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Psychotic symptoms in patients with bipolar mania
Journal of Affective Disorders 111 (2008) 164 – 169 www.elsevier.com/locate/jad
Research report
Psychotic symptoms in patients with bipolar mania Carla M. Canuso a,⁎, Cynthia A. Bossie a , Young Zhu a,1 , Eriene Youssef a , David L. Dunner b a
Ortho-McNeil Janssen Scientific Affairs, L.L.C., Titusville, New Jersey, United States b Center for Anxiety and Depression, Mercer Island, Washington, United States
Received 12 July 2007; received in revised form 11 February 2008; accepted 12 February 2008 Available online 2 April 2008
Abstract Background: Psychosis has been identified in as many as 68% of patients with bipolar mania. This analysis identified psychotic symptoms in these patients. Methods: Data were from two placebo-controlled, 3-week studies in patients with an acute episode of bipolar mania. Symptoms were identified by the 30-item Positive and Negative Syndrome Scale (PANSS; item ratings, 1 = absent to 7 = extremely severe), the Young Mania Rating Scale, and the Global Assessment Scale. Results: Psychotic features at study entry were diagnosed in 264 (51.3%) of the 515 patients. At baseline, these patients had significantly more severe scores on the PANSS, Young Mania Rating Scale, and Global Assessment Scale than patients without psychotic features. Patients with psychotic features had mean (±SD) scores of mild (3) or greater on six PANSS items: grandiosity (4.5 ± 1.4), delusions (4.4 ± 1.4), lack of judgment/insight (4.1 ± 1.5), excitement (3.9 ± 1.3), suspiciousness/persecution (3.1 ± 1.6), and hostility (3.1 ± 1.5). Grandiosity symptoms of delusional proportions (scores ≥ 4) were noted in 205 (78%) of patients with a diagnosis of psychotic features and in 113 (45%) patients without the diagnosis. Limitations: The study was not specifically designed to assess patients with psychotic features and the PANSS was developed to evaluate symptoms of schizophrenia. Conclusions: These findings support prior reports indicating high rates of psychosis in patients with bipolar mania and identify the most prominent symptoms in these patients. © 2008 Elsevier B.V. All rights reserved. Keywords: Bipolar mania; Psychotic symptoms
1. Introduction
⁎ Corresponding author. Ortho-McNeil Janssen Scientific Affairs, L.L.C., 1125 Trenton-Harbourton Road, Titusville, New Jersey 08560, United States. Tel.: +1 609 730 7732; fax: +1 609 730 3125. E-mail address: [email protected] (C.M. Canuso). 1 At the time of this analysis, an employee of Ortho-McNeil Janssen Scientific Affairs, L.L.C., Titusville, New Jersey, United States. 0165-0327/$ - see front matter © 2008 Elsevier B.V. All rights reserved. doi:10.1016/j.jad.2008.02.014
More than half of patients with bipolar disorder will experience psychotic symptoms in their lifetime (Dunayevich and Keck, 2000) and, in patients with bipolar mania, rates of psychotic symptoms as high as 68% have been reported (Pope and Lipinski, 1978; Coryell et al., 2001; Keck et al., 2003). It has been estimated that 48% of patients experiencing a manic episode present with at least
C.M. Canuso et al. / Journal of Affective Disorders 111 (2008) 164–169
one delusion, 19% with one thought disorder (defined by the authors as “problems in the ability to attend, abstract, conceptualize, express or continue coherent thought”) and 15% with one hallucination (Goodwin and Jamison, 1990). Grandiose delusions are the most common type of psychotic symptom, but thought disorder, hallucinations, mood-incongruent psychotic symptoms, and catatonia can also present as part of a manic episode (Dunayevich and Keck, 2000). Possible risk factors for psychosis in mania include increased severity of mania and early age at onset of illness (McElroy et al., 1996). Carlson and Goodwin (1973) reported that as core manic symptoms increased in severity during an acute episode, psychotic symptoms became more common, prominent, and bizarre. Although early age at onset of bipolar disorder is associated with a higher incidence of psychosis, early onset is not necessarily associated with a poor long-term outcome (Rosen et al., 1983a; McGlashan, 1988). The prognostic significance of psychotic symptoms in patients with bipolar disorder is inconclusive. Rosen et al. (1983b) reported poorer social functioning in 79 bipolar patients who had been designated “psychotic” at some time during the course of their illness. In a 4-year follow-up study of 75 patients by Tohen et al. (1990), predictors of an unfavorable outcome included psychotic features and symptoms of depression during the index manic episode. In contrast, Rosenthal et al. (1979) reported that in 66 bipolar patients treated with lithium, psychosis during mania appeared to be associated with “especially good early lithium prophylaxis.” Harrow et al. (1990) and Goldberg et al. (1995), however, reported no association between the presence of psychotic features at baseline and treatment outcome in manic patients during follow-ups of 1.7–4.5 years. Psychosis may be even more common in bipolar patients than is typically diagnosed, yet its recognition and treatment are important components in the effective management of these patients (Krishnan, 2005). The objective of the current analysis was to further explore the spectrum of psychosis in patients with bipolar mania. We hypothesized that psychotic symptoms are more common in patients with bipolar mania than are diagnosed at study entry.
165
in patients with acute manic or mixed episodes associated with bipolar I disorder. The primary results of the two trials, conducted in the United States (Hirschfeld et al., 2004) and in India (Khanna et al., 2005), have been published. In both trials, eligible subjects were men and women aged 18 years or older with a DSM-IV diagnosis of bipolar I disorder with or without psychotic features. The patients were voluntarily hospitalized at the time of enrollment and had a mean baseline Young Mania Rating Scale (YMRS) scores ≥ 20. Patients with DSMIV criteria for schizoaffective disorders, rapid cycling, borderline or antisocial personality disorder and recent history of substance dependence were excluded. Other exclusion criteria were risk of suicide or violent behavior, seizure disorder and unstable medical illness. Subjects were randomized to receive flexible doses of risperidone (1–6 mg/day) or placebo for 3 weeks. Randomization was stratified by the presence or absence of psychotic features at baseline, treatment center, and, in one study, by manic or mixed episodes (mixed patients were not enrolled in the second study). Once enrolled the patients remained in the hospital for at least 7 days. Concomitant treatment with other psychotropic agents, including antimania and antidepressant Table 1 Baseline characteristics of patients with and without psychotic features at baseline With psychotic features (n = 264)
Without psychotic features (n = 251)
36.6 ± 11.7
37.1 ± 12.9
160 (60.6) 104 (39.4)
147 (58.6) 104 (41.4)
167 (63.3) 58 (22.0) 26 (9.8) 13 (4.9) 258 (97.7) 6 (2.3) 64.9 ± 15.3 a 23.7 ± 4.7 9.1 ± 3.8 13.3 ± 5.3 12.0 ± 4.1 7.0 ± 3.7 36.4 ± 7.9 a 33.5 ± 9.8 a 4.2 ± 0.9
119 (47.4) 106 (42.2) 21 (8.4) 5 (2.0) 246 (98.0) 5 (2.0) 55.2 ± 14.1 16.0 ± 4.3 8.9 ± 3.4 11.8 ± 4.3 10.7 ± 3.6 7.8 ± 3.8 30.5 ± 6.9 39.8 ± 8.8 3.6 ± 0.7
2.1. Study design
Age (mean ± SD) Sex, n (%) Male Female Race, n (%) Asian Indian Non-Hispanic White Black Hispanic Manic, n (%) Mixed, n (%) PANSS total (mean ± SD) Positive symptoms Negative symptoms Disorganized thoughts Hostility/excitement Anxiety/depression YMRS total (mean ± SD) GAS total (mean ± SD) CGI-S total (mean ± SD)
In this post-hoc analysis, data were analyzed from two 3-week, randomized, double-blind, placebo-controlled, multicenter studies of risperidone monotherapy
CGI-S = Clinical Global Impressions-Severity; GAS = Global Assessment Scale; PANSS = Positive and Negative Syndrome Scale; YMRS = Young Mania Rating Scale. a p b 0.001 versus patients without psychotic features.
2. Methods
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Table 2 Patient disposition With psychotic features (N = 264)
Completed study, n (%) Discontinued, n (%) Reasons, n (%) Insufficient response Withdrew consent Adverse event Lost to follow-up Noncompliant Other
Without psychotic features (N = 251)
Risperidone (N = 134)
Placebo (N = 130)
Risperidone (N = 131)
Placebo (N = 120)
101 (75.4) 33 (24.6) 15 (11.2) 9 (6.7) 4 (3.0) 2 (1.5) 1 (0.7) 2 (1.5) 2 (1.5)
77 (59.2) 53 (40.8) 41 (31.5) 5 (3.8) 2 (1.5) 3 (2.3) 1 (0.8) 1 (0.8) 1 (0.8)
96 35 11 9 9 3 2 1 1
73 (60.8) 47 (39.2) 22 (18.3) 12 (10.0) 8 (6.7) 3 (2.5) 0 (0.0) 2 (1.7) 2 (1.7)
medications, was not permitted, except for rescue lorazepam during the first 10 days of the study. 2.2. Assessments Patients were screened for psychotic features at baseline by means of the Structured Clinical Interview for DSM-IV. Symptoms were identified and rated by the 30-item Positive and Negative Syndrome Scale
(73.3) (26.7) (8.4) (6.9) (6.9) (2.3) (1.5) (0.8) (0.8)
(PANSS) (item ratings, 1 = absent, 2 = minimal, 3 = mild, 4 = moderate, 5 = moderate–severe, 6 = severe and 7 = extremely severe). The 30-item PANSS was originally constructed to evaluate symptoms in patients with schizophrenia (Kay et al., 1987), but it is now frequently used to evaluate psychotic symptoms in patients with other disorders, including bipolar disorder (Lindenmayer et al., 2004; Vieta et al., 2004; Daneluzzo et al., 2002). Other assessments included the Clinical
Fig. 1. Mean baseline scores on the 30 PANSS items in patients with and without psychotic features and SD of each score in the two groups (PANSS ratings: 1 = absent, 2 = minimal, 3 = mild, 4 = moderate, 5 = moderate–severe, 6 = severe, 7 = extreme). PANSS = Positive and Negative Syndrome Scale. ap b 0.05. bp b 0.01, cp b 0.001 versus patients without psychotic symptoms at baseline.
C.M. Canuso et al. / Journal of Affective Disorders 111 (2008) 164–169 Table 3 PANSS items rated ≥3 in patients with psychotic features at baseline (mean ± SD scores)
Grandiosity Delusions Lack of judgment/insight Excitement Suspiciousness/persecution Hostility
With psychotic features (n = 264)
Without psychotic features (n = 251)
4.5 ± 1.4 a 4.4 ± 1.4 a 4.1 ± 1.5 a 3.9 ± 1.3 3.1 ± 1.6 a 3.1 ± 1.5 a
3.2 ± 1.3 1.8 ± 1.1 3.0 ± 1.5 3.7 ± 1.1 2.1 ± 1.2 2.6 ± 1.5
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entry. Baseline characteristics of the patients in the diagnostic and treatment groups are listed in Table 1. The mean PANSS and YMRS scores at baseline were significantly higher in patients with psychotic features than in patients without psychotic features and GAS scores were significantly lower (Table 1). Patient disposition is shown in Table 2. 3.2. Identifying psychotic symptoms at baseline Mean scores on each of the PANSS items in patients with and without psychotic features at study entry are shown in Fig. 1. Patients diagnosed with psychotic features had mean PANSS scores of mild or greater (≥3) on six PANSS items: grandiosity, delusions, lack of judgment/insight, excitement, suspiciousness/persecution and hostility (Table 3). Mean scores ≥3 were observed on three of these items in the patients diagnosed without psychotic features (excitement, grandiosity and lack of judgment/insight). Significant differences (p b 0.001) in scores between the two groups were noted on all of these items except excitement (Table 3; Fig. 1). Two of the seven items that make up the PANSS positive factor were not included among the six items with baseline scores ≥3 in patients with psychotic features. These were conceptual disorganization (mean score, 2.7 ± 1.4 in patients with psychotic features and 2.1 ± 1.1 in patients without psychotic features) and hallucinatory behavior (2.1 ± 1.5 and 1.1 ± 0.4, respectively).
PANSS = Positive and Negative Syndrome Scale. a p b 0.001 versus patients without psychotic features.
Global Impressions-Severity (CGI-S) scale, the YMRS and the Global Assessment Scale (GAS). 2.3. Statistical methods The analysis was performed on the intent-to-treat group of patients with data stratified by patients with and without psychotic features at study entry. Analyses of covariance were used, controlling for trial, randomization group, baseline score and psychotic features where indicated. Statistical significance was obtained with 0.05 type-I error control. Analysis of variance was used to compare baseline continuous measures, controlling for trial and randomization group. Cochran–Mantel–Haenszel tests were used to compare categorical variables between randomization groups or between subjects with versus without psychotic features at study entry.
3.3. Incidence of psychotic symptoms Approximately half (264/515; 51.3%) of the patients were diagnosed with psychotic features at study entry. However, symptoms of grandiosity that were of delusional proportions (scores ≥ 4) were reported in 78.0% of the patients diagnosed with psychotic features and in 45.0% of the patients diagnosed without psychotic features. Among the patients diagnosed with
3. Results 3.1. Subjects Data were available for 515 patients, of whom 264 (51.3%) were diagnosed with psychotic features at study
Table 4 Mean PANSS total and YMRS total change scores at endpoint in patients with and without psychotic features receiving risperidone or placebo With psychotic features
PANSS total Change, mean ± SE YMRS total Change, mean ± SE
Without psychotic features
Risperidone (n = 134)
Placebo (n = 130)
Risperidone (n = 131)
Placebo (n = 120)
− 13.4 ± 1.3 a
−2.7 ± 1.3
− 10.8 ± 1.3 a
− 3.6 ± 1.3
− 17.4 ± 1.1 a
−6.5 ± 1.1
− 16.5 ± 1.0 a
− 8.9 ± 1.1
PANSS = Positive and Negative Syndrome Scale; YMRS = Young Mania Rating Scale. a p b 0.001 for risperidone versus placebo. Changes from baseline on both measures were significant in all groups ( p b 0.05).
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psychotic features, 98.1% had scores ≥ 4 on one or more PANSS item(s) compared with 61.4% of patients without psychotic features. 3.4. Responses to treatment There was a significantly greater response to treatment compared with placebo (as measured by PANSS or YMRS) in patients both with and without psychotic features (Table 4). Overall completion rates were also similar across populations, although some differences were observed regarding reasons for discontinuation (Table 2). 4. Discussion 4.1. Summary of the results The results of these analyses support previous findings of high rates (up to 68%) of psychotic features in patients with bipolar mania (Dunayevich and Keck, 2000; Pope and Lipinski, 1978; Coryell et al., 2001; Goodwin and Jamison, 1990; Keck et al., 2003). In the present study, diagnosis with psychotic features was made at baseline in 264 (51.3%) of the 515 patients. In addition, symptoms of psychosis (grandiosity of delusional proportions) were identified further in 113 patients (22% of the total) who were not diagnosed as having psychotic features at baseline. The results also reveal significantly more severe symptoms (PANSS, YMRS, and GAS scores) at baseline in patients with than without psychotic features. To identify the most prominent symptoms in the patients with psychotic features at baseline, scores on each of the 30 PANSS items were assessed. PANSS items with the highest scores included grandiosity, delusions, lack of judgment/insight, excitement, suspiciousness/persecution and hostility. Of these six items, excitement and hostility are not defined by a psychotic dimension according to the PANSS User's Manual (Kay et al., 2000), and perhaps reflect the symptoms that are characteristic of a manic episode. In contrast, the remaining four items—grandiosity, delusions, lack of judgment/insight and suspiciousness/persecution— each have a delusional/hallucinatory component at some PANSS severity rating, suggesting that they represent symptoms of psychosis most prevalent in bipolar mania. Indeed, grandiosity is a hallmark feature of mania. Of note, in patients diagnosed without psychotic symptoms the items with the highest scores were excitement, grandiosity, and lack of judgment/insight.
Interestingly, lack of judgment/insight emerged in both populations of patients as one of the PANSS items with the highest score, reflecting another key feature of the manic state. While conceptual disorganization and hallucinatory behavior are core features of the psychosis observed in schizophrenia, they emerged with low PANSS scores in this manic sample. 4.2. Study implications The significantly more severe PANSS, YMRS, and GAS scores at baseline in patients with versus without psychotic features suggest that psychosis is associated with generally more severe illness according to several measures (Swann et al., 2004). The finding of higher YMRS scores in the patients with psychosis confirms previous reports of more severe manic symptoms in patients with than without psychosis (McElroy et al., 1996; Carlson and Goodwin, 1973; Coryell et al., 2001; Azorin et al., 2007). Treatment outcome was similar in patients with and without psychotic features in the present study (Table 4). In a review of six long-term studies that examined the prognostic significance of psychosis in patients with bipolar disorder, Keck et al. (2003) found a wide range of both positive and negative outcomes. The authors concluded that the results were inconclusive regarding the general prognostic impact of psychotic features in bipolar patients. 4.3. Study limitations A limitation of our analysis is that the studies were not specifically designed to assess patients with psychotic features. Nevertheless, 264 of the 515 patients (51.3%) experiencing an acute manic episode had psychotic features at study baseline, a rate that is consistent with other reports on the presence of psychosis in bipolar mania (Pope and Lipinski, 1978; Coryell et al., 2001). Another possible limitation is that the PANSS was designed to evaluate symptoms of schizophrenia. However, this validated scale has been widely used to measure psychotic domains in patients with other diagnoses, including bipolar disorder (Rosenthal et al., 1979; Harrow et al., 1990; Goldberg et al., 1995; Krishnan, 2005; Khanna et al., 2005). 4.4. Conclusions These findings confirm previous findings of a high incidence of psychotic symptoms in patients with bipolar mania and suggest that these symptoms may be more prevalent than clinicians often recognize.
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Role of funding source The authors of this report who are or were employees of the funding source (noted below) were involved in the design of the study, data analysis and interpretation, and the preparation of this report. This research is funded by the Ortho-McNeill Janssen Scientific Affairs, L.L.C. Conflict of interest Carla M. Canuso, MD, Cynthia A. Bossie, PhD, Young Zhu, PhD, and Eriene Youssef, PharmD, declare that they are or were full-time employees with Ortho-McNeil Janssen Scientific Affairs, L.L.C., Titusville, NJ. David L. Dunner, MD, has received grant support from Eli Lilly, Pfizer, GlaxoSmithKline, Wyeth, Bristol-Myers Squibb, Cyberonics, Ortho-McNeil Janssen Scientific Affairs, L.L.C., and Novartis. He has consulted and been on the advisory board for the following companies: Eli Lilly, Pfizer, GlaxoSmithKline, Wyeth, Bristol-Myers Squibb, Roche Diagnostics, Cypress, Corcept, OrthoMcNeil Janssen Scientific Affairs, L.L.C., Novartis, Shire, Somerset, and Otsuka. Dr Dunner has served on the Speaker's Bureau for Eli Lilly, Pfizer, GlaxoSmithKline, Wyeth, Bristol-Myers Squibb, Organon, and Forest. Dr Dunner is a full-time employee with the Center for Anxiety and Depression, Mercer Island, Washington.
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Hirschfeld, R.M.A., Keck Jr., P.E., Kramer, M., Karcher, K., Canuso, C., Eerdekens, M., Grossman, F., 2004. Rapid antimanic effect of risperidone monotherapy: a 3-week multicenter, double-blind, placebo-controlled trial. Am. J. Psychiatry 161, 1057–1065. Kay, S.R., Fiszbein, A., Opler, L.A., 1987. The positive and negative syndrome scale (PANSS) for schizophrenia. Schizophr. Bull. 13, 261–276. Kay, S.R., Opler, L.A., Fiszbein, A., 2000. Positive and Negative Syndrome Scale User's Manual. Multi-Health Systems Inc., North Tonawanda, NY. Keck, P.E., McElroy, S.L., Havens, J.R., Altschuler, L.L., Nolen, W.A., Frye, M.A., Suppes, T., Denicoff, K.D., Kupka, R., Leverich, G.S., Rush, J.A., Post, R.M., 2003. Psychosis in bipolar disorder: phenomenology and impact on morbidity and course of illness. Comp. Psychiatry 44, 263–269. Khanna, S., Vieta, E., Lyons, B., Grossman, F., Eerdekens, M., Kramer, M., 2005. Risperidone in the treatment of acute mania: double-blind, placebo-controlled study. Br. J. Psychiatry 187, 229–234. Krishnan, K.R., 2005. Psychiatric and medical comorbidities of bipolar disorder. Psychosom. Med. 67, 1–8. Lindenmayer, J.P., Brown, E., Baker, R.W., Schuh, L.M., Shao, L., Tohen, M., Ahmed, S., Stauffer, V.L., 2004. An excitement subscale of the Positive and Negative Syndrome Scale. Schizophr. Res. 68, 331–337. McElroy, S.L., Keck Jr., P.E., Strakowski, S.M., 1996. Mania, psychosis, and antipsychotics. J. Clin. Psychiatry 57 (Suppl 3), 14–26. McGlashan, T.H., 1988. Adolescent versus adult onset of mania. Am. J. Psychiatry 145, 221–223. Pope, H.G., Lipinski, J.F., 1978. Diagnosis in schizophrenia and manic–depressive illness: a reassessment of the specificity of ‘schizophrenic’ symptoms in the light of current research. Arch. Gen. Psychiatry 35, 811–828. Rosen, L.N., Rosenthal, N.E., Van Dusen, P.H., Dunner, D.L., Fieve, R.R., 1983a. Age at onset and number of psychotic symptoms in bipolar I and schizoaffective disorder. Am. J. Psychiatry 140, 1523–1524. Rosen, L.N., Rosenthal, N.E., Dunner, D.L., Fieve, R.R., 1983b. Social outcome compared in psychotic and nonpsychotic bipolar I patients. J. Nerv. Ment. Dis. 171, 272–275. Rosenthal, N.E., Rosenthal, L.N., Stallone, F., Fleiss, J., Dunner, D.L., Fieve, R.R., 1979. Psychosis as a predictor of response to lithium maintenance treatment in bipolar affective disorder. J. Affect. Disord. 1, 237–245. Swann, A.C., Daniel, D.G., Kochan, L.D., Wozniak, P.J., Calabrese, J.R., 2004. Psychosis in mania: specificity of its role in severity and treatment response. J. Clin. Psychiatry 65, 825–829. Tohen, M., Waternaux, C.M., Tsuang, M.T., 1990. Outcome in mania: a 4-year prospective follow-up of 75 patients utilizing survival analysis. Arch. Gen. Psychiatry 47, 1106–1111. Vieta, E., Brugue, E., Goikolea, J.M., Sanchez-Moreno, J., Reinares, M., Comes, M., Colom, F., Martinez-Aran, A., Benabarre, A., Torrent, C., 2004. Acute and continuation risperidone monotherapy in mania. Hum. Psychopharmacol. 19, 41–45.
Research report
Psychotic symptoms in patients with bipolar mania Carla M. Canuso a,⁎, Cynthia A. Bossie a , Young Zhu a,1 , Eriene Youssef a , David L. Dunner b a
Ortho-McNeil Janssen Scientific Affairs, L.L.C., Titusville, New Jersey, United States b Center for Anxiety and Depression, Mercer Island, Washington, United States
Received 12 July 2007; received in revised form 11 February 2008; accepted 12 February 2008 Available online 2 April 2008
Abstract Background: Psychosis has been identified in as many as 68% of patients with bipolar mania. This analysis identified psychotic symptoms in these patients. Methods: Data were from two placebo-controlled, 3-week studies in patients with an acute episode of bipolar mania. Symptoms were identified by the 30-item Positive and Negative Syndrome Scale (PANSS; item ratings, 1 = absent to 7 = extremely severe), the Young Mania Rating Scale, and the Global Assessment Scale. Results: Psychotic features at study entry were diagnosed in 264 (51.3%) of the 515 patients. At baseline, these patients had significantly more severe scores on the PANSS, Young Mania Rating Scale, and Global Assessment Scale than patients without psychotic features. Patients with psychotic features had mean (±SD) scores of mild (3) or greater on six PANSS items: grandiosity (4.5 ± 1.4), delusions (4.4 ± 1.4), lack of judgment/insight (4.1 ± 1.5), excitement (3.9 ± 1.3), suspiciousness/persecution (3.1 ± 1.6), and hostility (3.1 ± 1.5). Grandiosity symptoms of delusional proportions (scores ≥ 4) were noted in 205 (78%) of patients with a diagnosis of psychotic features and in 113 (45%) patients without the diagnosis. Limitations: The study was not specifically designed to assess patients with psychotic features and the PANSS was developed to evaluate symptoms of schizophrenia. Conclusions: These findings support prior reports indicating high rates of psychosis in patients with bipolar mania and identify the most prominent symptoms in these patients. © 2008 Elsevier B.V. All rights reserved. Keywords: Bipolar mania; Psychotic symptoms
1. Introduction
⁎ Corresponding author. Ortho-McNeil Janssen Scientific Affairs, L.L.C., 1125 Trenton-Harbourton Road, Titusville, New Jersey 08560, United States. Tel.: +1 609 730 7732; fax: +1 609 730 3125. E-mail address: [email protected] (C.M. Canuso). 1 At the time of this analysis, an employee of Ortho-McNeil Janssen Scientific Affairs, L.L.C., Titusville, New Jersey, United States. 0165-0327/$ - see front matter © 2008 Elsevier B.V. All rights reserved. doi:10.1016/j.jad.2008.02.014
More than half of patients with bipolar disorder will experience psychotic symptoms in their lifetime (Dunayevich and Keck, 2000) and, in patients with bipolar mania, rates of psychotic symptoms as high as 68% have been reported (Pope and Lipinski, 1978; Coryell et al., 2001; Keck et al., 2003). It has been estimated that 48% of patients experiencing a manic episode present with at least
C.M. Canuso et al. / Journal of Affective Disorders 111 (2008) 164–169
one delusion, 19% with one thought disorder (defined by the authors as “problems in the ability to attend, abstract, conceptualize, express or continue coherent thought”) and 15% with one hallucination (Goodwin and Jamison, 1990). Grandiose delusions are the most common type of psychotic symptom, but thought disorder, hallucinations, mood-incongruent psychotic symptoms, and catatonia can also present as part of a manic episode (Dunayevich and Keck, 2000). Possible risk factors for psychosis in mania include increased severity of mania and early age at onset of illness (McElroy et al., 1996). Carlson and Goodwin (1973) reported that as core manic symptoms increased in severity during an acute episode, psychotic symptoms became more common, prominent, and bizarre. Although early age at onset of bipolar disorder is associated with a higher incidence of psychosis, early onset is not necessarily associated with a poor long-term outcome (Rosen et al., 1983a; McGlashan, 1988). The prognostic significance of psychotic symptoms in patients with bipolar disorder is inconclusive. Rosen et al. (1983b) reported poorer social functioning in 79 bipolar patients who had been designated “psychotic” at some time during the course of their illness. In a 4-year follow-up study of 75 patients by Tohen et al. (1990), predictors of an unfavorable outcome included psychotic features and symptoms of depression during the index manic episode. In contrast, Rosenthal et al. (1979) reported that in 66 bipolar patients treated with lithium, psychosis during mania appeared to be associated with “especially good early lithium prophylaxis.” Harrow et al. (1990) and Goldberg et al. (1995), however, reported no association between the presence of psychotic features at baseline and treatment outcome in manic patients during follow-ups of 1.7–4.5 years. Psychosis may be even more common in bipolar patients than is typically diagnosed, yet its recognition and treatment are important components in the effective management of these patients (Krishnan, 2005). The objective of the current analysis was to further explore the spectrum of psychosis in patients with bipolar mania. We hypothesized that psychotic symptoms are more common in patients with bipolar mania than are diagnosed at study entry.
165
in patients with acute manic or mixed episodes associated with bipolar I disorder. The primary results of the two trials, conducted in the United States (Hirschfeld et al., 2004) and in India (Khanna et al., 2005), have been published. In both trials, eligible subjects were men and women aged 18 years or older with a DSM-IV diagnosis of bipolar I disorder with or without psychotic features. The patients were voluntarily hospitalized at the time of enrollment and had a mean baseline Young Mania Rating Scale (YMRS) scores ≥ 20. Patients with DSMIV criteria for schizoaffective disorders, rapid cycling, borderline or antisocial personality disorder and recent history of substance dependence were excluded. Other exclusion criteria were risk of suicide or violent behavior, seizure disorder and unstable medical illness. Subjects were randomized to receive flexible doses of risperidone (1–6 mg/day) or placebo for 3 weeks. Randomization was stratified by the presence or absence of psychotic features at baseline, treatment center, and, in one study, by manic or mixed episodes (mixed patients were not enrolled in the second study). Once enrolled the patients remained in the hospital for at least 7 days. Concomitant treatment with other psychotropic agents, including antimania and antidepressant Table 1 Baseline characteristics of patients with and without psychotic features at baseline With psychotic features (n = 264)
Without psychotic features (n = 251)
36.6 ± 11.7
37.1 ± 12.9
160 (60.6) 104 (39.4)
147 (58.6) 104 (41.4)
167 (63.3) 58 (22.0) 26 (9.8) 13 (4.9) 258 (97.7) 6 (2.3) 64.9 ± 15.3 a 23.7 ± 4.7 9.1 ± 3.8 13.3 ± 5.3 12.0 ± 4.1 7.0 ± 3.7 36.4 ± 7.9 a 33.5 ± 9.8 a 4.2 ± 0.9
119 (47.4) 106 (42.2) 21 (8.4) 5 (2.0) 246 (98.0) 5 (2.0) 55.2 ± 14.1 16.0 ± 4.3 8.9 ± 3.4 11.8 ± 4.3 10.7 ± 3.6 7.8 ± 3.8 30.5 ± 6.9 39.8 ± 8.8 3.6 ± 0.7
2.1. Study design
Age (mean ± SD) Sex, n (%) Male Female Race, n (%) Asian Indian Non-Hispanic White Black Hispanic Manic, n (%) Mixed, n (%) PANSS total (mean ± SD) Positive symptoms Negative symptoms Disorganized thoughts Hostility/excitement Anxiety/depression YMRS total (mean ± SD) GAS total (mean ± SD) CGI-S total (mean ± SD)
In this post-hoc analysis, data were analyzed from two 3-week, randomized, double-blind, placebo-controlled, multicenter studies of risperidone monotherapy
CGI-S = Clinical Global Impressions-Severity; GAS = Global Assessment Scale; PANSS = Positive and Negative Syndrome Scale; YMRS = Young Mania Rating Scale. a p b 0.001 versus patients without psychotic features.
2. Methods
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Table 2 Patient disposition With psychotic features (N = 264)
Completed study, n (%) Discontinued, n (%) Reasons, n (%) Insufficient response Withdrew consent Adverse event Lost to follow-up Noncompliant Other
Without psychotic features (N = 251)
Risperidone (N = 134)
Placebo (N = 130)
Risperidone (N = 131)
Placebo (N = 120)
101 (75.4) 33 (24.6) 15 (11.2) 9 (6.7) 4 (3.0) 2 (1.5) 1 (0.7) 2 (1.5) 2 (1.5)
77 (59.2) 53 (40.8) 41 (31.5) 5 (3.8) 2 (1.5) 3 (2.3) 1 (0.8) 1 (0.8) 1 (0.8)
96 35 11 9 9 3 2 1 1
73 (60.8) 47 (39.2) 22 (18.3) 12 (10.0) 8 (6.7) 3 (2.5) 0 (0.0) 2 (1.7) 2 (1.7)
medications, was not permitted, except for rescue lorazepam during the first 10 days of the study. 2.2. Assessments Patients were screened for psychotic features at baseline by means of the Structured Clinical Interview for DSM-IV. Symptoms were identified and rated by the 30-item Positive and Negative Syndrome Scale
(73.3) (26.7) (8.4) (6.9) (6.9) (2.3) (1.5) (0.8) (0.8)
(PANSS) (item ratings, 1 = absent, 2 = minimal, 3 = mild, 4 = moderate, 5 = moderate–severe, 6 = severe and 7 = extremely severe). The 30-item PANSS was originally constructed to evaluate symptoms in patients with schizophrenia (Kay et al., 1987), but it is now frequently used to evaluate psychotic symptoms in patients with other disorders, including bipolar disorder (Lindenmayer et al., 2004; Vieta et al., 2004; Daneluzzo et al., 2002). Other assessments included the Clinical
Fig. 1. Mean baseline scores on the 30 PANSS items in patients with and without psychotic features and SD of each score in the two groups (PANSS ratings: 1 = absent, 2 = minimal, 3 = mild, 4 = moderate, 5 = moderate–severe, 6 = severe, 7 = extreme). PANSS = Positive and Negative Syndrome Scale. ap b 0.05. bp b 0.01, cp b 0.001 versus patients without psychotic symptoms at baseline.
C.M. Canuso et al. / Journal of Affective Disorders 111 (2008) 164–169 Table 3 PANSS items rated ≥3 in patients with psychotic features at baseline (mean ± SD scores)
Grandiosity Delusions Lack of judgment/insight Excitement Suspiciousness/persecution Hostility
With psychotic features (n = 264)
Without psychotic features (n = 251)
4.5 ± 1.4 a 4.4 ± 1.4 a 4.1 ± 1.5 a 3.9 ± 1.3 3.1 ± 1.6 a 3.1 ± 1.5 a
3.2 ± 1.3 1.8 ± 1.1 3.0 ± 1.5 3.7 ± 1.1 2.1 ± 1.2 2.6 ± 1.5
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entry. Baseline characteristics of the patients in the diagnostic and treatment groups are listed in Table 1. The mean PANSS and YMRS scores at baseline were significantly higher in patients with psychotic features than in patients without psychotic features and GAS scores were significantly lower (Table 1). Patient disposition is shown in Table 2. 3.2. Identifying psychotic symptoms at baseline Mean scores on each of the PANSS items in patients with and without psychotic features at study entry are shown in Fig. 1. Patients diagnosed with psychotic features had mean PANSS scores of mild or greater (≥3) on six PANSS items: grandiosity, delusions, lack of judgment/insight, excitement, suspiciousness/persecution and hostility (Table 3). Mean scores ≥3 were observed on three of these items in the patients diagnosed without psychotic features (excitement, grandiosity and lack of judgment/insight). Significant differences (p b 0.001) in scores between the two groups were noted on all of these items except excitement (Table 3; Fig. 1). Two of the seven items that make up the PANSS positive factor were not included among the six items with baseline scores ≥3 in patients with psychotic features. These were conceptual disorganization (mean score, 2.7 ± 1.4 in patients with psychotic features and 2.1 ± 1.1 in patients without psychotic features) and hallucinatory behavior (2.1 ± 1.5 and 1.1 ± 0.4, respectively).
PANSS = Positive and Negative Syndrome Scale. a p b 0.001 versus patients without psychotic features.
Global Impressions-Severity (CGI-S) scale, the YMRS and the Global Assessment Scale (GAS). 2.3. Statistical methods The analysis was performed on the intent-to-treat group of patients with data stratified by patients with and without psychotic features at study entry. Analyses of covariance were used, controlling for trial, randomization group, baseline score and psychotic features where indicated. Statistical significance was obtained with 0.05 type-I error control. Analysis of variance was used to compare baseline continuous measures, controlling for trial and randomization group. Cochran–Mantel–Haenszel tests were used to compare categorical variables between randomization groups or between subjects with versus without psychotic features at study entry.
3.3. Incidence of psychotic symptoms Approximately half (264/515; 51.3%) of the patients were diagnosed with psychotic features at study entry. However, symptoms of grandiosity that were of delusional proportions (scores ≥ 4) were reported in 78.0% of the patients diagnosed with psychotic features and in 45.0% of the patients diagnosed without psychotic features. Among the patients diagnosed with
3. Results 3.1. Subjects Data were available for 515 patients, of whom 264 (51.3%) were diagnosed with psychotic features at study
Table 4 Mean PANSS total and YMRS total change scores at endpoint in patients with and without psychotic features receiving risperidone or placebo With psychotic features
PANSS total Change, mean ± SE YMRS total Change, mean ± SE
Without psychotic features
Risperidone (n = 134)
Placebo (n = 130)
Risperidone (n = 131)
Placebo (n = 120)
− 13.4 ± 1.3 a
−2.7 ± 1.3
− 10.8 ± 1.3 a
− 3.6 ± 1.3
− 17.4 ± 1.1 a
−6.5 ± 1.1
− 16.5 ± 1.0 a
− 8.9 ± 1.1
PANSS = Positive and Negative Syndrome Scale; YMRS = Young Mania Rating Scale. a p b 0.001 for risperidone versus placebo. Changes from baseline on both measures were significant in all groups ( p b 0.05).
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psychotic features, 98.1% had scores ≥ 4 on one or more PANSS item(s) compared with 61.4% of patients without psychotic features. 3.4. Responses to treatment There was a significantly greater response to treatment compared with placebo (as measured by PANSS or YMRS) in patients both with and without psychotic features (Table 4). Overall completion rates were also similar across populations, although some differences were observed regarding reasons for discontinuation (Table 2). 4. Discussion 4.1. Summary of the results The results of these analyses support previous findings of high rates (up to 68%) of psychotic features in patients with bipolar mania (Dunayevich and Keck, 2000; Pope and Lipinski, 1978; Coryell et al., 2001; Goodwin and Jamison, 1990; Keck et al., 2003). In the present study, diagnosis with psychotic features was made at baseline in 264 (51.3%) of the 515 patients. In addition, symptoms of psychosis (grandiosity of delusional proportions) were identified further in 113 patients (22% of the total) who were not diagnosed as having psychotic features at baseline. The results also reveal significantly more severe symptoms (PANSS, YMRS, and GAS scores) at baseline in patients with than without psychotic features. To identify the most prominent symptoms in the patients with psychotic features at baseline, scores on each of the 30 PANSS items were assessed. PANSS items with the highest scores included grandiosity, delusions, lack of judgment/insight, excitement, suspiciousness/persecution and hostility. Of these six items, excitement and hostility are not defined by a psychotic dimension according to the PANSS User's Manual (Kay et al., 2000), and perhaps reflect the symptoms that are characteristic of a manic episode. In contrast, the remaining four items—grandiosity, delusions, lack of judgment/insight and suspiciousness/persecution— each have a delusional/hallucinatory component at some PANSS severity rating, suggesting that they represent symptoms of psychosis most prevalent in bipolar mania. Indeed, grandiosity is a hallmark feature of mania. Of note, in patients diagnosed without psychotic symptoms the items with the highest scores were excitement, grandiosity, and lack of judgment/insight.
Interestingly, lack of judgment/insight emerged in both populations of patients as one of the PANSS items with the highest score, reflecting another key feature of the manic state. While conceptual disorganization and hallucinatory behavior are core features of the psychosis observed in schizophrenia, they emerged with low PANSS scores in this manic sample. 4.2. Study implications The significantly more severe PANSS, YMRS, and GAS scores at baseline in patients with versus without psychotic features suggest that psychosis is associated with generally more severe illness according to several measures (Swann et al., 2004). The finding of higher YMRS scores in the patients with psychosis confirms previous reports of more severe manic symptoms in patients with than without psychosis (McElroy et al., 1996; Carlson and Goodwin, 1973; Coryell et al., 2001; Azorin et al., 2007). Treatment outcome was similar in patients with and without psychotic features in the present study (Table 4). In a review of six long-term studies that examined the prognostic significance of psychosis in patients with bipolar disorder, Keck et al. (2003) found a wide range of both positive and negative outcomes. The authors concluded that the results were inconclusive regarding the general prognostic impact of psychotic features in bipolar patients. 4.3. Study limitations A limitation of our analysis is that the studies were not specifically designed to assess patients with psychotic features. Nevertheless, 264 of the 515 patients (51.3%) experiencing an acute manic episode had psychotic features at study baseline, a rate that is consistent with other reports on the presence of psychosis in bipolar mania (Pope and Lipinski, 1978; Coryell et al., 2001). Another possible limitation is that the PANSS was designed to evaluate symptoms of schizophrenia. However, this validated scale has been widely used to measure psychotic domains in patients with other diagnoses, including bipolar disorder (Rosenthal et al., 1979; Harrow et al., 1990; Goldberg et al., 1995; Krishnan, 2005; Khanna et al., 2005). 4.4. Conclusions These findings confirm previous findings of a high incidence of psychotic symptoms in patients with bipolar mania and suggest that these symptoms may be more prevalent than clinicians often recognize.
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Role of funding source The authors of this report who are or were employees of the funding source (noted below) were involved in the design of the study, data analysis and interpretation, and the preparation of this report. This research is funded by the Ortho-McNeill Janssen Scientific Affairs, L.L.C. Conflict of interest Carla M. Canuso, MD, Cynthia A. Bossie, PhD, Young Zhu, PhD, and Eriene Youssef, PharmD, declare that they are or were full-time employees with Ortho-McNeil Janssen Scientific Affairs, L.L.C., Titusville, NJ. David L. Dunner, MD, has received grant support from Eli Lilly, Pfizer, GlaxoSmithKline, Wyeth, Bristol-Myers Squibb, Cyberonics, Ortho-McNeil Janssen Scientific Affairs, L.L.C., and Novartis. He has consulted and been on the advisory board for the following companies: Eli Lilly, Pfizer, GlaxoSmithKline, Wyeth, Bristol-Myers Squibb, Roche Diagnostics, Cypress, Corcept, OrthoMcNeil Janssen Scientific Affairs, L.L.C., Novartis, Shire, Somerset, and Otsuka. Dr Dunner has served on the Speaker's Bureau for Eli Lilly, Pfizer, GlaxoSmithKline, Wyeth, Bristol-Myers Squibb, Organon, and Forest. Dr Dunner is a full-time employee with the Center for Anxiety and Depression, Mercer Island, Washington.
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