Raymond C. Love

Cigarette Smoking and Mortality Risk in People With Schizophrenia

This study examined effects of cigarette smoking on mortality risk in 1213 persons aged 19-69 years with schizophrenia-related psychotic disorders admitted to State of Maryland Hospitals between 1994 and 2000. Inpatient medical records from 7 hospitals were reviewed to obtain demographic information, diagnosis, medication use, as well as smoking and other substance use. Social Security Death Index data were used to identify deaths in the study group between 1994 and 2004. Death records were reviewed to obtain manner of death and underlying disorders. Of the 1213, 55% were smokers and 71% abused substances. There was an age × smoking interaction (χ(2) = 14.6, df = 1, P = .0001) for mortality, with estimated hazard ratios (HRs) for smokers vs nonsmokers of 2.1 among 35- to 54-year olds and HR of 0.7 among those aged 55-69 years. Five- and 10-year mortality rates for smokers aged 35-54 years were 7.0% and 14.2%, compared with 3.3% and 10.0% for nonsmokers, respectively (χ(2) = 5.53, df = 1, P = .019). Cardiac causes were identified in 43% of deaths in smokers but only 19% of deaths in nonsmokers (P < .006). For those aged 35-54 years, the odds of cardiac related death was increased by 12 fold in smokers relative to nonsmokers (HR = 12.4, χ(2) = 12.0, df = 1, P = .0005). Among people aged 35-54 years, those smoking greater than one pack daily have a significantly increased total mortality risk (HR = 2.7) vs nonsmokers. Cigarette smoking, particularly in people aged 35-54 years, contributes to an increased risk of death. Greater smoking severity significantly increases this risk. Smoking cessation in people with schizophrenia deserves significant attention.

Cardiovascular disease mortality in patients with chronic schizophrenia treated with clozapine: a retrospective cohort study.

BACKGROUND Cardiovascular disease (CVD) mortality in schizophrenia is more frequent than in the general population. Whether second-generation antipsychotics (SGAs) increase risk of CVD morbidity and mortality has yet to be determined. METHOD We conducted a retrospective cohort study using an administrative database to identify patients with DSM-III- or DSM-IV-diagnosed schizophrenia, treated in Maryland, who started clozapine treatment (n = 1,084) or were never treated with clozapine (initiated on risperidone; n = 602) between 1994 and 2000. Deaths between 1994 and 2004 were identified by the Social Security Death Index, and death records were obtained. RESULTS During the 6- to 10-year follow-up period, there were 136 deaths, of which 43 were attributed to CVD. Cardiovascular disease mortality in patients aged younger than 55 years at medication start was approximately 1.1% (clozapine, 1.1%; risperidone, 1.0%) in both groups at 5 years and 2.7% (clozapine) and 2.8% (risperidone) at 10 years (chi(2)(1) = 0.12, P = .73). Patients who started treatment at ages >or= 55 years had CVD mortality of 8.5% (clozapine) and 3.6% (risperidone) at 5 years and 16.0% (clozapine) and 5.7% (risperidone) at 10 years (chi(2)(1) = 2.13, P = .144). In a Cox regression model, patients aged >or= 55 years were at greater risk of mortality than younger patients (hazard ratio = 4.6, P < .001); whites were at greater risk than nonwhites (HR = 2.1, P = .046); however, SGA treatment (HR = 1.2; 95% CI, 0.6-2.4; P = .61) and sex (HR = 0.9, P = .69) were not statistically significant predictors of CVD, nor was there a significant age x clozapine interaction (chi(2)(1) = 1.52, P = .22). Age-, race-, and gender-adjusted standardized mortality ratios were significantly elevated (clozapine, 4.70; 95% CI, 3.19-6.67; risperidone, 2.88; 95% CI, 1.38-5.30) compared to year 2000 rates for the Maryland general population but did not differ by antipsychotic group (chi(2)(1) = 1.42, P = .23). CONCLUSIONS The risk of CVD mortality in schizophrenia does not differ between clozapine and risperidone in adults despite known differences in risk profiles for weight gain and metabolic side effects. However, we cannot rule out an increased risk of CVD mortality among those starting treatment at ages 55 years or older.

Rehospitalization Risk with Second-Generation and Depot Antipsychotics

Decreasing hospital admissions is important for improving outcomes for people with schizophrenia. Second-generation antipsychotics (SGAs) are better tolerated for long-term therapy than traditional medications and may contribute to a lower rehospitalization risk, but have not been compared to depot forms with regard to long-term outcomes. This study evaluates the risk of readmission in patients discharged from six State of Maryland inpatient mental health facilities between Jan. 1, 1997 and Dec. 31, 1997 on clozapine (N = 41), risperidone (N = 149), and olanzapine (N = 103). These patients were compared with those discharged from the two largest state facilities during the same time period on fluphenazine decanoate (N = 59) or haloperidol decanoate (N = 59). One-year readmission risk (measured by Kaplan–Meier survival analysis with Holms adjustment for multiple comparison on Log Rank tests) were 10% for clozapine, 12% for risperidone, and 13% for olanzapine. These risks were not significantly lower than the readmission risk for fluphenazine decanoate (21%) but were significantly lower than haloperidol decanoate (35%) for all three SGAs. Demographic and clinical variables did not predict readmission for any of the medications. In patients with similar demographic and clinical characteristics, 1-year risk of readmission for patients treated with SGAs were at least comparable to the 1-year risk for patients receiving fluphenazine decanoate and lower than the risk for patients treated with haloperidol decanoate. SGAs may provide better long-term prognoses and outcomes for patients with schizophrenia.

Risperidone, quetiapine, and fluphenazine in the treatment of patients with therapy-refractory schizophrenia

This 12-week, double-blind study evaluated the effectiveness of risperidone (4 mg/day), quetiapine (400 mg/day), or fluphenazine (12.5 mg/day) in a stringently defined treatment-resistant population of people with schizophrenia. No differences were noted in total Brief Psychiatric Rating Scale (BPRS) or Clinical Global Impression scores among the drug groups (n = 38). More subjects tended to complete the study on risperidone (69%) or quetiapine (58%) than those treated with fluphenazine (31%; P value not significant). Eighty-nine percent of those who discontinued on fluphenazine (8 of 9) were due to lack of efficacy. Discontinuation due to adverse effects was low, with only 2 subjects (both on quetiapine) stopping due to side effects. Three of 13 risperidone-treated subjects (23%) and 3 of 12 quetiapine-treated subjects (25%) met response criteria (decrease of 20% of total BPRS score), whereas 2 of 13 subjects (15%) responded to fluphenazine. Side effect occurrence was similar among drug groups and EPS ratings on the Simpson Angus Scale improved in all drug groups (quetiapine, 1.64; risperidone, 1.30; fluphenazine, 0.69; P value not significant). Despite the newer class of second-generation antipsychotic medications, this treatment-resistant population remains difficult to treat. Many people have only minimal to modest improvements with antipsychotic treatment and most continue to have residual psychotic symptoms. Treatment with first- and second-generation antipsychotics may demonstrate similar efficacy; however, patients treated with second-generation antipsychotics may be more likely to adhere to treatment.

Novel Factor-Based Symptom Scores in Treatment Resistant Schizophrenia: Implications for Clinical Trials

To study the factor structure of symptoms in patients with treatment resistant schizophrenia and whether it is altered by treatment, we analyzed ratings on the Brief Psychiatric Rating Scale (BPRS) from two independent groups of patients with treatment resistant schizophrenia. With confirmatory factor analysis of pre-clozapine BPRS scores in 1074 patients in an administrative data base, the Clozapine Authorization and Monitoring Program (CAMP), we assessed the fit of published factor models and developed a better-fitting model. Model fit was validated in an independent group of 197 research unit participants. Stability of model fit six months post-clozapine was assessed in 834 CAMP patients. A new 4-factor model (negative symptoms, reality distortion, disorganization, and anxiety/depression) had better fit in both data sets than two commonly used factor models, and also fit better post-clozapine. We recommend these four factor scores as clinical trial outcomes in patients with treatment resistant schizophrenia.

Novel versus Conventional Antipsychotic Drugs

Novel antipsychotic agents differ from conventional ones in several key characteristics, including effectiveness, adverse reactions, and receptor‐binding profile. Most of the newer agents have an affinity for the serotonin 5HT2 receptor that is at least f 0 times greater than that for the dopamine D2 receptor. This increased affinity for the serotonin receptor may be responsible for another distinguishing characteristic of novel antipsychotic agents—decreased frequency of extrapyramidal side effects. These side effects, which include pseudoparkinsonism, acute dystonias, and akathisia, frequently are the reason for noncompliance with conventional drug therapy. The newer drugs are often effective in patients resistant to treatment with conventional agents. They also appear to reduce the negative symptoms of schizophrenia in many patients.

Metabolic risk with second-generation antipsychotic treatment: a double-blind randomized 8-week trial of risperidone and olanzapine.

BACKGROUND The second-generation antipsychotics are effective for treating psychotic disorders and incur fewer motor side effects than are commonly experienced with the use of first-generation antipsychotics. However, their use is commonly associated with weight gain and metabolic disturbances. This study examined weight and metabolic changes with two widely used antipsychotics, risperidone and olanzapine; addressing the issue of early monitoring for metabolic side effects. METHODS This 8-week double blind randomized trial included patients with schizophrenia or schizoaffective disorder (N = 377) randomly assigned to risperidone (2-6 mg/day) or olanzapine (5-20 mg/day). Weight, BMI, HbA1C, total cholesterol (TC), LDL-C, HDL-C and triglycerides (TG) were monitored. RESULTS Mean BMI increases were higher in the olanzapine group as compared to risperidone (1.3 kg/m(2)(SD = 0.13) vs. 0.7 kg/m(2) (SD = 0.13)(p < 0.001). Increases in mean TC (13.5 mg/dl (SD 2.4), LDL-C (11.0 mg/dl (SD 2.2)) and TG (14.8 mg/dl (SD = 7.6)) occurred in the olanzapine group while significant changes in TC (-3.9 mg/dl (SD = 2.5)) and TG (-32.8 mg/dl (SD = 7.8)) were noted in the risperidone group. Men (not women) on olanzapine had higher than expected increases in lipids given the amount of weight gain. Baseline values and prior therapy did not contribute to the significant differences, however BMI increases (p = 0.0002) were linked to study discontinuation in both drug groups. CONCLUSIONS The fact that significant metabolic changes occurred (both positive and negative) in eight weeks is important to clinical care. Monitoring for metabolic changes may be important within the first eight weeks of treatment, as changes can be determined very early in antipsychotic treatment.

Atypical Antipsychotic Use in a State Hospital Inpatient Adolescent Population

Atypical antipsychotics are now the most commonly prescribed antipsychotics in young patients. These drugs are increasingly being used because of better tolerance and safety as seen in the adult populations. Youth with more severe psychopathology who are treated in the inpatient setting have been overlooked in much of the published research, and the extent of use and rationale in this population is unknown. This naturalistic retrospective study examined a population of adolescents in an inpatient state hospital setting with regard to their use of atypical antipsychotics. All patients who received an inpatient prescription for atypical antipsychotics between January 1, 1997 and June 1, 2000 and were ages 18 or younger at the time of medication initiation were included in the study. Twenty-three percent (88/380) of patients received an atypical antipsychotic: 68% (60/88) risperidone, 27% (24/88) olanzapine, and 5% (4/88) quetiapine. Psychotic disorders were considered as the primary diagnosis in only 17% of patients treated with atypical antipsychotics, and no particular diagnosis was predictive of monotherapy with an atypical antipsychotic. In the adolescent populations, atypical antipsychotics are being used for a wide variety of diagnoses and are commonly used adjunctively (more than 80%) with many concomitant psychotropic medications. More research is needed to develop useful and specific practice guidelines in children and adolescents for these commonly used medications.

Pharmacology and clinical experience with risperidone.

Risperidone (Risperdal®, Janssen Pharmaceutica) is a second generation antipsychotic (SGA) for the treatment of schizophrenia and other psychotic disorders. It is a potent antagonist of serotonin-2 (5-HT2) and dopamine-2 (D2) receptors in the brain. In comparison to conventional antipsychotics, risperidone demonstrates superior efficacy against the positive and negative symptoms of schizophrenia and a decreased occurrence of extrapyramidal side effects (EPS). Risperidone causes less weight gain than other marketed SGAs, but can increase prolactin levels and cause EPS in a dose-related manner. In a variety of pharmacoeconomic analyses, it has proven to be a cost-effective addition to the antipsychotic armamentarium. As the first SGA available for front line use, risperidone has established a new standard of care for the treatment of individuals with psychotic disorders.

Cardiac-related findings at autopsy in people with severe mental illness treated with clozapine or risperidone

Clozapine is a superior agent for treatment-refractory patients with schizophrenia, but is underutilized in the US, likely due to the risk of side effects. This study examined all available autopsy data on cardiac disease and risk factors in people with schizophrenia in a sample of deceased persons with severe mental illness who had received clozapine (N=62) or risperidone (N=42). The mean body mass index (BMI) at the time of death was 31.4+/-8.8 kg/m2 and 27.1+/-8.2 kg/m2 in the clozapine and risperidone groups respectively (t=1.98, df=60, p=0.052). Cardiac related measures examined included: abdominal wall thickness, heart weight, left ventricle thickness, right ventricle thickness, presence of notable cardiac involvement (atherosclerosis, fibrosis and hypertrophy) and number of cardiac arteries occluded. No significant differences in any of the cardiac findings were noted between patients in the clozapine and risperidone groups. Independent of treatment, cardiomyopathy deaths were associated with a higher abdominal wall thickness (p=0.042) and a tendency towards higher BMI (p=0.051) as compared to the other causes of death. The results of this study suggest that while clozapine is associated with weight gain and metabolic abnormalities, there does not appear to be an increased occurrence of cardiac abnormalities in deceased persons who were treated with clozapine as compared to risperidone.