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Axis I comorbidity in bipolar disorder with psychotic features. S Pini, L Dell'Osso, C Mastrocinque, G Marcacci, A Papasogli, S Vignoli, S Pallanti and G Cassano BJP 1999, 175:467-471. Access the most recent version at DOI: 10.1192/bjp.175.5.467 References Reprints/ permissions You can respond to this article at Downloaded from This article cites 0 articles, 0 of which you can access for free at: http://bjp.rcpsych.org/content/175/5/467#BIBL To obtain reprints or permission to reproduce material from this paper, please write to [email protected] http://bjp.rcpsych.org/cgi/eletter-submit/175/5/467 http://bjp.rcpsych.org/ on January 9, 2012 Published by The Royal College of Psychiatrists To subscribe to The British Journal of Psychiatry go to: http://bjp.rcpsych.org/site/subscriptions/ Axis I comorbidity in bipolar disorder with psychotic features STEFANO PINI, LlLlANA DELL'OSSO. CONCETTINA MASTROCINQUE, GlOVANNl MARCACCI, ALESSANDRA PAPASOGLI, SERENA VIGNOLI. STEFANO PALLANTI and GlOVANNl CASSANO Background Axis l comorbidities are prevalent among patients with severe bipolar disorder but the clinical and psychopathologicalimplications are not clear. Aims To investigate characteristics offour groups of patients categorisedas follows: substance abuse only (group I), substance abuse associated with other Axis I disorders (group 2), non-substanceabuse Axis I comorbidity (group 3), no psychiatric comorbidity (group 4). Method Consecutive patients with bipolar disorder with psychotic features (n=125) were assessed using the Structured Clinical Interview for DSM- Ill- R - patient version, and several psychopathological scales. Results By comparisonwith group 4, group I had a higher riskof having mood-incongruent delusions, group 2 had an earlier age at onset of mood disorder, a more frequent onset with a mixed state and a higher riskof suicide, and group 3 had more severe anxiety and a better awareness of illness. Conclusions Substance abuse, nonsubstance-abuseAxis I comorbidity and their reciprocal association are associated with different characteristicsof bipolar disorder. Declaration of interest This study was supported by funds from the Departmentof Psychiatry, University of Pisa. The prevalence of psychiatric comorbidity in bipolar disorder with psychotic features ranges from 13% to 73.4%, with substanceuse disorders being the most common condition, followed by anxiety and eating disorders (Black et al, 1988; Strakowsky et al, 1992; Kessler et al, 1997). Such comorbidities are associated with more severe psychotic features, longer stays in hospital, low recovery rates and earlier age at onset of mood disorder (Some et al, 1994; Brady & Some, 1995; Cassano et al, 1998; Scott et al, 1998; Strakowsky et al, 1998). However, the extent to which such clinical correlates were due to substance abuse andlor non-abuse Axis I comorbidity was not exhaustively clarified. In this study we investigated the clinical characteristics of psychotic bipolar disorder in patients categorised into four groups according to their patterns of comorbidity: substance abuse only (group I), substance abuse associated with other Axis I disorders (group 2), non-substance-abuse Axis I comorbidity (group 3), no psychiatric comorbidity (group 4). METHOD The method of this study and the characteristics of the Pisa Centre have been described in detail elsewhere (Cassano et al, 1998). Consecutively hospitalised patients with psychotic bipolar disorder (n=125) were recruited and included in this study on the basis of the following criteria: age over 16 years; presentation with psychotic symptoms (i.e. formal thought disorders, delusions, hallucinations, grossly disorganised behaviour); provision of informed written consent and approval from the local ethical committee. Patients were selected independently of previous stays in hospital and/or prior antipsychotic or mood-stabiser treatments and independently of having had single or multiple episodes of psychosis. Patients were excluded from the study if psychotic symptoms either were secondary to acute intoxication or withdrawal from alcohol or other substances or were presenting with concomitant severe medical conditions defined according to Black et a1 (1998) as any serious or acute life-threatening illness such as cancer, myocardial infarction, stroke, or hepatic insufficiency. The inclusion diagnosis of psychosis was made by three senior psychiatrists who were not directly involved in the study, on the basis of their clinical judgement and reading of patient records. Then, the Structured Clinical Interview for DSM-111-R - patient version (SCID-P; Spitzer et al, 1987) was administered in the week preceding the patient's discharge by three residents in psychiatry who had been trained in the use of the SCID-P. As recommended by Spitzer et a1 (1987), SCID-P interviewers were skilled clinical researchers with at least three years of clinical experience and with substantial familiarity with DSM-III-R criteria (American Psychiatric Association, 1987). In previous studies, psychiatric comorbidity has been defined as the presence of an antecedent or concurrent DSM-111-R Axis I diagnosis in addition to the principal diagnosis. Ten Axis I diagnoses were assessed in the present study (panic disorder, social phobia, simple phobia, obsessive-compulsive disorder, somatoform disorder, undifferentiated somatoform disorder, chronic pain disorder, hypochondria, anorexia and bulimia). Substance abuse (involvingstimulants, sedatives, opiates, hallucinogens, cocaine, cannabis, alcohol and multiple drugs) was also assessed by the SCID-P. In completing the SCID-P, information was obtained from any source available in addition to the patient interview, including medical records, first-degree relatives and treating clinicians. Age at onset was investigated by the SCID-P. Comorbid diagnoses were defined as antecedent if patients endorsed full syndrome criteria more than one year before the onset of bipolar disorder. Psychopathology was assessed using the 18-item version of the Brief Psychiatric Rating Scale (BPRS; Overall & Gorharn, 1962). Negative symptoms were assessed using the Scale for the Assessment of Negative Symptoms (SANS; Andreasen, 1983). The awareness of illness was evaluated by means of the Scale for the Unawareness of Mental Disorder (SUMD; Amador et al, 1993). In this scale, scores range from 1 to 5, with higher scores indicating poorer awareness of illness. Interrater reliability for the SCID-P, BPRS, SANS and SUMD was assessed in a small sample study (n=8) on the basis of joint records for both principal and comorbid diagnoses. Good reliability established from joint ratings was obtained for both principal and comorbid diagnoses (~=0.87 and ~=0.82, respectively). Socio-demographic characteristics As shown in Table 2, group 2 was significantly younger than group 4 (PcO.05). Males were significantly more represented among substance users, with or without other Axis I comorbidity, than those without any comorbidity (P c 0.05). Married patients were significantly more frequent in group 4 than in the other three groups (P< 0.05). Statistical analyses Analysis of variance (ANOVA) was performed on key demographic variables in order to determine whether there were any significant difkrences across groups. The ANOVA was then performed on psychopathological variables by group. Pairwise comparisons were performed on the psychopathological and clinical variables to determine which groups sigrhcantly differed from each other. All results at Pd0.05 were judged to be sigmficant. The overall error rate was also controlled for by making pairwise comparisons using the Tukey test of significant differences. Categorical variables were analysed by the 2 test. The age at onset of bipolar disorder in the four groups was assessed by means of survival analyses with the Wicoxon (Gehan) test (Gehan, 1997) for overall and painvise comparisons. Multiple logistic regression analysis was performed in order to estimate the strength of association between clinical variables and comorbidity after controlling for the principal psychotic diagnosis and socio-demographic variables. All analyses were performed using SPSS version 7.0 for Widows 95. Age at onset of bipolar disorder, substance abuse and Axis I comorbidities Mean age at onset of bipolar disorder was 22.8 Years 5.7) in group 1, 21.2 (s.d.=4.6) in group 2, 25.3 (s.d.=8.8) in group 3 and 26.1 (s.d.=7.7) in group 4. As shown in Fig. 1, pairwise comparisons from survival analysis showed that the mean age at onset of bipolar disorder was sigmficantly lower in group 2 than in group 4 (F=7.140, d.f.=l, P<0.01). Mean age at onset of substance abuse was 19.6 years (s.d.=S.S), with stimulant abuse being earliest (15.8 years, s.d.=2.9) and alcohol abuse the latest (22.9 years, s.d.=8.6), while mean age at onset of non-abuse Axis I comorbidity was 22.1 years (s.d.=9.5), with social phobia being earliest (8.5, s.d.=2.1) and generalised anxiety disorder the latest (31.4, s.d.=18.9) (see Table 1).The onset of substance abuse preceded that of mood disorder in 23 (74.9%) abusers. The onset of non-abuse Axis I comorbidity preceded the onset of psychotic disorder in 20 (44.4%) patients with Axis I comorbidity without substance abuse. Age at onset of mood disorder was significantly earlier in subjects with cannabis abuse than in those without (20.4, s.d.= 4.7 v. 25.6, s.d.=7.9; t=3.037, d.f.=123, P<0.01), but not in those with alcohol abuse (22.4, s.d.=5.2 v. 25.1, s.d.=8.0; t=1.408, d.f.=149, P<0.162). We also found a significant negative correlation between age at 0of bipolar disorder andcannabisabuse (Kenddl'srbtest=0.247, Pc0.01) and panic disorder (Kendall's rb test=-0.187, PcO.OS), but not with any of the other &s I diagnoses. Psychopathology As shown in Table 3, levels of patients' awareness of illness, of effects of medications and of social consequences of mental disorder showed differences between the four groups. Overall, group 3 had a better insight than both group 4 and group 1. There were no significant differences between the four groups on BPRS scores with the exception of the anxietyldepression T.ble I Frequency &Axis I comorbidity and age of onset in 125 consecutively hospitalid patients with bipdv disorder with psychic features DSM-III-R Axis I diagnosis Patients with bipolar disorder with psychotic features (n=lX) n (%) Mean age at onset (years)(s.d.) 3 (2.4) 17 (13.6) 4 (3.2) 4 (3.2) 7 (5.6) 3 (24) 5 (4.0) 4 (3.2) 23 (18.4) 5 (4.0) 4 (3.2) 16 (12.8) 3 (24) 19 (15.2) 125(100) 39 (31.2) 5 (4.0) 8.5 (2.1) I I .9 (3.7) 16.0 (2.7) 16.0 (2.5) 18.4 (3.2) 16.3 (9.5) 18.1 (3.1) 18.3 (0.5) 18.6 (3.4) 20.3 (5.5) 18.8 (2.4) 23.4 (9.9) 23.0 (7.1) 23.0 (7. I) 24.7 (7.6) 25.2 (9.1) 31.4 (18.9) RESULTS The total cohort of 125 bipolar patients was categorised into the four groups as follows: group 1 (patients with substance abuse disorder without any other axis I comorbidity) consisted of nine patients (7.2%), group 2 (substance abuse plus at least one other Axis I comorbid disorder) consisted of 22 patients (17.6%), group 3 (at least one non-abuse Axis I disorder) consisted of 45 patients (36.0%), and group 4 (neither substance abuse nor other Axis I comorbidities)consisted of 49 patients (39.2%). Frequencies and mean age of onset of comorbid diagnoses and of bipolar disorder are shown in Table 1. Overall, total rates of substance-abuse and non-abuse Axis I comorbidity were 24.8% (n=31) and 36.0% (n=45), respectively. Simple phobia Social phobia Multiple drug abuse Stimulants abuse Cocaine use Anorexia Hallucinogens use Opiate use Cannabis use Bulimia Sedative abuse Obreuive-compulsivedisorder Somatofonn disorders Alcohol abuse Bipolar disorder Panic disorder Generalised anxiety disorder AXIS I COMORBIDITY IN B I P O L A R Tabla 2 Sdi-demographic a d clinical chuacterirtkr of 125 DISORDER hospitalid patieno with bipdv disorder with psychotic features - - -- - - - - -- -- - - Substance rburc/no Substance abuse plus Axis l comorbidkyl N o Axis l or rubstance ANOVA (Tukey pairwise Axis Icornorbidiiy Axis Icomorbidky no substance abuse abuse comorbidky (n=9) (n=22) (n=45) (n=49) 34.4 (s.d. 14.0) 30.6 (s.d. 7.3) 35.4 (s.d. 1 1.7) 39.2(s.d. 12.3) 10.7 (s.d. 3.6) 10.6 (s.d. 3.8) I1.6 (rd. 3.5) 9.9 (rd. 4.1) NS 5 (55.6%) I5 (68.2%) 20 (4.4%) 16 (32.7%) xL8.21 I.P<0.05 0 (0%) 4 (4.4%) 2 (9.1 %) 12 (54.5%) I0 (22.2%) 19 (38.8%) ~'=11.171. P<O.M 23 (51.1%) 14 (28.6%) NS DSM-III-R global functioning 33.7 (s.d. 15.8) 30.4 (s.d. 12.5) 28.9 (s.d. 1 1.4) 34.1 (s.d. 12.9) NS Length of last stay in hospiial (days) 47.1 (s.d. 25.8) 33.1 (s.d. 25.5) 29.2 (s.d. 19.0) 29.7 (rd. 23.0) NS 2.8 (s.d. 1.6) 3.3 (s.d. 1.6) 2.4 (s.d. 1.5) 2.9 (s.d. 1.6) NS Characteristic Mean age Educational level (years of school) Gendcc male (n(%)) Married UflemploYed (n(%)) Total number d stays in hospital subscale, which scored significantly higher in group 3 than in group 4 (2.74, s.d.=1.22 v. 2.02, s.d.=1.02; F=3.804, P<0.02). Among the 18 BPRS items, only 'depressed mood' (F=1.795, d.f.=3,124, P<O.OS) scored higher in group 3 than in group 1. As to the SANS, only the sub-scale anhedonialasociality was significantly more severe in group 3 than in group 4 (10.11, s.d.=5.99 v. 5.48, s.d.=7.59; F=4.178, d.f.=3,124, P<0.01). comparisons) F=4.323, P<O.OI (2<4) 1.2 7 1.O - - 0.8 - '5 - a Q .z - 0.6 3 Results of logistic regression analyses The association of each of the four comorbidity groups with a series of clinical variables was analysed by composite logistic regression models. Delusions and hallucinations, formal thought disturbances, affective flattening, polarity of first affective episode, suicide attempts, and good insight were used as dependent variables. Group, gender, age and principal diagnosis of bipolar disorder were used as independent variables. A. shown in 4' mood-incongruent delusions were significantly associated with group 1, an onset with a mixed episode and a history of previous suicide attempts with group 2. An onset with a manic episode was negatively and good awareness of illness positively associated with group 3. DISCUSSION This study aimed to investigate clinical characteristics associated with substance abuse and non-abuse Axis I comorbidity in a cohort of patients with bipolar disorder with psychotic features. Overall, 60.8% of our patients had at least one Axis I comorbid disorder. Our centre specialises in the S o 0.4 - 0.2 - 0.0 gmup 4 ( n = 49) - - - group3(n=45) -group 2 ( n = 22) ..... group 1 ( n = 9) , I I -10 0 10 I I 20 30 i 40 50 60 Age at onset of bipolar disorder Fig. I Comparison dwrvival experience using theWlc-n 2<group 4; Wikomn=7.I4OOd.f.=l. P<0.01). treatment of mood and aruciety disorders; addicted patients are usually referred to other centres. This might have contributed to an under-representation of substance abuse; our figures probably do not reflect a true prevalence among bipolar patients. However, consistent with previous studies (Strakowsky et al, 1992; Kessler et al, 1997), our results indicate that a substantial propomon of subjects with psychotic bipolar disorder were complicated by additional Axis I conditions. (Gehan) statistic (pairwise comparison: group Substance abuse without other Axis I comorbidity (group I) In group 1, onset of substance abuse preceded onset of affective illness in the majority (64%)of cases. Logistic regression analysis showed that this group had a higher risk of having mood-incongruent delusions than the rest of the subjects. The reason for this last association not being found in group 2 is difficult to define. It is possible that these abusers, who were also W e 3 Results of analysis of variance' for the Sale for the Unawareness of Mental Disorder (awareness of illness): six general items scores in 125 consecutively hosplralised patients with bipolar disorder with psychotic features Substance abuselno Substance abuse plus Axis l comorbidity/ No Axis Ior substance Axis Icomorbidity Axis Icornorbidity no substance abuse abuse cornorbidity ANOVA (Tukey paimise (n=9) (mean (s.d.)) (n=22) (mean (s.d.)) (n=45) (mean (s.d.)) (n=49) (mean (s.d.)) comparisons) Current episode 2.67 (1.73) 2.95 (1.68) 2.80 (1.44) 3.38 (1.44) NS Past episcde 3.43 (1.51) 3.m (1.84) 3.13 (1.41) 3.82 (148) F=2.360, P c 0.05 (3 <4) Current episode 3.33 (1.41) 2.86 (1.55) 2.58 (1.47) 3.16(1.45) NS Past episode 3.43 (0.98) 3.39 (1.61) 2.78 (1.49) 3.69 (1.34) F=2.791. P c 0.05 (3 c 4 ) Current episode 3.43 (1.81) 2.91 (1.69) 2.81 (1.56) 3.47 (1.47) NS - 3.40 (1.52) 3.39 (1.65) 3.05 (1.47) 3.92 (1.38) F=2.226, P < 0.05 (3 <4) Awareness of illness Awarenest of treatment efficacy Awarmes of social consequencesof Past episode I. Pon hocTukcyitests am significant a t the P ~ 0 . 0 5bvel. 1 .4 Results of logistic regressionanalyses for the association of groups ofcomorMdiy with fm features Dependent variable Independent variables' (odds ratio (95%confidence interval)) Substance abuse/ Substance abuse Axis Icomorbidiiy/ no Axis I plus Axis I cornorbidity comorbidity - 2.41 (1.03-8.29) - - 0.34 (O.IC0.81) No Axis l or no substance abuse substance abuse mmorbidity delusions Onset with a mixed episode Onset with a manic episode Suicide attempts Goad insight in group 1also suggests that non-abuse Axis I comorbidity may play an important role in anticipating the onset of psychosis. 6.75 (1.36-33.41) - - 2.98 (1.32-6.42) - I. Gender, age and dbgnorir of bipolar disorder were also induded in the m o d s as independentvariables. found to have low levels of insight, represent a subgroup of subjects with a greater likelihood of having a bipolar disorder with schizophrenia-like features than other subgroups. However, larger samples are needed to support such a hypothesis empirically. Substance abuse plus other Axis I comorbidity (group 2) The co-occurrence of substance abuse and other Axis I diagnoses was associated with a younger patient, an earlier age at onset of bipolar disorder, an onset of illness with a mixed manic episode, and a greater risk of suicide attempts. Although this group had a lower risk of having mood-incongruent delusions than the group with substance abuse only, it showed a greater morbidity in terms of course of illness and life-threatening risk. The role of cannabis use in anticipating the onset of psychotic illness appeared to be more pronounced than that of alcohol abuse. This finding is consistent with a recent study by Brook et a1 (1998), which reports a sigtllficant relationship between earlier adolescent drug use and later depressive and disruptive disorders in young adulthood, controlling for earlier psychiatric disorders. Strakowsky et a1 (1996) found that patients with bipolar disorder and antecedent alcohol abuse had a later onset of affective illness, arguing that perhaps this represented a subgroup of patients in whom previous alcohol abuse was only necessary to precipitate an affective episode. Furthermore, given the remarkably earlier age at onset of cannabis abuse than of bipolar illness or alcohol abuse, our data give support to the hypotheses that soft-drug abuse is likely to anticipate the onset of psychosis, while alcohol is more likely to complicate it. However, the fact that the onset of mood disorder was earlier in group 2 than Non-abuse Axis I comorbidity (group 3) By comparison with the group without comorbidity, the group with non-abuse Axis I comorbidity had higher levels of anxiety and depression, more anhedonid asociality and a greater likelihood of having an onset of illness with a mixed or depressive affective episode. Overall, the onset of Axis I comorbidity preceded that of bipolar disorder in 43% of cases. This group appeared to have fewer psychotic symptoms and a lower risk of serious suicide attempts than the other groups. These features, and the more negative selfexperience of psychopathology - reflected by a better insight of illness and a higher level of anxiety - that characterisesthese patients, suggest that the boundaries between psychosis and neurosis are likely to be less marked in this cluster than in the others. These findings seem to support the hypothesis of Black et a1 (1988) that manic patients with non-abuse comorbidity resemble in many respects the 'neurotic' secondary depression described by Wiokur et al (1988). Limitations It is important to acknowledge several limitations of this study. We investigated only hospitalised patients, limiting the applicability of these results in relation to patients with bipolar disorder in general. Rates of lifetime substance abuse and Axis I comorbidity, as well as of psychopathology AXIS I C O M O R B I D I T Y I N BIPOLAR D I S O R D E R by patients' or relatives' recall bias. Analyses were performed independently of whether bipolar patients had prevalently manic or depressive episodes. The small size of the cohort examined did not allow us to investigate the effect of each single comorbid Axis I disorder on psychotic phenomenology. Implications and futura directions Our results support the importance of dacctlng specific patterns of comorbidity in patients with severe bipolar disorder (Cassano et al, 1998, 1999; Schatzberg, 1998). Either substance abuse or non-abuse Axis I comorbidity may have an impact on phenomenology of bipolar disorder. These associations in their various forms should be investigated further because of potential implications on age of onset of affective illness and risk of suicide. C l d c a t i o n of the relationships between bipolar disorder and other Axis I conditions, which are traditionally situated at a lower hierarchical level, may be of great value in bemr understanding the course of bipolar illness and the phenomenology of acute and interepisodic phases, and in desaibii subsets of patients whose symptoms are not entirely accounted for by mood disorder. Furthermore, comorbidity may have clear implications for treatment. Different forms of bipolar disorder, for example, could have different treatment responses, and it would be inmesting to see whether cornorbidity prcdicts treatment outcome. REFERENCES !STEFAN0 PINI. MD. UUANA DEUYKXX MD. CONCETTlNA MASTROUNQUE. MD, GIOVANNI MARCACCI. MD. ALESSANDRA PAW\SOCU. MD, SWNAWGNOU. MD. !STEFAN0PAUANTI. MD. GIOVANNI B. CASSANQ FRCF3ych. Department of Rychiiry, Neurobidogy, Pharmacology and Biotechdogy, U n i i y of Pisa. Italy Correspondence: D r Stefano Pini. DPNFB-Department of Psychiatry,University of Pisa, via Roma 67, 56100 Pisa. ltaly.Tel: +39 50 835-419; Fax: +39 50 21-581 (First received 18 August 1998. final revision II February 1999. accepted 9 March 1999) -. -.-. u d (1999) Multiple anxiety disorders comorbidity in patients with mood spectrum d i r s with psrchotic features. Americwr Jomdof R y d m q w t r ) c In,345-350. G.k.n,E. A. (lr)The scientifi~basis of clinical trials. Uinicol k r c h . 31 2587-2590. sonm,tC..~K.T.&~.WA. 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