Causes and predictors of premature death in first‐episode schizophrenia spectrum disorders
Authors: Ingrid Melle, Jan Olav Johannesen, Ulrik H. Haahr, Wenche ten Velden Hegelstad, Inge Joa, Johannes Langeveld, Tor K. Larsen, Stein Ilner Opjordsmoen, Ping Qin, Jan Ivar Røssberg, Bjørn Rishovd Rund, Erik Simonsen, Per J.W. Vaglum, Thomas H. McGlashan, Svein Friis
Journal: World Psychiatry (2017)

As highlighted by the Forum in the February 2017 issue of this journal1, patients with schizophrenia spectrum disorders have significantly higher risk of premature death due to suicide and physical illness; their expected reduction in life expectancy is 10-20 years2-4. Since the disorders affect 2-3% of the population, with peak onsets in early adulthood, their impact on public health is considerable5. We report findings from a 10-year prospective study of 281 patients with DSM-IV schizophrenia spectrum disorders recruited consecutively at first treatment in four Nordic catchment areas over four years. They were assessed during their first week of treatment, with follow-ups after one, two, five and ten years6, 7. Data were linked to the central registries of persons and causes of death at Statistics Norway and Statistics Denmark. Information about two- and ten-year average age-specific mortalities was used to compute cause-specific expected numbers of deaths. Crude standardized mortality ratios (SMRs) were calculated as observed deaths/expected deaths. Thirty-one participants (11%) were dead at follow-up (SMR 11.56; 95% CI: 7.86-16.42). Sixteen (6%) died by suicide (SMR 46.50, 95% CI: 26.58-75.51); seven (2.5%) by accidental overdoses or other accidents, and eight (2.8%) from physical illnesses, including three (1%) from cardiovascular illness. Time to death was significantly shorter in those who committed suicide compared to the two other groups (mean 1,274 ± 1,032 days vs. 2,706 ± 1,046 days for accidents and 3,000 ± 792 days for natural deaths, p<0.001). Six (37.5%) of those who died by suicide did so within the first two years (two-year SMR estimate 81.91, 95% CI: 30.05-178.28). Only one accident and no natural deaths occurred in this period. All-cause mortality was higher for men than for women. Univariate analyses showed that those alive at the ten-year follow-up were significantly older at baseline compared to those who died by suicide, and significantly younger than those who died from other reasons. Those alive had significantly shorter duration of untreated psychosis (DUP), lower baseline rates of drug and alcohol misuse, longer education and higher employment than those with all-cause deaths. There were no significant associations with baseline clinical symptoms or lifetime/current measures of depression/suicidal behaviors and no significant between-group differences in time to first remission or time being psychotic or in treatment during the first two years (including length/dosage of antipsychotic medication and number/length of hospital admissions). Measures of depression and suicidal behavior at last follow-up were, however, significantly higher in those who died by suicide. A multinomial logistic regression analysis indicated significant influences of lower age, longer DUP and baseline alcohol misuse on increasing risk of death by suicide; and of higher age, longer DUP and baseline drug misuse on increasing risk of death from other reasons. Kaplan-Meyer survival analyses showed that long DUP and baseline substance misuse (alcohol + drugs) were significantly increasing risk of all-cause mortality (Mantel-Cox χ2 (3)=36.98, p<0.001), with a significant contribution of substance misuse also after removing overdose deaths. Our results confirm previous findings of high mortality rates in patients with schizophrenia spectrum disorders. We clearly demonstrate for the first time that long DUP is a significant risk factor for all-cause mortality, including suicides, accidents and physical illnesses. Long DUP can in this context best be seen as a marker of problematic help-seeking behaviors, in line with recent register studies reporting that patients with schizophrenia dying from physical illnesses enter treatment late8. That substance use diagnoses increase risk of premature death in patients with severe mental disorders has been demonstrated previously9. We here show that also substance use below the diagnostic threshold for use disorders is a risk factor. The strong association between baseline substance misuse and all-cause mortality is striking. This can be based in shared underlying risk factors for suicide, including impulsivity, emotion regulation difficulties and interpersonal problems. The effects of substances during intoxication can also increase impulsive behavior and lack of self-care, adding to risks for accidents or physical illnesses. The two-year SMR estimate for suicide was >80. Previous studies have shown a particularly high suicide risk before or during the first months of treatment10. Our participants were recruited through an early treatment and intervention study and thus very early compared to studies recruiting at discharge from first inpatient treatment or later. The findings can thus be seen as an illustration of the particularly high risk for suicide at this early stage, and underline that mortality estimates based on multi-episode patient samples significantly underestimate the suicide risk in schizophrenia spectrum patients. The number of deaths from cardiovascular disorders was low. The participants were, however, still in their late thirties and not yet into the main cardiovascular risk period. In conclusion, we found a high mortality rate during the first ten years of treatment, with the risk of dying by suicide being particularly high during the first two years. Long DUP and substance misuse at baseline were significant predictors of all-causes mortality. This is of clinical importance, since help-seeking behaviors and substance use can be responsive to interventions. Ingrid Melle1, Jan Olav Johannesen2,3, Ulrik H. Haahr4,5, Wenche ten Velden Hegelstad2, Inge Joa2,3, Johannes Langeveld2, Tor K. Larsen2,6, Stein Ilner Opjordsmoen7,8, Ping Qin9, Jan Ivar Røssberg7,8, Bjørn Rishovd Rund10,11, Erik Simonsen5,12, Per J.W. Vaglum13, Thomas H. McGlashan14, Svein Friis7,8 1NORMENT K.G. Jebsen Centre for Psychosis Research, Institute of Clinical Medicine, University of Oslo and Oslo University Hospital, Oslo, Norway; 2Division of Psychiatry, Stavanger University Hospital, Stavanger, Norway; 3Faculty of Social Sciences, University of Stavanger, Stavanger, Norway; 4Early Psychosis Intervention Center, Roskilde, Denmark; 5Institute of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark; 6Department of Clinical Medicine, University of Bergen, Bergen, Norway; 7Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway; 8Division of Mental Health and Addiction, Institute of Clinical Medicine, University of Oslo, Oslo, Norway; 9National Center for Suicide Research and Prevention, Institute of Clinical Medicine, University of Oslo, Oslo, Norway; 10Department of Psychology, University of Oslo, Oslo, Norway; 11Vestre Viken Hospital Trust, Drammen, Norway; 12Institute of Clinical Medicine, University of Copenhagen, Roskilde, Denmark; 13Department of Behavioural Sciences in Medicine, University of Oslo, Oslo, Norway; 14Department of Social and Behavioral Health, Yale School of Medicine, New Haven, CT, USA The study has been supported by grants from the Research Council of Norway; the Norwegian Department of Health and Social Affairs; the National Council for Mental Health/Health and Rehabilitation; Rogaland County; Oslo County; the Theodore and Vada Stanley Foundation; the Regional Health Research Foundation for Eastern Region, Denmark; Roskilde County; Lundbeck Pharma, Eli Lilly, and Janssen-Cilag Pharmaceuticals, Denmark; the National Alliance for Research on Schizophrenia and Depression; the US National Institute of Mental Health; the Regional Health Authority in Western Norway; and the Regional Health Authority in South-Eastern Norway.