Clinical and demographic features of mood disorder subtypes

Psychiatry Research 112 (2002) 195–210

Clinical and demographic features of mood disorder subtypes Alessandro Serretti*, Laura Mandelli, Enrico Lattuada, Cristina Cusin, Enrico Smeraldi Department of Psychiatry, Vita-Salute University, San Raffaele Institute, Via Luigi Prinetti 29, 20127 Milan, Italy Received 14 September 2001; received in revised form 8 March 2002; accepted 1 May 2002

Abstract The aim of this study was to investigate demographic, clinical and symptomatologic features of the following mood disorder subtypes: bipolar disorder I (BP-I); bipolar disorder II (BP-II); major depressive disorder, recurrent (MDR); and major depressive episode, single episode (MDSE). A total of 1832 patients with mood disorders (BPIs863, BP-IIs141, MDRs708, and MDSEs120) were included in our study. The patients were assessed using structured diagnostic interviews and the operational criteria for psychotic illness checklist (ns885), the Hamilton depression rating scale (ns167), and the social adjustment scale (ns305). The BP-I patients were younger; had more hospital admissions; presented a more severe form of symptomatology in terms of psychotic symptoms, disorganization, and atypical features; and showed less insight into their disorder than patients in the other groups. Compared with the major depressive subgroups, BP-I patients were more likely to have an earlier age at onset, an earlier first lifetime psychiatric treatment, and a greater number of illness episodes. BP-II patients had a higher suicide risk than both BP-I and MDSE patients. MDSE patients presented less severe symptomatology, lower age at observation, and a higher number of males. The retrospective approach and the selection constraints due to the inclusion criteria are the main limitations of the study. Our data support the view that BP-I disorder is quite different from the remaining mood disorders from a demographic and clinical perspective, with BP-II disorder having an intermediate position to MDR and MDSE, that is, as a less severe disorder. This finding may help in the search for the biological basis of mood disorders. 䊚 2002 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Bipolar disorder; Depressive disorder; Symptomatology; Suicide; Psychosis

1. Introduction Long after the pioneering work of Kraepelin (1909–1915), manic-depressive illness has been thoroughly investigated only during recent decades. In the late 1960s, it was divided into bipolar *Corresponding author. Department of Neuroscience, Istituto Scientifico H San Raffaele, Vita-Salute University, School of Medicine, Via Luigi Prinetti 29, 20127 Milan, Italy. Tel.: q 39-2-2643-3250; fax: q39-2-2643-3265. E-mail address: [email protected] (A. Serretti).

and unipolar disorders. Then, bipolar disorder was subdivided into bipolar I (BP-I) and bipolar II (BP-II) disorders, and unipolar disorder into major depressive disorder, recurrent (MDR) and major depressive disorder, single episode (MDSE). Other forms of mood disorders, such as dysthymia and minor depression, have also been identified, but they will not be analyzed in this study. Lifetime prevalences reported in the literature account for 10–15% for major depressive disorder,

0165-1781/02/$ - see front matter 䊚 2002 Elsevier Science Ireland Ltd. All rights reserved. PII: S 0 1 6 5 - 1 7 8 1 Ž 0 2 . 0 0 2 2 7 - 5

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0.1–1.7% for BP-I disorder, and 0.5–1.9% for BPII (Kaplan and Sadock, 1995; Angst, 1998). Recently, Angst (1995, 1998) found a prevalence rate of 5.5% for bipolar disorder, widely defined to include manias and hypomanias. The bipolar spectrum accounts for 30–55% of all major depressions, and a ratio approximately 1:1 of unipolar depression to bipolar disorder has been reported (Angst et al., 1978; Akiskal et al., 2000). The prevalence of BP-II disorder has been estimated as between 10 and 40%, but rates as high as 45% have been found with wider inclusion criteria (Benazzi, 1997, 1999b). 1.1. Bipolar vs. major depressive disorder A number of differences have been reported between bipolar and major depressive subjects. In 1921, Kraepelin advised that manic-depression differed from melancholia in respect to a more pronounced volition inhibition and less prominent dysphoria. In later years, bipolar disorder was further distinguished by its earlier age of onset (Peselow et al., 1982; Goodwin and Jamison, 1990; Winokur et al., 1993; McMahon et al., 1994; Angst and Preisig, 1995; Rouillon, 1997), more acute onset (Winokur et al., 1993), more frequent episodes (Goodwin and Jamison, 1990; Angst and Preisig, 1995), higher number of total episodes (Goodwin and Jamison, 1990; Winokur et al., 1993; Angst and Preisig, 1995), equal proportion of men and women (Goodwin and Jamison, 1990; Winokur et al., 1993; Rouillon, 1997), higher probability to affect persons who were divorced, separated or had never married (Rouillon, 1997), greater incidence of psychotic features (Akiskal et al., 1983; Weissman et al., 1984), greater risk of completed suicide (Goodwin and Jamison, 1990) or attempted suicide (Lester, 1993), and higher number of post-partum episodes (Goodwin and Jamison, 1990). BP-I disorder has also been characterized by higher rates family members of manic episodes and psychiatric diseases (Goodwin and Jamison, 1990; Heun and Maier, 1993; Winokur et al., 1993, 1995b, Cvjetkovic-Bosnjak, 1998), alcoholism (Maier et al., 1995; Winokur et al., 1995a), and substance abuse (Rouillon, 1997; Winokur et al., 1998). A positive family history

for psychiatric diseases has also been considered to be a predictor of future mania (Johnson and Hunt, 1979; Akiskal et al., 1983; Bourgeois et al., 1988; Coryell et al., 1995). Other predictors of a future manic episode after a depressive onset are reported to be early age of onset (Akiskal et al., 1983), post-partum onset (Bourgeois et al., 1988), hypersomnia (Akiskal et al., 1983; Bourgeois et al., 1988), more marked self-reproach and guilt (Winokur and Wesner, 1987), psychotic depression (Bourgeois et al., 1988; Goodwin and Jamison, 1990; Coryell et al., 1995), and psychomotor retardation (Bourgeois et al., 1988; Goodwin and Jamison, 1990), even if in other studies psychomotor retardation is considered less common and agitation more likely in bipolar patients (Mitchell et al., 1992). On the other hand, major depressives have been characterized by a greater number of lifetime medicalysurgical interventions (Winokur et al., 1993), by older age (Goodwin and Jamison, 1990; Cvjetkovic-Bosnjak, 1998), by being more often female (Goodwin and Jamison, 1990; CvjetkovicBosnjak, 1998), and by symptomatology characterized by agitation (Goodwin and Jamison, 1990; Cvjetkovic-Bosnjak, 1998), anxiety (Donnelly et al., 1978; Goodwin and Jamison, 1990; Cvjetkovic-Bosnjak, 1998), weight loss (Goodwin and Jamison, 1990), and higher risk for completed suicide (Lester, 1993). 1.2. Mood disorder subtype analyses Recently, many analyses have compared mood disorder subtypes, i.e. BP-I and BP-II, MDR, and MDSE. Some reports have suggested that BP-II disorder can be distinguished from both BP-I and major depressive disorder on the basis of prior course, characteristics of prior episode, familial history (Dunner et al., 1976; Endicott et al., 1985; Cassano et al., 1992; Heun and Maier, 1993; Coryell, 1996; Angst, 1998) and higher risk for suicide attempt for BP-II (Dunner et al., 1976; Goldring and Fieve, 1984; Goodwin and Jamison, 1990; Rihmer and Pestality, 1999). On the other hand, others consider BP-II similar to BP-I disorder for sex, although, females are more strongly represented in the BP-II group (Hendrick et al.,

A. Serretti et al. / Psychiatry Research 112 (2002) 195–210

2000); for age at onset (Angst, 1986; McMahon et al., 1994; Benazzi, 1999c; Hendrick et al., 2000); for high likelihood of psychomotor retardation during depressive phases (Dunner, 1983; Andreasen et al., 1988); for recurrence rate (Coryell et al., 1989; Hendrick et al., 2000); and for number of hospitalizations (Hendrick et al., 2000). Age of onset in BP-II was found intermediate between BP-I and MDR (Peselow et al., 1982). BP-II disorder has been differentiated from MDR by earlier age of onset (Goodwin and Jamison, 1990; Benazzi, 1997, 2001b; Allilaire et al., 2001); higher morbid risk in relatives for depression (Kupfer et al., 1988), bipolar disorder (Dunner et al., 1976), and mental disorders in general (Allilaire et al., 2001); greater incidence of past suicidal attempts (Dunner et al., 1976; Goldring and Fieve, 1984; Kupfer et al., 1988; Allilaire et al., 2001); greater frequency of psychomotor retardation (Kupfer et al., 1988), atypical features (Benazzi, 1997, 1999d,e,f, 2000, 2001b; Angst, 1998; Perugi et al., 1998) and number of recurrences (Benazzi, 2001b). Treatment response was reported to be similar between BP-II and MDR (Kupfer et al., 1988; Goodwin and Jamison, 1990), as well as personality disorder after recovery (Kupfer et al., 1988) and symptoms of anxiety and agitation (Goodwin and Jamison, 1990). Others found a higher prevalence of personality disorders in BPII (Akiskal et al., 1995; Allilaire et al., 2001). Recently, a French multicenter study (EPIDEP, Allilaire et al., 2001), comparing MDR and BP-II, detected an overrepresentation of ‘suicidal thoughts,’ ‘guilt feelings,’ ‘depersonalization– derealization,’ ‘hypersomnia,’ and ‘weight gain’ in BP-II, while MDR patients were marked by ‘psychic anxiety’ and ‘initial insomnia.’ That study also reported higher recurrence rates and more hospitalizations in BP-II than in MDR. Predictors of the shift from nonbipolar to BP-II disorder were found to be young age at intake and at onset and chronicity of the index episode (Akiskal et al., 1995; Coryell et al., 1995). MDSE patients compared with MDR patients had a later age of onset and a less represented family history for major depressive disorder (Bland et al., 1986). By contrast, a higher risk of recurrence was associated with an early age of onset, a

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positive family history for major depressive disorder (Bland et al., 1986; Merikangas et al., 1994), suicide attempts (Merikangas et al., 1994), comorbidity with anxiety disorders (Wilhelm et al., 1999), dysphoric mood or a higher number of symptoms (Merikangas et al., 1994; Lewinsohn et al., 1999), dysfunctional thinking, and major life stress (Lewinsohn et al., 1999). A study by Cassano et al. (1993) that evaluated MDSE disorder detected two profiles: the first characterized by early onset, more severe depression and greater potential for recurrence, and the second characterized by late onset, greater life stressors, and lesser likelihood of recurrence. Social function usually improves after recovery from an acute mood disorder episode (Goodwin and Jamison, 1990; Harrow et al., 1990; Maj et al., 1992; Judd et al., 2000), but many authors have described poor social inter-episode adjustment (Weissman et al., 1971, 1978; Paykel and Weissman, 1973; Weissman and Bothwell, 1976; Paykel et al., 1978; De Lisio et al., 1986; Pardoen et al., 1993; Serretti et al., 1999a). BP-I patients have poor adjustment in the areas of relationships with friends (Coryell et al., 1993) and marital role (Coryell et al., 1993; Serretti et al., 1999a), while MDR patients have impaired social interaction (Coryell et al., 1993). Finally, some authors reported that adjustment is worse in BP-I than in MDR patients (Harrow et al., 1990), but others failed to confirm this finding (Dorz et al., 2000). In an attempt to resolve some of the discrepancies in the literature, we have investigated demographic, clinical, symptomatologic, and social adjustment features in a large number of subjects affected by mood disorders, divided by subtypes. 2. Methods 2.1. Sample A total of 1832 patients affected by major depressive disorder (ns828) or bipolar disorder (ns1004), consecutively admitted to the Mood Disorder Center of the Department of Psychiatry at St. Raffaele Hospital, Milan, were included in the study. Two independent psychiatrists made lifetime diagnostic assessments on the basis of

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interviews and medical records according to DSMIII-R and DSM-IV criteria (American Psychiatric Association, 1987, 1994). Course of illness and life events were assessed by clinical interviews. Other information was gathered from the patient’s family and, wherever possible, from clinical records following a best estimate procedure (Leckman et al., 1982). The present sample includes subjects from clinical (Bellini et al., 1992; Benedetti et al., 1996a,b, 1999a,b; Gatti et al., 1996; Lattuada et al., 1999; Serretti et al., 1998b, 1999a,d; Zanardi et al., 1997, 1998, 2000a,b) and genetic studies (Serretti et al., 1998a,c, 1999b,e,f; Serretti and Smeraldi, 1999). The patients were included in the studies after they had given informed consent and after the local ethical committee had reviewed the procedure. The sample consisted of 1170 females and 662 males (63.9y36.1%), mainly inpatients (87.1%). Subjects are described in the tables (BP-Is863, BP-IIs141, MDRs708, MDSEs120). They were all Caucasians. The mean age at admission was 48.1""13.8 years. The mean age at onset was 32.9"12.4 years. 2.2. Ratings All patients were assessed with the following instruments: schedule for affective disorders and schizophrenia (Endicott and Spitzer, 1978), structured clinical interview for DSM-III-R, version 1.0 (Spitzer et al., 1990) andyor operational criteria for psychotic illness checklist (OPCRIT McGuffin et al., 1991) with a lifetime perspective (Farmer et al., 1994). The Hamilton rating scale for depression (HAMD-21 Hamilton, 1967) was administered at the index episode, before treatment, during depressive phases by trained psychiatrists. The HAMD items were then pooled into the following factors: Core (items 1, 2, 7, 8, 10, 13), Sleep (items 4, 5, 6), Activity (items 7, 8), Psychic anxiety (items 9, 10), Somatic anxiety (items 11, 12, 13), and Delusion (items 2, 15, 20) (Bellini et al., 1992; Bech et al., 1993; Lattuada et al., 1999; Serretti et al., 1998b, 1999c; Sobin and Sackeim, 1997). Factor analysis of the OPCRIT checklist has been previously reported (Cardno et al., 1996; Serretti et al., 1996). The factor com-

position is as follows: Excitement (items: Excessive activity, Reduced need for sleep, Pressured speech, Elevated mood, Thoughts racing, Increased sociability, Increased self-esteem, Irritable mood, Distractibility, Agitated activity, Dysphoria, Grandiose delusions, and Reckless activity), Depression (items: Loss of pleasure, Loss of energyytiredness, Diminished libido, Excessive self-reproach, Slowed activity, Poor appetite, Poor concentration, Suicidal ideation, Weight loss, Diurnal variation, Early morning awakening, and Delusions of guilt), Delusions (items: Persecutory delusions, Wellorganized delusions, Delusions of influence, Widespread delusions, Primary delusional perception, Delusions and hallucinations lasting for 1 week, Persecutoryyjealous delusions and hallucinations, Thought insertion, Thought withdrawal, Thought broadcast, and Third person auditory hallucinations), Disorganization (items: Speech difficult to understand, Incoherent, Positive formal thought disorder, Inappropriate affect, Bizarre behavior, and Bizarre delusions) and Negative symptoms (items: Blunted affect, Negative formal thought disorder, Restricted affect, and Catatonia). Factor scores were calculated as the sum of binarized items divided by the number of items in each factor. Melancholia was defined using the following OPCRIT items: Slowed activity, Diurnal variation, Excessive self-reproach, and Early morning awakening. The four items range from 0 to 1, such that the factor ‘melancholia’ therefore ranges from 0 to 4. Atypical features were defined using the following OPCRIT items: Excessive sleep and Weight gain. The two items range from 0 to 1, such that the factor ‘Atypical features’ therefore ranges from 0 to 4. Course of illness was assessed following the conceptualizations of remission, recovery, relapse and recurrence of Frank et al. (1991). Inter-episode functioning was evaluated after 3 months of remission from the index episode using the social adjustment scale (SAS, Weissman et al., 1971); a preliminary analysis of data for 185 subjects was previously reported (Serretti et al., 1999a). The current evaluation was performed in our outpatient clinic during regular follow-up. The SAS includes a total of 54 multiple-choice items, subdivided into the following seven sub-areas: (1) Work, (2)

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Spare time (social and leisure activities), (3) Extended family, (4) Marital role, (5) Parental role, (6) Family unit, and (7) Finance. Scores are inversely related to the levels of social adjustment (range 1–5 for sub-areas and 1–7 for total scores) and the scale is self-administered (Bauwens et al., 1991). The scale is routinely used for research purposes and has been validated in multiple samples (Weissman and Bothwell, 1976; Weissman et al., 1978). The subjects were selected from groups of patients enrolled in studies with different protocols; for this reason, information was not complete for the whole sample, as detailed information was collected only for some of the protocols here pooled (see Tables). In particular, we could retrieve only a small part of the item-by-item HAMD scores. Two hundred and forty-two subjects were collected in the context of the European Collaborative Project on Affective Disorders (Souery et al., 1998). Individuals with DSM-IV axis I comorbidity, mental retardation, dementia, substance abuseydependence, neurological disorder, or clinicalylaboratory indications of severe organic disease were excluded from all studies. An evaluation of personality disorders was performed in agreement with DSM-III-R or DSM-IV criteria on the basis of clinical interviews after remission from the acute phase. Differences were assessed by t-test (with pooled or separate variances). Analysis of covariance was used to include possible stratification biases. Frequencies were compared by x2 test. Alpha coefficients were conservatively considered significant when 0.0025 (Bonferroni-corrected).

resented in MDSE, while female patients predominated in the other diagnoses. BP-I patients had a higher mean level of education than MDR patients and, marginally, than BP-II patients. We observed a trend for BP-I patients not to be married compared with MDR patients. No differences emerged among the diagnostic subgroups with regard to positive family history of psychiatric disorder or medical status.

3. Results

3.3. Symptomatological features

3.1. Demographic features

BP-I patients showed a much higher lifetime incidence of psychotic symptoms, both delusions and hallucinations, than did the other subtypes. Patients with BP-II, MDR, and MDSE diagnoses showed similar rates of psychotic symptoms, ranging from 21.9% (BP-II) to 26.9% (MDR) (Tables 1 and 2). MDR patients showed higher depression scores than BP-I patients (Table 2). BP-I patients showed higher disorganization scores than MDR, BP-II, and MDSE patients. No differences were

In our sample, BP-I patients had the strongest representation, accounting for 47.1% of all major depressions. MDR patients accounted for 38.6%, BP-II patients for the 7.7%, and MDSE patients for 6.6%. MDR and BP-II patients were generally older than BP-I and MDSE patients. The ratio of females was decreasing from MDR, BP-II, BP-I to MDSE. In particular, gender was equally rep-

3.2. Clinical features BP-I patients had a lower age at onset and age at first lifetime psychiatric treatment than MDR and MDSE patients. These differences are independent from the presence of psychotic features. BP-II patients did not significantly differ from the remaining mood disorder types. We observed that MDSE patients had a higher incidence of life events at onset compared with BP-I subjects and, as a trend, BP-II and MDR patients, but no differences for post-partum onset. Subtypes did not differ for total duration of illness (MDSE was not included in this comparison). Both types of bipolar disorders showed a higher number of episodes compared with the MDR subtype. BP-I patients had been hospitalized more frequently than MDR and BP-II patients (MDSE was not included in this comparison). Comorbidity of personality disorders was not significantly different between subgroups. BP-II patients had more suicide attempts than MDSE and BP-I patients. No differences were found with regard to the violence of suicide attempts between mood disorder subtypes.

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Table 1 Demographic and clinical features BP-I

BP-II %

Sexa Female Male

517 346

59.9 40.1

Marital status (calculated for 1102 subjects)b Single Married Separatedydivorced Widowed

136 251 64 20

Psychotic features (calculated for 1411 subjects)c No Yes

%

No.

%

No.

%

89 52

63.1 36.9

504 204

71.2 28.8

60 60

50.0 50.0

28.9 53.3 13.6 4.2

38 78 9 8

28.6 58.6 6.8 6.0

83 240 43 26

21.2 61.2 11.0 6.6

25 72 7 2

23.6 67.9 6.6 1.9

231 383

37.6 62.4

107 30

78.1 21.9

395 145

73.1 26.9

93 27

77.3 22.7

Delusion (calculated for 1411 subjects)d No Yes

237 377

38.6 61.4

108 29

78.8 21.2

403 137

74.6 25.4

93 27

77.5 22.5

Hallucinations (calculated for 904 subjects)e No Yes

256 115

69.0 31.0

104 7

93.7 6.3

305 27

91.9 8.1

87 3

96.7 3.3

Personality disorder comorbidity (calculated for 865 subjects) (n.s.) No Yes

122 242

33.5 66.5

47 61

43.5 56.5

146 192

43.2 56.8

25 30

45.5 54.5

Life events at onset (calculated for 636 subjects)f No Yes Post-partum

84 115 36

35.7 49.0 15.3

33 46 7

38.4 53.5 8.1

56 137 41

23.9 58.6 17.5

14 60 7

17.3 74.1 8.6

Suicide attempt (calculated for 1166 subjects)g No Yes

366 123

74.8 25.2

82 54

60.3 39.7

315 114

73.4 26.6

88 24

78.6 21.4

74 40

64.9 35.1

37 14

72.5 27.5

67 35

65.7 34.3

17 7

70.8 29.2

136 67

67.0 33.0

39 41

48.7 51.3

115 83

58.1 41.9

33 20

62.3 37.7

Suicide violence (calculated for 291 subjects) (n.s.) No Yes Medical history other than psychiatric disease (calculated for 534 subjects) (n.s.) No Yes

No.

MDSE

A. Serretti et al. / Psychiatry Research 112 (2002) 195–210

No.

MDR

Table 1 (Continued) BP-I

Psychiatric family history (calculated for 1037 subjects) (n.s.) Negative Positive

BP-II %

No.

%

No.

%

No.

%

58 366

13.7 86.3

11 112

8.9 91.1

73 313

18.9 81.1

21 83

20.2 79.8

a

BP-II

MDR

MDSE

Mean

S.D.

Mean

S.D.

Mean

S.D.

Mean

S.D.

45.9 10.2 30.5 32.5 15.8 5.8 3.5 4.1

14.2 4.3 11.2 11.8 11.7 4.3 3.4 3.8

50.6 9.8 33.6 35.3 17.8 5.3 4.8 2.7

14.9 4.4 13.5 12.9 13.3 4.5 4.5 3.0

50.9 9.3 35.0 37.6 16.5 4.0 4.0 2.2

12.5 4.1 12.8 13.4 12.0 5.9 5.9 2.3

46.1 10.7 37.7 38.4 – 1.0 1.0 –

13.9 4.1 13.3 14.8 – 0.0 0.0 –

DMR have a higher female sex incidence than MDSE (x2s20.1; d.f.s1; Ps0.0001) and than BP-I (x2s21.5; d.f.s1; Ps0.0001). BP-I subjects show a trend to have a higher probability to be single instead of married than MDR (x2s7.4; d.f.s1; Ps0.0064). c BP-I have a higher incidence of history of psychotic symptoms than MDSE (x2s65.2; d.f.s1; Ps0.0001), BP-II (x2 s76.4; d.f.s1; Ps0.0001) and MDR (x2s150.0; d.f.s1; Ps0.0001). d BP-I subgroup has a higher risk of delusions than BP-II (x2s75.7; d.f.s1; Ps0.0001), MDSE (x2 s63.1; d.f.s1; Ps0.0001) and MDR (x2s155.3; d.f.s1; Ps0.0001). e BP-I have a higher risk of hallucinations than MDSE (x2 s38.8; d.f.s1; Ps0.0001), BP-II (x2 s33.8; d.f.s1; Ps0.0001) and MDR (x2s60.8; d.f.s1; Ps 0.0001). f MDSE has a higher incidence of life events at onset than BP-I (x2s13.6; d.f.s1; Ps0.0022) and BP-II (x2s9.6; d.f.s1; Ps0.0019). g BP-II have a higher risk of suicide attempt than MDSE (x2 s9.7; d.f.s1; Ps0.0018) and BP-I (x2 s10.6; d.f.s1; Ps0.0011) and a similar trend was observed towards MDR (x2s8.2; Ps0.0041). h MDR are older than BP-I (t-valuesy6.8; d.f.s1399; Ps0.0001) and MDSE (t-values3.8; d.f.s729; Ps0.0002). BP-II are older than BP-I (t-valuesy3.6; d.f.s729; Ps0.0004). i BP-I have higher education than MDR (t-values3.1; d.f.s840; Ps0.0024). MDSE show a trend to have higher education than MDR (t-values3.0; d.f.s490; Ps0.0027). j BP-I have lower age at onset than MDR (t-valuesy7.1; d.f.s1371; Ps0.0001) and DMSE (t-valuesy6.4; d.f.s890; Ps0.0001). k BP-I have a significantly lower age at first treatment onset than MDR (t-values5.6; d.f.s759; Ps0.0001), and MDSE (t-values4.1; d.f.s503; Ps0.0001). l Psn.s. m BP-I have a higher number of total episodes than MDR (t-values4.6; d.f.s503; Ps0.0001). n BP-II show a trend to have more depressive episodes than BP-I (t-values3.0; d.f.s429; Ps0.0026). o BP-I have a significantly higher number of hospitalizations than MDR (t-values7.9; d.f.s731; Ps0.0001) and BP-II (t-value 3.6; d.f.s506; Ps0.0004). b

A. Serretti et al. / Psychiatry Research 112 (2002) 195–210

Age (years) Education (years)i Age at onset (years)j Age at first lifetime treatment (years)k Total duration of illness (years)l Number of total episodesm Number of depressive episodesn Number of hospitalizationso

MDSE

No.

BP-I

h

MDR

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A. Serretti et al. / Psychiatry Research 112 (2002) 195–210

202 Table 2 OPCRIT factor scores OPCRIT scores

a

Excitement Delusionb Depressionc Disorganizationd Negative Melancholic featurese Atypical featuresf Lack of insightg

BP-I

BP-II

MDR

MDSE

Mean

S.D.

Mean

S.D.

Mean

S.D.

Mean

S.D.

0.72 0.19 0.72 0.20 0.09 3.75 0.51 0.46

0.3 0.2 0.3 0.2 0.2 1.5 0.9 0.5

0.63 0.07 0.82 0.08 0.05 3.96 0.49 0.21

0.3 0.1 0.1 0.1 0.1 1.4 1.0 0.4

0.10 0.08 0.82 0.07 0.06 4.10 0.24 0.24

0.2 0.2 0.1 0.1 0.2 1.3 0.7 0.4

0.06 0.06 0.84 0.05 0.03 4.43 0.02 0.20

0.1 0.2 0.1 0.1 0.1 0.9 0.1 0.4

Calculated for 885 subjects (BP-Is458; BP-IIs87; MDRs293; MDSEs47). a BP-I have higher excitement scores than MDR (t-values36.4; d.f.s749; Ps0.0001) and MDSE (t-values17.0; d.f.s503; Ps0.0001). BP-II have higher excitement scores than MDR (t-values23.1; d.f.s378; Ps0.0001) and MDSE (t-values14.6; d.f.s132; Ps0.0001). b BP-I have higher delusion scores than MDR (t-values8.2; d.f.s749; Ps0.0001), BP-II (t-values6.0; d.f.s543; Ps0.0001) and MDSE (t-values4.7; d.f.s503; Ps0.0001). c MDR have higher depression scores than BP-I (t-valuesy6.0; d.f.s749; Ps0.0001). BP-II have higher depression scores than BP-I (t-valuesy3.4; d.f.s543; Ps0.0008). MDSE show a similar trend towards BP (t-values3.0; d.f.s503; Ps0.0030). d BP-I have higher disorganization scores than MDR (t-values9.2; d.f.s749; Ps0.0001), BP-II (t-values4.9; d.f.s543; Ps 0.0001) and MDSE (t-values4.6; d.f.s503; Ps0.0001). e BP-I have fewer melancholic features than MDR (t-values3.2; d.f.s749; Ps0.0013) and they show a similar trend towards MDSE (t-values3.0; d.f.s503; Ps0.0027). f BP-I have more atypical features than MDR (t-values4.3; d.f.s749; Ps0.0001) and MDSE (t-values3.7; d.f.s503; Ps 0.0003. BP-II have more atypical symptoms than MDSE (t-values2.0; d.f.s132; Ps0.0009) and they show a similar trend towards MDR (t-values2.8; d.f.s378; Ps0.0056). g BP-I have more lack of insight than BP-II (t-values4.5; d.f.s543; Ps0.0001), MDR (t-values6.3; d.f.s749; Ps0.0001), and MDSE (t-values3.5; d.f.s503; Ps0.0004).

found among mood disorder subgroups for negative scores. MDR patients had more melancholic features than BP-I patients, while atypical symptoms decreased from BP-I to MDSE through BPII and MDR. Finally, BP-I patients had significantly lower scores on illness perception than did patients in the other diagnostic categories. Covariance for sex and onset did not significantly affect the results. 3.4. HAMD scores No significant difference was found for baseline HAMD factor scores between mood disorder subsamples, but some trends were observed. BP-II patients showed less early insomnia than BP-I and MDR patients. Retardation was markedly lower in MDSE patients. Paranoid symptoms were more frequent in BP-I than in BP-II and MDSE subgroups. Finally, BP-I patients had higher scores for

the Activity factor than MDSE patients. Covariance for sex and onset did not significantly affect the results (Table 3). 3.5. SAS scores No significant difference was found for interepisode social adjustment among the mood subtypes, although BP-I patients tended to have worse adjustment in the areas of work and family (Table 4). Covariance for sex and onset did not significantly affect the results. 4. Discussion The aim of this study was to investigate differences and similarities in demographics, clinical, symptomatology, and social features among mood disorder subtypes in a large, selected sample of mood disorder patients studied in a specialized

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203

Table 3 HAMD scores HAMD scores

(1) Depressed mood (n.s) (2) Guilt (n.s) (3) Suicide (n.s) (4) Early insomniaa (5) Middle insomnia (n.s) (6) Late insomnia (n.s) (7) Work and interests (n.s) (8) Retardationb (9) Agitation (n.s) (10) Anxiety psychic (n.s) (11) Anxiety somatic (n.s) (12) Gastrointestinal (n.s) (13) Fatigue (n.s) (14) Genital symptoms (n.s) (15) Hypochondriasis (n.s) (16) Weight loss (n.s) (17) Insight (n.s) (18) Diurnal variation (n.s) (19) Derealization (n.s) (20) Paranoid symptomsc (21) Obsessional symptoms (n.s) Core (n.s) C-core (n.s) Insomnia (n.s) Activityd Psychic anxiety (n.s) Somatic anxiety (n.s) Delusion (n.s) HAMD total (n.s)

BP-I

BP-II

MDR

MDSE

Mean

S.D.

Mean

S.D.

Mean

S.D.

Mean

S.D.

3.6 2.3 1.3 1.5 1.3 1.6 3.8 1.4 1.2 2.4 1.6 1.0 1.3 1.5 0.8 0.5 0.5 0.7 0.3 1.4 0.2 14.7 7.2 4.4 5.2 3.5 4.0 4.4 30.0

0.6 1.1 1.0 0.5 0.6 0.6 0.5 1.1 1.0 1.1 0.9 0.6 0.6 0.6 1.2 0.6 0.6 0.8 0.7 1.4 0.5 2.8 1.9 1.4 1.3 1.9 1.4 2.3 6.2

3.5 1.8 1.5 1.1 1.3 1.6 3.5 1.4 1.1 1.7 1.5 1.0 1.2 1.4 1.2 0.9 0.6 0.7 0.2 0.4 0.3 13.1 6.8 4.0 4.9 2.8 3.7 3.4 27.9

0.7 0.9 1.1 0.6 0.7 0.5 0.7 0.5 0.9 1.1 0.7 0.0 0.4 0.7 1.0 0.6 0.7 0.5 0.6 1.0 0.7 2.4 2.0 1.4 1.0 1.8 0.8 1.3 4.2

3.5 2.2 1.3 1.6 1.5 1.6 3.5 1.2 1.3 2.2 1.5 1.2 1.4 1.6 0.8 0.6 0.6 0.6 0.2 1.0 0.2 14.0 7.0 4.6 4.8 3.5 4.1 4.0 29.4

0.7 1.0 0.9 0.6 0.6 0.7 0.8 0.9 1.2 1.2 0.9 0.6 0.5 0.6 1.2 0.8 0.7 0.6 0.6 1.4 0.4 2.9 1.6 1.5 1.3 2.2 1.4 2.3 6.7

3.7 1.9 1.3 1.4 1.5 1.2 3.8 0.4 0.8 1.9 1.9 1.1 1.4 1.4 1.2 0.6 0.6 0.5 0.1 0.4 0.0 13.1 6.9 4.1 4.2 2.7 4.4 3.5 27.1

0.5 1.0 1.0 0.7 0.7 0.6 0.4 0.5 0.6 1.0 0.7 0.3 0.5 0.5 1.5 0.5 0.7 0.5 0.3 1.0 0.0 1.7 1.8 1.1 0.6 1.4 0.8 2.7 4.2

Calculated for 167 subjects (BP-Is76, BP-IIs10, MDRs71, MDSEs10). a BP-II show a trend to have lower scores for early insomnia than BP-I (t-values2.4; d.f.s84; Ps0.0183) and MDR (t-values 2.3; d.f.s79; Ps0.0242). b MDSE have lower scores for retardation than BP-II (t-values4.3; d.f.s18; Ps0.0004), and similar trends toward BP-I (tvalues2.9; d.f.s84; Ps0.0050) and MDR (t-values2.8; d.f.s79; Ps0.0061). c BP-I show a trend to have higher scores for paranoid symptoms than BP-II (t-values2.1; d.f.s84; Ps0.0364) and MDSE (tvalues2.1; d.f.s84; Ps0.0364). d BP-I show a trend to have higher scores for activity than MDSE (t-values2.3; d.f.s84; Ps0.0209).

center. Bipolar disorders were strongly represented (55%) in the sample. This finding support previous observations of a high prevalence of bipolar disorders among depressed patients (Angst et al., 1978; Angst, 1995, 1998; Akiskal et al., 2000; Benazzi, 2001a). Nevertheless, the lower prevalence of BP-II disorder relative to BP-I disorder could reflect the tertiary care setting in which the study was performed and, consequently, the severity of illness.

Overall, our data support previous findings of a decreasing level of severity from BP-I to MDSE through BP-II and MDR subgroups. In detail, MDR were older (Cvjetkovic-Bosnjak, 1998; Goodwin and Jamison, 1990) and more likely to be female than bipolar patients, who showed instead a more balanced proportion of men and women (Winokur and Crowe, 1983; Goodwin and Jamison, 1990; Rouillon, 1997; CvjetkovicBosnjak, 1998; Hendrick et al., 2000). We only

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204

Table 4 SAS scores for major depressive and bipolar disorders BP-I

BP-II

MDR

MDSE

No of subjects

Mean

S.D.

Mean

S.D.

Mean

S.D.

Mean

S.D.

Total SAS score (n.s)

2.0

0.6

2.2

0.5

1.9

0.5

1.7

0.6

302

SAS sub-areas Worka Spare time (n.s) Familyb Children (n.s) Family unit (n.s) Finance (n.s)

2.0 2.7 2.2 1.5 1.7 1.7

1.1 0.9 0.8 0.5 0.8 0.9

2.2 2.4 2.2 1.5 1.9 1.7

1.2 0.8 0.4 0.9 1.3 1.1

1.6 2.8 1.9 1.6 1.5 1.6

0.7 0.9 0.8 0.6 0.6 0.8

1.2 2.4 1.5 1.5 1.8 1.5

0.2 1.2 0.4 0.7 1.2 0.7

225 299 302 124 195 263

Calculated for 305 subjects (BP-Is163; BP-IIs15; MDRs124; MDSEs3). a BP-I show a trend to have higher scores for work than MDR (t-values2.9; d.f.s215; Ps0.0042). In the non-psychotic subgroup, BP-II have higher scores than MDR (t-values2.2; d.f.s70; Ps0.0310). b BP-I show a trend to have higher scores for family than MDR (t-values3.0; d.f.s144; Ps0.0032).

found a trend for BP-I patients to be more likely single than married (Rouillon, 1997). In accord with previous findings, BP-I patients had an earlier age at onset (Peselow et al., 1982; Goodwin and Jamison, 1990; Winokur et al., 1993; McMahon et al., 1994; Angst and Preisig, 1995; Rouillon, 1997). On the other hand, unlike previous investigators (Angst, 1986; McMahon et al., 1994; Benazzi, 1997, 1999c, 2001b; Hendrick et al., 2000; Allilaire et al., 2001), we observed that BPII patients had a marginally higher (NS) age at onset than BP-I patients, instead of a similar age at onset. Age at onset in BP-II patients was intermediate between than in MDR and BP-I patients (Peselow et al., 1982), but we could not support the difference between BP-II and MDR patients (Goodwin and Jamison, 1990; Benazzi, 1997, 2001b; Allilaire et al., 2001). Further, we could not replicate findings of a similar number of hospitalizations in BP-I and BP-II patients (Hendrick et al., 2000) and more hospitalizations in BP-II than MDR patients (Allilaire et al., 2001). In our sample BP-I patients had more hospitalizations than both MDR and BP-II patients, and MDR and BP-II patients were hospitalized a similar number of times. We did not observe an earlier age of onset in MDR patients compared with MDSE patients (Bland et al., 1986; Cassano et al., 1993; Merikangas et al., 1994), and we did not find a worse medical status in major depressive

patients than in bipolar patients (Winokur et al., 1993). However, we only considered the health condition at assessment, not during the lifetime. In agreement with previous reports, BP-I patients showed a higher number of total episodes than in the subgroups (Goodwin and Jamison, 1990; Winokur et al., 1993; Angst and Preisig, 1995). BP-I patients have been reported to have more precipitants of illness and more post-partum episodes (Goodwin and Jamison, 1990), but we could not replicate those findings. We were unable to investigate the greater impact of life stressors in MDSE compared with MDR patients (Cassano et al., 1993; Lewinsohn et al., 1999), but in our sample MDSE patients had the highest rate of life events at onset—a difference that was statistically significant only with regard to the BP-I subgroup. We also could not confirm a higher prevalence of personality disorders in BP-II patients (Kupfer et al., 1988; Akiskal et al., 1995; Allilaire et al., 2001), but this could be due to the lack of a uniform standardized assessment. We found a higher suicide risk for BP-II disorder than for BPI disorder (Dunner et al., 1976; Goldring and Fieve, 1984; Goodwin and Jamison, 1990; Rihmer and Pestality, 1999) and, as a trend, major depression (Dunner et al., 1976; Goldring and Fieve, 1984; Kupfer et al., 1988; Allilaire et al., 2001), though some studies reported an overall greater risk of suicide attempts in bipolar disorders (Good-

A. Serretti et al. / Psychiatry Research 112 (2002) 195–210

win and Jamison, 1990). BP-I and BP-II patients showed a more severe level of retardation than MDSE patients, and this finding is in accordance with a number of previous reports (Dunner, 1983; Andreasen et al., 1988; Bourgeois et al., 1988; Kupfer et al., 1988). On the other hand, we could not replicate the finding of a higher level of agitation, alternatively attributed to bipolar (Mitchell et al., 1992) and to major depressive patients (Cvjetkovic-Bosnjak, 1998; Goodwin and Jamison, 1990). There is agreement about a greater incidence of psychotic features in bipolar disorder (Akiskal et al., 1983; Weissman et al., 1984), and we did indeed find a more severe degree of delusional symptomatology and a greater incidence of both delusions and hallucinations in BP-I patients compared with major depressive and BPII patients. According to previous studies (Bourgeois et al., 1988; Benazzi, 1997, 1999a,e,f, 2000; Perugi et al., 1998), bipolar disorders showed a higher rate of atypical symptoms. We could not replicate the results of a higher representation of ‘suicidal thoughts,’ ‘guilt feelings’ and ‘depersonalization’ in BP-II patients in contrast to a higher representation of ‘psychic anxiety’ in MDR patients (Allilaire et al., 2001). We did, however, find trends for a higher incidence of atypical features in BPII patients (Benazzi, 1997, 1999a,e, 2001b; Perugi et al., 1998; Allilaire et al., 2001) and more frequent early insomnia in MDR patients (Allilaire et al., 2001). In disagreement with studies reporting differences for family psychiatric history among mood disorder subtypes (Johnson and Hunt, 1979; Endicott et al., 1985; Bland et al., 1986; Bourgeois et al., 1988; Cassano et al., 1992, 1993; Heun and Maier, 1993; Winokur et al., 1993, 1995b; Merikangas et al., 1994; Maier et al., 1995; Coryell, 1996; Cvjetkovic-Bosnjak, 1998; Allilaire et al., 2001), we found similar rates among the subtypes. However, in our sample the rates for positive family history were very high, and this fact reflects the selection criteria for genetic studies, where the presence of multiple affected subjects in the pedigree is required. Inter-episode levels of social adjustment have at times been described as equal (Goodwin and Jamison, 1990; Harrow et al., 1990; Judd et al.,

205

2000; Maj et al., 1992) or worse than control levels (Weissman et al., 1971; Paykel and Weissman, 1973; Weissman and Bothwell, 1976; Paykel et al., 1978; Weissman et al., 1978; De Lisio et al., 1986; Serretti et al., 1999a) in mood disorders, and also described as equal (Dorz et al., 2000) or differing between bipolar and major depressive patients (Harrow et al., 1990; Coryell et al., 1993; Serretti et al., 1999a). The addition of 116 subjects to our previous study on social adjustment (Serretti et al., 1999a) in the present study confirmed that BP-I patients have a marginally worse social adjustment, in particular in the areas of family and work. A major limitation of our study is its retrospective approach, a factor that could bias data collection toward decreased detection of past episodes and unreliable estimates of clinical variables (Keller et al., 1987). To limit this bias, we used a set of strategies: information about the illness was collected by an experienced psychiatrist who interviewed subjects, family members, and previous health professionals and obtained records when possible (Leckman et al., 1982); a second experienced psychiatrist reviewed the chart, and unreliability was assessed and considered an exclusion criteria (Shapira et al., 1996). A further limitation is linked to the inclusion criteria: this sample was intentionally selected to exclude rapid cycling and comorbidity with substance or alcohol abuse and anxiety disorders. The inclusion of subjects from different trials did not allow us to obtain complete data for all of them. Moreover, subjects were mainly inpatients (87.1%). Selection factors decreased the sample size and detracted from the sample’s representativeness for the general population of depressed patients. In fact, our center is a tertiary care setting, and therefore we cannot exclude a potential bias associated with severity of illness as revealed by the high proportion of delusional and bipolar subjects, and the high mean HAMD score. We derived melancholic features and atypicality from OPCRIT scores, limiting comparability with other reported measures. Inclusion criteria varied across studies, and previous treatments were not uniformly assessed, which should be considered as another possible bias. In fact it has been reported that only

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a sub-sample of individuals with major depression receive psychiatric treatment for depression (Hirschfeld et al., 1997), and patients may only seek treatment for the most persistent or most severe of their episodes—characteristics that most probably apply to the patients included in our study. Overall our findings support the view that BP-I disorder is different from the remaining subtypes, while BP-II disorder is close to major depressive disorders. Many differences emerged between BPI and BP-II disorders compared with those pointed out between major depressive disorders and BP-II disorder. BP-I and BP-II patients differed for age; number of depressive episodes; number of hospitalizations; suicide attempts; psychotic, depressive, and disorganization symptomatology; and illness perception. Differences between major depressive disorders and BP-II disorder were fewer and principally concerned atypical symptomatology. Finally, MDSE showed a less severe level of symptomatology overall. Our results are relevant to both the clinician and the researcher. In clinical terms, we demonstrated how the same disorder may differ significantly for a number of clinical variables, a finding that is of importance for targeted therapies. The identification of subpopulations of subjects defined by homogeneous features may be key in genetic research or pharmacological studies where homogeneity is crucial (Cloninger, 1994; Risch and Botstein, 1996). References ¨ Akiskal, H.S., Bourgeois, M.L., Angst, J., Post, R., Moller, H., Hirschfeld, R., 2000. Re-evaluating the prevalence of and diagnostic composition within the broad clinical spectrum of bipolar disorders. Journal of Affective Disorders 59, S5–S30. Akiskal, H.S., Maser, J.D., Zeller, P.J., Endicott, J., Coryell, W., Keller, M., Warshaw, M., Clayton, P., Goodwin, F., 1995. Switching from ‘unipolar’ to bipolar II. An 11-year prospective study of clinical and temperamental predictors in 559 patients. Archives of General Psychiatry 52, 114–123. Akiskal, H.S., Walker, P., Puzantian, V.R., King, D., Rosenthal, T.L., Dranon, M., 1983. Bipolar outcome in the course of depressive illness. Phenomenologic, familial, and pharmacologic predictors. Journal of Affective Disorders 5, 115–128.

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