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

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.

Two recent meta-analyses have addressed the relationship between cannabis use and neurocognition in schizophrenia. Yücel and colleagues²⁵ published a meta-analysis that focused on the effects of cannabis on neurocognition in patients with established schizophrenia. Our group recently examined the same relationship while controlling for the confounding influence of other substance use disorders. Findings from both meta-analyses show superior neurocognitive performance among cannabis-using patients versus non-using patients.

Schnell and colleagues²⁰ investigated the impact of cannabis use disorders and patterns of consumption on neurocognition in a large sample of schizophrenia patients. The cannabis-using group performed better on tests of verbal and working memory, visuomotor speed (Digit Symbol Test), and executive function. More frequent cannabis use was associated with better performance in attention and working memory tasks. Jockers-Scherübl and colleagues²⁶ evaluated the effects of long-term cannabis consumption on neurocognition in schizophrenia patients and controls. Schizophrenia patients performed significantly better than controls on a test of psychomotor speed, while control cannabis users showed impaired performance. Results were even more pronounced when patients began regular cannabis consumption before the age of 17.

Indeed, patients with comorbid cannabis use disorders may belong to a subgroup of schizophrenia patients with better premorbid adjustment and socialization.²⁷ Drug-seeking individuals may possess essential skills required in communicating with drug dealers and negotiating the subculture required to procure illicit drugs; such traits have been associated with higher neurocognitive capacities among those with schizophrenia.²⁸

Findings from other studies show no significant difference in neurocognitive performance between schizophrenic cannabis users and non-users across various cognitive domains, including decision making, while others report worse performance on tasks assessing verbal learning and memory, executive function, working memory, and semantic fluency among cannabis-using patients.^29,30

While positive effects of cannabis may be unexpected, they should also be interpreted with caution. The majority of studies assessing this relationship employed cross-sectional designs. Longitudinal studies that examine the effects of cannabis on neurocognition in schizophrenia are needed to determine the true effects of cannabis on core symptoms associated with the illness.

Future studies should control for potential confounding variables, such as premorbid IQ and other substance use, especially tobacco, given its modulating role on neurocognitive processes. How investigators define cannabis-using status should also be uniform across studies. Furthermore, the amount of cannabis used should be taken into account, by using indices that capture cumulative consumption, such as joint-years. Thus, both confounding factors and methodological differences between previous studies may be responsible for the discrepant findings across studies.

Treatment strategies

Pharmacotherapies that target the nAChRs, which mediate the reinforcing properties and neurocognitive effects of nicotine in smokers, may have therapeutic effects on neurocogni-tive dysfunction in schizophrenia.^7,12 Several promising nAChR agents, including galantamine (an allosteric modulator of central nAChRs), DMXB-A (α₇-selective agonist), TC-5619 (a selective α₄β₂ nAChR agonist), and varenicline (α₄β₂ partial agonist), have been studied in patients with schizophrenia.^31-34 A recent study by Hong and colleagues³⁵ found that varenicline treatment in stable, medication-compliant schizophrenia patients for 8 weeks (1 mg/d) improved sensory gating, startle reactivity, and executive function. However, there were no significant effects on other neurocognitive domains, such as spatial working memory, sustained attention, and processing speed.

Cannabinoid antagonists or partial agonists have also been suggested to improve neurocognition in patients with schizophrenia given that cannabinoids increase prefrontal norepinephrine, acetylcholine, dopamine, and glutamate levels. Verrico and colleagues³⁶ established that acute administration of a synthetic CB1 receptor agonist selectively decreased medial prefrontal cortical dopamine turnover in rodents. Thus, caution needs to be used because cannabinoid agonism may increase neurocognitive deficits in patients with schizophrenia by exacerbating frontal cortical dopamine, a critical neurotransmitter involved in neurocognitive processes.

Although there are reports of improved attention, processing speed, and executive function with cannabis use in schizophrenia, negative effects on other domains of neurocognition, such as immediate memory, have also been reported.³⁷ Are these probable benefits worth the trade-off for impairments across certain aspects of memory? Coulston and colleagues³⁷ argue that indeed the trade-off may be beneficial because high-order prefrontal brain processes could, in turn, help patients compensate for other neurocognitive shortfalls (eg, memory). Future investigations are required to determine whether specific neurocognitive components are more beneficial to functioning in schizophrenia than other components.

The second most abundant cannabinoid, cannabidiol (CBD) constitutes up to 40% of cannabis extracts.³⁸ Recently, CBD has been deemed as a safe and efficacious treatment option for schizophrenia.³⁸ Comparable to typical neuroleptics and unlike tetrahydrocannabinol (THC), CBD has been found to induce proneurocognitive, anxiolytic, and antipsychotic effects.³⁸ A recent functional MRI study showed that THC and CBD exerted opposite effects on activation in the striatum, hippocampus, amygdala, superior temporal cortex, and occipital cortex.³⁹ The researchers also found that pretreatment with CBD averted the induction of psychotogenic effects typically produced by THC.

Understanding the mechanisms by which nicotine and cannabis influence neurocognition in schizophrenia may help guide future rehabilitation strategies. The best approach may be an integrative one that combines pharmacotherapy with psychosocial interventions (eg, neurocognitive enhancement therapies). The development of novel agents that target neurocognitive dysfunction in substance-dependent schizophrenia patients is an important endeavor, given the clinical importance of tobacco and cannabis use in schizophrenia.

Conclusions

Future research should consider comorbid substance dependence among persons with schizophrenia in order to eliminate confounding variables that distort the association between smoking (eg, nicotine or cannabis) and neurocognitive performance. It is also important to consider whether neurocognition is altered in a general manner or whether specific neuropsychological parameters are affected differently by nicotine and cannabis.

The general consensus on the effects of nicotine on neurocognition in schizophrenia seems to be that nicotine transiently improves spatial working memory and sustained attention. On the other hand, the effects of cannabis on other domains of neurocognition remain unclear. Future studies are required to evaluate the true nature of this relationship.

Clinicians who treat patients with schizophrenia need to be aware of several caveats. While the research suggests opposite effects of nicotine and cannabis on neurocognitive function in patients with schizophrenia, treating comorbid tobacco and cannabis dependence should be a priority, given their negative health effects. In addition, when neurocognitive assessments of patients with schizophrenia are conducted, knowledge of tobacco and cannabis use status is important in interpreting the test results. The findings that constituents of tobacco (nicotine) and cannabis (CBD) may have therapeutic effects on neurocognition in schizophrenia hold promise for the development of novel treatments for cognitive dysfunction in persons with schizophrenia.

Acknowledgments-The preparation of this manuscript was supported in part by grants from the Canadian Institutes of Health Research (MOP#115145), the Ontario Mental Health Foundation, and the Chair in Addiction Psychiatry at the University of Toronto to Dr George.

Disclosures:

Ms Sharif-Razi is a research analyst at the Centre for Addiction and Mental Health (CAMH), Toronto. Ms Rabin is a PhD student at the Institute of Medical Sciences at the University of Toronto. Dr George is Professor of Psychiatry at the University of Toronto and Chief of the Schizophrenia Division at the CAMH. Ms Sharif-Razi and Ms Rabin report no conflicts of interest concerning the subject matter of this article; Dr George reports that in the past 3 years he has been a consultant to Novartis, Bristol-Myers Squibb, and Pfizer, and has had investigator-initiated and industry-sponsored grant support from Pfizer.

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