Transition of Substance-Induced, Brief, and Atypical Psychoses to Schizophrenia: A Systematic Review and Meta-analysis

Search Strategy

PsychINFO, MEDLINE, and Embase were searched via Ovid for peer-reviewed, English-language publications reporting follow-up diagnoses in people with substance-induced psychoses, brief psychosis, atypical psychosis, schizophreniform psychosis, and psychosis not otherwise specified from 1980 to 2018. A broad search strategy was used because substance-induced psychoses are often reported as a subgroup in multi-diagnostic psychosis cohorts where they are not the primary focus. Titles, abstracts, and keywords were searched for: (first episode OR drug induced OR substance induced OR stimulant induced OR hallucinogen induced OR cannabis induced OR marijuana induced OR amphetamine induced OR cocaine induced OR LSD induced OR lysergic acid induced OR angel dust induced OR PCP induced OR phencyclidine OR psilocybin induced OR alcohol induced OR opioid induced OR benzodiazepine induced) AND (psychosis OR psychotic) AND (diagnostic stability OR outcome OR follow up OR course OR prognosis OR transition OR conversion OR longitudinal). The reference lists of identified studies were hand-searched for further relevant studies. The literature search was conducted by 1 author (B.M.) and hand searching of reference lists by 2 authors (B.M. and G.S.).

Inclusion and Exclusion Criteria

Studies were included which reported (1) a baseline diagnosis of substance-induced, brief, atypical, not otherwise specified (NOS) or schizophreniform psychoses, (2) a follow-up diagnosis in the same subjects with a minimum follow-up period of 6 months, and (3) the number of persons with a diagnosis of schizophrenia at the follow-up assessment. Case-series, case-control studies, cohort studies, and randomized-controlled trials were included. Commentaries, book chapters, conference abstracts, editorials, reviews, single case studies, gray literature, and qualitative studies were excluded. Two authors (B.M. and G.S.) selected the studies independently and resolved differences on inclusion and exclusion by consensus.

Psychoses were defined using syndromal diagnoses made according to DSM, ICD, or other recognized diagnostic criteria: studies which defined psychosis by symptom scales or self-report were excluded. The specific psychosis subtype or grouping used by the study authors was recorded. Where specified, the type of substance was recorded for subgroup analysis. Schizoaffective disorders were typically grouped with schizophrenia by authors: where schizophrenia and schizoaffective disorder follow-up diagnoses were reported separately these were combined into a single estimate by the addition of the numbers in each subsample. Substance-induced psychoses associated with methamphetamine, amphetamine, or cocaine were recorded as stimulant-induced psychoses, and those associated with methylene-dioxy-methamphetamine (MDMA), lysergic acid diethylamide (LSD), phencyclidine (PCP) or psilocybin as hallucinogen-induced psychoses. Estimates for delusional disorder were excluded from analysis.

If several publications reported on the same cohort, only the largest was included. On full-text review a number of studies appeared likely to have collected relevant information but reported it in an aggregated form, preventing extraction of data for the specific psychosis subgroup or specific substances. For example, some studies identified the proportion with different psychosis types at baseline (substance-induced, brief, affective etc.) but reported a pooled rate of transition to a later schizophrenia diagnosis. The corresponding author of these studies was e-mailed to seek supplementary data. The authors of 16 studies were contacted for supplementary information^19,30–45 and additional data were provided for 3.^19,41,42

Outcome and Moderator Variables

The primary outcome measure was the proportion of the original cohort with a follow-up diagnosis of schizophrenia. Potential moderator variables examined included: (1) service setting (inpatient, community, or mixed); (2) country; (3) location within country (urban, rural, or mixed); (4) average age of cohort; (5) percent of cohort who were male; (6) diagnostic system used (DSM, ICD, or other); (7) diagnostic method (file review, routine clinical diagnoses, or structured interview); (8) duration of follow-up period; (9) drop-out rate between baseline and follow-up assessment; (10) Positive and Negative Symptom Scale (PANSS) positive, negative, and total symptom scores; (11) Brief Psychiatric Rating Scale (BPRS) scores; (12) Global Assessment of Function (GAF) ratings; (13) whether cohort was limited to first-episode/incident episodes; (14) year of follow-up, using median year for multi-year studies, and publication year when data collection year was not specified, and (15) whether toxicology (blood, urine, or hair assays) were used in establishing diagnoses of substance-induced conditions. Where studies reported BPRS but not PANSS, Leucht's equipercentile method⁴⁶ was used to estimate a PANSS total score.

Two authors (B.M. and G.S.) extracted all data independently: differences were resolved by joint examination of papers by a third author (J.L.). Subgroup characteristics were extracted separately for each diagnostic subgroup where these were reported. Study quality was rated by the same authors using the Newcastle-Ottawa Scale for cohort studies.⁴⁷ Studies were rated as more representative if drawn from mixed hospital and community cohorts. Diagnostic quality (at baseline and outcome) was rated as higher when based on structured diagnostic interview or detailed file review, and lower when based on routine clinical diagnosis.

Meta-analysis

Meta-analysis was conducted using CMA.⁴⁸ Analysis was conducted in 2 stages. First, substance-induced psychoses were compared to other brief and atypical psychoses, using a single estimate per study. Second, to examine differences between types of substance, meta-analysis was conducted only for studies of substance-induced psychosis, analyzing each substance type as a separate subgroup. All analyses employed mixed-effects models (random effects within-subgroup and fixed effects between-subgroup), logit-transformed event rates and z-distribution confidence intervals.

For studies of substance-induced psychosis, subgroup analysis was used to examine potential moderators of the primary outcome. These were conducted using study-level data because substance-specific estimates within studies were considered not to be independent observations. Between-subgroup heterogeneity was assessed using the q-value. Because of the number of planned subgroup analyses, a Bonferroni correction was applied: a threshold of P < .01 was used for defining significant subgroup differences. Continuous variables, such as average age and follow-up period, were analyzed via meta-regression. Publication bias was assessed using Egger's test, and if significant bias existed a revised estimate was calculated using Duval and Tweedie's trim and fill test.

Search Results

The search strategy identified 6097 potentially relevant publications, of which 5906 were excluded following abstract review, and a further 141 excluded after review of full text (figure 1). Four additional papers were identified through hand searching, resulting in 50 eligible studies included.

The 50 eligible studies^{11–13,16,17,19,36,41,42,49–89} (table 1) provided 79 estimates of transition to a diagnosis of schizophrenia among 40 783 people, including 25 studies of substance-induced psychosis (34 244 people). The mean follow-up period was 4.0 years (range 1–20 y) or 8.4 years when weighted by the number of participants in each study. Study samples included more males than females (mean study proportion male 61%, weighted mean 72%). The mean study age was 28 years (weighted mean 29 y). Studies were from 25 countries including England (5 studies), Denmark (4), United States (4), Ireland, Sweden, Germany, and India (3 each): these were aggregated into regional groupings for subgroup analysis. Diagnoses were most often made by structured interview (22) or by extraction of routine clinical diagnoses from medical records or registers (16). For most studies, the index diagnosis was made in hospital (27) or in mixed hospital and community (13) settings. All but 8 studies^{13,17,61,70,72–74,85} examined first-episode cohorts. All eligible studies used a cohort design.

Pooled Rate of Transition to Schizophrenia

Overall one-quarter (25%, 95% CI 18%–35%) of people with substance-induced psychosis had a follow-up diagnosis of schizophrenia (table 2). This pooled estimate was lower than that for brief, atypical, NOS psychoses, and schizophreniform psychosis (between-group Q 5,830, df 3, P < .0001). There was substantial heterogeneity between studies with non-substance-induced psychosis (table 2). Amongst the brief, atypical, and NOS group, transition rates were lower in those with brief and atypical psychoses (26 estimates, 30% transition, 95% CI 23%–38%) than in psychosis NOS (18 estimates, 46% transition, 95% CI 40%–52%).

The 25 studies of substance-induced psychosis provided 43 substance-specific estimates (table 2). Substance-specific estimates differed significantly (Q 137, df 6, P < .0001). Pooled estimates of transition to schizophrenia were highest (34%, 95% CI 25%–46%) for cannabis-induced psychoses, intermediate for amphetamines and hallucinogens, and lowest for alcohol-, sedative- and opioid-induced psychoses. Within-group heterogeneity (I²) exceeded 90% for all substance types where it could be meaningfully estimated on the basis of more than 3 samples.

Subgroup Analysis

Subgroups of the studies examining substance-induced psychosis were compared (table 3). After correction for multiple comparisons, study design characteristics did not predict significant between-group differences. Continuous moderators were examined using meta-regression (table 4). Studies of older cohorts reported lower rates of transition to schizophrenia. There was no association between transition rate and sex, duration of follow-up, proportion of sample followed up or year of publication. There were insufficient studies for meta-regression of PANSS positive, negative, or total scores (reported by 3 studies), percent with comorbid substance use (4 studies) or GAF scores (4 studies).

Study Quality

Study quality did not predict significant between-group differences: studies scoring above and below the median (5 or more on the Newcastle-Ottawa Scale) did not differ in estimates (table 3). Potential impact of study quality was also examined by subgroup analysis for each integer value of the quality scale, and by meta-regression on quality scores as a continuous variable (supplementary material): no significant effects of study quality were observed using any method.

Publication Bias

There was no apparent impact of publication bias on pooled estimates for psychosis subtypes (table 5). Egger's test was not significant for any psychosis subgroup, and Duval and Tweedie's trim and fill test was therefore not conducted. Funnel plots for psychosis subgroups are provided as supplementary material.

Clinical and Service Implications

These findings have important implications for mental health care and services. Substance-induced psychoses are common reasons for seeking mental health care: in younger Australians more than one-fifth of first hospital admissions for psychosis are due to substance-induced psychosis.⁹¹ This study has found that substance-induced psychoses (particularly cannabis-, hallucinogen- and amphetamine-induced psychoses) are associated with a significant risk of receiving a later diagnosis of schizophrenia, and that this risk is only slightly less than that observed for some other brief psychotic disorders. Yet despite this, people with substance-induced psychoses are often excluded from early psychosis services or assertive mental health care due to a perception that these are benign or self-limiting conditions.⁹ This perception may be reinforced by the frequent exclusion of substance-induced psychosis from both primary research studies^28,92 and reviews⁹³ of psychosis outcomes. The findings of this study suggest that decisions about the care of people with substance-induced psychoses should consider the different level of risk associated with different types of substances, rather than seeing all substance-induced psychoses as equivalent.

In particular, the treatment of psychoses induced by cannabis, amphetamines, and hallucinogens should be considered within the same framework of assertive early psychosis intervention as for other brief psychotic disorders. All persons with these disorders should ideally receive a comprehensive psychiatric assessment which considers their individual risk factors and the potential need for assertive monitoring and support.⁹⁴

The importance of assertive intervention in this group is underlined by evidence that integrated care which addresses substance use disorders and psychosis can have a significant impact on course. Such care can double the likelihood of remission in early psychosis,^92,95 reduce the risk for hospital re-admission⁹⁶ and lead to better symptomatic, drug use and functional outcomes at 10-year follow-up.^97,98

Clinical care should always consider factors potentially associated with higher risk in some individuals. The current study found few meta-analytically derived demographic predictors of transition to schizophrenia in substance-induced psychosis. However, predictors of greater rates of transition are likely to be similar to those reported in other first episode psychoses, including younger age of first psychosis,^{16,17,49,75,80} longer duration of untreated psychosis^78,80,84 and impaired premorbid social function.^{17,49,79,80,84}

Cannabis and Transition to Schizophrenia

The rate of transition to schizophrenia was higher following cannabis-induced psychosis (34%) than other substance-induced psychoses, including those associated with amphetamines and hallucinogens. Three studies provided separate estimates for cannabis and other substances.^16,17,50 All found that cannabis-induced psychoses had the highest rate of transition to schizophrenia, although in one of these studies⁵⁰ the difference from stimulants was not significant. These consistent within-study findings suggest that the higher transition rate in cannabis-induced psychosis is unlikely to merely reflect methodological differences between studies. They are also consistent with findings that among young people with brief and atypical psychoses, comorbid cannabis use disorders were associated with a greater risk for transition to schizophrenia than comorbid amphetamine disorders.¹⁹

A study by Kendler and colleagues,⁹⁹ published after the inclusion period for the current review, examined the interaction between substance type and other risk factors in the transition from substance-induced psychosis to schizophrenia. Kendler found that cannabis-induced psychoses were associated with the highest risk of later schizophrenia, and that this was not due to younger age of onset, or differences in gender or service setting. They found that amongst people with substance-induced psychosis, familial risk scores for psychosis were twice as high in those with a later diagnosis of schizophrenia. This study adds to evidence that cannabis interacts with other risk factors to double the risk for schizophrenia in vulnerable individuals.^93,100 Reduced engagement in treatment and follow-up also contributes to this association,¹⁰¹ further underlining the importance of assertive engagement and care in this group.

While finding the same gradient of risk when comparing individual substance types, Kendler's study reported lower proportions of transition to schizophrenia than some other comparable studies. The cumulative hazard was 11.3% for all substance-induced psychoses and 18.0% for cannabis-induced psychoses. They suggest that this may reflect a narrower definition of schizophrenia than some comparable studies. Their study also included a higher proportion of subjects from community settings, who they found had lower risk of transition to schizophrenia than people admitted to hospital.

Limitations

The current study has a number of limitations. First, variability in study design and the substantial heterogeneity of estimates are likely to have contributed to the lack of demonstrable associations with some known or likely risk factors for schizophrenia, including gender, urban setting, hospital setting, or longer duration of follow-up. Many subgroup analyses included small numbers of studies, resulting in significant uncertainty in subgroup estimates.

Second, and likely to contribute to these negative findings of studies reporting different subgroups of psychosis, almost none reported age, sex, or other demographics separately for each subgroup. Therefore, the pooled demographic characteristics for all subgroups were used for those studies.

Third, the studies reviewed include insufficient data to allow meta-analytic comparison of several important potential confounders. In particular, very few studies provided detailed information on the amount or duration of substance use prior to the episode of psychosis, the rate and type of comorbid substance use disorder at the index diagnosis, or the rate of ongoing substance use during follow-up. All these factors are likely to moderate the risk of transition to schizophrenia in people with substance-induced and other brief and atypical psychoses. In particular, there is evidence that ongoing substance use is a critical risk factor, with reduced likelihood of further admissions or transition to schizophrenia in people who cease substance use after a substance-related psychoses but increased risks in people with ongoing use.^19,96

Fourth, the estimates reported here rely on the accuracy of diagnoses in the studies included. Most used diagnoses recorded in registers from routine clinical care (10 studies, 15 059 persons) or from file review (7 studies 19 038 persons). Only 8 studies (127 persons) used research diagnostic interviews. Routine diagnoses of substance-induced, atypical, and brief psychoses are often imprecise due to overlap in diagnostic constructs and variation in clinical practice.⁷ Subgroup analysis did not suggest any systematic difference in estimates associated with these different sources of diagnosis, but the small number of studies using research diagnostic interviews may have prevented identification of possible differences.

Fifth, too few studies reported values for relevant moderators, such as duration of psychosis, symptom scores, global functioning, and rates of ongoing substance use, to allow completion of the planned meta-regression analyses.

Finally, the research team did not have the resources or expertise to review studies in languages other than English, which may bias findings.¹⁰² However, nearly half of the included studies of substance-induced psychosis (11 of 25) came from European, Scandinavian, and southern and eastern Asian countries.

Conclusions

Substance-induced psychoses are common and serious conditions. They are associated with a substantial risk for transition to schizophrenia. The risk of transition to schizophrenia is particularly increased following cannabis-induced psychosis, which should be responded to with assertive attempts at engagement, assessment, and care.