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


This meta-analysis of transition from substance-induced psychosis to a diagnosis of schizophrenia identified 25 studies of substance-induced psychosis, which provided 43 substance-specific estimates in 34 244 individuals. The overall proportion transitioning to schizophrenia was 25%. The strongest predictor of transition was the type of substance: one-third (34%) of people with cannabis-induced psychosis transitioned to a later diagnosis of schizophrenia, based on estimates from 6 studies and 3040 people. Rates were intermediate for hallucinogens and amphetamines, and below 10% for alcohol and sedative-induced psychoses. There was significant heterogeneity of estimates, and the likelihood of transition to schizophrenia was not predicted by sex, country, study setting, urban or rural location, diagnostic system, diagnostic methods or completeness or duration of follow-up. Studies of older cohorts reported a reduced proportion transitioning to schizophrenia. This may, however, be an ecological association rather than indicating reduced risk in older individuals: studies with a high average age also had a high proportion of people with alcohol-induced psychosis, which was associated with a lower rate of transition to schizophrenia.

Substance-induced psychosis had a lower rate of transition to schizophrenia than for other brief, atypical, and unspecified psychoses. However, the pooled rate of transition for substance-induced psychoses was similar to that for brief and atypical psychoses (excluding psychosis not otherwise specified). The available data, therefore, suggest that people with substance-induced psychoses, particularly those associated with cannabis, have almost the same rate of transition to schizophrenia as those with other brief and atypical psychoses.

The estimate of a 25% probability of transition in substance-induced psychoses is slightly higher than the previously reported meta-analytic estimate of 21%.[18] There are several likely reasons for this difference. The current study included additional studies published since July 2015.[17,50,71,72,81] It employed broader search criteria, resulting in the inclusion of several large population-based studies which used first hospital admission to define incident episodes.[16,19,56] The current study also included 4 studies of substance-induced psychosis which were not limited to incident episodes,[13,17,61,72] though this group did not have significantly higher rates of transition.

Consistent with other reviews,[18] we found that around two-thirds (65%) of people with a diagnosis of schizophreniform psychoses received a later diagnosis of schizophrenia. This is likely to reflect the significant overlap in diagnostic criteria, with the 2 conditions being mainly distinguished on the basis of duration of illness. However, a significant subgroup of people with these diagnoses do not receive a later diagnosis of schizophrenia,[90] emphasizing the need for a recovery-focused approach in early psychosis, regardless of diagnosis.

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 reviews[93] 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-admission[96] 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 studies[50] 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.


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.


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.