Is unipolar mania a distinct subtype?

Comprehensive Psychiatry 48 (2007) 213 – 217 www.elsevier.com/locate/comppsych

Is unipolar mania a distinct subtype? Giulio Perugi

a,b,4

, M. Chiara Sanna Passinob, Cristina Tonib, Icro Maremmania,b, Jules Angstc a

Department of Psychiatry, University of Pisa, 56100 Pisa, Italy b Institute of Behavioral Sciences, Pisa, 56127 Pisa, Italy c Psychiatric University Hospital, CH-8029 Zurich, Switzerland

Abstract Background: Some recent reports raised the question whether unipolar mania, without severe or mild depression, really exists and whether it defines a distinct disorder. Literature on this topic is still scarce, although this was a matter of debate since several decades. Method: Eighty-seven inpatients with Diagnostic and Statistical Manual of Mental Disorder, Revised Third Edition, manic episode and at least 3 major affective episodes, in 10 years of illness duration, were systematically evaluated to collect demographic and clinical information. The symptomatological evaluation was conducted by means of the Comprehensive Psychopathological Rating Scale. Clinical features, social disability, first-degree family history, and temperaments were compared between unipolar and bipolar manics. Results: Nineteen (21.8%) of 87 patients presented a course of illness characterized by recurrent unipolar manic episodes without history of major or mild depression (MAN). When this group was compared with 68 (78.2%) manic patients with a previous history of depressive episodes (BIP), we found substantial similarities in most demographic, familial, and clinical characteristics. MAN group reported more congruent psychotic symptoms and more frequent chronic course of the current episode in comparison to BIP group. In the MAN patients, we also observed a high percentage of hyperthymic temperament and a complete absence of depressive temperament. This latter difference was statistically significant. MAN patients compared with BIP ones also reported lower severity scores in social, familial, and work disability, and they showed less depressive features, hostility, and anxiety. Conclusion: The numerous demographic, clinical, and psychopathological overlapping characteristics in unipolar and bipolar mania raise questions about the general nosographic utility of this categorization. Nonetheless, our data suggest a clinical and prognostic validity of keeping unipolar manic patients as a separate subgroup, in particular, as social adjustment and disability are concerned. D 2007 Elsevier Inc. All rights reserved.

1. Introduction Although unipolar mania is considered rare in clinical samples, the reported prevalence rates are ranging from 5% to 28% [1-15], probably depending on the criteria used for the definition of the disorder (number of episodes, length of follow-up, etc) and the prospective or retrospective design of the different studies. Several reports pointed out a considerable prevalence of unipolar mania in nonwestern countries such as China and Nigeria [5,7,10]. More recently, Aghanwa [12] found pure mania in 40 (47%) of 82 bipolar I patients in the Fiji Islands. A recent report [14] used stringent criteria and prospective observations. Patients diagnosed as having Research Diagnostic Criteria for mania at intake were prospectively

4 Corresponding author. Department of Psychiatry, University of Pisa, 56100 Pisa, Italy. Tel.: +39 50 835414; fax: +39 50 21581. E-mail address: [email protected] (G. Perugi). 0010-440X/$ – see front matter D 2007 Elsevier Inc. All rights reserved. doi:10.1016/j.comppsych.2007.01.004

followed for up to 20 years. Twenty-seven subjects had the diagnosis of unipolar mania at the time they entered the study; after 20 years of follow-up, still, 7 of these subjects did not suffer any episodes of major depression, supporting the diagnostic validity of unipolar mania. Reports concerning clinical and familial correlates of unipolar mania have been contradictory. Asberg et al [16] found among 156 manic-depressives 19 cases (12.2%) with unipolar mania and compared them with 138 bipolars and 139 unipolar depressives. In the first-degree relatives of unipolar manics, he found no depression but did find an elevated morbidity risk for bipolar disorder, suicide and schizophrenia, similar to that of bipolar probands (7.6% vs 10.2%, 5.7% vs 4.9%, and 3.3% vs 1.0%, respectively). Abrams and Taylor [6] observed pure mania in 14 (28%) of 50 manic-depressive cases and found significantly less affective illness and alcoholism among first-degree relatives of unipolar than in those of bipolar manics. In a replication study [1], they examined 77 manic patients, of whom 29 had

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never suffered from a depressive illness. These patients were similar to the 48 bipolar manics except for a striking excess of males and an increased risk for unipolar depression in first-degree relatives. Nurnberger et al [17] found that 38 (15.7%) of 241 bipolar I patients in their lithium clinic had never been hospitalized or treated for depression. They differed from the bipolar patients in lower rates of rapid cycling and suicide attempts. No differences were found in risk of illness in first-degree relatives. Pfohl et al [8], examining the chart reviews of 247 patients admitted to the University of Iowa with a history of at least one manic episode, noted that 87 had apparently never experienced a depressive episode. They compared them with a subgroup of 92 patients who had a history of affective disorder. There were no clinically meaningful differences between patients with unipolar mania and bipolar disorder on demographic, symptomatic, or familial variables. Shulman and Tohen [11] combined a retrospective chart review with a follow-up of 3 to 10 years (mean, 5.6 years) and identified 6 (12%) of 50 elderly manic patients as pure manics. Compared with the bipolars, the manic patients had an earlier age of onset and a longer duration of illness. The authors concluded that a firm diagnosis of unipolar mania should not be confirmed for at least 10 years. Recently, Yazici et al [13] reviewed the literature on unipolar mania and studied a clinical population of 272 bipolar patients. Patients with at least 4 manic episodes in 4 years of follow-up without any depressive episodes were classified as unipolar manics. They found these latter, who were 16% of the whole sample, to have more psychotic features than the remainder bipolar I patients and to be less responsive to lithium. Interestingly enough, there was no positive family history for suicide among pure manics. Angst et al [15] reported data on a large sample of patients (n = 406) with mood disorders hospitalized at some time during the period of 1959 to 1963 and followed up every 5 years until 1985. Major mood disorders were classified according to their hospitalization for depression (D) and/or mania (M); 30 manic patients (M/Md), 130 bipolar I (MD), 60 bipolar II patients (Dm), and 186 major depressive patients (D) were compared. The M/Md differed from the MD in several variables: better school achievement, milder course of the illness (fewer recurrences), significantly less suicidality, and a trend to less chronicity and more recovery. M/Md patients required less long-term medication than MD, and they differed in personality types from bipolars, the personality of M/Md patients being more often of the manic rather than the melancholic type. The family history data showed that the overall morbidity risk of first-degree relatives of M/Md patients was significantly lower than that of MD patients. In summary, attempting to support unipolar mania as a distinct entity from bipolar disorder has produced conflicting results. Some studies have initially reported very few differences from a clinical point of view; thus, unipolar mania has generally been accepted as a variant of bipolar

disorder [18]. However, recent studies individuated important clinical and familial characteristics. In particular, in at least 2 studies unipolar manics have shown a different course of illness [11,14,15], lower suicidality [13,15], better long-term functional adjustment [14,15], and less family load for depression [13,15] than do classic bipolars. To our knowledge, the symptomatological differences between unipolar and bipolar mania have never been investigated. In the present study, to define the clinical and nosographic utility of this categorization, we compared anamnestic and symptomatological characteristics, social disability, first-degree family history, and premorbid temperaments in 2 groups of manics with and without (unipolar) history of major or minor depressive episodes. 2. Patients and method From a sample of 155 consecutive inpatients with diagnosis of mania, according to Diagnostic and Statistical Manual of Mental Disorder, Revised Third Edition (DSMIII-R), criteria (American Psychiatric Association, 1987), seen at the Institute of Psychiatry at the University of Pisa, Italy, and affiliated clinical facilities over a 5-year period, we selected patients with at least 3 major affective episodes and 10 years of illness duration. The study population comprised 87 inpatients; 39 (44.8%) were males and 48 (55.8%) females. Their age at index evaluation ranged from 16 to 69 years. The patients came from a variety of sources, about equally divided between referrals from general practitioners and various medical specialists and psychiatrists. The sample was comprised entirely of primary mood disorders, which was obtained after excluding preexisting organic mental, psychoactive substance use, and schizoaffective and schizophrenic disorders. We also excluded patients with established neurologic diagnoses (eg, Parkinson’s disease, multiple sclerosis, brain tumor), as well as those with serious or disabling medical conditions. All patients participated voluntarily after informed consent was obtained, and the study was approved by the human subject committee of the University of Pisa. All patients were assessed by a third-year psychiatric resident with special training in mood disorders; they administered the Semistructured Interview for Mood Disorders (SIMD) [19]. This instrument, which systematically collects demographic, anamnestic, and clinical information, explores the presence of DSM-III-R criteria for major depressive episode and mania. An initial section is specifically addressed to the exclusion of preexisting organic mental, psychoactive substance use, and schizoaffective and schizophrenic disorders. History of previous hypomanic episodes, temperamental characteristics (hyperthymic or depressive) and first-degree family history for mood and specific anxiety disorders, schizophrenia, as well as for drug and alcohol abuse are also explored. All information is gathered from the patient and at least one close relative (usually parents, siblings); in addition, all

G. Perugi et al. / Comprehensive Psychiatry 48 (2007) 213–217 Table 1 Clinical features and first-degree family history in manic patients with unipolar mania vs bipolar disorder

Age, mean (SD) Age at onset, mean (SD) Age at first treatment, mean (SD) n, hospitalization, mean (SD) n, episodes mean (SD) Depression Mania Mixed Hypomania Total Age at first hospitalization, mean (SD) Psychotic features, n (%) Congruent Incongruent Stressors, n (%) Suicide attempts, current episode, n (%) Rapid cycling, n (%) Hyperthymic temperament, n (%) Depressive temperament, n (%) Chronic course ( N 2 y), n (%) Social disability, mean (SD) Family Social Work First-degree family history, Major depression Bipolar disorder Schizophrenia Alcohol abuse a b c d

Mann-Whitney, Z Mann-Whitney, Z Mann-Whitney, Z Mann-Whitney, Z

t or v 2 (df = 1)

MAN (n = 19)

BIP (n = 68)

43.5 (14.1) 28.2 (9.9) 28.4 (10.1)

44.4 (11.7) 25.5 (8.4) 27.3 (9.2)

0.3 1.2 0.4

ns ns ns

6.3 (5.3)

4.4 (4.5)

1.6

ns

–

P

5.9 0.9 0.2 7.0 29.8

(5.3) (2.2) (0.2) (7.1) (10.9)

2.4 4.3 1.5 1.3 9.5 30.6

(4.7) (4.4)a (1.6)b (3.1)c (7.2)d (13.3)

0.2

ns

17 17 10 7 0

(89.5) (89.5) (52.6) (10.1) (0.0)

47 39 31 8 1

(69.1) (57.4) (45.6) (9.3) (1.4)

3.1 6.7 0.3 0.3 .2

ns .005 ns ns ns

0 (0.0) 14 (73.7)

6 (8.8) 39 (57.4)

1.8 1.7

ns ns

0 (0.0)

14 (20.6)

4.7

.03

7 (36.8)

10 (14.7)

4.2

.04

2.6 3.0 2.8

.01 .004 .007

0.7 0.5 0.9 0.6

ns ns ns ns

3.37 (1.6) 3.42 (1.6) 4.26 (1.0) n (%) 4 (21.1) 5 (26.3) 1 (5.3) 1 (5.3)

4.17 (1.0) 4.34 (1.0) 4.90 (1.2) 17 13 1 6

(25.0) (19.1) (1.5) (8.8)

= 2.0, P = .04. = 2.0, P = .04. = 0.2, P = ns. = 1.94, P = .05.

available clinical records are carefully examined. Family history data are assessed by the method of the Research Diagnostic Criteria [20]. Inquiry on temperamental attributes is made about the habitual self of the patient—during periods free from affective episodes—from patient and significant others. Our operational criteria for depressive and hyperthymic temperaments represent the University of Tennessee [21] modification of the schneiderian descriptions [22]. Interrater reliability estimate of j = 0.837 (n = 20) was obtained with the investigators of the present study, indicating excellent reproducibility for temperamental evaluation. The SIMD has been used with more than 2000 patients at the time of writing: its reliability for diagnostic assessment of patients, and their temperaments has been documented elsewhere [23,24].

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To define the specific characteristics associated with unipolar mania, the subjects were divided into 2 groups, with (BIP) and without (MAN) history of major or minor depressive episodes. For the assessment of symptomatology, psychiatrists completed the Comprehensive Psychopathological Rating Scale [16] with the purpose of investigating the general psychopathologic characteristics. Eighteen signs and symptoms relevant to classic mania and to the mixed bipolar state were selected [25]; each feature was scored from 0 to 3. The 18 features entered in this comparative analysis were euphoria, irritability, pessimistic thought, suicidal thoughts or behavior, anxious worry, decreased sleep, increased sexual interest, persecutory delusions, grandiosity, other delusions, depressed mood, elated mood, hostility, pressured speech, racing thoughts, increased motor activity, agitation, and lack of insight. Because we were interested in qualitative differences between the symptomatological patterns of mania, we used these scales in a categorical fashion (presence N 1 or absence 0 of the item in question). Comparative analysis for familial, symptomatological, clinical, and course characteristics were conducted using the Student t test for the dimensional variables (Mann-Whitney when appropriated), and the v 2 analysis and the Fisher exact test for categorical characteristics. Given the low number of subjects with unipolar course and the exploratory nature of our study, we considered 2-tailed levels of significance with P b .05, without correction for multiple comparisons. This procedure increase the likelihood of type I error (some differences can be attributed by chance) but reduce the possibility of type II (some difference are not individuated). 3. Results Of the 87 manic patients of our sample, 19 (21.8%) presented unipolar recurrent manic episodes without history of major or mild depression. 3.1. Demographic data The mean index age is comparable in MAN patients and in BIP ones (43.5 F 14.1 vs 44.4 F 11.7, respectively, t = 0.3, P = ns). Males represent 36.8% (n = 7) of the first and 47.2% (n = 32) of the second group (v 21 = 0.6, P = ns). MAN and BIP patients were similar also as regard marital status (unmarried, 26.4% vs 30.9%; married, 52.6% vs 48.5%; separated/divorced, 15.8% vs 21.1%; and widowed, 5.3% vs 4.4%; v 23 = 0.2, P = ns), level of education (b 7 years of school, 31.5% vs 25.0%; high school, 52.6% vs 63.2%; university, 15.8% vs 11.8%; v 22 = 0.7, P = ns), and work activity (students, 5.3% vs 6.2%; unemployed, 5.3% vs 12.5%; housewife, 26.3% vs 20.3%; employed, 42.1% vs 40.6%; retired, 21.0% vs 20.3%; v 24 = 1.0, P = ns). 3.2. Clinical and course characteristics Mean age at onset of the mood disorder and mean age at first treatment are similar in the 2 groups, as well as the

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Table 2 Symptomatological features in manic patients with unipolar mania vs bipolar disorder

Euphoria Irritability Reduced sleep Increased sexual interest Elated mood Depressive mood Pessimistic thoughts Suicidal ideation Anxious worry Hostility Pressured speech Racing thoughts Increased motor activity Agitation Ideas of persecution Grandiosity Other delusions Lack of insight

MAN (n = 19)

BIP (n = 68)

v 2 (df = 1)

P

18 (94.7) 11 (57.9) 14 (77.8) 8 (42.1) 15 (78.9) 0 (0.0) 0 (0.0) 0 (0.0) 1 (5.3) 4 (21.1) 14 (73.7) 11 (57.9) 13 (68.4) 15 (78.9) 7 (36.8) 16 (84.2) 1 (5.3) 16 (84.2)

51 40 54 21 58 12 8 4 20 37 59 41 57 50 28 49 9 50

3.52 .01 .07 .84 0.44 3.89 2.46 2.18 4.73 6.63 1.88 0.01 2.24 0.23 0.55 0.98 0.93 0.91

ns (.06) ns ns ns ns .05 ns ns .03 .01 ns ns ns ns ns ns ns ns

(75.0) (58.2) (80.6) (30.4) (85.3) (17.7) (11.8) (5.9) (29.4) (54.4) (86.8) (60.3) (83.8) (73.5) (40.2) (73.1) (13.2) (76.5)

Finally, hostility is significantly more reported in BIP than in MAN (Table 2). 4. Discussion

number of hospitalizations, mean age at first hospitalization, mean length of current episode, and number of stressors. By definition, MAN patients have no depressive episodes; they also have more manic and less hypomanic episodes and lower total mean number of affective episodes than BIP (Table 1). Rapid cycling is absent in the MAN group, but because the frequency of rapid cyclicity is low in the entire sample, the difference with BIP is not statistically significant. The only statistically significant differences we observed between MAN and BIP concern the rates of patients with mood congruent psychotic features and chronic course of mania, which are significantly higher in the MAN group. Moreover, depressive temperament is absent in MAN, and it is more represented in BIP. Finally, it is noteworthy that lower levels of disability scores are recorded in MAN than in BIP, regarding either familial, social, or work adjustment. 3.3. Family history First-degree family history for major depression and bipolar disorder is present in a similar percentage in both groups. The same is true for family history for schizophrenia and alcohol abuse. 3.4. Symptomatology With regard to the symptomatological aspects investigated by means of 18 Comprehensive Psychopathological Rating Scale items, depressed mood and anxious worry were higher in BIP than in MAN patients. Other depressive features like pessimistic thoughts and suicidal ideation are reported only by BIP patients and are absent in MAN; anyhow, these differences are not statistically significant.

In our sample, the comparison of unipolar with bipolar mania reveals a large overlap in demographic and clinical characteristics. Sex distribution, age, age at onset, age of first treatment, and polarity of the first episode appear similar in the 2 groups. Although some authors [11] have reported a correlation between early age at onset and unipolar course of mania, our data are consistent with the findings of those who have not found such a relationship [1]. Moreover, unlike Nurnberger et al [17], we did not find any difference in morbidity risk for affective disorders in first-degree relatives. This finding is consistent with most literatures [13]. Despite these similarities, we observed in unipolar patients some characteristics that might be considered of clinical and prognostic interest: that is, absence of suicidal ideas or attempts, no premorbid depressive temperament, and no depressive features in the symptomatological scales. Unipolar manics also reported a higher percentage of chronic course and less severe work, and familial and social disability than bipolars. The first finding is consistent with Shulman and Tohen’s data [11] that showed in elderly population of bipolar patients that clinical course was significantly longer, whereas it is in contrast with the study of Angst et al [15] in which a trend to a lower rates of chronic outcomes and a higher rates of recovery in unipolar than in bipolar manics were reported. It is possible that, in our sample, the rate of chronicity is inflated by the selection criteria of patients with at least 3 major affective episodes and 10 years of illness duration. The second point is also supported by other studies that reported long-term average level of psychosocial functioning in unipolar manics from fair to very good [14] and a more benign course of the illness as far as last interval outcome and school achievement are concerned [15]. In our sample, lower disability in MAN patients might be partially a function of fewer total episodes. Consistently with other reports [13,15], our MAN patients showed a higher percentage of congruent, but not incongruent, psychotic features. The congruent-incongruent distinction is based on DSM-III-R criteria. Mood-incongruent psychotic features refer to delusions or hallucinations whose content does not involve typical manic themes. Included are such symptoms as persecutory delusions (not directly related to grandiose or depressive themes), thought insertion, and delusions of being controlled. The presence of incongruent psychotic features during manic episodes has been considered as a negative long-term prognostic factor. A negative relationship between psychotic symptoms, therapeutic response, and time spent in remission has been ascertained [26-28]. In particular, poor treatment outcome has been associated with presence of hallucinations [29], persecutory delusions [29-31], or formal thought disorder [28].

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Interestingly, besides psychotic features, unipolar manics show less depressive features, hostility, and anxiety compared with bipolars. This may be the result of mood instability, and/or it might reflect the pathoplastic effect of premorbid depressive temperament in some subjects of the bipolar group. As proposed by Akiskal [32] and subsequently confirmed by Italian [24,25,33] and French studies [34], polarity of temperament seems to fashion the phenomenology of manic and mixed states differentially. In the present study, hyperthymic temperament seems to underlie the most grandiose and chronic manic excitements, and, by contrast, the depressive temperament seems to be associated with a mixed manic-depressive phenomenology. High rates of hypomanic personality type and hyperthymia among unipolar manics have been also observed by Angst et al [15] and Yazici et al [13]. The main limitations of the study are that the retrospective nature of the diagnosis of unipolar mania and the possibility that future depressive episodes may occur. However, the validity of the diagnosis of unipolar mania is increased by the use of standardized instruments and interviews with significant others. The likelihood of a future depressive episode is actually impossible to exclude, although the relatively long illness duration, and high number of episodes in our sample my have some validity in reducing this possibility. In conclusion, numerous demographic, clinical, and psychopathological overlapping characteristics in unipolar and bipolar mania raise questions about the general nosographic validity of this categorization. Nonetheless, our data suggest some clinical and prognostic implication of keeping unipolar manic patients as a separate subgroup. Further research is needed to elucidate therapeutic options and disclose the view to possible genetic implications. References [1] Abrams R, Taylor MA, Hayman MA, Krishna NR. Unipolar mania revisited. J Affect Disord 1979;1(1):59 - 68. [2] Nurnberger Jr J, Roose SP, Dunner DL, Fieve RR. Unipolar mania: a distinct clinical entity? Am J Psychiatry 1979;136(11):1420 - 3. [3] Koehler K, Jacoby C. Acute confabulatory psychosis: a rare form of unipolar mania? Acta Psychiatr Scand 1978;57(5):415 - 25. [4] Shulman KI, Tohen M, Satlin A, Mallya G, Kalunian D. Mania compared with unipolar depression in old age. Am J Psychiatry 1992; 149(3):341 - 5. [5] Makanjuola RO. Recurrent unipolar manic disorder in the Yoruba Nigerian: further evidence. Br J Psychiatry 1985;147:434 - 7. [6] Abrams R, Taylor MA. Unipolar mania: a preliminary report. Arch Gen Psychiatry 1974;30(4):441 - 3. [7] Makanjuola RO. Manic disorder in Nigerians. Br J Psychiatry 1982; 141:459 - 63. [8] Pfohl B, Vasquez N, Nasrallah H. Unipolar vs bipolar mania: a review of 247 patients. Br J Psychiatry 1982;141:453 - 8. [9] Pfohl B, Vasquez N, Nasrallah H. The mathematical case against unipolar mania. J Psychiatr Res 1981;16(4):259 - 65. [10] Lee S, Yu H. Unipolar mania in non-Western cultures. Br J Psychiatry 1994;165(3):413. [11] Shulman KI, Tohen M. Unipolar mania reconsidered: evidence from an elderly cohort. Br J Psychiatry 1994;164(4):547 - 9.

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