Faculty Bibliography

BACKGROUND: There is substantial current interest in the cognitive deficits associated with schizophrenia, particularly those in the realm of memory. Yet the exact nature of these deficits remains a matter of some debate. This study sought to examine performance on two distinct aspects of memory performance: familiarity-based and source-based memory processes. METHODS: Eighteen medicated outpatients with schizophrenia and eighteen healthy adult control subjects performed an external source memory task. Key measures included the ability to distinguish old (previously experienced) items from new items, the ability to correctly identify the source (male voice or female voice) of previously experienced items, and the reaction time associated with these responses. RESULTS: Patients with schizophrenia showed an impaired ability to distinguish old from new items, but intact performance in correctly identifying the source of items recognized as old. Whereas control subjects showed a rapid response to items deemed unfamiliar, particularly in rejecting novel items, these responses were slowed in patients with schizophrenia. This was not attributable to a generalized diminution in processing speed, as reaction times to correctly recognized old items (regardless of source accuracy) did not differ between the two groups. CONCLUSIONS: Patients with schizophrenia demonstrated impaired familiarity-based and intact source-based memory performance. In addition, the reaction time for novelty detection, an important component of familiarity-based memory, was significantly delayed in patients compared to controls, while the response times for source-based decisions were completely overlapping. Considered together, these findings suggest a deficit in the familiarity-based aspect of episodic memory in at least some patients with 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

Abundant evidence indicates that the neuronal nicotinic acetylcholine receptor (nAChR) system is integral to regulation of attentional processes and is dysregulated in schizophrenia. Nicotinic agonists may have potential for the treatment of cognitive impairment in this disease. This study investigated the effects of transdermal nicotine on attention in individuals with schizophrenia (n=28) and healthy controls (n=32). All participants were nonsmokers in order to eliminate confounding effects of nicotine withdrawal and reinstatement that may occur in the study of smokers. Subjects received 14 mg transdermal nicotine and identical placebo in a randomized, placebo-controlled, crossover design. A cognitive battery was conducted before and 3 h after each patch application. The primary outcome measure was performance on the Continuous Performance Test Identical Pairs (CPT-IP) Version. Nicotine significantly improved the performance on the CPT-IP as measured by hit reaction time, hit reaction time standard deviation and random errors in both groups. In addition, nicotine reduced commission errors on the CPT-IP and improved the performance on a Card Stroop task to a greater extent in those with schizophrenia vs controls. In summary, nicotine improved attentional performance in both groups and was associated with greater improvements in inhibition of impulsive responses in subjects with schizophrenia. These results confirm previous findings that a single dose of nicotine improves attention and suggest that nicotine may specifically improve response inhibition in nonsmokers with schizophrenia

BACKGROUND: Folate deficiency may contribute to negative symptoms in schizophrenia, but the underlying mechanism remains uncertain. We examined whether the methylenetetrahydrofolate reductase (MTHFR) C677T and A1298C functional polymorphisms contribute to negative symptoms. METHODS: Outpatients with schizophrenia (n = 200) were evaluated with the Positive and Negative Syndrome Scale (PANSS). Subjects also provided a blood sample for MTHFR genotype and serum chemistries. Comparisons of PANSS symptoms, folate, and homocysteine status were conducted based on genotype. RESULTS: The 677T allele load was associated with negative symptom severity. Contrary to our expectations, the T allele was also found to be protective against positive symptoms. The A1298C polymorphism did not contribute to negative symptoms, and only weakly to positive symptoms. The specific effects of the C677T polymorphism were confirmed with haplotype analysis. Among patients homozygous for the 667T allele, serum folate levels correlated with negative symptom severity. CONCLUSIONS: Increased MTHFR 677T allele load confers risk for negative symptoms in schizophrenia, while reducing severity of positive symptoms. Further, the biochemical interaction of low serum folate with 677T-variant MTHFR may induce downstream effects salient to the expression of negative symptoms

OBJECTIVE:: Lamotrigine previously was found to attenuate ketamine-induced behavioral changes and, in 2 placebo-controlled trials, to improve psychosis when added to antipsychotic medication. We sought to evaluate the potential role of lamotrigine augmentation in schizophrenia patients resistant to atypical antipsychotic medication. METHODS:: Two multicenter, randomized, double-blind, 12-week, parallel-group trials were conducted to compare flexibly dosed lamotrigine (100-400 mg/d) with placebo as add-on treatment in schizophrenia patients with stable, residual psychotic symptoms. The primary end point was changed in Positive and Negative Syndrome Scale total score at week 12. RESULTS:: Two hundred seventeen patients were enrolled in study 1 and 212 in study 2; completion rates in the intent-to-treat samples were 71% and 74%, respectively, and did not differ between treatment groups. Overall, mean Positive and Negative Syndrome Scale total scores improved in both studies and did not differ between treatment groups. In study 1, the Scale for Assessment of Negative Symptoms total score and Clinical Global Impression improved more with placebo than with lamotrigine; in study 2, the cognitive composite score improved more with lamotrigine than with placebo. CONCLUSIONS:: Results from these 2 studies do not support the use of lamotrigine as an adjunct to atypical antipsychotics in patients with refractory psychosis. It is unclear why positive results from previous lamotrigine trials were not replicated. The positive effect of lamotrigine on cognition in one trial, while of uncertain significance, may merit further study

The anterior cingulate cortex (ACC) is a key component of a network that directs both spatial attention and saccadic eye movements, which are tightly linked. Diffusion tensor imaging (DTI) has demonstrated reduced microstructural integrity of the anterior cingulum bundle as indexed by fractional anisotropy (FA) in schizophrenia, but the functional significance of these abnormalities is unclear. Using DTI, we examined the white matter underlying anterior cingulate cortex in schizophrenia to determine whether reduced FA is associated with prolonged latencies of volitional saccades. Seventeen chronic, medicated schizophrenia outpatients and nineteen healthy controls had high-resolution DTI scans. FA maps were registered to structural scans and mapped across participants using a surface-based coordinate system. Cingulate white matter was divided into rostral and dorsal anterior regions and a posterior region. Patients showed reduced FA in cingulate white matter of the right hemisphere. Reduced FA in the white matter underlying anterior cingulate cortex, frontal eye field, and posterior parietal cortex of the right hemisphere was associated with longer saccadic latencies in schizophrenia, though given the relatively small sample size, these relations warrant replication. These findings demonstrate that in schizophrenia, increased latency of volitional saccades is associated with reduced microstructural integrity of the white matter underlying key cortical components of a right-hemisphere dominant network for visuospatial attention and ocular motor control. Moreover, they suggest that anterior cingulate white matter abnormalities contribute to slower performance of volitional saccades and to inter-individual variability of saccadic latency in chronic, medicated schizophrenia

Patients who present with a first episode of psychosis pose many challenges to psychiatry. While some morbidity from schizophrenia is probably not modifiable once acute psychosis has occurred, the best management of this stage of illness nevertheless holds the promise of improving long-term outcomes. We review the clinical literature on first-episode psychosis to derive clinical guidance with regard to timely diagnosis and optimal pharmacological and nonpharmacological treatment. We describe the illness course and the prognosis for this acute phase of illness and the immediate, postpsychotic period

Hepatitis C virus (HCV) infection occurs in up to 20% of patients with chronic mental illnesses. To determine the prevalence of hepatitis C in a diagnostically well-defined sample, the authors screened all schizophrenia outpatients in a clozapine clinic (N=98) for HCV antibodies. Eight patients were positive for hepatitis C antibodies (antibody-positive prevalence: 8.2%); of those, 50% had detectable viral loads (viremia-positive prevalence: 4.1%). Screening for HCV infection should be considered for outpatients with schizophrenia. However, clinical experience treating HCV in schizophrenia patients is limited; in this cohort, 2 years after screening, no patient had received interferon/ribavirin treatment

The objective of this study was to examine whether there is a benefit of adding bupropion SR to high-dose combination nicotine replacement therapy (NRT) and weekly group cognitive behavioral therapy (CBT) for smoking reduction or cessation in schizophrenia. Fifty-one adult smokers with schizophrenia were randomly assigned to a 12-week trial of bupropion SR 300 mg/d or placebo added to transdermal nicotine patch, nicotine polacrilex gum, and CBT. The treatment goal was smoking cessation. The primary outcome measure was biochemically confirmed 7-day point-prevalence of 50% to 100% smoking reduction at week 12. Secondary outcomes were biochemically confirmed tobacco abstinence and change from baseline in expired air carbon monoxide (CO) and psychiatric symptoms. Subjects on bupropion + NRT had a greater rate of 50% to 100% smoking reduction at weeks 12 (60% vs. 31%; P = 0.036) and 24, a lower expired air CO in the treatment and follow-up periods, (F = 13.8; P < 0.001) and a greater continuous abstinence rate at week 8, before NRT taper, (52% vs. 19%; P = 0.014). However, relapse rates in subjects on bupropion + dual NRT were 31% during NRT taper (weeks 8-12) and 77% at the 12-month follow-up. Abstinence rates did not differ by treatment group at weeks 12 (36% vs. 19%), 24 (20% vs. 8%), or 52 (12% vs. 8%). Because abstinence rates were high during treatment with combination pharmacotherapy and relapse rates were very high during taper and after discontinuation of treatment, study of longer term treatment with combination pharmacotherapy and CBT for sustained abstinence is warranted in those who attain initial abstinence with this intervention