First Impact Factor released in June 2010 and now listed in MEDLINE!
bs_bs_banner
Early Intervention in Psychiatry 2014; ••: ••–••
doi:10.1111/eip.12138
Original Article Cannabis use in first-treatment bipolar I disorder: relations to clinical characteristics Levi R. Kvitland,1 Ingrid Melle,1 Sofie R. Aminoff,2 Trine V. Lagerberg,1 Ole A. Andreassen1 and Petter A. Ringen3 Abstract
1 NORMENT, KG Jebsen Centre for Psychosis Research, Division of Mental Health and Addiction, Oslo University Hospital and Institute of Clinical Medicine, University of Oslo, 3Division of Mental Health and Addiction, Oslo University Hospital, Oslo, and 2Division of Mental Health Services, Akershus University Hospital, Lørenskog, Norway
Corresponding author: Mr Levi R. Kvitland, NORMENT, KG Jebsen Centre for Psychosis Research, Division of Mental Health and Addiction, Oslo University Hospital and Institute of Clinical Medicine, University of Oslo, N-0424 Oslo, Norway. Email: [email protected] Received 5 November 2013; accepted 28 February 2014
Aims: The aim of this study was to investigate the associations between recent cannabis use, current symptomatology and age at onset of first manic, depressive and psychotic episodes in a large sample with firsttreatment bipolar I disorder (BD I). Methods: One hundred one patients with first-treatment Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) bipolar I disorder were included as part of the Thematically Organized Psychosis study. The Structural Clinical Interview for DSM-IV was used for DSM-IV diagnosis and identification of episodes of illness. Earlier suicide attempts were recorded. Manic, depressive and psychotic symptoms were rated using the Young Mania Rating Scale, Inventory of Depressive Symptoms and Positive and Negative
Results: After controlling for confounders, recent cannabis use was significantly associated with lower age at onset of first manic and psychotic episode, but not with onset of first depressive episode (both P < 0.05). Recent use was also associated with more lifetime suicide attempts (P < 0.01). No group differences were found on symptom levels. Conclusions: The present study confirms earlier findings of an association between cannabis use and a lower age at onset. Recent cannabis use was also associated with more lifetime suicide attempts. The current findings suggest that recent cannabis use is associated with a more severe course of illness in the early phase of BD I.
Key words: age at onset, bipolar I, cannabis, first treatment.
INTRODUCTION Bipolar disorder (BD) ranks among the top 10 contributors to the global burden of disease.1,2 Identifying risk factors associated with the onset of BD is as a key target for research.3 However, few risk factors have been identified apart from a family history of bipolar disorder.4 Cannabis use is prevalent in BD,5,6 also before the start of first treatment.7,8 The evidence for cannabis as a risk factor in BD is weaker than for schizophrenia,9 but recent research, including studies of large epidemiological and clinical samples from the United States and Europe, clearly indicate an effect of cannabis in lowering the age at onset across age cohorts.10,11 Cannabis use has further been shown to increase the risk for mania, © 2014 Wiley Publishing Asia Pty Ltd
Syndrome Scale correspondingly. Cannabis use within the six last months was recorded.
prolong the duration of manic episodes10–12 and increase suicide risk. Cannabis use also seems to increase the risk for developing BD in depressed individuals.13 However, previous studies showing an effect of cannabis on age at onset mainly comprise multiepisode patients. This makes it difficult to rule out the alternative explanation, for instance, that the more severe course seen in early-onset patients could increase the risk for cannabis use after onset or in other ways interacts with negative effects of cannabis use in this time period. Study samples with longer duration of illness are also more vulnerable to attrition bias and thus potentially less representative of the BD patient population than first-treatment samples. Furthermore, these 1
Cannabis in early bipolar disorder I samples are more vulnerable to recall bias regarding potential risk factors before onset of the illness, compared with first-treatment samples. First-treatment BD samples are scarce and they often have a low number of participants and/or other methodological limitations. Existing largescale studies have included only patients with psychotic BD14,15 or hospitalized inpatients,12,16 excluded patients with previous self-remitting mood episodes17 or relied on clinical expert diagnoses rather than systematized research diagnoses.10 To our knowledge, the current study is the largest naturalistic sample to date with a broad, representative spectrum of recent onset, first-treatment patients with bipolar I disorder (BD I), including both inpatients and outpatients with both psychotic and nonpsychotic BD, and not excluding patients with comorbid illnesses. The current study aims at answering the following main research questions: 1 Is recent cannabis use associated with younger age at onset of first manic, depressive or psychotic episode in first-treatment BD I? 2 What are the associations between recent cannabis use and current affective and psychotic symptoms and history of suicidal behaviour in first-treatment BD I?
METHODS Sample One hundred one patients with recent onset Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV)18 BD I participated in the study as part of The Thematically Organized Psychosis (TOP) Study at the University of Oslo and Oslo University Hospital. The inclusion criteria were as follows: meeting the DSM-IV diagnosis of BD I, within the first year of receiving their first adequate inpatient or outpatient treatment for a manic episode, age between 17 and 65 and ability to give written informed consent. Patients entered the study in the first year after first treatment because of the ethical and practical problems of recruiting and achieving informed consent from unstable patients in the acute manic phase of BD. The patients were recruited consecutively from 2003 until 2013 from all major hospitals in the Oslo area. All clinicians at all inpatient and outpatient units at our participating hospitals were asked to identify patients with established or suspected bipolar disorder, and motivate the patients to be referred to our study. This recruitment design has shown to give a high degree of representativity 2
towards the general patient population in Oslo.6 The exclusion criteria were pronounced cognitive deficits (intelligence quotient (IQ) lower than 70), moderate/severe head injury, neurological disorder, not being able to speak a Scandinavian language or not being able to give a written informed consent. All patients received a complete description of the study before giving consent to participation. The study was approved by the Regional Committee for Medical Research Ethics and the Norwegian Data Inspectorate. Assessments Assessments were carried out by trained medical doctors and clinical psychologists. Diagnosis and episodes of illness, including age at onset of first manic, depressive and psychotic episode in addition to previous suicide attempts were determined using the Structural Clinical Interview for DSM-IV Axis I disorders (SCID module I, chapters A-E)19 with the aid of medical charts. Patients were interviewed about type of substance use the past 6 months as well as age at first exposure to the specific substances. The SCID-I module E19 was used for obtaining a diagnosis of substance abuse/dependency. Questions about substance use were part of a semistructured interview, based on a detailed manual designed for the current study. Current depressive symptoms were rated using the Inventory of Depressive Symptoms-Clinician rated (IDS-C),20 and current manic symptoms were rated using the Young Mania Rating Scale.21 Global functioning was measured by the Global Assessment Functioning scale (GAF), split version.22,23 Current negative and positive psychotic symptoms were assessed with the Positive and Negative Syndrome Scale (PANSS).24,25 The PANSS was added to assess psychotic symptoms in the sample, as such symptoms are prevalent in BD I and is considered a relevant measure of illness severity.24,25 Sociodemographic and medication data were obtained by clinical interviews and medical charts. General intelligence level (IQ) was measured by the Wechsler Abbreviated Scale of Intelligence.26 All assessment personnel completed a training programme based on the programme at the University of California, Los Angeles27 and participated in regular diagnostic consensus meetings led by experienced clinical experts in the field of diagnostics of severe mental illness. Inter-rater reliability for diagnosis had an overall kappa score of 0.77 (95% CI (0.60, 0.94)). The interrater reliability of the assessments in the TOP study has been shown to be good, with an intraclass © 2014 Wiley Publishing Asia Pty Ltd
L. R. Kvitland et al. TABLE 1. Demographic and clinical characteristics of patients with and without recent cannabis use No cannabis use last 6 months
Cannabis use last 6 months
N = 77
N = 24
Age (years) Education (years) IDS total score YMRS total score PANSS positive total score PANSS negative total score GAF-S GAF-F Duration between first mood episode and treatment (years)
Female sex Not currently a student or employed In a relationship Daily smoking Of European origin Psychotic features
P
N
Mean
SD
N
Mean
SD
77 74† 76† 77 77 77 77 77 77
32.5 14.7 15.4 4.5 10.3 10.0 58.6 51.3 5.1
11.3 2.9 10.7 6.4 4.6 3.2 14.1 12.7 7.7
24 24 22† 24 24 24 24 24 24
26.7 13.1 20.5 6.4 11.2 9.4 54.3 50.9 5.0
6.6 2.5 14.1 6.0 2.6 2.5 10.1 10.8 7.3
N
%
N
%
P
51 36 38 34 65 50
66.2 46.8 49.4 44.7 84.4 64.9
10 15 6 22 22 15
41.7 62.5 25.0 91.7 91.7 62.5
0.054 0.234 0.058 0.000 0.509 0.813
0.002 0.011 0.177 0.208 0.428 0.177 0.849 0.844 0.939
†Missing data. IDS, Inventory of Depressive Symptoms; GAF, Global Assessment Functioning Scale; PANSS, Positive and Negative Syndrome Scale; SD, standard deviation; YMRS, Young Mania Rating Scale.
coefficient 28 for PANSS positive symptoms of 0.82 and for the GAF of 0.86.6 Statistical analyses The analyses were conducted by using the statistical package for the social sciences (SPSS) version 19.0 (SPSS Inc, Chicago, IL, USA). Group comparisons for continuous variables were evaluated with independent sample t-tests, group comparisons for dichotomous data were evaluated with chi-squared tests or Fischer’s exact tests. Level of significance was set to P < 0.05, two-sided. The sample was divided into those who had used any cannabis at all over the past 6 months (recent use) and those without any use in this period (no cannabis use; Table 1). Since several demographic and clinical characteristics were associated with both recent use and age at onset (Table 3), we conducted a series of hierarchical block-wise multiple linear regression analyses to test for possible confounders of their associations. For lifetime suicidal attempts we conducted a logistic regression analysis based on the same principles. We included the variables with the highest significant correlation (P < 0.01) with the dependent variable in step one, and the variables either correlated to recent use or with the least significant correlation (P. < 05) with the dependent © 2014 Wiley Publishing Asia Pty Ltd
variable at the next step, before adding information about recent use on the third and last step. We did not include daily smoking as this is strongly associated with recent use in this (Table 1) and previous studies,16 nor did we include age in the analyses since age at onset in a first-episode sample is highly correlated with current age (r = 0.8 in the current sample). To explore any age or cohort effects on recent cannabis use, we instead conducted a series of hierarchical block-wise multiple linear regression analyses including the age at onset for cannabis (age at first exposure) use in the last step of the model. The main analyses were repeated including only patients experiencing their first ever episode of mania. This did not give any differences in results (data not shown). RESULTS Mean age of the sample was 31.1 years (SD: 10.6 years), N = 61 (60%) were female. Lifetime cannabis use was reported in 55%. There were more males in the ‘recent use’ group (P = 0.05) than in the ‘no cannabis use’. The ‘recent use’ group was also significantly younger and had significantly less education (Table 1). The ‘recent use’ group was significantly younger at the onset of their first manic, depressive and 3
Cannabis in early bipolar disorder I TABLE 2. Age at onset, medication use and suicide attempts in patients with and without recent cannabis use
Age Age Age Age Age
at at at at at
onset onset onset onset onset
first psychotic episode first manic episode first depressive episode first psychotic episode BD I regardless of episode type‡
Current use of antipsychotics Current use of mood stabilizers One or more suicide attempts, lifetime
No cannabis use last 6 months
Cannabis use last 6 months
N = 77
N = 24
N
Mean
SD
N
Mean
SD
50† 74† 57† 50† 77 N 57 19 16
29.5 28.9 24.9 29.5 24.5 % 74.0 24.7 28.1
10.4 11.2 11.0 10.4 10.4
15† 21† 21† 15† 24 N 10 4 12
22.1 23.3 19.8 22.1 20.1 % 41.7 16.7 63.2
3.5 7.0 6.2 3.5 6.6
P
0.000 0.008 0.013 0.000 0.018 P 0.006 0.579 0.012
†Lower N because not all patients experienced this episode. ‡Psychotic, manic, depressive or mixed onset. BD I, bipolar I disorder; SD, standard deviation.
psychotic episodes, and thus also at the age at onset of their illness, regardless of the characteristics of their first episode. There were no significant differences between the groups regarding current symptoms and functioning, but the ‘recent use’ group used antipsychotics to a significantly lower degree compared with the ‘no cannabis use’ group. They had also significantly more often a lifetime history of suicide attempts (Table 2). After controlling for possible confounders of the relationship between age at onset and recent use (Table 3), we found that recent use contributed significantly to age at onset of first manic episode, age at onset of first psychotic episode and to age at onset of first depressive episode. Education and sex also contributed significantly to the age at onset of first manic episode in the final model. We found an even stronger association between lifetime suicide attempts and recent use after controlling for possible confounders (Table 4a–d). In the follow-up analyses, age at first exposure to cannabis contributed significantly (beta 0.956, P < 0.001) to age at onset of the first manic episode (final model (F 8.232 P < 0.001, adj. r2 0.430). Likewise, age at first exposure use contributed significantly (beta 1.131, P < 0.001) to age at onset of first psychotic episode (final model F 6.858 P < 0.001 adj. r2 0.442). Likewise, age at first exposure contributed significantly (beta 0.777, P < 0.01) to age at onset of first depressive episode (final model F 2.938 P < 0.05 adj. r2 0.177). DISCUSSION There are two main results of the current study. Firstly, that recent cannabis use had a significant 4
association with the age at onset of the first episodes of mania, psychosis and depression in a highly representative sample of patients with first-treatment BD, also after controlling for relevant confounders. Secondly, that any lifetime suicidal attempt was more prevalent in the recent use group. There were no significant differences in other clinical characteristics between recent cannabis users and the rest of the patients. The finding of an association between recent use and earlier age at onset for bipolar disorder confirms findings from previous research comprising multi-episode patients.4,8,10,29–33 It supports the hypothesis that cannabis may increase the risk for bipolar disorder, in particular manic and psychotic episodes, interacting with individual genetic vulnerability and other environmental stressors.33–38 However, since this is a cross-sectional study, we do not know in the case of individual patients if the cannabis use started before, at the same time or after the onset of the first manic and/or psychotic episode. Since this is a first-treatment sample, with a short time period from the first mood episode to time of first treatment, we can, to a large extent, rule out the hypothesis that the more severe course seen in early-onset BD increases the risk for later cannabis use.39 Furthermore, it is of interest to notice that a recent review did not find support for a role for self-medication in these associations.40 Another explanation could be that there are common underlying risk factors for both mood instability, psychosis and substance use, in line with what is hypothesized for schizophrenia.41 As we did not control for current age in the analyses for statistical reasons, it is not possible to completely rule out that our findings are reflections of © 2014 Wiley Publishing Asia Pty Ltd
© 2014 Wiley Publishing Asia Pty Ltd
1 0.806‡ 0.843‡ 0.827‡
0.792‡ 0.390‡ −0.211† −0.101 −0.408‡ 0.069 0.071 −0.231† 0.566‡
−0.222
−0.322‡
−0.191
−0.236† −0.245† −0.214† −0.134
0.209† 0.089 0.140
0.352‡
−0.264
−0.219†
−0.219†
1
2
†Correlation is significant at the 0.05 level (two-tailed). ‡Correlation is significant at the 0.01 level (two-tailed).
Cannabis use last 6 months (1) Age at onset first manic episode (2) Age at onset first depressive episode (3) Age at onset first psychotic episode (4) Age of onset of BD regardless of episode type (5) Age (6) Education (7) Sex (8) A student or employed (9) In a relationship (10) Of European origin (11) Alcohol abuse/dependency (12) Cocaine or amphetamine use last 6 months (13) Age at first exposure
1
0.483‡
−0.217
−0.356‡ 0.064 0.053
0.740‡ 0.252† −0.080 −0.092
0.865‡
0.832‡
1
0.806‡
−0.222
3
0.618‡
−0.145
−0.408‡ 0.211 0.152
0.841‡ 0.299† −0.027 −0.116
0.820‡
1
0.832‡
0.843‡
−0.322‡
4
0.429‡
−0.236†
−0.407‡ 0.084 0.052
0.666‡ 0.235† −0.214† 0.017
1
0.820‡
0.865‡
0.827‡
−0.191
5
0.555‡
−0.193
−0.429‡ 0.190 0.153
1 0.394‡ −0.181 −0.163
0.666‡
0.841‡
0.740‡
0.792‡
−0.236†
6
0.008
−0.230†
−0.178 0.204† −0.211†
0.394‡ 1 0.038 0.051
0.235†
0.299†
0.252†
0.390‡
−0.245†
7
8
−0.246
0.090
−0.058 0.027 −0.148
−0.181 0.038 1 −0.089
−0.214†
−0.027
−0.080
−0.211†
−0.214†
TABLE 3. Bivariate correlations (Pearson’s R) between cannabis use, clinical and sociodemographic variables
−0.074
−0.142
−0.009 −0.004 0.004
−0.163 0.051 −0.089 1
0.017
−0.116
−0.092
−0.101
−0.134
9
0.080
0.187
1 −0.121 0.108
−0.429‡ −0.178 −0.058 −0.009
−0.407‡
−0.408‡
−0.356‡
−0.408‡
0.209†
10
−0.014
0.013
−0.121 1 0.096
0.190 0.204† 0.027 −0.004
0.084
0.211
0.064
0.069
0.089
11
0.252
0.072
0.108 0.096 1
0.153 −0.211† −0.148 0.004
0.052
0.152
0.053
0.071
0.140
12
−0.246
1
0.187 0.013 0.072
−0.193 −0.230† 0.090 −0.142
−0.236†
−0.145
−0.217
−0.231†
0.352‡
13
1
−0.246
0.080 −0.014 0.252
0.555‡ 0.008 −0.246 −0.074
0.429‡
0.618‡
0.483‡
0.566‡
−0.264
14
L. R. Kvitland et al.
5
Cannabis in early bipolar disorder I TABLE 4A. Multiple regression analysis with age at first manic episode as dependent variable Block no. variable
Block model summary for each step R2 change
Contribution of separate variables for last step
F change
Beta
t
P value
95% CI of B Lower
Constant 1 Education In a relationship 2 Female sex Cocaine or amphetamine use last 6 months 3 Cannabis use last 6 months
ND 0.121
0.122
0.246
ND 30.154
ND
Upper
2.470
0.017
3.013
29.566
0.937 −4.128
2.078 −1.434
0.043 0.158
0.029 −9.923
1.845 1.668
−5.870 −5.481
−2.160 −1.250
0.036 0.218
−11.346 −14.318
−0.394 3.356
0.956
4.552
0.000
0.532
1.379
3.554
20.716
Total model F 8.232 P < 0.001. Adj. r2 0.430. CI, confidence interval; ND, no data.
TABLE 4B. Multiple regression analysis with age at first depressive episode as dependent variable Block no. variable
Block model summary for each step R2 change
Constant 1 In a relationship 2 Education Cocaine or amphetamine use last 6 months Female sex 3 Cannabis use last 6 months
F change
ND 0.019
ND 0.843
0.058
0.863
0.191
Contribution of separate variables for last step Beta
ND
t
P value
95% CI of B Lower
Upper
9.461
0.000
18.396
28.354
−2.808
−0.918
0.364
−8.974
3.357
0.077 −4.140
0.159 −1.000
0.875 0.323
−0.900 −12.500
1.054 4.214
−3.031
−1.001
0.323
−9.146
3.085
0.777
3.236
0.002
0.292
1.262
10.473
Total model F 2.938 P < 0.05. Adj r2 0.177. CI, confidence interval; ND, no data.
higher rates of cannabis use in the 15–24 contra the 25–34 age groups as indicated by European epidemiological data.42 However, recent Norwegian epidemiological data43 show smaller age effects. In the current sample, we find no differences in recent cannabis use between the 18–24 and 25–34 age groups. The findings of an association between cannabis use and suicide attempts may be taken as a support of the view that cannabis negatively affects the course of illness.33,44 The findings are in line with studies showing more suicidal behaviour in BD patients with early onset,45 in particular in the context of cannabis use.46 The alternative explanation, that more depressive symptoms may provoke 6
cannabis craving, cannot be ruled out. However, this interpretation appears to be less plausible in the current sample as there were no significant differences in depressive symptoms between groups. There was also a lack of difference in the prevalence of psychotic symptoms and other clinical measures between groups. However, there was less use of antipsychotic medication in the recent use group. This could be due to the known problem of low medication adherence in younger patients in general and in BD patients using cannabis specifically.47 Male sex contributed significantly to a lower age at onset for the first manic episode, supporting previous findings of a poorer course of illness in © 2014 Wiley Publishing Asia Pty Ltd
L. R. Kvitland et al. TABLE 4C. Multiple regression analysis with age at first psychotic episode as dependent variable Block no. variable
Block model summary for each step R2 change
Constant 1 In a relationship 2 Cocaine or amphetamine use last 6 months Education Female sex 3 Cannabis use last 6 months
F change
ND 0.038
ND 1.416
0.044
0.527
0.435
Contribution of separate variables for last step Beta
t
P value
95% CI of B Lower
Upper
ND
12.141
0.000
24.728
34.647
−3.824
−1.190
0.822
−10.342
2.694
−7.505
−1.008
0.321
−22.659
7.649
0.312 −0.957
0.483 −0.286
0.632 0.777
−1.001 −7.769
1.624 5.856
1.131
5.373
0.000
0.702
1.560
28.865
Total model F 6.858 P < 0.001. Adj r2 0.442. CI, confidence interval; ND, no data.
TABLE 4D. Multiple logistic regression analysis with one or more suicide attempts lifetime as dependent variable Variable
Suicide attempts lifetime Coefficient
Step 1 Age Female sex In a relationship Step 2 Age Female sex In a relationship Alcohol abuse/dependency Cocaine or amphetamine use last 6 months Step 3 Age Female sex In a relationship Alcohol abuse/dependency Cocaine or amphetamine use last 6 months Cannabis use last 6 months
P
OR
95% CI of OR Lower
Upper
−0.020 1.395 −0.160
0.49 0.01 0.78
0.98 4.04 0.85
0.926 1.365 0.278
1.037 11.929 2.615
−0.021 1.379 −0.036 0.358 −0.905
0.49 0.01 0.95 0.62 0.35
0.98 3.97 0.97 1.43 0.41
0.992 1.318 0.305 0.351 0.062
1.039 11.973 3.052 5.836 2.661
−0.008 2.134 0.156 0.051 0.356 2.259
0.81 0.01 0.80 0.949 0.754 0.01
0.99 8.45 1.17 1.05 1.43 9.57
0.927 2.012 0.343 0.222 0.155 1.952
1.061 35.504 3.979 4.975 13.175 46.921
Nagelkerke r2 0.31. CI, confidence interval; OR, odds ratio.
males,14 and to the association between early onset and more severe symptoms.48 Cannabis users and BD patients in general are less likely to be in a relationship compared with the population at large.49–51 Patients currently in a relationship had a later age at onset for manic, depressive and psychotic episodes and also lower levels of cannabis use. The crosssectional nature of the study makes it difficult to know whether there are common underlying factors © 2014 Wiley Publishing Asia Pty Ltd
to both relational capacities and an early onset, or if patients with early onset have problems with taking on age-appropriate social roles such as entering relationships. Strengths and limitations The main strength of the study is the large and welldocumented sample of patients in the early course 7
Cannabis in early bipolar disorder I of bipolar disorder, avoiding many of the methodological limitations of previous studies in patients with longer course of illness. The thorough protocol allowed for a systematic approach, discerning the role of possible confounders for the association between recent use and significant patient characteristics and outcomes. The sampling procedure including both inpatients and outpatients with consecutive recruitment from a catchment area-based health service gives the sample a high degree of representativity.6 However, since Norwegian law and the Regional Committee for Medical Research Ethics do not allow us to access the medical charts of patients that have not consented to research participation, we are unable to give a full account of eligible patients that might not have been referred. The main weakness is the cross-sectional design that makes it impossible to answer questions about causality. The ascertainments of age at onset and illness history were partly retrospective, based on patients’ reports and thus suffer from potential recall bias. The proximity to events in this recent onset sample is still a comparative strength of the study. The patients were included in close proximity to their manic episode, having a mildly depressed mood on group level at point of inclusion, as reflected in the IDS-C scores. CONCLUSION In conclusion, the current study shows that patients with cannabis use at the start of the first treatment for a BD I disorder have an earlier age at onset for their first manic or psychotic episode, and more often have attempted suicide. Longitudinal studies are warranted to questions about causative factors. REFERENCES 1. Salomon JA, Vos T, Hogan DR et al. Common values in assessing health outcomes from disease and injury: disability weights measurement study for the Global Burden of Disease Study 2010. Lancet 2013; 380: 2129–43. 2. Murray CJ, Vos T, Lozano R et al. Disability-adjusted life years (DALYs) for 291 diseases and injuries in 21 regions, 1990– 2010: a systematic analysis for the Global Burden of Disease Study 2010. Lancet 2013; 380: 2197–223. 3. Kroon JS, Wohlfarth TD, Dieleman J et al. Incidence rates and risk factors of bipolar disorder in the general population: a population-based cohort study. Bipolar Disord 2013; 15: 306–13. 4. Lagerberg TV, Sundet K, Aminoff SR et al. Excessive cannabis use is associated with earlier age at onset in bipolar disorder. Eur Arch Psychiatry Clin Neurosci 2011; 261: 397–405. 5. Najt P, Fusar-Poli P, Brambilla P. Co-occurring mental and substance abuse disorders: a review on the potential predictors and clinical outcomes. Psychiatry Res 2011; 186: 159– 64.
8
6. Ringen PA, Lagerberg TV, Birkenaes AB et al. Differences in prevalence and patterns of substance use in schizophrenia and bipolar disorder. Psychol Med 2008; 38: 1241–9. 7. Strakowski SM, DelBello MP, Fleck DE et al. Effects of co-occurring cannabis use disorders on the course of bipolar disorder after a first hospitalization for mania. Arch Gen Psychiatry 2007; 64: 57–64. 8. van Laar M, van Dorsselaer S, Monshouwer K, de Graaf R. Does cannabis use predict the first incidence of mood and anxiety disorders in the adult population? Addiction 2007; 102: 1251–60. 9. De HM, Wampers M, Jendricko T et al. Effects of cannabis use on age at onset in schizophrenia and bipolar disorder. Schizophr Res 2011; 126: 270–6. 10. Tohen M, Vieta E, Gonzalez-Pinto A, Reed C, Lin D. Baseline characteristics and outcomes in patients with first episode or multiple episodes of acute mania. J Clin Psychiatry 2010; 71: 255–61. 11. Strakowski SM, DelBello MP, Fleck DE, Arndt S. The impact of substance abuse on the course of bipolar disorder. Biol Psychiatry 2000; 48: 477–85. 12. Baethge C, Hennen J, Khalsa HM, Salvatore P, Tohen M, Baldessarini RJ. Sequencing of substance use and affective morbidity in 166 first-episode bipolar I disorder patients. Bipolar Disord 2008; 10: 738–41. 13. Ostacher MJ, Perlis RH, Nierenberg AA et al. Impact of substance use disorders on recovery from episodes of depression in bipolar disorder patients: prospective data from the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD). Am J Psychiatry 2010; 167: 289–97. 14. Cotton SM, Lambert M, Berk M et al. Gender differences in first episode psychotic mania. BMC Psychiatry 2013; 13: 82. 15. Salvatore P, Baldessarini RJ, Tohen M et al. McLean-Harvard International First-Episode Project: two-year stability of ICD-10 diagnoses in 500 first-episode psychotic disorder patients. J Clin Psychiatry 2011; 72: 183–93. 16. Heffner JL, DelBello MP, Anthenelli RM, Fleck DE, Adler CM, Strakowski SM. Cigarette smoking and its relationship to mood disorder symptoms and co-occurring alcohol and cannabis use disorders following first hospitalization for bipolar disorder. Bipolar Disord 2012; 14: 99–108. 17. Yatham LN, Kauer-Sant’Anna M, Bond DJ, Lam RW, Torres I. Course and outcome after the first manic episode in patients with bipolar disorder: prospective 12-month data from the Systematic Treatment Optimization Program for Early Mania project. Can J Psychiatry 2009; 54: 105–12. 18. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders: DSM-IV. Washington: American Psychiatric Association, 1994. 19. First M, Spitzer RL, Gibbon M, Williams J. Structural Clinical Interview for DSM-IV Axis I Disorders – Clinical Version (SCIDCV). Washington DC: American Psychiatric Press, 1997. 20. Rush AJ, Giles DE, Schlesser MA, Fulton CL, Weissenburger J, Burns C. The Inventory for Depressive Symptomatology (IDS): preliminary findings. Psychiatry Res 1986; 18: 65–87. 21. Young RC, Biggs JT, Ziegler VE, Meyer DA. A rating scale for mania: reliability, validity and sensitivity. Br J Psychiatry 1978; 133: 429–35. 22. Endicott J, Spitzer RL, Fleiss JL, Cohen J. The global assessment scale. A procedure for measuring overall severity of psychiatric disturbance. Arch Gen Psychiatry 1976; 33: 766– 71. 23. Pedersen G, Hagtvet KA, Karterud S. Generalizability studies of the Global Assessment of Functioning-Split version. Compr Psychiatry 2007; 48: 88–94. 24. Kay SR, Fiszbein A, Opler LA. The positive and negative syndrome scale (PANSS) for schizophrenia. Schizophr Bull 1987; 13: 261–76. © 2014 Wiley Publishing Asia Pty Ltd
L. R. Kvitland et al. 25. Lindenmayer JP, Bossie CA, Kujawa M, Zhu Y, Canuso CM. Dimensions of psychosis in patients with bipolar mania as measured by the positive and negative syndrome scale. Psychopathology 2008; 41: 264–70. 26. Wechsler D. Wechsler Abbreviated Scale of Intelligence (WASI). Norwegian Manual Supplement. Stockholm: Pearson Assessment, 2007. 27. Ventura J, Liberman RP, Green MF, Shaner A, Mintz J. Training and quality assurance with the Structured Clinical Interview for DSM-IV (SCID-I/P). Psychiatry Res 1998; 79: 163–73. 28. Shrout PE, Fleiss JL. Intraclass correlations: uses in assessing rater reliability. Psychol Bull 1979; 86: 420–8. 29. Ongur D, Lin L, Cohen BM. Clinical characteristics influencing age at onset in psychotic disorders. Compr Psychiatry 2009; 50: 13–9. 30. Kaymaz N, van Os J, de Graaf R, Ten HM, Nolen W, Krabbendam L. The impact of subclinical psychosis on the transition from subclinicial mania to bipolar disorder. J Affect Disord 2007; 98: 55–64. 31. Henquet C, Krabbendam L, de Graaf R, Ten HM, van Os J. Cannabis use and expression of mania in the general population. J Affect Disord 2006; 95: 103–10. 32. Agrawal A, Nurnberger JI Jr, Lynskey MT. Cannabis involvement in individuals with bipolar disorder. Psychiatry Res 2011; 185: 459–61. 33. Lev-Ran S, Le FB, McKenzie K, George TP, Rehm J. Bipolar disorder and co-occurring cannabis use disorders: characteristics, co-morbidities and clinical correlates. Psychiatry Res 2013; 209: 459–65. 34. Henquet C, van Os J, Kuepper R et al. Psychosis reactivity to cannabis use in daily life: an experience sampling study. Br J Psychiatry 2010; 196: 447–53. 35. Baethge C, Baldessarini RJ, Khalsa HM, Hennen J, Salvatore P, Tohen M. Substance abuse in first-episode bipolar I disorder: indications for early intervention. Am J Psychiatry 2005; 162: 1008–10. 36. Batalla A, Garcia-Rizo C, Castellvi P et al. Screening for substance use disorders in first-episode psychosis: implications for readmission. Schizophr Res 2013; 146: 125–31. 37. Bahorik AL, Newhill CE, Eack SM. Characterizing the longitudinal patterns of substance use among individuals diagnosed with serious mental illness after psychiatric hospitalization. Addiction 2013; 108: 1259–69. 38. Post RM, Kalivas P. Bipolar disorder and substance misuse: pathological and therapeutic implications of their comorbidity and cross-sensitisation. Br J Psychiatry 2013; 202: 172–6.
© 2014 Wiley Publishing Asia Pty Ltd
39. Khantzian EJ. The self-medication hypothesis of addictive disorders: focus on heroin and cocaine dependence. Am J Psychiatry 1985; 142: 1259–64. 40. Dekker N, Linszen DH, De HL. Reasons for cannabis use and effects of cannabis use as reported by patients with psychotic disorders. Psychopathology 2009; 42: 350– 60. 41. Chambers RA, Krystal JH, Self DW. A neurobiological basis for substance abuse comorbidity in schizophrenia. Biol Psychiatry 2001; 50: 71–83. 42. European Monitoring Centre for Drugs and Drug Addiction. A Cannabis Reader: Global Issues and Local Experiences. Lisbon: EMCDDA, 2008. 43. Norwegian Institute for Alcohol and Drug Research. The drug situation in Norway 2010 – annual report to the European Monitoring Centre for Drugs and Drug Addiction – EMCDDA. 2010. SIRUS/EMCDDA. 15-1-2014. Ref Type: Serial (book, monograph). 44. van Rossum I, Boomsma M, Tenback D, Reed C, van Os J. Does cannabis use affect treatment outcome in bipolar disorder? A longitudinal analysis. J Nerv Ment Dis 2009; 197: 35–40. 45. Azorin JM, Bellivier F, Kaladjian A et al. Characteristics and profiles of bipolar I patients according to age-at-onset: findings from an admixture analysis. J Affect Disord 2013; 150: 993–1000. 46. Etain B, Lajnef M, Bellivier F et al. Clinical expression of bipolar disorder type I as a function of age and polarity at onset: convergent findings in samples from France and the United States. J Clin Psychiatry 2012; 73: e561–6. 47. Gonzalez-Pinto A, Reed C, Novick D, Bertsch J, Haro JM. Assessment of medication adherence in a cohort of patients with bipolar disorder. Pharmacopsychiatry 2010; 43: 263– 70. 48. Baldessarini RJ, Bolzani L, Cruz N et al. Onset-age of bipolar disorders at six international sites. J Affect Disord 2010; 121: 143–6. 49. Lieberman DZ, Massey SH, Goodwin FK. The role of gender in single vs married individuals with bipolar disorder. Compr Psychiatry 2010; 51: 380–5. 50. McPherson HM, Dore GM, Loan PA, Romans SE. Socioeconomic characteristics of a Dunedin sample of bipolar patients. N Z Med J 1992; 105: 161–2. 51. Agrawal A, Lynskey MT. Correlates of later-onset cannabis use in the National Epidemiological Survey on Alcohol and Related Conditions (NESARC). Drug Alcohol Depend 2009; 105: 71–5.
9
bs_bs_banner
Early Intervention in Psychiatry 2014; ••: ••–••
doi:10.1111/eip.12138
Original Article Cannabis use in first-treatment bipolar I disorder: relations to clinical characteristics Levi R. Kvitland,1 Ingrid Melle,1 Sofie R. Aminoff,2 Trine V. Lagerberg,1 Ole A. Andreassen1 and Petter A. Ringen3 Abstract
1 NORMENT, KG Jebsen Centre for Psychosis Research, Division of Mental Health and Addiction, Oslo University Hospital and Institute of Clinical Medicine, University of Oslo, 3Division of Mental Health and Addiction, Oslo University Hospital, Oslo, and 2Division of Mental Health Services, Akershus University Hospital, Lørenskog, Norway
Corresponding author: Mr Levi R. Kvitland, NORMENT, KG Jebsen Centre for Psychosis Research, Division of Mental Health and Addiction, Oslo University Hospital and Institute of Clinical Medicine, University of Oslo, N-0424 Oslo, Norway. Email: [email protected] Received 5 November 2013; accepted 28 February 2014
Aims: The aim of this study was to investigate the associations between recent cannabis use, current symptomatology and age at onset of first manic, depressive and psychotic episodes in a large sample with firsttreatment bipolar I disorder (BD I). Methods: One hundred one patients with first-treatment Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) bipolar I disorder were included as part of the Thematically Organized Psychosis study. The Structural Clinical Interview for DSM-IV was used for DSM-IV diagnosis and identification of episodes of illness. Earlier suicide attempts were recorded. Manic, depressive and psychotic symptoms were rated using the Young Mania Rating Scale, Inventory of Depressive Symptoms and Positive and Negative
Results: After controlling for confounders, recent cannabis use was significantly associated with lower age at onset of first manic and psychotic episode, but not with onset of first depressive episode (both P < 0.05). Recent use was also associated with more lifetime suicide attempts (P < 0.01). No group differences were found on symptom levels. Conclusions: The present study confirms earlier findings of an association between cannabis use and a lower age at onset. Recent cannabis use was also associated with more lifetime suicide attempts. The current findings suggest that recent cannabis use is associated with a more severe course of illness in the early phase of BD I.
Key words: age at onset, bipolar I, cannabis, first treatment.
INTRODUCTION Bipolar disorder (BD) ranks among the top 10 contributors to the global burden of disease.1,2 Identifying risk factors associated with the onset of BD is as a key target for research.3 However, few risk factors have been identified apart from a family history of bipolar disorder.4 Cannabis use is prevalent in BD,5,6 also before the start of first treatment.7,8 The evidence for cannabis as a risk factor in BD is weaker than for schizophrenia,9 but recent research, including studies of large epidemiological and clinical samples from the United States and Europe, clearly indicate an effect of cannabis in lowering the age at onset across age cohorts.10,11 Cannabis use has further been shown to increase the risk for mania, © 2014 Wiley Publishing Asia Pty Ltd
Syndrome Scale correspondingly. Cannabis use within the six last months was recorded.
prolong the duration of manic episodes10–12 and increase suicide risk. Cannabis use also seems to increase the risk for developing BD in depressed individuals.13 However, previous studies showing an effect of cannabis on age at onset mainly comprise multiepisode patients. This makes it difficult to rule out the alternative explanation, for instance, that the more severe course seen in early-onset patients could increase the risk for cannabis use after onset or in other ways interacts with negative effects of cannabis use in this time period. Study samples with longer duration of illness are also more vulnerable to attrition bias and thus potentially less representative of the BD patient population than first-treatment samples. Furthermore, these 1
Cannabis in early bipolar disorder I samples are more vulnerable to recall bias regarding potential risk factors before onset of the illness, compared with first-treatment samples. First-treatment BD samples are scarce and they often have a low number of participants and/or other methodological limitations. Existing largescale studies have included only patients with psychotic BD14,15 or hospitalized inpatients,12,16 excluded patients with previous self-remitting mood episodes17 or relied on clinical expert diagnoses rather than systematized research diagnoses.10 To our knowledge, the current study is the largest naturalistic sample to date with a broad, representative spectrum of recent onset, first-treatment patients with bipolar I disorder (BD I), including both inpatients and outpatients with both psychotic and nonpsychotic BD, and not excluding patients with comorbid illnesses. The current study aims at answering the following main research questions: 1 Is recent cannabis use associated with younger age at onset of first manic, depressive or psychotic episode in first-treatment BD I? 2 What are the associations between recent cannabis use and current affective and psychotic symptoms and history of suicidal behaviour in first-treatment BD I?
METHODS Sample One hundred one patients with recent onset Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV)18 BD I participated in the study as part of The Thematically Organized Psychosis (TOP) Study at the University of Oslo and Oslo University Hospital. The inclusion criteria were as follows: meeting the DSM-IV diagnosis of BD I, within the first year of receiving their first adequate inpatient or outpatient treatment for a manic episode, age between 17 and 65 and ability to give written informed consent. Patients entered the study in the first year after first treatment because of the ethical and practical problems of recruiting and achieving informed consent from unstable patients in the acute manic phase of BD. The patients were recruited consecutively from 2003 until 2013 from all major hospitals in the Oslo area. All clinicians at all inpatient and outpatient units at our participating hospitals were asked to identify patients with established or suspected bipolar disorder, and motivate the patients to be referred to our study. This recruitment design has shown to give a high degree of representativity 2
towards the general patient population in Oslo.6 The exclusion criteria were pronounced cognitive deficits (intelligence quotient (IQ) lower than 70), moderate/severe head injury, neurological disorder, not being able to speak a Scandinavian language or not being able to give a written informed consent. All patients received a complete description of the study before giving consent to participation. The study was approved by the Regional Committee for Medical Research Ethics and the Norwegian Data Inspectorate. Assessments Assessments were carried out by trained medical doctors and clinical psychologists. Diagnosis and episodes of illness, including age at onset of first manic, depressive and psychotic episode in addition to previous suicide attempts were determined using the Structural Clinical Interview for DSM-IV Axis I disorders (SCID module I, chapters A-E)19 with the aid of medical charts. Patients were interviewed about type of substance use the past 6 months as well as age at first exposure to the specific substances. The SCID-I module E19 was used for obtaining a diagnosis of substance abuse/dependency. Questions about substance use were part of a semistructured interview, based on a detailed manual designed for the current study. Current depressive symptoms were rated using the Inventory of Depressive Symptoms-Clinician rated (IDS-C),20 and current manic symptoms were rated using the Young Mania Rating Scale.21 Global functioning was measured by the Global Assessment Functioning scale (GAF), split version.22,23 Current negative and positive psychotic symptoms were assessed with the Positive and Negative Syndrome Scale (PANSS).24,25 The PANSS was added to assess psychotic symptoms in the sample, as such symptoms are prevalent in BD I and is considered a relevant measure of illness severity.24,25 Sociodemographic and medication data were obtained by clinical interviews and medical charts. General intelligence level (IQ) was measured by the Wechsler Abbreviated Scale of Intelligence.26 All assessment personnel completed a training programme based on the programme at the University of California, Los Angeles27 and participated in regular diagnostic consensus meetings led by experienced clinical experts in the field of diagnostics of severe mental illness. Inter-rater reliability for diagnosis had an overall kappa score of 0.77 (95% CI (0.60, 0.94)). The interrater reliability of the assessments in the TOP study has been shown to be good, with an intraclass © 2014 Wiley Publishing Asia Pty Ltd
L. R. Kvitland et al. TABLE 1. Demographic and clinical characteristics of patients with and without recent cannabis use No cannabis use last 6 months
Cannabis use last 6 months
N = 77
N = 24
Age (years) Education (years) IDS total score YMRS total score PANSS positive total score PANSS negative total score GAF-S GAF-F Duration between first mood episode and treatment (years)
Female sex Not currently a student or employed In a relationship Daily smoking Of European origin Psychotic features
P
N
Mean
SD
N
Mean
SD
77 74† 76† 77 77 77 77 77 77
32.5 14.7 15.4 4.5 10.3 10.0 58.6 51.3 5.1
11.3 2.9 10.7 6.4 4.6 3.2 14.1 12.7 7.7
24 24 22† 24 24 24 24 24 24
26.7 13.1 20.5 6.4 11.2 9.4 54.3 50.9 5.0
6.6 2.5 14.1 6.0 2.6 2.5 10.1 10.8 7.3
N
%
N
%
P
51 36 38 34 65 50
66.2 46.8 49.4 44.7 84.4 64.9
10 15 6 22 22 15
41.7 62.5 25.0 91.7 91.7 62.5
0.054 0.234 0.058 0.000 0.509 0.813
0.002 0.011 0.177 0.208 0.428 0.177 0.849 0.844 0.939
†Missing data. IDS, Inventory of Depressive Symptoms; GAF, Global Assessment Functioning Scale; PANSS, Positive and Negative Syndrome Scale; SD, standard deviation; YMRS, Young Mania Rating Scale.
coefficient 28 for PANSS positive symptoms of 0.82 and for the GAF of 0.86.6 Statistical analyses The analyses were conducted by using the statistical package for the social sciences (SPSS) version 19.0 (SPSS Inc, Chicago, IL, USA). Group comparisons for continuous variables were evaluated with independent sample t-tests, group comparisons for dichotomous data were evaluated with chi-squared tests or Fischer’s exact tests. Level of significance was set to P < 0.05, two-sided. The sample was divided into those who had used any cannabis at all over the past 6 months (recent use) and those without any use in this period (no cannabis use; Table 1). Since several demographic and clinical characteristics were associated with both recent use and age at onset (Table 3), we conducted a series of hierarchical block-wise multiple linear regression analyses to test for possible confounders of their associations. For lifetime suicidal attempts we conducted a logistic regression analysis based on the same principles. We included the variables with the highest significant correlation (P < 0.01) with the dependent variable in step one, and the variables either correlated to recent use or with the least significant correlation (P. < 05) with the dependent © 2014 Wiley Publishing Asia Pty Ltd
variable at the next step, before adding information about recent use on the third and last step. We did not include daily smoking as this is strongly associated with recent use in this (Table 1) and previous studies,16 nor did we include age in the analyses since age at onset in a first-episode sample is highly correlated with current age (r = 0.8 in the current sample). To explore any age or cohort effects on recent cannabis use, we instead conducted a series of hierarchical block-wise multiple linear regression analyses including the age at onset for cannabis (age at first exposure) use in the last step of the model. The main analyses were repeated including only patients experiencing their first ever episode of mania. This did not give any differences in results (data not shown). RESULTS Mean age of the sample was 31.1 years (SD: 10.6 years), N = 61 (60%) were female. Lifetime cannabis use was reported in 55%. There were more males in the ‘recent use’ group (P = 0.05) than in the ‘no cannabis use’. The ‘recent use’ group was also significantly younger and had significantly less education (Table 1). The ‘recent use’ group was significantly younger at the onset of their first manic, depressive and 3
Cannabis in early bipolar disorder I TABLE 2. Age at onset, medication use and suicide attempts in patients with and without recent cannabis use
Age Age Age Age Age
at at at at at
onset onset onset onset onset
first psychotic episode first manic episode first depressive episode first psychotic episode BD I regardless of episode type‡
Current use of antipsychotics Current use of mood stabilizers One or more suicide attempts, lifetime
No cannabis use last 6 months
Cannabis use last 6 months
N = 77
N = 24
N
Mean
SD
N
Mean
SD
50† 74† 57† 50† 77 N 57 19 16
29.5 28.9 24.9 29.5 24.5 % 74.0 24.7 28.1
10.4 11.2 11.0 10.4 10.4
15† 21† 21† 15† 24 N 10 4 12
22.1 23.3 19.8 22.1 20.1 % 41.7 16.7 63.2
3.5 7.0 6.2 3.5 6.6
P
0.000 0.008 0.013 0.000 0.018 P 0.006 0.579 0.012
†Lower N because not all patients experienced this episode. ‡Psychotic, manic, depressive or mixed onset. BD I, bipolar I disorder; SD, standard deviation.
psychotic episodes, and thus also at the age at onset of their illness, regardless of the characteristics of their first episode. There were no significant differences between the groups regarding current symptoms and functioning, but the ‘recent use’ group used antipsychotics to a significantly lower degree compared with the ‘no cannabis use’ group. They had also significantly more often a lifetime history of suicide attempts (Table 2). After controlling for possible confounders of the relationship between age at onset and recent use (Table 3), we found that recent use contributed significantly to age at onset of first manic episode, age at onset of first psychotic episode and to age at onset of first depressive episode. Education and sex also contributed significantly to the age at onset of first manic episode in the final model. We found an even stronger association between lifetime suicide attempts and recent use after controlling for possible confounders (Table 4a–d). In the follow-up analyses, age at first exposure to cannabis contributed significantly (beta 0.956, P < 0.001) to age at onset of the first manic episode (final model (F 8.232 P < 0.001, adj. r2 0.430). Likewise, age at first exposure use contributed significantly (beta 1.131, P < 0.001) to age at onset of first psychotic episode (final model F 6.858 P < 0.001 adj. r2 0.442). Likewise, age at first exposure contributed significantly (beta 0.777, P < 0.01) to age at onset of first depressive episode (final model F 2.938 P < 0.05 adj. r2 0.177). DISCUSSION There are two main results of the current study. Firstly, that recent cannabis use had a significant 4
association with the age at onset of the first episodes of mania, psychosis and depression in a highly representative sample of patients with first-treatment BD, also after controlling for relevant confounders. Secondly, that any lifetime suicidal attempt was more prevalent in the recent use group. There were no significant differences in other clinical characteristics between recent cannabis users and the rest of the patients. The finding of an association between recent use and earlier age at onset for bipolar disorder confirms findings from previous research comprising multi-episode patients.4,8,10,29–33 It supports the hypothesis that cannabis may increase the risk for bipolar disorder, in particular manic and psychotic episodes, interacting with individual genetic vulnerability and other environmental stressors.33–38 However, since this is a cross-sectional study, we do not know in the case of individual patients if the cannabis use started before, at the same time or after the onset of the first manic and/or psychotic episode. Since this is a first-treatment sample, with a short time period from the first mood episode to time of first treatment, we can, to a large extent, rule out the hypothesis that the more severe course seen in early-onset BD increases the risk for later cannabis use.39 Furthermore, it is of interest to notice that a recent review did not find support for a role for self-medication in these associations.40 Another explanation could be that there are common underlying risk factors for both mood instability, psychosis and substance use, in line with what is hypothesized for schizophrenia.41 As we did not control for current age in the analyses for statistical reasons, it is not possible to completely rule out that our findings are reflections of © 2014 Wiley Publishing Asia Pty Ltd
© 2014 Wiley Publishing Asia Pty Ltd
1 0.806‡ 0.843‡ 0.827‡
0.792‡ 0.390‡ −0.211† −0.101 −0.408‡ 0.069 0.071 −0.231† 0.566‡
−0.222
−0.322‡
−0.191
−0.236† −0.245† −0.214† −0.134
0.209† 0.089 0.140
0.352‡
−0.264
−0.219†
−0.219†
1
2
†Correlation is significant at the 0.05 level (two-tailed). ‡Correlation is significant at the 0.01 level (two-tailed).
Cannabis use last 6 months (1) Age at onset first manic episode (2) Age at onset first depressive episode (3) Age at onset first psychotic episode (4) Age of onset of BD regardless of episode type (5) Age (6) Education (7) Sex (8) A student or employed (9) In a relationship (10) Of European origin (11) Alcohol abuse/dependency (12) Cocaine or amphetamine use last 6 months (13) Age at first exposure
1
0.483‡
−0.217
−0.356‡ 0.064 0.053
0.740‡ 0.252† −0.080 −0.092
0.865‡
0.832‡
1
0.806‡
−0.222
3
0.618‡
−0.145
−0.408‡ 0.211 0.152
0.841‡ 0.299† −0.027 −0.116
0.820‡
1
0.832‡
0.843‡
−0.322‡
4
0.429‡
−0.236†
−0.407‡ 0.084 0.052
0.666‡ 0.235† −0.214† 0.017
1
0.820‡
0.865‡
0.827‡
−0.191
5
0.555‡
−0.193
−0.429‡ 0.190 0.153
1 0.394‡ −0.181 −0.163
0.666‡
0.841‡
0.740‡
0.792‡
−0.236†
6
0.008
−0.230†
−0.178 0.204† −0.211†
0.394‡ 1 0.038 0.051
0.235†
0.299†
0.252†
0.390‡
−0.245†
7
8
−0.246
0.090
−0.058 0.027 −0.148
−0.181 0.038 1 −0.089
−0.214†
−0.027
−0.080
−0.211†
−0.214†
TABLE 3. Bivariate correlations (Pearson’s R) between cannabis use, clinical and sociodemographic variables
−0.074
−0.142
−0.009 −0.004 0.004
−0.163 0.051 −0.089 1
0.017
−0.116
−0.092
−0.101
−0.134
9
0.080
0.187
1 −0.121 0.108
−0.429‡ −0.178 −0.058 −0.009
−0.407‡
−0.408‡
−0.356‡
−0.408‡
0.209†
10
−0.014
0.013
−0.121 1 0.096
0.190 0.204† 0.027 −0.004
0.084
0.211
0.064
0.069
0.089
11
0.252
0.072
0.108 0.096 1
0.153 −0.211† −0.148 0.004
0.052
0.152
0.053
0.071
0.140
12
−0.246
1
0.187 0.013 0.072
−0.193 −0.230† 0.090 −0.142
−0.236†
−0.145
−0.217
−0.231†
0.352‡
13
1
−0.246
0.080 −0.014 0.252
0.555‡ 0.008 −0.246 −0.074
0.429‡
0.618‡
0.483‡
0.566‡
−0.264
14
L. R. Kvitland et al.
5
Cannabis in early bipolar disorder I TABLE 4A. Multiple regression analysis with age at first manic episode as dependent variable Block no. variable
Block model summary for each step R2 change
Contribution of separate variables for last step
F change
Beta
t
P value
95% CI of B Lower
Constant 1 Education In a relationship 2 Female sex Cocaine or amphetamine use last 6 months 3 Cannabis use last 6 months
ND 0.121
0.122
0.246
ND 30.154
ND
Upper
2.470
0.017
3.013
29.566
0.937 −4.128
2.078 −1.434
0.043 0.158
0.029 −9.923
1.845 1.668
−5.870 −5.481
−2.160 −1.250
0.036 0.218
−11.346 −14.318
−0.394 3.356
0.956
4.552
0.000
0.532
1.379
3.554
20.716
Total model F 8.232 P < 0.001. Adj. r2 0.430. CI, confidence interval; ND, no data.
TABLE 4B. Multiple regression analysis with age at first depressive episode as dependent variable Block no. variable
Block model summary for each step R2 change
Constant 1 In a relationship 2 Education Cocaine or amphetamine use last 6 months Female sex 3 Cannabis use last 6 months
F change
ND 0.019
ND 0.843
0.058
0.863
0.191
Contribution of separate variables for last step Beta
ND
t
P value
95% CI of B Lower
Upper
9.461
0.000
18.396
28.354
−2.808
−0.918
0.364
−8.974
3.357
0.077 −4.140
0.159 −1.000
0.875 0.323
−0.900 −12.500
1.054 4.214
−3.031
−1.001
0.323
−9.146
3.085
0.777
3.236
0.002
0.292
1.262
10.473
Total model F 2.938 P < 0.05. Adj r2 0.177. CI, confidence interval; ND, no data.
higher rates of cannabis use in the 15–24 contra the 25–34 age groups as indicated by European epidemiological data.42 However, recent Norwegian epidemiological data43 show smaller age effects. In the current sample, we find no differences in recent cannabis use between the 18–24 and 25–34 age groups. The findings of an association between cannabis use and suicide attempts may be taken as a support of the view that cannabis negatively affects the course of illness.33,44 The findings are in line with studies showing more suicidal behaviour in BD patients with early onset,45 in particular in the context of cannabis use.46 The alternative explanation, that more depressive symptoms may provoke 6
cannabis craving, cannot be ruled out. However, this interpretation appears to be less plausible in the current sample as there were no significant differences in depressive symptoms between groups. There was also a lack of difference in the prevalence of psychotic symptoms and other clinical measures between groups. However, there was less use of antipsychotic medication in the recent use group. This could be due to the known problem of low medication adherence in younger patients in general and in BD patients using cannabis specifically.47 Male sex contributed significantly to a lower age at onset for the first manic episode, supporting previous findings of a poorer course of illness in © 2014 Wiley Publishing Asia Pty Ltd
L. R. Kvitland et al. TABLE 4C. Multiple regression analysis with age at first psychotic episode as dependent variable Block no. variable
Block model summary for each step R2 change
Constant 1 In a relationship 2 Cocaine or amphetamine use last 6 months Education Female sex 3 Cannabis use last 6 months
F change
ND 0.038
ND 1.416
0.044
0.527
0.435
Contribution of separate variables for last step Beta
t
P value
95% CI of B Lower
Upper
ND
12.141
0.000
24.728
34.647
−3.824
−1.190
0.822
−10.342
2.694
−7.505
−1.008
0.321
−22.659
7.649
0.312 −0.957
0.483 −0.286
0.632 0.777
−1.001 −7.769
1.624 5.856
1.131
5.373
0.000
0.702
1.560
28.865
Total model F 6.858 P < 0.001. Adj r2 0.442. CI, confidence interval; ND, no data.
TABLE 4D. Multiple logistic regression analysis with one or more suicide attempts lifetime as dependent variable Variable
Suicide attempts lifetime Coefficient
Step 1 Age Female sex In a relationship Step 2 Age Female sex In a relationship Alcohol abuse/dependency Cocaine or amphetamine use last 6 months Step 3 Age Female sex In a relationship Alcohol abuse/dependency Cocaine or amphetamine use last 6 months Cannabis use last 6 months
P
OR
95% CI of OR Lower
Upper
−0.020 1.395 −0.160
0.49 0.01 0.78
0.98 4.04 0.85
0.926 1.365 0.278
1.037 11.929 2.615
−0.021 1.379 −0.036 0.358 −0.905
0.49 0.01 0.95 0.62 0.35
0.98 3.97 0.97 1.43 0.41
0.992 1.318 0.305 0.351 0.062
1.039 11.973 3.052 5.836 2.661
−0.008 2.134 0.156 0.051 0.356 2.259
0.81 0.01 0.80 0.949 0.754 0.01
0.99 8.45 1.17 1.05 1.43 9.57
0.927 2.012 0.343 0.222 0.155 1.952
1.061 35.504 3.979 4.975 13.175 46.921
Nagelkerke r2 0.31. CI, confidence interval; OR, odds ratio.
males,14 and to the association between early onset and more severe symptoms.48 Cannabis users and BD patients in general are less likely to be in a relationship compared with the population at large.49–51 Patients currently in a relationship had a later age at onset for manic, depressive and psychotic episodes and also lower levels of cannabis use. The crosssectional nature of the study makes it difficult to know whether there are common underlying factors © 2014 Wiley Publishing Asia Pty Ltd
to both relational capacities and an early onset, or if patients with early onset have problems with taking on age-appropriate social roles such as entering relationships. Strengths and limitations The main strength of the study is the large and welldocumented sample of patients in the early course 7
Cannabis in early bipolar disorder I of bipolar disorder, avoiding many of the methodological limitations of previous studies in patients with longer course of illness. The thorough protocol allowed for a systematic approach, discerning the role of possible confounders for the association between recent use and significant patient characteristics and outcomes. The sampling procedure including both inpatients and outpatients with consecutive recruitment from a catchment area-based health service gives the sample a high degree of representativity.6 However, since Norwegian law and the Regional Committee for Medical Research Ethics do not allow us to access the medical charts of patients that have not consented to research participation, we are unable to give a full account of eligible patients that might not have been referred. The main weakness is the cross-sectional design that makes it impossible to answer questions about causality. The ascertainments of age at onset and illness history were partly retrospective, based on patients’ reports and thus suffer from potential recall bias. The proximity to events in this recent onset sample is still a comparative strength of the study. The patients were included in close proximity to their manic episode, having a mildly depressed mood on group level at point of inclusion, as reflected in the IDS-C scores. CONCLUSION In conclusion, the current study shows that patients with cannabis use at the start of the first treatment for a BD I disorder have an earlier age at onset for their first manic or psychotic episode, and more often have attempted suicide. Longitudinal studies are warranted to questions about causative factors. REFERENCES 1. Salomon JA, Vos T, Hogan DR et al. Common values in assessing health outcomes from disease and injury: disability weights measurement study for the Global Burden of Disease Study 2010. Lancet 2013; 380: 2129–43. 2. Murray CJ, Vos T, Lozano R et al. Disability-adjusted life years (DALYs) for 291 diseases and injuries in 21 regions, 1990– 2010: a systematic analysis for the Global Burden of Disease Study 2010. Lancet 2013; 380: 2197–223. 3. Kroon JS, Wohlfarth TD, Dieleman J et al. Incidence rates and risk factors of bipolar disorder in the general population: a population-based cohort study. Bipolar Disord 2013; 15: 306–13. 4. Lagerberg TV, Sundet K, Aminoff SR et al. Excessive cannabis use is associated with earlier age at onset in bipolar disorder. Eur Arch Psychiatry Clin Neurosci 2011; 261: 397–405. 5. Najt P, Fusar-Poli P, Brambilla P. Co-occurring mental and substance abuse disorders: a review on the potential predictors and clinical outcomes. Psychiatry Res 2011; 186: 159– 64.
8
6. Ringen PA, Lagerberg TV, Birkenaes AB et al. Differences in prevalence and patterns of substance use in schizophrenia and bipolar disorder. Psychol Med 2008; 38: 1241–9. 7. Strakowski SM, DelBello MP, Fleck DE et al. Effects of co-occurring cannabis use disorders on the course of bipolar disorder after a first hospitalization for mania. Arch Gen Psychiatry 2007; 64: 57–64. 8. van Laar M, van Dorsselaer S, Monshouwer K, de Graaf R. Does cannabis use predict the first incidence of mood and anxiety disorders in the adult population? Addiction 2007; 102: 1251–60. 9. De HM, Wampers M, Jendricko T et al. Effects of cannabis use on age at onset in schizophrenia and bipolar disorder. Schizophr Res 2011; 126: 270–6. 10. Tohen M, Vieta E, Gonzalez-Pinto A, Reed C, Lin D. Baseline characteristics and outcomes in patients with first episode or multiple episodes of acute mania. J Clin Psychiatry 2010; 71: 255–61. 11. Strakowski SM, DelBello MP, Fleck DE, Arndt S. The impact of substance abuse on the course of bipolar disorder. Biol Psychiatry 2000; 48: 477–85. 12. Baethge C, Hennen J, Khalsa HM, Salvatore P, Tohen M, Baldessarini RJ. Sequencing of substance use and affective morbidity in 166 first-episode bipolar I disorder patients. Bipolar Disord 2008; 10: 738–41. 13. Ostacher MJ, Perlis RH, Nierenberg AA et al. Impact of substance use disorders on recovery from episodes of depression in bipolar disorder patients: prospective data from the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD). Am J Psychiatry 2010; 167: 289–97. 14. Cotton SM, Lambert M, Berk M et al. Gender differences in first episode psychotic mania. BMC Psychiatry 2013; 13: 82. 15. Salvatore P, Baldessarini RJ, Tohen M et al. McLean-Harvard International First-Episode Project: two-year stability of ICD-10 diagnoses in 500 first-episode psychotic disorder patients. J Clin Psychiatry 2011; 72: 183–93. 16. Heffner JL, DelBello MP, Anthenelli RM, Fleck DE, Adler CM, Strakowski SM. Cigarette smoking and its relationship to mood disorder symptoms and co-occurring alcohol and cannabis use disorders following first hospitalization for bipolar disorder. Bipolar Disord 2012; 14: 99–108. 17. Yatham LN, Kauer-Sant’Anna M, Bond DJ, Lam RW, Torres I. Course and outcome after the first manic episode in patients with bipolar disorder: prospective 12-month data from the Systematic Treatment Optimization Program for Early Mania project. Can J Psychiatry 2009; 54: 105–12. 18. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders: DSM-IV. Washington: American Psychiatric Association, 1994. 19. First M, Spitzer RL, Gibbon M, Williams J. Structural Clinical Interview for DSM-IV Axis I Disorders – Clinical Version (SCIDCV). Washington DC: American Psychiatric Press, 1997. 20. Rush AJ, Giles DE, Schlesser MA, Fulton CL, Weissenburger J, Burns C. The Inventory for Depressive Symptomatology (IDS): preliminary findings. Psychiatry Res 1986; 18: 65–87. 21. Young RC, Biggs JT, Ziegler VE, Meyer DA. A rating scale for mania: reliability, validity and sensitivity. Br J Psychiatry 1978; 133: 429–35. 22. Endicott J, Spitzer RL, Fleiss JL, Cohen J. The global assessment scale. A procedure for measuring overall severity of psychiatric disturbance. Arch Gen Psychiatry 1976; 33: 766– 71. 23. Pedersen G, Hagtvet KA, Karterud S. Generalizability studies of the Global Assessment of Functioning-Split version. Compr Psychiatry 2007; 48: 88–94. 24. Kay SR, Fiszbein A, Opler LA. The positive and negative syndrome scale (PANSS) for schizophrenia. Schizophr Bull 1987; 13: 261–76. © 2014 Wiley Publishing Asia Pty Ltd
L. R. Kvitland et al. 25. Lindenmayer JP, Bossie CA, Kujawa M, Zhu Y, Canuso CM. Dimensions of psychosis in patients with bipolar mania as measured by the positive and negative syndrome scale. Psychopathology 2008; 41: 264–70. 26. Wechsler D. Wechsler Abbreviated Scale of Intelligence (WASI). Norwegian Manual Supplement. Stockholm: Pearson Assessment, 2007. 27. Ventura J, Liberman RP, Green MF, Shaner A, Mintz J. Training and quality assurance with the Structured Clinical Interview for DSM-IV (SCID-I/P). Psychiatry Res 1998; 79: 163–73. 28. Shrout PE, Fleiss JL. Intraclass correlations: uses in assessing rater reliability. Psychol Bull 1979; 86: 420–8. 29. Ongur D, Lin L, Cohen BM. Clinical characteristics influencing age at onset in psychotic disorders. Compr Psychiatry 2009; 50: 13–9. 30. Kaymaz N, van Os J, de Graaf R, Ten HM, Nolen W, Krabbendam L. The impact of subclinical psychosis on the transition from subclinicial mania to bipolar disorder. J Affect Disord 2007; 98: 55–64. 31. Henquet C, Krabbendam L, de Graaf R, Ten HM, van Os J. Cannabis use and expression of mania in the general population. J Affect Disord 2006; 95: 103–10. 32. Agrawal A, Nurnberger JI Jr, Lynskey MT. Cannabis involvement in individuals with bipolar disorder. Psychiatry Res 2011; 185: 459–61. 33. Lev-Ran S, Le FB, McKenzie K, George TP, Rehm J. Bipolar disorder and co-occurring cannabis use disorders: characteristics, co-morbidities and clinical correlates. Psychiatry Res 2013; 209: 459–65. 34. Henquet C, van Os J, Kuepper R et al. Psychosis reactivity to cannabis use in daily life: an experience sampling study. Br J Psychiatry 2010; 196: 447–53. 35. Baethge C, Baldessarini RJ, Khalsa HM, Hennen J, Salvatore P, Tohen M. Substance abuse in first-episode bipolar I disorder: indications for early intervention. Am J Psychiatry 2005; 162: 1008–10. 36. Batalla A, Garcia-Rizo C, Castellvi P et al. Screening for substance use disorders in first-episode psychosis: implications for readmission. Schizophr Res 2013; 146: 125–31. 37. Bahorik AL, Newhill CE, Eack SM. Characterizing the longitudinal patterns of substance use among individuals diagnosed with serious mental illness after psychiatric hospitalization. Addiction 2013; 108: 1259–69. 38. Post RM, Kalivas P. Bipolar disorder and substance misuse: pathological and therapeutic implications of their comorbidity and cross-sensitisation. Br J Psychiatry 2013; 202: 172–6.
© 2014 Wiley Publishing Asia Pty Ltd
39. Khantzian EJ. The self-medication hypothesis of addictive disorders: focus on heroin and cocaine dependence. Am J Psychiatry 1985; 142: 1259–64. 40. Dekker N, Linszen DH, De HL. Reasons for cannabis use and effects of cannabis use as reported by patients with psychotic disorders. Psychopathology 2009; 42: 350– 60. 41. Chambers RA, Krystal JH, Self DW. A neurobiological basis for substance abuse comorbidity in schizophrenia. Biol Psychiatry 2001; 50: 71–83. 42. European Monitoring Centre for Drugs and Drug Addiction. A Cannabis Reader: Global Issues and Local Experiences. Lisbon: EMCDDA, 2008. 43. Norwegian Institute for Alcohol and Drug Research. The drug situation in Norway 2010 – annual report to the European Monitoring Centre for Drugs and Drug Addiction – EMCDDA. 2010. SIRUS/EMCDDA. 15-1-2014. Ref Type: Serial (book, monograph). 44. van Rossum I, Boomsma M, Tenback D, Reed C, van Os J. Does cannabis use affect treatment outcome in bipolar disorder? A longitudinal analysis. J Nerv Ment Dis 2009; 197: 35–40. 45. Azorin JM, Bellivier F, Kaladjian A et al. Characteristics and profiles of bipolar I patients according to age-at-onset: findings from an admixture analysis. J Affect Disord 2013; 150: 993–1000. 46. Etain B, Lajnef M, Bellivier F et al. Clinical expression of bipolar disorder type I as a function of age and polarity at onset: convergent findings in samples from France and the United States. J Clin Psychiatry 2012; 73: e561–6. 47. Gonzalez-Pinto A, Reed C, Novick D, Bertsch J, Haro JM. Assessment of medication adherence in a cohort of patients with bipolar disorder. Pharmacopsychiatry 2010; 43: 263– 70. 48. Baldessarini RJ, Bolzani L, Cruz N et al. Onset-age of bipolar disorders at six international sites. J Affect Disord 2010; 121: 143–6. 49. Lieberman DZ, Massey SH, Goodwin FK. The role of gender in single vs married individuals with bipolar disorder. Compr Psychiatry 2010; 51: 380–5. 50. McPherson HM, Dore GM, Loan PA, Romans SE. Socioeconomic characteristics of a Dunedin sample of bipolar patients. N Z Med J 1992; 105: 161–2. 51. Agrawal A, Lynskey MT. Correlates of later-onset cannabis use in the National Epidemiological Survey on Alcohol and Related Conditions (NESARC). Drug Alcohol Depend 2009; 105: 71–5.
9
