November 17, 2011 — Heavy methamphetamine use may be associated with an increased risk for schizophrenia, new research suggests.
A large cohort study of California inpatients without a history of psychiatric disorders found that those with methamphetamine-related conditions were 9 times more likely to have a subsequent schizophrenia diagnosis than non–drug users, and an almost 1.5- to 3-fold diagnosis risk compared with heavy users of cocaine and opioids, but not cannabis.
"This provides the first world-wide evidence for a long-standing debate that suggests that methamphetamines may facilitate the development of schizophrenia in a small subset of users," lead author Russell C. Callaghan, PhD, research scientist at the Center for Addiction and Mental Health (CAMH) in Toronto, Canada, told Medscape Medical News.
"Methamphetamine users often present to clinical and emergency department settings with psychosis. And our findings suggest that these people need to be monitored closely for an attenuation of their psychotic symptoms. Also, given the side effects with antipsychotic medications, I think we really need to prescribe those treatments judiciously," said Dr. Callaghan.
He added that the study findings do not apply to patients who take lower and controlled doses of amphetamines for medical purposes, such as for attention-deficit/hyperactivity disorder.
Nora Volkow, MD, director of the National Institute on Drug Abuse, told Medscape Medical News that although the results need to be replicated, they are important clinically.
"As with anything else in science, one study can wake you up and tell you that you need to be alert. Many times things are right in front of your eyes, but if you're not looking for them you don't see them," she said.
"I would hope that this paper would make clinicians much more aware of the possibilities that methamphetamines could increase the vulnerability for schizophrenia."
The study was published online November 8 in the American Journal of Psychiatry.
Link to Parkinson's Disease
As previously reported by Medscape Medical News, the same research team found evidence for a possible association between heavy methamphetamine use and Parkinson's disease.
Although previous studies from Japanese researchers have also suggested a connection between methamphetamine use and "a persistent schizophrenia-like psychosis," most have lacked long-term follow-up.
According to Dr. Callaghan, many North American researchers have discounted this link because they believe the psychosis was already present and undiagnosed in the methamphetamine users.
"So we wanted to examine this issue and compare it between several large groups initially free of persistent psychosis, including those using drugs other than methamphetamines," he said.
The investigators evaluated California hospital records for adult patients admitted between 1990 and 2000 for dependence or abuse of methamphetamines (n = 42,412), cannabis (n = 23,335), alcohol (n = 408,604), cocaine (n = 39,390), or opioids (n = 56,844).
In addition, records from a group of non–drug-using patients with appendicitis were included as a population proxy, "healthy control" comparison group (n = 188,732).
Similar Risk for Cannabis Use
Appendicitis was chosen because "it is a relatively common reason for hospital admissions, is not associated with socioeconomic status, does not appear on theoretical grounds to be related to schizophrenia or substance use disorders, [and] has a well-defined clinical course," explain the researchers.
Readmission records for up to 10 years later for all study participants were then examined for a schizophrenia diagnosis (disorganized, catatonic, paranoid, or residual type), as specified in the International Classification of Diseases, Ninth Revision.
Results showed that the group of heavy methamphetamine users had a significantly higher risk for a schizophrenia diagnosis than did the healthy comparison group (hazard ratio [HR], 9.37; P < .001).
In fact, the risk for schizophrenia was significantly higher for all drug cohorts than for the appendicitis group (P < .001 for all).
The risk was also significantly higher for the methamphetamine group compared with those using opioids (HR, 2.81; P < .001), alcohol (HR, 1.68; P < .001), and cocaine (HR, 1.46; P = .002).
However, there was no significant risk difference between users of methamphetamines and cannabis.
"Our findings add to the growing literature on cannabis as a risk factor for schizophrenia and, in addition, suggest that methamphetamine use sufficient to warrant a hospital diagnosis may also be a risk factor," write the investigators.
They add, however, that they have "some skepticism about the suggestion" that this risk is increased in all major drug use groups and that it will need replication.
"We really do not understand how these drugs might increase schizophrenia risk," co-investigator Stephen Kish, MD, senior scientist and head of the Human Brain Laboratory at CAMH, said in a release.
"Perhaps repeated use of methamphetamine and cannabis in some susceptible individuals can trigger latent schizophrenia by sensitizing the brain to dopamine, a brain chemical thought to be associated with psychosis."
The investigators note that further research is needed, including long-term follow-up studies. Dr. Callaghan reported that his team is now working on extending the current study to Sweden and other states in the United States, and eventually to western Australia, "to see if these patterns can replicate."
"We hope that understanding the mechanism of the drug addiction-schizophrenia relationship will help in the future development of better therapies for both conditions," he said.
"The overall finding was surprising because the field has not really paid attention to these potential issues, although there has been a lot of interest in marijuana use," said Dr. Volkow.
"We've known that methamphetamine use produces psychosis, but it tends to be of short duration and then disappear. This data is showing that that's not necessarily the case and there are some subjects that may go on to have a full-blown diagnosis of schizophrenia."
Dr. Volkow added that this study confirms findings from previous imaging studies, using both animal and human populations, showing that repeated exposure to drugs affects the biochemistry, function, and even structure of the brain.
She also noted that the finding that alcohol use increased the risk for schizophrenia was unusual and unexpected.
"The investigators discuss that they aren't clear why this happened. So it will be interesting to see if it replicates."
Study limitations voiced by the investigators and Dr. Volkow included concerns about the retrospective design and the accuracy of the schizophrenia diagnoses.
"Also, how do you ensure that individuals who started to have a psychotic break, and therefore started using methamphetamines as a way to try and compensate, weren't confounders?"
"It is replication that will really determine whether in fact this is a concern or not. But until then, I think we need to keep our eyes open," concluded Dr. Volkow.
The study was supported indirectly by an institutional grant from the Ontario Ministry of Health and Long-Term Care. Dr. Volkow and 6 of the 8 study authors, including Dr. Callaghan, have disclosed no relevant financial relationships. Dr. Kish reports having received research funding from the National Institute on Drug Abuse and remuneration as an expert witness on amphetamine toxicity. Co-investigator Gary Remington, MD, PhD, reports having received research support from Medicure, Neurocrine Biosciences, and Novartis and serving as an advisor to Roche.
Am J Psychiatry. Published online November 8, 2011. Abstract
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