Association between alcohol and substance use disorders and all-cause and cause-specific mortality in schizophrenia, bipolar disorder, and unipolar depression: a nationwide, prospective, register-based study (2015)

Background: People with severe mental illness have both increased mortality and are more likely to have a substance use disorder. We assessed the association between mortality and lifetime substance use disorder in patients with schizophrenia, bipolar disorder, or unipolar depression.
Methods: In this prospective, register-based cohort study, we obtained data for all people with schizophrenia, bipolar disorder, or unipolar depression born in Denmark in 1955 or later from linked nationwide registers. We obtained information about treatment for substance use disorders (categorised into treatment for alcohol, cannabis, or hard drug misuse), date of death, primary cause of death, and education level. We calculated hazard ratios (HRs) for all-cause mortality and subhazard ratios (SHRs) for cause-specific mortality associated with substance use disorder of alcohol, cannabis, or hard drugs. We calculated standardised mortality ratios (SMRs) to compare the mortality in the study populations to that of the background population.
Findings: Our population included 41 470 people with schizophrenia, 11 739 people with bipolar disorder, and 88 270 people with depression. In schizophrenia, the SMR in those with lifetime substance use disorder was 8.46 (95% CI 8.14-8.79), compared with 3.63 (3.42-3.83) in those without. The respective SMRs in bipolar disorder were 6.47 (5.87-7.06) and 2.93 (2.56-3.29), and in depression were 6.08 (5.82-6.34) and 1.93 (1.82-2.05). In schizophrenia, all substance use disorders were significantly associated with increased risk of all-cause mortality, both individually (alcohol, HR 1.52 [95% CI 1.40-1.65], p<0.0001; cannabis, 1.24 [1.04-1.48], p=0.0174; hard drugs, 1.78 [1.56-2.04], p<0.0001) and when combined. In bipolar disorder or depression, only substance use disorders of alcohol (bipolar disorder, HR 1.52 [95% CI 1.27-1.81], p<0.0001; depression, 2.01 [1.86-2.18], p<0.0001) or hard drugs (bipolar disorder, 1.89 [1.34-2.66], p=0.0003; depression, 2.27 [1.98-2.60], p<0.0001) increased risk of all-cause mortality individually.
Interpretation: Mortality in people with mental illness is far higher in individuals with substance use disorders than in those without, particularly in people who misuse alcohol and hard drugs. Mortality-reducing interventions should focus on patients with a dual diagnosis and seek to prevent or treat substance use disorders.
Funding: The Lundbeck Foundation.