|Year : 2014 | Volume
| Issue : 3 | Page : 147-154
Symptom resolution in acute mania with co-morbid cannabis dependence
Santosh Kumar1, Suprakash Chaudhury2, Vidhata Dixit1
1 Department of Psychiatry, Rohilkhand Medical College and Hospital, Bareilly, Uttar Pradesh, India
2 Department of Psychiatry, Pravara Institute of Medical Sciences, Deemed University, Rural Medical College, Loni, Maharashtra, India
|Date of Web Publication||7-Oct-2014|
Department of Psychiatry, Pravara Institute of Medical Sciences, Deemed University, Rural Medical College, Loni - 413 736, Ahmednagar, Maharashtra
Source of Support: None, Conflict of Interest: None
Context : Though the co-morbidity of cannabis use disorder is common in patients of bipolar disorder, there is a paucity of Indian studies evaluating the effects of cannabis on symptoms of bipolar disorder. Aim : To study pattern of resolution of symptoms of acute psychotic mania with and without co-morbid cannabis dependence. Materials and Methods : Thirty inpatients of acute psychotic mania with co-morbid cannabis dependence (Group-I) and 30 without co-morbid cannabis dependence (Group-II) were assessed on day-0, day-7, day-14, day-21, day-28, and day-42 for manic and psychotic symptoms with the help of Young Mania Rating Scale (YMRS) and the Brief Psychiatric Rating Scale (BPRS). Results : Acute phase treatment response was noticed around day 21-28 of admission in majority of the patients of both groups. Both the groups were comparable on manic and psychotic symptoms prior to day-28 assessment. Patients of Group-I obtained significantly higher mean score of the item 'irritability' of YMRS and 'psychological discomfort' subscale of BPRS on day 28 and day 42. Group-I patients required significantly higher doses of mood stabilizers and antipsychotics compared to Group-II patients. Conclusion : Patients of mania with co-morbid cannabis dependence showed delayed resolution of manic and psychotic symptoms, specifically irritability and psychological discomfort, and needed higher doses of medication for control of symptoms in comparison to mania patients without co-morbid cannabis dependence. Comprehensive evaluation of patients with bipolar disorder should include a detailed assessment for cannabis use disorder.
Keywords: Acute mania, co-morbid cannabis dependence, symptom resolution
|How to cite this article:|
Kumar S, Chaudhury S, Dixit V. Symptom resolution in acute mania with co-morbid cannabis dependence. Saudi J Health Sci 2014;3:147-54
| Introduction|| |
The co-morbidity of substance-use disorders is very common in bipolar disorder, , more so in bipolar-I than bipolar-II disorder,  and appears to have an indirect and deleterious effect on the course of this disorder. , Barring nicotine intake in different forms, typically alcohol and cannabis are the most often abused substances in patients of bipolar disorder.  In bipolar disorder patients, particularly those of younger age, the rates of cannabis use disorder (CUD) equals or exceeds those of alcohol abuse or dependence. , In India, the use of milder forms of cannabis preparations made of Bhang, which is prepared from dried leaves and flowering-shoots of the cannabis plants, are not legally prohibited and are frequently used by people on different ceremonial occasions.  This results in many patients of bipolar disorders being exposed to this substance. Further, the exposure to stronger cannabis preparations (like ganja, charas etc., with higher amount of delta 9 -tetrahydrocannabinol (Δ9 -THC)), too is on rise.
Advances in cannabinoid receptors and endogenous ligands have renewed interest in the mechanisms by which cannabis can cause major psychiatric disorders.  The endocannabinoid system represents a new signaling process in the nervous system that regulates neurotransmitter systems, energy metabolism, and immune function.  Cannabis consumption during critical phases of brain development can lead to a strong disturbance of the endocannabinoid system and ultimately cause an inappropriate hardwiring of the brain. , Cannabis modulates the activity of dopaminergic, gamma-aminobutyric acid (GABA) ergic, and glutamatergic neurons in the brain and its active ingredient, delta 9 -tetrahydrocannabinol (Δ9 -THC), produces psychotic and hypomanic symptoms.  Repeated and intermittent exposure to cannabis for a long time can bring about a dysregulated hyperdopaminergic state, which may lead to development of psychosis or mania. , In view of these findings and recent claims that "development of manic symptoms in general population is not due to the acute effects of cannabis but to its longer-term exposure"  as well as the finding that among bipolar patients with co-occurring CUD, the median number of manic and hypomanic episodes per year was significantly greater compared to individuals without CUD",  there is a theoretical possibility that co-morbid cannabis dependence can influence presentation and resolution of symptoms of bipolar mania.
The diagnosis of 'Cannabis-modified mania' has been used since the 1970s.  Subsequently, few systematic studies published suggested that cannabis abuse was associated with higher levels of illness severity,  poor treatment adherence,  increased duration or severity of mania, , negative outcome in bipolar disorder. , more hospitalizations, increased risk of suicide, aggression and a poor response to lithium.  It is also claimed that duration of cannabis abuse is positively correlated with duration of mania in new-onset bipolar disorder cases and thereby increasing the duration of manic cycles. 
Prospective studies suggest that cannabis use may affect population expression of manic symptoms (and subsequent risk to develop bipolar disorder). , However, this relationship is not well studied in clinical samples. In a recent study, no significant difference in general manic symptoms between cannabis abusers and nonusers was observed among psychiatric inpatients admitted with various diagnoses like schizophrenia, major affective and anxiety disorders, organic psychotic and affective disorders etc., However, cannabis users were less depressed and showed more severe thought/language disturbances and poorer insight than cannabis non-users. 
Overall, it appears that there is a paucity of research on cannabis and acute manic symptomatology in clinical populations in India, in particular how cannabis use affects presentation and recovery of acute mania. Prompt symptomatic management of acute mania is often desirable in view of substantial legal, civil, work related and social repercussions of acute symptoms of mania, which necessitate hospitalization of the patients. A rapid resolution of acute mania can reduce the substantial personal and economic burdens on patients, their families, and society.  Thus there is urgent need to have evidence of how cannabis does influence the resolution of acute mania. This is important in developing effective treatment strategies for manic patients with this co-morbid CUD. In countries like India, where chance of cannabis abuse in patients of mania/bipolar disorder is high, this idea becomes more pertinent. So, this study was undertaken to evaluate the short-term course of acute psychotic mania to assess any possible effect of co-morbid cannabis dependence on symptom resolution.
| Materials and methods|| |
This hospital based case-control study was carried out at a tertiary care psychiatric teaching hospital. The protocol of the study was submitted to and approved by the institutional ethical committee. All the subjects of the study gave written informed consent.
With the help of purposive sampling technique, 30 matched male inpatients in the age group of 18-45 years were enrolled for the study in two groups as under:
Patients with "Bipolar affective disorder, current episode manic with psychotic symptoms (F31.2)" and "Mental and behavioral disorders due to use of cannabinoids; Dependence syndrome, currently using the substance [active dependence] (F12.24)" as per ICD-10, DCR.  Patients were free from oral psychotropic medication for at least four weeks and from injectable (depot) psychotropic medication for at least six weeks and scored above the cut off score of '8' on Cannabis Use Disorder Identification Test (CUDIT).  Patients with other co-morbid psychiatric disorders or harmful use or dependence of any substance other than nicotine, caffeine and cannabis were excluded. Patients were also excluded, if the psychiatric symptoms were due to acute medical illness or acute drug withdrawal.
Patients with the diagnosis of "Bipolar affective disorder, current episode manic with psychotic symptoms (F31.2)" as per ICD-10, DCR and free from oral psychotropic medication for at least four weeks and for injectable (depot) psychotropic medication for at least six weeks.
Patients were excluded, if their psychiatric symptoms were due entirely to acute medical illness or acute drug withdrawal. Patients with co-morbid psychiatric disorders or harmful use or dependence of any substance other than nicotine and caffeine were also excluded.
Tools for assessment
Socio-demographic and clinical data sheet [self-prepared]
0This data sheet included information like age, religion, marital status, education, occupation, residence, socio-economic status, and family type as well as clinical details such as age of onset, duration of illness, episodes, previous hospitalizations, treatment details etc.
Young mania rating scale (YMRS)
The YMRS is widely used to assess manic symptoms because of its brevity and ease of administration. It has a good inter-rater reliability (0.84-0.93 for total score), internal consistency (0.80), criterion validity (r = 0.82) as well as convergent validity (0.71-0.88). The scale is responsive to change, and has been used in clinical research to evaluate severity and monitor treatment response. 
Brief psychiatric rating scale-anchored version (BPRS-A)
The anchored version of the scale consists of 18 items, which are rated by a clinician on a 7-point scale, with anchors in the form of behavior examples provided for each item's rating options. , The anchored version is a reliable and valid measure to identify treatment response accurately in acute psychiatric inpatients.  Psychometric analysis reported adequate reliability for BPRS total and subscale scores (Cronbach's alpha range = 0.68 to 0.80; N = 1,556) and inter-rater reliability (range of intra-class correlation coefficients = 0.57 to 0.84, N = 131).  We used the approach proposed by Lachar et al.,  to characterize symptom severity in the BPRS. They have formulated 4 different factors, each containing different items of the scale, namely 'Resistance'/'Manic Symptoms' (Uncooperativeness, Hostility, Excitement, Grandiosity); 'Positive Symptoms' (Unusual Thought Content, Conceptual Disorganization, Hallucinatory Behavior, Suspiciousness, Disorientation) and 'Negative Symptoms' (Blunted Affect, Emotional Withdrawal, Motor Retardation); and 'Psychological Discomfort' (Anxiety, Somatic Concerns, Guilt Feelings, Tension, Depressive Mood, Mannerisms and Posturing).
Cannabis use disorders identification test (CUDIT)
This is a 10-question, self-report screening instrument for cannabis abuse or dependence. The maximum score possible is 40 with a cut-off of 8 demonstrating a positive predictive value of 81.8% and sensitivity of 73.3%. 
Consecutive patients of either group, who fulfilled the respective inclusion and exclusion criteria, were enrolled into the study. After taking the informed consent, the initial details were taken on self-prepared socio-demographic and clinical data sheet. CUDIT was specifically applied to the patients of Group-I to screen them for significant cannabis abuse/dependence. YMRS and BPRS were principal tools to assess manic and psychotic symptoms respectively and were applied on each patient on day 0, day 7, day 14, day 21, day 28 and day 42 of admission in the psychiatric wards. The first (i.e. day 0) assessment was done before starting any psychopharmacological intervention. Subsequent assessments (i.e. day 7, day 14, day 21, day 28 and day 42) were done while psychopharmacological management was being done by consultant psychiatrists who were kept blind to the scores of the rating scales of subjects under study.
Analysis of data
The data was analyzed using the computer software program- Statistical Package for Social Sciences-version 16.0 (SPSS Inc.), with different parametric and nonparametric tests, as indicated. The level of significance was taken as P < 0.05. The steps of analysis were as follows:
The Chi-square test for categorical variables and independent t-test for continuous variables were done both as shown in [Table 1] (socio-demographic details) and [Table 2] (clinical details) as applicable. The statistical significance of group difference of total scores of YMRS and BPRS, as well as the scores of individual YMRS items and subscales of BPRS were analyzed with the Mann-Whitney U test [Table 3]. Differences in total scores of YMRS as well as BPRS between subsequent ratings of patients of both groups [Table 4] were analyzed with the help of Mann-Whitney U test. In [Table 5], the Wilcoxon-signed-ranks test was utilized to compare the reduction of total scores on YMRS and BPRS scales on two successive assessments i.e. from day 7 to day14; day 14 to day 21; day 21 to day 28; and day 28 to day 42. In [Table 6], group difference for treatment details (for different categorical variables) was done with the help of Chi square test or Fisher's exact test as applicable.
|Table 1: Comparison of Socio-demographic Variables between Group-I (Acute Mania with CD) and Group-II (Acute Mania without CD)|
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|Table 2: Comparison of clinical variables between Group-I (Acute mania with CD) and Group-II (Acute mania without CD)|
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|Table 3: Group differences in total YMRS and BPRS scores between Group-I (Acute mania with CD) and Group-II (Acute mania without CD) on six consecutive assessments|
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|Table 4: Group differences in change in YMRS and BPRS scores from baseline (Day 0) between Group-I (Acute Mania with CD) and Group-II (Acute ania without CD)|
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|Table 5: Reduction in total YMRS and BPRS Scores from Baseline (Day 0) in Group-I (Acute Mania with CD) and Group-II (Acute Mania without CD)|
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|Table 6: Details of psychopharmacological treatment of Group-I (Acute Mania with CD) and Group-II (Acute Mania without CD) patients|
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| Results|| |
There were no significant differences in terms of socio-demographic details or clinical variables in patients of Group-I and Group-II [Table 1] and [Table 2]. In Group 1 patients, the mean total duration of cannabis intake was found to be 9.70 ± 7.02 years with mean age of onset of cannabis intake to be 19.30 ± 5.35 years, while mean duration of dependence was 6.90 ± 5.72 years. Last intake of cannabis was 2.37 ± 2.24 days before the first (i.e. day 0) assessment. Onset of cannabis intake was prior to first affective episode in 21 (70%) patients; during the first affective episode in 3 (10%) and after the first affective episode in 6 (20%) patients. The duration of cannabis intake in the 21 subjects whose cannabis use preceded the manic episode ranged from 1to 8 years with a mean of 2.88 (±2.07) years.
On CUDIT screening, the mean of total scores was 35.17 ± 6.25, which is far higher than its cutoff value of 8. The principal cannabis preparation used by these patients was ganja (66.7%) and the remaining used either bhang (13.3%) or both ganja and bhang (20%). The majority of ganja smokers used "chillum" (61.5%) as the principal mode of ganja smoking whereas rest of them (38.5%) used ganja filled in cigarettes i.e. joints as the principal mode of smoking.
[Table 3] compares the mean YMRS and BPRS scores between Group-I and Group-II on six consecutive assessments. The mean total scores of YMRS were comparable in two groups on all consecutive assessments except a trend of higher mean total YMRS score in Group-I at day 42. Further, mean scores of individual YMRS items too were compared between two groups on each assessment from day 0 to day 42 and were found to be comparable in two groups at all assessments except on day 28 and day 42. The mean score of the item 'irritability' only was significantly higher in patients of Group-I as compared to Group-II at day 28 (1.43 ± 1.04 vs 0.80 ± 1.00; Mann-Whitney U = 300, P = 0.005) and day 42 (0.93 ± 1.01 vs 0.27 ± 0.69; Mann-Whitney U = 315, P = 0.023).
On the BPRS, the significant group difference was noted between Group-I and Group-II alone on day 42 [Table 3]. Further, mean scores of all 4 subscales of BPRS too were compared between two groups on each assessment from day 0 to day 42 and were found to be comparable in two groups at all assessments except on day 28 and day 42. The mean score of the subscale 'psychological discomfort' was significantly higher in Group-I as compared to Group-II at day 28 (8.03 ± 1.40 vs 7.33 ± 1.30; Mann-Whitney U = 313.5, P = 0.036), and with a higher trend at day 42 in Group-I as compared to Group-II (7.80 ± 2.14 vs 6.90 ± 0.80; Mann-Whitney U = 327.5, P = 0.059).
[Table 4] shows the mean differences in total YMRS and BPRS scores at two subsequent ratings across six consecutive assessments (from day 0 down to day 42) in two groups. It was found that there was similar reduction in YMRS scores in two groups at all the assessments. On the BPRS there was a trend of lesser mean reduction in total BPRS scores from day 21 to day 28 in Group-I (0.13 ± 2.78) than Group-II (1.70 ± 3.59).
[Table 5] shows pattern of symptoms resolution on YMRS in each group individually with the help of Wilcoxon-signed-ranks test. There was comparable significant reduction of median total YMRS scores from day 7 to day14; day 14 to day 21; day 21 to day 28; and day 28 to day 42 in both groups. There was comparable significant reduction of median total BPRS scores at all successive assessments in both groups except no reduction of median total BPRS scores between day 21 and day 28 in patients of Group-I only.
Details of the psychopharmacological treatment received by patients of Group-I and Group-II are shown in [Table 6]. A need of dose increment of the mood stabilizer (as observed over 6 weeks period) was significantly (P < 0.05) more common in patients of Group-I (70%) in comparison to patients of Group-II (33.3%). Rescue injections were used significantly (P < 0.05) more commonly in patients of Group-I (73.3%) than those in Group-II (46.7%). In majority of the patients of both the groups, acute phase treatment response (i.e. 50% or more reduction of total scores obtained at day 0) was seen on day 21 to 28 after admission.
| Discussion|| |
There were many interesting findings with the analysis of one and half months stay of patients of acute mania with and without co-morbid cannabis dependence. The finding that in majority of patients (70%), the onset of cannabis use preceded the first affective episode is in agreement with an earlier study,  and suggests that cannabis use can exacerbate manic symptoms  and increases the risk of subsequent manic symptoms. , The finding that in 30% patients cannabis intake followed the onset of manic symptoms is also in agreement with recent findings that manic or hypomanic symptoms increase the risk of future cannabis use. ,
In the present study, patients of acute psychotic mania with co-morbid cannabis dependence did not differ from those without co-morbid cannabis dependence in terms of presentation of either manic or psychotic symptoms at initial presentation. This finding is not in agreement with a recent study, which reported that patients with substance-induced psychosis had more severe mania and disturbed behavior at admission. However, in that study patients with cannabis or amphetamine induced psychosis were included, which could explain the discrepancy. 
After psychopharmacological treatment, acute phase treatment response (i.e. 50% or more reduction in total scores on YMRS and BPRS from day 0 assessment) was seen on day 21 to 28 of admission in majority of the patients of both groups. Till the acute phase treatment response, there was no significant difference in either manic or psychotic symptoms in patients of both groups. This finding is well supported by a recent study, which found no significant difference in general manic symptoms between cannabis abusers and nonusers observed among psychiatric inpatients of Israel admitted with various diagnoses like schizophrenia, major affective and anxiety disorders, organic psychotic and affective disorders etc. 
On last two assessments of 6 weeks inpatient stay of the patients, it was seen that the patients of acute psychotic mania with co-morbid cannabis dependence, in comparison to those without co-morbid cannabis dependence, displayed difference in manic and psychotic symptoms in terms of mean total scores of YMRS and BPRS. To clarify it further, when individual items of YMRS and subscales of BPRS were compared between two groups on each assessment, it was found that the patients with co-morbid cannabis dependence had more scores on item 'Irritability' of YMRS as well as on subscale 'Psychological Discomfort' of BPRS on last two assessments i.e. day 28 and day 42. This finding raised a possibility of difference in the pattern of resolution of both manic and psychotic symptoms in patients of both groups.
The pattern of symptom resolution separately in each group, assessed by the reduction of median total YMRS as well as BPRS scores revealed that there was almost uniform resolution of both manic and psychotic symptoms in patients of both groups [Table 5]. However, when the pattern of resolution of symptoms was compared, in terms of mean differences in total YMRS as well as BPRS scores at two subsequent ratings across six consecutive assessments between two groups, it was found that the patients of Group I had delay in resolution of both manic and psychotic symptoms on last assessment [Table 4]. Taking lead from the finding in above paragraph, it can be speculated that it were items like 'Irritability' of YMRS and 'Psychological Discomfort' of BPRS, which made the differences and were significantly more obvious in patients of co-morbid cannabis dependence even at the last assessment.
Resolution of mania per se has been discussed very little in literature. The concentration has been on the psychopathological aspects of resolution. In most of them, the patterns of symptom resolution i.e. changes in symptom scores have been variable with some symptoms resolving quickly and some persisting for a longer time. ,, In general, our findings are consistent with these studies. However, only some of them have seen the effect of co-morbid substance abuse/dependence in general on pattern of manic symptom resolution. An early study compared resolution of manic symptoms in substance abusers and non-abusers hospitalized for acute manic episode for 12 weeks and found that substance abuse/dependence was the single most consistent factor found to be associated with resolution of symptoms on a stepwise multiple regression analysis using mania score as dependent variable.  A recent study found that Cannabis use was associated with more time in affective episodes and with rapid cycling.  Our findings of delayed resolution of manic and psychotic symptoms after hospitalization in patients with cannabis dependence, in comparison to those without cannabis dependence are consistent with these studies. The observation that patients with mania and co-morbid cannabis dependence required higher doses of mood stabilizers and antipsychotics [Table 6] is consistent with the earlier studies, which concluded that co-occurring CUD is associated with a more severe course of illness among individuals with bipolar disorder. Comprehensive evaluation of patients with bipolar disorder should include a detailed assessment for CUD. ,,
| Conclusions|| |
The patients of Acute Mania with co-morbid cannabis dependence had delayed resolution of manic and psychotic symptoms more specifically of symptoms like irritability of YMRS and psychological discomfort of BPRS and required higher doses of mood stabilizers and antipsychotic drugs, as compared to patients of Acute Mania without co-morbid cannabis dependence. Comprehensive evaluation of patients with bipolar disorder should include a detailed assessment for CUD.
| Limitations|| |
The present study had a few limitations. The sample size was relatively small. The screening of cannabis dependence was based on self report data and one screening tool CUDIT only and not supplemented by laboratory screening tests (like urine strip test for cannabinoids), which to certain extent might have resulted in under reporting of the active dependence of cannabis. The assessment personality profile of the patients, childhood traumatic experiences, recent life events etc., was not the focus of this study but these also may have influenced the symptom profile and its resolution in patients of mania with or without co-morbid cannabis dependence. Only male patients were taken in the study and this limits the generalization of findings. The resolution of symptoms was observed only for 42 days, which is less than the usual duration of a manic episode.
Studies with larger sample size and increased duration of observation should be undertaken. Studies should check mediation effects of variables like personality characteristics, childhood traumatic experiences, recent life events etc., in clinical expression of bipolar disorder and substance use disorder. Similar studies employing only female patients should be done, because gender differences are well known in manic symptoms evolution, presentation and resolution. The assessment of cannabis abuse/dependence should be supplemented by means of laboratory screening tests (urine tests). There is need to explore suitable psychopharmacological agents to treat the manic episode with co-morbid cannabis dependence effectively without any delay in resolution.
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[Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6]