Treatment of Schizophrenia With Long-Acting Fluphenazine, Haloperidol, or Risperidone

Mark Olfson; Steven C. Marcus; Haya Ascher-Svanum

Abstract
Objective: This study compares 3 cohorts of patients with schizophrenia before, during, and after initiating treatment with fluphenazine decanoate (FD), haloperidol decanoate (HD), or long-acting injectable risperidone (LAR).

Methods: Administrative data are analyzed from California Medicaid (Medi-Cal) beneficiaries with schizophrenia who initiated FD, HD, or LAR treatment. Patients were required to have been continuously enrolled in Medi-Cal for 180 days before and 180 days after the start of the new episode of long-acting antipsychotic therapy.

Results: There were few demographic and clinical differences among patients initiating FD, HD, and LAR. During the 180 days before starting long-acting injections, most patients initiating FD 53.5%, HD 58.5%, and LAR 61.2% received oral antipsychotic medications for less 80% of the days in this period (medication possession ratio: small than 0.80). The mean duration of depot treatment episodes was 58.3 days. Few patients who started on FD 5.4%, HD 9.7%, or LAR 2.6% continued for at least 180 days. Most patients in each group FD 77.4%, HD 78.9%, and LAR 75.5% received oral antipsychotic medications during the 45 days after discontinuing long-acting injections. Coprescription with antidepressants, mood stabilizers, and benzodiazepines was common.

Conclusions: Patients treated with long-acting antipsychotic injections tend to have complex pharmacological regimens and recent medication nonadherence. A great majority of patients initiating long-acting antipsychotic medications discontinue use within the first few months of treatment.

Introduction
Long-acting antipsychotic medication injections are thought to help improve medication adherence in schizophrenia.Theoretical advantages of long-acting antipsychotic injections over oral medications include guaranteed delivery of medication, reliable monitoring of treatment adherence, and an increased opportunity for the treatment team to intervene as soon as a patient misses a dose. Clinical research and expert opinion support use of long-acting injection antipsychotic medications as maintenance treatment for patients with a history of medication nonadherence.

Approximately 15% of schizophrenia patients in maintenance antipsychotic treatment receive depot preparations. In one recent study, 29.9% of patients with schizophrenia and a recent history of antipsychotic nonadherence were currently being prescribed a long-acting injection antipsychotic medication. In the United States, psychiatrists tend to select long-acting injection medications for patients who have persistent psychotic symptoms and who frequently receive more than one concurrent antipsychotic medication. Use of depot antipsychotic medications may be increased among African Americans and patients with substance use problems.

Three antipsychotic medications are currently available in the United States as long-acting injections: fluphenazine decanoate (FD) or enanthate, haloperidol decanoate (HD), and long-acting injectable risperidone (LAR). These medications differ from one another in their pharmacokinetic and side-effect profiles. Little is known about the characteristics and service use patterns of patients who are treated with these medications in community practice.

In the current report, we use a large administrative database to compare and contrast the characteristics of schizophrenia patients starting FD, HD, and LAR and assess the continuity of their antipsychotic treatment. We also describe the use of oral antipsychotic and other psychotropic medications, treatment for selected comorbid conditions, and service use before, during, and after treatment with long-acting antipsychotic medications.

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Haloperidol Versus Chlorpromazine for Treatment of Schizophrenia

C. Leucht; M. Kitzmantel; L. Chua; J. Kane; S. Leucht

Introduction
Chlorpromazine and haloperidol are benchmark antipsychotic drugs which are frequently used as standards in antipsychotic drug trials. For example, in the review on second-generation antipsychotic drugs by Davis et al., haloperidol was by far the most frequently used comparator followed by chlorpromazine. To better define the relative efficacy and safety of both compounds is therefore important for the methodology of randomized controlled trials (RCTs) and for clinical practice where both agents are still frequently used.

Objectives
To compare the effects of haloperidol and chlorpromazine for people with schizophrenia and schizophrenia-like psychoses.

Search Strategy
We searched the Cochrane Schizophrenia Group's register (August 2006). We searched references of all included studies for further trials. We contacted pharmaceutical companies and authors of relevant trials.

Selection Criteria
We included all RCTs that compared haloperidol with chlorpromazine for people with schizophrenia and/or schizophrenia-like psychoses.

Data Collection and Analysis
Citations and, where possible, abstracts were independently inspected by at least 2 reviewers, and papers ordered,reinspected, and quality assessed. We independently extracted data. For dichotomous data, we calculated the relative risk (RR), 95% confidence interval (CI), and, where appropriate, the number needed to treat (NNT) on an intention-to-treat basis using a random-effects model. For continuous data, we calculated weighted mean differences.

Results
We found 14 relevant studies, mostly of short duration, poorly reported, and conducted in the 1970s (total n = 794 participants). Nine of these compared oral formulations of both compounds and 5 compared intramuscular formulations.

Haloperidol was associated with significantly fewer people leaving the studies early. The efficacy outcome 'no significant improvement' tended to favor haloperidol, but this difference was not statistically significant. Movement disorders were more frequent in the haloperidol groups ('at least one extrapyramidal side-effect', see Figure 1), while chlorpromazine was associated with more frequent hypotension (see Figure 2). Similar trends were found when studies comparing intramuscular formulations and studies comparing oral formulations were analyzed separately.

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Association Between Paternal Schizophrenia and Low Birthweight: A Nationwide Population-Based Study

Herng-Ching Lin; Chao-Hsiun Tang; Hsin-Chien Lee

Abstract
Using a nationwide population-based dataset, the aim of the present study was to investigate the association between paternal schizophrenia and the risk of low birthweight (LBW). This study linked the 2001 Taiwan National Health Insurance Research Data set with Taiwan's birth and death certificate registries. In total, 220 465 singleton live births were included. The key dependent variable was whether or not an infant's father was diagnosed with schizophrenia, while the independent variable of interest was whether an infant had LBW.

Multivariate logistic regression analysis was performed to explore the relationship between paternal schizophrenia and the risk of LBW, after adjusting for the infant and parents' characteristics. The results show that infants whose fathers had schizophrenia were more likely to have LBW than those whose fathers did not (12.6% vs 8.0%). Infants whose fathers had schizophrenia were found to be 1.58 times more likely to have LBW than their counterparts whose fathers did not have schizophrenia, following adjustment for gestational week at birth, parity, paternal age and highest educational level, family monthly incomes, and marital status. We conclude that the offspring whose fathers had a diagnosis of schizophrenia had increased risk of LBW compared with those whose fathers had no schizophrenia. This finding paves the way for further studies and suggests that there may be potential benefit to early intervention to prevent LBW in pregnant women with husbands with schizophrenia.

Introduction
Increasing attention has been paid to the effect of paternal characteristics on adverse pregnancy outcomes, particularly infant
birthweight, during the past decade. A growing number of studies have reported that paternal characteristics such as age,
height, weight, race, educational level, and occupation were associated with variation in birthweight, after adjusting for maternal and pregnancy-specific factors. Some researchers have suggested that because the placenta is largely dependent the expression of genes of paternal origin, it is biologically plausible that fetal growth is influenced by paternal factors. With regard to mental illness, literature reviews reveal that women with schizophrenia have an increased risk of giving birth to low birthweight (LBW) babies, compared with healthy pregnant women. Still, to the best of our knowledge, few attempts have been made to examine the relationship between paternal mental illness and adverse pregnancy outcomes.

Schizophrenia is considered strongly influenced by genetic inheritance,whether traceable to maternal or paternal schizophrenia. Thus,it seems reasonable to assume that not only children of mothers with schizophrenia but also those with fathers with schizophrenia might be at increased risk of neurodevelopmental impairment. Recently, Webb et al published a study on the association between paternal schizophrenia and fatal birth defects. They used the data on all singleton live births in Denmark during 1973-1998 but found no elevation in risk of fatal birth defects relating to paternal schizophrenia. However, their study measured only severely adverse birth outcomes, and a substantial proportion of the paternal data was missing.

Such limitations preclude unequivocal acceptance of their findings. Using a Taiwan nationwide population-based dataset, the aim of the present study is to investigate the association between paternal schizophrenia and the risk of LBW, after adjusting for the characteristics of infant, mother, and father. LBW is associated not only with neurodevelopmental impairment but also with increased risk of mortality and morbidity in infants, as well as adverse long-term consequences for the child. LBW may be preventable, however. Therefore, exploring the association between paternal schizophrenia and the risk of LBW might not only help researchers understand the possible genetic or environmental mechanisms linking parental mental illness and fetal birth weight but could also generate opportunities for clinicians to provide specific, optimal prenatal care.

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