Faculty Bibliography

BACKGROUND: Phosphodiesterase 5 (PDE5) inhibitors increase cyclic guanosine monophosphate (cGMP) concentrations in the intracellular pathway activated by N-methyl-D-aspartic acid receptors which is believed to mediate long-term potentiation and memory consolidation. The PDE5 inhibitor sildenafil has been shown to enhance memory in animal models. In addition, neuronal nitric oxide synthase, another component of the NMDA/nitric oxide/cGMP intracellular pathway, has been reported to be dysregulated in schizophrenia patients. MATERIALS AND METHODS: Seventeen adult schizophrenia outpatients treated with a stable dose of antipsychotic received a single oral dose of placebo, sildenafil 50 mg, and sildenafil 100 mg in random order with a 48-h interval between administrations. Psychiatric symptom ratings and a cognitive battery were performed at baseline and 1 hour following each administration of the study drug. In addition, memory consolidation was examined by testing recall 48 h later, prior to the next administration of the study drug. RESULTS: Fifteen subjects completed all three treatment conditions. One subject developed irritability and required hospitalization 2 days after receiving sildenafil 100 mg. Neither dose of sildenafil significantly affected cognitive performance or symptom ratings compared to the placebo. CONCLUSION: Despite evidence for cognitive-enhancing effects of sildenafil in animal models, the strategy for treating putative NMDA receptor-mediated memory deficits in schizophrenia with sildenafil 50 and 100 mg was not successful. It is possible that the doses used in this study were not optimal or that repeated dosing may be necessary to achieve therapeutic effects. Agents under development that inhibit other subtypes of PDE remain promising for schizophrenia and dementia

It has been proposed that the loose associations characteristic of thought disorder in schizophrenia result from an abnormal increase in the automatic spread of activation through semantic memory. We tested this hypothesis by examining the time course of neural semantic priming using event-related potentials (ERPs). ERPs were recorded to target words that were directly related, indirectly related, and unrelated to their preceding primes, while thought-disordered (TD) and non-TD schizophrenia patients and healthy controls performed an implicit semantic categorization task under experimental conditions that encouraged automatic processing. By 300-400 milliseconds after target word onset, TD patients showed increased indirect semantic priming relative to non-TD patients and healthy controls, while the degree of direct semantic priming was increased in only the most severely TD patients. By 400-500 milliseconds after target word onset, both direct and indirect semantic priming were generally equivalent across the 3 groups. These findings demonstrate for the first time at a neural level that, under automatic conditions, activation across the semantic network spreads further within a shorter period of time in specific association with positive thought disorder in schizophrenia.

BACKGROUND: In patients with schizophrenia, the smoking cessation rate is low and the burden of smoking-related morbidity and mortality is high. Identification of factors associated with abstinence may allow clinicians to optimize treatment prior to a smoking cessation attempt. METHOD: To identify factors associated with successful smoking cessation in patients with a DSM-IV diagnosis of schizophrenia, we analyzed baseline data from 114 stable outpatient smokers with schizophrenia who participated in 1 of 2 smoking cessation trials. The outcome of interest was 4 weeks' continuous abstinence at the end of a 12-week nicotine dependence treatment intervention. Baseline factors associated with abstinence were identified with univariate methods and entered into a manual, forward-selection multivariable regression model to identify independent predictors of abstinence. The study was conducted from March 1999 to February 2004. RESULTS: Fourteen of 114 participants (12%) had biochemically verified 4 weeks' continuous abstinence at week 12. We included 10 noncorrelated variables with a univariate association with abstinence in a multivariable model, controlling for pharmacotherapy, age, and gender. Age at initiation of smoking and baseline variability in attentiveness, as measured by Continuous Performance Test-AX (CPT-AX) hit reaction time standard error, were independently associated with abstinence. For every year increase in age at initiation of smoking, the OR for abstinence was 1.36 (95% CI = 1.01 to 1.83), p = .048. For every millisecond decrease in the variability of the reaction time of CPT-AX, the OR for achieving abstinence was 1.55 (95% CI = 1.07 to 2.24), p = .021. CONCLUSION: Later initiation of smoking was associated with increased and baseline attentional impairment with reduced odds of abstinence. Additional research to further our understanding of the relationship between attentional impairment and cigarette smoking in schizophrenia may lead to improved nicotine dependence treatments for this group

Understanding how risk genes cumulatively impair brain function in schizophrenia could provide critical insights into its pathophysiology. Working memory impairment in schizophrenia has been associated with abnormal dopamine signaling in the prefrontal cortex, which is likely under complex genetic control. The catechol-O-methyltransferase (COMT) 158Val --> Met polymorphism (rs4680), which affects the availability of prefrontal dopamine signaling, consistently stratifies prefrontal activation during working memory performance. However, the low-dopamine COMT 158Val allele does not confer increased risk for schizophrenia, and its effects on prefrontal function are not specific to the disorder. In the setting of other genetic variants influencing prefrontal dopamine signaling, COMT 158Val --> Met genotype may exert disease-specific effects. A second polymorphism, methylenetetrahydrofolate reductase (MTHFR) 677C --> T (rs1801133), has been associated with overall schizophrenia risk and executive function impairment in patients, and may influence dopamine signaling through mechanisms upstream of COMT effects. We found that the hypofunctional 677T variant was associated with decreased working memory load-dependent activation in the prefrontal and insular cortices in 79 schizophrenia patients, but not in 75 demographically matched healthy controls. Further, significant MTHFR x COMT genotype interactions were observed, which differed by diagnostic group: Reduced prefrontal activation was associated with the 677T and 158Val alleles in patients, but with 677C/C and 158Met/Met genotype in controls. These findings are consistent with epistatic effects of the COMT and MTHFR polymorphisms on prefrontal dopamine signaling, and suggest that in schizophrenia patients, the MTHFR 677T allele exacerbates prefrontal dopamine deficiency. The findings also suggest the importance of weighing COMT effects on prefrontal function within the context of MTHFR genotype

The P21-activated kinase PAK3 is critical for cognitive development and truncating mutations cause non-syndromic mental retardation (MR). Missense mutations are also associated with psychotic disorders, most commonly with schizophrenia involving premorbid MR, namely 'pfropfschizophrenie'. We set out to measure the frequency of sequence variants in PAK3 in schizophrenia without premorbid MR. We conducted complete gene reseqeuncing of all coding exons and exon-intron boundaries in patients with schizophrenia with cognitive impairment but without premorbid MR. Deleterious variants in schizophrenia alone were rare (<1/159 or 0.6%). Thereby, while PAK3 remains a strong biological candidate in psychosis, evidence from human genetics provides strongest support for a link to pfropfschizophrenie and not to schizophrenia without premorbid intellectual disability

BACKGROUND: Daily dosing with d-cycloserine has inconsistently improved negative symptoms in schizophrenia patients, whereas intermittent dosing significantly facilitated exposure-based therapy in two studies of patients with phobic anxiety. In animal models, single-dose administration enhances memory consolidation, but tachyphylaxis develops with repeated dosing. The objective of this exploratory study was to assess whether once-weekly dosing with d-cycloserine will produce persistent improvements in negative symptoms and cognition. METHODS: Fifty stable adult schizophrenia outpatients treated with any antipsychotic except clozapine were enrolled and 38 were randomized, double-blind, in a parallel-group, eight-week add-on trial of d-cycloserine 50 mg or placebo administered once-weekly. Symptom rating scales and a cognitive battery were administered at baseline and week 8 before the dose of study drug. As an exploratory analysis of memory consolidation, the Logical Memory Test, modified to measure recall after 7 days, was administered at baseline and after the first weekly dose of d-cycloserine. The primary outcome measures were change from baseline to week 8 on the SANS total score and on a composite cognitive score. RESULTS: Thirty-three subjects (87%) completed the trial. d-cycloserine significantly improved SANS total scores compared to placebo at week 8. Cognitive performance did not improve with d-cycloserine at 8 weeks. Delayed thematic recall on the Logical Memory Test was significantly improved with the first dose of d-cycloserine compared to placebo. Performance on immediate thematic recall and item recall on the Logical Memory Test did not differ between treatments. CONCLUSIONS: Once-weekly dosing with d-cycloserine for 8 weeks produced persistent improvement of negative symptoms compared to placebo, although statistical significance was, in part, the result of worsening of negative symptoms with placebo. Consistent with animal models, a single dose of d-cycloserine facilitated memory consolidation tested after 7 days on a test of thematic recall. These results must be considered preliminary since a number of outcomes were examined without correction for multiple tests. These findings suggest that once-weekly dosing with d-cycloserine for the treatment of negative symptoms merits further study, as do d-cycloserine effects on memory consolidation

OBJECTIVE: Persons with schizophrenia die earlier than the general population, in large part due to cardiovascular disease. The study objective was to examine effects of different antipsychotic treatments on estimates of 10-year coronary heart disease (CHD) risk calculated by the Framingham Heart Study formula. METHOD: Change in 10-year risk for CHD was compared between treatment groups in 1125 patients followed for 18 months or until treatment discontinuation in the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) Schizophrenia Trial. RESULTS: The covariate-adjusted mean change in 10-year CHD risk differed significantly between treatments. Olanzapine was associated with a 0.5% (SE 0.3) increase and quetiapine, a 0.3% (SE 0.3) increase; whereas risk decreased in patients treated with perphenazine, -0.5% (SE 0.3), risperidone, -0.6% (SE 0.3), and ziprasidone -0.6% (SE 0.4). The difference in 10-year CHD risk between olanzapine and risperidone was statistically significant (p=0.004). Differences in estimated 10-year CHD risk between drugs were most marked in the tertile of subjects with a baseline CHD risk of at least 10%. Among individual CHD risk factors used in the Framingham formula, only total and HDL cholesterol levels differed between treatments. CONCLUSIONS: These results indicate that the impact on 10-year CHD risk differs significantly between antipsychotic agents, with olanzapine producing the largest elevation in CHD risk of the agents studied in CATIE