Marijuana use in the immediate 5-year premorbid period is associated with increased risk of onset of schizophrenia and related psychotic disorders

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Abstract

Objectives

Several studies suggest that adolescent marijuana use predicts earlier age at onset of schizophrenia, which is a crucial prognostic indicator. Yet, many investigations have not adequately established a clear temporal relationship between the use and onset.

Methods

We enrolled 247 first-episode psychosis patients from six psychiatric units and collected data on lifetime marijuana/alcohol/tobacco use, and ages at onset of prodrome and psychosis in 210 of these patients. Cox regression (survival analysis) was employed to quantify hazard ratios (HRs) for effects of diverse premorbid use variables on psychosis onset.

Results

Escalation of premorbid use in the 5 years prior to onset was highly predictive of an increased risk for onset (e.g., increasing from no use to daily use, HR = 3.6, p < 0.0005). Through the analysis of time-specific measures, we determined that daily use approximately doubled the rate of onset (HR = 2.2, p < 0.0005), even after controlling for simultaneous alcohol/tobacco use. Building on previous studies, we were able to determine that cumulative marijuana exposure was associated with an increased rate of onset of psychosis (p = 0.007), independent of gender and family history, and this is possibly the reason for age at initiation of marijuana use also being associated with rate of onset in this cohort.

Conclusions

These data provide evidence of a clear temporal relationship between escalations in use in the five years pre-onset and an increased rate of onset, demonstrate that the strength of the association is similar pre- and post-onset of prodromal symptoms, and determine that early adult use may be just as important as adolescent use in these associations.

Introduction

Recent evidence shows a link between marijuana use and psychotic disorders, and this association has remained significant when controlling for other substance use (van Os et al., 2002, Zammit et al., 2002, Barnes et al., 2006, Gonzalez-Pinto et al., 2008). Subsequent reports have thus tried to determine the origins of this link; specifically, whether there is merely shared etiology or a possible causal relationship. One key piece of evidence for causation would be a temporal relationship between the initiation of substance use and the onset the disorder. A number of studies have shown that marijuana use often predates onset of psychotic disorders, providing some evidence of a possible causal link (Allebeck et al., 1993, Arseneault et al., 2002, Buhler et al., 2002, Zammit et al., 2002, Semple et al., 2005, Mauri et al., 2006). However, these analyses have only been able to demonstrate broadly defined temporal links, and most studies have not specifically targeted premorbid use as a predictor.

To further refine evidence of the causal hypothesis, later empirical efforts focused specifically on the link between marijuana use and age at onset of psychosis (Van Mastrigt et al., 2004, Veen et al., 2004, Barnes et al., 2006, Gonzalez-Pinto et al., 2008, Compton et al., 2009b, Sevy et al., 2010, Large et al., 2011), rather than a diagnosis of a psychotic disorder. However, these studies present methodological challenges, such as varying definitions of onset. While some have used age at initiation of treatment (Fergusson et al., 2005, Di Forti et al., 2014), others have used personal histories to determine the age at first psychotic symptom. Given that there are typically highly variable durations of treatment delays, using age at first treatment may not offer the best evidence of a causal link.

A possible causal association would also be supported if there were a dose–response relationship. However, most studies of substance use (Hambrecht and Hafner, 1996, Rabinowitz et al., 1998, Van Mastrigt et al., 2004), and marijuana use in particular (Buhler et al., 2002, Green et al., 2004, Barnes et al., 2006), were comparisons of those meeting abuse/dependence criteria (current or lifetime) with a suitable control group, or comparisons of users at any level to nonusers (Arseneault et al., 2002, Zammit et al., 2002, Veen et al., 2004, Moore et al., 2007, Di Forti et al., 2014). Only a few investigations have been able to assess frequency/amount of use or change in use over time, and these were limited to broad use level categories. Even so, there has been evidence that more frequent use is associated with an increased risk of psychosis (van Os et al., 2002, Zammit et al., 2002, Fergusson et al., 2005), as well as earlier onset of psychosis (Gonzalez-Pinto et al., 2008). In addition, it has been shown that faster progression to high levels of use is also associated with increased risk of psychosis (Boydell et al., 2006) and earlier onset (Compton et al., 2009b). Age of initiation of marijuana use is also associated with age at onset of psychosis (Arseneault et al., 2002, Leeson et al., 2012, Stefanis et al., 2013, Di Forti et al., 2014) indicating a possible cumulative dose effect. The resulting interpretations of these data could be confirmed through the use of more detailed retrospective information.

Additionally, there is often a prodromal period during which evidence of an emerging disorder is present, though not yet clinically manifest. Marijuana use during that period would also be of interest when trying to determine any possible links to development of the full disorder. A few studies have shown that marijuana use was also a predictor of onset of psychiatric symptoms (the prodrome), as well as onset of psychosis (Compton et al., 2009b, Leeson et al., 2012). However, onset of the prodrome is coincident with onset of psychosis for some patients, either due to actual illness course or possible measurement error. Thus, a more comprehensive assessment of the effects on onset of prodromal symptoms would be to evaluate its role as a possible moderator of the relationship between use and risk of onset.

The current study was designed specifically to address these issues by providing a thorough retrospective assessment of premorbid marijuana use, from age 12 until psychosis onset, in a well-defined and extensively characterized sample of first-episode patients. This allowed us to focus on quantitative amounts of use in the time immediately preceding psychosis onset in order to establish a more clearly defined temporal link, while simultaneously examining dose-related effects. These data also gave the unique opportunity to test for the effects of use at specific time periods in order to clarify key outstanding questions in the literature. While this is the most comprehensive dataset to date to test these effects, we acknowledge that any retrospective assessment is subject to recall error or bias, and thus the demonstrated relationships should be interpreted with that caveat in mind.

Section snippets

Settings and subjects

Consecutively admitted patients with first-episode psychosis were approached for study participation. N = 247 were enrolled from August 2008 to June 2013 from three inpatient psychiatric units in Atlanta, Georgia and three in Washington, D.C. Eligible patients were 18–40 years of age, English-speaking, and able to give informed consent. Exclusion criteria included known or suspected mental retardation, a Mini-Mental State Examination (Folstein et al., 1975, Cockrell and Folstein, 1988) score of < 

Descriptive associations with use variables

As expected, males exhibited a significantly higher prevalence of use of all substances, including marijuana (91% vs 65%), alcohol (89% vs 69%), and tobacco (82% vs 55%). In contrast, having a family history of psychosis was associated with a lesser prevalence of marijuana use (69% vs 88%), but was not associated with either alcohol or tobacco use. Total, cumulative amount of lifetime premorbid use (“dosage”) showed a similar pattern to binarized use, in that males had a higher dosage and those

Discussion

Our current data allowed us to determine the effects of premorbid marijuana use and changes in use in the five years preceding psychosis onset. These data indicate that it is the escalation of use that is the most predictive, with greater increases in use increasing the rate of onset in a dose–response manner. Secondly, the data suggests that any increase in use during the pre-onset period increases the rate of onset, and that this may be more important than the level of use alone. This is

Role of the funding source

This work was supported by grant R01 MH081011 from the National Institute of Mental Health to the last author. The funding source had no role in data analyses, the writing of the manuscript, or the decision to submit it for publication.

Contributors

All authors contributed to the conceptualization and writing of this article, and all approved the final version for publication.

Conflicts of interest

The authors know of no conflicts of interest pertaining to this research.

Acknowledgments

Research reported in this publication was supported by the National Institute of Mental Health grant R01 MH081011 (“First-Episode Psychosis and Pre-Onset Cannabis Use”) to the last author. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health or National Institute of Mental Health. The authors report no financial relationships with commercial interests.

The authors thank the staff and patients of Grady

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