Secondary Schizophrenia (69 page)

18 predicted an increased risk of psychotic symptoms
Arseneault and colleagues found a relationship
at age 21 years (RR of 2.3). This association was smaller
between cannabis use by age 15 and an increased risk
but still significant after adjustment for potential con-of psychotic symptoms by age 26. Controlling for other
founders (RR of 1.8).

drug use did not affect the relationship. The relation-More recently, Fergusson and colleagues exam-ship was no longer statistically significant after adjustined the association between cannabis and psychotic
ment for reporting psychotic symptoms at age 11,
symptoms until age 25 years with the same cohort of
which probably reflected the small number of psy-young adults, using a more sophisticated fixed-effects
chotic disorders observed in the sample. The small
regression analysis and structural equations modeling
number of cases also limited the ability of the study
to account for both observed and nonobserved con-to examine predictors of psychotic disorders at age
founding factors
[35]
. As with their earlier study, they
26. The measurement of cannabis and other drug use
concluded that the association between cannabis and
was crude (i.e., none, 1, 2, and 3 or more times),
psychosis did not appear to be explained by measured
although this was more likely to work against finding
or unmeasured confounding factors. The structural
relationships. There was no relationship between other
equations modeling suggested that the direction of the
drug use and psychotic disorders and no relationship
association appeared to be from cannabis use to psy-between cannabis use and depression. There was also
chotic symptoms rather than vice versa.

an interaction between psychosis risk and the age of
The longitudinal studies have found consistent
onset of cannabis use, with earlier onset being more
associations between cannabis use in adolescence and
strongly related to psychosis. In addition, there was the
psychotic symptoms in early adult life but all share
suggestion of an interaction between cannabis use and
a weakness: uncertainty about the temporal relation-vulnerability, with a higher risk of psychosis among
ship between cannabis use and the timing of the
cannabis users who reported psychotic symptoms at
onset of psychotic symptoms. Subjects in these studies
age 11.

have usually been assessed once a year (or less often)
Caspi and colleagues
[33]
subsequently reported
and they have typically reported retrospectively on
an analysis of data from this cohort on an interaction
their cannabis use during the preceding period, often
172

between risk of psychosis and cannabis use and a func-crudely as to the number of times that cannabis was
Chapter 11 – Schizophrenia secondary to cannabis use

used, or the number of times it was typically used per
medication hypothesis; the relationship flowed from
week or month.

early cannabis use to psychosis rather than vice versa.

A French study provides greater detail on the tem-Their negative results have been supported by the Ver-poral relationship between cannabis use and psychotic
doux and colleagues study of the temporal relation-symptoms using an experience sampling method
[36].

ship between cannabis use and psychotic symptoms
These investigators asked 79 college students to report
using an experience sampling method
[43];
and in a
on their drug use and experience of psychotic symp-recent prospective Australian study of persons with
toms at randomly selected time points, several times
psychosis who used cannabis
[37].
This evidence does
each day over 7 consecutive days. The ratings were
not rule out the possibility that persons with psy-prompted by randomly programmed signals sent to
chosis use cannabis to control some of their symp-a portable electronic device that the students carried.

toms or to improve their mood but it makes it unlikely
The students were a stratified sample from a larger
that the self-medication hypothesis wholly explains
group so that high cannabis users (N
=
41) and stu-the relationship observed between cannabis use and
dents identified as vulnerable to psychosis (N
=
16)
psychosis.

were over-represented in the sample. Vulnerability to
psychosis was indicated by reporting one or more psy-

Intervention studies

chotic symptoms in the past month during a personal
If we could reduce cannabis use among patients with
interview.

schizophrenia, then we could discover if their risk of
Verdoux and colleagues
[36]
found a positive
relapse was reduced. The major challenge in doing so
association between self-reported cannabis use and
is, knowing how to reduce cannabis use in persons with
unusual perceptions and a negative association
schizophrenia. There are very few controlled outcome
between cannabis use and hostility. That is, in time
studies of substance abuse treatment in schizophrenia
periods when cannabis was used, users reported
[44]
and few of these have produced large enough ben-more unusual perceptions and less hostility. These
efits of treatment or treated a large enough number of
relationships depended upon vulnerability to psy-patients, to provide an adequate chance of detecting
chosis: in vulnerable individuals cannabis use was
any positive impacts of abstinence from cannabis on
more strongly associated with strange impressions
the course of the disorder. A recent Cochrane review
and unusual perceptions and its use did not decrease
identified only six relevant studies, four of which
feelings of hostility in the way that it did in individuals
were small
[45].
The few that have been large enough
who lacked this vulnerability.

[46]
have not reported results separately by diagnosis. The Cochrane review found no clear evidence that
The self-medication hypothesis

supported any type of substance-abuse treatment in
schizophrenia over standard care.

The reasons that most persons with schizophrenia give
for using alcohol, cannabis, and other illicit drugs are
similar to those given by persons who do not have
Biological plausibility

schizophrenia, namely, to relieve boredom, to pro-Recent evidence from research on the neurobiology of
vide stimulation, to feel good, and to socialize with
the cannabinoid system provides biological plausibil-peers
[37, 38, 39].
The drugs that are most often used
ity for a causal relationship between cannabis use and
by patients with schizophrenia are also those that are
psychotic symptoms. First, the principal psychoac-used by their peers, namely, tobacco, alcohol, and
tive ingredient of cannabis, THC, acts upon a spe-cannabis. There is some evidence that some patients
cific cannabinoid receptor (CB1) in the brain
[47]
that
with schizophrenia report using cannabis because its
appears to interact with the dopaminergic system of
euphoric effects help to relieve negative symptoms and
neurotransmission. Second, although the dopaminer-depression
[37, 40, 41, 42].

gic system of the brain has been considered to play
Nonetheless, the self-medication hypothesis was
an important role in psychotic disorders
[48],
there
not supported by the van Os, Henquet, or Fergusson
is increasing evidence that the cannabinoid system
studies
[30,
31, 34].
None of these studies found any
may be directly involved in schizophrenia and related
relationship between early psychotic symptoms and an
psychotic disorders
[49, 50, 51].
For example, CB1

173

increased risk of using cannabis as required by the self-receptor knockout mice show behaviors consistent
Organic Syndromes of Schizophrenia – Section 3

with some of the symptoms of schizophrenia, such as
symptom profiles of schizophrenic patients with his-reduced goal-directed activity and memory for tempo-tories of substance abuse, among whom cannabis was
ral representations
[49]
. Third, elevated levels of anan-the most heavily used drug. Comparisons revealed
damide, an endogenous cannabinoid agonist, have also
that drug abusers had a higher prevalence of hal-been found in the cerebrospinal fluid of persons with
lucinations, delusions, and positive symptoms than
schizophrenia
[52],
and a recent case-control study
those who did not abuse drugs. Jablensky and col-found that persons with schizophrenia had a greater
leagues
[57]
reported a 2-year follow-up of 1,202 first-density of CB1 receptors in the prefrontal cortex than
episode schizophrenic patients enrolled in 10 coun-controls
[53].
Fourth, D’Souza and colleagues
[54]

tries as part of a WHO collaborative study. They
have shown in a double-blind provocation study that
found that the use of “street drugs,” including cannabis
intravenous THC provokes positive and negative psy-and cocaine, during the 2-year follow-up period pre-chotic symptoms in a dose-dependent way in persons
dicted a poorer outcome, as assessed by psychotic
with schizophrenia. Fifth, Caspi and colleagues
[33]

symptoms and periods of hospitalization. Martinez-found a strong interaction between cannabis use and
Arevalo and colleagues
[58]
also reported that con-a common polymorphism in the COMT gene that is
tinued use of cannabis during a 1-year follow-up of
implicated in dopaminergic neurochemistry. This sug-62 DSM-diagnosed schizophrenic patients predicted a
gests a biological basis for the relationship that, if repli-higher rate of relapse and poorer compliance with anti-cated, would explain why the risk of developing a psy-psychotic drug treatment.

chosis after using cannabis is so modest in the popula-Prospective evidence that cannabis exacerbates
tion as a whole.

schizophrenic symptoms has been provided by
Linszen and colleagues
[59].
These investigators con-

Cannabis use and the exacerbation

ducted a prospective study of outcomes in 93 psychotic
patients whose symptoms were assessed monthly over
of schizophrenia

a year. Twenty-four of their patients were cannabis
There have been few controlled studies of relation-abusers (11 were “mild” or less than daily users and
ships between cannabis use and the clinical outcome of
13 were heavy or more than daily cannabis users).

schizophrenia. Negrete and colleagues
[55]
conducted
They found that the cannabis abusers as a whole
a retrospective study using clinical records of symp-relapsed to psychotic symptoms sooner, and had more
toms and treatment seeking among 137 schizophrenic
frequent relapses in the year of follow-up, than the
patients with a disorder of at least 6 months’ duration,
patients who had not used cannabis. There was also
and three visits to their psychiatric service during the
a dose-response relationship between cannabis use
previous 6 months. Negrete and colleagues compared
and the risk of relapse. The heaviest cannabis users
the prevalence of hallucinations, delusions, and hos-relapsed earlier, and more often, than the mild users
pitalizations among the active users (N
=
25), the past
who, in turn, relapsed sooner, and more often, than the
users (N
=
51), and those who had never used cannabis
patients who did not use cannabis. These relationships
(N
=
61). The crude comparison showed higher rates
persisted after adjustment for potential confounding
of continuous hallucinations, delusions, and hospital-variables, including premorbid adjustment, and
izations among active users. This pattern of results per-alcohol and other drug use during the follow-up
sisted after statistical control for differences in age and
period.

sex between the three user groups. They argued that
These results have recently been replicated in a
cannabis use exacerbated schizophrenic symptoms,
prospective study of 100 patients with schizophre-suggesting three possibilities: i) that cannabis disor-nia in Sydney, Australia
[37].
These patients were
ganizes psychological functioning; ii) that it causes a
assessed monthly on medication compliance, cannabis
toxic psychosis that accentuates schizophrenic symp-use, symptoms of depression, and symptoms of psy-tomatology, or iii) that it interferes with the therapeu-chosis over 10 months. Linear regression methods
tic action of antipsychotic medication.

were used to assess relationships between cannabis
More recently, Cleghorn and colleagues
[56],