled index medication) was used to define discontinuation of treatment as well as medication “episodes,” or the number of times a patient returned to the same index agent after discontinuation of treatment within a 1-year period. The study found that the 3 existing measures differed in their approaches in measuring treatment adherence, suggesting that studies using these different measures would generate different levels of treatment adherence across antipsychotic agents. Considering the measurement problems associated with each existing approach, we offered a new, medication episode-specific approach, which would provide a fairer comparison of the levels of treatment adherence across different antipsychotic agents.