Jari Haukka

11-year follow-up of mortality in patients with schizophrenia: a population-based cohort study (FIN11 study)

BACKGROUND 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. METHODS 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. FINDINGS 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<0.0001 for all other antipsychotic drugs). Long-term cumulative exposure (7-11 years) to any antipsychotic treatment was associated with lower mortality than was no drug use (0.81, 0.77-0.84). In patients with one or more filled prescription for an antipsychotic drug, an inverse relation between mortality and duration of cumulative use was noted (HR for trend per exposure year 0.991; 0.985-0.997). INTERPRETATION Long-term treatment with antipsychotic drugs is associated with lower mortality compared with no antipsychotic use. Second-generation drugs are a highly heterogeneous group, and clozapine seems to be associated with a substantially lower mortality than any other antipsychotics. Restrictions on the use of clozapine should be reassessed. FUNDING Annual EVO Financing (Special government subsidies from the Ministry of Health and Welfare, Finland).

Meta-analysis of observational studies of serum 25-hydroxyvitamin D levels and colorectal, breast and prostate cancer and colorectal adenoma.

Epidemiological studies have suggested a reduced risk of several cancers associated with high vitamin D status. We performed a systematic review with meta‐analyses of observational studies of serum 25‐hydroxyvitamin D level and colorectal, breast and prostate cancer and colonic adenoma. The literature of December 2009 was searched without language restriction. The meta‐regression analysis was done to compute dose‐response effects. Because in case‐control studies, serum 25‐hydroxyvitamin D level is measured after the diagnosis of cancer, separate analyses for case‐control and prospective studies were done. We identified 35 independent studies. The seven studies on colorectal adenomas were heterogeneous in terms of endpoint and control for major confounding factors, and we did not perform a meta‐analysis of these data. The summary relative risk (SRR) and (95% confidence interval) for a 10 ng/ml increase in serum 25‐hydroxyvitamin D was 0.85 (0.79; 0.91) for colorectal cancer (2,630 cases in 9 studies); 0.89 (0.81;0.98) for breast cancer (6,175 cases in 10 studies); and 0.99 (0.95;1.03) for prostate cancer (3,956 cases in 11 studies). For breast cancer, case‐control studies (3,030 cases) had major limitations and obtained SRR of 0.83 (0.79; 0.87) whereas SRR of prospective studies (3,145 cases) was 0.97 (0.92; 1.03). For colorectal and breast cancer, differences between cases and controls in the season of blood draw or in overweight/obesity or physical inactivity could not explain the results. In conclusion, a consistent inverse relationship between serum 25‐hydroxyvitamin D levels and colorectal cancer was found. No association was found for breast and prostate cancer.

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

Abstract Objective To study the association between prescribed antipsychotic drugs and outcome in schizophrenia or schizoaffective disorder in the community. Design Prospective cohort study using national central registers. Setting Community care in Finland. Participants Nationwide cohort of 2230 consecutive adults hospitalised in Finland for the first time because of schizophrenia or schizoaffective disorder, January 1995 to December 2001. Main outcome measures 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. Results 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). Conclusions 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.

Nocturia Frequency, Bother, and Quality of Life: How Often Is Too Often? A Population-Based Study in Finland

BACKGROUND Nocturia (ie, waking at night to void) is common and disrupts sleep. Traditionally, one nightly episode has been regarded as clinically meaningless, yet the justification for this belief remains weak. OBJECTIVE To evaluate the association among frequency of nocturia and bother and health-related quality of life (HRQoL). DESIGN, SETTING, AND PARTICIPANTS In 2003-2004, a survey was mailed to a random sample of 6000 subjects aged 18-79 yr who were identified from the Finnish Population Register Centre (response proportion was 62.4%; 53.7% were females). MEASUREMENTS HRQoL and bother from nocturia were examined in relation to self-reported nocturia frequency (using the American Urological Association Symptom Index and the Danish Prostatic Symptom Score). Bother from nocturia was assessed on a four-point scale (none, small, moderate, major). HRQoL was measured with the generic 15D instrument on a 0-1 scale with a minimum clinically important difference of 0.03. RESULTS AND LIMITATIONS Degree of bother increased with nocturia frequency (p<0.01). The most commonly cited degree of bother for those with one, two, and three nightly voids was no bother, small bother, and moderate bother, respectively. The mean age-adjusted 15D score for men (and women) without nocturia was 0.953 (0.950) and 0.925 (0.927) with one void per night, 0.898 (0.890) with two voids per night, and 0.833 (0.840) with three or more voids per night. Statistically significant decreases were found in 15D score and in all 15D dimensions except eating. Although the response rate was high, approximately one third of those contacted did not participate in the study. CONCLUSIONS At least two voids per night is associated with impaired HRQoL. The majority of people report having bother when the number of nocturia episodes is two and moderate or major bother when the number is three or more. One void per night does not identify subjects with interference from nocturia and, thus, is not a suitable criterion for clinically relevant nocturia.

Mortality in schizophrenia: a measurable clinical endpoint

Over the last five years, large data sets on mortality in schizophrenia have been published which have established mortality as a measurable clinical endpoint. Four issues need clarification: whether mortality rates are declining, what the causes of death are, the effects antipsychotic treatments have on mortality and whether these data inform as to how mortality may be reduced in the future. A PubMed search was carried out to identify relevant publications. The search strategy was conducted as a review focusing predominantly on data since 2006. A large number of retrospective epidemiological and prospective studies have been published on mortality rates and causation in schizophrenia, predominantly from 2006—2009. Data suggest that the mortality gap with the general population increased from the 1970s but may have peaked in the mid-1990s. The main causes of mortality are suicide, cancer and cardiovascular disease, with evidence that cancer mortality rates are similar to cardiovascular mortality rates. Mortality causation is dependent upon age of the cohort, length of follow up and type of study. Antipsychotic treatments reduce mortality when compared with no treatment and atypical antipsychotics do not appear to increase cardiovascular mortality and morbidity compared with conventionals; further research is required for any definitive conclusion.

Determinants and Outcomes of Serious Attempted Suicide: A Nationwide Study in Finland, 1996–2003

Suicide is among the 10 leading causes of death. Attempted suicide is 10-40 times more frequent than completed suicide and is the strongest single predictor of subsequent suicide. The current study population included all persons in Finland who were hospitalized with a diagnosis of attempted suicide between 1996 and 2003 (N = 18,199). Information on background variables and mortality was obtained by register linkage. The risk of repeated attempted suicide was 30% and the risk of suicide was 10%. The risks of repeated attempted suicide, completed suicide, and death from any cause were high immediately after discharge from the hospital. Analysis of competing causes of death revealed that while alcohol-related disorder was not associated with suicide, it markedly increased the risk of other violent death: The subdistribution hazards rate (SHR) was 2.61 (95% confidence interval (CI): 2.12, 3.21). Schizophrenia-related disorders (SHR = 1.87, 95% CI: 1.57, 2.21) and mood disorders (SHR = 1.72, 95% CI: 1.47, 2.01) were associated with the risk of suicide. The risks of suicide and all-cause mortality were extremely high immediately after hospitalization for attempted suicide.

Polypharmacy With Antipsychotics, Antidepressants, or Benzodiazepines and Mortality in Schizophrenia

CONTEXT Polypharmacy is widely used in the treatment of schizophrenia, although it is believed to have major adverse effects on the well-being of patients. OBJECTIVE To investigate if the use of benzodiazepines, antidepressants, or multiple concomitant antipsychotics is associated with increased mortality among patients with schizophrenia. DESIGN Registry-based case linkage study. SETTING Academic research. PATIENTS We linked national databases of mortality and medication prescriptions among a complete nationwide cohort of 2588 patients hospitalized in Finland for the first time with a diagnosis of schizophrenia between January 1, 2000, and December 31, 2007. MAIN OUTCOME MEASURES Hazard ratios (HRs) were computed for all-cause mortality during the use of antipsychotics, antidepressants, or benzodiazepines in outpatient care, adjusting for the effects of sociodemographic and clinical variables, geographic location, and current and past pharmacological treatments. RESULTS Compared with antipsychotic monotherapy, concomitant use of 2 or more antipsychotics was not associated with increased mortality (HR, 0.86; 95% CI, 0.51-1.44). Similarly, antidepressant use was not associated with a higher risk for mortality (HR, 0.57; 95% CI, 0.28-1.16) and was associated with markedly decreased suicide deaths (HR, 0.15; 95% CI, 0.03-0.77). However, benzodiazepine use was associated with a substantial increase in mortality (HR, 1.91; 95% CI, 1.13-3.22), and this was attributable to suicidal deaths (HR, 3.83; 95% CI, 1.45-10.12) and to nonsuicidal deaths (HR, 1.60; 95% CI, 0.86-2.97). In total, 826 of 904 patients (91.4%) who used benzodiazepines had purchased prescriptions that contained more than 28 defined daily doses, violating treatment guidelines. CONCLUSIONS Benzodiazepine use was associated with a marked increase in mortality among patients with schizophrenia, whereas the use of an antidepressant or several concomitant antipsychotics was not. Antidepressant use was associated with decreased suicide deaths. The literature indicates that long-term use of benzodiazepines among patients with schizophrenia is more prevalent in other countries (eg, the United States) compared with Finland, which suggests that benzodiazepine use may contribute to mortality among this patient population worldwide.

Incidence of cancer and statin usage—Record linkage study

The consumption of statins (HMG‐CoA reductase inhibitors) has been increasing, and a substantial part of the middle‐aged and elderly population use them continuously. Because a large fraction of the population is exposed, even a small excess of risk with respect to cancer should be considered. We carried out a record‐linkage study in Finland utilizing nationwide databases of reimbursed statin medication and cancer. The study population included all statin users in Finland who had purchased at least 1 prescription between 1996 and 2005 and who had no cancer diagnosis at the date of first purchase. A control population without statin usage was also included. Data consisted of 472,481 pairs of individuals that cumulated 4.2 million person years with an average of 8.8 years of follow‐up. Fifty thousand two hundred ninety‐four cancer cases were observed. Simvastatin and atorvastatin were the most used substances. The most frequent cancers were prostate, breast, lung, colon, and rectum cancer. In general, no association between the utilization of statins and cancer could be detected. In conclusion, this study adds large‐scale, population‐based results about the association between statin utilization and the incidence of cancer. We found neither beneficial nor harmful associations between the usage of statins and cancer.

Incidence and Predictors of Suicide Attempts in DSM-IV Major Depressive Disorder: A Five-Year Prospective Study

OBJECTIVE Prospective long-term studies of risk factors for suicide attempts among patients with major depressive disorder have not investigated the course of illness and state at the time of the act. Therefore, the importance of state factors, particularly time spent in risk states, for overall risk remains unknown. METHOD In the Vantaa Depression Study, a longitudinal 5-year evaluation of psychiatric patients with major depressive disorder, prospective information on 249 patients (92.6%) was available. Time spent in depressive states and the timing of suicide attempts were investigated with life charts. RESULTS During the follow-up assessment period, there were 106 suicide attempts per 1,018 patient-years. The incidence rate per 1,000 patient-years during major depressive episodes was 21-fold (N=332 [95% confidence interval [CI]=258.6-419.2]), and it was fourfold during partial remission (N=62 [95% CI=34.6-92.4]) compared with full remission (N=16 [95% CI=11.2-40.2]). In the Cox proportional hazards model, suicide attempts were predicted by the months spent in a major depressive episode (hazard ratio=7.74 [95% CI=3.40-17.6]) or in partial remission (hazard ratio=4.20 [95% CI=1.71-10.3]), history of suicide attempts (hazard ratio=4.39 [95% CI=1.78-10.8]), age (hazard ratio=0.94 [95% CI=0.91-0.98]), lack of a partner (hazard ratio=2.33 [95% CI=0.97-5.56]), and low perceived social support (hazard ratio=3.57 [95% CI=1.09-11.1]). The adjusted population attributable fraction of the time spent depressed for suicide attempts was 78%. CONCLUSIONS Among patients with major depressive disorder, incidence of suicide attempts varies markedly depending on the level of depression, being highest during major depressive episodes. Although previous attempts and poor social support also indicate risk, the time spent depressed is likely the major factor determining overall long-term risk.

Genetic Determinants of Height Growth Assessed Longitudinally from Infancy to Adulthood in the Northern Finland Birth Cohort 1966

Recent genome-wide association (GWA) studies have identified dozens of common variants associated with adult height. However, it is unknown how these variants influence height growth during childhood. We derived peak height velocity in infancy (PHV1) and puberty (PHV2) and timing of pubertal height growth spurt from parametric growth curves fitted to longitudinal height growth data to test their association with known height variants. The study consisted of N = 3,538 singletons from the prospective Northern Finland Birth Cohort 1966 with genotype data and frequent height measurements (on average 20 measurements per person) from 0–20 years. Twenty-six of the 48 variants tested associated with adult height (p<0.05, adjusted for sex and principal components) in this sample, all in the same direction as in previous GWA scans. Seven SNPs in or near the genes HHIP, DLEU7, UQCC, SF3B4/SV2A, LCORL, and HIST1H1D associated with PHV1 and five SNPs in or near SOCS2, SF3B4/SV2A, C17orf67, CABLES1, and DOT1L with PHV2 (p<0.05). We formally tested variants for interaction with age (infancy versus puberty) and found biologically meaningful evidence for an age-dependent effect for the SNP in SOCS2 (p = 0.0030) and for the SNP in HHIP (p = 0.045). We did not have similar prior evidence for the association between height variants and timing of pubertal height growth spurt as we had for PHVs, and none of the associations were statistically significant after correction for multiple testing. The fact that in this sample, less than half of the variants associated with adult height had a measurable effect on PHV1 or PHV2 is likely to reflect limited power to detect these associations in this dataset. Our study is the first genetic association analysis on longitudinal height growth in a prospective cohort from birth to adulthood and gives grounding for future research on the genetic regulation of human height during different periods of growth.