Kristian Wahlbeck

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).

Outcomes of Nordic mental health systems: life expectancy of patients with mental disorders

BACKGROUND People with mental disorders evince excess mortality due to natural and unnatural deaths. The relative life expectancy of people with mental disorders is a proxy measure of effectiveness of social policy and health service provision. AIMS To evaluate trends in health outcomes of people with serious mental disorders. METHOD We examined nationwide 5-year consecutive cohorts of people admitted to hospital for mental disorders in Denmark, Finland and Sweden in 1987-2006. In each country the risk population was identified from hospital discharge registers and mortality data were retrieved from cause-of-death registers. The main outcome measure was life expectancy at age 15 years. RESULTS People admitted to hospital for a mental disorder had a two- to threefold higher mortality than the general population in all three countries studied. This gap in life expectancy was more pronounced for men than for women. The gap decreased between 1987 and 2006 in these countries, especially for women. The notable exception was Swedish men with mental disorders. In spite of the positive general trend, men with mental disorders still live 20 years less, and women 15 years less, than the general population. CONCLUSIONS During the era of deinstitutionalisation the life expectancy gap for people with mental disorders has somewhat diminished in the three Nordic countries. Our results support further development of the Nordic welfare state model, i.e. tax-funded community-based public services and social protection. Health promotion actions, improved access to healthcare and prevention of suicides and violence are needed to further reduce the life expectancy gap.

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.

Excess mortality, causes of death and life expectancy in 270,770 patients with recent onset of mental disorders in Denmark, Finland and Sweden.

Background Excess mortality among patients with severe mental disorders has not previously been investigated in detail in large complete national populations. Objective To investigate the excess mortality in different diagnostic categories due to suicide and other external causes of death, and due to specific causes in connection with diseases and medical conditions. Methods In longitudinal national psychiatric case registers from Denmark, Finland, and Sweden, a cohort of 270,770 recent-onset patients, who at least once during the period 2000 to 2006 were admitted due to a psychiatric disorder, were followed until death or the end of 2006. They were followed for 912,279 person years, and 28,088 deaths were analyzed. Life expectancy and standardized cause-specific mortality rates were estimated in each diagnostic group in all three countries. Results The life expectancy was generally approximately 15 years shorter for women and 20 years shorter for men, compared to the general population. Mortality due to diseases and medical conditions was increased two- to three-fold, while excess mortality from external causes ranged from three- to 77-fold. Mortality due to diseases and medical conditions was generally lowest in patients with affective disorders and highest in patients with substance abuse and personality disorders, while mortality due to suicide was highest in patients with affective disorders and personality disorders, and mortality due to other external causes was highest in patients with substance abuse. Conclusions These alarming figures call for action in order to prevent the high mortality.

Glutamatergic drugs for schizophrenia: a systematic review and meta-analysis

OBJECTIVE To evaluate the efficacy of glutamatergic drugs, acting agonistically on the N-methyl-D-aspartate (NMDA) or the non-NMDA receptors, in schizophrenia. METHOD All relevant randomized controlled trials of glutamatergic drugs for schizophrenia were obtained from the Cochrane Schizophrenia Groups Register of Trials without any language or year limitations. Trials were classified according to their methodological quality. For binary and continuous data, relative risks and weighted (WMD) or standardized mean differences (SMD) were calculated, respectively. RESULTS Eighteen short-term trials with 343 randomized patients were included in the meta-analysis. In all of these trials, glycine, D-serine, D-cycloserine or ampakine CX516 was used to augment antipsychotics. NMDA receptor co-agonists glycine and D-serine are effective in reducing negative symptoms (N = 132, fixed effect model SMD = -0.66, 95% CI -1.02 to -0.29, p = 0.0004) of schizophrenia, the magnitude of the effect is moderate. D-Cycloserine, a partial agonist of NMDA receptors, is less effective towards negative symptoms (N = 119, fixed effect model SMD = -0.11, 95% CI -0.48 to 0.25, p = 0.6). Positive symptoms fail to respond to glutamatergic medication. Available derived data on cognitive functioning do not indicate a significant effect of glycine or D-serine (N = 80, random effect model WMD = -2.79, 95% CI -6.17 to 0.60, p = 0.11). CONCLUSIONS In the current limited data set, a moderate amelioration of negative symptoms of schizophrenia was found, but no other statistically significant beneficial effects on symptoms of schizophrenia.

The efficacy of lamotrigine in clozapine-resistant schizophrenia: a systematic review and meta-analysis.

BACKGROUND Clozapine is the drug of choice for patients with unsatisfactory response to routine antipsychotic treatment. Polypharmacy is widely used among patients having clozapine-resistant schizophrenia, although no solid evidence exists for any effective augmentation therapy for this patient population. We aimed to study the efficacy of lamotrigine in the treatment of clozapine-resistant schizophrenia. METHOD We conducted electronic searches of the Cochrane PsiTri database, the Website of metaRegister of Controlled Trials, including NIH ClinicalTrials.gov, and a clinical trial register by the manufacturer of lamotrigine (GlaxoSmithKline). All randomized placebo-controlled studies on patients receiving clozapine were included in the analysis. The primary outcome measure was a total score for symptoms of psychosis, and the secondary outcome measures were scores for positive and negative symptoms of psychosis. For continuous and binary data, standardized mean differences (SMD), and odds ratios (OR) and the number needed to treat (NNT) were calculated, respectively. RESULTS Five trials with 10 to 24 weeks duration and total of 161 randomized clozapine patients were included in the meta-analysis. Lamotrigine was superior to placebo augmentation in both the primary outcome measure (SMD 0.57, 95%CI 0.25-0.89, p<0.001; OR 0.19, 95%CI 0.09-0.43, p<0.001; NNT 4, 95%CI 3-6) and secondary outcome measures (SMD 0.34, 95%CI 0.02-0.65 for positive symptoms, SMD 0.43, 95%CI 0.11-0.75 for negative symptoms). CONCLUSIONS This meta-analysis suggests that lamotrigine augmentation may be an effective treatment for patients with clozapine-resistant schizophrenia. A substantial proportion of these most severely ill patients appeared to obtain clinically meaningful benefit from this combination treatment.

Life expectancy and death by diseases of the circulatory system in patients with bipolar disorder or schizophrenia in the Nordic countries.

Objective Excess mortality from diseases and medical conditions (natural death) in persons with psychiatric disorders has been extensively reported. Even in the Nordic countries with well-developed welfare systems, register based studies find evidence of an excess mortality. In recent years, cardiac mortality and death by diseases of the circulatory system has seen a decline in all the Nordic countries, but a recent paper indicates that women and men in Denmark, Finland, and Sweden, who had been hospitalised for a psychotic disorder, had a two to three-fold increased risk of dying from a cardiovascular disease. The aim of this study was to compare the mortality by diseases of the circulatory system among patients with bipolar disorder or schizophrenia in the three Nordic countries Denmark, Sweden, and Finland. Furthermore, the aim was to examine and compare life expectancy among these patients. Cause specific Standardized Mortality Rates (SMRs) were calculated for each specific subgroup of mortality. Life expectancy was calculated using Wiesler’s method. Results The SMR for bipolar disorder for diseases of the circulatory system was approximately 2 in all countries and both sexes. SMR was slightly higher for people with schizophrenia for both genders and in all countries, except for men in Denmark. Overall life expectancy was much lower among persons with bipolar disorder or schizophrenia, with life expectancy being from 11 to 20 years shorter. Conclusion Our data show that persons in the Nordic countries with schizophrenia or bipolar disorder have a substantially reduced life expectancy. An evaluation of the reasons for these increased mortality rates should be prioritized when planning healthcare in the coming years.

Actions to alleviate the mental health impact of the economic crisis.

The current global economic crisis is expected to produce adverse mental health effects that may increase suicide and alcohol-related death rates in affected countries. In nations with greater social safety nets, the health impacts of the economic downturn may be less pronounced. Research indicates that the mental health impact of the economic crisis can be offset by various policy measures. This paper aims to outline how countries can safeguard and support mental health in times of economic downturn. It indicates that good mental health cannot be achieved by the health sector alone. The determinants of mental health often lie outside of the remits of the health system, and all sectors of society have to be involved in the promotion of mental health. Accessible and responsive primary care services support people at risk and can prevent mental health consequences. Any austerity measures imposed on mental health services need to be geared to support the modernization of mental health care provision. Social welfare supports and active labour market programmes aiming at helping people retain or re-gain jobs can counteract the mental health effects of the economic crisis. Family support programmes can also make a difference. Alcohol pricing and restrictions of alcohol availability reduce alcohol harms and save lives. Support to tackle unmanageable debt will also help to reduce the mental health impact of the crisis. While the current economic crisis may have a major impact on mental health and increase mortality due to suicides and alcohol-related disorders, it is also a window of opportunity to reform mental health care and promote a mentally healthy lifestyle.

Community mental-health services and suicide rate in Finland: a nationwide small-area analysis

BACKGROUND In many countries, psychiatric services have been reformed by reducing the size of hospitals and developing community mental-health services. We investigated this reform by assessing the relation between suicide risk and different ways of organising mental-health services. METHODS We did a nationwide comprehensive survey of Finnish adult mental-health service units between Sept 1, 2004, and March 31, 2005. From health-care or social-care officers of 428 municipalities, we asked for information, classified according to the European service mapping schedule, about adult mental-health services. For each municipality, we measured age-adjusted and sex-adjusted suicide risk, pooled between 2000 and 2004, and then adjusted for register-derived socioeconomic factors. FINDINGS A wide variety of outpatient services (relative risk [RR] 0.92, 95% CI 0.87-0.96), prominence of outpatient versus inpatient services (0.93, 0.89-0.97), and 24-h emergency services (0.84, 0.75-0.92) were associated with decreased death rates from suicide. However, after adjustment for socioeconomic factors, only the prominence of outpatient services was associated with low suicide rate (0.94, 0.90-0.98). We replicated this finding even after adjustment for organisational changes and inpatient treatment. INTERPRETATION Well-developed community mental-health services are associated with lower suicide rates than are services oriented towards inpatient treatment provision. These data are consistent with the idea that population mental health can be improved by use of multifaceted, community-based, specialised mental-health services. FUNDING Academy of Finland.

Quality of life and metabolic status in mildly depressed women with type 2 diabetes treated with paroxetine: a single-blind randomised placebo controlled trial.

BackgroundDepression is prevalent in people with type 2 diabetes and affects both glycemic control and overall quality of life. The aim of this trial was to evaluate the effect of the antidepressant paroxetine on metabolic control, quality of life and mental well-being in mildly depressed women with type 2 diabetes.MethodsWe randomised 15 mildly depressed women with non-optimally controlled type 2 diabetes to a 10-week single-blind treatment with either paroxetine 20 mg per day or placebo. Primary efficacy measurements were glycemic control and quality of life. Glycosylated hemoglobin A1c (GHbA1c) was used as a measure of glycemic control. Quality of life was evaluated using RAND-36. Mental state was assessed using two clinician-rated scoring instruments, Hamiltons Anxiety Scale (HAM-A) and Montgomery-Åsbergs Depression Rating Scale (MADRS), and a patient-rated scoring instrument, Becks Depression Inventory (BDI).ResultsAt the end of the study no significant difference between groups in improvement of quality of life was found. A trend towards a superior improvement in glycemic control was found in the paroxetine group (p = 0.08). A superior increase in sex-hormone-binding-globuline (SHBG) levels was evidenced in the paroxetine group (p = 0.01) as a sign of improved insulin sensitivity. There was also a trend for superior efficacy of paroxetine in investigator-rated anxiety and depression. This notion was supported by a trend for superior decrease of serum cortisol levels in the paroxetine group (p = 0.06).ConclusionParoxetine has a beneficial effect on measures of insulin sensitivity and may improve glycemic control. Larger studies of longer duration are needed to verify the benefits of paroxetine in type 2 diabetes. While waiting for more conclusive evidence it seems sensible to augment standard care of type 2 diabetes with paroxetine even in patients who do not fulfil routine psychiatric criteria for initiation of antidepressant drug treatment.