Comorbidity of bipolar disorder and substance abuse in Costa Rica: pedigree- and population-based studies

Journal of Affective Disorders 71 (2002) 71–83 www.elsevier.com / locate / jad

Research report

Comorbidity of bipolar disorder and substance abuse in Costa Rica: pedigree- and population-based studies a, d c,f g g Michael A. Escamilla *, Steven Batki , Victor I. Reus , Mitzi Spesny , Julio Molina , b c,e,f e,f b,f g Susan Service , Sophia Vinogradov , Tom Neylan , Carol Mathews , Luis Meza , Alvaro Gallegos h , A. Patricia Montero g , Maria L. Cruz g , John Neuhaus i , Erin Roche b , Lauren Smith b , Pedro Leon g , Nelson B. Freimer b,c,f a

Department of Psychiatry, (7792), University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, TX 78229 -3900, USA b Neurogenetics Laboratory, San Francisco General Hospital, San Francisco, CA, USA c Center for Neurobiology and Psychiatry, San Francisco General Hospital, San Francisco, CA, USA d Department of Psychiatry, SUNY Upstate Medical Center, Syracuse, NY, USA e Department of Psychiatry, Veterans Administration Medical Center, San Francisco, CA, USA f Department of Psychiatry, University of California at San Francisco, San Francisco, CA, USA g Cell and Molecular Biology Research Center and Escuela de Medicina, Universidad de Costa Rica, San Jose´ , Costa Rica h Hospital Calderon Guardia, San Jose´ , Costa Rica i Department of Epidemiology, University of California at San Francisco, San Francisco, CA, USA Received 11 August 2000; accepted 30 April 2001

Abstract Background: The purpose of this study was to determine the prevalence of substance use disorders (substance abuse or substance dependence: SA / SD) in a large sample of Bipolar Type I (BPI) patients drawn from the Costa Rican population and to describe the effects of SA / SD on the course of their bipolar disorder. Method: 110 subjects from two high-risk (for BPI) Costa Rican pedigrees and 205 unrelated Costa Rican BPI subjects were assessed using structured interviews and a best estimate process. x 2 and survival analyses were performed to assess the effect of gender on comorbidity risk, and the effect of comorbidity on the clinical course of BPI. Results: SA / SD (primarily alcohol dependence) occurred in 17% of the BPI patients from the population sample and 35% of the BPI patients from the pedigree sample. Comorbid SA / SD was strongly associated with gender x 2 5 16.84, P 5 0.00004). In comorbid subjects, alcohol dependence tended to predate the first manic episode ( x 2 5 6.54, P , 0.025). History of SA / SD did not significantly alter the prevalence of psychosis or age of onset of mania in BPI subjects. Conclusions: These results suggest that SA / SD comorbidity rates are lower in this type of population than in BPI patient populations in the US. Gender is a strong predictor of comorbidity prevalence in BPI patients from this population. Although SA / SD may be a risk factor for precipitating BPI in those at risk, in this population comorbid BPI subjects do not have a different onset or course of BPI in comparison to BPI patients without comorbidity.  2002 Elsevier Science B.V. All rights reserved. Keywords: Bipolar disorder; Genetics; Substance abuse; Alcoholism

*Corresponding author. E-mail address: [email protected] (M.A. Escamilla). 0165-0327 / 02 / $ – see front matter  2002 Elsevier Science B.V. All rights reserved. PII: S0165-0327( 01 )00373-1

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1. Introduction The comorbidity of substance use disorders with bipolar disorder (BP) has been documented in numerous studies in non-Hispanic populations (Brady and Lydiard, 1992). Compared to other psychiatric disorders, BP individuals tend to have the highest associated comorbidity with substance abuse (SA) and dependence (SD) (Regier et al., 1990). In the US, whether studies of BP and SA comorbidity are drawn from the general population (Regier et al., 1990; Helzer and Pryzbeck, 1988) or from hospital settings (Winokur et al., 1995; Brady and Lydiard, 1992; Feinman and Dunner, 1996), the lifetime prevalence of SA in patients with BP is high, ranging from 21 to 60.7%. These findings raise a number of questions about the interaction of SA with BP. The high comorbidity of SA raises the possibility that SA may be a form of self-medication (during depressed or manic states) and / or a consequence of disinhibition (during manic states) for those with BP (Raimo and Schuckit, 1998). Yet another possibility is that SA initiates or maintains a mood state (Strakowski et al., 1998) and that patients abuse substances to achieve these states. The time course of SA and BP in those with comorbid diagnoses has been examined in only a few population based studies (Winokur et al., 1994; Feinman and Dunner, 1996; Strakowski et al., 1998) and it remains unclear which of the two illnesses might be secondary (temporally) to the first occurring illness. In addition, previous studies have suggested that SA might contribute to either the development of BP or to a worse course of illness in BP subjects (Tien and Anthony, 1990; Post et al., 1984; Sonne et al., 1994). In this article, we examined the interaction of BP and SA / SD in two samples drawn from the central valley of Costa Rica: the first sample (pedigree sample) consisted of individuals from two pedigrees densely affected with BPI, while the second sample (population sample) was drawn from unrelated Costa Rican individuals with severe BPI. Both BP and SA have genetic as well as environmental components (Pickens et al., 1991; Escamilla et al., 1997). For instance, monozygotic twins display a 60–80% concordance for BP, suggesting that there are environmental factors respon-

sible for whether BP is expressed in those at genetic risk for the illness. To date, no risk factor has been correlated with increased expression of BP, in part because few studies have been done on persons from a similar genetic background. The high coincidence of SA in BP has led to the suggestion that SA may contribute to the disabling of affective regulation (Post, 1992) and hence serve as a risk factor for BP development, but no evidence for this has been definitively seen in human studies. The major difficulty of carrying out studies of environmental risk factors in BP is the problem of controlling for genetic risk in the study sample. Population studies and hospital studies both contain individuals with widely differing genetic inheritance — therefore, when a more severe form of BP is found to correlate with individuals who also have SA, the possibility of the comorbid individuals having a more severe genetic loading for BP, SA or both disorders can never be ruled out. Focusing on individuals in large pedigrees from an area where genetic inheritance is relatively homogeneous (Escamilla et al., 1996), allows for a rough control of genetic risk for BP. Differences in onset or severity of BP in individuals from these pedigrees will be most likely due to environmental factors, epigenetic factors or modifying genes (and not to a completely different genetic form of BP) — thus allowing for a direct comparison of those BP individuals with SA and those without SA, with the goal of understanding if SA is indeed a risk factor in the development of the disease in these families. Our focus in this study was to first look at the individuals from two large Costa Rican pedigrees, to examine the effect of SA on the phenotype of BP illness in individuals who developed BPI. We also sought to clarify if there was a characteristic time course for the development of SA and BP for patients with comorbid BP/ SA. We investigated whether the presence of SA in these families, regardless of presence or absence of BP, was gender specific and hence, unrelated to the presence or absence of a BP gene (BP transmission in these families is consistent with an autosomal and not sex-linked disease). Finally, we tested several hypotheses drawn from our findings in these two pedigrees (that SA / SD was gender specific, that

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SA / SD occurred prior to onset of mania, that SA / SD did not contribute to earlier onset of BP) in the larger population based sample (unrelated Costa Rican individuals with severe BPI).

2. Methods In accordance with the policies of the University of California at San Francisco and the University of Costa Rica, all subjects provided informed consent after the research procedures had been fully explained. Participation rates for both pedigree- and population based studies were over 95%.

2.1. Costa Rican pedigree-based study These individuals were recruited as part of a genetic study of bipolar disorder in four Costa Rican pedigrees. Families were initially identified through clinical interviews at Columbia University in New York City and at the Calderon Guardia and National Psychiatric Hospitals in San Jose, Costa Rica. Each family was contacted and progressive assessments of individuals in the various branches of the pedigree were undertaken. Each member who agreed to participate was interviewed by a clinician, blinded to previous diagnoses of the individual, using the semistructured Schedule for Affective Disorders and Schizophrenia (SADS), Lifetime Version (Spitzer and Endicott, 1978). Family member interviews using the Research Diagnostic Criteria (RDC) family history protocol (Spitzer and Endicott, 1978) and medical records from both inpatient and outpatient sources were also collected. A second interview, by a psychiatrist who specializes in mood disorders (M.E., V.R., L.M., J.M., P.M.) using the Diagnostic Interview for Genetic Studies (DIGS) (Nurnberger et al., 1994) was completed in all individuals who received a diagnosis of any psychiatric or substance use disorder by the first interviewer. A number of individuals who had neither psychiatric or substance use disorders were also added to the list of persons who received second interviews, so that the second interviewer could remain blind to whether or not he was interviewing a patient with a psychiatric diagnosis. All information collected on the study subjects was then reviewed by a best estimate team composed

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of two out of five rotating best estimators (S.V., V.R., S.B., T.N., C.M.) who had to reach consensus diagnoses in order for an individual to be considered affected with a psychiatric or substance use diagnosis. Individuals did not best estimate cases in which they had done the interview. Consensus was also reached for the onset of substance abuse, manic episodes, major depressed episodes and other psychiatric disorders. For all disease categories, separate lists were generated using DSM III R criteria and RDC criteria (DSM IV criteria were not available at the time this study was initiated). For this paper, we analyzed only the findings using DSM III R criteria. Two study subjects, who were diagnosed as having Schizoaffective Disorder, Manic Type, were included with the BPI subjects in our analyses. The best estimate process has thus far been completed for a total of 110 individuals from two Costa Rican families of the Central Valley of Costa Rica (43 from family CR001 and 67 from family CR004). These two families (CR001 and CR004) are both descended from a common Spanish immigrant who came to Costa Rica in the early 18th century (Freimer et al., 1996). Within each family branch, the goal was to investigate all family members who agreed to participate, regardless of presence or absence of any type of disorder. Due to the design of the genetic study of these families, primary importance was placed on branches of the families that did show some evidence of BP.

2.2. Costa Rican population-based study These individuals were ascertained independently of the individuals in the pedigree studies. Details of the ascertainment and recruitment process are provided in Escamilla et al. (1996). In brief, we screened for patients who had had at least two hospitalizations at the National Psychiatric Hospital of Costa Rica, a discharge diagnosis of bipolar disorder, age of onset of the disorder at or before age 50, bilineal Spanish surnames, and who had Costa Rican ancestry. Subjects were eligible for inclusion regardless of presence or absence of a history of SA / SD. Assessments were performed by a psychiatrist (J.M., M.E.) who was blind to previous diagnoses, using the DIGS. This interview, a narrative written by the interviewing psychiatrist, and the

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patients’ medical records were reviewed by a best estimate team in the same manner as was done for the family studies and consensus diagnoses were derived for the same diagnostic categories used in the family study. The diagnostic procedure for these cases thus differed from the pedigree-based sample in two areas — probands from the population-based sample did not have a first interview with the SADS and we did not collect data from a family member for these individuals. Thus far, we have completed best estimate diagnoses for 232 individuals drawn from the population, and 205 of these have met the best estimate criteria for Bipolar Type I Disorder by DSM III R criteria. Best estimators were asked to focus on the most severe manic episode and to arrive at a consensus on which manic symptoms were present during that episode. This information was used to compare Bipolar Type I subjects with and without a history of alcohol dependence, to determine if there were any observable differences in symptom profiles between these two groups.

2.3. Statistical methods The relationship between the presence or absence of psychosis and alcohol dependence, and between gender and alcohol dependence were both examined using 2 3 2 x 2 contingency tables. Differences in the age of onset of BP in patients with and without alcohol dependence were evaluated graphically with Kaplan–Meier survival curves, and statistically with a nonparametric log-rank test (Harrington and Fleming, 1982).

3. Results

3.1. CR pedigree analysis The diagnostic characteristics of the 110 study subjects are shown in Table 1. There were a total of 45 males and 65 females. There were approximately equal numbers of female and male subjects with BPI (14 and 15, respectively). Since we had focused on studying branches of the families where there was evidence of BPI, the percentage of both men and women in the study with BPI is expectedly high,

Table 1 Characteristics of 110 subjects from two high-risk bipolar families

All subjects Gender (%) Age (average) a

BPI subjects BPI1SA / SD b SA / SD only c Neither BPI nor SA / SD d

Total

Females

Males

110 51

65 59.5 52

45 40.5 50

29 9 27 54

14 0 9 42

15 9 18 12

a

Includes one case of schizoaffective disorder, bipolar type. Includes one case of schizoaffective disorder, bipolar type. c Includes seventeen cases with mood disorders other than BPI (five with BPII, two with cyclothymia, five with hypomania only, one with Schizoaffective Disorder, Depressed Type and hypomania, three with a Major Depressive Episode, one with dysthymia). d Includes twenty-six cases with mood disorders other than BPI (five with BPII, thirteen with major depressive episodes only, two with organic mood disorder, four with hypomania only, one with cyclothymia, one with Depression not otherwise specified). b

averaging 22% of the women and 33% of the men. Mood disorders other than BPI were also seen in 43 (40%) of the subjects. Substance Abuse and Substance Dependence were collapsed into one category for the purpose of these analyses, with the reasoning that both types of disorder reflect a substantial and prolonged exposure to the substance of interest. The primary substance of abuse / dependence among these individuals was alcohol. Only 5% of the family study subjects had a history of substance abuse / drug dependence other than alcohol. Seventy-four of the 110 subjects had no SA / SD. Of the 36 subjects who had SA / SD, the substance of abuse / dependence was alcohol only for 31 subjects, marijuana only for one subject, amphetamines and alcohol for one subject, LSD and marijuana for one subject, and alcohol, cocaine, and amphetamines for one subject. Overall, 33 subjects had a history of alcohol abuse / dependence, three had a history of amphetamine abuse / dependence, two had a history of marijuana abuse / dependence, one had a history of cocaine abuse / dependence, and one had a history of LSD abuse / dependence. Comorbidity of SA / SD was 35% in BPI individuals. The rate of SA / SD was specific to gender in both BPI individuals (0% of BPI women, 64% of BPI men) and individuals without BPI (18% of

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non-BPI women, 60% of non-BPI men). When persons with mood disorders other than BPI (for instance BPII, MDE, Organic Mood Disorder, Dysthymia) were compared to persons with no evidence of mood disorder, there was a higher incidence of SA / SD in those with the mood disorders. Of the non-BPI mood disordered individuals 40% (17 / 43) had a history of SA / SD versus 26% (10 / 38) of individuals with no mood disorder. Time course data was evaluated for those individuals who had both a history of BPI and a history of SA / SD (n58). Date of onset of BPI, for the purposes of this study, was defined as the onset of the first manic episode. Of these eight individuals for whom dates of onset could be set, every one showed an age of onset of the first manic episode after or during the same year as the age of onset of the SA / SD. One of the individuals with a diagnosis of Schizoaffective disorder, bipolar type had comorbid SA / SD — in this individual, as opposed to the members diagnosed with BPI, age of onset of SA / SD postdated the age of onset of the first manic episode. Two indices, age of onset and presence of psychosis during illness, were used to investigate the severity of BPI in this family. Table 2 shows that the median age of onset of BPI was not substantially earlier among BPI individuals with comorbid SA / SD compared to BPI individuals with no history of SA / SD (25 versus 26). The lifetime prevalence of psychosis, however, was elevated in BPI individuals who had comorbid SA / SD.

3.2. CR population sample analysis Out of 205 patients with BPI in this population based sample, 34 (16.6%) had comorbid SA / SD (Table 3). The majority of those with comorbid

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SA / SD showed problems with alcohol alone (twenty-seven out of the thirty-four had comorbid diagnoses of alcohol dependence and three others had history of alcohol abuse). Only six out of the 205-BPI patients (3%) had comorbid substance abuse / dependence other than alcohol. As in the family study, gender was associated with the likelihood of comorbid SA / SD. There was a significant difference in the prevalence of alcohol dependence between males and females ( x 2 516.84; d.f.51 (P5 0.00004)). Evaluation of time course data also showed the same trend seen in the family sample. Twenty-two persons had data for both age of onset of BP (defined as the first manic episode) and age of onset of alcohol dependence. Of these, seventeen out of twenty-two had an age of onset of alcohol dependence equal to or earlier than the age of onset of BP. With the Yates correction, this is a significant finding ( x 2 56.54, x 2 (with Yates correction)55.5, P, 0.025). 50% showed age of onset of alcohol dependence preceding age of onset of first manic episode, 22% showed the age of onset of alcohol dependence occurring after age of first manic episode, with the remaining 27% showing age of onset of both disorders in the same year. The age of onset for BP was compared (using first manic episode as the age of onset) between AD (history of alcohol dependence) and NAD (no history of alcohol dependence) individuals, in the dataset as a whole (Fig. 1) and also split by gender (data not shown). As in the family data, the median age of onset of first manic episode was less in those BPI patients with comorbid alcohol dependence (23 years) compared to BPI patients without a history of alcohol dependence. We also compared, for AD and NAD individuals, the age of onset of the first depressed episode and age of onset of either first

Table 2 Median age of onset (years) and prevalence of psychosis in family study subjects evaluated for BPI and / or SA / SD

Total Onset of SA / SD Onset of BP a With psychosis, % (n /n) a

SA / SD only

BPI only

SA / SD1BPI

27 22 2 2

20 2 26.5 70 (14 / 20)

9 15 25 89 (8 / 9)

Onset defined here as the age at time of first manic episode.

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Table 3 Median age of onset (years) and prevalence of psychosis in population-based subjects evaluated for BPI and / or SA / SD (substance abuse / substance dependence)

Total Female (%) Onset of SA / SD Onset of BP With psychosis (%)

Diagnosis of BPI

BPI only

205 55

171 62 2 25 91 (155 / 171) 86 81 39 83 72 61 80 81 76 98 94 94 93 99 99 97

Depressed mood (%) Anhedonia (%) Loss of weight (%) Insomnia / hypersomnia (%) Feelings of worthlessness (%) Thoughts of death / suicidal ideation (%) Decreased concentration (%) Psychomotor agitation / retardation (%) Fatigue (%) Pressured speech (%) Racing thoughts (%) Grandiosity (%) Risky behaviors (%) Increased activities / psychomotor agitation (%) Decreased need for sleep (%) Distractability (%)

AA /AD a 1BPI 30 17 20 23 92.6

DA / DD b 1BPI

SA / SD c 1BPI

6 50 25 23

34 26 21 23

81 81 44 78 70 59 74 74 81 100 93 100 100 100 100 100

a

AA /AD — history of alcohol abuse or alcohol dependence. DA / DD — history of drug abuse or drug dependence. c Includes twenty-five with alcohol dependence alone, three with alcohol abuse alone, two with drug dependence alone, two with drug abuse alone, and two with alcohol dependence plus drug abuse. Of the six persons (3F, 3M) who had drug abuse / dependence, the following drugs were involved [marijuana — three cases (1M, 2F), cocaine — one case (F), marijuana1cocaine — two cases (2M)]. b

depressed episode or first manic episode (whichever came first). There were no significant differences in the age of onset of BP (regardless of definition) between AD and NAD individuals ( x 2 50.8, 1df, P50.36 for first onset of depression or mania; x 2 5 2.0, 1df, P50.16 for first episode of depression, x 2 50.6, 1df, P50.45 for first manic episode) and this is true when the data were split by gender as well. Although there were not significant differences here in age of onset of BP between AD and NAD patients, the same trend was found that was seen in the family sample — age of onset was less for the AD patients (this was true for both genders and for all three age of onset definitions (Tables 4 and 5)). The small sample size of AD patients likely resulted in low power for these comparisons. An individual was coded as having psychosis if they received a definite diagnosis of either mania

with psychosis or major depression with psychosis. The age of psychosis was taken to be the minimum age of onset of these two diagnoses (if both existed). In contrast to the family study, lifetime prevalence of psychosis was nearly identical among AD BPI individuals compared to NAD BPI individuals

Table 4 Median age of onset in bipolar patients with (AD) and without (NAD) alcohol dependence from the population sample Age of onset definition, years

1st episode of depression 1st episode of mania Earliest of 1st episode of mania or depression

AD (n)

NAD (n)

20 (19) 23 (27) 20 (27)

24.5 (147) 25 (177) 22 (178)

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Fig. 1. Survival curves showing the effects of alcohol dependence on the onset of mania and depression and the prevalence of psychosis in 205 individuals with Bipolar Affective Disorder Type I (NAD, no history of alcohol dependence, AD, history of alcohol dependence).

(Table 3). A total of 91% of NAD BPI individuals and 92.6% of AD BPI individuals experienced psychosis ( x 2 50.13 d.f.51, P50.723). When this was examined separately by gender, similar results were obtained. The age of onset of psychosis was not significantly different between AD and NAD individuals (Fig. 1). The median age of onset of psychosis for AD individuals was 23 years (n527)

and the median age of onset of psychosis for NAD individuals was 25 years (n5178). We also investigated the prevalence of particular symptoms of depression or mania (examined separately) in AD and NAD individuals (Table 3). The prevalence of the various symptoms were very similar in AD and NAD individuals (no statistically significant differences).

Table 5 Median age of onset by gender in bipolar patients with (AD) and without (NAD) alcohol dependence from the population sample Age of onset definition, years

1st episode of depression 1st episode of mania Earliest of 1st episode of mania or depression

AD males (n)

AD females (n)

NAD males (n)

NAD females (n)

19 (15) 24 (22) 19.5 (22)

22.5 (4) 21 (5) 21 (5)

24 (56) 25 (70) 22 (70)

25 (91) 24.5 (107) 22 (108)

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4. Discussion The results of the pedigree analyses suggested several hypotheses — that SA / SD and BPI comorbidity was strongly associated with gender, that the effect of comorbid SA / SD on age of onset of BPI was negligible, that there might be a measurable effect of SA / SD on prevalence of psychosis in BPI patients, and that there was a distinct temporal course regarding the onset of mania and SA / SD in those who were comorbid for SA / SD and BPI. With the exception of the psychosis prevalence hypothesis, all of these findings were supported in the population-based analyses as well, where statistics could be applied to assess the significance of those hypotheses. We will discuss the pertinent findings from each of these analyses (pedigree- and population-based) in the following two sections.

4.1. Pedigree-based study 4.1.1. Effect of SA /SD on age of onset and prevalence of psychosis In the family studies, our data only mildly supported earlier studies suggesting that BP patients with comorbid SA / SD had a greater incidence of psychosis and did not support earlier findings that SA / SD comorbidity was associated with an earlier age of onset of BP (Tien and Anthony, 1990; Brady and Lydiard, 1992). To our surprise, the results from the family analyses instead suggested that important aspects of the course of BPI in Costa Rican patients, such as age of onset and appearance of psychosis, might operate for the most part independently of exposure to substances of abuse / dependence.

4.1.2. Gender effects In our family study, the male gender was strongly associated with the presence of SA / SD in both the BPI individuals and those without BPI. In this sense, cultural / environmental factors or genetic factors unrelated to a BP predisposition gene(s) remain the primary determinant in the use of SA / SD. The presence of BPI did not have any observable effect on increased prevalence of SA / SD in either men or women from these families. These findings therefore

do not support the hypotheses of SA / SD being enhanced in BPI patients as a consequence of behavioral disinhibition or as a means of attempting to alleviate / induce symptoms and are at least consistent with interpretations by Raimo and Schuckit (1998) and Strakowski et al. (1998) that the high comorbidity of BP and alcoholism is most likely not due to self-medication of psychiatric syndromes.

4.1.3. SA /SD as a risk factor The hypothesis that SA / SD may be a triggering factor in the induction of mania in persons at risk for developing BP remains a tenable one, given our findings that in the majority of the comorbid cases in the family study (all but one), SA / SD occurred prior to or during the same year as the first manic episode. Our results, however, are most consistent with genetic loading for BP being the major risk factor in developing BPI during the course of one’s lifetime, regardless of patterns of SA / SD. The substantial number of BPI family members without a history of SA / SD provides evidence that SA / SD is by no means a necessary agent for the development of BPI in those at risk. Moreover, if SA / SD were a major risk factor in induction of BPI in those who are at risk (for developing BPI), one would assume that there would be a higher proportion of men in these families with BPI, since the men had a substantially higher rate of SA / SD; this was clearly not the case. If, indeed, a combination of predisposition gene and some other factor is required for arriving at a BPI phenotype in these families, SA / SD remains a candidate (operative more in males from these families) given the above time course results — additional, female specific, risk factors, such as hormonal cycling, would need to be hypothesized to explain the equal prevalence of BPI in females from these families.

4.1.4. SA /SD comorbidity in other mood disorders Persons in the family study with types of mood disorder other than BPI (BPII, Major Depression, etc.) present a special problem in interpreting results due to the ambiguity of their genotype with regard to BP. Some of these individuals may indeed carry a BP predisposition gene or genes and, over the course of

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time, go on to develop a manic episode and BPI. The theory that alcoholism may be ‘secondary’ to BP disorder in certain groups (Winokur et al., 1994, 1995) remains viable in these families only if one considers hypomania, depression and other sub-BPI mood disorders as leading to the syndromes of alcohol abuse or dependence. A percentage of persons with comorbid BPI and SA / SD in this study did experience this type of sequence prior to the onset of mania. The concept of ‘secondary’ SA / SD therefore would require a readjustment in that it is secondary not to BPI but to a forme fruste of BPI. When comparing BP spectrum patients from the Costa Rican family study to the North American BP spectrum patients studied by Feinman and Dunner (1996), we note similar high rates of comorbid SA / SD in the men (57 versus 55%). In the study of Feinman and Dunner (1996) the rate of SA / SD in women with a bipolar spectrum was much higher in comparison to women with a bipolar spectrum in the Costa Rican family study. This may indicate cultural differences between Latin American and North American cultures; Markides et al. (1990) have found that acculturation of Mexican Americans was positively correlated in women with frequency of alcohol consumption and likelihood to be an alcohol drinker. Marin and Posner (1995), in their study of Mexican Americans, found that a larger proportion of the acculturated females could be classified in the high drinking category. Both the studies of Markides et al. (1990) and Marin and Posner (1995) did not show an increase in drinking in Latino men who were more acculturated. Of course, Mexican and Costa Rican populations do have differences both in genetic and cultural heritage, and acculturation data from Mexicans in the US might not reflect what would be seen if Costa Ricans migrating to the US were studied.

4.1.5. Etiology of SA /SD Although the results presented here are inconsistent with the BPI predisposition gene (genes) in the two Costa Rican families leading to increased SA / SD in affected individuals, the possibility of a separate genetic disorder predisposing to SA / SD cannot be ruled out as existing in these families. SA / SD in the family study is therefore a consequence of environmental factors (including any

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psychosocial consequences of having BP in the families), a genetic predisposition to SA / SD different from the BP predisposition gene(s), or some combination of these factors.

4.2. Population-based sample As the subjects in the population based study are unrelated individuals (Escamilla et al., 1996), statistical calculations can be performed that allow us to test several hypotheses concerning the interaction of SA / SD and BPI that were suggested by the pedigree study. Analysis of comorbidity prevalence in the population based sample also allows us to make comparisons with similar studies done in the US or elsewhere (Table 6). The population sample is not as valuable in assessing the genetic interaction of BPI and SA / SD as the family sample, however, as several genetic forms of BPI might be present even in a population isolate such as Costa Rica and therefore, interactions between different genetic types of both BPI and SA / SD might actually be observed in the population sample. Although the pedigree study is not immune from similar problems, especially in very large pedigrees, it remains more naturally homogeneous than any entire population.

4.2.1. Type of SA /SD comorbidity Of the Costa Rican BPI patients with SA / SD, only 15% had drug abuse / dependence in addition to alcohol abuse / dependence. In the study of Strakowski et al. (1998), by comparison, 76% of the BPI patients with alcohol abuse / dependence had a further diagnosis of drug abuse / dependence. The availability of drugs and cultural factors which impinge on use of drugs most likely explain these major differences in drug abuse / dependence comorbidities between Costa Rican and US BPI patients. The fact that comorbid SA / SD in BPI patients in Costa Rica is much more likely to involve only comorbid alcohol abuse / dependence (and not other drugs of abuse) may, in part, explain the relatively lower overall percentage of SA / SD comorbidity in the Costa Rican sample compared to US-based studies. Interpretation of the results from these studies in Costa Rica should therefore take into account that in the majority of cases discussed below, alcohol abuse /

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Table 6 Comorbidity of BP and SA / SD in studies of North American, Central American and Chinese subjects Source

Diagnosis / diagnostic system

Population type sampled

Ethnicity

Men (%)

1988 NHIS

General

US white

12

2

7

General

US non-white

12

3

8

General

US white

14

5

10

General

US black

9

2

6

General

US hispanic

16

3

10

General General BPI

Central American Costa Rican US (unspecified ethnicity) US (unspecified ethnicity)

13 13 61

4 1 2d

8 7 2d

ECA

AA /AD a DSMIIIR AA /Ad a DSMIIIR AA /Ad a DSMIII AA /Ad a DSMIII AA /Ad a DSMIII High Drinking b Alcoholism AA /Ad a DSMIII AA /Ad a

56

2d

2d

Feinman and Dunner, 1996

DSMIII SA / SD c

35

46

SA / SD c

US (unspecified ethnicity) Costa Rican

55

Present study (pedigree sample)

BPI, BPII, cyclothymic and BPNOS BPI, BPII, cyclothymic and BPNOS

57

4

30

Feinman and Dunner, 1996

DSMIIIR SA / SD c

BPI

US (unspecified ethnicity)

2d

2d

29

BPI

Costa Rican

60

0

35

BPI

Costa Rican

28

7

17

BPI

Costa Rican

27

4

15

BPI1BPII

Taiwan Chinese

22

3

10 f

1988 NHIS ECA ECA ECA Marin and Posner, 1995 Bejarano and San Lee, 1997 ECA

Present study (pedigree sample) Present study (population sample) Present study (population sample) Tsai et al., 1997

DSMIIIR SA / SD c DSMIIIR SA / SD c DSMIIIR AA /Ad e DSMIIIR AA /Ad c

BPI,BPII

Women (%)

Men 1women (%)

a

AA /AD, history of alcohol abuse or alcohol dependence in the last year. High drinking, history of drinking six or more (for men) alcoholic drinks on days when they drank in the last 30 days (four or more alcoholic drinks for women). c SA / SD, lifetime history of alcohol abuse, alcohol dependence, substance abuse or substance dependence. d 2, not specified in the original article. e AD, lifetime history of alcohol dependence. f Total sample was skewed towards females (65 females, 36 males), resulting in an artificially low estimate of SA / SD for the combined sample. Alcohol was the only substance of abuse in this sample. b

dependence is the predominant and only substance of abuse / dependence.

4.2.2. Prevalence of BPI and SA /SD comorbidity Compared to rates of alcoholism in Costa Rican (Bejarano and San Lee, 1997) or Central American

(Marin and Posner, 1995) general populations, the rate of alcoholism was higher in our sample of Costa Rican BP subjects, suggesting that in this population, as in all previously studied populations, lifetime prevalence of SA / SD, particularly, alcohol abuse / dependence, is increased in those with a diagnosis of

M. A. Escamilla et al. / Journal of Affective Disorders 71 (2002) 71 – 83

BPI compared to the general population. It is interesting to note that the prevalence reported in our population study would be less than any reported in a North American population and would compare more closely with the prevalences reported in a Chinese population study (Tsai et al., 1997) (Table 6). Since our best estimators required a drug and alcohol free manic episode in order to diagnose a patient with BPI, it is possible that this more stringent criteria led to a lower percentage of our best-estimated BPI cases having comorbid SA / SD (i.e. patients who always had comorbid alcohol or drug use at the same time as their manic episodes would not have been diagnosed as BPI in this sample). If one includes the eleven subjects who were diagnosed as having primary SA / SD and were not given a diagnosis of BPI (even though they carried hospital diagnoses of BPI), the comorbidity of ‘BPI’ subjects who also have SA / SD increases to 45 out of 216 subjects, or 21% of subjects, which approaches the comorbidity rate reported by Brady and Lydiard (1992). As noted by Schuckit (1995), alcohol intoxication or protracted consumption can cause the symptoms associated with mania, and therefore true cases of comorbid bipolar disorder and SA / SD and cases where manic symptomatology are caused solely by SA / SD are impossible to distinguish in cases where manic episodes have never been clean. We therefore acknowledge that our comorbid prevalence rates are conservative in comparison to both the biological reality of these disorders and, most likely, to other studies of comorbidity.

4.2.3. Gender and comorbidity The population study supported the observation in the family study that SA / SD (specifically alcohol dependence) was very strongly associated with gender, both in persons with BPI and persons without BPI. This gender association has been reported in most studies of alcoholism in non-psychiatric samples from general populations, both within Latino cultures (Marin and Posner, 1995) and Anglo-American cultures (Helzer et al., 1991; Grant et al., 1992). In studies of bipolar patients, the same gender association has been seen as well (Tsai et al., 1997; Feinman and Dunner, 1996).

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4.2.4. Effect of SA /SD on age of onset and psychosis The population-based sample mirrored what was seen in the family sample, with regard to comorbidity of SA / SD having no statistically significant effect on the age of onset of BPI, even though, in the majority of cases, SA / SD predated the onset of mania. The population study did not support a statistically significant difference in the prevalence of psychosis of BPI patients with and without psychosis, and in this sense differed from what was suggested by the family study. The lifetime prevalence of psychosis in the BPI subjects drawn from the population (91%) is quite elevated in comparison with prevalences of psychosis reported in other studies of BPI performed with North American populations (70% in Carlson and Goodwin (1973); 72% in Rosenthal et al. (1979)). The higher prevalence seen in the population-based sample may in part be explained by the selection process. For instance, in the sample drawn from our family study, persons were eligible for inclusion as a BPI subject regardless of their hospitalization history and had a lifetime prevalence of psychosis of approximately 71%, which is in accord with the North American studies, whereas subjects chosen for the population study had at least two episodes of illness requiring hospitalization. The population sample may therefore have selected patients with symptoms that were more disabling (such as psychosis) and likely to require hospitalization. Alternate hypotheses would be that the Costa Rican population as a whole has a form of BPI that is more prone to psychosis than are BPI patients from the US, or that BPI patients in Costa Rica are more likely to experience ‘psychotic’ symptoms due to a cultural predisposition (i.e. beliefs involving ‘spirits’) (Fabrega, 1995).

4.2.5. Sequence of SA /SD and BPI onset In the population study, the same pattern was found as in the pedigree study, namely that the onset of SA / SD was more likely to occur before or at the same time as the onset of the first manic episode rather than after the onset of mania. This finding parallels what has been found in one of the few other studies which investigated relative age of onset of these disorders within individuals. Strakowski et al.

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(1998) in a US sample, found that in patients with comorbid BP and SA / SD, onset of SA / SD predated that of BP by over 1 year in 70% of the cases. In the Costa Rican family sample, SA / SD almost always occurred prior to or at the same time as the onset of the first manic episode — in comparison the Costa Rican population sample showed several individuals who clearly had their first mania prior to the onset of alcohol dependence. This may reflect a difference between the general population of Costa Rican BPI patients and a particular subset of BPI patients who have more in common genetically (and hence share a characteristic pattern of onset of BPI and SA / SD when these occur together).

5. Conclusion In closing, both the pedigree and population studies reported here supported hypotheses that SA / SD comorbidity is strongly associated with gender, that the age of onset of BPI is not affected by SA / SD comorbidity, and that SA / SD tends to begin prior to the onset of mania in the majority of persons who show comorbidity for these two illnesses. The pedigree study (a special subset of the Costa Rican population, chosen because of their having densely affected pedigrees), differed from the population study with regard to the effect of SA / SD on the prevalence of psychosis and the overall percentage of BPI cases with psychosis, suggesting that subjects from certain families (densely affected by BPI) will differ from the overall population of BPI subjects regarding certain parameters. Finally, the family study did not support the hypothesis of Post et al. (1984) and others that BPI causes an increase in SA / SD, at least in certain families with a high density of BPI. The phenotype, course of illness and response to treatment of BPI patients in Costa Rica have, in our studies, thus far have corresponded closely to descriptions of BPI from Europe and the US (Escamilla et al., 1996), suggesting that the findings in this current comorbidity study may have relevance to other BP individuals. The scientific understanding of genetic and environmental aspects of mental illnesses such as BP will ultimately require a combination of

population-based studies and focused pedigree studies, each of which will be able to test, in complementary manners, hypotheses of how psychiatric illnesses operate and interact. As actual genes associated with BPI are identified, more detailed analyses will be possible in pedigrees and population based studies, to both more accurately assess the phenotype associated with BPI predisposition genes and to assess the effects of SA / SD on those with the predisposition.

Acknowledgements Supported by grants from the National Institute of Mental Health (MH00916, MH49499, MH48695, MH47563) the National Alliance for Research on Schizophrenia and Depression, and the American Psychiatric Association’s Program for Minority Research Training in Psychiatry. The authors thank the mental health professionals and staff at the Hospital Nacional Psychiatrico in Pavas, Costa Rica, Carmen Araya, Xinia Araya and especially the study participants and their family members for their efforts on this project. We also thank Dr. Charles Bowden for his comments and suggestions.

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