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Background Cognitive dysfunction is a key predictor of functional disability in schizophrenia. Davunetide (AL-108, NAP) is an intranasally administered peptide currently being developed for treatment of Alzheimer's disease and related disorders. This study investigates effects of davunetide on cognition in schizophrenia. Method Sixty-three subjects with schizophrenia received davunetide at one of two different doses (5, 30 mg) or placebo for 12 weeks in a multicenter, double-blind, parallel-group randomized clinical trial. The MATRICS Consensus Cognitive Battery (MCCB) assessed cognitive effects. The UCSD Performance-based Skills Assessment (UPSA) and the Schizophrenia Cognition Rating Scale (SCoRS) assessed functional capacity. Subjects continued their current antipsychotic treatment during the trial. Results There were no significant differences in MCCB change between davunetide and placebo over the three treatment arms (p = .45). Estimated effect-size (d) values were .34 and .21 favoring the 5 and 30 mg doses vs. placebo, respectively. For UPSA, there was a significant main effect of treatment across study arms (p = .048). Between-group effect size (d) values were.74 and .48, favoring the 5 and 30 mg doses, respectively. No significant effects were observed on the SCoRS or on symptom ratings. No significant side effects or adverse events were observed. Conclusion Davunetide was well tolerated. Effects of davunetide on MCCB-rated cognition were not significant relative to placebo. In contrast, a significant beneficial effect was detected for the UPSA. Based upon effect-size considerations, sample sizes of at least 45–50 subjects/group would be required to obtain significant effects on both MCCB and UPSA, providing guidance for continued clinical development in schizophrenia.

Sponsored by the New York Academy of Sciences and with support from the National Institute of Mental Health, the Life Technologies Foundation, and the Josiah Macy Jr. Foundation, “Advancing Drug Discovery for Schizophrenia” was held March 9–11 at the New York Academy of Sciences in New York City. The meeting, comprising individual talks and panel discussions, highlighted basic, clinical, and translational research approaches, all of which contribute to the overarching goal of enhancing the pharmaceutical armamentarium for treating schizophrenia. This report surveys work by the vanguard of schizophrenia research in such topics as genetic and epigenetic approaches; small molecule therapeutics; and the relationships between target genes, neuronal function, and symptoms of schizophrenia.

Because reduction of psychotic symptoms in schizophrenia does not result in adequate community functioning, efforts have shifted to other areas, such as cognitive impairment. The U.S. Food and Drug Administration requires that drugs for cognition enhancement in schizophrenia show improvement on two distinct outcome measures in clinical trials: an accepted cognitive performance battery and a functionally meaningful coprimary measure. The authors examined the reliability, validity, and practicality of functionally meaningful measures.In this four-site validation study, schizophrenia patients were assessed at baseline (N=166) and 4 weeks later (N=144) on performance-based (Independent Living Scales, Test of Adaptive Behavior in Schizophrenia [TABS], and UCSD Performance-based Skills Assessment [UPSA]) and interview-based (Cognitive Assessment Interview and Clinical Global Impression Scale for Cognition) candidate coprimary measures. In addition, cognitive performance, community functioning, and clinical symptoms were assessed. Both full and short forms of the performance-based measures were evaluated.All measures were well tolerated by patients, had adequate test-retest reliability, and showed good utility as a repeated measure. Measures differed in their correlation with cognitive performance, with performance-based measures having stronger correlations than interview-based measures. None of the measures had notable floor or ceiling effects or missing data.Among the full-form measures, the UPSA was judged to have the strongest overall properties. Among the short forms, the TABS and UPSA appeared to have the strongest features. Use of the short forms saves time, but at the cost of lower test-retest reliability and weaker correlations with cognitive performance.

Risperidone has been used to treat behavioral symptoms, such as delusions and agitation, in people with Alzheimer's disease. The relationship between magnitude and variability of risperidone and 9-hydroxy risperidone exposure and the relationship with time to discontinuation of the medication were explored. Sixty-five subjects from the Clinical Antipsychotic Trial of Intervention Effectiveness-Alzheimer's Disease Trial that received risperidone were included in this study. Eighteen subjects completed the study without switching medication (completers on risperidone), whereas 47 discontinued the medication. Those who discontinued were divided into 2 groups according to responsiveness to therapy. Using Cox proportional survival regression analysis, we estimated time to discontinuation and factors associated with treatment discontinuation including age, dose, body mass index, neuropsychiatric inventory baseline score, and average exposure (area under the curve [AUC]) to risperidone and 9-hydroxy risperidone. Twenty-four and 17 subjects discontinued therapy because of inadequate therapeutic effect and side effects, respectively (6 subjects were excluded because of missing information about reason for switching or discontinuation). Discontinuation hazards for those with a higher than median AUC of the metabolite were 2.54 (P = 0.029; inadequate and side effect group combined) and 3.48 (P = 0.025; inadequate effect group) times that of those in the lower than median AUC group. None of the other covariates contributed significantly to the switching hazard. Risperidone metabolite, 9-hydroxy risperidone concentrations, correlated with the risk of switching or discontinuing the medication, suggesting that 9-hydroxy risperidone contributes to adverse events and intolerability in dementia patients.

In schizophrenia, treatments that improve outcomes have not been reliably disseminated. A major barrier to improving care has been a lack of routinely collected outcomes data that identify patients who are failing to improve or not receiving effective treatments. To support high quality care, the VA Mental Health QUERI used literature review, expert interviews, and a national panel process to increase consensus regarding outcomes monitoring instruments and strategies that support quality improvement. There was very good consensus in the domains of psychotic symptoms, side-effects, drugs and alcohol, depression, caregivers, vocational functioning, and community tenure. There are validated instruments and assessment strategies that are feasible for quality improvement in routine practice. © 2010 Springer Science+Business Media, LLC.

Background Several lines of evidence suggest that Herpes Simplex Virus type 1 (HSV-1) may contribute to cognitive impairment in schizophrenia. Herpes viruses are enveloped, double stranded DNA viruses that are capable of infecting human CNS resulting in life-long infection with over 40% of the population seropositive for this virus. Valacyclovir is an effective treatment for the suppression of herpes virus infections. A previous small clinical trial (N=24) assessed the efficacy of valacyclovir for cognitive impairment in patients with early phase schizophrenia who were seropositive for HSV-1 (Prasad et al 2013). Results indicate that adjunctive valacyclovir, as compared to placebo, showed improvement in working and visual memory. The current study was undertaken to confirm and extend these findings and determine if HSV-1 seropositive, as compared to those who were HSV-1 seronegative, derived cognitive improvement from adjunctive valacyclovir. We hypothesized that individuals who were HSV-1 positive, but not HSV-1 negative, would demonstrate significant valacyclovir efficacy for cognitive impairment. Methods An early psychosis network comprised of 12 US sites was established for the valacyclovir trial. Subjects had early phase schizophrenia (within 8 years since psychosis onset) and were randomized 1:1 to a 16-week trial of adjunctive valacyclovir (3 grams/day) or placebo. Assessments included cognitive domains (MATRICS), role functioning (UPSA-B, Q-LES-Q-SF, PSP), psychiatric symptoms (PANSS, NSA-16) and a range of inflammatory markers. The primary outcome was change in working (composite score of Spatial Span and Letter Number span) and visual (Brief Visuospatial Memory Test) as measured by the MATRICS. Results 170 subjects with early phase schizophrenia were stratified by HSV-1 status and randomized 1:1 to adjunctive valacyclovir or adjunctive placebo. Of those randomized, 74 were HSV-1 seropositive and 96 were seronegative. The valacyclovir vs. placebo groups, respectively, were well matched: age (28.4 vs. 27.5 years), gender (males: 69% vs. 77.9 %), race (white-caucasian: 28.6% vs. 33.7%) and duration of psychosis (3.7 vs. 4.0, years). Baseline working memory scores (Letter-Number Span) were significantly lower in HSV1 positive vs. negative subjects (mean/SD: vs. 35.1/9.0 vs 38.3/11.0, p=0.046). Treatment outcome analyses have only recently commenced and are ongoing. Full results of the cognitive, functioning, symptom and safety measures will be presented at the meeting. Discussion The current study included 170 patients with early phase schizophrenia randomized to valacyclovir or placebo and stratified by HSV1 sero-status. Baseline working memory scores (Letter-Number Span) were significantly lower in HSV1 positive compared to HSV1 negative subjects. As analyses of treatment effects are ongoing, detailed results of valacyclovir’s effects on cognitive domains, symptoms, functioning and safety will be presented at the meeting. Additional research is needed to determine the full therapeutic potential of valacyclovir and other medications targeting herpes viruses in the treatment of schizophrenia.

The Food and Drug Administration (FDA)-National Institute of Mental Health (NIMH)-Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) clinical trial guidelines for cognitive-enhancing drugs in schizophrenia and the MATRICS Consensus Cognitive Battery (MCCB) were designed to facilitate novel compound development in the treatment of cognitive impairments. Several studies have recently utilized the FDA-NIMH-MATRICS guidelines and MCCB and allow an evaluation of the feasibility of guideline implementation and MCCB performance. In light of the study results, we would recommend the following inclusion criteria revisions—(1) clinical status and symptom inclusion criteria: maximum allowed score for hallucinations and delusions should be increased from moderate to moderately severe and the negative symptom criterion should be dropped in phase 2 studies; (2) antipsychotic medication inclusion criteria: first-generation antipsychotics should be allowed, but only in the context of no concomitant anticholinergic agents and minimal extrapyramidal symptoms, and antipsychotic polypharmacy should be allowed in the absence of pertinent pharmacokinetic or pharmacodynamic considerations; and (3) people who use illicit substances should not be allowed in phase 1B or 2A proof-of-concept studies but may be included in phase 2B and 3 studies in which proof of effectiveness and generalizability of results become more important goals. These revisions are recommended to enhance recruitment while maintaining sufficient methodological rigor to ensure the validity of study results. The MCCB has been shown to have excellent psychometric characteristics, including reliability for multisite clinical trials, clinical relevance for real-world functioning, and possible sensitivity to behavioral treatment, and should continue to serve as the standard outcome measure for cognitive enhancement studies in schizophrenia.

The National Institute of Mental Health (NIMH)-Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) Project and related efforts have stimulated the initiation of several studies of pharmacologic treatments for cognitive impairment in schizophrenia. Cognitive remediation may provide an excellent platform for the provision of new learning opportunities and the acquisition of new skills for patients who are engaged in pharmacologic trials to improve cognition. However, it is not clear how a cognitive remediation intervention would be employed in multisite clinical trials. A meeting of experts on cognitive remediation and related methodological topics was convened to address the feasibility and study design issues for the development of a multisite trial of cognitive remediation in schizophrenia called the Cognitive Remediation in the Schizophrenia Trials Network study. This report details the findings from this meeting, which included the following 4 conclusions. (1) A multisite trial of a cognitive remediation intervention using a network of diverse research sites would be of great scientific value. (2) Various interventions could be employed for this multisite trial. (3) Programs that do not address key motivational and interpersonal aspects of cognitive remediation may benefit from supplementation with “bridging groups” that allows patients to meet with others and to apply their newly acquired cognitive skills to everyday life. (4) Before a multisite efficacy trial is initiated, a pilot study could demonstrate the feasibility of conducting a trial using a cognitive remediation intervention.

Introduction: This study describes how the negative subsyndrome of apathy develops over the first year in first episode psychosis (FEP) patients, with an emphasis on the prevalence of enduring apathy and the relationship between apathy, other symptoms and functioning. Methods: Eighty four FEP patients were assessed both at baseline and after one year with the abridged clinical version of the Apathy Evaluation Scale (AES-C-Apathy). Other symptoms were assessed with the Positive and Negative syndrome scale (PANSS) and functioning with the split version of the Global Assessment of Functioning Scale (GAF-F). Results: The mean level of AES-C-Apathy decreased from baseline to the one year follow up for the whole group of FEP patients. High levels of apathy at 1 year were best predicted by high levels of apathy at baseline, a long DUP and a diagnosis within the Schizophrenia spectrum. The presence of depression and level of medication only had a minor influence. AES-C-Apathy had a stronger association to GAF-F than other PANSS symptom areas. Twenty five (30%) FEP patients had high enduring levels of apathy. This group consisted of significantly more males, had a longer duration of untreated psychosis, a greater likelihood of a Schizophrenia spectrum diagnosis, fewer were in remission of positive symptoms and they had significantly poorer functioning at both baseline and follow up. Conclusion: This study confirms that the negative subsyndrome of apathy is significantly related to poor functioning in FEP. Including negative symptoms and its subsyndromes in early detection strategies are warranted.

OBJECTIVE Combining antipsychotics is common practice in the treatment of schizophrenia. This study investigated aripiprazole adjunctive to risperidone or quetiapine for treating schizophrenia and schizoaffective disorder. METHOD In this multicenter, double-blind, 16-week, placebo-controlled study conducted at 43 American sites from July 2006 to October 2007, patients with chronic, stable schizophrenia or schizoaffective disorder diagnosed with DSM-IV-TR were randomly assigned to receive aripiprazole (2-15 mg/d) or placebo in addition to a stable regimen of quetiapine (400-800 mg/d) or risperidone (4-8 mg/d). The primary outcome measure was the mean change from baseline to endpoint (week 16, last observation carried forward) in the Positive and Negative Syndrome Scale (PANSS) total score. RESULTS 323 subjects being treated with either risperidone (n = 177) or quetiapine (n = 146) were randomly assigned to receive adjunctive aripiprazole (n = 168) or placebo (n = 155). Baseline characteristics were similar (mean PANSS total score: aripiprazole, 74.5; placebo, 75.9) except for history of suicide attempts (aripiprazole, 27%; placebo, 40%). Nearly 70% of subjects in each arm completed the trial. Adjunctive aripiprazole and placebo groups were similar in the mean change from baseline to endpoint in the PANSS total score (aripiprazole, -8.8; placebo, -8.9; P = .942). The incidence of treatment-emergent adverse events was similar between groups. Mean changes in Simpson-Angus Scale, Abnormal Involuntary Movement Scale, and Barnes Akathisia Rating Scale scores were not statistically significantly different. Adjunctive aripiprazole was associated with statistically significantly greater decreases in mean serum prolactin levels from baseline than was adjunctive placebo (-12.6 ng/mL for aripiprazole vs -2.2 ng/mL for placebo; P < .001), an effect that was seen in the risperidone subgroup (-18.7 ng/mL vs -1.9 ng/mL; P < .001) but not in the quetiapine subgroup (-3.01 ng/mL vs +0.15 ng/mL; P = .104). CONCLUSIONS The addition of aripiprazole to risperidone or quetiapine was not associated with improvement in psychiatric symptoms but was generally safe and well tolerated. Further research is warranted to explore whether antipsychotic combination therapy offers benefits to particular patient populations-for example, in cases of hyperprolactinemia. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00325689.

Cognitive impairment in schizophrenia is often severe, enduring, and contributes significantly to chronic disability. But clinicians have difficulty in assessing cognition due to a lack of brief instruments. We evaluated whether a brief battery of cognitive tests derived from larger batteries could generate a summary score representing global cognitive function. Using data from 3 previously published trials, we calculated the corrected item-total correlations (CITCs) or the correlation of each test with the battery total score. We computed the proportion of variance that each test shares with the global score excluding that test (R(t)(2)=CITC(2)) and the variance explained per minute of administration time for each test (R(t)(2)/min). The 3 tests with the highest R(t)(2)/min were selected for the brief battery. The composite score from the trail making test B, category fluency, and digit symbol correlated .86 with the global score of the larger battery in 2 of the studies and correlated between .73 and .82 with the total battery scores excluding these 3 tests. A Brief Cognitive Assessment Tool for Schizophrenia (B-CATS) using the above 3 tests can be administered in 10-11 min. The full batteries of the larger studies have administration times ranging from 90 to 210 min. Given prior research suggesting that a single factor of global cognition best explains the pattern of cognitive deficit in schizophrenia, an instrument like B-CATS can provide clinicians with meaningful data regarding their patients' cognitive function. It can also serve researchers who want an estimate of global cognitive function without requiring a full neuropsychological battery.

A number of psychosocial treatments are available for persons with schizophrenia that include social skills training, cognitive behavioral therapy, cognitive remediation, and social cognition training. These treatments are reviewed and discussed in terms of how they address key components of functional recovery such as symptom stability, independent living, work functioning, and social functioning. We also review findings on the interaction between pharmacological and psychosocial treatments and discuss future directions in pharmacological treatment of schizophrenia. Overall, these treatments provide a range of promising approaches to helping patients achieve better outcomes far beyond symptom stabilization.

Despite the expansion of available antipsychotic drugs over the past 50 years, functional outcomes for individuals with schizophrenia have not markedly improved. These agents are efficacious for psychosis but do not adequately address other core domains of schizophrenia psychopathology, namely negative symptoms and cognitive impairment, which have a greater impact on functional outcomes, including vocational or academic performance and interpersonal relationships. In addition, treatment-refractory psychosis still precludes functional improvement in many patients. Schizophrenia is a clinical syndrome consisting of these domains, which likely have some disparities in their respective pathophysiologies. This suggests that drug development should look to other molecular targets besides the D2 receptor, which characterizes the mechanism of available medications for schizophrenia. In this report, we review novel pharmacologic approaches that aim to specifically address each individual domain of schizophrenia. The goal of this future pharmacotherapy strategy is to advance outcomes beyond psychosis remission and toward functional recovery.

Clozapine is known to be effective in treating schizophrenia patients with comorbid alcohol use disorders (AUD). However, few prospective studies have examined the effect of clozapine on community survival of the patient, which is one of the most important indicators of success for patients with schizophrenia. In this prospective, naturalistic, observational, community-survival-analysis study, we compared the effect of clozapine and risperidone on two-year psychiatric hospitalization rate and time to hospitalization in the treatment of patients with schizophrenia and comorbid AUD. We found that the clozapine treated patients were readmitted to hospital significantly later (mean survival = 526.5 days, n = 25 patients) than the risperidone treated patients (mean survival = 420.4 days, n = 36 patients). The survival curve for the clozapine-treated patients was significantly different from that of the risperidone treated patients (log-rank test, df = 1, p = .045). At the end of the two-year study period, 75% of the risperidone treated patients had been admitted to the hospital, compared to only 48% of the clozapine treated patients. These findings suggest that clozapine should be considered for the treatment of schizophrenia patients with comorbid AUD. However, due to the limitations of this study, further studies will be required to confirm these findings.

Objective: The lack of an accepted standard for measuring cognitive change in schizophrenia has been a major obstacle to regulatory approval of cognition-enhancing treatments. A primary mandate of the National Institute of Mental Health’s Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) initiative was to develop a consensus cognitive battery for clinical trials of cognition-enhancing treatments for schizophrenia through a broadly based scientific evaluation of measures. Method: The MATRICS Neurocognition Committee evaluated more than 90 tests in seven cognitive domains to identify the 36 most promising measures. A separate expert panel evaluated the degree to which each test met specific selection criteria. Twenty tests were selected as a beta battery. The beta battery was administered to 176 individuals with schizophrenia and readministered to 167 of them 4 weeks later so that the 20 tests could be compared directly. Results: The expert panel ratings are presented for th...

Background: The use of the term ‘recovered’ in outcome studies of schizophrenia has for a long time been problematic because of the many different definitions in use. In the present study different definitions of recovered in schizophrenia are reviewed and compared with similar definitions in other fields of medicine. Sampling and Methods: A literature searchwas done for criteria-based definitions of recovered as used in follow-up studies of patients with schizophrenia during the last 50 years and the current use of the term in other fields of medicine. Results: In medicine, only the field of psychiatry defines the term recovered to be synonymous with no or minimal signs of illness. Other fields only apply the term when studying the outcome of a specific function. In psychiatry, only the field of schizophrenia includes both symptoms and functioning in the definition. All but 1 of the 18 definitions found in use in the field of schizophrenia required minimal or no symptoms, while all differed in defining functional recovery. Recovered was seldom defined as following from a state of remission, and studies varied in requiring a stable phase. Conclusion: When using the term in the field of schizophrenia, a distinction should be made between symptomatic and functional recovery in order to place it in line with other fields of medicine. To avoid confusing the process of recovery from the state of being recovered, the term recovered should be reserved for use in outcome studies, following from a time in remission. We suggest 2 years.

Recent attention has focused on the limitations of current antipsychotic medications for improving community functioning in schizophrenia. The strong relationship between neurocognition and functional outcome has led to a focus on developing pharmacological agents that improve cognition. The potential of this target led to a National Institute of Mental Health initiative known as Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS). Through a series of consensus meetings that included representatives from academia, the pharmaceutical industry, and government, this initiative has developed a consensus battery of neuropsychological tests that can be used as an outcome measure in clinical trials, a pathway to drug approval that has been endorsed by the U.S. Food and Drug Administration, a priority list of molecular targets for new drug development, and a consensus regarding the design of clinical trials.

Background Paliperidone extended-release tablet (paliperidone ER; Invega, Janssen L.P., Titusville, New Jersey) is an oral psychotropic for schizophrenia treatment. Methods Efficacy and safety of once-daily paliperidone ER (6 and 12 mg) were assessed versus placebo in 444 patients with acute schizophrenia in a 6-week, multicenter, double-blind, randomized, parallel-group study. An olanzapine (10 mg) treatment arm was included to confirm trial validity. Results Both doses of paliperidone ER demonstrated significant improvement in Positive and Negative Syndrome Scale (PANSS) total score ( p ≤ .006) and certain PANSS Marder factor scores compared with placebo ( p ≤ .025); PANSS total score also improved in the olanzapine treatment arm. Paliperidone ER 6 mg ( p ≤ .008), but not 12 mg, was associated with significant improvements in personal and social performance. The incidence of treatment-emergent adverse events (AEs) for paliperidone ER 6 mg was comparable with placebo and slightly greater with paliperidone ER 12 mg. Changes in blood glucose and lipid levels with paliperidone ER were comparable with placebo. Two patients treated with paliperidone ER experienced glucose-related AEs. Body-weight increases of 1-2 kg were observed with paliperidone ER. Although there were increases in plasma prolactin levels with paliperidone ER treatment, the incidence of prolactin-related AEs was ≤1%. Conclusions In this study, paliperidone ER, particularly the 6-mg dose, was effective and well tolerated, and provides a valuable new treatment option for schizophrenia.

BACKGROUND: A panel of academic psychiatrists and pharmacists, clinicians from the Texas public mental health system, advocates, and consumers met in June 2006 in Dallas, Tex., to review recent evidence in the pharmacologic treatment of schizophrenia. The goal of the consensus conference was to update and revise the Texas Medication Algorithm Project (TMAP) algorithm for schizophrenia used in the Texas Implementation of Medication Algorithms, a statewide quality assurance program for treatment of major psychiatric illness. METHOD: Four questions were identified via premeeting teleconferences. (1) Should antipsychotic treatment of first-episode schizophrenia be different from that of multiepisode schizophrenia? (2) In which algorithm stages should first-generation antipsychotics (FGAs) be an option? (3) How many antipsychotic trials should precede a clozapine trial? (4) What is the status of augmentation strategies for clozapine? Subgroups reviewed the evidence in each area and presented their findings at the conference. RESULTS: The algorithm was updated to incorporate the following recommendations. (1) Persons with first-episode schizophrenia typically require lower antipsychotic doses and are more sensitive to side effects such as weight gain and extrapyramidal symptoms (group consensus). Second-generation antipsychotics (SGAs) are preferred for treatment of first-episode schizophrenia (majority opinion). (2) FGAs should be included in algorithm stages after first episode that include SGAs other than clozapine as options (group consensus). (3) The recommended number of trials of other antipsychotics that should precede a clozapine trial is 2, but earlier use of clozapine should be considered in the presence of persistent problems such as suicidality, comorbid violence, and substance abuse (group consensus). (4) Augmentation is reasonable for persons with inadequate response to clozapine, but published results on augmenting agents have not identified replicable positive results (group consensus). CONCLUSIONS: These recommendations are meant to provide a framework for clinical decision making, not to replace clinical judgment. As with any algorithm, treatment practices will evolve beyond the recommendations of this consensus conference as new evidence and additional medications become available. Language: en

Objective: Patients with schizophrenia frequently present with negative symptoms and cognitive impairments for which no effective treatments are known. Agents that act at the glycine site of the N -methyl- D -aspartic acid (NMDA) glutamatergic receptor have been suggested as promising treatments for moderate to severe negative symptoms and cognitive impairments. Method: The Cognitive and Negative Symptoms in Schizophrenia Trial (CONSIST) was a 16-week double-blind, doubledummy, parallel group, randomized clinical trial of adjunctive glycine, D-cycloserine, or placebo conducted at four sites in the United States and one site in Israel. The participants were 157 inpatients and outpatients who met DSM-IV criteria for schizophrenia or schizoaffective disorder and retrospective and prospective criteria for moderate to severe negative symptoms without marked positive, depressive, or extrapyramidal symptoms. The primary outcome measures were the average “rate of change” of Scale for the Assessment of Negative Symptoms (SANS) total scores and change in the average cognitive domain z scores. Results: There were no significant differences in change in the SANS total score between glycine and placebo subjects or D-cycloserine and placebo subjects. A prespecified test for the site-by-treatment-bytime interaction was significant in post hoc tests. One site had greater reduction in the SANS total score for patients receiving D-cycloserine relative to patients receiving placebo. A second site had greater reduction in the SANS total score for placebo patients compared with glycine patients. There were no significant differences between glycine and placebo or Dcycloserine and placebo subjects on the average cognition z score. Conclusions: The study results suggest that neither glycine nor D-cycloserine is a generally effective therapeutic option for treating negative symptoms or cognitive impairments.

Objective: This study examined the short-term effects of first- and second-generation antipsychotic medications on social cognition and basic cognition. Method: One hundred patients with schizophrenia or schizoaffective disorder participated in an 8 week, double-blind study of risperidone, olanzapine, and haloperidol. Participants were administered multiple measures of social cognition, basic cognition, and clinical symptoms at baseline, the end of week 4, and the end of week 8. Seventy-three patients completed the baseline assessment and at least one other assessment. Data were analyzed with mixed-effects analyses of covariance. For data reduction, the social cognitive measures were clustered into a summary score, and the cognitive measures were clustered into two summary scores: general cognitive ability and processing speed. (The effects on thinking of risperidone and olanzapine can be found at NCT00108368, www.clinicaltrials.gov.) Results: There were no treatment-related differences on any of the three summary scores. Social cognition did not show within-group changes over time either by itself or after control for the cognitive clusters. One cognitive score (general cognitive ability) increased during the study period for all three medication groups. Conclusions: The present study included a rather thorough assessment of social cognition and did not find any evidence of between-group or within-group effects of antipsychotic medication on social cognition.

Prepulse inhibition (PPI), whereby the startle eyeblink response is inhibited by a relatively weak non-startling stimulus preceding the powerful startle eliciting stimulus, is a measure of sensorimotor gating and has been shown to be deficient in schizophrenia patients. There is considerable interest in whether conventional and/or atypical antipsychotic medications can "normalize" PPI deficits in schizophrenia patients. 51 schizophrenia patients participated in a randomized, double-blind controlled trial on the effects of three commonly-prescribed antipsychotic medications (risperidone, olanzapine, or haloperidol) on PPI, startle habituation, and startle reactivity. Patients were tested at baseline, Week 4 and Week 8. Mixed model regression analyses revealed that olanzapine significantly improved PPI from Week 4 to Week 8, and that at Week 8 patients receiving olanzapine produced significantly greater PPI than those receiving risperidone, but not haloperidol. There were no effects of medication on startle habituation or startle reactivity. These results support the conclusion that olanzapine effectively increased PPI in schizophrenia patients, but that risperidone and haloperidol had no such effects. The results are discussed in terms of animal models, neural substrates, and treatment implications.

OBJECTIVE Patients with acute schizophrenia who are agitated typically manifest worse overall symptomatology and are generally more challenging to treat than nonagitated patients. In order to determine whether baseline agitation level influences treatment response, the effects of oral aripiprazole in acute patients with schizophrenia experiencing either higher or lower levels of agitation were examined. METHOD A post hoc analysis of pooled data from the first 4 or 6 weeks of 4 randomized, double-blind, placebo-controlled aripiprazole trials was conducted. Patients with a DSM-IV diagnosis of acute schizophrenia randomly assigned to treatment with either aripiprazole 10, 15, 20, or 30 mg/day (N = 790) or placebo (N = 397) were divided into groups experiencing higher or lower agitation at baseline. Higher agitation was defined as a baseline Positive and Negative Syndrome Scale (PANSS)-Excited Component (PEC) score of > or = 14 and a score of > or = 4 on at least 1 PEC item (excitement, hostility, tension, uncooperativeness, or poor impulse control). Analysis of covariance was used to evaluate PANSS total, Clinical Global Impressions-Improvement scale (CGI-I), and PEC scores between aripiprazole and placebo within the higher and lower agitation groups. RESULTS In both the higher and lower agitation groups, aripiprazole treatment produced significantly lower PANSS total, CGI-I, and PEC scores at weeks 2 to 6, compared with placebo (p < .05 for each measure). Percentage of concomitant benzodiazepine use was similar at end point for aripiprazole and placebo, and adverse events were generally mild across groups. CONCLUSIONS Aripiprazole significantly improved the core symptoms of acute schizophrenia regardless of baseline agitation level. In particular, agitation symptoms were significantly decreased in patients with higher baseline agitation. Improvements appeared to be independent of benzodiazepine use or excessive sedation effects. These results suggest that oral aripiprazole is an effective and safe treatment option for patients with acute schizophrenia who manifest agitation symptoms.

An accurate, rapid and simple liquid chromatography–tandem mass spectrometry (LC–MS–MS) assay method was developed for the determination of ziprasidone (ZIP) in the plasma of schizophrenia patients. A simple one step liquid–liquid extraction with 20% methylene dichloride in pentane was used to isolate ZIP and the internal standard from the plasma matrix. The compounds were separated on a C-18 column by an isocratic elution and the eluted compounds were analyzed by a triple quadrupole mass spectrometer with a TurboIon spray interface using the positive ion atmospheric pressure electrospray ionization method and detected using multiple reaction monitoring mode. The ZIP standard calibration curve was linear over the range of 0.25–500 ng/ml when 0.5 ml of plasma was used for the analysis ( r 2 > 0.998). The intra-assay (within-day) and inter-assay (between-day) variations were less than 12% for the spiked standard curve and quality control samples. The absolute extraction efficiency was 82% for ZIP and 68% for INS-RSP. The analysis time for each sample was less than 3 min and useful for high turnaround plasma level determinations. This LC–MS–MS assay method for ZIP is highly specific, sensitive, accurate and rapid and is currently being used for the plasma level determination of ZIP in schizophrenia patients treated with various daily oral doses of ZIP. The data showed large inter-individual variations.

Despite the growing importance of social cognition in schizophrenia, fundamental issues concerning the nature of social cognition in schizophrenia remain unanswered. One issue concerns the strength of the relationships between social cognition and key features of the disorder such as neurocognitive deficits and negative symptoms. The current study employed structural equation modeling to examine three key questions regarding the nature of social cognition in schizophrenia: 1) Are social cognition and neurocognition in schizophrenia better modeled as one or two separate constructs? 2) Are social cognition and negative symptoms in schizophrenia better modeled as one or two separate constructs?, and 3) When social cognition, neurocognition, and negative symptoms are included in a single model, is social cognition more closely related to neurocognition or to negative symptoms? In this cross sectional study, one hundred outpatients with schizophrenia or schizoaffective disorder were administered measures of social cognition, neurocognition, and negative symptoms. A two-factor model that represented social cognition and neurocognition as separate constructs fit the data significantly better than a one-factor model, suggesting that social cognition and neurocognition are distinct, yet highly related, constructs. Likewise, a two-factor model that represented social cognition and negative symptoms as separate constructs fit the data significantly better than a one-factor model, suggesting that social cognition and negative symptoms are distinct constructs. A three-factor model revealed that the relationship between social cognition and neurocognition was stronger than the relationship between social cognition and negative symptoms. The current findings start to provide insights into the structure of social cognition, neurocognition, and negative symptoms in schizophrenia.

If treatments for cognitive impairment are to be utilized successfully, clinicians must be able to determine whether they are effective and which patients should receive them. In order to develop consensus on these issues, the International Society for CNS Clinical Trials and Methodology (ISCTM) held a meeting of experts on March 20, 2014, in Washington, DC. Consensus was reached on several important issues. Cognitive impairment and functional disability were viewed as equally important treatment targets. The group supported the notion that sufficient data are not available to exclude patients from available treatments on the basis of age, severity of cognitive impairment, severity of positive symptoms, or the potential to benefit functionally from treatment. The group reached consensus that cognitive remediation is likely to provide substantial benefits in combination with procognitive medications, although a substantial minority believed that medications can be administered without nonpharmacological therapy. There was little consensus on the best methods for assessing cognitive change in clinical practice. Some participants supported the view that performance-based measures are essential for measurement of cognitive change; others pointed to their cost and time requirements as evidence of impracticality. Interview-based measures of cognitive and functional change were viewed as more practical, but lacking validity without informant involvement or frequent contact from clinicians. The lack of consensus on assessment methods was viewed as attributable to differences in experience and education among key stakeholders and significant gaps in available empirical data. Research on the reliability, validity, sensitivity, and practicality of competing methods will facilitate consensus.

Long-acting, injectable, second-generation antipsychotic medication has tremendous potential to bring clinical stability to persons with schizophrenia. However, long-acting medications are rarely used following a first episode of schizophrenia.To compare the clinical efficacy of the long-acting injectable formulation of risperidone with the oral formulation in the early course of schizophrenia.A randomized clinical trial performed at a university-based research clinic, between 2005 and 2012. Eighty-six patients with recent onset of schizophrenia were randomized to receive long-acting injectable risperidone or oral risperidone. Half of each group was simultaneously randomized to receive cognitive remediation to improve cognitive functioning or healthy-behaviors training to improve lifestyle habits and well-being. An intent-to-treat analysis was performed between October 4, 2012, and November 12, 2014.A 12-month trial comparing the long-acting injectable vs oral risperidone and cognitive remediation vs healthy-behaviors training.Psychotic relapse and control of breakthrough psychotic symptoms.Of the 86 patients randomized, 3 refused treatment in the long-acting injectable risperidone group. The psychotic exacerbation and/or relapse rate was lower for the long-acting risperidone group compared with the oral group (5% vs 33%; χ21 = 11.1; P .001; relative risk reduction, 84.7%). Long-acting injectable risperidone better controlled mean levels of hallucinations and delusions throughout follow-up (β = -0.30; t68 = -2.6, P = .01). The cognitive remediation and healthy-behaviors training groups did not differ significantly regarding psychotic relapse, psychotic symptom control, or hospitalization rates, and there were no significant interactions between the 2 medications and the 2 psychosocial treatments. Discontinuations owing to inadequate clinical response were more common in the oral group than in the long-acting risperidone group (χ21 = 6.1; P = .01). Adherence to oral risperidone did not appear to differ before randomization but was better for the long-acting risperidone group compared with the oral group (t80 = 5.3; P.001). Medication adherence was associated with prevention of exacerbation and/or relapse (χ21 =11.1; P = .003) and control of breakthrough psychotic symptoms (β = 0.2; t79 = 2.1; P = .04).The use of long-acting injectable risperidone after a first episode of schizophrenia has notable advantages for clinical outcomes. The key clinical advantages are apparently owing to the more consistent administration of the long-acting injectable. Such formulations should be offered earlier in the course of illness.clinicaltrials.gov Identifier: NCT00333177.

A key obstacle to the development of new drugs to treat the cognitive deficits of schizophrenia was the absence of a standard by which to measure their efficacy. Before granting approval for any new drug for this condition, the US Food and Drug Administration wanted a standard cognitive endpoint based on a broad consensus-based method. To address this obstacle, the Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) intiative oversaw a process to develop a consensus neurocognitive battery. Its development included a ten-step process that is described in this article.

The impairments now called negative symptoms have long been noted as common features of schizophrenia, and the concept of negative symptoms itself has a long history.1,2 Patients who exhibit significant negative symptoms have particularly poor function and quality of life,3–8 and this aspect of schizophrenia has been proposed as a separate domain with distinctive pathophysiological and therapeutic implications since at least 1974.9 Despite the attention these problems receive, no drug has received Food and Drug Administration (FDA) approval for an indication of negative symptoms, and available data indicate that second-generation antipsychotic medications have not met early hopes for a highly effective treatment for alleviation of negative symptoms.10 Because of limited progress in the development of effective treatments for negative symptoms, under the auspices of the National Institute of Mental Health (NIMH), Drs. Steve Marder, Wayne Fenton, William T. Carpenter, Jr, and Brian Kirkpatrick initiated a process to examine issues that may interfere with treatment development. The NIMH had previously focused attention on impaired cognition as a therapeutic target with the Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) project. The success of the MATRICS process suggested similar progress could be made in the area of negative symptoms and provided a possible model for proceeding in the area of negative symptoms. Marder, Fenton, Carpenter, and Kirkpatrick organized a consensus development conference, which was held at the NIMH Neuroscience Center in Rockville, Maryland, on January 26–27, 2005. Those attending are listed in the appendix. The mission statement of the meeting was: To review the data relating to the existence of separate domains within negative symptoms, as a prerequisite for choosing appropriate measures of these domains in clinical trials. To initiate a process for developing or identifying widely acceptable, evidence-based measures and methodologies needed to establish the efficacy of treatments that target negative symptoms. Prior to the meeting, the organizers asked experts to address a series of questions: What are the separate components of negative symptoms? Are they independent, or components of the same latent construct? Which aspect of each domain belongs to the negative symptom construct? Does this area need a separate assessment? What is the best assessment method for clinical trials? Since research has suggested that both negative symptoms and cognitive impairments were significant determinants of poor outcome in schizophrenia, an additional set of questions related to the relationship between these domains of psychopathology was also addressed at the conference: Which aspects of cognition are part of the negative symptom construct? Which are independent? Which are uncertain? Articles that more fully address the topics of these presentations can be found in this issue of Schizophrenia Bulletin. Those articles address regulatory issues and negative symptoms,11 negative symptoms as a therapeutic target,12 the factor structure of negative symptoms,13 restricted affect,14 anhedonia,15 and the relationship between negative symptoms and cognitive impairment.16 At the conference other presentations were also made: Wayne Fenton spoke on “Meeting Goals and Objectives: The NIMH Perspective,” Robert Buchanan on “Summary of the MATRICS Process,” William Carpenter, Jr, on “Study Design and the “Pseudospecificity' Problem,” Michael Green on “Social Cognition,” Nancy Andreasen on “Alogia,” and Jeffrey Cummings on “Apathy.”

Aripiprazole is the first atypical antipsychotic introduced to medical practice with partial dopamine-serotonin agonist properties. Other new molecular entities such as bifeprunox, a partial agonist at the dopamine D2 and serotonin 5- HT1A receptors, are currently being evaluated in early stage drug development as potential antipsychotic agents. As a partial agonist, whether aripiprazole displays an agonist effect or attenuates dopaminergic neurotransmission may depend on regional variations in endogenous dopamine tone. Hence, aripiprazole offers a therapeutic advantage to differentially modulate dopaminergic activity in brain regions in a graded fashion. This mechanism of action is intriguing when considered in the context of the dopamine hypothesis of schizophrenia whereby positive symptoms (e.g. hallucinations and delusions) are associated with increased mesolimbic dopaminergic activity while reduced activity in mesocortical dopaminergic pathways underlies negative symptoms (e.g. avolition and anhedonia) and cognitive deficits. Despite its therapeutic promise, antipsychotic response to aripiprazole is highly variable, and some patients do not respond at all to drug therapy. Treatment-emergent adverse events associated with aripiprazole include insomnia, anxiety, akathisia or worsening of psychosis in some patients. These observations suggest that the underlying mechanism of action of aripiprazole in psychotic disorders is more complex than what would be anticipated solely by simple partial agonist effects at the dopamine D2 receptor. For example, while aripiprazole attenuates dopaminergic hyperactivity it does not increase locomotor activity in reserpinized (hypodopaminergic) rats, which is not fully consistent with a partial agonist mode of action. Aripiprazole can induce a diverse range of effects at dopamine D2 receptors (agonism, antagonism, partial agonism) depending on the cellular milieu defined by promiscuous interactions with a host of signaling partners and variability in local G protein complement and concentration. This diversity provides an opportunity to illustrate the importance of integrating data on genetic variation in pharmacokinetic pathways and molecular targets for antipsychotics including biogenic amine receptors and their downstream signaling partners. Theragnostics, a new subspecialty of molecular medicine formed by combination of therapeutics with diagnostics, offers the potential to synthesize different types of biomarkers (DNA and protein-based) in the context of antipsychotic treatment outcomes. Because the dopamine receptor genetic variation is extensively reviewed elsewhere, we discuss the pharmacogenomic significance of variability in genes encoding for the 5-HT1A (HTR1A) and 5-HT2A (HTR2A) receptors and CYP2D6- and CYP3A4-mediated aripiprazole metabolism. As the field moves toward predictive genetic testing for newer antipsychotics, we emphasize the need for collaboration among pharmacogeneticists, bioethicists and specialists in science and technology studies.

OBJECTIVE: The purpose of this investigation was to evaluate the effects of clozapine and risperidone on spatial working memory in patients with schizophrenia. METHOD: Spatial working memory performance was evaluated at baseline and after 17 and 29 weeks in 97 patients with schizophrenia participating in a multisite trial. RESULTS: Compared with baseline performance while receiving conventional antipsychotic medication, risperidone improved, and clozapine worsened, spatial working memory performance. CONCLUSIONS: The differential effects of these medications on spatial working memory may be due to the anticholinergic effects of clozapine and prefrontal dopamine-enhancing effects of risperidone.

Despite the advances in antipsychotic pharmacotherapy over the past decade, many atypical antipsychotic agents are not readily accessible by patients with major psychosis or in developing countries where the acquisition costs may be prohibitive. Olanzapine is an efficacious and widely prescribed atypical antipsychotic agent. In theory, olanzapine therapeutic dose requirement may be reduced during concurrent treatment with inhibitors of drug metabolism. In vitro studies suggest that smoking-inducible cytochrome P450 (CYP) 1A2 contributes to formation of the metabolite 4'-N-desmethylolanzapine. The present prospective study tested the hypothesis that olanzapine steady-state doses can be significantly decreased by coadministration of a low subclinical dose of fluvoxamine, a potent inhibitor of cytochrome P450 1A2. The study design followed a targeted "at-risk" population approach with a focus on smokers who were likely to exhibit increased cytochrome P450 1A2 expression. Patients with stable psychotic illness (N = 10 men, all smokers) and receiving chronic olanzapine treatment were evaluated for steady-state plasma concentrations of olanzapine and 4'-N-desmethylolanzapine. Subsequently, olanzapine dose was reduced from 17.5 +/- 4.2 mg/d (mean +/- SD) to 13.0 +/- 3.3 mg/d, and a nontherapeutic dose of fluvoxamine (25 mg/d, PO) was added to regimen. Patients were reevaluated at 2, 4, and 6 weeks during olanzapine-fluvoxamine cotreatment. There was no significant change in olanzapine plasma concentration, antipsychotic response, or metabolic indices (eg, serum glucose and lipids) after dose reduction in the presence of fluvoxamine (P > 0.05). 4'-N-desmethylolanzapine/olanzapine metabolic ratio decreased from 0.45 +/- 0.20 at baseline to 0.25 +/- 0.11 at week 6, suggesting inhibition of the cytochrome P450 1A2-mediated olanzapine 4'-N-demethylation by fluvoxamine (P < 0.05). In conclusion, this prospective pilot study suggests that a 26% reduction in olanzapine therapeutic dose requirement may be achieved by coadministration of a nontherapeutic oral dose of fluvoxamine.

New advances in the understanding of schizophrenia etiology, course, and treatment have increased interest on the part of patients, families, advocates, and professionals in the development of consensus-defined standards for clinical status and improvement, including illness remission and recovery. As demonstrated in the area of mood disorders, such standards provide greater clarity around treatment goals, as well as an improved framework for the design and comparison of investigational trials and the subsequent evaluation of the effectiveness of interventions. Unlike the approach to mood disorders, however, the novel application of the concept of standard outcome criteria to schizophrenia must reflect the wide heterogeneity of its long-term course and outcome, as well as the variable effects of different treatments on schizophrenia symptoms. As an initial step in developing operational criteria, an expert working group reviewed available definitions and assessment instruments to provide a conceptual framework for symptomatic, functional, and cognitive domains in schizophrenia as they relate to remission of illness. The first consensus-based operational criteria for symptomatic remission in schizophrenia are based on distinct thresholds for reaching and maintaining improvement, as opposed to change criteria, allowing for alignment with traditional concepts of remission in both psychiatric and nonpsychiatric illness. This innovative approach for standardizing the definition for outcome in schizophrenia will require further examination of its validity and utility, as well as future refinement, particularly in relation to psychosocial and cognitive function and dysfunction. These criteria should facilitate research and support a positive, longer-term approach to studying outcome in patients with schizophrenia.

Schizophrenia is associated with several chronic physical illnesses and a shorter life expectancy, compared with life expectancy in the general population. One approach to improving the health of patients with schizophrenia is to improve the monitoring of physical health that occurs in psychiatric settings. The authors discuss a consensus panel's recommendations for improving the physical health monitoring of patients with schizophrenia who are treated in outpatient settings.A consensus meeting including psychiatric and other medical experts assembled on October 17-18, 2002, to evaluate the existing literature and to develop recommendations for physical health monitoring of patients with schizophrenia. Conference participants reviewed the literature in the following areas: 1) weight gain and obesity; 2) diabetes; 3) hyperlipidemia; 4) prolongation of the QT interval on the ECG; 5) prolactin elevation and related sexual side effects; 6) extrapyramidal side effects, akathisia, and tardive dyskinesia; 7) cataracts; and 8) myocarditis. Experts for each topic area formulated monitoring recommendations that were discussed by all of the participants until a consensus was reached.Consensus recommendations included regular monitoring of body mass index, plasma glucose level, lipid profiles, and signs of prolactin elevation or sexual dysfunction. Information from monitoring should guide the selection of antipsychotic agents. Specific recommendations were made for cardiac monitoring of patients who receive medications associated with QT interval prolongation, including thioridazine, mesoridazine, and ziprasidone, and for monitoring for signs of myocarditis in patients treated with clozapine. Patients who receive both first- and second-generation antipsychotic medications should be examined for extrapyramidal symptoms and tardive dyskinesia. Patients with schizophrenia should receive regular visual examinations.The conference participants recommended that mental health care providers perform physical health monitoring that typically occurs in primary care settings for their patients who do not receive physical health monitoring in those settings. This change in usual practice is recommended on the basis of the conference participants' belief that this additional monitoring will result in the earlier detection of common, serious risk factors that could, without detection and intervention, contribute to impaired health of patients with schizophrenia.

Background The authors review the clinical features, epidemiology, pathophysiology, medical management, dental findings and dental management of patients who have bipolar I disorder, or BD, previously known as manic-depressive disorder. Types of Studies Reviewed The authors conducted a MEDLINE search for the period 1995 through 2001 using the key terms “bipolar disorder,” “epidemiology,” “pathophysiology,” “treatment” and “dentistry.” The articles they selected for further review included those published in English in peer-reviewed journals; they gave preference to articles reporting randomized, controlled trials. Results BD is a psychiatric illness characterized by extreme mood swings. Mania is accompanied by euphoria, grandiosity, racing thoughts and lack of insight. Depression is characterized by marked sadness or loss of interest or pleasure in daily activities. The unpredictable mood swings can distress the person, can impair social function and quality of life and are associated with a significant increase in the risk for substance abuse and suicide. BD is common in the United States, with a lifetime prevalence rate of 1.6 percent and recurrence rate of more than 50 percent. Clinical Implications The prevalence of dental disease usually is extensive because of poor oral hygiene and medication-induced xerostomia. Preventive dental education, saliva substitutes and anticaries agents are indicated. To avoid adverse drug interactions with the usually prescribed psychiatric medications, special precautions should be taken when administering certain antibiotics, analgesics and sedatives.

Decisions regarding the pharmacotherapy of schizophrenia are based on a number of individual patient characteristics, including their clinical signs and symptoms, sensitivity to side effects, and psychiatric and medical comorbidities. The publication of recent guidelines from the American Psychiatric Association and the Schizophrenia Patient Outcome Research Team provides guidance for clinicians who are attempting to individualize pharmacologic treatment. Guidance is also provided from clinical studies that have demonstrated the effectiveness of new formulations of second-generation antipsychotics and studies that evaluated the effectiveness of these agents in long-term studies. Recent data have also focused on important side effects of second-generation agents that can affect the long-term health of patients. These studies as well as recommendations from experts can assist clinicians who are selecting an antipsychotic for patients with serious medical problems such as sexual dysfunction, diabetes, obesity, and hyperlipidemias.

OBJECTIVE: The purpose of this investigation was to evaluate the effects of clozapine and risperidone on social skill and problem solving in patients with schizophrenia. METHOD: The Wisconsin Card Sorting Test and the Maryland Assessment of Social Competence were administered at baseline, week 17, and week 29 of a multisite clinical trial. RESULTS: Despite evidence of clinical improvement with both medications, there was virtually no medication effect on either social competence or problem solving. CONCLUSIONS: These findings underscore the circumscribed nature of symptomatic improvement in the broader spectrum of clinical outcomes and suggest that new-generation medications may not be expected to produce substantial changes in social role functioning or social problem-solving capacity in the community. The generalizability of the findings should be viewed cautiously because of the low power of this trial, and replication is warranted.

PTSD is a chronic mental illness that may arise after an individual experiences or witnesses a life-threatening event. Symptoms consist of persistent reexperiencing of the event, avoidance of reminders of the event, a numbing of positive emotions, and social withdrawal. A depressed mood and excessive use of alcohol and tobacco may accompany the disorder. PTSD afflicts approximately 5% of men and 11% of women. Dental disease may be extensive because of neglect of oral hygiene compounded by cigarette smoking. Dental treatment includes preventive education, oral cancer screening, and prescribing saliva substitutes or stimulants and anticaries agents to combat medication-induced xerostomia. Precautions must be taken when prescribing or administering certain analgesics, antibiotics, or sedative agents that may adversely interact with the psychiatric medications or when performing surgery because of the long-term effects of alcohol abuse.

Although skills training is a validated psychosocial treatment for schizophrenia, generalization of the skills to everyday life has not been optimal. This study evaluated a behaviorally oriented method of augmenting clinic-based skills training in the community with the aim of improving opportunities, encouragement, and reinforcement for outpatients to use their skills in their natural environment.Sixty-three individuals with schizophrenia were randomly assigned to 60 weeks of clinic-based skills training alone or of clinic-based skills training supplemented with manual-based generalization sessions in the community. Patients were also randomly assigned to receive either haloperidol or risperidone. Therapists' fidelity to the manuals was measured. Patients' acquisition of the skills from pre- to posttraining was evaluated. The primary outcome measures were the Social Adjustment Scale-II and the Quality of Life Scale.Seventy-one percent of the patients completed the trial. Only six participants experienced psychotic exacerbations during the trial. There was no evidence of a differential medication effect on social functioning. Social functioning improved modestly in both psychosocial conditions over time; participants who received augmented skills training in the community showed significantly greater and/or quicker improvements.Given judicious and effective antipsychotic medication that limited exacerbations to less than 10% during the trial, a wide range of outpatients with schizophrenia demonstrated substantial learning of illness management and social skills in the clinic. When clinic-based skills training was augmented by in vivo training and consultation, transfer of the skills to everyday life was enhanced. These benefits were established regardless of the medications prescribed.

Background The authors review the clinical features, epidemiology, pathophysiology, medical management, dental findings and dental treatment of patients with alcoholism. Literature Reviewed The authors conducted a MEDLINE search for 1995 through 2001 using the key terms of alcoholism, epidemiology, pathophysiology, treatment and dentistry. Reports selected for further review included those published in English in peer-reviewed journals. The authors gave preference to articles reporting randomized, controlled trials. Conclusions Alcoholism is a chronic and progressive psychiatric illness that afflicts more than 14 million Americans. It is characterized by a loss of control over the use of alcohol, resulting in impaired social functioning, and the consequent development of medical illnesses. The disease arises in genetically vulnerable people when they are overwhelmed by their cravings for the alcohol-associated euphoria that results from the actions of several neurotransmitter systems in the brain's pleasure center. New medications to counteract alcohol-induced neurotransmission imbalance may assist patients in reducing their craving. Clinical Implications The prevalence of dental disease usually is extensive because of a disinterest in performing appropriate oral hygiene techniques and diminished salivary flow. Concurrent abuse of tobacco products worsens dental disease and heightens the risk of developing oral cancer. Identification of the alcohol-abusing patient, a cancer-screening examination, preventive dental education, and use of saliva substitutes and anticaries agents are indicated. Special precautions must be taken when performing surgery and when prescribing or administering analgesics, antibiotics or sedative agents that are likely to have an adverse interaction with alcohol or psychiatric medications.

BACKGROUND: The aim of this study was to examine differences in the improvement of clinical psychopathology and in fine motor functions at 2 doses of risperidone in first-episode, acutely psychotic patients. METHOD: In a double-blind, fixed-dose study, 49 acutely psychotic, neuroleptic-naive patients who were admitted for the first time and who met DSM-IV criteria for schizophrenia, schizophreniform disorder, or schizoaffective disorder were randomly assigned to 2 or 4 mg/day of risperidone. Treatment efficacy was measured using the Brief Psychiatric Rating Scale, the Scale for the Assessment of Negative Symptoms, The Clinical Global Impressions scale, and the Social and Occupational Functioning Assessment Scale. Fine motor functions were assessed using a computerized device (the Vienna Test System) and were compared with those of a control group of 20 healthy subjects who were matched for age, gender, and educational level. RESULTS: Treatment with doses of 2 and 4 mg of risperidone daily significantly reduced positive (p < .0001) and negative (p < .01) symptoms at 8 weeks. Although there were no significant differences in motor movements as measured using the Barnes Akathisia Scale and the Simpson-Angus Scale, computerized fine motor assessment showed significantly less motor dysfunction in the 2-mg/day group at 8 weeks. No significant correlations to plasma concentration of active moiety were found for data on psychopathology and fine motor functions. CONCLUSION: The 2 doses of risperidone did not differ in terms of clinical improvement, but the 2-mg/day dose produced fewer fine motor dysfunctions. These results suggest that a dose as low as 2 mg/day of risperidone may be effective for patients with first-episode psychosis.

Background: The novel antipsychotics are extensively used based on their favorable extrapyramidal side effect profiles. However, accumulating evidence suggests that these agents, particularly clozapine and olanzapine, have serious side effects of their own, including weight gain and elevated glucose and triglyceride levels. The goal of this study is to compare the effects of novel antipsychotics clozapine, olanzapine, risperidone, and quetiapine and typical antipsychotics haloperidol and fluphenazine on glucose and lipid levels. Method: The charts of 590 patients were retrospectively reviewed. Of those, 215 patients had adequate laboratory data for inclusion. Glucose and lipid level data from 21/2 years before and after initiation of the target antipsychotic were included. Covariates, including patients' age, the duration of antipsychotic treatment, other medications that may affect glucose or lipid levels, and the initial laboratory values, were controlled for in the analyses. Results: Glucose levels were increased from baseline for patients treated with clozapine, olanzapine, and haloperidol. There were statistically and clinically significant differences among the medications' effects on lipid profiles (p

Background The authors review the clinical features, epidemiology, pathophysiology, medical management, dental findings and dental management of patients who have bipolar I disorder, or BD, previously known as manic-depressive disorder. Types of Studies Reviewed The authors conducted a MEDLINE search for the period 1995 through 2001 using the key terms "bipolar disorder," "epidemiology," "pathophysiology," "treatment" and "dentistry." The articles they selected for further review included those published in English in peer-reviewed journals; they gave preference to articles reporting randomized, controlled trials. Results BD is a psychiatric illness characterized by extreme mood swings. Mania is accompanied by euphoria, grandiosity, racing thoughts and lack of insight. Depression is characterized by marked sadness or loss of interest or pleasure in daily activities. The unpredictable mood swings can distress the person, can impair social function and quality of life and are associated with a significant increase in the risk for substance abuse and suicide. BD is common in the United States, with a lifetime prevalence rate of 1.6 percent and recurrence rate of more than 50 percent. Clinical Implications The prevalence of dental disease usually is extensive because of poor oral hygiene and medication-induced xerostomia. Preventive dental education, saliva substitutes and anticaries agents are indicated. To avoid adverse drug interactions with the usually prescribed psychiatric medications, special precautions should be taken when administering certain antibiotics, analgesics and sedatives.

Background : The novel antipsychotic medications offer a more favorable extrapyramidal side effect profile than conventional agents. It is uncertain that the novel antipsychotics have a benefit in terms of sexual side effects. Methods : We prospectively administered a survey of sexual functioning to 25 male patients with DSM-IV schizophrenia, taking conventional and novel antipsychotics. Contrasts were made between three treatment groups: clozapine (CLOZ), risperidone (RIS), and a combined haloperidol/fluphenazine (HAL/FLU) group. Results : A decrease in overall sexual functioning was reported in all medication groups (40–71%). The majority of subjects taking RIS or HAL/FLU reported a decline in one or more aspects of sexual functioning. Examining specific aspects of sexual functioning revealed that, a decline in sexual interest was significantly less common on CLOZ compared to RIS (0 vs. 64%; χ 2 =6.1, df=1, p =0.01) or HAL/FLU (0 vs. 67%; χ 2 =5.2, df=1, p =0.02), while a decline in the erectile frequency was significantly more common on RIS compared to CLOZ (40 vs. 93%; χ 2 =6.2, df=1, p =0.01) or HAL/FLU (50 vs. 93%; χ 2 =4.8, df=1, p =0.03) (0%). For enjoyment of orgasm and ejaculatory volume, significantly fewer CLOZ compared to RIS subjects reported a decline (20 vs. 86%; χ 2 =7.4, df=1, p =0.01). Conclusions : Sexual side effects are common clinically pertinent adverse effects associated with both novel and conventional antipsychotic medications. They deserve increased attention in clinical work and future research with emerging antipsychotic drugs.