Text version
Randy is a not-entirely-hypothetical 28-year-old with a diagnosis of schizophrenia. His treatment has been complicated by his use of cannabis and alcohol. In this, he is not alone. Approximately 40% of all patients with schizophrenia use significant amounts of cannabis, alcohol, or illicit substances. Multiple motivation strategies have been tried to help move Randy away from the regular use of cannabis and alcohol to no avail. He doesn’t appear to recognize that these substances could be a problem. But his insight is not zero. He takes 3 mg of oral risperidone daily, suggesting that he perceives some direct benefit from it. And perhaps for that reason, despite the near complete collapse of his social world, job, school, and apparently zero functional relationships, he’s not been offered an alternative antipsychotic, such as clozapine. Could switching to clozapine have an impact on his substance use?
Hi! Jim Phelps here for the Psychopharmacology Institute. We might find some insights into that question in this examination of 2 national cohorts from Sweden and Finland totaling 45,000 patients. Actually, I found most of the relevant insights in the article’s introduction. For example, other studies have found that patients with schizophrenia are more likely to remit from alcohol use when using clozapine vs other antipsychotics. But 1 of the citations is the most intriguing. A 2012 study by Dr. Marise Machielsen and her Dutch colleagues looked at 30 patients with a diagnosis of schizophrenia and significant cannabis use compared with 8 patients with that diagnosis but no cannabis use and 20 healthy controls. They found that the cannabis users had notable subjective craving when shown cannabis-related images more than the nonusers and the controls. Well, that’s not too surprising, right? And also perhaps no surprise that, in addition to greater craving, the cannabis users also had greater brain activation in substance use-related regions on functional MRI scans when shown the cannabis images. Those regions include the ventral striatum and amygdala.
But now for the key finding. Dr. Machielsen and colleagues proceeded to randomize the patients, not the controls, to clozapine or risperidone. Yeah, the sample is small, and the trial was open label, but of course, the MRI machine doesn’t require blinding as to what medication the patient is taking. And the question was: Will clozapine dampen the functional MRI signal associated with craving more than risperidone? And why should we care? Well, remember, risperidone and the typical antipsychotics cause a hypodopaminergic state in the mesolimbic cortex. Dr. Machielsen and others have speculated that this iatrogenic hypodopaminergic state could cause craving for substances that increase limbic dopamine, like dopaminergic stimulants but also the THC in cannabis because THC reduces the release of GABA in the striatum, which in turn causes a dopaminergic neuron to release more dopamine. So, you see here, the implication is that D2 blockade with antipsychotics could actually set people up for cannabis use. They’re trying to get back some of the dopaminergic activity that we’re suppressing. From what I could see in these articles that this notion of an iatrogenic contribution to cannabis and craving is mostly speculation. In any case, the implication is that clozapine by working through means other than D2 blockade would not create craving for cannabis that risperidone might. So, let’s see.
In that functional MRI study of patients with a schizophrenia diagnosis and a history of regular cannabis use, remember, the sample of 38 patients was randomized to risperidone or clozapine—actually just the patient part of the sample—and the outcome measure was functional MRI activation of mesolimbic structures when viewing cannabis-related issues. Sure enough, compared with their baseline response, after 4 weeks of treatment, those receiving clozapine showed a larger decrease in amygdala activation than those randomized to risperidone. Well, that’s all background for this new epidemiologic study from Finland and Sweden, which further supports the idea that clozapine offers some protection against the development of a substance use problem in patients with a diagnosis of schizophrenia more than other antipsychotics. However, the notion that D2 blockade might promote craving for dopamine-enhancing substances including cannabis is not unequivocally supported in this study because second to clozapine for the prevention of substance use was antipsychotic polytherapy and long-acting injectables. The latter findings are tangled up in potential confounders more than the clozapine superiority finding.
So, here’s the bottom line. If no other means is found to address Randy’s dual diagnosis of schizophrenia and cannabis and alcohol use, switching his risperidone to clozapine might lead to a better outcome. Of course, clozapine has more severe metabolic problems. But with the advent of the GLP-1 agonists for weight control and weight loss, maybe clozapine’s risk–benefit ratio could radically improve here soon. That’s an issue, including an economic and social justice issue, for another Quick Take.
For more on all this, I’ve obviously skimmed over most of this new epidemiologic study, which is linked here at the Psychopharmacology Institute. You’ll see more of its structure and its main results in its Figure 1.
Abstract
Associations Between Antipsychotic Use, Substance Use, and Relapse Risk in Patients with Schizophrenia: Real-World Evidence From 2 National Cohorts
Markku Lähteenvuo, Jurjen J Luykx, Heidi Taipale, Ellenor Mittendorfer-Rutz, Antti Tanskanen, Albert Batalla, Jari Tiihonen
Background: Research on the effectiveness of pharmacotherapies for schizophrenia and comorbid substance use disorder (SUD) is very sparse, and non-existent on the prevention of the development of SUDs in patients with schizophrenia.
Aims: To compare the real-world effectiveness of antipsychotics in schizophrenia in decreasing risk of developing an initial SUD, and psychiatric hospital admission and SUD-related hospital admission among patients with an SUD.
Method: Two independent national cohorts including all persons diagnosed with schizophrenia (N = 45 476) were followed up for 22 (Finland: 1996-2017) and 11 (Sweden: 2006-2016) years. Risk of developing an SUD was calculated with between-individual models, and risks of psychiatric and SUD-related hospital admission were calculated with within-individual models, using Cox regression and adjusted hazard ratios (aHRs) for using versus not using certain antipsychotics.
Results: For patients with schizophrenia without an SUD, clozapine use (Finland: aHR 0.20, 95% CI 0.16-0.24, P < 0.001; Sweden: aHR 0.35, 95% CI 0.24-0.50, P < 0.001) was associated with lowest risk of developing an initial SUD in both countries. Antipsychotic polytherapy was associated with second lowest risk (aHR 0.54, 95% CI 0.44-0.66) in Sweden, and third lowest risk (aHR 0.47, 95% CI 0.42-0.53) in Finland. Risk of relapse (psychiatric hospital admission and SUD-related hospital admission) were lowest for clozapine, antipsychotic polytherapy and long-acting injectables in both countries. Results were consistent across both countries.
Conclusions: Clozapine and antipsychotic polytherapy are most strongly associated with reduced risk of developing SUDs among patients with schizophrenia, and with lower relapse rates among patients with both diagnoses.
Download PDF and other files
Reference
Lähteenvuo, M., Luykx, J. J., Taipale, H., Mittendorfer-Rutz, E., Tanskanen, A., Batalla, A., & Tiihonen, J. (2022). Associations between antipsychotic use, substance use and relapse risk in patients with schizophrenia: real-world evidence from two national cohorts. The British Journal of Psychiatry, 221(6), 758-765.
Related References
- Machielsen, M. W., Veltman, D. J., van den Brink, W., & de Haan, L. (2018). Comparing the effect of clozapine and risperidone on cue reactivity in male patients with schizophrenia and a cannabis use disorder: A randomized fMRI study. Schizophrenia Research, 194, 32-38.
- Machielsen, M., Beduin, A. S., Dekker, N., Kahn, R. S., Linszen, D. H., van Os, J., … & Myin-Germeys, I. (2012). Differences in craving for cannabis between schizophrenia patients using risperidone, olanzapine or clozapine. Journal of Psychopharmacology, 26(1), 189-195.
