Centre for Basic Psychiatric Research, Aarhus University Hospital, Risskov
Unit for Psychiatric Research, Aalborg Psychiatric Hospital, Aarhus University Hospital, Aalborg, Denmark
Correspondence: Mikkel Arendt,Centre for Basic Psychiatric Research, Aarhus University Hospital, Skovagervej 2, DK-824 0 Risskov, Denmark. E-mail: mca{at}psykiatri.aaa.dk
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ABSTRACT |
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Aims To establish whether cannabis-induced psychotic disorders are followed by development of persistent psychotic conditions, and the timing of their onset.
Method Data on patients treated for cannabis-induced psychotic symptoms between 1994 and 1999 were extracted from the Danish Psychiatric Central Register. Those previously treated for any psychotic symptoms were excluded. The remaining 535 patients were followed for at least 3 years. In a separate analysis, the sample was compared with people referred for schizophrenia-spectrum disorders for the firsttime, but who had no history of cannabis-induced psychosis.
Results Schizophrenia-spectrum disorders were diagnosed in 44.5% of the sample. New psychotic episodes of any type were diagnosed in 77.2%. Male gender and young age were associated with increased risk. Development of schizophrenia-spectrum disorders was often delayed, and 47.1% of patients received a diagnosis more than a year after seeking treatment for a cannabis-induced psychosis. The patients developed schizophrenia at an earlier agethanpeople in the comparison group (males, 24.6 v. 30.7 years, females, 28.9 v. 33.1 years).
Conclusions Cannabis-induced psychotic disorders are of greatclinical and prognostic importance.
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INTRODUCTION |
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In this study we use an epidemiological approach to describe a substantial number of patients treated for cannabis-induced psychotic disorder with no prior history of psychotic symptoms. Patients were followed for at least 3 years, with the aim of determining the proportion and types of subsequent schizophrenia-spectrum disorders, the timing of onset, and whether the patients developed these conditions at an earlier age than other patients with schizophrenia but with no history of cannabis-induced psychotic symptoms.
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METHOD |
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The second analysis was concerned with the average age at the time schizophrenia-spectrum disorders were first diagnosed. The cannabis group was compared with a group consisting of all first-time referrals with schizophrenia-spectrum disorders between 2002 and 2003, with no history of cannabis-induced psychotic symptoms. In the comparison group, those with a history of psychotic episodes according to ICD-8 (assigned before 1994) were also excluded. The latter exclusion criterion was necessary because the diagnostic categories from ICD-8 cannot be translated into ICD-10 diagnoses in a meaningful way.
The registers
Data were extracted from the Danish Psychiatric Central Register. This
register contains information on all treatment provided by Danish psychiatric
hospitals and departments since 1970. Out-patient treatment has only been
registered since 1995. After each contact with the psychiatric system patients
receive a diagnosis code. Up to 1993 these were assigned using ICD-8, and
thereafter ICD-10 has been used; ICD-9 was never in use in Denmark.
Only psychiatrists responsible for the treatment are allowed to enter diagnoses into the register. They generally have knowledge of prior hospitalisations and diagnoses based on case files and use this information in their evaluation of the patients. There are no private psychiatric facilities in Denmark and treatment is free of charge. Information on patients who died during the study period was retrieved from the Danish Cause of Death Registry. Registrations are person identifiable using the Central Persons Register Number. This is a unique number given to every Danish citizen at birth or at time of migration, and it is used in all official registers in Denmark. Knowledge of this number allows age and gender to be determined.
Analysis
For this study the outcome schizophrenia-spectrum disorders
was defined as schizophrenia (ICD-10 code F20), schizotypal disorder (ICD-10
code F21) and schizoaffective disorders (ICD-10 code F25). Separate analyses
were made for other psychotic conditions. Most patients received several
different diagnoses during the course of the follow-up. Treatment episodes
after index were therefore put into a hierarchy. Schizophrenia-spectrum
disorders were given highest priority, followed by the remaining F20
diagnoses, bipolar disorder, acute and transient psychotic conditions,
substance-induced psychotic disorders, and other diagnoses (predominantly
mood, anxiety and personality disorders).
In the analysis of timing of onset of schizophrenia-spectrum disorders, the time lapse between index and first referral with such diagnoses was recorded. The average age at first referral with a schizophrenia-spectrum disorder among patients with a history of cannabis-induced psychoses was compared with that of others who developed a schizophrenia-spectrum disorder but had no recorded history of cannabis-induced cannabis-induced psychotic symptoms.
Statistics
Model checking showed that the distributions for age and number of
subsequent referrals were skewed. Log Gaussian regression models were
therefore used, and the back-transformed estimates and confidence intervals
are reported. The effects of age and gender on risk of subsequent
schizophrenia-spectrum disorder were evaluated using Cox regression. A
survival curve, showing the time from index to first treatment for a
schizophrenia-spectrum disorder, was estimated for each gender using a Cox
regression model adjusting for age. Because of unequal variance of age between
the patients and the comparison group, Satterthwaite approximated degrees of
freedom were used in the t-tests comparing age at first episode of
various psychotic conditions. Stata Statistical Software release 8.0 was used
for all analyses.
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RESULTS |
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The mean age at time of first treatment for cannabis-induced symptoms was 27.0 years (s.d.=7.7, 25th percentile=20.9, median=25.5, 75th percentile=31.2); 441 (82.4%) were male. A total of 379 patients were admitted to hospital for a median stay of 13 days (25th percentile=4, 75th percentile=29, mean=30.6) and 156 patients received out-patient treatment only. The mean length of follow-up was 5.9 years (s.d.=1.7). Twenty-two patients died during the follow-up period, 13 within 3 years of index and 9 after. Causes of death were suicide (n=7), accident (n=4), natural causes (n=4) and unknown (n=7). Of the 13 who died within 3 years, 7 had been diagnosed with a schizophrenia-spectrum disorder. Of the remaining 9 patients, 6 received such diagnoses before death.
There were 2721 patients in the comparison group. In this group the mean age at onset of schizophrenia-spectrum disorders was 33.8 years (s.d.=13.9, 25th percentile=23.5, median=30.7, 75th percentile=41.2); 1560 (57.3%) were male.
Subsequent psychotic conditions
Table 1 lists the most
severe diagnoses recorded during follow-up. A total of 238 people (44.5%)
diagnosed with cannabis-induced psychotic symptoms later developed a
schizophrenia-spectrum disorder. This proportion increases with length of
follow-up. Of the patients admitted to treatment in 1994, nearly half (48.9%)
received this diagnosis, whereas the proportion was 35.7% for patients
admitted between 1 July 1998 and 1 July 1999. Another 9.0% developed
persistent delusional disorders, other or unspecified non-organic psychoses,
or bipolar affective disorder at some point, raising the total estimate of
patients developing persistent psychotic conditions to 53.5%. In total, 77.2%
experienced new psychotic episodes after index, if transient psychotic
conditions and substance-induced psychoses are included. Only 15.9% remained
out of psychiatric care throughout the follow-up period.
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Men had an increased risk of developing schizophrenia-spectrum disorders compared with women (47.6% v. 29.8%). Using a Cox regression model controlling for age, the hazard ratio was 1.82 (95% CI 1.21-2.74, P<0.002). Young age was also related to increased risk. Controlling for gender, the proportional hazard ratio when increasing the age by 1 year was 0.97 (95% CI 0.95-0.99, P<0.003).
Number of subsequent treatment episodes
The average number of treatment episodes caused by schizophrenia-spectrum
disorders was estimated for the 238 patients who developed these conditions.
The mean number was 1.2 per person-year (95% CI 1.0-1.4) for men and 0.7 per
person-year (95% CI 0.4-1.1) for women. Altogether 176 patients (73.9%)
received treatment for a schizophrenia-spectrum disorder on three or more
separate occasions after index.
Pattern of subsequent diagnoses
Most patients were treated many times during follow-up, and the diagnoses
often changed. Table 2 presents
the prevalence rates for the entire population of 535 patients. Paranoid
schizophrenia was the most common condition, followed by acute and transient
psychotic disorders, personality disorders and unspecified schizophrenia. A
separate analysis was performed of the last schizophrenia-spectrum diagnosis
for each patient within the observation period (results not shown). This
revealed that, of the 238 patients who received such diagnoses, 58.0% were
treated for paranoid schizophrenia at the most recent contact with a
psychiatric department and 20.2% were treated for unspecified schizophrenia.
In total, 211 (88.7%) of the patients sought treatment for schizophrenia at
their latest contact with the psychiatric care system.
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Timing of onset
The first episode of schizophrenia-spectrum disorder occurred after a
substantial delay for most of the 238 patients
(Fig. 1). It was registered
more than 1 year after index for 47.1% of the patients, and 17.2% developed
such conditions more than 3 years later.
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When more than 5 patients from the cannabis group had a specific type of schizophrenia, analyses were performed for the subgroups. This revealed that male patients treated for paranoid schizophrenia (t=7.2, d.f.=119, P<0.001), undifferentiated schizophrenia (t=3.4, d.f.=42, P0.002) and unspecified schizophrenia (t=2.2, d.f.=96, P<0.03) were younger at first episode than people from the comparison group. For simple schizophrenia there was no significant difference in age. Female patients from the cannabis group, treated for paranoid schizophrenia, were younger than those from the comparison group (t=3.1, d.f.=15, P<0.007); there was no significant difference for unspecified schizophrenia.
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DISCUSSION |
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Outcome
It was established that almost half of the patients in our study treated
for a cannabis-induced psychotic disorder developed a schizophrenia-spectrum
disorder subsequently. A substantial number of patients were diagnosed with
paranoid schizophrenia, and the vast majority of those who developed a
schizophrenia-spectrum disorder were given this diagnosis at the most recent
hospitalisation. New psychotic episodes developed in 77.2% of the entire
sample and only 15.9% did not receive psychiatric treatment at any point after
index. Male gender and young age were associated with more severe outcome.
Most patients were treated on numerous occasions for schizophrenia-spectrum
disorders, and in almost half of the cases the first episode occurred with a
delay of more than a year. Compared with patients without a history of
cannabis-induced psychosis, they developed schizophrenia at a significantly
younger age. This effect was most marked for paranoid schizophrenia.
For the majority of patients, cannabis-induced psychotic symptoms proved to be a first step in the development of a schizophrenia-spectrum disorder or other severe psychopathology. This is inconsistent with findings from previous studies generally reporting complete remission when patients abstain from further cannabis use (Talbott & Teague, 1969; Kolansky & Moore, 1971; Thacore, 1973; Thacore & Shukla, 1976; Rottanburg et al, 1982; Carney et al, 1984; Drummond, 1986; Cohen & Johnson, 1988; Chaudry et al, 1991; Wylie, 1995; Basu et al, 1999), although some have reported that a minority of patients with pre-existing mental problems had a less favourable outcome (Bromberg, 1939; Bernhardson & Gunne, 1972; Tennant & Groesbeck, 1972; Chopra & Smith, 1974; Pålsson et al, 1982). However, patients had generally not been followed after the cannabis-induced psychotic condition remitted, and no study included data on all patients more than 3 months after the end of treatment. Many of the same investigations have reported that cannabis-induced psychoses subside more quickly than psychoses that are not substance-induced (Talbott & Teague, 1969; Bernhardson & Gunne, 1972; Tennant & Groesbeck, 1972; Thacore, 1973; Chopra & Smith, 1974; Thacore & Shukla, 1976; Pålsson et al, 1982; Rottanburg et al, 1982; Carney et al, 1984; Drummond, 1986; Cohen & Johnson, 1988; Chaudry et al, 1991; Wylie, 1995; Basu et al, 1999). This is consistent with findings in our study. Many patients received out-patient treatment only, and the length of stay was generally short for those who were admitted to hospital. Combining these factors probably explains why the evaluation of the outcome in this study differs so markedly from other studies. The lack of long-term follow-up of the patients means that delayed onset of severe psychopathological symptoms might have been undetected in previous studies.
Existence of cannabis psychosis
In accordance with our results, some authors have claimed that
cannabis-induced psychotic symptoms are often a sign of underlying
psychopathology and that the condition is easily confused with schizophrenia
(Weil, 1970;
Thornicroft, 1990;
Thomas, 1993;
Poole & Brabbins, 1996).
However, data have been lacking in attempts to substantiate this. Criticism
has centred on the concept of cannabis psychosis, and has
primarily been based on studies failing to show a symptom profile distinct
from other psychoses (Imade & Ebie,
1991; Mathers & Ghodse,
1992; McGuire et al,
1995). Numerous symptom clusters have been described as
characteristic of cannabis psychosis, and an exact meaning of
the concept has never been established
(Thornicroft, 1990;
Hall & Degenhardt, 2004).
However, even the critics have accepted that psychotic symptoms can be induced
by cannabis, and that such symptoms generally wear off quickly and with
complete remission. It has never before been shown that cannabis-induced
psychoses are followed by development of long-term psychotic conditions in
people with no history of psychosis, and this is the first study to show that
such symptoms, in most cases, can be regarded as the first manifestations of
long-term psychotic illness. The results do not disprove the existence of
cannabis psychosis, but clearly show that cannabis-induced
psychotic symptoms must be regarded as important risk factors for subsequent
development of schizophrenia-spectrum disorders.
The question of causality
Recent studies have established that cannabis use increases the risk of
developing severe psychotic disorders
(Arseneault et al,
2004), although the findings are not conclusive
(Macleod et al,
2004). Whether cannabis was causally linked with development of
schizophrenia among patients in our investigation cannot be determined since,
owing to the study design, it was not possible to control for factors such as
hereditary predisposition, other drug use and socio-economic status. However,
the fact that patients with cannabis-induced psychotic symptoms developed
schizophrenia at a younger age than patients with no recorded history of
cannabis-induced psychosis indicates that cannabis use may hasten the
pathogenesis. This is in accordance with a recent study showing that the age
at onset of schizophrenia is lower among patients using cannabis
(Veen et al, 2004)
and further validates this significant finding.
Cannabis use in Denmark
The incidence of cannabis-induced psychotic disorders in Denmark was
estimated to be 2.7 per 100 000 person-years. This confirms that such
conditions are rare. In the interpretation of this number, it is important to
note that in Denmark cannabis is predominantly smoked as hashish, which is
more potent than marijuana. A recent publication from the Danish National
Board of Health (2003) shows
that 40.9% of all Danish citizens aged 16-24 years have used cannabis at some
point in their lifetime, and that 19.7% had used the substance in the previous
month.
Limitations
The results of this study must be evaluated considering its limitations.
Data were not specifically collected for this investigation, so it was not
possible to validate the diagnosis of cannabis-induced psychosis. It may be
difficult to distinguish between this diagnosis and early signs of
schizophrenia. However, many patients only received out-patient treatment for
the cannabis-induced symptoms, and for those who were admitted to hospital the
length of stay was typically short. Furthermore, there was a substantial delay
before schizophrenia-spectrum disorders emerged in most patients. This
indicates that the cannabis-induced symptoms were short-lived and that
temporary remission was probably achieved in most cases.
It could not be ascertained that the patients fulfilled the diagnostic criteria for schizophrenia-spectrum disorders either. Furthermore, we were not able to control for regular use of cannabis or other drugs, such as stimulants, during the follow-up period. It might be argued that the diagnoses assigned to the patients during follow-up were merely new instances of substance-induced symptoms being misclassified. On the other hand, the fact that 73.9% of the patients were given schizophrenia-spectrum diagnoses on at least three separate occasions is inconsistent with this. In addition, psychiatrists use prior case records upon referral, so previous problems with substance misuse are likely to be detected. Finally, it is standard procedure to enquire about substance use among patients presenting with psychotic symptoms.
Some confounders might have influenced the evaluation of age at first treatment for schizophrenia. It is well established that cannabis use is most common among adolescents and young adults. If we suppose that cannabis use and schizophrenia are unrelated, and the first signs of schizophrenia happen to co-occur with cannabis use, then the symptoms might erroneously be attributed to cannabis. If this were the case, it might lead to bias when evaluating the age at first episode of schizophrenia in the cannabis group. Other factors that we were not able to control for (e.g. socio-economic status and other drug use) might also have influenced these results.
Finally, the patients in our study possibly represent more severe cases of cannabis-induced psychotic symptoms; therefore, the results may not generalise to people who develop psychotic symptoms that are less persistent, or who for other reasons do not present for treatment. Conversely, there is some indication that any occurrence of psychotic symptoms after cannabis intake could constitute a risk for subsequent schizophrenia-spectrum disorders (Verdoux, 2004). If this can be corroborated it would have clear implications for the ongoing search for early signs of schizophrenia. This should be further investigated in the future.
Implications
Our study shows that cannabis-induced psychotic symptoms are an important
risk factor for subsequent development of severe psychopathological disorder.
This is in contrast to previous studies describing the condition as harmless.
Although it cannot be determined that cannabis has a causal impact on the
subsequent development, the findings have clear implications for clinicians
who encounter a patient with cannabis-induced psychotic disorder. The
prognosis for the patient is poor, and attention needs to be given to early
intervention.
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Clinical Implications and Limitations |
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LIMITATIONS
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Received for publication September 16, 2004. Revision received March 21, 2005. Accepted for publication March 24, 2005.
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