- Email: [email protected]
Use of olanzapine in dysphoric mania
Journal of Affective Disorders 66 (2001) 247–253 www.elsevier.com / locate / jad
Research report
Use of olanzapine in dysphoric mania ´ A. Gonzalez-Pinto a , *, B. Lalaguna a , F. Mosquera a , J.L. Perez de Heredia a , M. Gutierrez a , a b c,d J. Ezcurra , I. Gilaberte , M. Tohen a
Psychiatric Department, Santiago Apostol Hospital, Osakidetza Mental Health System, Olaguibel 29, 01004 Vitoria, Spain b Clinical Research Department, Lilly, Vitoria, Spain c Department of Psychiatry, Harvard Medical School, McLean Hospital, Belmont, MA, USA d Lilly Research Laboratories, Indianapolis IN, USA Received 3 May 2000; received in revised form 11 September 2000; accepted 20 September 2000
Abstract Background: The simultaneous presentation of both manic and depressive symptoms has long been recognized. Nevertheless, a variable prevalence of dysphoric mania has been reported. The aim of this study was to estimate the prevalence of dysphoric mania among hospitalized patients and to assess the effectiveness of olanzapine in this type of patients. Methods: Eighty-six patients who met DSM-IV criteria for mania were evaluated at admission with a protocol that included McElroy’s criteria for dysphoric mania [Am. J. Psychiatry 149 (1992) 1633]. Treatment was administered according to clinical need, using mood stabilizers combined with antipsychotics. Sequential assessments were conducted throughout the study. Results: Forty-four patients (51.2%) fulfilled McElroy’s criteria for dysphoric mania. Fourteen of these dysphoric patients were treated with olanzapine in combination with mood-stabilizers. All patients improved in manic symptoms but patients treated with olanzapine improved significantly more than those treated with other antipsychotics in depressive symptoms. Limitations: The lack of randomization is a methodological limitation of this study, so these findings should be considered as preliminary. Conclusions: Dysphoric symptoms are common in this population of manic patients. Olanzapine in combination with mood-stabilizers may be effective in these patients. Additional controlled studies are needed to replicate these results. 2001 Elsevier Science B.V. All rights reserved. Keywords: Dysphoric mania; Naturalistic study; Olanzapine; Prevalence
1. Introduction
*Corresponding author. Tel.: 1 34-945-007-769; fax: 1 34945-007-764. E-mail address: [email protected] (A. GonzalezPinto).
Mania and depression are frequently viewed as polar opposites. However some manic patients simultaneously experience prominent depressive symptoms (Goodwin and Jamison, 1990). Carlson and Goodwin (1973) described that, before the
0165-0327 / 01 / $ – see front matter 2001 Elsevier Science B.V. All rights reserved. PII: S0165-0327( 00 )00313-X
248
A. Gonzalez-Pinto et al. / Journal of Affective Disorders 66 (2001) 247 – 253
psychopharmacological era, mania had three stages. In the third stage, the most severe form, psychotic symptoms and dysphoria were prominent. Dysphoric or mixed mania was described by Kraepelin in his book Manic-Depressive Insanity and Paranoia (Kraeplin, 1920). The course of mixed states, in Kraepelin’s words, ‘‘appears in general to be lingering and may be regarded as unfavorable forms of manic depressive insanity’’. Kraepelin included in the mixed states six different types of manic and depressive symptom combinations, so there were manic phases with depressive symptoms and also depression phases with manic symptoms. These states included depressive or anxious mania, excited or agitated depression, mania with poverty of thought, manic stupor, depression with flight of ideas, and inhibited mania. In a very interesting paper about mixed states, Perugi et al. (1997) found that the majority of the mixed states defined by Kraepelin are manic or mixed phases with depressive symptoms, and only 17.5% were depressions. As DSM-IV criteria are especially restrictive — it is necessary to have a complete mania and a complete depression for the diagnosis — this syndrome has been considered rather infrequent and has provoked little attention in the literature. Nevertheless, some authors have recently tried to change this position. McElroy used the term dysphoric or mixed as equivalents and proposed diagnostic criteria for dysphoric or mixed mania using DSM-III-R criteria for affective disorders (McElroy et al., 1992). According to McElroy, the simultaneous presence of mania and at least two associated depressive symptoms is considered as a probable diagnosis of dysphoric mania. More recently there have been some authors that have proposed that mania has a dysphoric dimension (Cassidy et al., 1998; Dilsaver et al., 1999), with a bimodal distribution according to Cassidy. That affirmation obliges one to look for depressive symptoms in patients suffering from mania, and to assess also the outcome of these depressive symptoms in the clinical trials of mania. Criteria used by different authors have contributed to the variable prevalence for this disorder across studies and populations. At least 30–40% of all manic states are probably dysphoric, although there have been reports of rates from 5 to 70% (Goodwin and Jamison, 1990). The high energy and impulsivity
typically associated with this disorder create a substantial risk of suicide (Swann, 1995). Pharmacotherapy in general may be less effective for patients in mixed states. Dilsaver et al. (1993) reported that patients with mixed states were significantly less responsive to monotherapy with any mood-stabilizer than were patients with pure mania. These patients responded to treatment with combinations of lithium, valproate, and / or carbamazepine, or with electroconvulsive therapy. In a retrospective study, it was found that patients treated with divalproex sodium or with lithium / carbamazepine combinations had significantly shorter lengths of hospital than patients treated with lithium or carbamazepine alone (Frye et al., 1996). Olanzapine is a new antipsychotic effective in schizophrenia and schizophreniform disorders. Preliminary data suggest that olanzapine may have antimanic properties in adults with schizoaffective disorder, bipolar type (Tohen et al., 1998; Tran et al., 1999). Recently it has been reported that olanzapine was superior to placebo (Tohen et al., 1999a,b) and at least as effective as lithium (Berk et al., 1999) in the treatment of the acute mania. Olanzapine, added to the previous drug regime, has also been reported to be effective and well-tolerated in an open trial in nine patients with bipolar mixed state previously refractory to mood-stabilizers used alone or in combination with antipsychotics (Sharma and Pistor, 1999). Considering the high prevalence of dysphoric symptoms in acute mania, we conducted a study to estimate the prevalence and severity of dysphoric symptoms in patients suffering from mania. We also evaluated the effectiveness of olanzapine in these patients in a naturalistic setting.
2. Method All patients admitted to the Santiago Hospital Psychiatric Unit, with a DSM-IV (American Psychiatric Association, 1994) diagnosis of bipolar disorder, manic or mixed episode, were included in this study. Santiago Hospital receives patients from a catchment area of 350 000 inhabitants and is the only psychiatric general hospital for acute patients in the state.
A. Gonzalez-Pinto et al. / Journal of Affective Disorders 66 (2001) 247 – 253
Diagnoses were made by at least two research psychiatrists (BL, JPH) using the Structured Clinical Interview for DSM-IV, Patient Version (SCID-P). A best estimated procedure was established to determine the final diagnosis. When there was any doubt about diagnoses, another research psychiatrist was consulted, and if there was no agreement between both diagnosticians, patients were excluded from the study. Researchers assessed patients during hospitalization while blind to prescribed medication. At least one family member always corroborated the patient’s history. A total of 86 patients were evaluated during a 2-year period between March 1996 and February 1998, with a clinical protocol at admission and discharge. In addition to the SCID-P for DSM-IV, the protocol included McElroy’s criteria for dysphoric mania, the Hamilton Depression Rating Scale (HAMD), the Young Mania Rating Scale (YMRS), the Positive and Negative Syndrome Sclae (PANSS), and the Clinical Global Impressions (CGI) scale. For the diagnosis of dysphoric mania, we used the McElroy’s criteria for probable dysphoric mania (two or more depressive symptoms). Treatment was administered with clinical criteria. We reported here the follow-up of 44 of these patients who were diagnosed of dysphoric mania with this protocol. Fourteen patients with dysphoric mania were treated with olanzapine in combination with mood-stabilizers, and were compared with 30 dysphoric patients treated with other antipsychotics in combination with mood-stabilizers. Of the 30 patients treated with other antipsychotics, 27 were treated with combinations of haloperidol and levomepromazine (haloperidol 10–30 mg / day and levomepromazine 75– 300 mg / day) and three were treated with haloperidol (haloperidol 10–20 mg / day). A descriptive statistical analysis was carried out, bivariant using x 2 -test for the comparison of qualitative variables and Student’s t-test for quantitative variables were used. When there was not a normal distribution of the variables non-parametric tests were performed (Mann–Whitney U-test). All tests were two-tailed and a 0.05 level of significance was used. A logistic regression model was adjusted with a predictive aim to assess a favourable outcome in depressive symptoms measured by a decrease of at
249
least 80% in the Hamilton Depression Rating Scale. Variables previously related with outcome in bipolar disorder were included (Goldberg and Harrow, 1999); two demographic variables (age and gender), four variables related with the course of the illness (age of onset, years of illness, number of episodes and suicidal attempts), and two related with drug administered (lithium and olanzapine). In addition, we also included two variables related with hospitalization (compulsory admission and length of hospitalization) that could also be related with outcome on these patients.
3. Results Forty-four patients (51.2%) fulfilled McElroy’s criteria for dysphoric mania (23 women, 21 men), and 42 (48.8%) had one or fewer symptoms (17 women, 25 men). The average age was 37.1611.8 years. The mean age of onset of illness was 26.369.7 years, with a median age of 24 years, and 25.58% of the sample was married. The average number of previous episodes was 4.664.5. There were more women with dysphoric mania, although the differences were non-significant (Pearson x 2 5 1.2; df 5 1; P 5 0.27) (Table 1). Patients with dysphoric symptoms had significantly fewer manic symptoms measured by YMRS (separate variances, t 5 2 3.25; P 5 0.002) at admission and a tendency to have fewer manic symptoms at discharge (t 5 2 1.9; df 5 83; P 5 0.06). Dysphoric patients had more depressive symptoms at admission (separate variances, t 5 2.9; df 5 83.4; P 5 0.005), but not at discharge (t 5 1.049; df 5 84; P 5 0.29). All manic patients, dysphoric and non-dysphoric, were treated with mood stabilizers and antipsychotics. Pharmacological treatment was recorded in all but one patient. Patients with dysphoric mania were treated more frequently with valproate (Table 1). Fourteen dysphoric manic patients were treated with olanzapine (5–20 mg / day) at variable doses, depending on clinical state and with clinical criteria. Olanzapine was used in combination with moodstabilizers (lithium and valproate). The remaining 30 patients were treated with other antipsychotics, mostly haloperidol and levomepromazine. There were no
A. Gonzalez-Pinto et al. / Journal of Affective Disorders 66 (2001) 247 – 253
250
Table 1 Demographic and clinical characteristics of patients with dysphoric a and pure mania Variable
Pure mania (n 5 42)
Dysphoric mania (n 5 44)
Statistics
P Value
Age (mean6S.D.) Male, n (%) Compulsory admission Years of illness (mean6S.D.) Days of hospitalization (mean6S.D.) Number of previous episodes Valproate, n (%)
36.09613.07 25 (29.07) 24 (27.91) 10.9611.66 17.22611.97 5.0765.77 15 (17.65%)
38.08610.44 21 (24.42) 18 (20.93) 11.33610 20.77610.4 4.2562.8 34 (40%)
t 5 0.77 x 2 5 1.20 x 2 5 2.26 UMW 5 774.0 UMW 5 630.5 UMW 5 902.0 x 2 5 14.39
NS NS NS NS P 5 0.036 NS P , 0.001
a
Two or more symptoms of McElroy criteria.
severe adverse effects during the hospitalizations. Patients receiving olanzapine did not experience any extrapyramidal symptoms. Characteristics of the patients treated with olanzapine were not different from those treated with other antipsychotics, except in their baseline scores on the YMRS (Table 2). Patients treated with olanzapine improved more than those treated with other antipsychotics in manic symptoms (differential YMRS score in the olanzapine group, mean 5 29.35; S.D. 5 9,73; non-olanzapine group, mean 5 19.6; S.D. 5 12,45; t 5 2.82; df 5 32,1; P 5 0.008) and in depressive symptoms (differential HAMD punctuation in the olanzapine group, mean 5 15.71; S.D. 5 5.22; non-olanzapine group, mean 5 11.9; S.D. 5 7.08; separate variances, t 5 2.00; df 5 33.8; P 5 0.05) (Fig. 1). There were no significant differences between the groups in terms of hospital length of stay (olanzapine group,
Fig. 1. Differential scores in the YMRS and HAMD. ** P 5 0.008; * P 5 0.05.
22.1468.19 days; non-olanzapine group, 20.10610.78 days; t 5 0.67; df 5 32.1; P 5 0.5). In a logistic regression model conducted to analyze the differences between patients with poorer and better
Table 2 Characteristics of the sample treated and untreated with olanzapine a Variable
Olanzapine (n 5 14)
Non-olanzapine (n 5 30)
Statistics
P value
Age (mean6S.D.) Male, n (%) Compulsory admission Lithium Valproate Number of episodes Days of hospitalization Years of illness PANSS admission YMRS admission HAMD admission CGI admission
39.1468.37 5 (11.36) 7 (15.91) 7 (15.91) 12 (27.27) 5.2162.88 22.1468.49 12.4269.26 77.57614.16 33.6468.68 19.0066.61 5.0760.91
37.58611.37 16 (36.36) 11 (25%) 12 (27.27) 22 (50%) 3.8062.80 20.10610.78 10.80610.46 74.13618.66 24.39614.25 16.8667.58 4.7561.32
t 5 0.50 x 2 5 1.18 x 2 5 0.7 x 2 5 0.38 Fisher exact test UMW 5 14.65 UMW 5 185.5 UMW 5 172.0 UMW 5 186.5 t 5 2.67 UMW 5 180.5 UMW 5 181.0
NS NS NS NS NS NS NS NS NS P 5 0.01 NS NS
a
CGI, Clinical Global Impressions scale; HAMD, Hamilton Depression Rating Scale; PANSS, Positive and Negative Syndrome Scale; YMRS, Young Mania Rating Scale.
A. Gonzalez-Pinto et al. / Journal of Affective Disorders 66 (2001) 247 – 253
251
Table 3 Logistic regression model of variables associated with a hamilton decrease of 80% or more Parameter
Estimate
S.E.
t value
P value
Odds ratio
Constant Male Age . 30 Number of episodes $ 5 Years of illness . 10 Age at onset . 25 Suicidal attempts Days of hospitalization $ 21 Compulsory admission Olanzapine Lithium
2 2.930 2 0.250 6.786 2 2.061 2 2.661 2 2.811 2 0.333 0.260 2 0.728 2.404 0.579
1.865 1.052 2.602 1.234 1.685 1.805 1.074 0.983 0.996 1.196 0.995
2 1.571 2 0.237 2.608 2 1.669 2 1.580 2 1.557 2 0.310 0.265 2 0.731 2.009 0.583
0.116 0.813 0.009 0.095 0.114 0.119 0.757 0.791 0.465 0.045 0.560
0.779 885.092 0.127 0.070 0.060 0.717 1.297 0.483 11.063 1.785
outcomes in depressive symptoms measured with the HAMD, we found that being older than 30 years, and being treated with olanzapine were the two factors associated with better outcome (Table 3).
4. Discussion Almost half of patients admitted to our hospital with acute mania experienced two or more depressive symptoms. It is important to notice that we included in our sample all manic patients hospitalized in an area of 350 000 inhabitants. Therefore, it is a representative sample of the disease in the general population. In a multicenter study conducted by Akiskal in France, 37% of their sample of mania were diagnosed of dysphoric mania when they used McElroy criteria (Akiskal et al., 1998). Our rates are slightly higher probably because our patients are all hospitalized, so there are no patients with mild manic symptoms in our sample. It is clear, at this point, that mixed mania is a frequent syndrome, and that depressive symptoms are common during mania (Prien et al., 1988). However, this fact is not reflected on the assessment scales of mania which do not include depressive symptoms, and for this reason, these symptoms could be non-appropriate assessed with the current instruments. Cassidy et al. (1998) investigating the dimensions of mania have considered that any of the current mania scales is suitable to assess the dysphoric aspect of the mania. However, the high percentage of patients with depressive symptoms
during mania should cause us to reflect on the need to evaluate this type of patients more precisely. This is especially important because it has therapeutic implications and suicidality is linked with mixed manic states (Goldberg et al., 1998). These affective states do not seem to respond well to conventional pharmacotherapy for mania and depression. Mixed states tend to respond better to anticonvulsants than to lithium salts, and for that reason dysphoric patients of our sample are treated significantly more frequently with divalproex. Dysphoric patients have also significantly longer inpatient stays than purely manic patients. As we show in our data, other reports on current literature have also found longer hospitalizations in patients with dysphoric or mixed episodes than pure manic (Keller et al., 1986; Devenand et al., 2000): Keller et al. found in a sample of 130 patients that episodes of dysphoric mania had significantly longer duration than episodes of pure mania and major depression; also, in that sense, Devenand et al. found that patients with mixed mania receiving ECT had longer hospitalizations than pure mania and major depression treated also with ECT. So it seems that the prolonged time to recovery in dysphoric patients is related not only to the difficulty in finding the appropriate treatment, but also to the pathophysiology of the disease. The prolonged time to recovery is associated with poor outcome in bipolar disorder (Keck et al., 1998). We find in our sample that being older than 30 years is a factor indicative of a better outcome in depressive symptoms during a mixed episode. This can be related to the fact that patients with mixed
252
A. Gonzalez-Pinto et al. / Journal of Affective Disorders 66 (2001) 247 – 253
states tend to have higher rates of depression early in the course of the illness (McElroy et al., 1992) and also that maturity can help complete recovery. All patients improved in manic symptoms. Patients treated with olanzapine improved more than those treated with other antipsychotics in manic symptoms, but we have to consider that their baseline scores on the Young Mania Rating Scale were higher; hence the differences could be biased by group differences at admission. Patients treated with olanzapine improved more in depressive symptoms than those treated with other antipsychotics during the hospitalizations. There are some cases in the literature of olanzapine augmentation in mixed episodes (Ketter et al., 1998; Sharma and Pistor, 1999; Zullino and Baumann, 1999). We report here a naturalistic assessment of olanzapine in dysphoric mania. Our results suggest that olanzapine combined with mood-stabilizers appears to be more effective than typical antipsychotics in the treatment of the depressive symptoms of dysphoric mania. Our preliminary observations have some methodological limitations. Patients were not randomized, although assessments were blind (clinical raters blind to the treatment group). The lack of randomization might have contributed to a differential treatment by the treating clinicians. Olanzapine was administered concomitantly with other mood-stabilizers, so the benefit of this treatment may be due to olanzapine alone or to a synergistic effect of olanzapine with mood-stabilizers. For all these reasons, these findings need to be considered as preliminary, pending substantiation replication in controlled trials. However, even when these limitations are considered, olanzapine appeared to show superior efficacy in the depressive symptoms of dysphoric mania.An advantage of our study compared with controlled doubleblind trials is that we include all manic patients, including a representative sample of a clinical population of an area without using strict selection criteria. In contrast, clinical trials often may not include the type of patients clinicians ordinarily treat (Goldberg and Harrow, 1999). Moreover, the naturalistic characteristics of this study provides additional and complementary information to clinical trials very valuable for clinicians (Blacker and Mortimore, 1996).
Acknowledgements This work was supported by a grant of the FIS no. 97 / 0851, and in part by a small grant from Lilly SA (Spain).
References Akiskal, H.S., Hantouche, E.G., Bourgeois, M.L., Azorin, J.M., ˆ Sechter, D., Allilaire, J.F., Lancrenon, S., Fraud, J.P., Chatenetˆ Duchene, L., 1998. Gender, temperament and the clinical picture in dysphoric mixed mania: findings for a french national study (EPIMAN). J. Affect. Dis. 50, 175–186. American Psychiatric Association, 1994. Diagnostic and Statistical Manual of Mental Disorders, 4th Edition. American Psychiatric Press, Washington, DC. Berk, M., Ichim, L., Brook, S., 1999. Olanzapine compared to lithium in mania: a double-blind randomized controlled trial. Int. Clin. Psychopharmacol. 14, 339–343. Blacker, C.V.R., Mortimore, C., 1996. Randomized controlled trials and naturalistic data: time for a change? Hum. Psychopharmacol. 11, 353–363. Carlson, G.A., Goodwin, F.K., 1973. The stages of mania: a longitudinal analysis of the manic episode. Arch. Gen. Psychiatry 28, 221–228. Cassidy, F., Forest, K., Murry, E., Carroll, B.J., 1998. A factor analysis of the signs and symptoms of mania. Arch. Gen. Psychiatry 55, 27–32. Devenand, D.P., Polanco, P., Cruz, R., Shah, S., Pykina, N., Singh, K., Majors, L., 2000. The efficacy of ECT in mixed affective states. J. ECT 16, 32–37. Dilsaver, S.C., Swann, A.C., Shoaib, A.M., Bowers, T.C., Halle, M.T., 1993. Depressive mania associated with nonresponse to antimanic agents. Am. J. Psychiatry 150, 1548–1551. Dilsaver, S.C., Chen, Y.R., Shoaib, A.M., Swann, A.C., 1999. Phenomenology of mania: evidence for distinct depressed, dysphoric and euphoric presentations. Am. J. Psychiatry 156, 426–430. Frye, M.A., Altshuler, L.L., Szuba, M.P., Finch, N.N., Mintz, J., 1996. The relationship between antimanic agents for treatment of classic or dysphoric mania and length of hospital stay. J. Clin. Psychiatry 57, 17–22. Goldberg, J.F., Garno, J.L., Leon, A.C., Kocsis, J.H., Portera, L., 1998. Association of recurrent suicidal ideation with nonremission from acute mixed mania. Am. J. Psychiatry 155, 1753– 1755. Goldberg, J.F., Harrow, M., 1999. Poor-outcomes. In: Goldberg, J.F., Harrow, M. (Eds.), Bipolar Disorders: Clinical Course and Outcomes. American Psychiatric Press, Washington, DC. Goodwin, F.K., Jamison, K.R., 1990. Diagnosis. In: Goodwin, F.K., Jamison, K.R. (Eds.), Manic Depressive Illness. Oxford University Press, New York, NY. Kraepelin E., 1920. Die Erscheinungsformen des Irreseins. Z ges
A. Gonzalez-Pinto et al. / Journal of Affective Disorders 66 (2001) 247 – 253 Neurol Psychiatr 62:1-29. Translated by H. Marshall, 1974, in Themes and Variations in European Psychiatry. Hirsch, Sheperd (Editors). University Press of Virginia, Charlottesville, VA. Keck, P.E., McElroy, S.L., Strakowsky, S.M., West, S.A., Sax, K.W., Hawkins, J.M., Bourne, M.L., Haggard, P., 1998. 12month outcome of patients with bipolar disorder following hospitalization for a manic or mixed episode. Am J Psychiatry 155, 646–652. Keller, M.B., Lavori, P.W., Coryell, W., Andreasen, N.C., Endicott, J., Clayton, P.J., Klerman, G.L., Hirschfeld, R.M.A., 1986. Differential outcome of pure manic, mixed / cycling, and pure depressive episodes in patients with bipolar illness. J. Am. Med. Assoc. 255, 3138–3142. Ketter, T.A., Winsberg, M.E., De Golia, S.G., Dunai, M., Tate, D.L., Strong, C.M., 1998. Rapid efficacy of olanzapine augmentation in nonpsychotic bipolar mixed states. J. Clin. Psychiatry 59, 83–84, (Letter). McElroy, S.L., Keck, Jr. P.E., Pope, H.G., Hudson, J.I., Faeda, G.L., Swann, A.C., 1992. Clinical and research implications of the diagnosis of dysphoric or mixed mania. Am. J. Psychiatry 149, 1633–1644. Perugi, G., Akiskal, H.S., Micheli, C., Musetti, L., Paiano, A., Quilici, C., Rossi, L., Cassano, G.B., 1997. Clinical subtypes of bipolar mixed states: Validating a broader European definition in 143 cases. J. Affect. Disord. 43, 169–180.
253
Prien, R.F., Himmelholch, J.M., Kupfer, D.J., 1988. Treatment of mixed mania. J. Affect. Disord. 15, 9–15. Sharma, V., Pistor, L., 1999. Treatment of bipolar mixed state with olanzapine. J. Psychiatry Neurosci. 24, 40–44. Swann, A.C., 1995. Mixed or dysphoric manic states: psychopathology and treatment. J. Clin. Psychiatry 56 (suppl 3), 6–10. Tohen, M., Greenfield, S.F., Weiss, R.D., Zarate, Jr. C.A., Vagge, L.M., 1998. The effect of comorbid substance use disorders on the course of bipolar disorder: a review. Harv. Rev. Psychiatry 6, 133–141. Tohen, M., Sanger, T.M., McElroy, S. et al., 1999a. Olanzapine versus placebo in the treatment of acute mania. Am. J. Psychiatry 156, 702–709. Tohen M., Jacobs T., Sanger T. 1999b. Is olanzapine a mood stabilizer? Presented at: Annual Meeting of the American College of Neuropsychopharmacology; Acapulco, Mexico, December, 1999. Tran, P.V., Tollefson, G.D., Sanger, T.M., Lu, Y., Berg, P.H., Beasley, Jr. C.M., 1999. Olanzapine versus haloperidol in the treatment of schizoaffective disorder: acute and long-term therapy. Br. J. Psychiatry 174, 15–22. Zullino, D., Baumann, P., 1999. Olanzapine for mixed episodes of bipolar disorder. J. Psychopharmacol. 13, 198, (Letter).
Research report
Use of olanzapine in dysphoric mania ´ A. Gonzalez-Pinto a , *, B. Lalaguna a , F. Mosquera a , J.L. Perez de Heredia a , M. Gutierrez a , a b c,d J. Ezcurra , I. Gilaberte , M. Tohen a
Psychiatric Department, Santiago Apostol Hospital, Osakidetza Mental Health System, Olaguibel 29, 01004 Vitoria, Spain b Clinical Research Department, Lilly, Vitoria, Spain c Department of Psychiatry, Harvard Medical School, McLean Hospital, Belmont, MA, USA d Lilly Research Laboratories, Indianapolis IN, USA Received 3 May 2000; received in revised form 11 September 2000; accepted 20 September 2000
Abstract Background: The simultaneous presentation of both manic and depressive symptoms has long been recognized. Nevertheless, a variable prevalence of dysphoric mania has been reported. The aim of this study was to estimate the prevalence of dysphoric mania among hospitalized patients and to assess the effectiveness of olanzapine in this type of patients. Methods: Eighty-six patients who met DSM-IV criteria for mania were evaluated at admission with a protocol that included McElroy’s criteria for dysphoric mania [Am. J. Psychiatry 149 (1992) 1633]. Treatment was administered according to clinical need, using mood stabilizers combined with antipsychotics. Sequential assessments were conducted throughout the study. Results: Forty-four patients (51.2%) fulfilled McElroy’s criteria for dysphoric mania. Fourteen of these dysphoric patients were treated with olanzapine in combination with mood-stabilizers. All patients improved in manic symptoms but patients treated with olanzapine improved significantly more than those treated with other antipsychotics in depressive symptoms. Limitations: The lack of randomization is a methodological limitation of this study, so these findings should be considered as preliminary. Conclusions: Dysphoric symptoms are common in this population of manic patients. Olanzapine in combination with mood-stabilizers may be effective in these patients. Additional controlled studies are needed to replicate these results. 2001 Elsevier Science B.V. All rights reserved. Keywords: Dysphoric mania; Naturalistic study; Olanzapine; Prevalence
1. Introduction
*Corresponding author. Tel.: 1 34-945-007-769; fax: 1 34945-007-764. E-mail address: [email protected] (A. GonzalezPinto).
Mania and depression are frequently viewed as polar opposites. However some manic patients simultaneously experience prominent depressive symptoms (Goodwin and Jamison, 1990). Carlson and Goodwin (1973) described that, before the
0165-0327 / 01 / $ – see front matter 2001 Elsevier Science B.V. All rights reserved. PII: S0165-0327( 00 )00313-X
248
A. Gonzalez-Pinto et al. / Journal of Affective Disorders 66 (2001) 247 – 253
psychopharmacological era, mania had three stages. In the third stage, the most severe form, psychotic symptoms and dysphoria were prominent. Dysphoric or mixed mania was described by Kraepelin in his book Manic-Depressive Insanity and Paranoia (Kraeplin, 1920). The course of mixed states, in Kraepelin’s words, ‘‘appears in general to be lingering and may be regarded as unfavorable forms of manic depressive insanity’’. Kraepelin included in the mixed states six different types of manic and depressive symptom combinations, so there were manic phases with depressive symptoms and also depression phases with manic symptoms. These states included depressive or anxious mania, excited or agitated depression, mania with poverty of thought, manic stupor, depression with flight of ideas, and inhibited mania. In a very interesting paper about mixed states, Perugi et al. (1997) found that the majority of the mixed states defined by Kraepelin are manic or mixed phases with depressive symptoms, and only 17.5% were depressions. As DSM-IV criteria are especially restrictive — it is necessary to have a complete mania and a complete depression for the diagnosis — this syndrome has been considered rather infrequent and has provoked little attention in the literature. Nevertheless, some authors have recently tried to change this position. McElroy used the term dysphoric or mixed as equivalents and proposed diagnostic criteria for dysphoric or mixed mania using DSM-III-R criteria for affective disorders (McElroy et al., 1992). According to McElroy, the simultaneous presence of mania and at least two associated depressive symptoms is considered as a probable diagnosis of dysphoric mania. More recently there have been some authors that have proposed that mania has a dysphoric dimension (Cassidy et al., 1998; Dilsaver et al., 1999), with a bimodal distribution according to Cassidy. That affirmation obliges one to look for depressive symptoms in patients suffering from mania, and to assess also the outcome of these depressive symptoms in the clinical trials of mania. Criteria used by different authors have contributed to the variable prevalence for this disorder across studies and populations. At least 30–40% of all manic states are probably dysphoric, although there have been reports of rates from 5 to 70% (Goodwin and Jamison, 1990). The high energy and impulsivity
typically associated with this disorder create a substantial risk of suicide (Swann, 1995). Pharmacotherapy in general may be less effective for patients in mixed states. Dilsaver et al. (1993) reported that patients with mixed states were significantly less responsive to monotherapy with any mood-stabilizer than were patients with pure mania. These patients responded to treatment with combinations of lithium, valproate, and / or carbamazepine, or with electroconvulsive therapy. In a retrospective study, it was found that patients treated with divalproex sodium or with lithium / carbamazepine combinations had significantly shorter lengths of hospital than patients treated with lithium or carbamazepine alone (Frye et al., 1996). Olanzapine is a new antipsychotic effective in schizophrenia and schizophreniform disorders. Preliminary data suggest that olanzapine may have antimanic properties in adults with schizoaffective disorder, bipolar type (Tohen et al., 1998; Tran et al., 1999). Recently it has been reported that olanzapine was superior to placebo (Tohen et al., 1999a,b) and at least as effective as lithium (Berk et al., 1999) in the treatment of the acute mania. Olanzapine, added to the previous drug regime, has also been reported to be effective and well-tolerated in an open trial in nine patients with bipolar mixed state previously refractory to mood-stabilizers used alone or in combination with antipsychotics (Sharma and Pistor, 1999). Considering the high prevalence of dysphoric symptoms in acute mania, we conducted a study to estimate the prevalence and severity of dysphoric symptoms in patients suffering from mania. We also evaluated the effectiveness of olanzapine in these patients in a naturalistic setting.
2. Method All patients admitted to the Santiago Hospital Psychiatric Unit, with a DSM-IV (American Psychiatric Association, 1994) diagnosis of bipolar disorder, manic or mixed episode, were included in this study. Santiago Hospital receives patients from a catchment area of 350 000 inhabitants and is the only psychiatric general hospital for acute patients in the state.
A. Gonzalez-Pinto et al. / Journal of Affective Disorders 66 (2001) 247 – 253
Diagnoses were made by at least two research psychiatrists (BL, JPH) using the Structured Clinical Interview for DSM-IV, Patient Version (SCID-P). A best estimated procedure was established to determine the final diagnosis. When there was any doubt about diagnoses, another research psychiatrist was consulted, and if there was no agreement between both diagnosticians, patients were excluded from the study. Researchers assessed patients during hospitalization while blind to prescribed medication. At least one family member always corroborated the patient’s history. A total of 86 patients were evaluated during a 2-year period between March 1996 and February 1998, with a clinical protocol at admission and discharge. In addition to the SCID-P for DSM-IV, the protocol included McElroy’s criteria for dysphoric mania, the Hamilton Depression Rating Scale (HAMD), the Young Mania Rating Scale (YMRS), the Positive and Negative Syndrome Sclae (PANSS), and the Clinical Global Impressions (CGI) scale. For the diagnosis of dysphoric mania, we used the McElroy’s criteria for probable dysphoric mania (two or more depressive symptoms). Treatment was administered with clinical criteria. We reported here the follow-up of 44 of these patients who were diagnosed of dysphoric mania with this protocol. Fourteen patients with dysphoric mania were treated with olanzapine in combination with mood-stabilizers, and were compared with 30 dysphoric patients treated with other antipsychotics in combination with mood-stabilizers. Of the 30 patients treated with other antipsychotics, 27 were treated with combinations of haloperidol and levomepromazine (haloperidol 10–30 mg / day and levomepromazine 75– 300 mg / day) and three were treated with haloperidol (haloperidol 10–20 mg / day). A descriptive statistical analysis was carried out, bivariant using x 2 -test for the comparison of qualitative variables and Student’s t-test for quantitative variables were used. When there was not a normal distribution of the variables non-parametric tests were performed (Mann–Whitney U-test). All tests were two-tailed and a 0.05 level of significance was used. A logistic regression model was adjusted with a predictive aim to assess a favourable outcome in depressive symptoms measured by a decrease of at
249
least 80% in the Hamilton Depression Rating Scale. Variables previously related with outcome in bipolar disorder were included (Goldberg and Harrow, 1999); two demographic variables (age and gender), four variables related with the course of the illness (age of onset, years of illness, number of episodes and suicidal attempts), and two related with drug administered (lithium and olanzapine). In addition, we also included two variables related with hospitalization (compulsory admission and length of hospitalization) that could also be related with outcome on these patients.
3. Results Forty-four patients (51.2%) fulfilled McElroy’s criteria for dysphoric mania (23 women, 21 men), and 42 (48.8%) had one or fewer symptoms (17 women, 25 men). The average age was 37.1611.8 years. The mean age of onset of illness was 26.369.7 years, with a median age of 24 years, and 25.58% of the sample was married. The average number of previous episodes was 4.664.5. There were more women with dysphoric mania, although the differences were non-significant (Pearson x 2 5 1.2; df 5 1; P 5 0.27) (Table 1). Patients with dysphoric symptoms had significantly fewer manic symptoms measured by YMRS (separate variances, t 5 2 3.25; P 5 0.002) at admission and a tendency to have fewer manic symptoms at discharge (t 5 2 1.9; df 5 83; P 5 0.06). Dysphoric patients had more depressive symptoms at admission (separate variances, t 5 2.9; df 5 83.4; P 5 0.005), but not at discharge (t 5 1.049; df 5 84; P 5 0.29). All manic patients, dysphoric and non-dysphoric, were treated with mood stabilizers and antipsychotics. Pharmacological treatment was recorded in all but one patient. Patients with dysphoric mania were treated more frequently with valproate (Table 1). Fourteen dysphoric manic patients were treated with olanzapine (5–20 mg / day) at variable doses, depending on clinical state and with clinical criteria. Olanzapine was used in combination with moodstabilizers (lithium and valproate). The remaining 30 patients were treated with other antipsychotics, mostly haloperidol and levomepromazine. There were no
A. Gonzalez-Pinto et al. / Journal of Affective Disorders 66 (2001) 247 – 253
250
Table 1 Demographic and clinical characteristics of patients with dysphoric a and pure mania Variable
Pure mania (n 5 42)
Dysphoric mania (n 5 44)
Statistics
P Value
Age (mean6S.D.) Male, n (%) Compulsory admission Years of illness (mean6S.D.) Days of hospitalization (mean6S.D.) Number of previous episodes Valproate, n (%)
36.09613.07 25 (29.07) 24 (27.91) 10.9611.66 17.22611.97 5.0765.77 15 (17.65%)
38.08610.44 21 (24.42) 18 (20.93) 11.33610 20.77610.4 4.2562.8 34 (40%)
t 5 0.77 x 2 5 1.20 x 2 5 2.26 UMW 5 774.0 UMW 5 630.5 UMW 5 902.0 x 2 5 14.39
NS NS NS NS P 5 0.036 NS P , 0.001
a
Two or more symptoms of McElroy criteria.
severe adverse effects during the hospitalizations. Patients receiving olanzapine did not experience any extrapyramidal symptoms. Characteristics of the patients treated with olanzapine were not different from those treated with other antipsychotics, except in their baseline scores on the YMRS (Table 2). Patients treated with olanzapine improved more than those treated with other antipsychotics in manic symptoms (differential YMRS score in the olanzapine group, mean 5 29.35; S.D. 5 9,73; non-olanzapine group, mean 5 19.6; S.D. 5 12,45; t 5 2.82; df 5 32,1; P 5 0.008) and in depressive symptoms (differential HAMD punctuation in the olanzapine group, mean 5 15.71; S.D. 5 5.22; non-olanzapine group, mean 5 11.9; S.D. 5 7.08; separate variances, t 5 2.00; df 5 33.8; P 5 0.05) (Fig. 1). There were no significant differences between the groups in terms of hospital length of stay (olanzapine group,
Fig. 1. Differential scores in the YMRS and HAMD. ** P 5 0.008; * P 5 0.05.
22.1468.19 days; non-olanzapine group, 20.10610.78 days; t 5 0.67; df 5 32.1; P 5 0.5). In a logistic regression model conducted to analyze the differences between patients with poorer and better
Table 2 Characteristics of the sample treated and untreated with olanzapine a Variable
Olanzapine (n 5 14)
Non-olanzapine (n 5 30)
Statistics
P value
Age (mean6S.D.) Male, n (%) Compulsory admission Lithium Valproate Number of episodes Days of hospitalization Years of illness PANSS admission YMRS admission HAMD admission CGI admission
39.1468.37 5 (11.36) 7 (15.91) 7 (15.91) 12 (27.27) 5.2162.88 22.1468.49 12.4269.26 77.57614.16 33.6468.68 19.0066.61 5.0760.91
37.58611.37 16 (36.36) 11 (25%) 12 (27.27) 22 (50%) 3.8062.80 20.10610.78 10.80610.46 74.13618.66 24.39614.25 16.8667.58 4.7561.32
t 5 0.50 x 2 5 1.18 x 2 5 0.7 x 2 5 0.38 Fisher exact test UMW 5 14.65 UMW 5 185.5 UMW 5 172.0 UMW 5 186.5 t 5 2.67 UMW 5 180.5 UMW 5 181.0
NS NS NS NS NS NS NS NS NS P 5 0.01 NS NS
a
CGI, Clinical Global Impressions scale; HAMD, Hamilton Depression Rating Scale; PANSS, Positive and Negative Syndrome Scale; YMRS, Young Mania Rating Scale.
A. Gonzalez-Pinto et al. / Journal of Affective Disorders 66 (2001) 247 – 253
251
Table 3 Logistic regression model of variables associated with a hamilton decrease of 80% or more Parameter
Estimate
S.E.
t value
P value
Odds ratio
Constant Male Age . 30 Number of episodes $ 5 Years of illness . 10 Age at onset . 25 Suicidal attempts Days of hospitalization $ 21 Compulsory admission Olanzapine Lithium
2 2.930 2 0.250 6.786 2 2.061 2 2.661 2 2.811 2 0.333 0.260 2 0.728 2.404 0.579
1.865 1.052 2.602 1.234 1.685 1.805 1.074 0.983 0.996 1.196 0.995
2 1.571 2 0.237 2.608 2 1.669 2 1.580 2 1.557 2 0.310 0.265 2 0.731 2.009 0.583
0.116 0.813 0.009 0.095 0.114 0.119 0.757 0.791 0.465 0.045 0.560
0.779 885.092 0.127 0.070 0.060 0.717 1.297 0.483 11.063 1.785
outcomes in depressive symptoms measured with the HAMD, we found that being older than 30 years, and being treated with olanzapine were the two factors associated with better outcome (Table 3).
4. Discussion Almost half of patients admitted to our hospital with acute mania experienced two or more depressive symptoms. It is important to notice that we included in our sample all manic patients hospitalized in an area of 350 000 inhabitants. Therefore, it is a representative sample of the disease in the general population. In a multicenter study conducted by Akiskal in France, 37% of their sample of mania were diagnosed of dysphoric mania when they used McElroy criteria (Akiskal et al., 1998). Our rates are slightly higher probably because our patients are all hospitalized, so there are no patients with mild manic symptoms in our sample. It is clear, at this point, that mixed mania is a frequent syndrome, and that depressive symptoms are common during mania (Prien et al., 1988). However, this fact is not reflected on the assessment scales of mania which do not include depressive symptoms, and for this reason, these symptoms could be non-appropriate assessed with the current instruments. Cassidy et al. (1998) investigating the dimensions of mania have considered that any of the current mania scales is suitable to assess the dysphoric aspect of the mania. However, the high percentage of patients with depressive symptoms
during mania should cause us to reflect on the need to evaluate this type of patients more precisely. This is especially important because it has therapeutic implications and suicidality is linked with mixed manic states (Goldberg et al., 1998). These affective states do not seem to respond well to conventional pharmacotherapy for mania and depression. Mixed states tend to respond better to anticonvulsants than to lithium salts, and for that reason dysphoric patients of our sample are treated significantly more frequently with divalproex. Dysphoric patients have also significantly longer inpatient stays than purely manic patients. As we show in our data, other reports on current literature have also found longer hospitalizations in patients with dysphoric or mixed episodes than pure manic (Keller et al., 1986; Devenand et al., 2000): Keller et al. found in a sample of 130 patients that episodes of dysphoric mania had significantly longer duration than episodes of pure mania and major depression; also, in that sense, Devenand et al. found that patients with mixed mania receiving ECT had longer hospitalizations than pure mania and major depression treated also with ECT. So it seems that the prolonged time to recovery in dysphoric patients is related not only to the difficulty in finding the appropriate treatment, but also to the pathophysiology of the disease. The prolonged time to recovery is associated with poor outcome in bipolar disorder (Keck et al., 1998). We find in our sample that being older than 30 years is a factor indicative of a better outcome in depressive symptoms during a mixed episode. This can be related to the fact that patients with mixed
252
A. Gonzalez-Pinto et al. / Journal of Affective Disorders 66 (2001) 247 – 253
states tend to have higher rates of depression early in the course of the illness (McElroy et al., 1992) and also that maturity can help complete recovery. All patients improved in manic symptoms. Patients treated with olanzapine improved more than those treated with other antipsychotics in manic symptoms, but we have to consider that their baseline scores on the Young Mania Rating Scale were higher; hence the differences could be biased by group differences at admission. Patients treated with olanzapine improved more in depressive symptoms than those treated with other antipsychotics during the hospitalizations. There are some cases in the literature of olanzapine augmentation in mixed episodes (Ketter et al., 1998; Sharma and Pistor, 1999; Zullino and Baumann, 1999). We report here a naturalistic assessment of olanzapine in dysphoric mania. Our results suggest that olanzapine combined with mood-stabilizers appears to be more effective than typical antipsychotics in the treatment of the depressive symptoms of dysphoric mania. Our preliminary observations have some methodological limitations. Patients were not randomized, although assessments were blind (clinical raters blind to the treatment group). The lack of randomization might have contributed to a differential treatment by the treating clinicians. Olanzapine was administered concomitantly with other mood-stabilizers, so the benefit of this treatment may be due to olanzapine alone or to a synergistic effect of olanzapine with mood-stabilizers. For all these reasons, these findings need to be considered as preliminary, pending substantiation replication in controlled trials. However, even when these limitations are considered, olanzapine appeared to show superior efficacy in the depressive symptoms of dysphoric mania.An advantage of our study compared with controlled doubleblind trials is that we include all manic patients, including a representative sample of a clinical population of an area without using strict selection criteria. In contrast, clinical trials often may not include the type of patients clinicians ordinarily treat (Goldberg and Harrow, 1999). Moreover, the naturalistic characteristics of this study provides additional and complementary information to clinical trials very valuable for clinicians (Blacker and Mortimore, 1996).
Acknowledgements This work was supported by a grant of the FIS no. 97 / 0851, and in part by a small grant from Lilly SA (Spain).
References Akiskal, H.S., Hantouche, E.G., Bourgeois, M.L., Azorin, J.M., ˆ Sechter, D., Allilaire, J.F., Lancrenon, S., Fraud, J.P., Chatenetˆ Duchene, L., 1998. Gender, temperament and the clinical picture in dysphoric mixed mania: findings for a french national study (EPIMAN). J. Affect. Dis. 50, 175–186. American Psychiatric Association, 1994. Diagnostic and Statistical Manual of Mental Disorders, 4th Edition. American Psychiatric Press, Washington, DC. Berk, M., Ichim, L., Brook, S., 1999. Olanzapine compared to lithium in mania: a double-blind randomized controlled trial. Int. Clin. Psychopharmacol. 14, 339–343. Blacker, C.V.R., Mortimore, C., 1996. Randomized controlled trials and naturalistic data: time for a change? Hum. Psychopharmacol. 11, 353–363. Carlson, G.A., Goodwin, F.K., 1973. The stages of mania: a longitudinal analysis of the manic episode. Arch. Gen. Psychiatry 28, 221–228. Cassidy, F., Forest, K., Murry, E., Carroll, B.J., 1998. A factor analysis of the signs and symptoms of mania. Arch. Gen. Psychiatry 55, 27–32. Devenand, D.P., Polanco, P., Cruz, R., Shah, S., Pykina, N., Singh, K., Majors, L., 2000. The efficacy of ECT in mixed affective states. J. ECT 16, 32–37. Dilsaver, S.C., Swann, A.C., Shoaib, A.M., Bowers, T.C., Halle, M.T., 1993. Depressive mania associated with nonresponse to antimanic agents. Am. J. Psychiatry 150, 1548–1551. Dilsaver, S.C., Chen, Y.R., Shoaib, A.M., Swann, A.C., 1999. Phenomenology of mania: evidence for distinct depressed, dysphoric and euphoric presentations. Am. J. Psychiatry 156, 426–430. Frye, M.A., Altshuler, L.L., Szuba, M.P., Finch, N.N., Mintz, J., 1996. The relationship between antimanic agents for treatment of classic or dysphoric mania and length of hospital stay. J. Clin. Psychiatry 57, 17–22. Goldberg, J.F., Garno, J.L., Leon, A.C., Kocsis, J.H., Portera, L., 1998. Association of recurrent suicidal ideation with nonremission from acute mixed mania. Am. J. Psychiatry 155, 1753– 1755. Goldberg, J.F., Harrow, M., 1999. Poor-outcomes. In: Goldberg, J.F., Harrow, M. (Eds.), Bipolar Disorders: Clinical Course and Outcomes. American Psychiatric Press, Washington, DC. Goodwin, F.K., Jamison, K.R., 1990. Diagnosis. In: Goodwin, F.K., Jamison, K.R. (Eds.), Manic Depressive Illness. Oxford University Press, New York, NY. Kraepelin E., 1920. Die Erscheinungsformen des Irreseins. Z ges
A. Gonzalez-Pinto et al. / Journal of Affective Disorders 66 (2001) 247 – 253 Neurol Psychiatr 62:1-29. Translated by H. Marshall, 1974, in Themes and Variations in European Psychiatry. Hirsch, Sheperd (Editors). University Press of Virginia, Charlottesville, VA. Keck, P.E., McElroy, S.L., Strakowsky, S.M., West, S.A., Sax, K.W., Hawkins, J.M., Bourne, M.L., Haggard, P., 1998. 12month outcome of patients with bipolar disorder following hospitalization for a manic or mixed episode. Am J Psychiatry 155, 646–652. Keller, M.B., Lavori, P.W., Coryell, W., Andreasen, N.C., Endicott, J., Clayton, P.J., Klerman, G.L., Hirschfeld, R.M.A., 1986. Differential outcome of pure manic, mixed / cycling, and pure depressive episodes in patients with bipolar illness. J. Am. Med. Assoc. 255, 3138–3142. Ketter, T.A., Winsberg, M.E., De Golia, S.G., Dunai, M., Tate, D.L., Strong, C.M., 1998. Rapid efficacy of olanzapine augmentation in nonpsychotic bipolar mixed states. J. Clin. Psychiatry 59, 83–84, (Letter). McElroy, S.L., Keck, Jr. P.E., Pope, H.G., Hudson, J.I., Faeda, G.L., Swann, A.C., 1992. Clinical and research implications of the diagnosis of dysphoric or mixed mania. Am. J. Psychiatry 149, 1633–1644. Perugi, G., Akiskal, H.S., Micheli, C., Musetti, L., Paiano, A., Quilici, C., Rossi, L., Cassano, G.B., 1997. Clinical subtypes of bipolar mixed states: Validating a broader European definition in 143 cases. J. Affect. Disord. 43, 169–180.
253
Prien, R.F., Himmelholch, J.M., Kupfer, D.J., 1988. Treatment of mixed mania. J. Affect. Disord. 15, 9–15. Sharma, V., Pistor, L., 1999. Treatment of bipolar mixed state with olanzapine. J. Psychiatry Neurosci. 24, 40–44. Swann, A.C., 1995. Mixed or dysphoric manic states: psychopathology and treatment. J. Clin. Psychiatry 56 (suppl 3), 6–10. Tohen, M., Greenfield, S.F., Weiss, R.D., Zarate, Jr. C.A., Vagge, L.M., 1998. The effect of comorbid substance use disorders on the course of bipolar disorder: a review. Harv. Rev. Psychiatry 6, 133–141. Tohen, M., Sanger, T.M., McElroy, S. et al., 1999a. Olanzapine versus placebo in the treatment of acute mania. Am. J. Psychiatry 156, 702–709. Tohen M., Jacobs T., Sanger T. 1999b. Is olanzapine a mood stabilizer? Presented at: Annual Meeting of the American College of Neuropsychopharmacology; Acapulco, Mexico, December, 1999. Tran, P.V., Tollefson, G.D., Sanger, T.M., Lu, Y., Berg, P.H., Beasley, Jr. C.M., 1999. Olanzapine versus haloperidol in the treatment of schizoaffective disorder: acute and long-term therapy. Br. J. Psychiatry 174, 15–22. Zullino, D., Baumann, P., 1999. Olanzapine for mixed episodes of bipolar disorder. J. Psychopharmacol. 13, 198, (Letter).