Abstract
Schizophrenia is a severe psychiatric disorder which is worsened substantially by substance abuse/addiction. Substance abuse affects nearly 50% of individuals with schizophrenia, extends across several drug classes (e.g. nicotine, cannabinoids, ethanol, psychostimulants) and worsens overall functioning of patients. Prominent theories explaining schizophrenia and addiction comorbidity include the primary addiction hypothesis (i.e. schizophrenia susceptibility primes drug reward circuits, increasing drug addiction risk following drug exposure), the two-hit hypothesis (i.e. drug abuse and other genetic and/or environmental risk factors contribute to schizophrenia development) and the self-medication hypothesis (i.e. drug use alleviates schizophrenia symptoms). Animal models can be used to evaluate the utility and validity of these theories. Since this literature was last reviewed by Ng and colleagues in 2013 [Neurosci Biobehav Rev, 37(5)], significant advances have been made to our understanding of schizophrenia and substance abuse comorbidity. Here we review advances in the field since 2013, focussing on two key questions: 1) Does schizophrenia susceptibility increase susceptibility to drug addiction (assessing the primary addiction hypothesis), and 2) Do abused drugs exacerbate or ameliorate schizophrenia symptoms (assessing the two-hit hypothesis and the self-medication hypothesis). We addressed these questions using data from several schizophrenia preclinical models (e.g. genetic, lesion, neurodevelopmental, pharmacological) across drug classes (e.g. nicotine, cannabinoids, ethanol, psychostimulants). We conclude that addiction-like behaviour is present in several preclinical schizophrenia models, and drugs of abuse can exacerbate but also ameliorate schizophrenia-relevant behaviours. These behavioural changes are associated with altered receptor system function (e.g. dopaminergic, glutamatergic, GABAergic) critically implicated in schizophrenia and addiction pathology.
Highlights
IntroductionSchizophrenia is a severe psychiatric illness affecting approximately 1% of the population worldwide [1], and is characterised by a combination of positive symptoms (e.g. delusions, hallucinations, conceptual disorganisation), negative symptoms (e.g. apathy, social withdrawal, emotional blunting) and cognitive impairment (e.g. impaired executive function, working memory and attention) [2]
Schizophrenia is a severe psychiatric illness affecting approximately 1% of the population worldwide [1], and is characterised by a combination of positive symptoms, negative symptoms and cognitive impairment [2]
There has been a vast addition to the preclinical literature investigating schizophrenia and drug abuse comorbidity since 2013, and it is becoming increasingly apparent that drug addiction behaviours and susceptibility to effects of abused drugs exist in many schizophrenia models
Summary
Schizophrenia is a severe psychiatric illness affecting approximately 1% of the population worldwide [1], and is characterised by a combination of positive symptoms (e.g. delusions, hallucinations, conceptual disorganisation), negative symptoms (e.g. apathy, social withdrawal, emotional blunting) and cognitive impairment (e.g. impaired executive function, working memory and attention) [2]. 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; chronic drug abuse can develop after disease onset, indicating a complex bidirectional relationship [12]. Several drug classes are abused in schizophrenia, including cannabis, psychostimulants (e.g. methamphetamine, cocaine), alcohol and nicotine [5]. Despite high rates of substance abuse in schizophrenia and the significant problems it causes, the causes of comorbidity are unclear
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