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theHealth 2013; 4(2): 14-19
Research Article
Emerging psychoses due to cannabinoid use Clozapine as a tool for early intervention
Sarhandi I
Department of Psychiatry, Sulaiman-Al-Rajhi Colleges, Bukyria, Qaseem, Kingdom of Saudi Arabia
Correspondence
Ishaque Sarhandi
Department of Psychiatry,
Sulaiman-Al-Rajhi Colleges,
Bukyria, Qaseem, Kingdom of
Saudi Arabia
E-mail:
[email protected]
Keywords:
Cannibinoids, Clozapine, Early
intervention, Psychoses
Abstract
Background: With an estimate, 150m people worldwide are smoking or eating marijuana
leaves annually. About 12% of patients having their first episode of psychoses emerging due to
Marijuana use, are later on diagnosed as having schizophrenia. This study was conducted to see
the effects of clozapine in patients presented with emerging psychoses due to marijuana use for
the first time.
Methods: An observational study was conducted on patients of either sex irrespective of age
Funding
None
presenting psychotic symptoms due to marijuana use for the first time having no co-morbid
physical illness were included in the study. Outcome evaluations were carried out by a rather
blinded to the treatment history of the subjects. Statistical analysis was performed by SPSS-17.
Competing Interest
None
Results: Patients showed remarkable improvement in their clinical state as p-value stands
Received: March 21, 2013
Accepted: June 22, 2013
significant (<0.001) in terms of their PANNS and BPRS scores during their first 6 months of
treatment. The CGI was 6+1 during the same period. The p-value for total neutrophil count,
systolic and diastolic blood pressure along with the weight was also significant (<0.001).
Conclusions: Clozapine offers promise to mitigate emerging pscyhoses due to marijuana use.
The difficulties of using clozapine have reduced its acceptability to patients and still pose a major
hurdle to its more widespread use.
Introduction
With an estimated 150 million people worldwide smoking or eating marijuana leafs annually, an annual prevalence rate as high as
13.7% has been reported in the USA.1, 2 Unlike
alcohol, cocaine or heroin, marijuana is perceived as an innocuous drug in many circles
due to its association with cultural and religious
rituals. Nevertheless, this perception is fast
changing due to induction of illicit psychotic
disorders.3-5 Given the seriousness of the problem, it is therefore imperative to sort out the
disagreement and uncertainty surrounding the
nature of the interaction between cannabis and
psychotic disorders.6
ISSN (print): 2218-3299
ISSN (online): 2219-8083
In addition to other constituents, cannabis delta- 9 -tetrahydro-cannabinol (THC) is the main
psychoactive constituent in cannabis which interacts with the endogenous cannabinoid receptor system consisting of G-protein-coupled
receptors CB1 and CB2.7 CB1 receptors are
highly concentrated in brain region with specific localization on pre-synaptic terminals of
both inhibitory and excitatory neurons.8 Their
activation mediates behavioral and physiological effects of both endogenous and exogenous
cannabinoids in the brain.9 Moreover, CB1
14 | theHealth | Volume 4 | Issue 2
receptor activation modulates neurotransmitter
release to maintain homeostasis via suppression
of neuronal activity in the central nervous system.10 While elucidating the mechanism, it was
observed that THC enhanced the dopaminergic
activity in mesolimbic reward pathway which
was responsible for the abusive property of
the drug and for the positive psychotic symptoms induced by THC.11 Recurrent cannabis use
produces excessive stimulation of CB1 receptor
to disrupt endo-cannabinoid system function. It
has also been proposed that CB1 receptor
overstimulation contributes in triggering THCinduced psychosis.12
Clinical studies showed up to 40% increased
risk of psychosis in a dose-dependent manner
in cannabis users as compared to the non-users
and increased from 50% to 200% in the frequent users as compared to the non-users.13
These data has been validated by two other
clinical studies which reported primary psychotic disorder odds ratio of 2.6 for patients who
had ever used cannabis compared with nonusers.14 Further analysis of the data showed that
the onset of psychosis in cannabis users was
multi factorial wherein the age at which cannabis use was started remained a key determinant factor to increase the risk of schizophrenia
Emerging psychoses due to cannabinoid use
during the later part of their life.15 The propensity and extent
to which cannabis use alters the clinical course of schizophrenia remains a point of contention.16 There is mounting evidence in literature that schizophrenics who use cannabis experience increased psychotic symptoms as well as relapse of
the symptoms and have greater likelihood of rehospitalization and poor therapeutic response to antipsychotic medication.17 Furthermore, pre-onset cannabis use triggers
an earlier age of dose-dependent onset of psychosis which is
of critical importance given the negative prognostic features
associated with earlier onset.18
Clozapine treatment of schizophrenic patients co-morbid with
substance abuse had good prognosis and that too without
any fatal adverse or disabling side effects in comparison
with schizophrenic psychoses with complete abstinence or
partial reduction in use (amount) of canibinoids.19-21 A 10
year follow-up study showed that clozapine more effectively
reduced the substance misuse besides diminished incidence of
relapse as compared to other antipsychotic agents.22 There
was lack of evidence that clozapine can be offered to patients as first line of treatment to treat psychoses, but now
there is an evidence that it has been offered in the first month
of their treatment for first episode of psychoses. 23
A survey of the patients taking clozapine showed that in 87%
patients the advantages of the clozapine out-weighed the
disadvantages.24 In the light of these data, reluctance of clinicians to prescribe clozapine even for treatment of resistant
schizophrenia is being regarded as a negative belief linked
to limited experience and knowledge in terms of advantages
of the agent.25 It is now agreed that the patients who develop psychotic illness without treatment for long periods develop biological, psychological and social effects which add to
subsequent chronicity of the illness.16
These facts have forced us to see the effects of clozapine in
patients presenting with emerging psychoses due to cannabinoid (marijuana) use for the first time as a tool for early
intervention to prevent further episodes of psychoses, emergence of schizophrenia or psychoses attaining chronicity.
Methods
The study is a multi-center prospective observational study
and was conducted at psychiatry department of the tertiary
care hospitals and a private psychiatric hospital from 1st Jan
to 31st Jan 2011. Every patient who was included in the
study was given an informational care session along with his
attendants regarding use of clozapine and the necessity of
using clozapine on that particular patient to reach the level
of informed consent, which is to be signed by the patients’
blood relative. Ethical approval was obtained from the concerned ethical committee.
Inclusion & exclusion criteria
Patient (all male) from age group >15 years, having no comorbid physical illness or pre-existing psychiatric illness were
included in the study. Only the patients’ exhibiting psychotic
symptoms due to use of cannabinoids for the first time in their
life time were included in the study. The personality issue was
not assessed to limit the extent of the study.
Patient of any age group having any pre-existing psychiatric
illness or any physical illness were excluded from the study
even if they were using cannabinoid and developed psychotic episode (Fig. 1).
Assessments
The assessment was done at week zero marking this assessment as baseline control for comparison with the final assessment in the same group. The assessments were done on the
first day of 6th month and the last day of the year. Outcome
evaluation was carried out by a rater who was a post
Study Population (n=53)
Lost follow up (n=12)
Stopped taking medication
during the study (n=11)
Dropped in the beginning of
the study (n=7)
American citizens from Pakistani origin (n=3), Pakistani (n=7), and Afghani (n=2)
Duration of compliance
ranged from 4-6 months and
restarted with marijuana.
Completed study (n=23).
Clozapine was stopped after
one year. There was no history
of relapse observed in patients who completed their
study period.
Relapsed within 3 months
(n=6) of restarting with
marijuana. The researcher
tried to communicate with
the other five patients’ and
their families to extend help
but they were not interested.
Attending follow up clinic for
therapy session (n=23)
Figure 1: Classification of study population
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Emerging psychoses due to cannabinoid use
Table 1: Characteristics of the study population
Characteristics
Table 2: Comparison of patients with emerging psychoses
N (=53)
Variable
PANSS
BPRS
Single
31
Baseline (n=53)
96.3 (16.6)
38.4 (9.7)
Married
07
6 Months (n=41)
17.3 (9.2)
3.1 (1.8)
Separated
15
12 Months (n=23)
5.2 (3.6)
-
Divorced
0
P-value
Widowed
0
Data is mentioned as number (SD).
Age - yrs
14-20
21-25
26-30
31-35
36 and above
<0.001
PANSS, blood CP, BP and weight from baseline to 12 months
follow-up whereas Student t-test was used to compare means
± SD of BPRS from baseline to 6 months follow-up. P-value
<0.05 was considered statistically significant.
13
22
07
10
0
Results
graduate student in discipline of psychiatry trained to do so,
supervised by a senior psychiatrist, both blinded to the treatment history of the subjects.
The clozapine was started as per protocol of manufacturers20, increment of 25mg per week was added to the starting
dose (25mg). The maximum dose used was 350mg. Mean
dose calculated was 172.5mg. The variation in dosage was
due to varying intensity of psychotic process of the patients.
Psychosocial measures contingency management along with
early behavioral intervention approaches26 were used as an
adjuvant measures to control the weight gain, dropouts and
the side effects of the medications. Injection Haloperidal
PRN 5mg to 15 mg was used in the initial period of management at the time of emergency to control the unmanageability of the patients during the initial phase of the study.
The ICD-10 was used as the diagnostic tool during the study.
Complete record of blood CP, blood pressure and weight
was kept during each assessment of every patient. The instruments used were six point version of positive and negative
syndrome scale (PANSS), brief psychiatric rating scale (BPRS)
and clinical global impression scale (CGI).
Statistical analysis
Data was analysed by SPSS version 17. Frequencies computed for categorical variables like marital status and age
groups. Mean ± Standard Deviation (SD) computed for numerical variables like PANSS, BPRS, CGI, blood CP, BP and
weight. ANOVA was applied to compare the means + SD of
The total number of patients’ were 53. The age of the patients’ ranged from 14 to > 36 years (table 1). The number
of the single and separated patients were 31 and 15 respectively. During the recruitment process most of the participants included in study were very young belonging to the
age group of 14 to 25 years. This observation indicated that
major portion of the participants were young and had their
first episode of psychoses in their early age. P-value stands
significant for the PANSS from baseline to 6 months and further reduced at the end of the study (Table 2).
The BPRS showed the decline in 6 months (Table 2). The CGI
at the baseline was 6±1 showed encouraging reduction to
2±1 at 6th month. The patients exhibited improvement.
Table 3 describes most feared side effects related to the use
of clozapine. The variation in the neutrophil count varied from
10.1 ± 2 to 9.4 ± 1 and 9.1 ± 1 respectively from baseline
to 6 months and 1 year. The variations in the systolic BP at
the same time period of assessment were recorded as ranging from 115mmHg + 5 to 105mmHg + 4 and 101mmHg +
4 respectively. The diastolic BP at the same assessment period was recorded as 79mmHg + 4 to 69mmHg + 3 and
76mmHg + 4 at the end assessment after one year. The assessment on weight gain showed significant values ranged
from 45.7kg + 6.7 at the base line to 46.1kg + 4.2 at the
6th months period to 50.3kg + 3.1 at the end of the study
period.
Table 3: Comparison of patients with emerging psychoses
Variable
Baseline (n=53)
6 Months (n=41)
12 Months (n=23)
P-value
Total leucocyte count
10.2 (2)
10.6 (1)
10.5 (1)
0.32
Total platelet count
302 (26)
301 (21)
291 (13)
0.01
Total neutrophil count
10.1 (2)
9.4 (1)
9.1 (1)
<0.001
Systolic BP - mmHg
115 (5)
105 (4)
101 (4)
<0.001
Diastolic BP - mmHg
79 (4)
69 (3)
76 (4)
<0.001
45.7 (6.7)
46.1 (4.2)
50.3 (3.1)
<0.001
Weight - kg
Data is mentioned as number (SD).
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Emerging psychoses due to cannabinoid use
Discussion
This study has surely made an effort to look for a strategy
for managing these patients. Its a fact that compared to psychoses unrelated to marijuana, marijuana associated psychoses is emerging as more challenging to treat.
A 10 year follow-up study showed that schizophrenic patients
on clozapine and in remission had 8% relapse risk in following year compared to 40% on typical antipsychotics.27
Whatever approach the clinicians have in their mind to deal
with the illness, the psychoses must be addressed at the earliest. If the psychosis is allowed to progress, the symptoms tend
to run amok, they may trigger plastic changes in circuit synapses, recruiting additional sick circuits. Thus in turn eliminating healthy compensatory mechanisms henceforth triggering
the phosphorylation of the critical regulatory proteins. So, a
bad situation gets worse.28 The present trend as evident from
the various clinical studies has shown that, the clozapine is
now very frequently used in the indications not approved by
Food and Drug Administration (FDA).29 It is a valid point to
note that the clozapine is now been used in the first episode
of psychoses as early as in the first month of psychoses. 23
Furthermore, early onset psychoses is resistant to treat and
may convert into a chronic one along with the tendency to
relapse frequently causing serious impairment in their development and functioning.30 In the present study most of the
participants belong to the age group of 14 to 25 yrs exhibiting an early psychoses due to cannabinoid use. This observation is highly alarming and with the warning trends globally
that psychoses in the early age is dangerous and is been
taken as a key determinant factor to increase the risk of
schizophrenia.15
The pre-onset cannabis use triggers an earlier age of dosedependent psychosis which is of critical importance given the
negative prognostic features associated with earlier onset.18
Here the debate is, weather we are ready to be vigilant
enough at this point in time for these patients or will not
change our mind set and continue with the unjustified strategies as studied by Taylor24 and Nelson.25
Given with all the above discussion, a case is always on for
the clinicians to think for the need to look for doing something
else instead of going in with old strategies which stand less
effective22 to some different kind of strategy, expecting to
prove better for the patients and could subsequently save
them from lending into a chronic psychotic state.
It is encouraging for the researchers to look on to the findings
of a survey where 87% of patients taking clozapine appreciated the advantages of the clozapine and out-weighed the
disadvantages.24 In addition to this observation, the reluctance of clinicians to prescribe clozapine even for the treatment resistant schizophrenia regarded as a negative belief
and is linked to the limited experience and knowledge in
terms of advantages of the clozapine.25 This has stigmatized
the clozapine use and rendered it as a dangerous or orphan
agent.
As a psychiatrist, it is our ethical duty to analyze the facts on
true basis without fear, look into the material available carefully and decide about it’s use based on evidence. A recent
and very welcome debate is on the changing trends from
evidence based medicine to the preference based medicine.
Where a clinician has to develop a proper setup, has to look
into values, has to de-bias strategies, has to respond to the
emotions, has to tailor a recommendation and has to seek
consensus, thus will be reducing the debatable issue of putting too much burden on patients in the interest of patients
autonomy.31 This newer trends provides ground for the clinicians to try and tailor a new strategy for the patients without
fearing for an adverse situation which is not based on reality,
rather based on the clinician’s limited experience and
knowledge, who are switching into poly-pharmacy as an answer instead of using clozapine, henceforth add to the burden of side effects as compared to the side effects caused
by clozapine.32
This study has tested clozapine as a tool for early intervention to save bad situation getting worse. As evident from the
results, PANSS showed declining scores from 96.3 at zero
baseline control week to 16.6 at 6 months and 5.2 after 1
year. Same was also observed with BPRS, the decline was
from 38.4 at zero baseline control week to 3.1 at 6 months.
The CGI was almost touching the baseline after 2 months
starting from 6 on baseline control week. These results are
promising and require further testing with increased number
of patients and at different centers with different researchers
using the same parameters.
The most feared side effects of agranulocytosis was not seen
in any of the patient included in the study, even with those
who remained in till very end of the study. This fact has been
proved by other studies done in Europe33, USA34, India34 and
Pakistan.35
Another deleterious and feared side effect is the weight
gain, the mean weight gain exhibited in this study was 4.4kg
in a year and the major duration of weight gain is seen in
between 6 months to 1 year, that is 3.2 kg.
Comparing the results of this study with other international
studies in terms of weight gain and appearance of metabolic
syndrome, there is no doubt that these are the most common
deleterious side effects following treatment with second generation antipsychotic drugs such as clozapine and olanzapine.
However, the exact mechanisms underlying these negative
effects of second generation antipsychotic drugs are not fully
understood.36
In general, the clinician use various strategies to reduce the
cardio-metabolic risk of antipsychotics switching to various
techniques, however, each of these strategies has only been
shown to be modestly effective. Among different behavioral
interventions, dietary counseling and cognitive-behavioral
therapy seem to be more effective.37 The contingency management and Mario’s early behavioral intervention technique
were used in this study to counter the excessive weight gain
caused by the clozapine.26
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Emerging psychoses due to cannabinoid use
The vigilance and the motivation on part of the researcher to
implement these techniques are looked as working and could
be one of the reason for comparatively less weight gain in
the present study as compared to other studies which exhibit
weight gain up to 17 pounds in a year.38 Other observations
regarding weight gain include maximum weight gain acquired by the patients in between 6 months to 12 months
during the study. The probable explanation to this observation stands with the statement that, the increase in weight
during this period probably as the first instance was due to
increased follow-up period of patients (1 month) . Secondly
the patients because of this period were away from vigilance
practiced by the clinicians to implement the behavioral interventions provided to them, along with the contingency management approaches, in a way it can be assumed that there
was lack of compliance for the adjuvant measures by the
patients, and the better compliance was observed when patients were followed up on frequent intervals. So this point
stresses upon the need to strive for required modifications in
the adjuvant measures. Whatever the reason may be, the
weight gain by all means is a major cause of concern and
stress the need for more effective tools, so that the weight
gain could be minimized.
The observation related to the age of the participants in present study, as evident most of the participants were from the
age group 14 to 25 years. It has been suggested from various studies that as an individual land up into the ageing process, a decrease in our physical abilities lead to a decrease
in our metabolic rate, which in turn contributes to weight gain.
The physiological changes that accompany increasing age
affect body’s composition, thus reducing our ability to work,
exercise, and lose weight.37 The debate on weight gain
caused by clozapine, a point worth mentioning over here. Is
clozapine is the only agent causing excessive weight gain,
this has been proved by many studies that this is not the
case.37, 38
If this is not the case, why only clozapine is been accused,
where olanzapine is the agent which causes more weight
gain as compared to clozapine.37 If we agree to this statement, a question is very pertinent here; are we equally cautious to start with olanzapine? Are we using the same kind of
parameters in patients on olanzapine? The clinician know that
the status while using other antipsychotics is totally different,
though all the atypical antipsychotics cause weight gain.
These days a debate is focused on the role of gene variance
in causing weight gain to individuals, it is postulated that individuals having gene coding of T-allele and G-allele are
prone to have more weight. An individual who happen to be
a patient and been put on clozapine or any other atypical
antipsychotics having above mentioned alleles, will eventually
gain weight.37
With all these arguments, statement stands valid here; we as
a clinician should evaluate the issue of using clozapine, based
on the update knowledge and one should always avoid those
attitudes exhibited by the clinicians studied by Taylor24 and
18 | theHealth | Volume 4 | Issue 2
Nelson25 to come up with making an excuse to use clozapine.
The present study was designed keeping all these issues in
mind with due vigilance towards any side effects and hoping
for a good outcome during the course of study which is evident from the results from PANSS, BPRS and CGI scores declining to satisfactory levels in due course of time and there
were none of feared side effects seen leading to their better
quality of life.
Almost all therapeutic agent exhibit side effects, but they are
used whenever they are needed, the strategy is to save the
life of the patient. Schizophrenia is an illness if started in the
early age, is going to have a lifelong impact on the developing brain of the patients and it is the time when most of the
faculties are maturing for an individual to have a lasting and
stable application of his/her personality.30
The present study has it’s worth as an attempt to try clozapine as an effort to save the situation in landing into a state
mentioned above, as a tool in addition to what we have in
hand for patients suffering from cannibinoid induced psychoses and especially for those who have developed this kind of
psychoses in their early age.
The limitations to study were, the sample size of population
was small and there were no females in the study. So a major
part of population remained untested. After dropouts, lost to
follow-up and noncompliance of patients the number of remaining patients were low. A long term follow-up of patients
for those who has completed their study period would have
been very interesting.
Conclusion
Much more effort and research as the present one is the need
of the time to address the issue of emerging psychoses due to
marijuana use. Presently, as the medication like Rimnobant
and other pharmacological agents are in pipeline and remain to be tested. Clozapine as one of the atypical antipsychotics offering some promise to mitigate the emerging psychoses due to marijuana use as a tool for early intervention.
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