Adam Savitz

Proof-of-Concept Trial with the Neurosteroid Pregnenolone Targeting Cognitive and Negative Symptoms in Schizophrenia

The neurosteroid pregnenolone and its sulfated derivative enhance learning and memory in rodents. Pregnenolone sulfate also positively modulates NMDA receptors and could thus ameliorate hypothesized NMDA receptor hypofunction in schizophrenia. Furthermore, clozapine increases pregnenolone in rodent hippocampus, possibly contributing to its superior efficacy. We therefore investigated adjunctive pregnenolone for cognitive and negative symptoms in patients with schizophrenia or schizoaffective disorder receiving stable doses of second-generation antipsychotics in a pilot randomized, placebo-controlled, double-blind trial. Following a 2-week single-blind placebo lead-in, patients were randomized to pregnenolone (fixed escalating doses to 500 mg/day) or placebo, for 8 weeks. Primary end points were changes in BACS and MCCB composite and total SANS scores. Of 21 patients randomized, 18 completed at least 4 weeks of treatment (n=9/group). Pregnenolone was well tolerated. Patients receiving pregnenolone demonstrated significantly greater improvements in SANS scores (mean change=10.38) compared with patients receiving placebo (mean change=2.33), p=0.048. Mean composite changes in BACS and MCCB scores were not significantly different in patients randomized to pregnenolone compared with placebo. However, serum pregnenolone increases predicted BACS composite scores at 8 weeks in the pregnenolone group (rs=0.81, p=0.022). Increases in allopregnanolone, a GABAergic pregnenolone metabolite, also predicted BACS composite scores (rs=0.74, p=0.046). In addition, baseline pregnenolone (rs=−0.76, p=0.037), pregnenolone sulfate (rs=−0.83, p=0.015), and allopregnanolone levels (rs=−0.83, p=0.015) were inversely correlated with improvements in MCCB composite scores, further supporting a possible role for neurosteroids in cognition. Mean BACS and MCCB composite scores were correlated (rs=0.74, p<0.0001). Pregnenolone may be a promising therapeutic agent for negative symptoms and merits further investigation for cognitive symptoms in schizophrenia.

Effectiveness of a two-phase cognitive rehabilitation intervention for severely impaired schizophrenia patients

BACKGROUND Several small-N, uncontrolled reports have demonstrated that the behavioral technique of attention shaping has significantly increased attention span among severely ill schizophrenia patients. METHOD In this study, we evaluated the effectiveness of using an individually administered intervention for improving sustained attention, Attention Process Training (APT), followed by an attention-shaping procedure within the context of an ongoing skills training group. Patients were randomly assigned to receive either the APT and attention-shaping sequence (n = 18) or equivalent hours of treatment in the same intensive behavioral rehabilitation program (n = 13). RESULTS Results indicated dramatic improvements in attentiveness in the cognitive rehabilitation condition compared with the control condition, which demonstrated essentially no change in attentiveness over the 12 weeks of treatment. The attention-shaping intervention appeared to account for the majority of the effect. In contrast to the observational data, performance on neuropsychological tests was unaffected by the cognitive interventions. CONCLUSIONS This two-phase intervention demonstrated effectiveness in promoting attentive behavior among chronic schizophrenia patients with severe attentional impairment.

Reduced top-down influences in contour detection in schizophrenia

Introduction. Chronic schizophrenia patients have previously demonstrated performance deficits in contour integration tasks. The purpose of this study was to investigate whether schizophrenia patients, spanning a range of illness severity, would demonstrate responsiveness to manipulations that recruit top-down processing strategies involving learning and sequencing effects in a contour integration task. Methods. We administered a contour integration test over four consecutive days and in two different presentation conditions each day. In one condition, the stimuli were administered in order of increasing difficulty, and in the other they were presented in random order. The order in which these two conditions were presented was counterbalanced across days and participants. In addition, a nonschizophrenia psychotic disorders control group was included to determine if past findings of a contour integration deficit in schizophrenia could be replicated in the presence of a symptomatically similar control group. Results. All groups demonstrated similar learning curves across the four days and generally similar overall levels of performance, with the exception of the group of the most chronic schizophrenia patients. In addition, the order in which the stimuli were presented to subjects affected their performance, with higher scores achieved for all groups in the condition where the stimuli were presented in increasing order of difficulty. Interaction effects revealed that the effects of order presentation were greater for nonpatient than for psychotic patients. Conclusions. These data are further evidence that perceptual organization impairments in schizophrenia are illness severity-related, and that schizophrenia patients as a whole are less sensitive to top-down manipulations in this type of task.

Behavioral Rehabilitation of the "Treatment-Refractory" Schizophrenia Patient: Conceptual Foundations, Interventions, and Outcome Data

This article describes an intensive, inpatient behavioral rehabilitation program for patients with schizophrenia who have been considered “treatment-refractory” at state hospitals. The program is a public–private partnership involving state and private hospitals and community residence providers. The essential elements of this program are described, along with the conceptual and philosophical bases of its treatment and examples of staff behaviors critical to treatment success. Outcome data are then discussed to emphasize the point that when evidence-based psychological treatment is implemented with this population, outcomes can be positive in most cases, and therefore, the number of treatment-refractory patients is actually far less than is estimated on the basis of response to medication alone. Schizophrenia is a serious mental disorder that affects approximately 1% of the population worldwide, with a current global incidence calculated at over 20 million people (Jablensky, 2000). The consequences of schizophrenia, in terms of both public health costs and effects on lives are enormous. For example, it has been estimated that as many as 10% of all disabled persons in the United States have schizophrenia (Rupp & Keith, 1993), and the disorder accounts for 75% of all mental health expenditures and approximately 40% of all Medicaid reimbursements (Martin & Miller, 1998). Among people with the disorder, only between 10%–30% are employed at any one time (Attkisson et al., 1992), and few of these people are able to maintain consistent employment (Policy Study Associates, 1989). Studies have consistently found that quality of life among people with schizophrenia is significantly poorer than among the rest of the population (Lehman, Ward, & Linn, 1982). Schizophrenia typically is diagnosed in late adolescence or early adulthood, and traditionally, approximately 50 –70% of cases are characterized by a chronic, relapsing course with high morbidity and permanent disability. In addition, rates of mortality and somatic morbidity are higher in schizophrenia than in the general population (Lieberman & Coburn, 1986), and the rate of attempted suicide equals that of major depression (Simpson & Tsuang, 1996). The economic costs of treating schizophrenia have been estimated to be

A comparative study of the MATRICS and IntegNeuro cognitive assessment batteries

62.7 billion (e.g., including direct treatment costs and lost business productivity due to patient and family caretaker work absence; Wu et al.,

Group Cognitive Behavioral Therapy for Delusions: Helping Patients Improve Reality Testing

Cognitive impairment is prevalent in schizophrenia and is related to poorer functional and treatment outcomes. Cognitive assessment is therefore now a routine component of clinical trials of new treatments for schizophrenia. The current gold-standard for cognitive assessment in clinical trials for schizophrenia is the MATRICS (Measurement and Treatment Research to Improve Cognition in Schizophrenia) Consensus Cognitive Battery (MCCB), which was developed based on expert consensus and incorporates paper-and-pencil tests (and one computerized measure) with an established history in the field of neuropsychology. Recently, however, interest has increased in using computerized batteries for clinical trials. In this study, we tested 155 people with schizophrenia and 75 healthy control participants on both the MCCB and IntegNeuro, a touch-screen-based computerized battery with previously demonstrated high levels of reliability and validity, to determine comparability between test scores. In addition, we assessed test–retest reliability and practice effects over a one-month interval for both batteries and determined correlations between cognitive test scores and scores on functional outcome measures. High levels of agreement were observed between total battery composite scores (r > .80) and, in a canonical correlation analysis, between all critical single test scores from each battery (r c > .90). The batteries demonstrated essentially equivalent sensitivity in discriminating between patients and controls and equivalent levels of test–retest reliability and practice effects. Correlations between cognitive test scores and functional outcome measures were equivalent between the two batteries and low in nearly all cases. The number of missing data points was greater with IntegNeuro, highlighting the requirements for test administrator involvement even with computerized batteries.

Carbon dioxide induction of panic anxiety in schizophrenia with auditory hallucinations

Group Cognitive Behavior Therapy (CBT) was used to treat residual delusions in patients with schizophrenia. Initially all patients (N = 6) reported delusions of various types, such as persecution, body/mind control, grandiosity, and religious themes. The group format allowed patients to share their experiences and beliefs, thereby eliminating shame and providing support and coping strategies; as well as allowing for peer–peer discussion of irrationalities and inconsistencies in each others beliefs. After 13 sessions there was a statistically significant reduction in delusional conviction, unhappiness associated with thinking about a delusion, intensity of distress associated with delusion, and an increased ability to dismiss a delusional thought.

An examination of neurocognition and symptoms as predictors of post-hospital community tenure in treatment resistant schizophrenia.

Panic is commonly co-morbid with schizophrenia. Panic may emerge prodromally, contribute to specific psychotic symptoms, and predict medication response. Panic is often missed due to agitation, impaired cognition, psychotic symptom overlap and limited clinician awareness. Carbon dioxide exposure has been used reliably to induce panic in non-psychotic panic subjects, but has not been systematically studied in schizophrenia. Eight inpatients with schizophrenia, recent auditory hallucinations, none preselected for panic, all on antipsychotic medication, received a structured Panic and Schizophrenia Interview (PaSI), assessing DSM-IV panic symptoms concurrent with paroxysmal auditory hallucinations. On that interview, all eight subjects reported panic concurrent with auditory hallucinations. At one sitting, subjects were exposed, in random order, to 35% carbon dioxide and to placebo room air, blinded to condition. All subjects experienced panic to carbon dioxide, one with limited symptoms. Only one subject panicked to placebo. One subject (one of only two without antipanic medication) had paroxysmal voices concurrent with induced panic. With added adjunctive clonazepam, that patient had marked clinical improvement and no response to carbon dioxide re-challenge. This first systematic examination offers preliminary evidence that carbon dioxide safely induces panic symptoms in schizophrenia. Panic may be prevalent and pathophysiologically significant in schizophrenia with auditory hallucinations.

Erratum: A comparative study of the MATRICS and IntegNeuro cognitive assessment batteries (Journal of Clinical and Experimental Neuropsychology (2010) 32:9 (937-952) DOI: 10.1080/13803391003596496)

Neurocognition and psychopathology are robust predictors of community functioning and relapse/rehospitalization in schizophrenia. Existing studies are however limited because they have ignored the most chronic, treatment-resistant patients. Moreover, the prediction of functional outcomes has yet to be extended to the duration of community tenure, an indicator of the capacity of chronically-hospitalized patients to gain traction in the community. The current study examined neurocognition and symptom severity at discharge as potential predictors of community tenure in chronically-hospitalized treatment-resistant patients. The study recruited 90 people with treatment-resistant schizophrenia who received services on an inpatient unit. Participants completed measures of psychopathology and neurocognition prior to discharge. Following discharge, participants were tracked at current residences six months and one year post-discharge to assess community tenure. The percentage of individuals who continued to live in the community at 12-month follow-up was 51%. Severe negative symptoms but not neurocognitive impairment or positive symptoms was a significant predictor of shorter post-hospital community tenure. Of the negative symptoms domain, anhedonia-asociality proved to be the most relevant predictor of community tenure in the sample. The capacity to elicit goal-directed behaviors in response to anticipated physical and social rewards may be an important treatment target for sustaining community tenure.

Attention Shaping: a Reward-Based Learning Method to Enhance Skills Training Outcomes in Schizophrenia

Please note that in the article entitled “A Comparative Study of the MATRICS and IntegNeuro Cognitive Assessment Batteries” by Silverstein, S. M., Jaeger, J., Donovan-Lepore, A. M., Wilkniss, S. M., Savitz, A., Malinovsky, I., Hawthorne, D., Raines, S., Carson, S., Marcello, S., Zukin, S. R., Furlong, S., and Dent G. J., published online ahead of print (May 7, 2010; DOI: 10.1080/13803391003596496) and in the November 2010 print issue (Volume 32, Issue 9, pp. 937–952) for the Journal of Clinical and Experimental Neuropsychology, there was an author error. Silverstein et al. (2010) reported use of the UCSD Performance Based Skill Assessment, version 2 (UPSA-2); however, the version that was used was the original version of the UPSA.