Quetiapine in the treatment of rapid cycling bipolar disorder

Copyright ª Blackwell Munksgaard 2002 Bipolar Disorders 2002: 4: 335–340 BIPOLAR DISORDERS ISSN 1398-5647 Original Article Quetiapine in the treatment of rapid cycling bipolar disorder Vieta E, Parramon G, Padrell E, Nieto E, Martinez-Arán A, Corbella B, Colom F, Reinares M, Goikolea JM, Torrent C. Quetiapine in the treatment of rapid cycling bipolar disorder. Bipolar Disord 2002: 4: 335–340. ª Blackwell Munksgaard, 2002 Introduction: This prospective open-label study assessed the impact of add-on quetiapine in the treatment of rapid cycling bipolar patients. Methods: Fourteen rapid cycling bipolar patients were treated with quetiapine, which was added to their ongoing medication regimen for 112 ± 33 days. At the beginning of the study, five were manic, three were in a mixed state, three were depressed, two hypomanic and one was euthymic. Patients were assessed prospectively with a modified version of the Clinical Global Impression Scale for Bipolars (CGI-BP), the Young Scale for mania (YMRS) and the Hamilton Scale for Depression (HDRS). Eduard Vieta, Gemma Parramon, Elena Padrell, Evaristo Nieto, Anabel Martinez-Arán, Barbara Corbella, Francesc Colom, Maria Reinares, Jose M Goikolea and Carla Torrent Bipolar Disorders Program, Hospital Clı́nic, University of Barcelona, Barcelona, Spain Results: A significant reduction of the following scale scores was observed: • a 1.8 point reduction for the general CGI-BP (p ¼ 0.013), • a –1.3 point for the mania subscale (p ¼ 0.016), • a –1.01 point for the YMRS (p ¼ 0.025). Improvement in depressive symptoms was not significant, neither in the CGI-BP (–1 point, p ¼ 0.074) nor in the HDRS (–5.2 points, p ¼ NS). The most common side-effect was sedation (n ¼ 6, 43%). Doses of quetiapine were significantly reduced by the end of the study (443 ± 235 mg/day versus 268 ± 190 mg/day, p ¼ 0.008) and they also differed according to the initial episode to be treated (720 ± 84 mg/day for mania, and 183 ± 29 mg/day for depression, p ¼ 0.023). Key words: bipolar disorder – clinical trial – mania – quetiapine – rapid cycling Conclusions: Quetiapine could possibly be an effective treatment for rapid cycling bipolar patients. Adequate doses for acute episodes could significantly differ according to the episode polarity and the length of treatment. Corresponding author: Dr Eduard Vieta, Hospital Clı́nic, University of Barcelona, Villarroel 170, 08036 Barcelona, Spain. Tel.: +34 93 2275401; fax: +34 93 2275477; e-mail: evieta@clinic.ub.es Quetiapine is an atypical antipsychotic that has proven to be efficacious in the treatment of schizophrenia with a rather benign side-effect profile (1, 2). Controlled data on the treatment of bipolar disorder with this drug are not available yet, but Ghaemi and Katzow (3) have published good results with six treatment resistant patients, and Zarate et al. (4), in a retrospective study, analysed the quetiapine response in a heterogeneous group of psychotic patients. Among all of them, bipolar patients sustained the highest response rate. Finally, Sajatovic et al. (5) found quetiapine to be Received 4 September 2001, revised and accepted for publication 28 February 2002 effective in bipolar patients who were sub-optimally responsive to mood-stabilizers alone. Given the scant data regarding the use of quetiapine in bipolar disorder, the present study was designed to assess the short and long-term impact of add-on quetiapine in rapid cycling bipolar patients. Patients and methods After giving informed consent, 14 DSM-IV rapid cycling bipolar patients participated in this study. 335 Vieta et al. All patients had previously received a number of treatments for their illness. When they started the quetiapine treatment, five patients met DSM-IV criteria for a manic episode, three for a mixed episode, three for a depressive episode, two for a hypomanic episode and one was euthymic. Quetiapine was added to their ongoing psychotropic treatment, while the other medication dosage was maintained. All of them had a history of enduring rapid cycling despite stopping antidepressants. Table 1 summarizes the clinical characteristics of the cohort and the concomitant medication that they were taking during the study, together with pre- and post-quetiapine long-term course data. Quetiapine dosage was titrated by the physicians according to tolerability and the observed clinical response. The starting dose was 50 mg/day, and it was increased every 2–4 days, except for manic patients, who deserved a more rapid titration. The efficacy of quetiapine was evaluated using the Global Clinical Impression for Bipolar Disorder scale (CGI-BP, 6). The CGI-BP scale has three sub-scales, a general one, a manic and a depressive one with seven severity degrees for each. At each visit, besides the CGI-BP, the Young Mania Rating Scale ratings (YMRS, 7), the 17-item Hamilton Depression Rating Scale ratings (HDRS, 8) and side-effects were also assessed. Patients were seen at first every 2 weeks and later on, on a monthly basis. They were instructed to contact the clinic as soon as they would notice any serious side-effect or any prodromal symptoms. (3 ± 1.9 versus 2 ± 0.8, Wilcoxon z ¼ –1.78, p ¼ 0.074). According to the CGI-BP overall evaluation, six patients (43%) were in complete remission (normal or minimally ill). The improvement of manic symptoms was also observed with the YMRS (17.2 ± 11.6 versus 7.1 ± 4.7, Wilcoxon z ¼ –2.23, p ¼ 0.025). Those patients who were manic at the the beginning of the study experienced an average reduction of 16.4 points in the YMRS (27 ± 3.9 versus 10.6 ± 11.2, Wilcoxon z ¼ –1.82, p ¼ 0.067). The patients who were either hypomanic or in a mixed state, showed an average decrease on their YMRS score of 13.5 and 13.0 points, respectively. Regarding depressive symptoms, what could be observed was a nonsignificant reduction of the HDRS average score for all patients included in the study (12.3 ± 9.6 versus 7.1 ± 4.7, Wilcoxon z ¼ –1.41, p ¼ NS), which was obviously more prominent in those patients (25.3 ± 1.2 versus 9.7 ± 3.2, Wilcoxon z ¼ –1.60, p ¼ 0.11) with a depressive index episode. A patient who was included in the study with a manic episode, responded well at first instance but had to be subsequently hospitalized for another manic episode 8 weeks later. Two other patients who were included in the study, one in a manic state, the other hypomanic, they both cycled to depressive episodes, although without the need for admission. One of them continued cycling with the same frequency as before the treatment with quetiapine (see comments in Table 1). Results The 14 rapid cyclers included in the study were prospectively followed and evaluated during a period of 112 ± 33 days (range: 63–167). A complete evaluation was obtained for all patients at least for the first three visits. After that, four patients dropped out, two because of lack of response or worsening of symptoms, one for undesirable side-effects (weight gain) and another because of poor compliance. Efficacy The addition of quetiapine produced a statistically significant improvement on two of the three CGIBP sub-scales. On intent to treat analysis, these were the observations: a reduction of 1.8 points on the general sub-scale (4.5 ± 1.2 versus 2.7 ± 1.4, Wilcoxon z ¼ –2.39, p ¼ 0.013), a reduction of 1.3 points on the manic sub-scale (3.5 ± 1.7 versus 2.2 ± 1.5, Wilcoxon z ¼ –2.39, p ¼ 0.016) and a 1 point reduction for the depression sub-scale 336 Tolerability The study ended with only one drop-out because of adverse side-effects (4.2 kg weight increase in a 6-week period). Although three other patients also complained of weight gain they chose to stay in treatment because of its efficacy. The most common side-effect was drowsiness (n ¼ 6, 43%). Most side-effects were low or moderately severe. Six patients (43%) did not report any side-effect. There was no single case of tardive dyskynesia reported. Individual safety is provided in Table 1. Dosage The average dose of quetiapine was very different according to the index episode and the duration of the treatment. Patients who started in a manic state received a mean dose of 720 ± 84 mg/day by day 15 of treatment, but by the 12th week their average dose had been reduced to 360 ± 270 mg/day (Wilcoxon z ¼ –1.82, p ¼ 0.068). Table 1. Summary of data of the follow-up of 14 rapid cycling bipolar patients treated with adjunctive quetiapine Patient Age Sex Index episode Duration of Maximal Final Drop treatment (days) dose dose out Diagnosis Duration of illness History of Substance Suicide psychosis abuse attempts Inpatient (Y) No episodes last year Duration of rapid cycling Concomitant medication Side effects Outcome 32 F Hypomania 300 300 No 139 B II No Yes Yes No 8 11 3 Lithium Topiramate Flunitrazepam None Stopped cycling with quetiapine 2 45 M Mania 800 300 No 127 BI No No No No 23 4 1 Carbamazepine Clothiapine Thyroxine Biperiden Clonazepam Akathysia Tremor Nausea Drowsiness Switched to depression but improved after a reduction of the dose of quetiapine and remained slightly depressed 3 23 F Depresssion 200 200 No 88 BI Yes Yes No No 3 8 2 Carbamazepine Venlafaxine Paroxetine None Stopped cycling with quetiapine 4 35 M Mania 600 400 No 112 BI Yes Yes No Yes 6 6 2 Carbamazepine Topiramate Levomepromazine Clonazepam Weight gain Headache Drooling Drowsiness Responded well initially but relapsed with mania after decreasing the dose, and responded again at higher doses 5 34 F Euthymia 200 200 Yes 63 BI No Yes Yes No 12 10 4 Valproate Lamotrigine Paroxetine Clomipramine Lorazepam None Dropped out because of poor compliance 6 47 F Mixed 400 400 Yes 90 BI Yes Yes Yes Yes 8 12 2 Lithium Valproate Clothiapine Clonazepam Weight gain Drowsiness Dropped out because of lack of efficacy 7 22 F Depression 150 100 No 98 BI No No No No 4 5 1 Lithium Gabapentin Lorazepam Paroxetine None Stopped cycling with quetiapine; slightly depressed Quetiapine in the treatment of rapid cycling 337 1 Vieta et al. 338 Table 1. (Continued) Patient Age Sex Index episode Duration of Maximal Final Drop treatment (days) dose dose out Diagnosis Duration of illness History of Substance Suicide psychosis abuse attempts Inpatient (Y) No episodes last year Duration of rapid cycling Concomitant medication Side effects Outcome 8 31 M Mania 700 200 No 167 BI Yes No No Yes 9 5 2 Lithium Valproate Topiramate Clonazepam None Stopped cycling with quetiapine 9 56 F Depression 200 50 No 123 BI No No Yes No 24 8 7 Valproate Carbamazepine Venlafaxine Mirtazapine Lorazepam Dizziness Drymouth Tremor Drowsiness Stopped cycling with quetiapine; slightly depressed 10 43 M Mania 700 100 No 156 BI No No No No 5 4 1 Lithium Valproate Lorazepam Flunitrazepam Drowsiness Nausea Dizziness Fatigue Continued cycling at a less severe stage; does not tolerate high doses 11 38 F Mixed 450 300 No 156 BI No Yes Yes No 10 4 1 Lithium Mirtazapine Levomepromazine Drowsiness Dry mouth Stopped cycling with quetiapine 12 27 M Mania 800 800 Yes 69 BI No No No Yes 7 6 2 Lithium Valproate Gabapentin Lorazepam Weight gain Headache Nausea Dropped out because of lack of efficacy 13 33 F Mixed 300 100 No 100 BI No No No No 15 6 1 Valproate Carbamazepine Venlafaxine Clonazepam None Stopped cycling with quetiapine 14 49 F Hypomania 400 300 Yes 86 B II No Yes Yes No 13 13 3 Lithium Lamotrigine Thyroxine Weight gain Drowsiness Dropped out because of weight gain, and continued cycling Quetiapine in the treatment of rapid cycling The average maximum dose for depressed patients was 183 ± 29 mg/day, and by the end of the study, their average dose was 117 ± 76 mg/ day. Differences in the mean quetiapine dose between manic and depressed patients were statistically significant (Mann–Whitney z ¼ –2.28, p ¼ 0.023). The highest doses for mixed or hypomanic patients were 363 ± 76 and 350 ± 71 mg/ day, respectively. For the sample as a whole, the maximum average dose was 443 ± 235 mg/day and the final mean dose was 268 ± 190 mg/day (Wilcoxon z ¼ –2.66, p ¼ 0.008). Other medications The original psychotropic regimen for each patient was not modified, except for some benzodiazepines that were reduced. Blood levels of mood-stabilizers were observed not to significantly change after quetiapine addition. The concomitant treatments appear in Table 1. Eight patients were taking lithium (57%), seven valproate (50%) and five carbamazepine (36%), either alone or in combination. Discussion This add-on open-label study assessed the impact of quetiapine in the treatment of rapid cycling bipolar patients. Despite small sample size and open design, it stands as one of the few reports on the use of quetiapine in bipolar illness. It also has the limitation of the absence of a control group and the use of other medications concomitantly, but it may provide some information which is difficult to obtain from randomized clinical trials (9): ‘real world’, difficult-to-treat patients were included (generalizability), the safety of the combination of quetiapine with mood-stabilizers and other drugs could be assessed, and dosage was flexible giving some clues about the optimal use of the drug in real clinical conditions. Besides, the follow-up was longer than most standard clinical trials. The results suggest that quetiapine is an effective and safe treatment for rapid cycling bipolar patients. Results regarding quetiapine’s tolerance can be considered favourable. The most common sideeffect was sedation, which in some cases may be a reason to interrupt treatment, and in others a desirable effect for more agitated manic patients. Weight gain, a known side-effect for most atypical antipsychotics (10) was a complaint for 29% patients and the cause of only one treatment withdrawal. The low incidence of extrapyramidal effects and the absence of any tardive dyskinesia should also be mentioned, although the sample size was too small to draw any relevant conclusions. A very important issue regarding the use of quetiapine in bipolar patients is selecting the optimal dose. Again, one must be cautious to extrapolate results from this small sample, but significant dosage differences appeared. It seems that manic patients have a need for higher doses at first, allowing for a substantial reduction later on. Instead, depressed patients offer a better response to the low range doses. Thus, the higher the dose, the more antidopaminergic and inversely less antiserotonergic activity occur (11). Zarate et al. (4) in their retrospective study, found that the average dose for their moderate to good responders was higher (245 mg/day) than the average dose used in the minimum or non-responder cases (188 mg/day) and the responders were mostly bipolar patients. Another relevant aspect concerning the use of quetiapine is titration. Hence, this study throws some light into the titration rate of quetiapine in bipolar patients. The fact that only two patients reported hypotension and/or dizziness, plus the fact that sedation was not a major handicap, suggest that drug titration could have been a little faster, particularly for manic patients, as none of them suffered from hypotension. Naturally, other factors to be taken into account would be patients’ age, medical status and the concomitant medication used. With hypomanic, depressed or euthymic patients, rapid titration may not be so necessary. In rapid cyclers, the real treatment goal is not so much as to treat the current episode but to reduce the cycle frequency and to improve their long-term outcome (12). One of the most important reasons to be cautious with the interpretation of these results is the concomitant use of quetiapine with other psychotropics. However, when it comes to rapid cyclers, very often, polypharmacy is the only way to obtain euthymia (13). Given that the study respected the original dose of the other drugs and also kept at the same range the blood levels of mood-stabilizers, we believe that the observed effects on the patients were indeed the result of quetiapine addition. Nevertheless, in general, rapid cyclers and treatment-refractory bipolars respond poorly to placebo, especially long-term. On the other hand, the combination of quetiapine with the drugs listed in Table 1 proved to be feasible and safe. We believe that quetiapine may be a safe and effective therapeutical tool for the mid- and longterm treatment of rapid cyclers. The same has 339 Vieta et al. already been suggested for other atypical antipsychotics (14–16). Acknowledgements This study was supported by the Stanley Research Foundation (Bethesda, MD, USA), the Fondo de Investigaciones Sanitarias (FIS 00/1609) and Fundació Marató TV3 (01/2510). References 1. Borison RL, Arvanitis LA, Miller BG, US Seroquel Study Group. ICI 204, 636, an atypical antipsychotic. efficacy and safety in a multicenter, placebo–controlled trial in patients with schizophrenia. J Clin Psychopharmacol 1996; 16: 158–169. 2. Small JG, Hirsch SR, Arvanitis LA, Miller BG, Link CGG. Seroquel Study Group. Quetiapine in patients with schizophrenia: a high and low-dose double-blind comparison wit placebo. Arch Gen Psychiatry 1997; 54: 549–557. 3. Ghaemi SN, Katzow JJ. The use of quetiapine for treatment-resistant bipolar disorder: a case series. 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