J. Steven Lamberti

A Placebo-Controlled Add-On Trial of the Ampakine, CX516, for Cognitive Deficits in Schizophrenia

AMPA-receptor-positive modulators (Ampakines) facilitate learning and memory in animal models and in preliminary trials in human subjects. CX516 is the first Ampakine to be studied for cognitive enhancement in schizophrenia. Stable schizophrenia patients treated with clozapine (n=52), olanzapine (n=40), or risperidone (n=13) were randomly assigned to add-on treatment with CX516 900 mg three times daily or placebo for 4 weeks. Subjects were assessed with a cognitive battery at baseline, week 4, and at 4-week follow-up. Clinical scales and safety monitoring were also performed. The primary endpoint was the change from baseline in a composite cognitive score at week 4 for the intent-to-treat sample. Additional analyses examined change in symptom rating scores and examined drug effects on patients treated with clozapine separately from patients treated with either olanzapine or risperidone. A total of 105 patients were randomized and 95 (90%) completed the 4-week trial. Patients treated with CX516 did not differ from placebo in change from baseline on the composite cognitive score, or on any cognitive test at weeks 4 or 8. The between groups effect size at week 4 for the cognitive composite score was −0.19 for clozapine-treated patients and 0.24 for patients treated with olanzapine or risperidone. The placebo group improved more on the PANSS total score than the CX516 group; no other clinical rating differed between treatment groups. CX516 was associated with fatigue, insomnia and epigastric discomfort compared to placebo, but was generally well tolerated. CX516 was not effective for cognition or for symptoms of schizophrenia when added to clozapine, olanzapine, or risperidone.

Concurrent assessment of acoustic startle and auditory P50 evoked potential measures of sensory inhibition

The acoustic startle response (ASR) and midlatency auditory evoked potentials (AEP) have been utilized in the measurement of sensory inhibition. Using these different paradigms, abnormalities suggesting a lack of normal inhibition have been noted in a number of psychiatric syndromes. To date, the most commonly used sensory inhibition paradigms have not been studied in the same individuals, making generalizations across studies tenuous. In this report, reduction of ASR over multiple trials (habituation), prepulse inhibition (PPI) of ASR (decrease in ASR caused by low intensity prepulses) and P50 suppression (P50 AEP amplitude reduction in a paired-click paradigm) were measured in the same individuals. Relationships between these measures of acoustic startle and AEP inhibition were then assessed. Twenty subjects with no personal history of psychiatric disorder were tested and exhibited significant habituation and PPI of ASR as well as P50 suppression. Habituation of ASR was significantly and positively correlated with P50 suppression early, but not late, in AEP testing. Only a modest trend for a positive association between PPI and P50 suppression was noted. Habituation and PPI of startle were both highly correlated (positively) with P50 AEP amplitude. Habituation of startle remained significantly predictive of P50 suppression after controlling for P50 amplitude, whereas the modest association between PPI and P50 suppression was removed when P50 amplitude was factored out. Results indicate that habituation of acoustic startle, but not PPI, is highly associated with P50 suppression in control subjects. An unexpected finding was a robust positive correlation between P50 amplitude and both measures of startle inhibition. These findings and methodologic issues are discussed in terms of possible neural substrates involved in different measures of sensory inhibition.

The Mentally Ill in Jails and Prisons: Towards an Integrated Model of Prevention

Jails and prisons have become a final destination for persons with severe mental illness in America. Addiction, homelessness, and fragmentation of services have contributed to the problem, and have underscored the need for new models of service delivery. Project Link is a university-led consortium of five community agencies in Monroe County, New York that spans healthcare, social service and criminal justice systems. The program features a mobile treatment team with a forensic psychiatrist, a dual diagnosis treatment residence, and culturally competent staff. This paper discusses the importance of service integration in preventing jail and hospital recidivism, and describes steps that Project Link has taken towards integrating healthcare, criminal justice, and social services. Results from a preliminary evaluation suggest that Project Link may be effective in reducing recidivism and in improving community adjustment among severely mentally ill patients with histories of arrest and incarceration.

Effectiveness of Paliperidone Palmitate vs Haloperidol Decanoate for Maintenance Treatment of Schizophrenia: A Randomized Clinical Trial

IMPORTANCE Long-acting injectable antipsychotics are used to reduce medication nonadherence and relapse in schizophrenia-spectrum disorders. The relative effectiveness of long-acting injectable versions of second-generation and older antipsychotics has not been assessed. OBJECTIVE To compare the effectiveness of the second-generation long-acting injectable antipsychotic paliperidone palmitate with the older long-acting injectable antipsychotic haloperidol decanoate. DESIGN, SETTING, AND PARTICIPANTS Multisite, double-blind, randomized clinical trial conducted from March 2011 to July 2013 at 22 US clinical research sites. Randomized patients (n = 311) were adults diagnosed with schizophrenia or schizoaffective disorder who were clinically assessed to be at risk of relapse and likely to benefit from a long-acting injectable antipsychotic. INTERVENTIONS Intramuscular injections of haloperidol decanoate 25 to 200 mg or paliperidone palmitate 39 to 234 mg every month for as long as 24 months. MAIN OUTCOME MEASURES Efficacy failure, defined as a psychiatric hospitalization, a need for crisis stabilization, a substantial increase in frequency of outpatient visits, a clinicians decision that oral antipsychotic could not be discontinued within 8 weeks after starting the long-acting injectable antipsychotics, or a clinicians decision to discontinue the assigned long-acting injectable due to inadequate therapeutic benefit. Key secondary outcomes were common adverse effects of antipsychotic medications. RESULTS There was no statistically significant difference in the rate of efficacy failure for paliperidone palmitate compared with haloperidol decanoate (adjusted hazard ratio, 0.98; 95% CI, 0.65-1.47). The number of participants who experienced efficacy failure was 49 (33.8%) in the paliperidone palmitate group and 47 (32.4%) in the haloperidol decanoate group. On average, participants in the paliperidone palmitate group gained weight and those in the haloperidol decanoate group lost weight; after 6 months, the least-squares mean weight change for those taking paliperidone palmitate was increased by 2.17 kg (95% CI, 1.25-3.09) and was decreased for those taking haloperidol decanoate (-0.96 kg; 95% CI, -1.88 to -0.04). Patients taking paliperidone palmitate had significantly higher maximum mean levels of serum prolactin (men, 34.56 µg/L [95% CI, 29.75-39.37] vs 15.41 µg/L [95% CI, 10.73-20.08]; P <.001, and for women, 75.19 [95% CI, 63.03-87.36] vs 26.84 [95% CI, 13.29-40.40]; P<.001). Patients taking haloperidol decanoate had significantly larger increases in global ratings of akathisia (0.73 [95% CI, 0.59-0.87] vs 0.45 [95% CI, 0.31-0.59]; P=.006). CONCLUSIONS AND RELEVANCE In adults with schizophrenia or schizoaffective disorder, use of paliperidone palmitate vs haloperidol decanoate did not result in a statistically significant difference in efficacy failure, but was associated with more weight gain and greater increases in serum prolactin, whereas haloperidol decanoate was associated with more akathisia. However, the CIs do not rule out the possibility of a clinically meaningful advantage with paliperidone palmitate. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT01136772.

Randomized Multicenter Investigation of Folate Plus Vitamin B12 Supplementation in Schizophrenia

IMPORTANCE More effective treatments are needed for negative symptoms of schizophrenia, which are typically chronic, disabling, and costly. Negative symptoms have previously been associated with reduced blood folate levels, especially among patients with low-functioning variants in genes that regulate folate metabolism, suggesting the potential utility of folate supplementation. OBJECTIVES To determine whether folic acid plus vitamin B12 supplementation reduces negative symptoms of schizophrenia and whether functional variants in folate-related genes influence treatment response. DESIGN Parallel-group, randomized, double-blind, placebo-controlled clinical trial of 16 weeks of treatment with 2 mg of folic acid and 400 μg of vitamin B12. SETTING Three community mental health centers affiliated with academic medical centers in the United States. PARTICIPANTS Outpatients with chronic schizophrenia who were psychiatrically stable but displayed persistent symptoms despite antipsychotic treatment. Eligible patients were 18 to 68 years old, were treated with an antipsychotic agent for 6 months or more at a stable dose for 6 weeks or more, and scored 60 or more on the Positive and Negative Syndrome Scale. INTERVENTION One hundred forty subjects were randomized to receive daily oral folic acid plus vitamin B12 or placebo. MAIN OUTCOME MEASURES Change in negative symptoms (Scale for the Assessment of Negative Symptoms [SANS]), as well as positive and total symptoms (Positive and Negative Syndrome Scale). RESULTS Folate plus vitamin B12 improved negative symptoms significantly compared with placebo (group difference, -0.33 change in SANS score per week; 95% CI, -0.62 to -0.05) when genotype was taken into account but not when genotype was excluded. An interaction of the 484C>T variant of FOLH1 (rs202676) with treatment was observed (P = .02), where only patients homozygous for the 484T allele demonstrated significantly greater benefit with active treatment (-0.59 change in SANS score per week; 95% CI, -0.99 to -0.18). In parallel, we observed an inverse relationship between red blood cell folate concentration at baseline and 484C allele load (P = .03), which persisted until 8 weeks of treatment. Change in positive and total symptoms did not differ between treatment groups. CONCLUSIONS Folate plus vitamin B12 supplementation can improve negative symptoms of schizophrenia, but treatment response is influenced by genetic variation in folate absorption. These findings support a personalized medicine approach for the treatment of negative symptoms. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00611806.

Metformin for Weight Loss and Metabolic Control in Overweight Outpatients With Schizophrenia and Schizoaffective Disorder

OBJECTIVE The purpose of this study was to determine whether metformin promotes weight loss in overweight outpatients with chronic schizophrenia or schizoaffective disorder. METHOD In a double-blind study, 148 clinically stable, overweight (body mass index [BMI] ≥27) outpatients with chronic schizophrenia or schizoaffective disorder were randomly assigned to receive 16 weeks of metformin or placebo. Metformin was titrated up to 1,000 mg twice daily, as tolerated. All patients continued to receive their prestudy medications, and all received weekly diet and exercise counseling. The primary outcome measure was change in body weight from baseline to week 16. RESULTS Fifty-eight (77.3%) patients who received metformin and 58 (81.7%) who received placebo completed 16 weeks of treatment. Mean change in body weight was -3.0 kg (95% CI=-4.0 to -2.0) for the metformin group and -1.0 kg (95% CI=-2.0 to 0.0) for the placebo group, with a between-group difference of -2.0 kg (95% CI=-3.4 to -0.6). Metformin also demonstrated a significant between-group advantage for BMI (-0.7; 95% CI=-1.1 to -0.2), triglyceride level (-20.2 mg/dL; 95% CI=-39.2 to -1.3), and hemoglobin A1c level (-0.07%; 95% CI=-0.14 to -0.004). Metformin-associated side effects were mostly gastrointestinal and generally transient, and they rarely led to treatment discontinuation. CONCLUSIONS Metformin was modestly effective in reducing weight and other risk factors for cardiovascular disease in clinically stable, overweight outpatients with chronic schizophrenia or schizoaffective disorder over 16 weeks. A significant time-by-treatment interaction suggests that benefits of metformin may continue to accrue with longer treatment. Metformin may have an important role in diminishing the adverse consequences of obesity and metabolic impairments in patients with schizophrenia.

Variations in Mental Health Courts: Challenges, Opportunities, and a Call for Caution

Mental health courts have quickly proliferated in the United States and represent an attempt to expand legal leverage and enhanced treatment access to select persons with severe mental illness who are also involved in the criminal justice system. A national survey of mental health courts has begun to elucidate the procedural, clinical, and operational aspects of these courts and the defendants they adjudicate. A secondary analysis of survey data was performed to determine the similarities and differences among these courts. Results revealed large variability among existing mental health courts across multiple domains. The implications of this variability are discussed in terms benefits and limitations.ABSTRACTMental health courts have quickly proliferated in the United States and represent an attempt to expand legal leverage and enhanced treatment access to select persons with severe mental illness who are also involved in the criminal justice system. A national survey of mental health courts has begun to elucidate the procedural, clinical, and operational aspects of these courts and the defendants they adjudicate. A secondary analysis of survey data was performed to determine the similarities and differences among these courts. Results revealed large variability among existing mental health courts across multiple domains. The implications of this variability are discussed in terms benefits and limitations.

Persons with Severe Mental Disorders in the Criminal Justice System: Challenges and Opportunities

Persons with schizophrenia and other severe mental disorders are at risk for falling through the cracks between the criminal justice and mental health systems. This article is based on a panel discussion between representatives from both systems that recently convened at a regional conference to discuss integration of services. The purpose of the panel discussion was to identify challenges and opportunities related to integrating mental health and criminal justice services at each phase of the criminal justice process. A synopsis of the discussion is presented, along with new models of service delivery designed to prevent the inappropriate arrest and incarceration of persons with severe mental disorders.

Familial and sporadic schizophrenia: visual evoked potential differences.

Introduction The hete~genei~ of ~~zop~nia has been iong recognized (Tsuang 1975), and various methods of subclassification have been developed, including combinations of clinical and biological measures (Jeste 1982; Buchsbaum et al. 1983). Elec~ophysiological literature relevant to subtyping in schizophrenia includes: findings of varying electrodermal responses of patients depending on the severity of emotional withdrawal and disorganization (Straube 1979; Bernstein et al. 1981); evoked potential differences between chronic and acute patients, patients with differing clinical symptoms (Landau et al. 1975; Shagass 1980), and familial versus nonfamilial patients (Romani et al. 1986); lateral asymmetries of electroencephalogram (EEG) variables in patients with specific clinicai symptoms (Serafetinides et al. 198 1); and different patterns of evoked potentials and EEG variables in neuroleptic-responsive and unresponsive patients (Saletu 1977; hi1 et al. 1981). The utility of the familial/sporadic distinction in psychosis has recently been reviewed and may be a useful strategy for determining more homogeneous subgroups (Lewis et al. 1987). In the current study, we tested the hypothesis that visual evoked potential (VEP) latencies are prolonged in psychotic patients with a positive family history of psychosis (FH PGS) when compared to equaliy ill patients without a family history of psychosis (FH NEG).

Within-session changes in sensory gating assessed by p50 evoked potentials in normal subjects

1. The authors studied within-session changes in P50 suppression occurring in a group of 28 normal subjects. 2. A conditioning-testing paradigm was used with 120 pairs of 110 Db peak intensity clicks. Clicks were of 0.04 msec duration, 500 msec separation and delivered through headphones at 10 second intervals. 3. Mean P50 suppression ranged from 60.5% during the first 30 click pairs to -19.1% during the last 30 pairs, with an overall mean suppression of 25.4%. 4. The authors concluded that P50 suppression is a dynamic process in normal subjects, and that further work is necessary to elucidate the factors affecting P50 suppression.