Abstract
Bipolar disorder (BD) and nicotine dependence (ND) often co-occur. However, the mechanisms underlying this association remain unclear. We aimed to examine, for the first time in a national and representative sample, the magnitude and direction of the temporal relationship between BD and ND; and to compare, among individuals with lifetime ND and BD, the sociodemographic and clinical characteristics of individuals whose onset of ND preceded the onset of BD (ND-prior) with those whose onset of ND followed the onset of BD (BD-prior). The sample included individuals with lifetime BD type I or ND (n=7958) from the National Epidemiologic Survey on Alcohol and Related Conditions (NESARC, n=43093). Survival analyses and logistic regression models were computed to study the temporal association between ND and BD, and to compare ND-prior (n=135) and BD-prior (n=386) individuals. We found that ND predicted the onset of BD and BD also predicted the onset of ND. Furthermore, the risk of developing one disorder following the other one was greatest early in the course of illness. Most individuals with lifetime ND and BD were BD-prior (72.6%). BD-prior individuals had an earlier onset of BD and a higher number of manic episodes. By contrast, ND-prior individuals had an earlier onset of both daily smoking and ND, and an increased prevalence of alcohol use disorder. In conclusion, ND and BD predict the development of each other. The phenomenology and course of ND and BD varied significantly depending on which disorder had earlier onset.
Keywords: bipolar disorder, nicotine dependence, age of onset, smoking, epidemiology
1. Introduction
Smoking and nicotine dependence (ND) continue to be the leading cause of preventable death worldwide, and they are more frequent among psychiatric patients. In particular, individuals with bipolar disorder (BD) as compared to the general population are more likely to have a lifetime history of smoking (Diaz et al., 2009; Gonzalez-Pinto et al., 1998; Lasser et al., 2000), current smoking (Diaz et al., 2009; Lasser et al., 2000), and ND (Grant et al., 2004), as well as lower rates of smoking cessation (Diaz et al., 2009; Lasser et al., 2000). ND has been associated with BD in epidemiological (Grant et al., 2004) and in clinical samples (Chandra et al., 2005). Because patients with BD are more likely to have medical illnesses often caused or exacerbated by cigarette smoking (Garcia-Portilla et al., 2010), a better knowledge of the reasons for the co-occurrence of ND and BD could help avoid premature deaths in this population.
The possible mechanisms underlying the association between ND and BD remain unclear and proposed hypotheses are largely based on the (better developed) literature on smoking and depression (Heffner et al., 2011). These authors (Heffner et al., 2011) put forth three possibilities: BD increases the risk of ND, ND increases the risk of BD, and BD and ND share common risk factors. First, BD may increase the risk of ND as the result of a self-medication approach (i.e. patients with BD may use nicotine to alleviate symptoms or treat side-effects). This mechanism is supported by the finding that acute nicotine use may relieve depressed mood (Berlin and Anthenelli, 2001; Kenny et al., 2000). Second, ND by itself could affect somatic or mental health adversely and hasten the onset of BD. In this line, chronic nicotine consumption may impair serotonin function (Malone et al., 2003) and enhance the risk of depression. Under these two hypotheses, the onset of ND and its temporal relationship with the onset of BD could be relevant. If BD increases the risk of ND in a self-medication manner, the onset of BD must be earlier than the onset of ND; whereas if ND contributes causally to BD, the onset of ND must occur first.
The goal of this study was two-fold: 1) to examine the magnitude and direction of the temporal relationship between BD and ND, controlling for sex and family history of substance use disorders, mood disorders or antisocial behavior, following the model of (Kuo et al., 2006) that is, examining the temporal relationship between the onset of alcohol dependence and the onset of major depressive disorder; and, 2) among individuals with lifetime ND and BD, to compare sociodemographic and clinical characteristics between individuals whose age of onset of ND preceded (ND-prior) or followed (BD-prior) the age of onset of BD, drawing on data from the National Epidemiologic Survey on Alcohol and Related Conditions (NESARC).
2. Materials and methods
2.1 Sample
The National Epidemiologic Survey on Alcohol and Related Conditions (NESARC) was a face-to-face survey conducted by the US Census Bureau under the direction of the National Institute on Alcohol Abuse and Alcoholism (NIAAA) in 2001–2002 (Grant et al., 2003). The NESARC target population was the non-institutionalized, adult civilian population residing in the USA. The housing unit sampling frame was the US Bureau of the Census Supplementary Survey, which included the group quarters sampling frame derived from the Census 2000 Group Quarters Inventory. Blacks, Hispanics, and young adults (ages 18–24 years) were oversampled to provide more precision on the estimates for these groups.
The research protocol, including informed consent procedures, was approved by the Census Bureau’s Institutional Review Board and the US Office of Management and Budget. The final sample included 43,093 respondents, and the overall survey response rate was 81%. The NESARC sample was weighted to adjust for the probabilities of selection of: a sample housing unit or housing unit equivalent from the group quarters sampling frame, non-response at the household or person level, selection of one person per household, and oversampling of young adults. The weighted data were then adjusted for sociodemographic variables based on the 2000 Decennial Census. This study included all individuals with a lifetime history of BD-I or ND (n = 7958).
Although differences in rates of smoking or ND between BD type I (BD-I) and BD type II appear to be small (Grant et al., 2004; Waxmonsky et al., 2005), we focused exclusively on BD-I individuals to be consistent with most previous studies on smoking and BD (Gonzalez-Pinto et al., 1998; Heffner et al., 2012; Hughes et al., 1986; Itkin et al., 2001; Kreinin et al., 2012).
2.2 Measures
All diagnoses in the NESARC were made according to the DSM-IV (APA, 1994) criteria using the Alcohol Use Disorder and Associated Disabilities Interview Schedule-DSM-IV version (AUDADIS-IV) (Grant et al., 2001), a valid and reliable fully structured diagnostic interview designed for use by non-clinicians (Williams et al., 1992). The test-retest reliability of AUDADIS-IV was good for BD-I (κ = 0.65) and excellent for drug diagnoses (κ > 0.79) (Canino et al., 1999; Grant et al., 2003). The good test-retest reliability of the AUDADIS-IV mood sections was comparable to that obtained with the computerized DSM-IV version of the Composite International Diagnostic Interview (CIDI) (any BD: κ = 0.64) (Wittchen et al., 1998). In addition, validity of BD-I diagnosis was assessed using the Mental Component, Social Functioning, Role Emotional Functioning, and Mental Health scores of the Short Form-12v2 (SF-12v2), a reliable and valid impairment measure in population surveys (Ware et al., 2002).
Sociodemographic characteristics included race/ethnicity, sex, age, urbanicity (urban vs. rural), level of education, individual income and marital status. Information was also collected on history of alcohol use disorder, drug use disorder, and depression and antisocial behavior among first-degree relatives of the respondent.
The age of onset of BD was considered to be when the respondent first met DSM-IV criteria for a manic or major depressive episode. Nicotine dependence was assessed separately via extensive items covering the DSM-IV criteria (APA, 1994) which require meeting three or more of seven criteria within a 12-month period. The age of onset of ND was considered when the respondent first met three or more of seven DSM-IV criteria for ND. The age of onset of daily smoking was determined by asking respondents about the age at which they first “started smoking every day”. Finally, tobacco withdrawal symptoms were determined by asking respondents whether they experienced any of eight tobacco withdrawal symptoms (depression, sleep problems, difficulty concentrating, increased appetite, irritability or frustration, anxiety or nervousness, heart beating more slowly, restlessness) when attempting to quit smoking. Responses were summed for total withdrawal symptoms score (range 0–8; α = 0.93) (Weinberger et al., 2010).
Individuals with lifetime ND and BD (n=573) were classified as having age of onset of ND earlier than their age of onset of BD (ND-prior; n=135) or later (BD-prior; n=386). Individuals whose age of onset of ND was in the same year than age of onset of BD (n=52) were categorized as “concurrent” and excluded from analyses comparing ND-prior and BD-prior individuals, since we could not distinguish which one had an earlier onset.
2.3 Data analysis
Following the model of (Kuo et al., 2006), we used survival analyses to study the temporal association between ND and BD. We built three sets of Cox proportional hazard regression models including: 1) time-dependent diagnosis of each disorder, as well as family history of alcohol or drug use disorders, depression and antisocial behavior; 2) interactions of sex with time-dependent diagnosis and family history of the above psychiatric disorders; and 3) decay of the hazard modelled as logarithmic functions of time in order to test that the proportional hazard ratio (HR) held over time (Kuo et al., 2006).
We then computed weighted percentages and means to derive sociodemographic and clinical characteristics of BD respondents, ND-prior and BD-prior. Because the combined standard error of two means (or percents) is always equal or less than the sum of the standard errors of those two means, we conservatively consider two confidence intervals that share a boundary or do not overlap to be significantly different from one another (Agresti and Hartzel, 2000). Binary logistic regressions were conducted to compare the distribution of clinical variables between ND-prior and BD-prior respondents, adjusting for age and sex. We consider significant ORs those whose CI does not cross 1 (Agresti and Hartzel, 2000). All analyses, including point estimates, standard errors and 95% confidence intervals (CI) were performed using SUDAAN (Research, Triangle Institute 2004) to adjust for the complex design of the NESARC.
3. Results
Prevalence and age at onset of ND and BD, and the association of both conditions, are shown according to sex in Table 1. In the whole NESARC sample, males had a significantly higher prevalence of ND and a significantly earlier age of onset of both ND and BD than females (P<0.001). Among individuals with both ND and BD, there was a significantly higher proportion of ND-prior among males and a significantly higher proportion of BD-prior among females (P=0.03).
Table 1.
Prevalence and age at onset of nicotine dependence and bipolar disorder and the association of both conditions
Males | Females | t/χ2 | df | p-value | |
---|---|---|---|---|---|
NESARC sample (n = 43.093) | 18518 (47.9%) | 24575 (52.1%) | |||
Age of onset of ND a | 30.3 (0.3) | 31.9 (0.3) | −4.07 | <0.001 | |
Age of onset of first mood episode a | 27.9 (0.3) | 29.6 (0.2) | −4.43 | <0.001 | |
ND prevalence | 3404 (20.0%) | 3533 (15.6%) | 63.39 | 1 | <0.001 |
BD-I prevalence | 579 (3.2%) | 832 (3.4%) | 1.66 | 1 | 0.202 |
Co-morbid status | |||||
ND only | 3126 (18.5%) | 3210 (14.2%) | 23.53 | 3 | <0.001 |
BD-I only | 301 (1.6%) | 509 (2.05%) | |||
Co-morbidity of ND and BD | 278 (1.5%) | 323 (1.4%) | |||
Co-morbid sample (n = 573) b | |||||
BD-prior | 165 (59.9%) | 221 (72.0%) | 3.73 | 2 | 0.029 |
ND-prior | 75 (27.1%) | 60 (22.4%) | |||
Concurrent | 29 (13.0%) | 23 (5.6%) |
ND = nicotine dependence; BD-I = bipolar disorder type I; ND-prior = smokers whose age of onset of ND was before than their age of onset of first mood episode; BD-prior = smokers whose age of onset of ND was after than their age of onset of first mood episode; Co-morbid sample = ND + BD-I; Concurrent = age of onset of ND in the same year as age of onset of first mood episode.
Mean age at first onset, and standard error (SE) in parentheses
Temporal relation of ND and BD
A series of Cox proportional hazard models predicting risk for ND are displayed in Table 2. Risk of developing ND was increased by the main effect of male sex, BD diagnosis and family history of drug use disorders. None of the five sex interaction terms included in the second model was significant. In the final model, after dropping the non-significant sex-interaction terms from the previous model, prior BD diagnosis increased the risk of developing ND, and the HR for the decay variable was significant, with a value of less than 1.
Table 2.
Hazard ratio (and 95% confidence interval) for nicotine dependence among individuals with prior bipolar disorder (n=1393) controlling for sex and family history of drug use, depression and antisocial behavior
Predictors | HR (95% CI)
|
||
---|---|---|---|
Test for main effect | Test for sex interaction | Final model with decay | |
Sex a | 1.5 (1.2–1.8)*** | 1.30 (0.8–2.1) | 1.2 (0.9–1.5) |
BD_time-dependent | 1.5 (1.2–1.8)** | 1.32 (1.0–1.7) | 2.8 (2.1–3.8)*** |
Drug use family history | 1.3 (1.1–1.6)* | 1.34 (0.9–1.8) | 0.9 (0.7–1.1) |
Alcohol use family history | 1.1 (0.9–1.4) | 1.10 (0.8–1.6) | 0.7 (0.5–0.8)** |
Depression family history | 1.0 (0.8–1.3) | 0.96 (0.7–1.3) | 1.1 (0.9–1.4) |
Antisocial behavior family history | 1.1 (0.9–1.3) | 1.09 (0.8–1.5) | 1.2 (0.9–1.4) |
Sex x BD_time-dependent | 1.20 (0.8–1.8) | ||
Sex x Drug use family history | 0.96 (0.6–1.4) | ||
Sex x Alcohol use family history | 1.02 (0.6–1.6) | ||
Sex x Depression family history | 1.11 (0.7–1.7) | ||
Sex x Antisocial behavior family history | 0.96 (0.6–1.5) | ||
Decay by year b | 0.86 (0.8–0.9)*** |
HR = hazard ratio; CI = confidence interval.
Male = 1, female = 2
Decay as log (ND - BD age of onset)
p<0.05,
p<0.01,
p<0.001
Models predicting risk for BD (Table 3) show an increased risk for BD associated with having prior ND onset and family history of depression or antisocial behavior. None of the five sex interaction terms included in the second model was significant. In the final model, ND-prior diagnosis strongly affected the risk of BD and the decay variable was also significant, with a value of less than 1.
Table 3.
Hazard ratio (and 95% confidence interval) for bipolar disorder among individuals with prior nicotine dependence (n=6565) controlled for sex and family history of drug use, depression and antisocial behavior
Predictors | HR (95% CI)
|
||
---|---|---|---|
Test for main effect | Test for sex interaction | Final model with decay | |
Sex a | 1.1 (0.9–1.3) | 0.9 (0.6–1.4) | 0.8 (0.6–1.0) |
ND_time-dependent | 1.7 (1.3–2.2)*** | 1.4 (1.01–2.1)* | 25. 6 (13.0–50.4)*** |
Drug use family history | 1.2 (0.9–1.6) | 1.3 (0.9–1.8) | 1.1 (0.8–1.5) |
Alcohol use family history | 1.1 (0.9–1.4) | 1.2 (0.9–1.7) | 0.9 (0.7–1.4) |
Depression family history | 2.5 (1.9–3.2)*** | 2.3 (1.6–3.2)*** | 1.2 (0.9–1.7) |
Antisocial behavior family history | 1.7 (1.4–2.2)*** | 1.6 (1.1–2.2)** | 1.1 (0.8–1.6) |
Sex x ND_time-dependent | 1.4 (0.9–2.2) | ||
Sex x Drug use family history | 0.9 (0.5–1.5) | ||
Sex x Alcohol use family history | 0.9 (0.6–1.4) | ||
Sex x Depression family history | 1.2 (0.7–1.8) | ||
Sex x Antisocial behavior family history | 1.2 (0.7–1.9) | ||
Decay by year b | 0.79 (0.7–0.8)*** |
HR = hazard ratio; CI = confidence interval.
Male = 1, female = 2
Decay as log (BD - ND age of onset)
p<0.05,
p<0.01,
p<0.001
Among individuals with lifetime ND and BD, 72.6% were BD-prior and 27.4% were ND-prior. Compared to ND-prior respondents, BD-prior respondents were significantly more likely to be never married (Table 4). BD-prior individuals had an earlier age of onset of first mood episode, first depressive episode and first manic episode, and a greater number of manic episodes (Table 4), but a later age of onset of both daily smoking and ND. On the average, the transition time from daily smoking to ND was significantly longer for BD-prior individuals than for ND-prior ones (11.9 ± 0.7 vs. 4.4 ± 0.7 years, P<0.001).
Table 4.
Sociodemographic and clinical differences between bipolar disorder individuals whose onset of nicotine dependence was before their onset of bipolar disorder (ND-prior) and those whose onset of bipolar disorder was before their onset of nicotine dependence (BD-prior)
ND-prior (n = 135) | BD-prior (n = 386) | ORa | 95 % CI | |
---|---|---|---|---|
| ||||
% (SE) | % (SE) | |||
Sex: male | 56.5 (5.1) | 47.1 (2.9) | 1.4 | 0.9–2.4 |
Age | ||||
18–29 | 27.9 (4.3) | 36.6 (2.9) | 1.0 | 1.0–1.0 |
30–44 | 38.6 (4.6) | 35.9 (3.1) | 1.4 | 0.8–2.5 |
≥45 | 33.5 (4.7) | 27.5 (2.6) | 1.6 | 0.9–2.9 |
Race/ethnicity | ||||
White non Hispanic | 82.2 (4.3) | 77.4 (2.8) | 1.0 | 1.0–1.0 |
Other | 17.8 (4.3) | 22.6 (2.8) | 0.7 | 0.4–1.4 |
Education | ||||
≤ High school | 60.7 (4.8) | 53.3 (3.4) | 1.4 | 0.8–2.3 |
≥ College | 39.3 (4.8) | 46.7 (3.4) | 1.0 | 1.0–1.0 |
Marital status | ||||
Married | 58.3 (4.4) | 48.0 (3.2) | 1.0 | 1.0–1.0 |
Widowed/divorced/separated | 22.2 (4.2) | 24.1 (2.6) | 0.8 | 0.4–1.3 |
Never married | 19.6 (3.7) | 27.9 (2.5) | 0.6 | 0.3–0.9 |
Personal Income | ||||
$0–19,999 | 54.4 (4.6) | 65.75 (3.2) | 1.0 | 1.0–1.0 |
$20,000–34,999 | 25.8 (4.0) | 19.7 (2.4) | 1.6 | 0.9–2.6 |
≥$35,000 | 19.8 (4.0) | 14.5 (2.1) | 1.7 | 0.8–3.3 |
Urbanicity: rural | 20.5 (4.6) | 23.4 (3.5) | 0.8 | 0.5–1.5 |
| ||||
Mean (SE) | Mean (SE) | t-test | p-value | |
| ||||
Age of onset of first mood episode, years | 29.7 (1.3) | 18.2 (0.5) | 8.6 | <0.001 |
Age of first depressive episode, years | 30.4 (1.6) | 21.4 (0.7) | 5.1 | <0.001 |
Age of first manic episode, years | 30.1 (1.1) | 21.6 (0.6) | 7.0 | <0.001 |
Number of lifetime depression phases | 6.1 (1.4) | 9.5 (1.1) | −1.9 | 0.061 |
Number of lifetime manic phases | 4.2 (0.8) | 8.4 (1.0) | −3.2 | 0.002 |
Age of onset of first full cigarette smoked, years | 14.2 (0.4) | 14.5 (0.2) | −0.6 | 0.555 |
Age of onset of daily smoking, years | 16.05 (0.4) | 17.5 (0.3) | −3.2 | 0.002 |
Age of onset of nicotine dependence, years | 20.6 (0.7) | 29.5 (0.7) | −9.8 | <0.001 |
Number cigarettes smoked per day | 22.7 (1.4) | 20.0 (0.7) | 1.7 | 0.091 |
Number of withdrawal symptoms | 4.2 (0.2) | 4.4 (0.1) | −0.7 | 0.456 |
SF-12 | ||||
Mental Component Summary Score | 44.5 (1.3) | 41.7 (0.8) | 1.8 | 0.072 |
Physical Disability Scale Score | 48.7 (1.2) | 48.4 (0.7) | 0.2 | 0.847 |
BD-I = bipolar disorder type I; ND-prior = smokers whose age of onset of ND was before their age of onset of first mood episode; BD-prior = smokers whose age of onset of ND was after their age of onset of first mood episode. OR = odds ratio; CI = confidence interval; SE = standard error.
Patients whose age of onset of ND was in the same year of age of onset as first mood episode were excluded from analysis.
Compared with BD-prior individuals, ND-prior individuals had a significantly greater proportion of lifetime alcohol use disorder. There were no differences in rates of hospitalization for BD or in family history of alcohol or drug use disorder, depression or antisocial behavior (Table 5).
Table 5.
Personal and familial psychiatric history between bipolar disorder individuals whose onset of nicotine dependence was before their onset of bipolar disorder (ND-prior) and those whose onset of bipolar disorder was before their onset of nicotine dependence (BD-prior)
ND-prior (n = 135) | BD-prior (n = 386) | ORb | 95 % CI | |
---|---|---|---|---|
| ||||
% (SE) | % (SE) | |||
Any Axis I diagnosis a | 94.4 (2.2) | 92.7 (1.5) | 1.3 | 0.5–3.3 |
Any lifetime anxiety disorder | 61.3 (5.0) | 61.2 (2.9) | 1.0 | 0.6–1.7 |
Any lifetime alcohol use disorder | 87.0 (3.2) | 75.4 (2.5) | 2.1 | 1.1–4.2 |
Any lifetime drug use disorder | 62.0 (4.7) | 55.0 (3.2) | 1.4 | 0.8–2.3 |
Any personality disorder | 70.7 (4.9) | 70.3 (2.6) | 1.0 | 0.6–1.7 |
Any hospitalization | 31.2 (4.6) | 35.7 (3.1) | 0.7 | 0.4–1.3 |
Family history | ||||
Alcohol use disorder | 67.9 (4.7) | 64.7 (2.7) | 1.1 | 0.7–1.8 |
Drug use disorder | 45.3 (5.8) | 43.4 (3.1) | 1.1 | 0.6–1.9 |
Depression | 69.6 (5.1) | 74.1 (2.5) | 0.8 | 0.5–1.4 |
Antisocial behavior | 52.6 (5.1) | 54.1 (2.7) | 1.0 | 0.6–1.5 |
BD-I = bipolar disorder type I; ND-prior = smokers whose age of onset of ND was before their age of onset of first mood episode; BD-prior = smokers whose age of onset of ND was after their age of onset of first mood episode; OR = odds ratio; CI = confidence interval; SE = standard error.
Excluding BD-I and ND.
Adjusted for sex and age. Patients whose age of onset of ND was in the same year of age of onset as first mood episode were excluded from analysis.
4. Discussion
4.1 Main findings, strengths and limitations
In a large, nationally representative sample of US adults, survival analysis models showed that BD was associated with an increased risk of ND, of future onset of ND, and also, more strongly, with an increased risk of future BD. There were no significant sex interactions in the models, suggesting that these findings are similar among males and females. Moreover, the significant negative decay coefficients indicate that the risk of suffering one disorder after the other one decreased over time. When individuals with both BD and ND were compared according to which disorder had earlier onset, those who developed ND after the onset of BD (BD-prior) were more likely to have an earlier onset of BD and more manic episodes. By contrast, individuals who developed ND before the onset of BD (ND-prior) had an earlier onset of both daily smoking and ND, and increased odds of co-morbid alcohol use disorders. Finally, we found sex differences between ND-prior and BD-prior respondents (Table 1). The finding of a higher proportion of BD-prior among women could be related to the earlier onset of BD found among BD-prior respondents. However, the age of onset of BD in the total sample was significantly younger among men. The higher proportion of ND-prior among men could be attributed, at least in part, to an earlier onset of ND among men.
Some strengths of this study are the large sample size, the test-retest of the AUDADIS-IV for BD and drug diagnoses, and the consistency across analytic strategies which provide additional support for the validity of results. However, the potential limitations should be taken into consideration. First, the information regarding ND was based on self-report and not confirmed by objective methods. Second, diagnoses may be subject to recall bias. Third, consistent with DSM-IV, we considered the age of onset of BD as the age of onset of first manic or major depressive episode. However, some symptoms of BD, especially in youths, may be presented before the first full-threshold mood episode (Axelson et al., 2011). Finally, family history of BD or smoking was not collected in the NESARC.
4.2 Shared liability
In our sample, ND and BD predict the development of each other, indicating a bidirectional temporal relationship between BD and ND. One first possible explanation is that both disorders have shared or correlated risk factors, including genetic, physiological or environmental factors (Heffner et al., 2011). For example, genes encoding catechol-O-methyltransferase (COMT) or involving dopamine or serotonin systems may interact in predisposing for BD and substance use disorders (McEachin et al., 2010; Novak et al., 2010). In addition, brain structural and functional abnormalities shared between BD and ND may play an important role in the association of these two disorders. In particular, structural or dysfunctional abnormalities in the prefrontal cortex, which is involved in smoking and in ND (Chen et al., 2010; Janes et al., 2012), have been associated with the onset of mania and depression (Cummings, 1997). Aberrant amygdala activity has also been associated with BD (Cerullo et al., 2009) and ND (Mihov and Hurlemann, 2012). Finally, potentially shared environmental risk factors for BD and ND, including factors associated with alcohol and illicit drug use disorders and a history of childhood adversity, are likely to increase the risk for both disorders (Heffner et al., 2011). Prospective and longitudinal studies are needed to identify biological or environmental risk factors for these co-morbid disorders.
4.3 Phenotypic causation
Our results also support, at least in part, the phenotypic causation hypothesis to explain the co-morbidity between ND and BD. The prediction from BD to ND and the fact that most individuals with lifetime ND and BD in our sample were BD-prior respondents would suggest a phenotypic causation role from BD to ND. At the same time, the higher hazard ratio found for ND preceding BD suggest a potential contribution of ND in increasing the risk of BD. Several mechanisms may explain these relationships.
First, BD might increase risk of ND in accordance with the self-medication hypothesis. (Weiss et al., 2004) investigated reasons for substance use in BD and found that two-thirds of patients reported improvement in at least one BD symptom as a result of substance use. In addition, among individuals with major depressive disorder, symptoms may increase the risk of smoking because of the ability of tobacco to inhibit monoamine oxidase A and B (Berlin and Anthenelli, 2001) or to stimulate the release of serotonin and dopamine (Kenny et al., 2000). However, some of our findings in BD-prior subjects such as the co-occurrence of an earlier onset of BD and a later onset of ND (with a latency of 11 years on average) and the longer transition from daily smoking to ND seem to contradict the self-medication hypothesis as a way to explain the association between ND and BD. Still, our results do not allow us to fully exclude the use of nicotine as a maladaptive attempt at self-medication among BD subjects, given that other aspects potentially related to nicotine use, such as the improvement of cognitive functioning (Heffner et al., 2011) or the reciprocal effect between nicotine and antipsychotic or antiepileptic medication, were not examined in the present study.
On the other hand, ND could hasten the onset of BD or increase BD symptoms. Chronic nicotine consumption can impair serotonin function, producing an imbalance between serotonin and dopamine, which may lead to enhanced consumption of nicotine and other drugs or a reduction of the brain inhibitory control systems (Olausson et al., 2002). Human postmortem studies have shown that smoking is associated with significant decreases in the concentrations of serotonin and 5-hydroxindolacetic acid (5-HIAA) in the hippocampus (Benwell et al., 1990). In addition, Malone et al. (2003) using a sample of depressed subjects without current substance abuse or alcohol dependence, found an inverse correlation between the number of cigarettes and two indices of serotonin function, cerebrospinal fluid 5-HIAA level and prolactin response to fenfluramine. Smoking may also increase the likelihood of emotional disturbances by reducing oxygen flow to the brain (Johnson et al., 2000).
In this mutual prediction between BD and ND, the risk of developing one disorder after the other one was greatest early in the course of illness. This fact underscores the opportunity for smoking prevention or cessation early in BD treatment, and early focus on mood symptoms among people with ND.
4.4 Age at onset and course of illness
BD-prior individuals in our sample were more likely to have a severe course of BD as indicated by an earlier onset and more manic episodes. By contrast, ND-prior individuals had an earlier onset of both daily smoking and ND, and an increased probability of co-morbid alcohol use disorders. These results support the hypothesis that differences in relative ages at onset of ND and BD in individuals with both conditions may affect the course of BD. Specifically, BD-prior individuals would have a more severe course of BD with an earlier age of onset. According to our results, a higher number of manic episodes do not seem to be related to the onset of ND given the longer transition from daily smoking to ND among BD-prior compared to ND-prior subjects. Furthermore, we cannot exclude the role of BD in the development of ND since there may be cognitive, behavioral or psychosocial processes which we did not test and may have some influence, especially in a long term. On the other hand, ND-prior respondents would have less severe course of BD with an older age of onset, but more severe ND with earlier age of onset and a higher vulnerability for co-morbid alcohol use disorder. Our results are in line with those of (DelBello et al., 1999), who found that the age of onset of BD was older in patients with a history of alcohol dependence than in patients without such history. An older age of onset of BD has been associated with lower familial rates of BD (DelBello et al., 1999). ND may precipitate the onset of BD in less predisposed individuals whose genetic liability might have been otherwise insufficient to precipitate the symptoms of BD. Unfortunately, it is not possible to know whether there is difference in family history of BD between ND-prior and BD-prior since the NESARC does not contain information on family history of BD. Furthermore, since alcohol seems to predict tobacco use more strongly than vice versa (Jackson et al., 2002), the earlier onset of ND among ND-prior in our sample may be explained, at least in part, by the higher proportion of alcohol use disorder in these subjects. An earlier onset of ND should alert health care professionals as to the development of later psychopathology or other substance use disorders, particularly alcohol use disorders.
4.5 Conclusion
In conclusion, our findings suggest a strong association between ND and BD in both sexes. Although our results are consistent with both phenotypic causation and the existence of a shared underlying liability for the onset of both disorders, perhaps neither the phenotypic causation nor the correlated cause hypothesis can, by itself, explain this co-morbidity. The mechanisms responsible for co-morbidity of ND and BD could vary over individuals and families and represent etiologically distinct subgroups. A better understanding of the brain pathophysiology of ND may help us to better understand the brain pathophysiology of BD (Diaz et al., 2009). There is a significant need for research to afford better knowledge of such co-morbidity and to identify the best approaches toward facilitating long-term smoking abstinence for smokers with BD, thereby reducing the prevalence and consequences of this hazardous addiction (Heffner et al., 2011).
Acknowledgments
The National Epidemiologic Survey on Alcohol and Related Conditions was sponsored by the National Institute on Alcohol Abuse and Alcoholism (NIAAA). We thank the New York State Psychiatric Institute and the University of Granada.
The authors thank Professor Manuel Gurpegui, of the University of Granada, for suggesting the possible focus of research to JMMO and for critical comments of the manuscript.
Footnotes
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