Are cannabis use disorders associated with an earlier age at onset of psychosis? A study in first episode schizophrenia
Introduction
Lifetime prevalence of cannabis use disorders (CUD) in schizophrenia ranges from 13% to 64% (Barnes et al., 2006, Barnett et al., 2007, Buhler et al., 2002, Cantwell et al., 1999; Hambrecht and Hafner, 1996, Kovasznay et al., 1997, Linszen et al., 1994, Sevy et al., 2001, Van Mastrigt et al., 2004, Wade et al., 2006a). Several epidemiological studies in Sweden (Allebeck et al., 1993, Andreasson et al., 1987, Andreasson et al., 1989, Zammit et al., 2002), New Zealand (Arseneault, et al., 2002), The Netherlands (van Os, et al., 2002), and Israel (Weiser, et al., 2002) report an increased likelihood of developing schizophrenia in individuals who abuse cannabis. Several studies also suggest that the onset of cannabis use precedes the onset of positive symptoms in most schizophrenia subjects with cannabis use disorders (Allebeck et al., 1993, Buhler et al., 2002, Linszen et al., 1994, Mauri et al., 2006, Rabinowitz et al., 1998a), and the age at onset of psychosis is earlier in cannabis-abusing than non-substance abusing first-episode (Buhler et al., 2002, Green et al., 2004, Van Mastrigt et al., 2004) and multi-episode (Andreasson et al., 1989, Green et al., 2004, Hambrecht and Hafner, 1996, Veen et al., 2004) schizophrenia patients.
Several hypotheses have been put forward to explain an earlier age at onset of schizophrenia in patients abusing cannabis. One hypothesis suggests that cannabis abuse precipitates the onset of schizophrenia in patients at risk for the illness. The neurobiological mechanisms underlying this increased vulnerability to psychosis may be related to increased cannabinoid receptors in the dorsolateral prefrontal cortex (Dean, et al., 2001), and increased release of dopamine in the mesolimbic pathway by Δ9-tetrahydrocannabinol (Tanda, et al., 1997). Dopamine activation in the striatum involves direct interactions between the dopamine D2 receptors and CB1 receptors. Functional interactions between the endogenous cannabinoid anandamide and dopamine suggest a possible participation of the endogenous cannabinoid system in disorders that involve dysregulated dopamine neurotransmission (Giuffrida, et al., 1999). A second hypothesis postulates that cannabis abuse and schizophrenia share common etiologic factors such as genetic vulnerability (Caspi, et al., 2005) or developmental neuropathology (Chambers, et al., 2001). A third hypothesis proposes that the earlier age at onset of psychosis in CUD subjects compared to non-substance users is the result of factors unrelated to schizophrenia such as gender, pre-morbid adjustment, cognition and higher rates of cannabis use in young individuals. Indeed cannabis is the most widely used illicit drug among adolescents and young adults (SAMHSA, 2006). It is used more by males than females, and almost one half of the cannabis users start using it before age 18 (Gfroerer, et al., 2002). Several (Green et al., 2004, Linszen et al., 1994, Rabinowitz et al., 1998a, Veen et al., 2004) but not all (Barnett, et al., 2007) first-episode studies have also reported a higher proportion of males in CUD subjects compared to non-substance abusing subjects. Patients with schizophrenia and substance abuse have better premorbid social adjustments (Arndt et al., 1992, Breakey et al., 1974, Ritzler et al., 1977, Tsuang et al., 1982). Higher functioning patients may be more social and more exposed to opportunities for substance abuse (Arndt, et al., 1992) or more active in trying to cope with some of their symptoms by using substances (Ritzler, et al., 1977). Regarding cognition, earlier age at onset of psychosis has been associated with worse IQ (Woodberry, et al., 2008), attention (Frangou et al., 2008, Oie and Hugdahl, 2008, Thaden et al., 2006), executive function (Gunduz-Bruce et al., 2007, Jeste et al., 1998, Tuulio-Henriksson et al., 2004), psychomotor speed of processing (Hoff et al., 1996, Tuulio-Henriksson et al., 2004, White et al., 2006) and verbal learning and memory (Basso et al., 1997, Tuulio-Henriksson et al., 2004). Additionally, we also measured motor abnormalities which have been reported in drug-free first-episode schizophrenia (Honer et al., 2005, Pappa and Dazzan, 2009, Peralta et al). As spontaneous motor abnormalities increase with age (Fenton, 2000), a younger age at the onset of psychosis and at study entry may be associated with less spontaneous motor abnormalities in the CUD group compared to the non-substance abuse group.
Thus, the purpose of this study is to determine how specific the association between age at onset of psychosis and cannabis use disorders is in patients hospitalized for the first time for an episode of schizophrenia, schizophreniform or schizoaffective disorder (referred to as first-episode patients). Previously, we reported on the correlates of substance use disorders in subjects with first-episode schizophrenia and schizo affective disorder and found higher parental class, better premorbid cognitive functioning, higher IQ and better language skills, but no difference in age at onset of illness in 27 dual-diagnosis patients compared to 91 patients with no substance use disorders (Sevy, et al., 2001). Based on our previous findings and the above hypotheses, the present study focuses on cannabis use disorders and compares first episode schizophrenia subjects who have a lifetime history of cannabis use disorders (CUD) with non-substance abuser first-episode schizophrenia subjects for demographics, pre-morbid childhood adjustment, symptoms, cognition, and abnormal motor movements. By studying first-episode patients we rule out the use of cannabis as self-medication for side effects of antipsychotic medication, limit the exposure to prescribed medications that may influence study variables, and reduce problems of diagnosis, poor memory and inconsistent reporting for the onset of cannabis use and psychotic illness.
Section snippets
Methods
The present study was part of a prospective, randomized study comparing risperidone and olanzapine for the treatment of first episode patients with a diagnosis of schizophrenia, schizophreniform disorder, or schizoaffective disorder. Further details regarding this study were previously described (Robinson, et al., 2006). The study was conducted under the guidelines of the Institutional Review Board (IRB) of the North Shore-Long Island Jewish Health System (New York) and the Bronx Lebanon
Subject sample
Data for this report were collected from November 1998 to July 2004. Subject flow is described elsewhere (Robinson et al., 2006). One hundred and twelve subjects participated in the prospective randomized study comparing risperidone and olanzapine. Forty-nine subjects (44% of the total sample) met DSM-IV criteria for cannabis use disorders (cannabis abuse or dependence) (CUD) either prior to or at the time of study entry. Among the 49 CUD subjects, 36 subjects (74%) began using cannabis more
Discussion
In our sample of 112 first-episode subjects who participated in a randomized study comparing the efficacy and safety of two antipsychotics, lifetime prevalence rates of abuse or dependence were the highest for cannabis (44%), followed by alcohol (22%), and cocaine (4%). The lifetime prevalence rate of cannabis use disorders found in our sample of first-episode subjects is within lifetime prevalence rates (13% to 64%) previously reported in subjects with recent-onset schizophrenia. Our rates of
Role of funding source
Funding for this study was provided by NIH grants K23 DA015541 (SS), MH60004 (DR), MH41960, and RR018535. The NIH had no further role in study design; in the collection, analysis and interpretation of data; in the writing of the report; and in the decision to submit the paper for publication.
Contributors
Dr. Sevy assessed and treated subjects, participated in the statistical analysis, and wrote the first draft of the manuscript. Dr. Robinson wrote the protocol, recruited and assessed subjects, and participated in the statistical analysis. Ms. Napolitano undertook the statistical analysis and wrote part of the Results section. Dr. Patel, Dr. Gunduz-Bruce, Ms. Miller, Ms. McCormack, and Ms. Lorell recruited, assessed, and treated subjects. Dr. Kane participated in the writing of the protocol. All
Conflict of interest
Dr. Robinson has received grant support from Bristol-Meyers Squibb, Eli Lilly, and Janssen Pharmaceutica. He has served as a speaker for Astra Zeneca and Janssen Pharmaceutica. Dr. Kane has served as a consultant or speaker for Astra-Zeneca, Bristol-Myers Squibb, Cephalon, Eli Lilly, GSK, Janssen Pharmaceutica, Johnson and Johnson, Lundbeck, Organon, Otsuka, Pfizer Inc, PgXHealth, Proteus, Vanda, and Wyeth. He is a shareholder of MedAvante. Dr. Sevy, Ms. Napolitano, Dr. Gunduz-Bruce, Dr. Patel,
Acknowledgements
The authors thank Ms. Melissa Naraine who assisted with data collection, Mr. Sui Kwong Li who assisted with the preparation of the manuscript, and Dr. Anil Malhotra for his helpful comments.
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