Department of Forensic Psychiatry, University of Kuopio and Niuvanniemi Hospital, Department of Clinical Physiology, Kuopio University Hospital, Kuopio, Finland. jari.tiihonen@niuva.fi
The introduction of second-generation antipsychotic drugs during the 1990s is widely believed to have adversely affected mortality of patients with schizophrenia. Our aim was to establish the long-term contribution of antipsychotic drugs to mortality in such patients.
Nationwide registers in Finland were used to compare the cause-specific mortality in 66 881 patients versus the total population (5.2 million) between 1996, and 2006, and to link these data with the use of antipsychotic drugs. We measured the all-cause mortality of patients with schizophrenia in outpatient care during current and cumulative exposure to any antipsychotic drug versus no use of these drugs, and exposure to the six most frequently used antipsychotic drugs compared with perphenazine use.
Although the proportional use of second-generation antipsychotic drugs rose from 13% to 64% during follow-up, the gap in life expectancy between patients with schizophrenia and the general population did not widen between 1996 (25 years), and 2006 (22.5 years). Compared with current use of perphenazine, the highest risk for overall mortality was recorded for quetiapine (adjusted hazard ratio [HR] 1.41, 95% CI 1.09-1.82), and the lowest risk for clozapine (0.74, 0.60-0.91; p=0.0045 for the difference between clozapine vs perphenazine, and p
Notes
Comment In: Lancet. 2009 Nov 7;374(9701):1591; author reply 1592-319897117
Comment In: Lancet. 2009 Nov 7;374(9701):1591; author reply 1592-319897118
Comment In: Lancet. 2009 Aug 22;374(9690):590-219595448
Comment In: Lancet. 2009 Nov 7;374(9701):1592; author reply 1592-319897121
Comment In: Lancet. 2009 Nov 7;374(9701):1592; author reply 1592-319897120
Of 45 first admission schizophrenics from 1963, an incidence by first admission group for northern Alberta, 43 were followed-up 14 years later. Based on these figures the expectancy was found to be 0.49%. The proportion of patients who were married was less than expected in comparison with the general population, but amongst the married, fertility was probably comparable to the population's. At follow-up about half the patients were managing well with little or no disability, one quarter had moderate to marked disability and the remainder were socially, psychiatrically and occupationally disabled. From the time of first admission, patients had spent an average of 15% of their time in hospital and lost 28% of the total time due to psychiatric disability.
Centre for Neuropsychiatric Schizophrenia Research, Psychiatric Centre Glostrup, Copenhagen University Hospital, Glostrup, Nordre Ringvej 29-67, DK-2600 Glostrup, Denmark. lone.baandrup@cnsr.dk
OBJECTIVE: Concomitant prescription of more than 1 antipsychotic agent (antipsychotic polypharmacy) in the treatment of schizophrenia is prevalent, although monotherapy is generally recommended. Mortality from natural causes is markedly increased in schizophrenia, and the role of polypharmacy remains controversial. The objective was to investigate if antipsychotic polypharmacy is associated with the excess mortality from natural causes among patients with schizophrenia. METHOD: A population-based nested case-control study was conducted using patient data from January 1, 1996, to December 31, 2005, obtained from central Danish registers. From the study population of 27,633 patients with ICD-8- and ICD-10-diagnosed schizophrenia or other mainly nonaffective psychoses, aged 18-53 years, we identified 193 cases who died of natural causes within a 2-year period and 1,937 age- and sex-matched controls. Current drug use was defined as at least 1 prescription filled within 90 days before the date of death or the index date. The data were analyzed by conditional logistic regression. RESULTS: Risk of natural death did not increase with the number of concurrently used antipsychotic agents compared with antipsychotic monotherapy (no antipsychotics: adjusted odds ratio [OR] = 1.48 [95% CI, 0.89-2.46]; 2 antipsychotics: OR = 0.91 [95% CI, 0.61-1.36]; 3 or more antipsychotics: OR = 1.16 [95% CI, 0.68-2.00]). Current use of benzodiazepine derivatives with long elimination half-lives (more than 24 hours) was associated with increased risk of natural death in patients with schizophrenia treated with antipsychotics (OR = 1.78 [95% CI, 1.25-2.52]). CONCLUSIONS: Antipsychotic polypharmacy did not contribute to the excess mortality from natural causes in middle-aged patients with schizophrenia. The detected increased risk of death associated with benzodiazepines with long elimination half-lives calls for further clarification.
It is generally believed that long-term use of antipsychotics increases mortality and, especially, the risk of cardiovascular death. However, there are no solid data to substantiate this view.
We identified all individuals in Sweden with schizophrenia diagnoses before year 2006 (N = 21 492), aged 17-65 years, and persons with first-episode schizophrenia during the follow-up 2006-2010 (N = 1230). Patient information was prospectively collected through nationwide registers. Total and cause-specific mortalities were calculated as a function of cumulative antipsychotic exposure from January 2006 to December 2010.
Compared with age- and gender-matched controls from the general population (N = 214920), the highest overall mortality was observed among patients with no antipsychotic exposure (hazard ratio [HR] = 6.3, 95% CI: 5.5-7.3), ie, 0.0 defined daily dose (DDD)/day, followed by high exposure (>1.5 DDD/day) group (HR = 5.7, 5.2-6.2), low exposure (
Compared to the general population, people with schizophrenia are at risk of dying prematurely due to suicide and due to different somatic illnesses. The potential role of antipsychotic treatment in affecting suicide rates and in explaining the increased mortality due to somatic disorders is highly debated. A recent study of death registers in Finland compared the cause-specific mortality in 66,881 patients versus the total population (5.2 million) between 1996 and 2006, suggesting that antipsychotic use decreased all-cause mortality compared to no antipsychotic use in patients with schizophrenia, and that clozapine had the most beneficial profile in this regard (Tiihonen et al., 2009). The benefits of clozapine were conferred by significant protective effects for suicide compared to perphenazine, whereas, a mixed group of 'other' antipsychotics, haloperidol, quetiapine and risperidone were reported to be associated with significantly higher all-cause mortality than perphenazine. By contrast, despite known differences in effects on cardiovascular risk factors, there were no significant differences between any of the examined antipsychotics regarding death due to ischemic heart disease. A number of methodological and conceptual issues make the interpretation of these findings problematic, including incomplete reporting of data, questionable selection of drug groups and comparisons, important unmeasured risk factors, inadequate control for potentially confounding variables, exclusion of deaths occurring during hospitalization leading to exclusion of 64% of deaths on current antipsychotics from the analysis, and survivorship bias due to strong and systematic differences in illness duration across the treatment groups. Well designed, prospective mortality studies, with direct measurement of and adjustment for all known relevant risk factors for premature mortality, are needed to identify risk and protective medication and patient factors and to, ultimately, inform clinical practice.
Effectiveness of antipsychotic treatments in a nationwide cohort of patients in community care after first hospitalisation due to schizophrenia and schizoaffective disorder: observational follow-up study.
To study the association between prescribed antipsychotic drugs and outcome in schizophrenia or schizoaffective disorder in the community.
Prospective cohort study using national central registers.
Community care in Finland.
Nationwide cohort of 2230 consecutive adults hospitalised in Finland for the first time because of schizophrenia or schizoaffective disorder, January 1995 to December 2001.
Rates of discontinuation of drugs (all causes), rates of rehospitalisation, and mortality associated with monotherapy with the 10 most commonly used antipsychotic drugs. Multivariate models and propensity score methods were used to adjust estimates of effectiveness.
Initial use of clozapine (adjusted relative risk 0.17, 95% confidence interval 0.10 to 0.29), perphenazine depot (0.24, 0.13 to 0.47), and olanzapine (0.35, 0.18 to 0.71) were associated with the lowest rates of discontinuation for any reason when compared with oral haloperidol. During an average follow-up of 3.6 years, 4640 cases of rehospitalisation were recorded. Current use of perphenazine depot (0.32, 0.22 to 0.49), olanzapine (0.54, 0.41 to 0.71), and clozapine (0.64, 0.48 to 0.85) were associated with the lowest risk of rehospitalisation. Use of haloperidol was associated with a poor outcome among women. Mortality was markedly raised in patients not taking antipsychotics (12.3, 6.0 to 24.1) and the risk of suicide was high (37.4, 5.1 to 276).
The effectiveness of first and second generation antipsychotics varies greatly in the community. Patients treated with perphenazine depot, clozapine, or olanzapine have a substantially lower risk of rehospitalisation or discontinuation (for any reason) of their initial treatment than do patients treated with haloperidol. Excess mortality is seen mostly in patients not using antipsychotic drugs.
Notes
Cites: N Engl J Med. 2000 Jun 22;342(25):1887-9210861325
Cites: N Engl J Med. 2000 Jun 22;342(25):1878-8610861324
A retrospective study was performed to evaluate the effect of long-term treatment with clozapine in 96 schizophrenic or schizoaffective patients hospitalized at the Psychiatric Research Center in Uppsala during the period 1974-1986. All patients had previously been treated with different neuroleptics but with inadequate response or distressing side effects. The mean duration of the disorder at the start of clozapine treatment was 8 years and 9 months and the mean duration of the treatment 3 years and 11 months. Clozapine treatment was discontinued in 36% of the patients, mainly due to lack of efficacy, poor compliance or temporary withdrawal of the drug from the market in 1975. In two patients the reason was leukopenia or agranulocytosis. In another 10 patients a transient decrement of WBC was seen, which was normalized during ongoing treatment. Four patients died when on clozapine during the follow-up period, but no causal relationship to the treatment could be established. Eighty-five per cent of the patients could be discharged from the hospital. Of the 62 patients who were still on clozapine after 2 years, 18% had full time and 21% half-time employment. A global evaluation of the clinical efficacy revealed a significant improvement in 43% and a moderate improvement in 38% of the patients compared to previous neuroleptic treatments. Common but usually mild side effects were sedation, hypersalivation, weight gain, and obstipation. Four patients had grand mal seizures. No extrapyramidal side effects were observed during clozapine treatment.(ABSTRACT TRUNCATED AT 250 WORDS)
Non-compliance in neuroleptic maintenance treatment is a major concern in schizophrenia. Home-based outpatient care has been shown both to improve medication compliance and reduce relapse frequency. We analysed the need for hospitalisation, levels of functioning and mortality rate during the de-institutionalisation process in 41 schizophrenia patients with repeated hospitalisations and prolonged history of non-compliance. Eighteen of the patients received ambulatory outpatient care (AOC) after discharge. This treatment procedure focuses on enduring neuroleptic maintenance treatment. One of the hospital nurses takes care of home visits every 2-4 weeks. In the 4-year follow-up, half of the patients in the AOC group did not need hospitalisation at all and the number of days of hospitalisation in the whole group diminished by almost four-fifths compared with the previous 4 years. In the non-AOC group, there was a more limited decrease in the number of days of hospitalisation during the corresponding follow-up period. The mortality rates showed a slight tendency towards a better outcome in the AOC group. There was no change in the levels of functioning in the AOC group. This treatment can be carried out with limited resources. It clearly reduces the need for hospitalisation in a subgroup of schizophrenia patients having problems with compliance and recurrent relapse. The effectiveness of AOC on the mortality rates of schizophrenia patients needs further examination.
Mortality and Cumulative Exposure to Antipsychotics, Antidepressants, and Benzodiazepines in Patients With Schizophrenia: An Observational Follow-Up Study.
Although mortality related to psychotropic medications has received much attention in recent years, little is known about the relationship between risk of death and cumulative antipsychotic load, and even less about the relationship between mortality and cumulative exposure to antidepressants or benzodiazepines. The authors examined these relationships using nationwide databases.
The authors used prospectively collected nationwide databases to identify all individuals 16-65 years of age with a schizophrenia diagnosis (N=21,492) in Sweden. All-cause and cause-specific mortality rates were calculated as a function of cumulative low, moderate, and high exposure to antipsychotics, antidepressants, and benzodiazepines from 2006 through 2010.
Compared with no exposure, both moderate (adjusted hazard ratio=0.59, 95% CI=0.49-0.70) and high (adjusted hazard ratio=0.75, 95% CI=0.63-0.89) antipsychotic exposures were associated with substantially lower overall mortality. Moderate antidepressant exposure was associated with a lower mortality (adjusted hazard ratio=0.85, 95% CI=0.73-0.98), and high exposure, even lower (adjusted hazard ratio=0.71, 95% CI=0.59-0.86). Exposure to benzodiazepines showed a dose-response relationship with mortality (hazard ratios up to 1.74 [95% CI=1.50-2.03]).
Moderate and high-dose antipsychotic and antidepressant use were associated with 15%-40% lower overall mortality, whereas chronic high-dose use of benzodiazepines was associated with up to a 70% higher risk of death compared with no exposure. Since patients with anxiety and depressive symptoms may have a higher intrinsic risk of death, the finding for benzodiazepines may be attributable to some extent to residual confounding.
We investigated mortality and its determinants in people with psychotic disorder.
A nationally representative two-stage cluster sample of 8028 persons aged 30 years or older from Finland was selected for a comprehensive health survey conducted from 2000 to 2001. Participants were screened for psychotic disorder, and screen-positive persons were invited for a Structured Clinical Interview for DSM-IV. The diagnostic assessment of DSM-IV psychotic disorders was based on the Structured Clinical Interview for DSM-IV, case records from mental health treatments, or both. Mortality was followed up until September 2009 and analyzed using Cox proportional hazards model.
People with schizophrenia (hazard ratio [HR] = 3.03; 95% confidence interval [CI] = 1.93-4.77) and other nonaffective psychoses (HR = 1.84; 95% CI = 1.17-2.91) had elevated mortality risk, whereas people with affective psychoses did not (HR = 0.61; 95% CI = 0.24-1.55). Antipsychotic medication use was associated with increased mortality (HR = 2.34; 95% CI = 1.86-2.96). There was an interaction between antipsychotic medication use and the presence of a psychotic disorder: antipsychotic medication use was only associated with elevated mortality in persons who were using antipsychotics and did not have primary psychotic disorder. In persons with psychotic disorder, mortality was predicted by smoking and Type 2 diabetes at baseline survey.
Schizophrenia and nonaffective psychoses are associated with increased mortality risk, whereas affective psychoses are not. Antipsychotic medication use increases mortality risk in older people without primary psychotic disorder, but not in individuals with schizophrenia. Smoking and Type 2 diabetes are important predictors of elevated mortality risk in persons with psychotic disorder.
