Implementing harm reduction in non-urban communities affected by opioids and polysubstance use: A qualitative study exploring challenges and mitigating strategies.

BACKGROUND: Harm reduction services, which typically provide overdose education and prevention with distribution of naloxone and other supplies related to safer drug use, help reduce opioid-related overdose and infectious disease transmission. However, structural stigma and the ongoing criminalization of drug use have limited the expansion of harm reduction services into many non-urban communities in the United States that have been increasingly affected by the health consequences of opioid and polysubstance use. METHODS: We conducted qualitative interviews with 22 professionals working with people who use drugs in cities and towns across Rhode Island and Massachusetts to understand challenges and strategies for engaging communities in accepting harm reduction perspectives and services. RESULTS: Our thematic analysis identified several interrelated challenges to implementing harm reduction services in non-urban communities, including: (1) limited understandings of harm reduction practice and preferential focus on substance use treatment and primary prevention, (2) community-level stigma against people who use drugs as well as the agencies supporting them, (3) data reporting and aggregating leading to inaccurate perceptions about local patterns of substance use and related health consequences, and (4) a "prosecutorial mindset" against drug use and harm reduction. From key informants' narratives, we also identified specific strategies that communities could use to address these challenges, including: (1) identifying local champions to advocate for harm reduction strategies, (2) proactively educating communities about harm reduction approaches before they are implemented, (3) improving the visibility of harm reduction services within communities, and (4) obtaining "buy-in" from a wide range of local stakeholders including law enforcement and local government. CONCLUSION: These findings carry important implications for expanding harm reduction services, including syringe service programs and safe injection sites, into non-urban communities that have a demonstrated need for evidence-based interventions to reduce drug-related overdose and infectious disease transmission.

Building the Case for Localized Approaches to HIV: Structural Conditions and Health System Capacity to Address the HIV/AIDS Epidemic in Six US Cities.

Since the discovery of the secondary preventive benefits of antiretroviral therapy, national and international governing bodies have called for countries to reach 90% diagnosis, ART engagement and viral suppression among people living with HIV/AIDS. The US HIV epidemic is dispersed primarily across large urban centers, each with different underlying epidemiological and structural features. We selected six US cities, including Atlanta, Baltimore, Los Angeles, Miami, New York, and Seattle, with the objective of demonstrating the breadth of epidemiological and structural differences affecting the HIV/AIDS response across the US. We synthesized current and publicly-available surveillance, legal statutes, entitlement and discretionary funding, and service location data for each city. The vast differences we observed in each domain reinforce disparities in access to HIV treatment and prevention, and necessitate targeted, localized strategies to optimize the limited resources available for each city's HIV/AIDS response.

Drug use and phylogenetic clustering of hepatitis C virus infection among people who use drugs in Vancouver, Canada: A latent class analysis approach.

This study estimated latent classes (ie, unobserved subgroups in a population) of people who use drugs in Vancouver, Canada, and examined how these classes relate to phylogenetic clustering of hepatitis C virus (HCV) infection. HCV antibody-positive people who use drugs from two cohorts in Vancouver, Canada (1996-2012), with a Core-E2 sequence were included. Time-stamped phylogenetic trees were inferred, and phylogenetic clustering was determined by time to most common recent ancestor. Latent classes were estimated, and the association with the phylogenetic clustering outcome was assessed using an inclusive classify/analyse approach. Among 699 HCV RNA-positive participants (26% female, 24% HIV+), recent drug use included injecting cocaine (80%), injecting heroin (70%), injecting cocaine/heroin (ie, speedball, 38%) and crack cocaine smoking (28%). Latent class analysis identified four distinct subgroups of drug use typologies: (i) cocaine injecting, (ii) opioid and cocaine injecting, (iii) crack cocaine smoking and (iv) heroin injecting and currently receiving opioid substitution therapy. After adjusting for age and HIV infection, compared to the group defined by heroin injecting and currently receiving opioid substitution therapy, the odds of phylogenetic cluster membership was greater in the cocaine injecting group (adjusted OR [aOR]: 3.06; 95% CI: 1.73, 5.42) and lower in the crack cocaine smoking group (aOR: 0.06; 95% CI: 0.01, 0.48). Combining latent class and phylogenetic clustering analyses provides novel insights into the complex dynamics of HCV transmission. Incorporating differing risk profiles associated with drug use may provide opportunities to further optimize and target HCV treatment and prevention strategies.

Chronic hepatitis C virus (HCV) burden in Rhode Island: modelling treatment scale-up and elimination.

We utilized a disease progression model to predict the number of viraemic infections, cirrhotic cases, and liver-related deaths in the state of Rhode Island (RI) under four treatment scenarios: (1) current HCV treatment paradigm (about 215 patients treated annually, Medicaid reimbursement criteria fibrosis stage ⩾F3); (2) immediate scale-up of treatment (to 430 annually) and less restrictive Medicaid reimbursement criteria (fibrosis stage ⩾F2); (3) immediate treatment scale-up and no fibrosis stage-specific Medicaid reimbursement criteria (⩾F0); (4) an 'elimination' scenario (i.e. a continued treatment scale-up needed to achieve >90% reduction in viraemic cases by 2030). Under current treatment models, the number of cirrhotic cases and liver-related deaths will plateau and peak by 2030, respectively. Treatment scale-up with ⩾F2 and ⩾F0 fibrosis stage treatment criteria could reduce the number of cirrhotic cases by 21·7% and 10·0%, and the number of liver-related deaths by 19·3% and 7·4%, respectively by 2030. To achieve a >90% reduction in viraemic cases by 2030, over 2000 persons will need to be treated annually by 2020. This strategy could reduce cirrhosis cases and liver-related deaths by 78·9% and 72·4%, respectively by 2030. Increased HCV treatment uptake is needed to substantially reduce the burden of HCV by 2030 in Rhode Island.

Understanding the effects of different HIV transmission models in individual-based microsimulation of HIV epidemic dynamics in people who inject drugs.

We investigated how different models of HIV transmission, and assumptions regarding the distribution of unprotected sex and syringe-sharing events ('risk acts'), affect quantitative understanding of HIV transmission process in people who inject drugs (PWID). The individual-based model simulated HIV transmission in a dynamic sexual and injecting network representing New York City. We constructed four HIV transmission models: model 1, constant probabilities; model 2, random number of sexual and parenteral acts; model 3, viral load individual assigned; and model 4, two groups of partnerships (low and high risk). Overall, models with less heterogeneity were more sensitive to changes in numbers risk acts, producing HIV incidence up to four times higher than that empirically observed. Although all models overestimated HIV incidence, micro-simulations with greater heterogeneity in the HIV transmission modelling process produced more robust results and better reproduced empirical epidemic dynamics.

Second-order resummed thermodynamic perturbation theory for central-force associating potential: multi-patch colloidal models.

We propose a second-order version of the resummed thermodynamic perturbation theory for patchy colloidal models with arbitrary number of multiply bondable patches. The model is represented by the hard-sphere fluid system with several attractive patches on the surface and resummation is carried out to account for blocking effects, i.e., when the bonding of a particle restricts (blocks) its ability to bond with other particles. The theory represents an extension of the earlier proposed first order resummed thermodynamic perturbation theory for central force associating potential and takes into account formation of the rings of the particles. In the limiting case of singly bondable patches (total blockage), the theory reduces to Wertheim thermodynamic perturbation theory for associating fluids. Closed-form expressions for the Helmholtz free energy, pressure, internal energy, and chemical potential of the model with an arbitrary number of equivalent doubly bondable patches are derived. Predictions of the theory for the model with two patches appears to be in a very good agreement with predictions of new NVT and NPT Monte Carlo simulations, including the region of strong association.

Increases in the availability of prescribed opioids in a Canadian setting.

BACKGROUND: The nonmedical use of prescribed opioids (POs) has increased across North America over the past decade. Our objective was to identify changes in the availability of POs and other illicit drugs among drug users in a Canadian setting. METHODS: Information on the availability of illicit drugs was collected in standardized interviews from a large observational research program involving illicit drug users in Vancouver, British Columbia from 2006 to 2010. The primary outcome was the perceived availability of a set of six POs (aspirin/oxycodone, hydromorphone, oxycodone, morphine, acetaminophen/codeine and methadone) among individuals reporting ever using POs. Availability was measured in three levels: not available, delayed availability (available ≥10 min), and immediate availability (available <10 min). Multivariate ordinal logistic regression models were executed to estimate the trend in PO availability, controlling for individual characteristics hypothesized to influence availability. RESULTS: 1871 individuals were followed during the study period (2006-2010), including 583 (31.2%) women. The availability of POs increased over time, regardless of changes in the characteristics of cohort entrants. These increases were observed while the availability of traditional drugs of abuse (e.g., heroin and cocaine) remained constant. The adjusted odds of delayed availability vs. unavailability were between 34% (hydromorphone) and 71% (acetaminophen/codeine) greater in each calendar year. DISCUSSION: The availability of POs among drug users in a Canadian setting increased markedly over a relatively short timeframe, despite persistent and high availability of heroin and cocaine. Further study is required to determine the context of use of POs, associated harms, as well as policy responses to increasing availability.

Frequent methamphetamine injection predicts emergency department utilization among street-involved youth.

OBJECTIVES: Methamphetamine (MA) use has been associated with health problems that commonly present in the emergency department (ED). This study sought to determine whether frequent MA injection was a risk factor for ED utilization among street-involved youth. STUDY DESIGN: Prospective cohort study. METHODS: Data were derived from a street-involved youth cohort known as the 'At Risk Youth Study'. Behavioural data including MA use were linked to ED records at a major inner-city hospital. Kaplan-Meier and Cox proportional hazards methods were used to determine the risk factors for ED utilization. RESULTS: Between September 2005 and January 2007, 427 eligible participants were enrolled, among whom the median age was 21 (interquartile range 19-23) years and 154 (36.1%) were female. Within 1 year, 163 (38.2%) visited the ED, resulting in an incidence density of 53.7 per 100 person-years. ED utilization was significantly higher among frequent (i.e. ≥daily) MA injectors (log-rank P = 0.004). In multivariate analysis, frequent MA injection was associated with an increased hazard of ED utilization (adjusted hazard ratio = 1.84, 95% confidence interval 1.04-3.25; P = 0.036). CONCLUSIONS: Street-involved youth who frequently inject MA appear to be at increased risk of ED utilization. The integration of MA-specific addiction treatment services within emergency care settings for high-risk youth is recommended.

HIV knowledge and perceptions of risk in a young, urban, drug-using population.

BACKGROUND: Educational programs targeted towards youth to prevent HIV transmission are based on a model that increased knowledge equals reduced risk behaviour. This study explored HIV knowledge among a cohort of young drug users, and their perceptions of HIV risk acquisition. METHODS: Between September 2005 and August 2009, youth who used illegal drugs were recruited into a prospective cohort known as the at-risk youth study (ARYS) in Vancouver, Canada. Participants completed an 18 item HIV Knowledge Questionnaire (HIV-KQ-18) and responses were scored dichotomously (i.e., ≥15 indicating high knowledge and <15 indicating low knowledge). We compared high- and low-scoring youth using Pearson's chi-square test and logistic regression. We also examined youths' perceptions of risk for acquiring HIV compared to their peers. RESULTS: Of 589 youth recruited into ARYS, the mean age was 22 (interquartile range [IQR]: 20-24), 186 (31.6%) were female, and 143 (24.3%) were of Aboriginal ancestry. The median score on the HIV-KQ- 18 was 15 (IQR: 12-16). Internal reliability was high (Cronbach's α=0.82). The analyses demonstrated that youth with higher HIV knowledge were more likely to be older (adjusted odds ratio [AOR]=1.08, per year older p=0.031), completed high school (AOR=1.42, p=0.054), and engage in unprotected intercourse (AOR=1.73, p=0.023). The majority of respondents (77.6%) perceived themselves to be at lower risk for acquiring HIV in comparison to their peers. CONCLUSIONS: HIV knowledge scores of participants were surprisingly low for an urban Canadian setting as was their HIV risk perception. Higher HIV knowledge was not associated with reduced sexual risk behaviour. Results demonstrate that education programs are not reaching or impacting this high-risk population. Given the complex forces that promote HIV risk behaviour, prevention programs should be fully evaluated and must recognize the unique characteristics of drug-using youth and factors that drive risk among this population.

The effects of lesions in the dorsolateral pons on the coordination of swallowing and breathing in awake goats.

The purpose of this retrospective study was to gain insight into the contribution of the dorsolateral pons to the coordination of swallowing and breathing in awake goats. In 4 goats, cannulas were chronically implanted bilaterally through the lateral (LPBN) and medial (MPBN) parabrachial nuclei just dorsal to the Kölliker-Fuse nucleus (KFN). After >2weeks recovery from this surgery, the goats were studied for 5½h on a control day, and on separate days after receiving 1 and 10µl injections of ibotenic acid (IA) separated by 1week. The frequency of swallows did not change during the control and 1µl IA studies, but after injection of 10µl IA, there was a transient 65% increase in frequency of swallows (P<0.05). Under control conditions swallows occurred throughout the respiratory cycle, where late-E swallows accounted for 67.6% of swallows. The distribution of swallow occurrence throughout the respiratory cycle was unaffected by IA injections. Consistent with the concept that swallowing is dominant over breathing, we found that swallows increased inspiratory (T(I)) and expiratory (T(E)) time and decreased tidal volume (V(T)) of the breath of the swallow (n) and/or the subsequent (n+1) breath. Injections of 10µl IA attenuated the normal increases in T(I) and T(E) and further attenuated V(T) of the n breath. Additionally, E and I swallows reset respiratory rhythm, but injection of 1 or 10µl IA progressively attenuated this resetting, suggesting a decreased dominance over respiratory motor output with increasing IA injections. Post mortem histological analysis revealed about 50% fewer (P<0.05) neurons remained in the KFN, LPBN, and MPBN in lesioned compared to control goats. We conclude that dorsolateral pontine nuclei have a modulatory role in a hypothesized holarchical neural network regulating swallowing and breathing particularly contributing to the normal dominance of swallowing over breathing in both rhythm and motor pattern generation.

Site-specific effects on respiratory rhythm and pattern of ibotenic acid injections in the pontine respiratory group of goats.

To probe further the contributions of the rostral pons to eupneic respiratory rhythm and pattern, we tested the hypothesis that ibotenic acid (IA) injections in the pontine respiratory group (PRG) would disrupt eupneic respiratory rhythm and pattern in a site- and state-specific manner. In 15 goats, cannulas were bilaterally implanted into the rostral pontine tegmental nuclei (RPTN; n = 3), the lateral (LPBN; n = 4) or medial parabrachial nuclei (MPBN; n = 4), or the Kölliker-Fuse nucleus (KFN; n = 4). After recovery from surgery, 1- and 10-microl injections (1 wk apart) of IA were made bilaterally through the implanted cannulas during the day. Over the first 5 h after the injections, there were site-specific ventilatory effects, with increased (P < 0.05) breathing frequency in RPTN-injected goats, increased (P < 0.05) pulmonary ventilation (Vi) in LPBN-injected goats, no effect (P < 0.05) in MPBN-injected goats, and a biphasic Vi response (P < 0.05) in KFN-injected goats. This biphasic response consisted of a hyperpnea for 30 min, followed by a prolonged hypopnea and hypoventilation with marked apneas, apneusis-like breathing patterns, and/or shifts in the temporal relationships between inspiratory flow and diaphragm activity. In the awake state, 10-15 h after the 1-microl injections, the number of apneas was greater (P < 0.05) than during other studies at night. However, there were no incidences of terminal apneas. Breathing rhythm and pattern were normal 22 h after the injections. Subsequent histological analysis revealed that for goats with cannulas implanted into the KFN, there were nearly 50% fewer neurons (P < 0.05) in all three PRG subnuclei than in control goats. We conclude that in awake goats, 1) IA injections into the PRG have site-specific effects on breathing, and 2) the KFN contributes to eupneic respiratory pattern generation.

A role for the Kolliker-Fuse nucleus in cholinergic modulation of breathing at night during wakefulness and NREM sleep.

For many years, acetylcholine has been known to contribute to the control of breathing and sleep. To probe further the contributions of cholinergic rostral pontine systems in control of breathing, we designed this study to test the hypothesis that microdialysis (MD) of the muscarinic receptor antagonist atropine into the pontine respiratory group (PRG) would decrease breathing more in animals while awake than while in NREM sleep. In 16 goats, cannulas were bilaterally implanted into rostral pontine tegmental nuclei (n = 3), the lateral (n = 3) or medial (n = 4) parabrachial nuclei, or the Kölliker-Fuse nucleus (KFN; n = 6). After >2 wk of recovery from surgery, the goats were studied during a 45-min period of MD with mock cerebrospinal fluid (mCSF), followed by at least 30 min of recovery and a second 45-min period of MD with atropine. Unilateral and bilateral MD studies were completed during the day and at night. MD of atropine into the KFN at night decreased pulmonary ventilation and breathing frequency and increased inspiratory and expiratory time by 12-14% during both wakefulness and NREM sleep. However, during daytime studies, MD of atropine into the KFN had no effect on these variables. Unilateral and bilateral nighttime MD of atropine into the KFN increased levels of NREM sleep by 63 and 365%, respectively. MD during the day or at night into the other three pontine sites had minimal effects on any variable studied. Finally, compared with MD of mCSF, bilateral MD of atropine decreased levels of acetylcholine and choline in the effluent dialysis fluid. Our data support the concept that the KFN is a significant contributor to cholinergically modulated control of breathing and sleep.

The pontine respiratory group, particularly the Kölliker-Fuse nucleus, mediates phases of the hypoxic ventilatory response in unanesthetized goats.

The objective of the present study was to test the hypothesis that, in the in vivo awake goat model, perturbation/lesion in the pontine respiratory group (PRG) would decrease the sensitivity to hypercapnia and hypoxia. The study reported herein was part of two larger studies in which cholinergic modulation in the PRG was attenuated by microdialysis of atropine and subsequently ibotenic acid injections neurotoxically lesioned the PRG. In 14 goats, cannula were bilaterally implanted into either the lateral (n=4) or medial (n=4) parabrachial nuclei or the Kölliker-Fuse nucleus (KFN, n=6). Before and after cannula implantation, microdialysis of atropine, and injection of ibotenic acid, hypercapnic and hypoxic ventilatory sensitivities were assessed. Hypercapnic sensitivity was assessed by three 5-min periods at 3, 5, and 7% inspired CO2. In all groups of goats, CO2 sensitivity was unaffected (P>0.05) by any PRG perturbations/lesions. Hypoxic sensitivity was assessed with a 30-min period at 10.8% inspired O2. The response to hypoxia was typically triphasic, with a phase 1 increase in pulmonary ventilation, a phase 2 roll-off, and a phase 3 prolonged increase associated with shivering and increased metabolic rate and body temperature. In all groups of goats, the phase 1 of the hypoxic ventilatory responses was unaffected by any PRG perturbations/lesions, and there were no consistent effects on the phase 2 responses. However, in the KFN group of goats, the phase 3 ventilatory, shivering, metabolic rate, and temperature responses were markedly attenuated after the atropine dialysis studies, and the attenuation persisted after the ibotenic acid studies. These findings support an integrative or modulatory role for the KFN in the phase 3 responses to hypoxia.

Differences between three inbred rat strains in number of K+ channel-immunoreactive neurons in the medullary raphé nucleus.

Ventilatory sensitivity to hypercapnia is greater in Dahl salt-sensitive (SS) rats than in Fawn Hooded hypertensive (FHH) and Brown Norway (BN) inbred rats. Since pH-sensitive potassium ion (K(+)) channels are postulated to contribute to the sensing and signaling of changes in CO(2)-H(+) in chemosensitive neurons, we tested the hypothesis that there are more pH-sensitive K(+) channel-immunoreactive (ir) neurons within the medullary raphé nuclei of the highly chemosensitive SS rats than in the other two strains. Medullary tissues from male and female BN, FHH, and SS rats were stained with cresyl violet or with antibodies targeting TASK-1, K(v)1.4, and Kir2.3 channels. K(+) channel-ir neurons were quantified and compared with the total neurons in the region. The total number of neurons in the medullary raphé 1) was greater in male FHH than the other male rats, 2) did not differ among the female rats, and 3) did not differ between sexes. The average number of K(+) channel-ir neurons per section was 30-60 neurons higher in the male SS than in the other rat strains. In contrast, for the females, the number of K(+) channel-ir neurons was greatest in the BN. We also found significant differences in the number of K(+) channel-ir neurons between sexes in SS (males > females) and BN (females > males) rats, but not the FHH strain. Our findings support the hypothesis for males but not for females, suggesting that both genetic background and sex are determinants of K(+) channel immunoreactivity of medullary raphé neurons, and that the expression of pH-sensitive K(+) channels in the medullary raphé does not correlate with the ventilatory sensitivity to hypercapnia.

Micro-opioid receptor agonist injections into the presumed pre-Botzinger complex and the surrounding region of awake goats do not alter eupneic breathing.

Opioids are clinically important in the alleviation of pain. An undesirable side effect of opioids is depression of breathing. Data from isolated preparations suggest this effect is due to attenuation of discharge activity of neurons in the pre-Bötzinger complex (preBötzC), a medullary area with respiratory rhythmogenic properties. The purpose of this study was to examine how [d-Ala(2),N-Me-Phe(4),Gly(5)-ol]-enkephalin (DAMGO), a mu-opioid receptor agonist, affected breathing after injection into the presumed preBötzC of the adult awake goat. We hypothesized that DAMGO would cause breathing to decrease and become irregular when injected into the presumed preBötzC and the surrounding region of the conscious animal. We further hypothesized that ventilatory sensitivity to CO(2) and hypoxia would be blunted after the injection of DAMGO. Microtubules were bilaterally implanted into the presumed preBötzC of 10 adult female goats. After recovery from the surgery, DAMGO (0.5-10 mul, 1 nM-10 muM) was injected into the presumed preBötzC during the awake state. DAMGO had no effect on pulmonary ventilation [inspiratory minute ventilation (Vi)], respiratory rhythm and pattern, the activation pattern of inspiratory and expiratory muscles, or arterial blood gases during eupneic breathing conditions (P > 0.10). However, DAMGO attenuated (P < 0.05) the evoked increase in breathing frequency when inspired CO(2) was increased, and DAMGO attenuated the Vi response to reduction of inspired O(2) to 10.8% (P < 0.05). We conclude that our data do not provide support for the concept that in awake mammals opioid depression of breathing is due to a directed action of opioids on preBötzC neurons.

Condom use among injection drug users accessing a supervised injecting facility.

OBJECTIVES: Although supervised injecting facility (SIF) use has been associated with reductions in injection-related risk behaviours, the impact of SIFs on the sexual behaviour of injection drug users (IDUs) has not been thoroughly investigated. Therefore, we examined the patterns and predictors of condom use among SIF users in Vancouver, Canada. METHODS: We performed a longitudinal analysis of the factors associated with consistent condom use among IDUs recruited from within a SIF. RESULTS: Among 1090 individuals, 650 (59.6%) reported a sexual partner in the past 6 months at baseline. Consistent condom use was reported by 108 (25.3%) and 205 (61.6%) individuals reporting regular or casual partners, respectively. After 2 years of observation, these proportions increased to 32.9% and 69.8%, respectively. In multivariate analysis, predictors of consistent condom use with regular partners included HIV positivity (adjusted odds ratio (AOR) 2.23; 95% CI 1.51 to 3.31), injecting with a sex partner (AOR 0.50; 95% CI 0.37 to 0.68), enrollment in addiction treatment (AOR 0.68, 95% CI 0.52 to 0.89) and time since recruitment (AOR 1.29; 95% CI 1.06 to 1.55 per year). Predictors of consistent condom use with casual partners included HIV positivity (AOR 1.70; 95% CI 1.03 to 2.81), syringe borrowing (AOR 0.54; 95% CI 0.32 to 0.91) and syringe lending (AOR 0.52; 95% CI 0.32 to 0.84). CONCLUSIONS: Our results demonstrate that among SIF users, consistent condom use was more frequent among casual sex partners and among HIV positive individuals. Importantly, while the prevalence of consistent condom use was low at baseline, it increased over time. Our findings suggest a possible beneficial effect of the SIF on safer sexual practices.

Impact of risperidone versus haloperidol on activities of daily living in the treatment of refractory schizophrenia.

Risperidone has been shown to improve verbal working memory, executive functioning, attention, reaction time, and verbal learning, which, in turn, have been associated with improved functional outcomes. We tested whether risperidone was associated with greater improvements than haloperidol in activities of daily living (ADLs) among persons having treatment-refractory schizophrenia. In a double-blind, controlled trial of fixed and flexible doses of haloperidol and risperidone, changes in ADLs were operationally monitored on a behavior therapy unit of a state hospital. While no differential effects were noted between risperidone and haloperidol in ADLS, these self-care skills significantly improved as subjects spent longer times on the behavior therapy unit. Working memory and verbal learning did correlate with improvements in ADLs, independent of drug condition. The contingencies of reinforcement and specific training programs on the behavior therapy unit may have been prepotent for the learning of ADLs, obscuring any differential impact of risperidone. Moreover, ADLs may be governed more by "procedural" learning than by working memory or verbal learning, with the former not differentially influenced by typical verus atypical antipsychotics.

Risperidone in treatment-refractory schizophrenia.

OBJECTIVE: The purpose of this study was to evaluate the clinical safety and efficacy of risperidone compared to haloperidol in patients with treatment-refractory schizophrenia. METHOD: Sixty-seven medication-unresponsive subjects were randomly assigned to treatment with risperidone (N = 34) or haloperidol (N = 33). After a 3-7 day-placebo washout period, there was a 4-week, double-blind, fixed-dose comparison trial that was followed by a 4-week, flexible-dose phase. Measures of clinical change were quantified by standard psychopathologic and neuromotor instruments. RESULTS: Risperidone demonstrated clinical efficacy superior to that of haloperidol on the total Brief Psychiatric Rating Scale (BPRS) after the first 4 weeks of treatment. Risperidone did not show any advantage over haloperidol after an additional 4 weeks. Overall improvement on the BPRS at 4 weeks was significantly better for the risperidone group (24%) than for the haloperidol group (11%). Risperidone-treated subjects were significantly less likely than haloperidol-treated subjects to require concomitant anticholinergic medication after 4 weeks (20% versus 63%); they also had significantly les observable akathisia (24% versus 53%) and significantly less severe tardive dyskinesia. Baseline characteristics that correlated significantly with risperidone response were positive symptoms, conceptual disorganization, akathisia, and tardive dyskinesia. CONCLUSIONS: Risperidone was better tolerated and more effective in a subset of patients with treatment-refractory schizophrenia. Positive psychotic symptoms and extrapyramidal side effects at baseline appear to be powerful predictors of subsequent response to risperidone.

Risperidone versus haloperidol on secondary memory: can newer medications aid learning?

The introduction of the new generation of antipsychotic medications for the treatment of schizophrenia has been accompanied by a growing interest in the neurocognitive effects of these drugs. The present study compared the effects of risperidone and haloperidol on secondary memory in a group of treatment-resistant schizophrenia patients. The study design included a baseline phase and two double-blind phases in which patients were randomly assigned to medication under two different dose conditions (fixed dose and flexible dose). Secondary memory was assessed at baseline, fixed-dose, and flexible-dose phases, using the California Verbal Learning Test (CVLT). Six measures were selected, which formed three factors (general verbal learning ability, retention, and learning strategy). Risperidone-treated patients showed greater improvement than haloperidol-treated patients in general verbal learning ability, a finding characterized by significant treatment effects on CVLT measures of learning acquisition, recall consistency, and recognition memory. After controlling for benztropine status, differences on the measures of learning acquisition and recall consistency remained significant, and differences in recognition memory weakened slightly (p = 0.07). No significant treatment effects were noted on retention or learning strategy. These findings suggest that risperidone may exert a facilitating effect on the acquisition of new verbal information, an effect that does not appear to be due to the activation of semantic encoding strategies.