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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 theHealth | Volume 4 | Issue 2 | 15 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). 16 | theHealth | Volume 4 | Issue 2 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 theHealth | Volume 4 | Issue 2 | 17 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. References 1. United Nations Office on Drugs and Crime (UNODC). 2002. Global Illicit Drug Trends New York, NY. Available at: http://www.unodc.org/pdf/report_2002-06-26_1/report_2002-0626_1.pdf [Accessed on 27 June 2013]. 2. United Nations office on Drug and Crime (UNODC). 2011. World Drug report on Annual Cannabis use by Country. Available at: http://www.unodc.org/documents/data-andanalysis/WDR2011/World_Drug_Report_2011_ebook.pdf [Accessed on 27 June 2013]. 3. Iversen LL. The Science of Marijuana (2nd edition). 2008. New York: Oxford University Press. 4. 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Buckley P, Thompson P, Way L, Meltzer HY. Substance abuse among patients with treatment-resistant schizophrenia: characteristics and implications for clozapine therapy. Am J Psychiatry. 1994;151:385-9. 21. Drake RE, Xie H, McHugo GJ, Green AI. The effects of clozapine on alcohol and drug use disorders among patients with schizophrenia. Schizophr Bull. 2000;26:441-9. 36. Tarricone I, Casoria M, Gozzi BF, Grieco D, Menchetti M, et al. Metabolic risk factor profile associated with use of second generation antipsychotics: a cross sectional study in a Community Mental Health Centre. BMC Psychiatry. 2006;6:11. 37. Maayan L, Correll CU. Management of antipsychotic-related weight gain. Expert Rev Neurother. 2010;10:1175-200. 38. Downey M. Age related metabolic decline and weight gain. Life Extension Magazine. December 2012. 22. Ujike H, Morita Y. New perspectives in the studies on endocannabinoid and cannabis: cannabinoid receptors and schizophrenia. J Pharmacol Sci. 2004;96:376-81. theHealth | Volume 4 | Issue 2 | 19