Schizophrenia Research 54 (2002) 243251

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Precipitation and determination of the onset and course of

schizophrenia by substance abuse a retrospective and
prospective study of 232 population-based rst illness episodes
Babette Buhler a, Martin Hambrecht b, Walter Lofer a, Wolfram an der Heiden a,
Heinz Hafner a,*
a
Schizophrenia Research Unit, Central Institute of Mental Health, J5, D-68159 Mannheim, Germany
b
Department of Neurology and Psychiatry, University of Cologne School of Medicine, Joseph-Stelzmann-Str. 9, D-50924 Koln, Germany
Received 19 January 2001; accepted 10 April 2001

Abstract
Onset and lifetime prevalence of substance abuse were assessed retrospectively using the IRAOS interview in a population-
based, controlled sample of 232 rst episodes of schizophrenia (ABC sample). Subjects with schizophrenia were twice as likely
as controls to have a lifetime history of substance abuse at the age of rst admission (alcohol abuse: 23.7 versus 12.3%; drug
abuse: 14.2 versus 7.0%). 88% of the patients with drug abuse took cannabis. The sequence of substance abuse and schizo-
phrenia was studied on the timing of abuse onset and illness onset, the latter as based on various denitions: rst sign of the
disorder, rst psychotic symptom and rst admission. 62% of the patients with drug abuse and 51% of those with alcohol abuse
began the habit before illness onset ( rst sign of the disorder). Abuse onset and illness onset occurred highly signicantly
within the same month (drug abuse in 34.6%, alcohol abuse in 18.2%). Unexpectedly, no temporal correlation was found
between abuse onset and the onset of the rst psychotic episode. We concluded that a small proportion of schizophrenias might
have been precipitated by substance mainly cannabis abuse.
Long-term effects of early substance abuse were studied prospectively at six cross-sections over ve years from rst
admission on in a subsample of 115 rst episodes of schizophrenia. Abusers showed signcantly more positive symptoms
and a decrease in affective attening compared with controls. Five-year outcome as based on treatment compliance, utilization
of rehabilitative measures and rate of employment was also poorer for patients with than without early substance abuse. q 2002
Elsevier Science B.V. All rights reserved.
Keywords: Schizophrenia; Onset; Comorbidity; Drug abuse; Substance abuse; Early course; Consequences

1. Introduction rarely opioids, is more frequent in persons with schi-

The abuse of illegal drugs, such as cannabis,
amphetamines, cocaine and hallucinogens, more
* Corresponding author. Tel.: 149-621-1703725; fax: 149-621-
1703-266.
E-mail address: hhaefner@as200.zi-mannheim.de (H. Hafner).
0920-9964/02/$ - see front matter q 2002 Elsevier Science B.V. All rights reserved.
PII: S 0920-996 4(01)00249-3
zophrenia than in other mental patients or in the
general population (Smith and Hucker, 1994; Mueser
et al., 1992a,b; Kovasznay et al., 1997). According to
a metaanalysis of US studies every third person diag-
nosed with schizophrenia has an alcohol problem
(Cuffel, 1992).
The frequency of abuse as well as the type and
244 B. Buhler et al. / Schizophrenia Research 54 (2002) 243251
Fig. 1. ABC schizophrenia study, medium-term course. Source:
Hafner and an der Heiden 1999.
amount of the substances abused depend on the dura-
tion of exposition, e.g. length of illness and availabil-
ity of the substances of abuse in the population
studied. The overall lifetime prevalence of alcohol
abuse ranges from 12.3 (Alterman et al., 1981) to
42.8% (Barbee et al., 1989), that of cannabis abuse
from 35 to 60% (Negrete et al., 1986). DeLisi et al.
(1991) found a lifetime prevalence of 35% for drug
abuse among 100 rst-episode cases of schizophrenia
in the State of New York. Soyka et al. (1993) found a
lifetime prevalence of 21.8% for drug abuse among
patients with recent-onset schizophrenia and of 42.9%
among chronic patients in Bavaria/Germany. The
corresponding gures for alcohol abuse were 17.4
and 34.6%, respectively. In chronic schizophrenia
multiple abuse of different drugs and alcohol is wide
spread (Drake et al., 1989; Rosenthal et al., 1994).
Finally, as Mueser et al. (1992a,b) pointed out,
contributing to the high variation in the rates reported
are also methodological aws frequent in the studies,
such as non-uniform instruments of assessment, small
sizes and lack of representativity of the samples
studied.
Valid results on substance abuse in schizophrenia
can only be obtained by studying sufciently large
representative samples of persons with a diagnosis
of schizophrenia, by collecting precise data on the
duration of both the illness and substance abuse and
by comparing these cases with matched controls
drawn from the same population of origin. To nd
out whether schizophrenia is triggered by substance
abuse schizophrenia precise data on the time of onset
of both the disorder and substance abuse are needed
(Lieberman et al., 1990; Linszen et al., 1994).
2. Materials, methods and hypotheses
The design of the present study, which consists of a
retrospective and a prospective part, is shown in Fig.
1.
The retrospective part of the study relied on a popu-
lation-based sample of 232 rst episodes of broadly
dened schizophrenia (ICD-9: 295, 297, 298.3 and
298.4) ( 86% of consecutive rst admissions) in
age range 1259 years from a semi-rural, semi-
urban German population of about 1.5 million
(Mannheim, Ludwigshafen, Heidelberg, Rhine-
Neckar-District and Eastern Palatinate) (for a detailed
description of both sample and assessment method see
Hafner et al., 1993). A subsample of 57 schizophrenic
patients was compared with 57 age and sex matched
controls randomly drawn from the population register
of the city of Mannheim.
Another population-based subsample of 115 rst
illness episodes of the same diagnoses as the samples
above were assessed prospectively at six cross-
sections over ve years from rst admission on
using the PSE and the Fu-HSD (s. Fig. 1). From this
sample, 29 schizophrenic patients with a history of
alcohol and/or drug abuse before rst admission
were compared at the six cross-sections with 29 age-
and sex-matched patients without substance abuse. As
based on the IRAOS and the PSE, alcohol abuse was
dened as follows: for at least one month, the patient
had times of heavy drinking, problems with the family
due to drinking, missed work because of drinking or
showed withdrawal symptoms like morning shakes;
drug abuse was dened as a consumption of illegal
drugs more than once a week over at least one month.
These denitions more or less cover the diagnostic
categories of substance abuse in the ICD-9 and
DSM-IV.
The data were collected using our instrument for
the retrospective assessment of the onset of schizo-
phrenia (IRAOS) (Hafner et al., 1992, 1999a), and the
events recorded were entered in a time matrix. Three
sources were used: each patient and his/her closest
relative went through the interview, and additional
information was elicited from written documents
 B. Buhler et al. / Schizophrenia Research 54 (2002) 243251
Table 1
Age at onset of substance abuse and of schizophrenia and of the milestones of early illness course (Source: Hambrecht and Hafner 1996b,
modied; *p , :0:05***p , 0:001)
Drug abusers (n 29) a
Mean age (in years) at 18.6 (^5.7)
abuse onset
Onset of schizophrenia:
First sign 18.5 (^6.4)
First negative symptom 21.1 (^6.2)*
First positive symptom 24.3 (^7.3)***
a
Missing data in four cases.
(medical records, etc.). The reported time of onset of
schizophrenia, as based on various denitions, was
compared between the patients and their relatives,
and the following Pearson correlations were obtained:
0.77 for the month of appearance of the rst symptom,
0.93 for the rst positive symptom, 0.73 for the rst
negative symptom and .1 for rst admission. The
validity of this information was corroborated by
comparing the history of substance abuse as reported
by the patients and the relatives: the Pearson correla-
tion for the onset of alcohol abuse was 0.76 (kappa
0.65), for drug abuse 0.69 (kappa 0.52) (Hambrecht et
al., 1994).
The patients' social development and course of
treatment were assessed using the FU-HSD (WHO,
1980) at six cross-sections over ve years. To assess
positive symptoms, the PSE-9 (Wing et al., 1974), to
assess negative symptoms the SANS (Andreasen,
1981) were used. Social disability was assessed
using the DAS-M (WHO, 1988; Jung et al., 1989).
Positive symptoms were compared by means of the
DAH score (Delusional and hallucinatory syndrome
score) from the PSE-CATEGO system (Wing et al.,
1974).
The rst group of the hypotheses tested was about
the onset and early course of schizophrenia:
(1) In the early stages of illness, the abuse of illegal
drugs and alcohol is already more frequent among
schizophrenics than their matched peers from the
general population.
(2) In most cases, abuse onset precedes rst admis-
sion for schizophrenia.
(3) In some cases, illness onset ( rst sign of the
disorder) or the onset of the rst psychotic episode
is prematurely triggered by cannabis abuse.
245
Alcohol abusers (n 55)
22.6(^8.6)
20.8 (^9)*
23.0 (^9.5)
27.9 (^8.8)***
The second group of hypotheses dealt with the
consequences that alcohol and drug abuse in the
early course of schizophrenia might have for the
medium-term course of schizophrenia.
(4) Substance abuse in the early illness course
increases symptom persistance and time spent in
inpatient treatment in the further illness course.
(5) Substance abuse in the early course leads to
poor treatment compliance and poor social
outcome.
(6) Alcohol and drug abuse before rst admission
increases positive symptoms and decreases nega-
tive symptoms.
The data were evaluated using the Statistical Pack-
age for the Social Sciences (SPSS). For analysing
positive and negative symptoms and the number of
inpatient days t-tests for data with a normal distribu-
tion were used. The statistics on compliance and
social disability were calculated using the Mann
Whitney U test for data with a normal distribution.
For groupwise comparisons over time Manovas and
for comparisons at cross-sections t-tests were
performed.
3. Results
Of the 232 rst-episode patients at rst admission
(mean age: 30 years) 55 had a lifetime history of
alcohol abuse and 33 a lifetime history of drug
abuse. That yielded a lifetime prevalence rate of
23.7% for alcohol abuse among schizophrenics,
compared with 12.3% among controls, and a lifetime
prevalence rate of 14.2% for drug abuse among
246 B. Buhler et al. / Schizophrenia Research 54 (2002) 243251
Fig. 2. Age at onset of schizophrenia in patients with and without
substance abuse.
schizophrenics compared with 7% among controls
(Hambrecht and Hafner, 1996a,b) and, hence, an
odds ratio of 2 for both types of comorbidity.
88% of the patients with drug abuse had abused
cannabis and occasionally, mostly concomitantly,
hallucinogens. About a third of the drug abusers
reported to have occasionally taken cocaine and
amphetamines. Other drugs played a minor role, prob-
ably because of the patients' low mean age, their early
illness stage and a low prevalence of the abuse of
these substances in the population of origin.
The sex differences found coincided with the
results of a majority of the studies on the topic (DeLisi
et al., 1991; Mueser et al., 1992a,b; Soyka, 1994;
Kessler et al., 1994; Jenkins et al., 1997; Kandel,
2000). 39% of the male patients and 22% of the
females had a history of drug and/or alcohol abuse
at rst admission. Combined abuse was more often
seen in males (12%) than in females (5%).
The mean age at which the patients rst fullled the
criteria for abuse and the mean age at the onset of
schizophrenia as well as at the subsequent milestones
of the evolving disorder are given in Table 1. Based
on the age, the onset of drug abuse preceded the onset
of schizophrenia by about two years, whereas the
onset of alcohol abuse followed the onset of schizo-
phrenia by about two years, but took place long before
rst admission.
Fig. 2 gives age at illness onset for: schizophrenics
with drug abuse, with alcohol abuse and without
Fig. 3. Sequence of onset of drug abuse and rst sign of mental
disorder.
abuse. We found that both the onset of schizophrenia
and all the subsequent milestones of the early illness
course occurred 68 years earlier in patients with drug
abuse than in abstinent patients. This nding suggests
that substance abuse might have speeded up the onset
of schizophrenia (Gardner and Lowinson, 1991).
We therefore tested the following two sub-hypoth-
eses:
Cannabis or alcohol abuse might trigger
1. the onset of the rst symptom of schizophrenia and
2. the onset of the rst psychotic episode
in some patients. The latter hypothesis was more
likely to be conrmed than the former. Given the
dopamine agonistic effect of cannabis, it seemed plau-
sible to presume that this substance might trigger
psychotic symptoms by stimulating dopaminergic
neurotransmission, especially since higher doses of
cannabis intake have been shown to produce halluci-
nations and other psychotic phenomena.
In 73% of the cases, the rst sign of schizophrenia
was negative or non-specic, in 8% positive. In 18%
positive, negative and non-specic symptoms
appeared in the same month. In Figs. 36 we have
depicted the month in which the rst sign of schizo-
phrenia (from now on dening the onset of schizo-
phrenia) or the rst psychotic symptom (from now on
dening the onset of the rst psychotic episode)
appeared as the midpoint of two time-dimensions.
The top of each gure is based on years, the bottom
on months.
Fig. 3 (top) shows a surprising picture: in 34.6% of
 B. Buhler et al. / Schizophrenia Research 54 (2002) 243251
Fig. 4. Sequence of onset of alcohol abuse and rst sign of mental
disorder.
the cases the onset of both schizophrenia and drug
abuse occurred in the same month. In 27.5% schizo-
phrenia onset occurred some time before and in 38.1%
some time after the onset of drug abuse. In 10.3% of
the patients drug abuse began as long as ve years
before and in 17.3% more than ve years after schizo-
phrenia onset. The highly signicant excess of simul-
taneous onsets of schizophrenia and drug abuse
becomes even more striking when illustrated on a
monthly basis in the year before and after (Fig. 3,
bottom).
As Fig. 4 shows, at 18.2% the accumulation of
schizophrenia onsets in the month of the onset of
alcohol abuse was less pronounced.
Fig. 5. Sequence of onset of drug abuse and rst psychotic symp-
tom.
247
In sum, 62% of the patients with cannabis abuse
began the abuse before or in the month in which the
onset of schizophrenia occurred this was an aver-
age of ve years before the onset of the rst psychotic
episode , whereas only 51% of those with alcohol
abuse did so (in 32.7% alcohol abuse started before
the month of illness onset).
No temporal correlation above chance was found
between the onset of drug abuse and the onset of the
rst psychotic episode: there was neither an accumu-
lation of onsets of psychotic episodes in the month of
abuse onset nor an accumulation of onsets of drug
abuse in the 12 months before psychosis onset (Fig.
5). In contrast, the onset of alcohol abuse and psycho-
sis onset occurred within the same month at a slight
excess rate of 14.5% (Fig. 6), signicantly different
from the rates in the periods before and after.
But in about 87% of the cases with alcohol abuse the
abuse started before or in the month of psychosis onset.
The temporal patterns of onset suggest that canna-
bis abuse might in fact have speeded up the rst-ever
onset of schizophrenia, as hypothesised by Gardner
and Lowinson (1991); Mueser et al. (1990,
1992a,b), in a small proportion (one third at the
most) of the 35% of the rst-onset cases of schizo-
phrenia with drug abuse. Alcohol abuse seems to have
had a considerably weaker effect of the same type
(affected were about 15% of the cases). The precipita-
tion of the rst psychotic symptom by alcohol abuse
in a very small proportion of cases requires
replication.
Fig. 6. Sequence of onset of alcohol abuse and rst psychotic symp-
tom.
248 B. Buhler et al. / Schizophrenia Research 54 (2002) 243251
Fig. 7. Five-year course of positive symptoms by substance abuse in
the early course. Source: Hafner et al., 1999b, modied
3.1. Consequences of alcohol and drug abuse in the
early course for the medium-term course of
schizophrenia
Few studies have looked into the consequences that
a history of substance abuse before the rst treatment
contact might have for the further course of schizo-
phrenia. Most studies focus on substance abuse only
after rst contact, an event that takes place ve to six
years after the onset of the disorder on average
(Hafner et al., 1995). Most studies cover only short
follow-up periods of one or two years (Martinez-
Arevalo et al., 1994; Linszen et al., 1994). In one
controlled study (Caspari, 1999), schizophrenic
patients with cannabis abuse at index admission
were followed up over a period of 68.7 months on
average and compared with schizophrenic patients
without substance abuse, matched for age, sex and
year of hospital admission. The patients with cannabis
abuse had signicantly more inpatient days, poorer
social adjustment, a higher score of hostility and a
signicantly higher frequency of psychotic thought
disorders than controls.
Because of the small numbers we lumped patients
with cannabis (n 4), alcohol (n 13) and
combined abuse (n 12) together for this analysis.
The comorbid patients were compared with 29 non-
comorbid patients, matched for age and sex, from the
rst-episode sample (n 115). Fig. 7 shows the
scores for positive symptoms in the rst illness
episode and at ve following assessments over ve
years after rst admission. At each assessment the
substance-abusing group showed a higher CATEGO
DAH score ( positive symptoms) than the non-
abusing group with a signicant difference in the
overall test. As expected, the difference was most
pronounced in the periods characterized by high
symptom scores, i.e. in the rst psychotic episode
p , 0:003 and six months later p , 0:02. This
result is in line with results from other controlled
follow-up studies (Addington and Addington, 1998;
Caspari, 1999) and provided support for the hypoth-
esis (no. 4) postulating that substance abuse in the
initial stage of schizophrenia might increase positive
symptoms in the further illness course.
To test which category of positive symptoms was
inuenced most, we counted for each patient the
number of months per year spent with hallucinations,
delusions or psychotic thought disorders (Fig. 8). The
values for all three symptom categories were higher
for patients with than without substance abuse: hallu-
cinations were present for 1.8 months per year in
substance abusers and for 0.6 months p , 0:05 in
nonabusers. Psychotic thought disorders were present
for 2.8 months per year in substance abusers and for
1.3 months per year in nonabusers p , 0:09. For
delusions the corresponding gures were 2.4 as
against 1.4 months per year, but the difference missed
signicance due to the small numbers.
As to negative symptoms, substance abusers had
slightly, but non-signicantly lower SANS global
scores over the ve-year follow-up period. An analy-
sis of negative symptoms by the SANS subscales in
substance abusers showed that the trend of decrease
was most pronounced in affective attening. This
difference between abusers and nonabusers became
more marked over the ve-year period and attained
signicance at the last assessment p , 0:03 (Fig. 9).
Fig. 8. Prediction of psychotic symptoms ve years after rst admis-
sion by substance abuse in the early course.
 B. Buhler et al. / Schizophrenia Research 54 (2002) 243251
Fig. 9. Five-year course of affective attening in patients with and
without substance abuse in the early course.
3.2. Need for treatment and social outcome
Of the 29 patients without substance abuse 25
( 87.2%) could be assessed ve years after rst
admission, of the 29 patients with substance abuse,
only 21 ( 72.4%). The rest could not be reached
or were not available. No suicides occurred.
The number of days spent in hospital per patient in
the ve-year period was higher for patients with (170)
than without (131) substance abuse, but the difference
did not reach signicance. The number of months
with insufcient therapy compliance was cumulated
in the same way over the ve-year period: the group
with substance abuse showed a mean of 33.6 months,
the group without substance abuse a mean of 24.6
months p , 0:04. This result supports the hypoth-
esis (no. 5) postulating a poorer therapy compliance
and a tendency to a greater need for inpatient treat-
ment in schizophrenic patients with substance abuse.
Social disability was assessed using the DAS-M
(WHO, 1988; Jung et al., 1989). Patients without
substance abuse scored on average 1.65 on a ve-
point scale, whereas patients with substance abuse
had a slightly, but not signicantly higher score of
1.74 at the ve-year assessment.
As an indicator of ve-year social outcome, the
patients' occupational status was assessed, as based
on four categories: `in regular employment', `in
Table 2
Social status ve years after rst admission in schizophrenic patients with and without substance abuse
Employed In school or vocational training
Substance abusers 7 (33.3%) 1 (4.8%)
Non-abusers 10 (40.0%) 2 (8.0%)
249
school or occupational training', `unemployed' and
`in rehabilitation'.
33% of the patients with and 40% of those without
substance abuse had a regular job at the ve-year
assessment. At 57.1% almost twice as many patients
with than without substance abuse (28.0%) were
unemployed (hypothesis no. 6). This difference,
which did not attain signicance, was almost entirely
accounted for by the fact that only 4.8% of the
substance-abusers, but 24% of the nonabusers were
in rehabilitation p , 0:05 (Table 2). This result
presumably reects poorer compliance, which affects
not only pharmacotherapy, but also these patients'
willingness to participate in rehabilitative measures.
In any case it is notable that a lack of early rehabili-
tative measures may contribute to a poor social
outcome in comorbid patients.
4. Discussion
Our study conrmed that the abuse of illegal
drugs in the population studied especially of
cannabis and the abuse of alcohol, starting
somewhat later, set in at a surprisingly early
stage in schizophrenia. As many as 82.7% of the
schizophrenic patients with a history of drug abuse
and 72.7% of those with a history of alcohol abuse
had taken up the habit in the initial stage of schi-
zophrenia before the rst psychiatric contact. The
age of onset of schizophrenia is signicantly lower
for drug abusers than for alcohol abusers and
markedly lower than for patients without any
type of abuse. This temporal sequence and the
highly signicant accumulation of simultaneous
onsets of drug abuse and schizophorenia strongly
suggest that, in a small proportion, schizophrenia
onsets might be precipitated by the onset of drug
abuse and, more rarely, by the onset of alcohol
abuse in persons predisposed to schizophrenia
Unemployed In rehabilitation
12 (57.15%) 1 (4.8%)
7 (28.0%) 6 (24.0%)
250 B. Buhler et al. / Schizophrenia Research 54 (2002) 243251
(Mueser et al., 1990, 1992a,b; Gardner and Lowin-
son, 1991).
Unexpectedly, we were unable to conrm the
neurobiological hypothesis postulating that the
abuse of dopaminergic substances, such as cannabis,
might trigger rst psychotic episodes: in the case of
drug abuse our data ran counter to the hypothesis, in
the case of alcohol abuse, there seemed to be a small
likelihood of a premature precipitation of psychosis.
Our results on how substance abuse in the early
course of schizophrenia inuences the ve-year
course of schizophrenia from rst admission on are
more or less in line with results from rst-admission
studies (Allebeck et al., 1993; Rosenthal et al., 1994;
Soyka, 1994; Addington and Addington, 1998;
Caspari, 1999). Substance abuse in the early illness
course was associated with an increase in positive
symptoms, especially hallucinations and psychotic
thought disorders. The question whether the increase
in positive symptoms was accounted for by a direct
effect on dopaminergic neurotransmission or by
reduced compliance could not be answered from our
data, because the numbers were too small.
Unlike positive symptoms, negative symptoms
were slightly, though non-signicantly reduced, as
also reported by Addington and Addington 1998;
Peralta and Questa, 1992; Kovasznay et al., 1997.
Signicantly reduced and to an extent growing over
time was one component of the negative symptoma-
tology, namely affective attening. This result
suggests that some patients suffering from schizophre-
nia abuse drugs as a dysfunctional way of coping with
the unpleasant phenomena of bluntness and indiffer-
ence. In doing so, they seem to put up with an increase
in positive symptoms (Schneier and Siris, 1987;
Noordsy et al., 1991).
Both treatment and social outcome ve years after
rst admission are adversely inuenced by substance
abuse in the early illness course. Compliance with
antipsychotic medication is reduced, as also shown
by Martinez-Arevalo et al. (1994) and other authors.
As a consequence, the number of inpatient days was
slightly increased. An elevated rate of readmissions
has also been reported by Drake et al., (1989), and
Caspari (1999).
In our sample, the social consequences of substance
abuse were fairly moderate. Contrary to several
studies conducted among patients with chronic schi-
zophrenia our study did not yield markedly elevated
scores for social disability. But a signicantly
increased rate of unemployment at the ve-year
assessment emerged as a clear indicator of unfavour-
able social consequences. The excess unemployment
was mainly accounted for by a reluctance of substance
abusers to take part in rehabilitative measures.
Perhaps this was just one more sign of a poor treat-
ment compliance.
The result of fairly moderate social consequences in
our sample usually they emerge with a certain
delay can presumably be explained by the patients'
low mean age (27.6 years) and their early illness
stage. Another factor was probably the limited avail-
ability of hard illegal drugs and the low rate of their
abuse in the population studied.
Overall, our study indicated that alcohol and drug
abuse, astonishingly frequent among patients with
schizophrenia before rst admission, has considerable
effects on symptoms, need for treatment and social
outcome in the further course of the disorder. This
nding underscores the need for early intervention,
as already provided at the Australian EPPIC centre
(McGorry et al., 1996).
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