Journal of Affective Disorders 85 (2005) 135 – 145 www.elsevier.com/locate/jad Research report The cyclothymic temperament in healthy controls and familially at risk individuals for mood disorder: endophenotype for genetic studies? Pierre Chiaroni a,*, E.-G. Hantouche b, J. Gouvernet c, J.-M. Azorin a, H.S. Akiskal d a Service de Psychiatrie, Hôpital Sainte Marguerite, Bd. Sainte-Marguerite, 13009 Marseille, France b Université Paris VI, Hôpital Pitié-Salpétrière, Paris, France c Service de l’Information Médicale, Hôpital de la Timone, Marseille, France d International Mood Center, University of California at San Diego, San Diego, USA Received 12 March 2003; accepted 18 December 2003 Abstract Background: The modern concept of affective disorders focuses increasingly on the study of subthreshold conditions on the border of manic or depressive episodes. Indeed, a spectrum of affective conditions spanning from temperament to clinical episodes has been proposed by the senior author. As bipolar disorder is a familial illness, an examination of cyclothymic temperament (CT) in controls and relatives of bipolar patients is of major relevance. Methods: We recruited a total sample of 177 healthy symptom-free volunteers. These controls were divided into three groups. The first one is comprised of 100 normal subjects with a negative familial affective history (NFH); the second of 37 individuals, with positive affective family history (PFH); and a third of 40 subjects, with at least one sib or first-degree kin with bipolar disorder type I according to the DSM-IV (BPR). The last two groups defined at risk individuals. We interviewed all subjects with CT, as described by the senior author. Results: We found a statistically significant difference in the rates of CT between the subjects in BPR versus others. CT was also more prevalent in the PFH compared with NFH. Additionally, the simple numeration of the CT traits exhibited gradation in the distribution of individuals inside the NFH, PFH and BPR. Finally, categorically defined CT and CT traits predominated in females. Limitation and conclusion: Although not all relatives of bipolar probands were studied, our results exhibit an aggregation of CT in families with affective disorder—and more specifically those with bipolar background. These results allow us to propose the importance of including CT for phenotypic characterization of bipolar disorder. Furthermore, our results support a spectrum concept of bipolar disorder, whereby CT is distributed in ascending order in the well-relatives of those with depressive and bipolar disorders. We submit that this temperament represents a behavioral endophenotype, serving as a link between molecular and behavioral genetics. D 2004 Elsevier B.V. All rights reserved. Keywords: Affective temperament; Cyclothymic temperament; Cyclothymia; Bipolar disorder; Psychiatric genetics 1. Introduction * Corresponding author. Tel.: +33-4-9138-5568; fax: +33-49138-5085. E-mail address: pierre.chiaroni@wanadoo.fr (P. Chiaroni). 0165-0327/$ - see front matter D 2004 Elsevier B.V. All rights reserved. doi:10.1016/j.jad.2003.12.010 During the last three decades, modern bipolar concepts of a broader nature developed under the 136 P. Chiaroni et al. / Journal of Affective Disorders 85 (2005) 135–145 influence of many authorities (Akiskal et al., 1983; Angst et al., 1980; Goodwin and Jamison, 1990; Klerman, 1981). Beyond the classical manic-depressive illness leading to the proposal of a broad bipolar spectrum, which at present encompasses cyclothymia, hypomania, sporadic brief hypomania, recurrent brief hypomania and hypomania associated to other episodic disorders. In bipolar patients, the clinical focus has clearly shifted from the study of isolated episodes to attention to the entire lifetime, the personality and, especially, the temperament which is more and more part of this sub-affective spectrum definition. The temperament concept appeared with French and German classical authors at the beginning of this century, such as Kraepelin, Falret, and Baillarger (for review, see Brieger and Marneros, 1997; Kretschmer, 1930; Schneider, 1973). More recently, within this framework, the senior author (HAS) operationalized four temperaments, namely hyperthymic, depressive, irritable and cyclothymic, with empirical criteria to define them (Akiskal and Mallya, 1987). In general, temperament is considered as the biological and genetic base of the individual and, in particular, these different temperaments are described as trait sub-syndromic conditions of the affective pathology. They are likely to represent liability factors in the subsequent development of affective disorders (Akiskal, 1995). At present, the term cyclothymia defines a subaffective disorder (Diagnostic and Statistical Manual of Mental Disorders IV: American Psychiatric Association, 1995) as well as a temperament (Akiskal et al., 1979; Kraepelin, 1921; Kretschmer, 1930). The DSM and ICD classifications do not include a cyclothymic pattern in the personality disorders. This condition was removed from the rubric of personality disorder of the DSM-II (American Psychiatric Association, 1968) and classified in chronic mood disorders in DSM-III (American Psychiatric Association, 1968). Epidemiological investigations showed its prevalence in the general population to be from 3% to 6%, which is substantial when compared to the accepted 1% prevalence for manic depressive illness (Depue et al., 1981; Placidi et al., 1998a, b). However, some authors argued that this condition is heterogeneous and that its link with mood disorders must be clarified (Angst, 1978; Schneider, 1973; Wetzel et al., 1980). Some studies suggested a genetic association between cyclothymia and bipolar disorder (Akiskal et al., 1977; Depue et al., 1981; Dunner et al., 1982; Klein et al., 1986; Klein et al., 1988). Akiskal (1995) hypothesized that cyclothymia could evolve into bipolar disorder and that the same familial antecedents are found in subjects with cyclothymia as well as in patients suffering from manicdepressive illness. This is of major relevance because the manicdepressive condition is supposed to be at least partially of genetic etiology. Indeed cumulative data from traditional pedigree, twin, adoption studies and segregation analyses provided strong evidence that manic-depressive illness runs in families (Kelsoe, 2003). Further, the closer the kinship between the affected individuals and their relatives, the higher the risk of becoming affected to the latter. These observations strongly suggest a genetic liability in the etiology of bipolar disorders. However, the degree and the kind of this genetic contribution remain unknown until now, and no clear familial transmission patterns have emerged. In psychiatric genetics, studies generally employ either linkage or association analyses. Both are considered powerful and useful methods, although many obvious methodological differences separate these approaches. Briefly, the linkage approach, on the one hand, is strongly dependent on a priori hypotheses, especially the mechanism of inheritance. On the other hand, the association study is based on the ‘‘candidate gene’’ assumption, which postulates that the studied gene potentially participates in the physiopathology of the disorder and that its locus is assigned to a region in linkage with the condition. In both cases, however, two methodological contingencies are necessary. The first one is the clear definition of the phenotype; from this point of view, many clinical criteria are used to delineate symptoms and patterns of putative genetic relevance. The second is the strict distinction between affected and nonaffected individuals, especially under suspected polygenic hypotheses underlying processes of susceptibility. Indeed, discerning mental health from mental pathology, in terms of the absence or the existence of morbid episodes, could prove insufficient. So, this aspect is particularly important as many authors consider that temperamental characteristics are sub- P. Chiaroni et al. / Journal of Affective Disorders 85 (2005) 135–145 served by a genetic component and constitute a putative early phenotypic condition (Akiskal et al., 1983, 1985; Cassano et al., 1992; Cloninger et al., 1993). But, the main argument against this concept is the difficulty of linking the primacy of the temperamental characteristics to the illness (Hirschfeld et al., 1983, 1989). The aim of the present study is to compare the rates of the cyclothymic temperament (CT) in ‘‘supernormal’’ individuals (i.e. free of symptoms and without any familial history of affective disorders) and in genetically at risk subjects (i.e. individuals with affective disorders antecedents or with bipolar patients in their kin). As this temperament is evaluated as an independent variable, a positive result could constitute a new, indirect and strong argument for the hypothesis of an association between mood disorders and this temperament. 137 and/or had been specifically treated by psychotropic drugs for affective disorder. We thereby excluded eight subjects with a history of personal affective disorder (n = 7) or a family history of psychotic disorder (n = 1). We separated the remaining subjects into two subgroups (n = 137; 61 men and 76 women; mean age = 40.1 F 9.52 years, range = 22– 71; without a personal affective history, psychotropic treatment or psychiatric hospitalization) – the first one with negative affective disorder family history (NFH, n = 100; 48 men and 52 women; mean age = 38.3 F 9.1 years; range = 23 –60), – the other one with positive affective disorder family history (PFH, n = 37; 13 men and 24 women; mean age = 37.8 F 11.2 years; range = 22– 71). Further diagnostic information was obtained, as far as possible, from hospital records or from the physician who took charge of the patient. 2. Methods 2.1. Ethical considerations This study received the approbation of the local ethics committee [CCPPRB-Marseilles 1]. All participants were given a description of the aim and purpose of the investigation, and written informed consents were obtained from every subject included. 2.2. Populations selection 2.2.1. Controls Healthy unrelated Caucasian volunteers, recruited from the hospital staff in Marseilles, participated in this study (n = 145). For each subject, we conducted a semi-structured interview by the Schedules for Clinical Assessment in Neuropsychiatry (SCAN, PSE-10, Wing et al., 1990) to detect a lifetime process of psychotic or affective disorder. The clinician and principal investigator of this study (PIS: Dr. P.C.) is a senior experienced psychiatrist trained in such interviewing. A pedigree was assessed by at least two informative members of the family and limited to the first and second degree (Thompson et al., 1979). A psychiatric family history was considered positive each time a subject’s relative was hospitalized in a psychiatric service or consulted with a psychiatrist 2.2.2. The selection of bipolar patients’ relatives We matched to these controls a comparison group of individuals who had a positive family history of bipolar disorder in first degree. We also interviewed in the same manner 40 unrelated Caucasian subjects with kin with bipolar patients who participated in another genetic study (Chiaroni et al., 2000). Briefly, 60 unrelated Caucasians participated in this study. A consensus diagnosis for all was established by two experienced senior psychiatrists (including at all times the PIS and the physician who was in charge of the patient). All were Bipolar, type I, according to the Diagnostic and Statistical Manual of Mental Disorders (American Psychiatric Association, 1995). Likewise, the following items, concerning the development and course were recorded: age of illness onset (defined by the age of first hospitalization), recurrent episodes, polarity, and medications. From these 60 families, we excluded the families with one member and those who refused the interview for personal or material reasons. Then, among the families, we excluded the individuals with a diagnosis of affective disorder. Finally, among the kin (n = 92), only one relative in each family was assessed blindly. So, 40 were assessed for the present study (15 males and 25 females; mean age = 48.2 F 16.2 years; range = 138 P. Chiaroni et al. / Journal of Affective Disorders 85 (2005) 135–145 21 – 79). To date, none have developed an acute episode of affective disorder. significance was classically defined at the 0.05 level, two-tailed. 2.3. Data collection 3. Results In this study, the PIS interviewed all subjects, demographic data were systematically recorded. After a standardized explanation, each subject had to answer a questionnaire for the CT. The construction and validation of this instrument is described in Akiskal et al. (1979, 1998); Akiskal and Mallya (1987); Placidi et al. (1998a). This scale has eight items, scored by dichotomous ‘‘TRUE/FALSE’’ answers, exploring two clusters: – cluster A: multiple subjective manifestations including 1. lethargy and somatic discomfort versus eutonia, 2. dulling of senses versus keen perceptions, 3. slow-witted versus sharpened thinking, 4. shaky self-esteem alternating between low selfconfidence and overconfidence; – cluster B: behavioral manifestations including 1. hypersomnia versus decreased need for sleep, 2. introverted self-absorption versus uninhibited people seeking, 3. taciturn versus talkative, 4. unexplained tearfulness versus buoyant jocularity. A diagnosis of CT includes the following requirements: that these manifestations must be present since at least age 21, evolve in intermittent cycles with rapid oscillations, and characterize the habitual functioning of the individual. A defined CT requires at least two items in cluster A and three in cluster B. 2.4. Statistical procedures Results were analyzed using descriptive statistics. To compare groups for continuous variables, we used parametric tests, when possible (Student’s t-test, Fisher’s test and Pearson’s C v2)] or, conversely, non-parametric tests (Mann – Withney, M – W, or Kruskall– Wallis, K – W). For the qualitative variables, we used the v2 test or Fisher’s test. Statistical 3.1. Socio-demographic and clinical data The demographic data are summarized in Table 1. As regards gender, we observe a large prominence of females in the total sample: from the 177 recruited subjects, there are 101 women and 76 men. But this sex distribution does not significantly differ between the three subgroups (v2 = 2.45; P>0.29), even though the rates of women are higher in the PFH and BPR groups (62.5 and 64.8%, respectively) than in the NFH (52%). Also, the mean ages in the different subgroups are significantly different (K – W; P = 0.003): in comparison to the both controls groups, the BPR are older, on an average. Further, the range of ages indicates that a lot of people are in an age bracket where they are still at risk for bipolar disorder, and especially the bipolar type II, and could so be exposed to the risk of developing an affective episode. Concerning PFH subjects, when the diagnostic distribution is checked in each category of affective disorders, we find that 24.8% of the control sample (n = 34) have only depressive family history, and only 2.9% (n = 4) have a bipolar disorder familial history. Table 1 Socio-demographic characteristics of controls subgroups and bipolar Patients’ relatives NFH Females n % 52 52 PFH 24 64.9 BPR 25 62.5 TOTAL 101 57.62 Males n 48 13 15 76 % 48 35.1 37.5 42.93 n 100 37 40 177 % 100 100 100 100 Mean age [F] 38.3 [9.1] 37.8 [11.2] 48.2 [16.2] Min 23 22 21 Max 60 71 79 Median 38 35 49 A non-significant predominance of females vs. males [v2 = 2.45; P = 0.29], a statistically significant difference in mean ages [K – W; P = 0.003]. 139 P. Chiaroni et al. / Journal of Affective Disorders 85 (2005) 135–145 3.2. Cyclothymic temperament in controls versus bipolar relatives Table 3 Distribution of CT in NFH controls, PFH controls and BPR 3.2.1. Rates of cyclothymic temperament In the study population, 11 subjects have a CT, as strictly defined by the Akiskal and Mallya’s (1987) criteria; data are presented in Table 2. Inter-group comparison of the CT frequencies between the controls and the BPR exhibits a significant difference, with respectively 3.6 versus 15% (v2 = 6.84; P = 0.017). The calculated odd ratio is also statistically significant (OR = 4.66; confidence interval: 95%; 1.17 < OR <18.98). Further, when we examine the controls group in more detail (or more closely) as a function of the family history (Table 3), the distribution of the CT frequencies is radically different in NFH controls (1%) and PFH controls (10.8%). In this last group, when checking the typology of affective disorder in the familial history, we notice that all subjects have no more than recurrent depressive antecedents. This result actually indicates the very low CT rate in the ‘‘super normal’’ controls, who are not only free of affective symptoms but also free of familial mood disorder antecedents. So, when we compare the NFH versus the group that is at risk for affective disorder (PFH and BPR), we notice a significant difference (v2 = 10.72; P Fisher = 0.001) with an OR equal to 14.78 (confidence interval: 95%; 1.88 < OR < 315). Conversely, a tendency towards the same rates of CT are observed in the PFH, compared to the BPR and so, there is no statistical difference between the two groups (v2 = 0.30 with P Fisher = 0.74; and OR: 1.46; 0.32 < OR < 6.87). Cumulative data of the total sample of bipolar (controls and relatives) exhibit a frequency of 6 CT subjects in Non-CT n % 99 99 33 89.18 34 85 166 93.78 CT n % Total n Total % 1 1 100 100 4 10.81 37 100 6 15 40 100 11 6.21 177 NFH Table 2 Rates of definite CT, showing a statistically significant difference [v2 = 6.84; P = 0.017] Controls BPR Non-CT n % 132 96.4 34 85 CT n % n 5 3.64 137 6 15 40 PFH BPR Total NFH vs. PFH vs. BPR, v2 = 11.30; P = 0.001; NFH vs. [PFH and BPR] = 10.72; P Fisher = 0.001; OR = 14.78; PFH vs. BPR: v2 = 0.30; P Fisher = 0.74, non-significant; OR = 1.46. 44 (13.6%). On the other hand, 11.7% of the subjects with depressive antecedents have CT. 3.2.2. Socio-demographic characteristics of individual cyclothymic temperaments Looking at gender, comparison of the CT frequencies shows a higher rate in females: 72.3 versus 27.2% in males. But according to the overrepresentation of the females in the total sample, we observe a non-significant excess towards this prevalence (respectively 8/101 vs. 3/76, i.e. 7.9 vs. 3.9%: v2 = 1.17; P Fisher = 0.35; NS). Further, this result tends to be confirmed when we segregate the groups as a function of the family antecedents. So we observe respectively 12.5% females versus 7.6% males in PFH and 20 versus 6.6% in BPR. In the NFH, we count only one male. 3.2.3. Temperamental frequencies of individual cyclothymic items In Table 4 we summarize the distribution of the participants as a function of their scores on the cyclothymic scale. In the total sample, we previously found 11 individuals with CT and, conversely, only 90 responded negatively to all items, corresponding respectively to 63% of the NFH, 43.2% of the PFH and only 29.7% of the BPR. So all of these participants could be considered as strictly non-cyclothymic (non-CT). In addition to these two subgroups considering the strictly CT and non-CT individuals, we do observe that cyclothymic traits are quite widespread to some extent in the other subjects. Indeed, we count in total 140 P. Chiaroni et al. / Journal of Affective Disorders 85 (2005) 135–145 Table 4 Scores of the CT scale in different groups NFH, PFH and BPR Table 5 Socio-demographic characteristics of CT scale score subgroups CT scale score 0 From 1 up to 8 CT NFH n % CT scale score 63 63 36 36 1 1 PFH n % 16 43.24 17 45.94 4 10.81 BPR n % n % 11 27.5 90 50.84 23 57.5 76 42.93 6 15 11 6.23 NFH vs. PFH vs. BPR: [ P < 0.001], NFH vs. subjects at high risk [PFH and BPR]: P < 0.001. 42.9% of the controls versus 57.5% of the BPR who exhibit some positive responses to the scale (with total scores between 1 and 8), some exceeding, others without being strictly defined as CT according to the criteria of Akiskal and Mallya (1987). With respect to the familial antecedents, the distribution of these individuals differs significantly in the different subgroups NFH, PFH and BPR: respectively, 36 versus 45.9 versus 54.0% ( P exact < 0.001). Further, the NFH also differ significantly from the highrisk subjects ( P exact < 0.001). We notice, then, that one from the 76 subjects reaches the score threshold but cannot be considered as cyclothymic, because the distribution of these positive items do not respect the threshold of each cluster. As shown in Table 5, the mean ages in each group are very close to each other and do not exhibit a statistically significant difference (K – W = 0.389; P = 0.823; NS). Compared to the bipolar relatives without CT, we note that the mean age of the CT BPR is younger (41.5 F 14.1 vs. 49.2 F 16.3). The latter result raises the possibility that CT could evolve to affective disorder over the course of time. As regards gender, however, we show a statistically significant difference between the groups ( P = 0.02). As opposed to the NFH group, which shows a slight frequency of males, the females are largely more numerous in the subjects with CT or with cyclothymic scores between 1 and 8: respectively 51 versus 25 and 8 versus 3. So we found a large prevalence of female individuals with 59 subjects out of 87, on the whole (i.e. 67.8%), who 0 from 1 up to 8 CT Total Females n % 42 46.7 51 67.1 8 72.7 101 57.1 Males n % n % 48 53.3 90 100 25 32.9 76 100 3 27.3 11 100 76 42.9 177 100 40.6 [11.7] 39.8 [12.3] 41.5 [14.1] 40.3 [12.0] Age Mean years [F] The mean age are not significantly different [K – W = 0.389; P = 0.823]. The gender are not significantly different [v2 = 1.17; P Fisher = 0.35]. exhibit cyclothymic features to some extent. This result is, in our opinion, of major relevance as, we previously noticed the CT rates increase in the same subgroups. In Tables 6 and 7 we present respectively the recruitment of subjects as a function of number of positive responses to the cyclothymic scale and the rates of responses to each item. In a dimensional approach no symptomatic pattern is likely to emerge from these distributions. 3.3. Comparison of cyclothymic versus non-cyclothymic temperaments in bipolar families When we compared the clinical and socio-demographic characteristics of the probands’ bipolar disorder as a function of the temperament of their relatives, no statistical difference was observed on the following items: sex, polarity of the first episode, age of the first Table 6 Frequency of non-cyclothymic individuals as a function of number of positive response to constituent items or traits of the cyclothymic scale Non-CT score [range 1 – 8] [n = 76] 1 2 3 4 5 item items items items items 29 24 13 9 1 P. Chiaroni et al. / Journal of Affective Disorders 85 (2005) 135–145 Table 7 Item rates in individuals with positive response to the cyclothymic scale Cluster A Lethargy and somatic discomfort vs. eutonia Dulling of senses vs. keen perceptions Slow-witted vs. sharpened thinking Shaky self-esteem alternating between low Self-confidence and overconfidence Cluster B Hypersomnia vs. decreased need for sleep Introverted self-absorption vs. uninhibited people seeking Taciturn vs. talkative Unexplained tearfulness vs. buoyant jocularity n % 25 26 15 32.8 34.2 19.7 22 28.9 26 14 34.2 18.4 16 8 21.1 10.5 episode and number of episodes, therapeutic history (with special regards to antidepressives and normothymics), and alcohol familial history (data not shown). 4. Discussion 4.1. Major findings and methodologic limitations Compared to the prevalence of bipolar disorders, our study clearly shows that the CT rate in our total control sample is significant. This finding is in line with the previously reported data in the literature (ranging from 0.4 up to 6.3% (Depue et al., 1981; Kraepelin, 1921; Weissman and Myers, 1978; Wetzel et al., 1980)). Placidi et al. (1998a, b), with almost the same methodology as ours, found the highest prevalence (6.3%) in 1010 Italian students who were much younger (between 14 and 26) than our subjects. We observe a dramatically higher rate in subjects who are at risk for mood disorders when compared to the subjects without any positive familial history of mood disorder; that is to say, the controls who are first degree relatives of unipolar depressive patients and the subjects with bipolar kin. So, the CT is likely to aggregate in families with a history of affective disorder. Moreover, the CT rates increase from the depressive family group to the bipolar family group (kin). But an important bias deserves to be mentioned as well. Indeed, our interviewed BPR group is only a part of the total patients’ sibship and perhaps our 141 result could not be generalized to the entire family as this sample represents 36.8% of the total kin (data counted from the pedigrees). Thus, our percentage probably indicates a surprisingly high proportion. Nevertheless, as expected, this estimation in BPR is a lower than previously reported data on this temperament in bipolar patients themselves (Akiskal et al., 2003; Hantouche et al., 1998). Before discussing these specific findings, we will consider other methodological aspects that could affect our results. Of course, there are some inevitable limitations due to the design of this study. And so, our findings must of course be replicated in independent and larger samples (see Evans et al., 2004, this issue). First, the TRUE/FALSE answer format can habitually result in the collection of insufficient information. But in the present case, it is easily conceivable that this procedure tends to maximize the variance of the information, which could be strongly dependent on the subjects’ insight and on the degree of lived functional inconvenience and social impairment during the lifetime. Further, the ‘‘pessimistic’’ or ‘‘optimistic’’ state of the mind of the subject in CT (Bromet et al., 1986; Kandel and Davies, 1986) could largely influence the kind of given response studied, for example, by Platman et al. (1969) with the perception of self across the affective states. From this point of view, our 3 months’ test – retest procedure may not represent an adequate time frame to provide accurate results, but does require longer intervals of testing. However, in the Placidi et al. (1998b) study, cyclothymia was the most robust temperament over a 2year period of prospective follow-up. Also, the problem of the definition of the CT remains open. This problem is certainly of major relevance for at least two reasons. The first one is derived from the widespread scores, from 0 to 8, in the total sample individuals. Also, the distributions of these scores do not seem to be homogenous in the different subgroups. In a dimensional approach, a threshold for the global score of this questionnaire defines CT in subjects who never had psychiatric hospitalization nor consulted a psychiatrist. Therefore, we have to attribute to this definition an identical weighting to each item. In this hypothesis one could consider the CT to be an exaggeration of normal traits in the general population and we could think of a continuum from the non-CT to the CT. This is exactly 142 P. Chiaroni et al. / Journal of Affective Disorders 85 (2005) 135–145 in line with the typology of Kretschmer (1930); Schneider (1973) that considered a hard core and some doubtful cases for each described temperament or abnormal personality. So the accurate value of this threshold requires some prospective studies to validate its pertinence. But, even upon the seemingly straight-forward criteria of the evolution course, such as the appearance of pathological manifestation, we know perfectly that this design is methodologically really hard to develop, as the duration of such a prospective study should be equivalent to the investigator’s lifetime. But in an alternative categorical approach, we could hypothesize that the different items are not all equivalent to each other. The CT item frequencies we observed are likely to weaken this affirmation but a multivariate analysis, which we could not perform, would be more informative. Finally, a third way is to consider the CT as a heterogeneous condition (Howland and Thase, 1993). 4.2. Cyclothymic temperament and gender The CT seems to predominate in females. Furthermore, females present more cyclothymic traits in the non-CT subgroups. Higher prevalence of CT in female controls has also been observed by others in the general population (Depue et al., 1981; Placidi et al., 1998a) and among clinical cohorts (Akiskal et al., 1977; Alnaes and Torgensen, 1989; Dunner et al., 1982). In contrast, the patients’ gender received much attention in temperamental studies (Akiskal et al., 1998; Cassano et al., 1992; Dell’Osso et al., 1991; Nolen-Hoeksema et al., 1993; Perugi et al., 1990, 1997). But, to our knowledge, the CT was not reported to have distribution as a function of gender. Especially, Cassano and colleagues showed in 538 patients that the hyperthymic temperament was observed more commonly in men and that the depressive temperament was more prevalent in women. All these results can be contrasted with the equal sex distribution in bipolar disorder. In balance, it is uncertain if the gender effect represents a substantial bias for the generalization of our results. 4.3. Cyclothymic temperament and affective illness The results described herein indicate that most of the participants (90.9%) with a defined CT have a familial history of affective disorders, divided in 36.3% for the depressive disorder and 54.5% for the bipolar type I disorder, that is to say in subjects really at risk for mood disorders. When replicated and confirmed, these results could indicate that CT runs frequently in families with mood disorder history and especially in a statistically significant manner. When compared to NFH controls, they indicate furthermore an aggregation of CT and affective disorders, bipolar as well as unipolar, depressive disorders. This finding is similar, yet independently made discovery that goes beyond the study by Mendlowicz et al. (2004) (this issue) in showing an excess of CT in subjects who are actually symptom free as far as clinical episodes are concerned. But concerning specifically cyclothymic disorder, many authors subsequent to Jelliffe (1911), reported a frequent coexistence of bipolar and cyclothymic cases in families. In the studies of either cyclothymic or bipolar probands, all the conclusions are consistent with a strong association between the two conditions (Akiskal et al., 1977, 2003; Depue et al., 1981; Dunner et al., 1976, 1982; Endicott et al., 1985; Gershon et al., 1982; Klein et al., 1985, 1986). Many authors also reported that cyclothymia and CT evolved frequently into manic-depressive illness, especially at the beginning of this century (Jelliffe, 1911; Kraepelin, 1921; Kretschmer, 1930), and more recently (Akiskal et al., 1977, 1985; Klein and Depue, 1984; Waters, 1979). Concerning the problem of unipolar depressive disorder, the findings are more conflicting. The majority of authors reported no differences in the rate of cyclothymia between unipolar probands and controls (Dunner et al., 1976; Gershon et al., 1975, 1982; Klein et al., 1988; Weissman et al., 1984). But others have reported opposite findings (Depue et al., 1981; Dunner et al., 1982). Hantouche et al. (1998) recently showed in the EPIMAN study of 250 affective patients that CT was less frequent in pseudo-unipolar depressives. But these discrepancies are perhaps in relation to the degree of lesser certainty in the diagnosis of unipolar depression compared to that of frank bipolar disorder. In light of these results, we would hypothesize that some depressive relatives of the cyclothymic subject could be undoubtedly pseudounipolar patients or BP II, which could change the nature of our conclusions. So, given all the above, it is P. Chiaroni et al. / Journal of Affective Disorders 85 (2005) 135–145 likely to further hypothesize a common shared pathway between these CT individuals and subjects suffering from full-blown mood disorders. 4.4. Cyclothymic temperament and genetics of bipolar disorder From the differences in the rate between NFH controls, on the one hand, and at risk individuals, on the other, we could hypothesize that CT is unlikely to breed true as a genetic trait in subjects, but apparently segregates in families in which affective antecedents are present. Moreover, a familial aggregation of Cyclothymic temperamental features and acute clinical episodes could suggest a partially shared contribution of common genetic factors. More provocatively, the problem of temperaments could be of major relevance, especially concerning the problem of a genetic liability that could underlie the pathophysiology of bipolar illness. Indeed, a genetic component is relatively well established in bipolar illness, although the genes and the underlying pathogenic mechanisms remain mysterious. Several methodological limitations confront us. First, our results emphasize the importance of a careful selection of control groups. Of course, the identification of affected subjects has to be consistently related to a precise psychiatric illness and discerned from other diagnoses or social maladjustment. But, even in terms of the factor of predisposition, the distinction between screened and unscreened individuals, from the temperamental point of view, could be very important in genetic studies because it could delineate a clear distinction between subjects actually free of symptoms in ‘‘super normal’’ or at risk individuals as a function of the family history. This is of major relevance. So we join Tsuang et al. (1988) in proposing that both screened and unscreened controls must be included in the design of genetic studies to be compared to patients. Since absolutely no biological marker has been proven so far, it is clear that whatever the methodological approach used—association or linkage methods, for instance—an accurate definition of the phenotype is crucial in the design of genetic studies. So, in familial studies, do we have to consider ‘‘affected’’ the individuals with affective temperaments, and with especially CT? 143 Actually with our results, we have reasonable arguments to submit that CT could contribute to a broad phenotypic definition of the bipolar condition. This is in line with Kretschmer (1930) and subsequent reformulation by the senior author (Akiskal, 1977; Akiskal, 1995; Akiskal and Akiskal, 1996), or CT could merely play pathoplastic role in forecasting disability; it could actually be a valuable psychological marker for different methodologies in molecular biology. The focus in the field of genetic research may shift from the study of episodes, as it is unlikely that patients inherit the illness itself, but more probably some general predisposition to become affectively ill. Such an approach was fruitful when Ebstein et al. (1997); Staner et al. (1998) reported an association between human personality traits—respectively the reward dependence and the novelty seeking—and chromosomal loci, which encode for the 5-HT2C Receptor, the Dopamine D3 or D4 Receptor proteins. From this point of view, it could be informative to evaluate the different temperaments (depressive and hyperthymic as well as the cyclothymic) among all the kin of bipolar probands (Chiaroni et al., in press). In conclusion, such a perspective is a potentially productive approach in the investigation of genetic and environmental influences in the occurrence of acute episodes from a pathogenic as well as therapeutic point of view. 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