1. Drug-related predictors of schizophrenia readmission

2. Patients with schizophrenia and Sud have a severe course of illness
Compared to patients with schizophrenia only, patients with comorbid SUD have:
more positive symptoms and increased rates of relapse.
poorer medication compliance, health and self-care in general.
Previous studies have compared users and non-users, primarily regarding cannabis:
Cannabis users have a higher risk of schizophrenia relapse compared to non-users or former users.
We lack information about the role of specific substances from studies comparing substance abuse of different types of substances.
Wade et al (2006) Br J Psychiatry; Margolese et al (2004) Schzophr Res.

3. Drug-induced psychotic symptoms
Positive symptoms in schizophrenia are mediated by enhanced dopamine neurotransmission.
Common to all addictive substances is their ability to increase synaptic dopamine concentrations in the striatum.
A wide range of substances (e.g. cannabis, amphetamine, alcohol, cocaine) have been related to substance-induced psychotic symptoms:
Cannabinoids and amphetamine can induce transient psychotic symptoms in HV and exacerbate psychosis in individuals with a psychotic disorder.
Cocaine use can induce transient psychotic symptoms and behavioral symptoms, and possibly also psychosis.
Howes et al (2012) Arch Gen Psychiatry; Alharbi & el-guebaly (2016) Addict Disord Their Treat; D’souza et al (2009) Eur Arch Psychiatry Clin Neuro; Roncero et al (2014) Subst Abus.

4. Do specific drugs increase risk of schizophrenia readmission?
In summary:
Patients suffering from schizophrenia and SUD have a worse prognosis, including more positive symptoms and increased risk of relapse.
Different types of drugs can induce and exacerbate psychotic symptoms.
Despite this, we have limited knowledge of the role of specific substances in readmission for schizophrenia among individuals suffering from comorbid SUD.
AIM: Examine whether specific drugs increase risk of schizophrenia readmission.

5. A record-linkage study (N=634)
A record-linkage study was used to examine drug-related predictors of readmission to mental health treatment for schizophrenia (F20), using two registers:
The Registry of Drug Abusers Undergoing Treatment.
The Danish Central Psychiatric Research Register.
Cohort consisted of 634 patients with a history of schizophrenia, who were admitted to DUD treatment between 2000 and and tracked in the psychiatric register until 2013.
By looking at patients in DUD treatment we were able to examine effects of a range of substances incl. opioids, cannabis, amphetamine, alcohol, benzos, cocaine, and MDMA.

6. analysis
Outcome: Readmission for schizophrenia i.e. new treatment episode with a primary diagnosis of schizophrenia (F20), including emergency, outpatient, and inpatient settings.
Univariate and multivariate time-to-event regression analyses were used to examine associations, using the Fine and Gray method.
We included a broad range of variables:
Background: Age, Gender, Ethnicity, Living by independent means, Living with children under 25, Single, More than mandatory education, Active, Previous offences.
Psychiatric: Time since last psychiatric contact, Psychiatric inpatient past year, Psychiatric emergency services past year.
Substance: Opioids, Cannabis, Amphetamine, Alcohol, Benzos, Cocaine, MDMA.

7. DRUG-RELATED findings
Readmission for schizophrenia: 79% were readmitted, and 7% died without readmission.
Reported substance use (DUD treatment): opioids (50%), cannabis (45%), amphetamine (21%), alcohol (21%), benzos (18%), cocaine (16%), MDMA (3%).
UNIVARIATE ANALYSIS
Use of amphetamine at baseline was associated with elevated risk of readmission for schizophrenia (p = 0.015).
Being single (p = 0.036), and past year psychiatric emergency room (p < 0.000) and inpatient (p < 0.000) visits were associated with elevated risk of readmission.
Living by independent means (p = 0.008), living with children (p = 0.005) and time since last psychiatric contact (p < 0.000) were associated with lower risk of readmission.
The majority of patients were males (79.8%) and the mean age was 34.7 years.

8. DRUG-RELATED findings
MULTIVARIATE ANALYSIS*
Use of amphetamine (p = 0.014) and cannabis (p = 0.030) at baseline were associated with elevated risk of readmission for schizophrenia.
Past year psychiatric inpatient visit (p < 0.001) was associated with elevated risk of readmission for schizophrenia.
No associations with cocaine, opioids, alcohol, benzos and MDMA in the univariate or multivariate analyses.
*Only variables that were significant in the univariate analysis were subjected to multivariate analysis, except substance use variables which were included irrespectively.
The majority of patients were males (79.8%) and the mean age was 34.7 years.

9. Amphetamine use increases risk: Potential explanations
Our finding is in line with previous studies showing that:
Amphetamine can induce transient psychotic symptoms in HV and exacerbate psychosis in individuals with a psychotic disorder.
Why amphetamine, and not e.g. cocaine? – Due to different mechanisms of action?
Cocaine and amphetamine both work by inhibiting dopamine reuptake.
Amphetamine works through additional mechanisms that elevate presynaptic function, incl. mechanisms facilitating dopamine synthesis and increasing dopamine release.
Meta-analysis of PET-studies concluded: the primary dopaminergic abnormality in schizophrenia is elevated presynaptic function in the striatum, affecting dopamine synthesis capacity, baseline synaptic dopamine levels and dopamine release.
Calipari & Ferris (2013) J Neurosci; Sulzer (2011) Neuron; Howes et al (2012) Arch Gen Psychiatry.

10. Cannabis use increases risk: why is the association less robust?
Our finding is in line with previous studies showing that:
Cannabis use increases risk of relapse in patients with schizophrenia – however, the association is not always robust. Why is the link not stronger?
Importantly, our study, and previous studies, did not measure types of cannabis used:
Accumulating evidence that main cannabinoids, tetrahydrocannabinol (THC) and cannabidiol (CBD), have opposing effects on brain, cognition and behavior.
While THC increases risk of psychosis, CBD has shown antipsychotic effects.
Di Forti et al: daily use of high-potency, but not low-potency, cannabis is associated with a 5-fold risk of psychotic disorder in patients with first-episode psychosis.
Rømer Thomsen et al (2017) Neurosci biobeh rev; Iseger & Bossong (2015) Schizophr Res; Di Forti (2016) Lancet Psychiatry.

11. Thc levels have increased markedly: implications for generalizability
Since 2012 the increase in potency in cannabis resin has been dramatic
Similar development has taken place in
other European countries and in the US.
In Denmark, mean THC levels in cannabis
resin rose from 8% in 1992 to 29% in 2014.
We studied the cohort from 2000 to 2013.
New studies are needed to assess if the THC
increase impacts risk of cannabis use.
Fig 3. Mean THC and CBD content (%)
23% in 2016
THC
10% in 2009
CBD
Dujourdy & Besacier (2017) Forensic sci int.

12. clinical implications
The elevated risk related to amphetamine use indicates the importance of addressing amphetamine use in patients with a known history of schizophrenia.
Despite a less robust association, use of cannabis in this group should call for caution:
Other studies point to causal links between cannabis use and exacerbation of positive symptoms - particularly regarding high-potency cannabis.
The fact that there has been a dramatic increase in potency of street cannabis underscores the need to address use of cannabis in this patient group.
Di Forti et al (2016) Lancet Psychiatry; Rømer Thomsen et al (2017) Neurosci biobeh r; Dujourdy & Besacier (2017) Forensic sci int.

13. The study was done in close Collaboration with: birgitte thylstrup, michael m pedersen, mads uffe pedersen, erik simonsen & morten hesse