Do social anxiety disorder patients belong to a bipolar spectrum ...

Journal of Affective Disorders 86 (2005) 11 – 18 www.elsevier.com/locate/jad

Research report

Do social anxiety disorder patients belong to a bipolar spectrum subgroup? Alexandre M. Valenc¸a, Antonio E. Nardi*, Isabella Nascimento, Fabiana L. Lopes, Rafael C. Freire, Marco A. Mezzasalma, Andre´ B. Veras, Marcio Versiani Institute of Psychiatry, Federal University of Rio de Janeiro, R. Visconde de Piraja´, 407/702, Rio de Janeiro-RJ-22410-003, Brazil Received 3 November 2004; accepted 9 December 2004

Abstract Background: It has been proposed that all forms of bipolar disorder–perhaps all primary affective disorders–are best conceptualized as a spectrum of related illness, clinically overlapping but not necessarily genetically uniform illnesses. We aim to describe with retrospective methodology the demographic, clinical, and therapeutic response in a group of social anxiety disorder (SA) patients who improves while taking antidepressants and compare them with bipolar II (B-II) patients. Methods: 57 SA outpatients (DSM-IV) were diagnosed and naturalistic efficacious treated with selective serotonin reuptake inhibitors (SSRI). Their demographic, clinical features and therapeutic response were compared with 41 DSM-IV bipolar II patients in their starting evaluations in our outpatient clinic in the Federal University of Rio de Janeiro, Brazil. Results: There is a sub-group of SA patients who improves while taking antidepressants and presents a clear hypomanic phase. Their improvement is identical to a mild/moderate hypomaniac state. Without the antidepressant, the symptoms of SA return. The SA and B-II patients have a similar number of previous depressive episodes, alcohol abuse, suicide attempts, and family history for mood disorder. Limitations: It is a retrospective data description based on a naturalist follow-up. Conclusion: Some SA patients have demographic, clinical and therapeutic features similar to B-II patients and they might just be a Bipolar-III sub-group with a higher level of complains to social situations and without spontaneous hypomania during lifetime. D 2005 Elsevier B.V. All rights reserved. Keywords: Social phobia; Follow-up; Antidepressant; Hypomania; Bipolar subtype

1. Introduction * Corresponding author. Tel.: +55 21 2521 6147; fax: +55 21 2523 6839. E-mail address: [email protected] (A.E. Nardi). 0165-0327/$ - see front matter D 2005 Elsevier B.V. All rights reserved. doi:10.1016/j.jad.2004.12.007

The emerging concept of the bipolar spectrum represents a provocative working hypothesis to account for the interface of anxiety and mood

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A.M. Valenc¸a et al. / Journal of Affective Disorders 86 (2005) 11–18

disorders and bipolarity (Akiskal, 2003). In clinical reality the high prevalence of bipolar spectrum can no longer be in doubt (Akiskal, 1996), whereas 1% is too conservative and pertains primarily to bipolar I; and that at least 5% of the general population has disabling bipolar disorder and/or traits, and manifesting clinically largely within the dsoftT bipolar realm (Akiskal, 2003). Angst (1998) described based in the literature data the lifetime prevalence of the bipolar spectrum of 3–6.5% and the Zurich cohort study identified a prevalence rate up to age 35 of 5.5% of DSM-IV hypomania/mania and a further 2.8% for brief hypomania (recurrent and lasting 1–3 days). It has been proposed that all forms of bipolar disorder–perhaps all primary affective disorders–are best conceptualized as a spectrum of related illness (Gershon et al., 1982; Akiskal, 1983, 1996; Tsuang et al., 1985; Cassano et al., 1989), clinically overlapping but not necessarily genetically uniform illnesses. Robins and Guze (1970) pointed out that the criteria for validating a disorder has a long way through demographic, phenomenologic, comorbid, course, temperamental, familial, and whenever applicable, biological characteristics. The validity of DSMIV hypomania and brief hypomania was demonstrated by a family history of mood disorders, a history of suicide attempts and treatment for depression (Angst, 1998). Comorbidity with anxiety disorders and substance abuse was found equally in both subtypes of hypomania. Angst suggests that recurrent brief hypomania belongs to the bipolar spectrum (Angst, 1998). Bipolar disorder has always been highly recurrent and considered to have a poor prognosis (Angst and Sellaro, 2000). Bipolar patients who have been hospitalized spend about 20% of their lifetime from the onset of their disorder in episodes (Angst and Sellaro, 2000). Antidepressant and antimanic drugs have to be given as long as the natural episode lasts. Given the poor outcome of bipolar disorders found in naturalistic follow-up studies and our lifelong investigation, intensive antidepressant, antimanic, and mood-stabilizing treatments are required in most cases (Judd et al., 2003). Despite modern treatments full recovery without further episodes are rare, recurrence of episodes with incomplete remission is the rule, and the development of chronicity and suicide is still frequent (Angst and Sellaro, 2000).

We aim to describe with retrospective methodology the demographic, clinical, and therapeutic response in a group of social anxiety disorder (SA) patients who improves while taking antidepressants and compare then bipolar II (B-II) patients. We decided to compare with bipolar type II and not with bipolar type III as they are a more heterogeneous group although the clinical observation refers to the antidepressant use as with clinically and scientifically can not observe difference between these bipolar groups (Akiskal et al., 2003; Benazzi and Akiskal, 2003). Our hypothesis was that the some SA patients–those who are asymptomatic while taking antidepressants–have similar clinical and demographic features of B-II patients.

2. Method Participants were men and women who spontaneously looked for treatment in the Institute of Psychiatry, Federal University of Rio de Janeiro, Brazil, age between 18 and 60 years old, who met DSM-IV (American Psychiatric Association, 1994) criteria for SA, as determined by the Structured Clinical Interview (First et al., 1997) or for bipolar II for DSM-IV. Pregnant or nursing women were excluded from participation. Patients who met DSM-IV criteria for current major depression, bipolar I disorder, obsessive-compulsive disorder, schizophrenia, delusional or psychotic disorders, organic brain syndrome, epilepsy, or substance abuse or dependence (during the last year) were also excluded. Patients with comorbid dysthymic or generalized anxiety disorders could be included if the social anxiety disorder or bipolar II disorder was judged to be the principal diagnosis. Other reasons for exclusion included unstable medical conditions; or the presence of suicidal risk. The study design of the investigation was explained to the patients and a signed voluntary written inform consent for their participation in this study was obtained. The protocol complying with the principles laid down in the Declaration of Helsinki was approved by our local Ethics Committee. SA patients were assigned to a naturalist treatment in our outpatient clinic with a selective serotonin


reuptake inhibitor (SSRI) antidepressant for the SA. The SA patients who could not stand the adverse events of SSRI nor had any therapeutic response in a 2-month period were not evaluated in this study. The therapeutic response was previously decided as a Clinical Global Impression—severity of 1 or 2 (Guy, 1976) and a decrease in the total score of Liebowitz Social Anxiety Scale greater than 50% of the baseline score (Liebowitz et al., 1988). The patients were oriented to avoid the concomitant use of any other psychotropic drug including benzodiazepines. SA improving with SSRI continued taking that dose for usually 2 years. After 1 year of good-response treatment they were selected to answer some demographic and clinical data in order to compare their features. SA patients were seen for this evaluation after 1 year of efficacious treatment for SA and compared with bipolar II patients during their admission to our outpatient clinic. The principal instruments used were the collection of demographic and clinical data by two medical doctor interviewing the patient and at least one relative separately and the Beigel–Murphy Mania Scale (Beigel et al., 1971). 2.1. Statistical analysis Age and the age that the disorder started were compared with the Mann–Whitney test. Duration of illness was compared between groups at baseline using analysis of variance (ANOVA). Gender and ethnicity were compared using v 2 tests. Pair-wise comparisons among the treatment groups were performed at end-point, using Fisher’s protected least significant difference method. All p values are two-tailed, and statistical significance was set at 5% level ( pb0.05).

3. Results The patients who fulfilled SA and B-II diagnosis in their first visit to our center were invited to participate in our trial. Only after the acceptance and the written informed consent were obtained, all the inclusion and exclusion criteria were checked. From a sample of 193 SA patients naturalist treated in the outpatient clinic of the Institute of Psychiatry, Federal University of Rio de Janeiro, we selected for this comparison 57

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SA who fulfilled all the inclusion and exclusion criteria. The bipolar II 115 patients sample from our outpatient clinic was also selected based in the criteria to 41 patients to compare. Our group of SA patients who are asymptomatic while taking antidepressants for 1-year period and our sample of B-II patients in a hypomanic phase before starting their treatment– without any psychotropic medication–did not differ in terms of sex, age, level of education, marital status, occupation, family history of mood disorder, age Table 1 Demographic and clinical characteristics Social anxiety disorder (n=57) n (%) Sex Male 22 (38.6) Female 35 (61.4) Age (yearsFS.D.) 45.1F13.7 Educational level High school or less 32 (56.1) College or more 25 (43.9) Marital status Married 19 (33.3) Not married 38 (66.7) Occupation Active 47 (82.5) Inactive 10 (17.5) Family history of mood disorder Yes 35 (61.4) No 22 (38.6) Family history of bipolar I disorder Yes 10 (17.5) No 47 (82.5) Family history of suicide Yes 4 (7.0) No 53 (93.0) Age disorder started 20.6F8.9 (yearsFS.D.) Previous psychiatric treatment Yes 26 (45.6) No 31 (54.4) Previous depressive episodes Yes 34 (59.7) No 23 (40.3) Alcohol abuse Yes 20 (35.1) No 37 (64.9) Suicide attempt Yes 11 (19.3) No 46 (80.7) a b

Chi square test. Mann–Whitney.

Bipolar II (n=41) n (%)

p

14 (34.1) 27 (65.8) 42.6F11.5

0.632a

28 (68.3) 13 (31.7)

0.832a

13 (31.7) 28 (68.3)

0.720

33 (80.5) 8 (19.5)

0.452

31 (75.7) 10 (24.3)

0.167a

13 (31.7) 28 (68.3)

0.344a

7 (17.1) 34 (82.9) 15.2F10.6

0.794b

0.691a 0.285b

34 (82.9) 7 (17.1)

0.037a

30 (73.2) 11 (26.8)

0.418a

17 (41.5) 24 (58.5)

0.372a

9 (21.9) 32 (78.1)

0.711a

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Table 2 Mean change from baseline in clinician-rated social anxiety symptoms and avoidance behavior in social anxiety disorder (SA) patients (meanFS.D.) Efficacy variable SA patients (n=57) LSAS (chance from baseline) Total score* 33.8F15.7 Fear 17.9F10.5 Avoidance 15.9F10.4

F

p

14.168 9.240 8.490

0.0004 0.0003 0.001

* Fisher’s protected least significant difference (baseline vs. 1 year, F=18.47, df=2, pb.0001). LSAS—Liebowitz Social Anxiety Scale.

disorder started, previous depressive episodes, alcohol abuse, and suicide attempts (Table 1). The groups differ in the number of patients with previous psychiatric treatment as it was more frequent among the BII patients (Table 1).

The SA patients were followed through the year of treatment with the Liebowitz Social Anxiety Scale—LSAS (Liebowitz et al., 1988). After 1 year of an open treatment with a serotonin selective antidepressant—SSRI (mostly paroxetine and sertraline), the patients select to our comparison were significantly better in the LSAS (Table 2). The fear symptoms and the avoidance behavior were markedly improved and the Clinical Global Impression— Improvement had a meanFS.D. of 1.6F2.0 ( F=9.37, p=0.021). The Beigel–Murphy Mania Scale was applied to both groups (Table 3). There was no significant difference in any item. The score where taken during a hypomanic phase without any psychotropic medication for the bipolar II patients and at the end of 1year therapeutic response for the social anxiety disorder patients.

Table 3 Individual item scores of Beigel–Murphy Mania Scale

1—looks depressed 2—is talking 3—moves from one place to another 4—makes threats 5—has poor judgment 6—dresses inappropriately 7—looks happy and cheerful 8—seeks out others 9—is distractable 10—has grandiose ideas 11—is irritable 12—is combative or destructive 13—is delusional 14—verbalizes depressive feelings 15—is active 16—is argumentative 17—talks about sex 18—is angry 19—is careless about dress and grooming 20—has diminished impulse control 21—verbalizes feelings of well-being 22—is suspicious 23—makes unrealistic plans 24—demands contact with others 25—is sexually preoccupied 26—jumps from one subject to another

Social anxiety disorder (n=57)

Bipolar II (n=41)

F

p

1.2F3.4 13.1F4.3 9.5F6.4 3.5F2.1 7.5F6.3 2.9F4.3 10.6F5.8 11.8F5.2 11.1F6.7 7.9F5.9 12.1F9.3 3.5F3.9 1.0F0.3 4.9F3.0 11.5F7.0 9.2F6.6 3.9F4.0 6.1F3.7 2.6F6.0 9.5F5.3 9.9F7.3 5.7F3.7 6.2F3.9 8.7F8.8 5.6F4.2 8.2F5.7

1.5F2.5 14.7F5.0 13.0F7.1 4.9F3.9 9.7F7.5 3.8F5.5 13.0F6.9 14.3F4.5 10.4F5.6 8.8F6.4 12.7F7.0 4.6F4.0 1.2F0.5 2.8F4.3 14.5F6.9 10.3F7.5 5.4F3.8 6.4F4.4 3.7F5.6 11.7F6.2 11.8F6.4 4.6F4.9 5.3F4.8 8.5F9.2 5.8F4.0 7.6F5.3

18.54 17.92 11.31 10.32 12.27 8.56 10.77 4.42 15.67 14.26 19.61 14.39 16.45 1.27 8.56 4.23 2.35 18.73 9.92 14.40 13.26 12.87 14.84 16.67 14.83 13.75

0.734 0.682 0.537 0.435 0.562 0.311 0.298 0.129 0.765 0.723 0.816 0.804 0.687 0.078 0.267 0.191 0.084 0.755 0.317 0.656 0.458 0.342 0.698 0.819 0.792 0.744

MeanFS.D. The score where taken during a hypomanic phase for the bipolar II patients and at the end of 1-year therapeutic response for the social anxiety disorder patients.


4. Discussion Our data strongly suggest that a group of SA patients who responded to antidepressants may show their clinical improvement while taking antidepressants with symptoms similar to a hypomania. This clinical description is supported by concordance among these SA patients and bipolar II patients in some demographic data as family history of mood disorder, family history of bipolar I disorder, family history of suicide, age the disorder started, previous depressive episodes, alcohol abuse, and suicide attempt. Judd et al. (2003) comparing 135 definite RDC bipolar-I and 71 definite bipolar-II patients from the NIMH Collaborative Depression Study followed by 20 years observed similar demographic characteristics and ages of onset of their first affective episode. Both disorders had more lifetime comorbid substance abuse disorders than the general population. BP-II has a significantly higher lifetime prevalence of anxiety disorders in general, and social and simple phobias in particular, compared to BP-I. BP-II patients had a substantially more chronic course, with significant more major and minor depressive episodes and shorter inter-episode well intervals. The relationship between anxiety disorders and bipolar disorder has demonstrated high rates of comorbidity. Boylan et al. (2004) using structured clinical interviews in 138 patients with bipolar disorder and followed for up to 3 years with longitudinal clinical surveillance observed that 55.8% of the patients had at least 1 comorbid anxiety disorder, and 31.8% had 2 or more anxiety disorder diagnoses. The most common anxiety disorder was generalized anxiety disorder, followed by panic disorder. The generalized anxiety disorder and social phobia were more likely to be associated with poor outcome. Perhaps the poor outcome results could be justified by the patients having just a more severe bipolar II disorder and not due to the association of two theoretical disorders. One impressive data from our sample was the similar suicide attempt episodes between the groups. We consider this feature one of the most robust to support our hypothesis together with the family history of mood disorders, bipolar I disorder and suicide. Suicide is one of the most severe and frequent complications of bipolar disorder. Slama et al. (2004)

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studied 307 prospectively recruited DSM-IV-diagnosed bipolar I or II patients with semi-structured diagnostic interviews and identified that 129 bipolar patients (42%) had made at least 1 suicide attempt in their life. Lifetime history of suicidal behavior was associated with history of suicidal behavior in firstdegree relatives but not with a familial history of mood disorder. SA, early age at onset of mood disorder, total number of previous depressive episodes, alcohol and tobacco use, antidepressantinduced mania, and personal history of head injury were associated with suicidal behavior. No association was observed with gender or diagnosis of bipolar I or II disorder. Bipolar patients with early age at bipolar disorder onset, high number of depressive episodes, personal history of antidepressant-induced mania, comorbid alcohol abuse, and suicidal behavior constitute a clinical subgroup at risk of suicidal behavior. Our group had also an early onset of the disorders, a high comorbid alcohol abuse, and previous depressive episodes. Dilsaver and Chen (2003) studying subjects with pure mania and depressive mania described that none of the subjects with pure and 13 (68.4%) with depressive mania had an intra-episode of social phobia ( pb0.0001). One (4.0%) subject with pure and 12 (63.2%) subjects with depressive were suicidal. Twelve of 13 (92.3%) subjects with depressive mania met the criteria for an intra-episode of social phobia and an intra-episode of panic disorder concurrently ( pb0.0001). All were suicidal. Concurrence of the disorders seems to be the rule. The findings of Dilsaver and Chen (2003) suggest that databases disclosing a relationship between anxiety disorder, bipolar disorder and suicide attempts merit a specific attention. The family history of mood disorders, bipolar I disorder, and suicide is an important clinical data to diagnosis but is generally understudied (Robins and Guze, 1970). The family history of mood disorders was observed in our both groups in more than 60% of patients and is considered an important factor for our hypothesis. Benazzi (2004) described that bipolar II subjects had significantly more bipolar I, more bipolar II (50.7%), more major depressive episodes, and more social anxiety disorder in first-degree relatives than did unipolar subjects. Among the predictors of the diagnosis of bipolar II, bipolar II family history had the highest specificity (82.8%), while early onset had

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the highest sensitivity. If carefully detected, family history of mood disorders could reduce bipolar II misdiagnosis by inducing careful probing for a history of hypomania (Benazzi, 2004). SA is well suited to the spectrum concept because it has trait-like qualities of early onset, chronicity, and no empirically derived threshold that demarcates normal from clinically significant trait social anxiety (Schneier et al., 2002). Several disorders marked by social dysfunction or inhibition, including alcohol abuse, paranoid disorder, bipolar disorder, autism, and Asperger’s disorder, also may show some overlap with social anxiety disorder features (Schneier et al., 2002). Biologic measures of dopamine system hypoactivity have been linked to social anxiety disorder, trait detachment, and general deficits in reward and incentive function (Liebowitz et al., 1988). SA, shyness, and behavioral inhibition all seem to have a genetic component, but more research is needed to attempt to identify a more specifically heritable temperament associated with these conditions (Schneier et al., 2002). Although the notion of a single social anxiety disorder spectrum currently has some clinical use, Schneier et al. (2002) believe that exclusive focus on the notion of a single continuum with two extremes–from social disinhibition in mania to the most severe form of social anxiety, avoidant personality disorder–is premature and limiting in respect to etiologic research. A bottom-up biologic approach holds promise for identifying spectra with a common etiology that might respond to specific treatments. Taking a pluralistic view of the concept of spectrum at this stage may help accelerate our understanding of social anxiety and related disorders (Schneier et al., 2002). The alcohol abuse is recognized as another corroborating factor for the diagnosis of social anxiety disorder and bipolar disorder (Schneier et al., 2002; Perugi et al., 2002). Perugi et al. (2002), investigating the presence of lifetime comorbidity of alcohol abuse in a sample of 153 social anxiety disorder patients, observed that 34 patients (22.2%) had a past or current history of alcohol abuse for at least 1 year. Bipolar disorder type II was found almost exclusively among patients with alcohol abuse, as well as family history for bipolar disorders. Perugi et al. (2002) data indicate a strong relationship between bipolar II disorder and alcohol abuse comorbidity in patients with SP. As they

might undertake alcohol abuse as an attempt to overcome social difficulties, the presence of bipolar diathesis in patients presenting with social anxiety might explain their increased susceptibility to alcohol. Comorbidity in bipolar disorder is the rule rather than the exception more than 60% of bipolar patients have a comorbid diagnosis and is associated with a mixed affective or dysphoric state; high rates of suicidality; less favourable response to lithium and poorer overall outcome (Sasson et al., 2003). Although symptoms of anxiety as well as anxiety disorders commonly occur in patients with bipolar disorder, the pathophysiologic, theoretical, and clinical significance of their co-occurrence has not been well studied. A growing number of epidemiological studies have found that bipolar disorder significantly co-occurs with anxiety disorders at rates that are higher than those in the general population (Perugi et al., 1998; Freeman et al., 2002). Clinical studies have also demonstrated high comorbidity between bipolar disorder and panic disorder, OCD, SA, and posttraumatic stress disorder (Freeman et al., 2002; Sasson et al., 2003). Perugi et al. (2001) investigated family history, lifetime comorbidity, and demographic and clinical characteristics among 153 outpatients who met DSM-III-R diagnostic criteria for social anxiety disorder. Fourteen patients (9.1%) satisfied DSM-IIIR criteria for lifetime bipolar disorder not otherwise specified (bipolar II), while 71 (46.4%) had unipolar major depression and 68 (44.4%) had no lifetime history of major mood disorders. Comorbid panic disorder/agoraphobia, obsessive-compulsive disorder, and alcohol abuse were reported more frequently in the bipolar group than in the other two subgroups. Severity and generalization of the SA symptoms, prevalent interactional anxiety, multiple comorbidity, and alcohol abuse appeared to be the most relevant consequences of SA-bipolar coexistence. In a significant minority of cases, protracted social anxiety may hypothetically have represented, along with inhibited depression, the dimensional opposite of gregarious hypomania (Perugi et al., 1999; Perugi et al., 2001). Psychobiological mechanisms that may account for these high comorbidity rates likely involve a complicated interplay among various neurotransmitter systems, particularly norepinephrine, dopamine, gammaaminobutyric acid (GABA), and serotonin (Liebowitz et al., 1988; Schneier et al., 2002). There is also a


convincing evidence that rates of substance use and anxiety disorders are higher among patients with bipolar disorder compared to their rates in the general population (Sasson et al., 2003). As more than 40% of bipolar patients have anxiety disorder, it is indicated that while diagnosing bipolar patients, systematic enquiry about different anxiety disorders is called for (Sasson et al., 2003). This also presents a therapeutic challenge, since agents that effectively treat anxiety disorders are associated with the risk of induced mania. Therefore, the treating psychiatrist needs to carefully evaluate the potential benefit of treating the anxiety against the potential cost of inducing a manic episode. Sasson et al., 2003 suggested that the clinician attempt to ensure that the patient receives adequate treatment with mood stabilizers before slowly and carefully attempting the addition of anti-anxiety compounds with a relatively lower risk of mania induction. Himmelhoch (1998) studied the treatment outcome of 32 social anxiety disorder patients administered either the reversible monoamine oxidase inhibitor moclobomide or the irreversible inhibitor phenelzine and found that 18 had remission N50% of their socially anxious symptoms. Moreover, 14/18 of those improved became hypomanic, according to the Raskin Mania Scale and the Young Mania Scale coupled with expert clinical diagnosis. These findings possibly allude to a relationship of social phobia to bipolarity. Himmelhoch (1998) upholds the central role of depressive inhibition in bipolar disorder, which during antidepressant therapy often overshoots in a hypomanic direction; even in the absence of prior spontaneous hypomania, such disinhibition should classify this special subset of social anxiety disorder patients within the bipolar spectrum. As pointed out in our clinical-naturalist data of SA and B-II patients they have some similarity in demographic, familial, clinical, and therapeutic features. Some SA patients might just be a bipolar-III sub-group with a higher level of complains to social situations and without spontaneous hypomania during lifetime.

Acknowledgements Supported by the Brazilian Council for Scientific and Technological Development (CNPq), Grant

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