The link between schizophrenia and substance use disorder: A unifying hypothesis

Abstract

Substance use disorders occur commonly in patients with schizophrenia and dramatically worsen their overall clinical course. While the exact mechanisms contributing to substance use in schizophrenia are not known, a number of theories have been put forward to explain the basis of the co-occurrence of these disorders. We propose here a unifying hypothesis that combines recent evidence from epidemiological and genetic association studies with brain imaging and pre-clinical studies to provide an updated formulation regarding the basis of substance use in patients with schizophrenia. We suggest that the genetic determinants of risk for schizophrenia (especially within neural systems that contribute to the risk for both psychosis and addiction) make patients vulnerable to substance use. Since this vulnerability may arise prior to the appearance of psychotic symptoms, an increased use of substances in adolescence may both enhance the risk for developing a later substance use disorder, and also serve as an additional risk factor for the appearance of psychotic symptoms. Future studies that assess brain circuitry in a prospective longitudinal manner during adolescence prior to the appearance of psychotic symptoms could shed further light on the mechanistic underpinnings of these co-occurring disorders while identifying potential points of intervention for these difficult-to-treat co-occurring disorders.

Genome‐wide association study of cognitive performance in U.S. veterans with schizophrenia or bipolar disorder

“…Rates of substance abuse were similar for SZ and BP patients: 51.2% for lifetime abuse in SZ patients and 50.1% for BP. These estimates are consistent with previous reports (Cerullo & Strakowski, 2007;Khokhar, Dwiel, Henricks, Doucette, & Green, 2018). BP patients with substance abuse had poorer performance on the cognition latent trait (0.17 ± 0.51 vs. 0.21 ± 0.52), while SZ patients with and without substance abuse performed similarly, though worse overall than the BP patients (−0.27 ± 0.60 vs. 0.19 ± 0.51), a finding that will be followed up in detail in later analyses of this dataset.…”

Smoking and the risk for bipolar disorder: causal evidence from a bidirectional Mendelian randomization study

“…Many hypotheses exist to explain the high prevalence of smoking in severe mental illness. 33 The lack of a consistent, bidirectional effect and the causal evidence that smoking initiation liability increases the risk for bipolar disorder point toward the two-hit or diathesis-stress model. 34 This implies a neurobiological vulnerability for severe mental illness 35 interacting with an environmental stressor, such as smoking, leading to an increased vulnerability for severe mental illness.…”

Schizophrenia and drug addiction comorbidity: recent advances in our understanding of behavioural susceptibility and neural mechanisms

“…Due to the similarities between the two-hit hypothesis and the shared susceptibility hypothesis, we will evaluate environmental influences on substance abuse risk as part of the two-hit hypothesis. Clinical evidence mostly falls in favour of the primary addiction hypothesis and the two-hit hypothesis [12]; however, determining cause and effect can often be difficult in clinical samples due to the ethical implications of administering substances which increase psychotic symptoms to individuals with schizophrenia. Preclinical rodent models can thus facilitate our understanding of causative factors for substance abuse and schizophrenia comorbidity.…”

“…Drug abuse causes significant problems for patients by worsening symptoms, limiting treatment compliance, increasing psychotic relapse and hospitalisation, and increasing suicide risk [6][7][8][9][10][11]. Some drugs, such as cannabis and methamphetamine, increase risk for developing psychosis and schizophrenia; however, chronic drug abuse can also develop after disease onset, indicating a complex bidirectional relationship [12]. Several drug classes are abused in schizophrenia, including cannabis, psychostimulants (e.g.…”