Transition of Substance-Induced, Brief, and Atypical Psychoses to Schizophrenia

A Systematic Review and Meta-analysis

Benjamin Murrie; Julia Lappin; Matthew Large; Grant Sara


Schizophr Bull. 2020;46(3):505-516. 

In This Article


The study was registered with PROSPERO (CRD42018086734) and conducted in accordance with PRISMA and MOOSE guidelines. We aimed to examine rates of transition to schizophrenia associated with cannabis, hallucinogens, amphetamines, opioids, alcohol, sedatives, and multiple or not specified substance-induced psychosis and to compare rates of transition among those with brief and atypical psychosis, psychosis NOS, and schizophreniform psychosis. The term substance-induced was used because of convention and not because of a presumed causal link between the substance use and the psychosis.

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 method[46] 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 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.