Haloperidol dose when used as active comparator in randomized controlled trials with atypical antipsychotics in schizophrenia: comparison with officially recommended doses.

OBJECTIVE: To determine the doses of haloperidol as a comparator drug in randomized controlled trials (RCTs) with atypical antipsychotics in patients with schizophrenia and to compare these doses with the officially recommended doses for haloperidol in the United States and the United Kingdom. DATA SOURCES: We searched for RCTs conducted and published in English in full before January 2005 in which atypical antipsychotics were compared with haloperidol for the treatment of schizophrenia. We searched for Cochrane Reviews in which 1 of the following atypical antipsychotics was evaluated for the treatment of patients with schizophrenia, schizophreniform psychosis, or other primary psychosis: amisulpride, aripiprazole, olanzapine, quetiapine, risperidone, sertindole, and ziprasidone. For the gap between the end point of inclusion of the studies in the Cochrane Reviews and January 2005, we electronically searched the Cochrane Central Register of Controlled Trials for any further RCTs in which atypical antipsychotics were compared with haloperidol for the same indication. Search terms used were haloperidol and schizophren and haloperidol and psychotic, as well as the names of the selected atypical antipsychotics for the years that were not covered by the Cochrane Reviews. For each study, the required dose and mean dose of haloperidol were compared with officially recommended doses of haloperidol in U.S. (Food and Drug Administration) and U.K. (British National Formulary) guidelines. DATA SYNTHESIS: In all of the included studies (N = 49), the midpoints of the required doses were above the midpoint of the official recommended doses in the United States and United Kingdom for moderately ill patients. In 94% (U.S.) and 80% (U.K.) of the studies, they were above the upper border of the recommended doses. Compared with recommended doses for severely ill patients in both the United Kingdom and United States (range, 6-15 mg daily), in 17 studies (35%) the mean actual used dose was above the upper dose border for severely ill patients (15 mg daily). CONCLUSIONS: Nearly all randomized clinical trials used haloperidol in doses that were higher than the official recommended doses for moderately ill or even severely ill patients. Therefore, it is probable that the results of the RCTs were affected by the high dose of haloperidol, hampering the interpretation of the effects of atypical anti-psychotics in their comparison with haloperidol.

Association of risk of abnormal bleeding with degree of serotonin reuptake inhibition by antidepressants.

BACKGROUND: Serotonin plays a role in platelet aggregation. Because antidepressants influence blood serotonin levels, their use may be associated with an increased risk of abnormal bleeding. However, previous studies were inconclusive regarding this association. The aim of this study was to estimate the risk of abnormal bleeding associated with the use of antidepressants and to establish the relationship between serotonin reuptake inhibition and the risk of bleeding. METHODS: We used data collected from 1992 through 2000 to conduct a nested case-control study of a cohort of more than 64 000 new antidepressant users. Cases were identified as all patients hospitalized for a primary diagnosis of abnormal bleeding, and they were matched with controls for age and sex. We classified exposure according to the degree (high, intermediate, or low) of serotonin reuptake inhibition and performed logistic regression analysis to calculate odds ratios. RESULTS: There were 196 cases of abnormal bleeding. The risk of hospitalization increased with the use of inhibitors providing intermediate (odds ratio, 1.9; 95% confidence interval, 1.1-3.5) and high degrees of serotonin reuptake inhibition (odds ratio, 2.6; 95% confidence interval, 1.4-4.8). CONCLUSIONS: In a large population of new antidepressant users we found a significant association between degree of serotonin reuptake inhibition by antidepressants and risk of hospital admission for abnormal bleeding as the primary diagnosis. An increased risk of abnormal bleeding was strongly associated with the degree of serotonin reuptake inhibition.

Incidence and determinants of long-term use of antidepressants.

OBJECTIVES: The use of antidepressants has increased over the years, which may be due to more new antidepressant users, but also may be due to a longer duration of use. We aimed to assess the prevalence, incidence and average duration of selective serotonin reuptake inhibitor (SSRI) and tricyclic antidepressant (TCA) use in the Netherlands during 1992-2001. In addition, we assessed the incidence of long-term use of SSRIs and identified possible determinants of long-term use. METHODS: We assessed prevalence (number of current users of an antidepressant per 1000 persons assessed on a single day) and incidence (number of new users per 1000 persons per year) of antidepressant use for each year in the PHARMO record linkage system. Long-term use was defined as the consecutive use of any antidepressant for at least 12 months. Relative risks and hazard ratios were calculated and adjusted for possible determinants using Poisson and Cox regression analyses. RESULTS: Both prevalent and incident use of SSRIs increased during 1992-2001, while TCA use remained stable. A total of 9857 patients using SSRIs were included in a follow-up study. During the follow-up period, more patients became long-term users, either directly after the start of the initial SSRI or anytime during follow-up (29.5%). The average number of days before start of long-term use decreased from 595 days in 1991 to 19 days in 1997. Female patients, older age, previous use of benzodiazepines and being treated by a psychiatrist increased the probability of becoming a long-term user. CONCLUSION: Both prevalent and incident use of SSRIs increased during the 1990s, implicating an increased number of patients starting SSRIs, but also a longer duration of use of antidepressant therapy. Over the entire follow-up period, almost 30% of the patients became long-term users at anytime during the follow-up period.

Adverse events in users of sertraline: results from an observational study in psychiatric practice in The Netherlands.

PURPOSE: To evaluate the safety profile of sertraline versus other Selective Serotonin Reuptake Inhibitors (SSRIs) directly following the introduction of sertraline to the Dutch market. METHODS: In a prospective follow-up study, 109 psychiatrists included patients with a new episode of treatment with sertraline and an equal number of patients starting treatment with other SSRIs. All Adverse Events (AEs) during follow-up were recorded by the psychiatrists for the duration of SSRI treatment until discontinuation or until at least 12 months. RESULTS: A total of 1251 patients were included in the study of which 659 used sertraline and 592 used other SSRIs (paroxetine, fluoxetine or fluvoxamine). The most frequently reported events in sertraline users and users of other SSRIs were nausea (160 (24.3%) sertraline patients versus 160 (27.0%) patients using other SSRIs), headache (127 (19.3%) sertraline patients versus 101 (17.1%) patients using other SSRIs), diarrhoea (94 (14.0%) sertraline patients versus 40 patients using other SSRIs (6.8%, p < 0.05)), sweating (88 (13.4%) sertraline patients versus 69 (11.7%) patients using other SSRIs) and dizziness (75 (11.4%) sertraline patients versus 70 (11.8%) patients using other SSRIs). A total of 121 patients reported 134 different unlabelled AEs of which 10 were reported by more than 1% of the population. CONCLUSIONS: In this study we found that almost three out of four patients reported an adverse event. When comparing with other SSRIs and the literature, we found a similar distribution of the most frequently reported adverse events in patients using sertraline. However, in this observational study we found over 100 different unlabelled adverse events.