Psychiatric Comorbidities and Schizophrenia

Peter F. Buckley; Brian J. Miller; Douglas S. Lehrer; David J. Castle


Schizophr Bull. 2009;35(2):383-402. 

In This Article

Substance Abuse Comorbidity

The abuse of alcohol and/or illicit drugs by patients with schizophrenia is a remarkably common phenomenon ..."the rule rather than the exception.[10,191] In the ECA study, it was estimated that 47% of patients with schizophrenia also had a lifetime diagnosis of substance abuse disorder.[191] This is consistent with findings from a variety of other epidemiological and clinical studies, both in the United States and worldwide.[10,191,192,193,194] In general terms, substance abuse comorbidity is associated with a variety of negative consequences for the course of schizophrenia (see Table 5 ), with medication nonadherence often appearing as a "final common pathway" for these effects. Description of the epidemiology and consequences of substance abuse and schizophrenia is beyond the scope of this article and is accounted well elsewhere.[8] Suffice it to say that substance abuse comorbidity is common and is deleterious to the course and outcome of schizophrenia. The investigation of this co-occurrence has been (perhaps to a greater extent than the other comorbidities) hampered by a general effort to exclude patients with comorbid substance abuse when studying schizophrenia. Thus, sampling bias is an important consideration in evaluating this association.

Explanations for the common association of substance abuse with schizophrenia are highlighted. Firstly, one might consider this merely a chance co-occurrence, particularly because adolescents and young adults abuse drugs. Why should adolescents/young adults with schizophrenia be any less likely to do this? Epidemiological data and clinical experience suggest that this is not merely a "chance occurrence" and that it is frequent and beyond mere coincidence.[191,192,193] Furthermore, it seems that both patterns of use and motivations for use are very similar in individuals with schizophrenia, as in the nonschizophrenia population.

The second notion is that alcohol or drugs actually caused schizophrenia and that this explains the co-occurrence. Heavy and protracted abuse of alcohol has been causally associated with a discrete alcoholic hallucinosis, but this is relatively rare and the longitudinal course is usually not the same as schizophrenia, such that, eg, affect and personality are relatively preserved. Any strong causal association between alcohol and schizophrenia per se is difficult to envisage given the ubiquity of alcohol use and the fact that the vast majority of people who do use alcohol to excess do not develop schizophrenia. The evidence for illicit drugs being causally associated with schizophrenia is at best mixed but has been most compelling argued for cannabis. A number of cohort studies have now established a temporal relationship between cannabis exposure in adolescence or early adulthood, and later schizophrenia, with an odds ratio of just over 2.0 (2.09, with confidence intervals of 1.54-2.84) in a recent metaanalysis of these studies.[195] Additionally, some studies show a "dose-dependent" effect, such the more cannabis consumed the greater the likelihood of schizophrenia.[196] However, again the prevalence of schizophrenia is disproportionate to the ubiquitous smoking of cannabis, there is no clear association between rates of schizophrenia and rates of cannabis use in any given population, and most people who imbibe cannabis do not develop schizophrenia. Thus, it seems that cannabis can be conceptualized as a cumulative causal factor in some individuals, acting in concert with other vulnerability factors to promote the manifestation of the illness in some individuals who might otherwise have remained schizophrenia free. The effect is small, with a population attributable fraction of 5%-7%. Also, it does not appear that patients with schizophrenia and comorbid cannabis have any higher genetic loading for schizophrenia than patients with schizophrenia alone.[197]

Caton et al[198] examined the relationship between substance-induced psychosis and schizophrenia by longitudinally evaluating patients who presented acutely psychotic, all of whom had abused drugs or alcohol prior to this first ever presentation with psychosis. Forty-four percent of patients turned out over time to have had a drug-induced psychosis, while 56% of patients ultimately had schizophrenia as their primary diagnosis. Patients with a drug-related psychosis had marginally less positive and negative symptoms at initial presentation, they were more likely to have visual hallucinations, and their parents had a history of substance abuse. Caspi et al[11] examined this issue from a different, complementary perspective. As part of a large epidemiological study of schizophrenia in New Zealand, they found that those adolescents who possessed the "faulty" allele (val 158 met) polymorphism of the COMT (cathechol -O-methyl-transferase) gene were the people who had the vulnerability to cannabis abuse. This might help explain this association, which appears robust from epidemiological data but is still a small effect. There is a recent study of brain imaging in nonpsychotic cannabis abusers that shows progressive brain changes with heavy and chronic cannabis abuse.[199] The authors report some association between paranoid experiences in a subset of these patients and greater prominence of hippocampal changes. As a general observation, there have been few biological studies of this dual diagnosis patient population because substance abuse is more often than not an exclusionary criterion. On the other hand, there is a growing appreciation of potentially shared neurochemical vulnerability between substance abuse and schizophrenia.[200] Animal neurochemical and now human brain imaging studies point to the role of dopamine in the amygdala as being key to understanding drug craving and reward behaviors. In schizophrenia, pleasure and reward are blunted as part of negative symptoms. It is plausible that dopamine dysregulation might predispose patients with schizophrenia to abuse drugs.[194,200] It has also been explained that patients with schizophrenia who abuse drugs may actually have milder symptoms and that their poorer course is more attributable to the direct effect of drugs on worsening symptoms as well as the associated medication nonadherence. This is certainly intuitive in the sense that patients with more severe illness are less likely to have the opportunity and social context to acquire street drugs. It has also long been suggested that patients self medicate either to reduce their symptoms or to counteract the effects of antipsychotic medications.[201,202] Either association is plausible and in accord with clinical experience. However, the rate of substance abuse comorbidity has not seemed to diminish in an era of treatment with SGAs that have less motor and secondary negative symptom effects.[203] Regarding treatment of patients with substance abuse, these patients show similar responses to antipsychotic medications as nonabusing patients with schizophrenia -- once they take their medication, a major challenge in this patient group.[20,204] In the clinical antipsychotic trials of intervention effectiveness (CATIE) study, patients with comorbid substance abuse showed comparable responses with each SGA than patients without substance abuse.[205] There is some evidence that dual diagnosis patients might do better on clozapine, with less relapse into abuse of drugs or alcohol.[206]

Overall, while substance abuse comorbidity is remarkably common in schizophrenia, the evidence is lacking that this represents some distinct subgroup of etiopathological significance. While explanations toward a shared neurochemical, dopamine-mediated vulnerability to both schizophrenia and substance abuse are intuitively appealing, at present the evidence base is scant.[194] Moreover, the prevailing view in both the addiction field and in schizophrenia research is that this represents a co-occurrence of 2 conditions rather than some etiologically distinct subgroup of schizophrenia patients who are characterized by a proclivity to substance abuse.


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