Incidence, diagnostic stability and survival analysis of ...



Risk of transition to schizophrenia following first admission with substance-induced psychotic disorder: a population-based longitudinal cohort study

Helen L Alderson1*, David M Semple2, Chanpreet Blayney3, Filippo Queirazza4, Venkat Chekuri2, Stephen M Lawrie5

1. Queen Margaret Hospital, Whitefield Road, Dunfermline, Fife, KY12 0SU

2. Hairmyres Hospital, Eaglesham Road, East Kilbride, Glasgow, G75 8RG

3. Gartnavel Royal Hospital, 1055 Great Western Road, Glasgow, G12 0XH

4. Institute of Neuroscience and Psychology, 58 Hillhead Street, University of Glasgow, G12 8QW

5. University of Edinburgh, Department of Psychiatry, Royal Edinburgh Hospital, Edinburgh EH10 5HF

 

* Corresponding author:

Helen L Alderson

Department of Psychiatry, Phase 1, Queen Margaret Hospital, Whitefield Road, Dunfermline, Fife, UK, KY12 0SU

Email: h.alderson@

FINANCIAL SUPPORT

This research received no specific grant from any funding agency, commercial or not-for-profit sectors.

CONFLICT OF INTEREST

SML has received personal fees from Forum and Janssen and Sunovion, grants and personal fees from Roche, and a grant from Abbvie,  outside the submitted work. None of the other authors declared any conflicts of interest.

WORD COUNT 3643

BACKGROUND The potential for drugs of abuse to induce acute psychotic symptoms is well recognised. However, the likelihood of transition from initial substance-induced psychotic disorder (SIPD) to chronic psychosis is much less well understood. This study investigated the rate of SIPD transition to schizophrenia (F20), the time to conversion, and other possible related factors.

METHODS Using data from the Scottish Morbidity Record, we examined all patients (n=3486) since their first admission to psychiatric hospital with a diagnosis of SIPD (ICD-10 codes F10-F19, with third digit five) from January 1997 to July 2012. Patients were followed until first episode of schizophrenia (ICD-10 code F20, with any third digit) or July 2012. Any change in diagnosis was noted in the follow-up period, which ranged from one day to 15.5 years across the groups.

RESULTS The 15.5 year cumulative hazard rate was 17.3% (SE=0.007) for a diagnosis of schizophrenia. Cannabis, stimulant, opiate and multiple drug induced psychotic disorder were all associated with similar hazard rates. The mean time to transition to a diagnosis of schizophrenia was around 13 years, although over 50% did so within two years and over 80% of cases presented within five years of SIPD diagnosis. Risk factors included male gender, younger age, and longer first admission.

CONCLUSIONS SIPD episodes requiring hospital admission for more than two weeks are more likely to be associated with later diagnosis of schizophrenia. Follow-up periods of more than two years are needed to detect the majority of those individuals who will ultimately develop schizophrenia.

INTRODUCTION

The potential for drugs of abuse to induce psychosis is well known, with extensive evidence that acute psychotic symptoms can be induced by alcohol, amphetamines, LSD, phencyclidine and ketamine, as well as by synthetic novel psychoactive substances (Glass 1989; Paparelli et al 2011; Zawilska & Wojcieszak 2013). There is also evidence that regular use of psychoactive substances is associated with the development of schizophrenia in vulnerable individuals, with the strongest evidence for an association with cannabis use (Semple et al 2005; Callaghan et al 2012 ).

For many users, substance-induced psychotic symptoms resolve completely with abstinence, and this is defined in ICD-10 as a psychotic disorder due to a specified psychoactive substance or substance-induced psychotic disorder (SIPD) (World Health Organization, 1992). However, recent studies suggest that some patients who experience SIPD subsequently develop schizophrenia at a higher rate than would be expected. The strongest evidence is for transition to chronic psychosis following cannabis-, amphetamine- or alcohol-induced psychosis (Thirthalli & Benegal 2006), with estimates of between 25% and 50% converting (Arendt et al 2005; Caton et al 2007; Crebbin et al 2009; Kittirattanapaiboon et al 2010). It has also been reported that a previous history of stimulant or cannabis-related disorders is associated with increased likelihood of later diagnosis of schizophrenia following first admission with a brief psychotic episode (Sara et al 2014a; 2014b). Despite this, there have been few studies to date examining long term clinical outcomes at a population level following acute SIPD and comparing a range of drugs of abuse. One large register-based study from Finland (Niemi-Pynttari et al 2013) found the cumulative risk of conversion from SIPD to schizophrenia spectrum disorders to be 46%, 30%, and 5% for cannabis-, amphetamine, and alcohol-induced psychoses respectively, with the majority converting within three years.

An important question is whether patients who experience SIPD may constitute a clinically high risk group for schizophrenia (Fusar-Poli et al 2012). Evidence of a link would enable clinicians and patients to understand the risk of developing schizophrenia following an episode of SIPD, and to have an understanding of the length of follow up required to pick up as many as possible of those who go on to develop schizophrenia.

The current study sought to address these questions by analysing readmission patterns of all patients who had a first admission to a Scottish psychiatric hospital with a diagnosis of SIPD from 1st January 1997 to 31st July 2012. We aimed to establish the transition rate and mean time to transition to a diagnosis of schizophrenia from hospital admission with a new diagnosis of SIPD. We also aimed to establish whether any demographic (age at first presentation; gender) or clinical (substance attributed to psychotic episode; length of first admission) variables were significantly associated with a subsequent diagnosis of schizophrenia.

METHODS

Sample characteristics and inclusion criteria

The Information Services Division (ISD), a division of National Services Scotland, collects mental health activity data nationally from information routinely drawn from hospital administrative systems across NHS Scotland. The principal data source is the Scottish Morbidity Record Four (SMR04) return (), which contains information on all admissions to and discharges from NHS mental health hospitals and psychiatric in-patient units within general hospitals in Scotland. Diagnosis is coded by International Classification of Diseases, Tenth Revision (ICD-10) codes (World Health Organization 1992), which were first introduced in the SMR04 dataset in 1997. Anonymization of the national databases and adherence to a Statistical Disclosure Control Protocol () based on the guidance released by the UK Office of National Statistics ensure protection of any personally identifiable information.

In order to obtain an incidence cohort, we initially selected all “first admission” cases, that is, patients who had not previously received psychiatric inpatient care, hospitalised between 1st January 1997 and 31st July 2012. We selected all cases with a main diagnosis of SIPD on discharge recorded by ICD-10 codes F10.5, F11.5, F12.5, F13.5, F14.5, F15.5, F16.5, F17.5, F18.5, and F19.5. Age was defined as age at admission. We then retrieved all of each patient’s subsequent admissions to hospitals in Scotland over the follow-up period, which was until a patient’s first episode of schizophrenia, or July 2012, whichever came first.

Statistical analysis of sample characteristics

Independent t-tests, equal variances not assumed, were performed to compare age at first admission and length of first admission in males and females. Pearson Chi-square was used to compare gender distribution between those who went on to a diagnosis of schizophrenia (F20) with those who did not.

Transition rate and mean time to change to schizophrenia

The proportion of patients with a change in diagnosis to schizophrenia was calculated. Kaplan-Meier survival analysis with censoring was performed to examine the survival time of the entire dataset from first recorded diagnosis of SIP to specific diagnosis of schizophrenia (F20). Separate groups of subjects defined by specific substance, gender, length of first admission (>14 days) and age at first admission (≥30 years) were compared using plots of cumulative survival by period of observation. Tests of homogeneity of survival across these strata were conducted using the log-rank test and, where significant, were entered into a Cox proportional hazards analysis. Plots of cumulative survival, one minus cumulative survival, log survival, log minus log survival, and cumulative hazard were obtained for illustration and to check model assumptions. Interactions were also explored to examine any interdependence between the significant variables identified. For those patients who did convert to schizophrenia diagnosis, mean time to change was calculated.

We repeated these analyses for the broader outcome categories of schizophrenia spectrum disorders (see supplementary material). All data analysis was performed using the Statistical Package for Social Sciences (SPSS Statistics release 17.0.0).

RESULTS

There were 3486 cases of first episode SIPD identified in the Scottish hospital admission data between 1st January 1997 to 31st July 2012.

Whole sample characteristics

Table 1 shows the gender distribution of new diagnoses of SIPD by substance subcategory, mean and standard deviation (SD) of age at first admission and cumulative hazard (%) of diagnosis schizophrenia (F20). The overall male/female ratio was 3.1:1, with an average age of 33.7 years (SD=12.9), and an average length of stay in hospital of 31.1 days (SD=444.0). 517 patients (14.8%) were subsequently admitted to hospital with a diagnosis of schizophrenia (F20). This group had a significantly higher male/female ratio of 5.5:1, compared to those who were not later admitted with such a diagnosis (N=2969; male/female ratio 2.8:1 ); χ2(1, N = 3486) =26.43, p ................
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