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Schizophrenia, Neurocognitive Dysfunction, and Substance-Related Disorders: A Review

Schizophrenia, Neurocognitive Dysfunction, and Substance-Related Disorders: A Review

Effects of nicotine on neurocognition among individuals with schizophreniaTable 1
Effects of cannabis on neurocognition among individuals with schizophreniaTable 2

Schizophrenia affects approximately 1% of the general population. It is characterized by positive symptoms, such as delusions, hallucinations, and disorganized speech, and negative symptoms, including blunted affect, reduced motivation, and poor social relationships.1 In addition, studies have consistently identified neurocognitive deficits as clinically relevant core features that affect 75% to 85% of schizophrenia patients and that may serve as critical indices of social functioning, treatment strategies, and functional outcomes.2 Neurocognitive dysfunction is observed across several domains, including working memory, attention, executive function, response inhibition, and processing speed.3

Approximately 50% of patients with schizophrenia will have a comorbid lifetime substance use disorder.4 Tobacco and cannabis are the most commonly used substances among these patients.5 The presence of a substance use disorder has been associated with alterations in neurocognitive performance.5,6 While previous studies have found positive effects of nicotine and tobacco smoking on neurocognition in schizophrenia, the effects of cannabis on neurocognitive function in schizophrenia are inconsistent and inconclusive.7,8

The aim of this article is to evaluate the effects of nicotine and cannabis on neurocognitive function in individuals with schizophrenia and to review potential pharmacological treatment strategies.

Nicotine and tobacco

Persons with schizophrenia are more likely to smoke cigarettes and to begin smoking at a younger age, extract more nicotine from each cigarette, have a preference for higher-tar cigarettes, and have reduced smoking cessation rates.9 Hypotheses have been proposed to explain comorbid smoking behaviors in these patients. The self-medication hypothesis suggests that schizophrenia patients smoke, in part, to alleviate negative symptoms, dysphoric mood, and neurocognitive impairments by ameliorating a dysfunctional dopamine system.10 The addiction vulnerability hypothesis suggests that genetic and neurobiological factors associated with schizophrenia (ie, alterations in nicotinic acetylcholine receptors [nAChRs] and central dopamine systems) may predispose schizophrenia patients to nicotine addiction.11

Examining the effects of tobacco smoking on neurocognition in schizophrenia is crucial because it may help clarify the rationale for high consumption of tobacco products and inform treatment interventions. Table 1 summarizes the significant findings on the effects of nicotine on neurocognition in persons with schizophrenia. A recent cross-sectional study by Wing and colleagues6 found smoking history and current smoking status to be associated with neurocognition in schizophrenia. Patients without any history of tobacco smoking performed worse than former and current smokers with schizophrenia on neurocognitive tasks that assess processing speed, attention, and response inhibition.

A study of the effects of prolonged (up to 10 weeks) smoking abstinence on visuospatial working memory in patients with schizophrenia and controls found that the patients had impaired visuospatial working memory.12 Subsequently, a study by Sacco and colleagues7 examined visuospatial working memory under conditions of overnight smoking abstinence. They found that smoking abstinence specifically impaired visuospatial working memory in schizophrenia patients but not in controls. Abstinence-induced neurocognitive deficits were restored following restart of smoking. The effects of restarting smoking were blocked by treatment with the nAChR antagonist mecamylamine, which suggests that these pro-neurocognitive effects were dependent on nAChR stimulation.

On the basis of these studies, there is consensus that cigarette smoking may transiently enhance visuospatial working memory and attention in schizophrenia. Whether these pro-neurocognitive effects extend to other domains has not been studied extensively in the literature. While a few studies of cigarette smoking in patients with schizophrenia have found positive effects on tasks that involve sensory gating, motor speed, processing speed, working memory, and executive function, other studies have demonstrated no significant differences in neurocognitive performance apart from modest improvements on attentional and spatial processing tasks.6,13-15 Interestingly, the studies that reported modest effects used brief, general neurocognitive batteries, which are not as sensitive as more comprehensive batteries.14,15

Comparative analyses across studies may be difficult to interpret because of methodological differences. For instance, while some studies have participants abstain from smoking for 2 hours, other studies have participants refrain from smoking overnight or for up to 7 days.15 This may create discrepancies among samples because individuals with schizophrenia who can maintain abstinence for 7 days may represent a less neurocognitively vulnerable subgroup of patients, even more so than patients who are able to refrain from smoking for shorter periods, also hypothesized to be inherently less susceptible to neurocognitive deficits.6 Furthermore, several studies do not provide comprehensive information concerning confounders and use small samples, lack control groups, and employ cross-sectional designs without consideration of longitudinal outcomes. These limitations should be addressed in future studies to provide a more uniform picture about the effects of tobacco use and neurocognitive function in schizophrenia.

Cannabis (marijuana)

Epidemiological studies indicate high rates of cannabis use disorders among individuals with schizophrenia, with lifetime prevalence of 13% to 64%.16 Evidence from longitudinal studies shows an increased risk of schizophrenia and psychotic symptoms following heavy cannabis use.17 Previous studies have proposed self-medication with cannabis to remedy symptoms of schizophrenia.18 In contrast to these studies, recent data show that cannabis misuse often occurs before the onset of psychosis and that psychotic and affective symptoms worsen after cannabis use.19

Table 2 summarizes the significant findings on the effects of cannabis on neurocognition in persons with schizophrenia. Surprisingly, schizophrenia patients with a comorbid cannabis use disorder demonstrate superior neurocognitive performance compared with non–drug-using patients.20,21 This may be counterintuitive given that cannabis use among nonpsychiatric controls has been consistently shown to have a deteriorating effect on neurocognitive performance and has been associated with poorer prognosis among schizophrenia patients.22-24 Given that neurocognitive dysfunction is a core feature in patients with schizophrenia and the high rates of cannabis use in these patients, a closer look at the association between cannabis use and neurocognition is warranted.


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