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 Bipolar disorder is characterized by recurrent episodes of depression and either mania (type I) or hypomania (type II). It affects over 2.5% of the general population, although there is some evidence that this number is an underestimate if milder forms of BD are taken into consideration. There is a significant burden associated with BD and the WHO estimates that in 1990 it was the sixth leading worldwide cause of disability (1). BD is also associated with substance abuse, academic and work disruption, and relationship dysfunction (2). There are many effective treatments for the manic phase of the disorder, but treating depressive episodes (that is, bipolar depression) has proven difficult. The use of antidepressants alone increases the risk of a switch to mania or hypomania and may also increase the speed of cycling. Of all available mood stabilizers, only lithium salts and lamotrigine have shown some specific antidepressant effects; however, the response rate rarely exceeds 50%. Case reports and recent studies have indicated that the addition of an antipsychotic may be beneficial. Our clinical observations, including a retrospective chart review, also suggest that an addition of a well-tolerated and safe antipsychotic such as quetiapine may improve clinical outcomes. Quetiapine is now approved in Canada for treatment of schizophrenia and bipolar mania. Olanzapine, risperidone, and clozapine have received approval for use in the manic phase of BD. Further, an olanzapine–fluoxetine combination pill has recently been approved for the treatment of bipolar depression in the United States. Our trial was designed as a preliminary study to assess whether quetiapine is an effective addition in the treatment of the depressive phase of BD. If the results are statistically significant, further investigation is warranted, including randomized double-blind trials, larger sample populations, and greater frequency of assessment. Response is defined as a 50% reduction in the HDRS score or a score of 1 or 2 on the CGI, while remission is defined as a reduction of HDRS score to below 8. Our secondary objective is to assess the safety and tolerability of quetiapine in patients with BD. This study received ethics approval from the Research Ethics Board of Queen’s University in Kingston, Ontario. SampleThis prospective, open-label trial included patients recruited from an outpatient clinic in a specialized mood disorders service. To be included, patients were clinically diagnosed with type I or type II BD, were currently suffering from a major depressive episode, and had an HDRS score over 18. These patients were all aged 18 years and older and able to provide written informed consent. Patients were defined as having treatment-resistant bipolar depression if they had an HDRS score over 18 and 2 unsuccessful trials (that is, sufficient in dose and duration) of an antidepressant or mood stabilizer. A potential subject was excluded if he or she had current psychotic or mixed episode symptoms (as determined by an extensive initial assessment including a DSM-IVcriteria checklist), had taken other antipsychotics or depot neuroleptics within the 6 months prior to the study, or had been on an antidepressant for less than 1 month or changed the dosage less than 3 weeks prior to the start of the trial. We also excluded patients who had a known intolerance or sensitivity to quetiapine, a history of seizure disorders (except febrile seizures), were pregnant or lactating, or had an unstable or serious medical condition. There were 19 patients enrolled in this study. Of the participants, 6 were men and 13 were women. There were 6 patients diagnosed with type I BD and 13 patients diganosed with type II BD. The average age of patients was 49.4 years (range 26 to 70 years). At study entry, 10 patients were receiving both an antidepressant and a mood stabiliser, 4 were taking only an antidepressant, and 4 were taking only a mood stabiliser. Seven patients were also taking benzodiazepines or other sedatives (Table 1). The dosages of these medications were sufficient to achieve therapeutic effect and the dosages of the concomitant medications were kept stable or reduced through the course of the study. No new psychotropic medications were allowed during the study.
Patients had tried an average of 5.6 different psychotropic drugs over their lifetimes (range 1 to 13 drugs). They had an average of 2 prior hospital admissions (range 1 to 3 admissions). All 19 patients had previously reported suicidal ideation; 6 of these patients had previously attempted suicide. The mean age of first diagnosis of BD was 43.9, SD 9.7, years, but the mean length of the patients’ illness was 25.4, SD 8.2, years. Power analysis indicates that a sample size of 20 subjects would be sufficient to detect a change in HDRS score of at least 5 points with a one-sided alpha of 0.05 and a beta of 0.20 (that is, a power of 80%). These calculations are according to an estimated standard deviation of posttreatment change of 8 points on the HDRS. Therefore, a 5-point change in HDRS score would be considered significant. Study Design and AssessmentThis study is a prospective, open-label trial designed to augment standard naturalistic treatment of bipolar depression with quetiapine. After a 3-day washout period during which other antipsychotics were withdrawn (in the case of 6 patients), quetiapine was added to each patient’s treatment and titrated by starting at 50 mg daily and increasing the dosage over 2 weeks as clinically appropriate. The goal was to have each patient on at least 400 mg daily of quetiapine to a maximum of 800 mg daily if well tolerated, as described by the product monograph. If the dosage could not be tolerated, a lower dosage was allowed. Before beginning the trial, patients underwent a physical examination and an ECG. Patient data were collected at baseline and Months 1 through 12. These data included scores on the HDRS, the YMRS, the CGI, and the AIMS, as well as a measurement of the patient’s weight. Adverse events were elicited by the study investigators and recorded during each patient interview. Each adverse event was rated as mild, moderate, or severe and the possibility of a causal relation between quetiapine and the event was assessed. EPSEs were monitored with the AIMS. Statistical Analysis The change in HDRS scores from baseline to each of the 12 months was analyzed with a paired 2-tailed t test with a significance of level P < 0.001, a value used as significant change in most studies. ResultsOf the 19 patients who began this trial, 17 patients completed at least 2 assessments. There were 2 patients who could not tolerate the drug. One patient complained of chills, nausea, and malaise; the other complained of somnolence, migraine, and muscle pain. They were excluded from the study within one week of beginning the treatment course. The last observed HDRS values were carried forward (that is, LOCF). Of the 19 patients, 7 patients completed the 12-month trial and their HDRS scores were recorded as observed cases, 2 withdrew owing to side effects, 3 were lost to follow up, 2 withdrew owing to lack of efficacy, one chose to start antidepressant therapy, and 4 completed the 6-month trial and did not wish to continue. Patients were followed for an average of 31.5 weeks (Table 2).
The mean HDRS scores of the LOCF (n = 17) dropped from a baseline score of 27.2, SD 4.5, to 12.1, SD 8.1. This reflects a 55.5% mean reduction from baseline. Thirteen patients (76.5%) achieved a reduction of 50% in their HDRS scores and 9 of these patients (52.9%) maintained this reduction through the course of the trial. These values are statistically significant at P < 0.001. Of the 17 patients who were assessed at least twice, 9 (52.9%) met the criteria for response and 6 met the criteria for remission (35.3%). The mean HDRS scores of the observed cases (n = 7) at 12 months were 5.6, SD 3.9, a reduction of 79.4% (Figure 1). These values are statistically significant at P < 0.001. Of the 7 patients who completed the 12-month trail, 6 met response criteria and 5 met remission criteria. Item analysis of the core “depressed mood” item (that is, Item 1) of the HDRS showed a mean LOCF reduction from 2.8, SD 0.6, to 1.35, SD 1.3, and an observed cases reduction to 0.29, SD 0.5, which are reductions of 52.4% and 89.9%, respectively (Figure 2). Measures of anxiety (that is, HDRS Items 12, “psychic anxiety,” and 13, “somatic anxiety”) also showed improvement with the addition of quetiapine. The “psychic anxiety” score fell from 2.05, SD 0.9, to 0.88, SD 1.1, (LOCF) and 0.43, SD 0.5 (observed cases), which are reductions of 57.1% and 79.0%, respectively. Item analysis of the HDRS also showed a reduction in “insomnia.” The most significant improvement was seen in the “early insomnia” item, with scores falling from 0.95, SD 0.8, to 0.29, SD 0.7, (LOCF) and 0.14, SD 0.4, (observed cases), which are reductions of 69.5% and 85.3%, respectively. This substantial drop may be attributed to the sedative properties of quetiapine.
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 A reduction in insomnia scores indicated that 9 patients experienced sedative effects from quetiapine, and 8 patients showed no reduction in insomnia or somnolence reported as an adverse effect. The group of patients who did not experience somnolence showed a 60.9% reduction in mean HDRS scores, and 5 of these 8 patients (62.5%) showed a 50% reduction in HDRS scores. The group experiencing somnolence showed a 50.2% reduction in mean HDRS scores, with 4 of these 8 patients (50%) showing a 50% reduction in HDRS scores. Four patients met remission criteria in the nonsomnolent group, and 2 met the criteria in the group experiencing somnolence. The second item on the HDRS, “work and activities,” however, did not have the same level of response. The mean baseline score was 3.4, SD 0.6. The LOCF value after 12 months was 2.1, SD 1.3, with a change of 38.9%, which is not statistically significant. This indicates that the some patients still had trouble with their ability to work and participate in activities of daily living. In Table 3 we present the percentages of patients achieving response on the above 4 items.
The mean CGI scores, used as a secondary outcome measurement, also fell substantially from a baseline of 4.6, SD 0.6, to 2.6, SD 1.3, and 1.6, SD 0.8, (observed cases), which are changes of 42.6% and 65.2% respectively. The last remaining observed score reduction, however, did miss the response criterion of 50%. At Visit 3, one participant scored 19 on the YMRS. This later returned to normal. The other 16 participants remained well below the mania criterion of a score of 9. Interestingly, compared with the other measures, “irritability” was high and accounted for 58.8% of the itemized score at baseline. The “irritability” scores were less significantly decreased than other measures, at 42.2% (observed cases) and 53.2% (LOCF), respectively. Of the 72 reported drug-associated adverse events, 44 (61.1%) were mild and 25 (34.7%) were moderate. Somnolence, seen in 42.1% of patients (that is, reported as sedation, grogginess, and drowsiness), was the most common side effect. Dry mouth (31.6%), muscle pain (26.3%), nausea (26.3%), dream disturbances (26.3%), muscle twitching (26.3%), acid reflux (26.3%), constipation (15.8%), dyspnea (15.8%), headache (15.8%), and weight gain (15.8% were other common adverse events. Three of the reported drug-associated events were serious. One patient withdrew from the trial owing to severe EPSEs, including perioral movements and uncontrollable tremor, that were indicated by an AIMS rating of 17 at Month 6. This patient had no history of such problems and was also taking lithium at the time. He had a history of treatment with haloperidol. Although lithium had been well tolerated in the patient before the addition of quetiapine, when the lithium was withdrawn the symptoms resolved. The patient continued treatment with quetiapine outside the study without recurrence of the symptoms. Another patient reported severe sleep disturbances at Month 5 but was able to complete the study without symptom recurrence. A third patient complained of weight gain at Month 10 (after gaining 16.9 kg, with a change in BMI from 30.3 to 36.2) but also completed the trial. Weight gain is a significant issue in the use of atypical antipsychotics. Over the course of the 12-month period, each patient gained an average of 3.3 kg, raising the average BMI from 32.5 to 33.6. Four patients (23.5%) experienced significant weight gain (over 7% of their baseline body mass) with an average increase of 5.0%. DiscussionWhereas refractoriness in unipolar depression is defined as a depression that is unresponsive to treatment with 2 antidepressants from different classes lasting for at least 6 weeks, there are no hard criteria defining refractoriness in bipolar depression (3). Yatham and others define it as depression that fails to respond to a trial with therapeutic levels of lithium (3), and Sachs defines it as depression without remission despite 2 adequate trials of standard-class antidepressant agents (4). According to these definitions, 18 of the 19 patients in this trial (that is, those patients who tried an average of 5.6 psychotropic medications in their lifetimes) could be characterized as having refractory bipolar depression. When quetiapine was added to their treatment during this trial, we detected marked improvement. This suggests that quetiapine may be beneficial for treatment-resistant patients. Levine and others suggest that severe or refractory forms of BD may require polytherapy to be successful (5). While anticonvulsants, including valproic acid and lamotrigine (as seen in 10 of 19 sample patients), are the typical second-line treatment options for bipolar depression, additional treatment with atypical antipsychotics has become increasingly common. Atypical antipsychotics have been used to effectively treat the manic phase of BD. Although atypical antipsychotics were originally used to treat schizophrenia, they have also been approved to treat acute mania and for relapse prevention following successful treatment of the manic episode. Quetiapine has also been used as monotherapy (6) and has augmented treatment in severe bipolar mania. Other studies have also indicated that atypical antipsychotics are an effective treatment option for bipolar depression (7). The improvement of patients in this trial demonstrates the benefits of quetiapine as a possible therapy for bipolar depression. Quetiapine’s side effect profile is also an important factor in its consideration for treatment. Although all atypical antipsychotics are associated with weight gain, studies have shown that they vary in their propensity to cause weight change with long-term treatment. Follow-up studies show that the largest weight gains are associated with clozapine and olanzapine and that the smallest weight gains are associated with quetiapine and ziprasidone (8). In this study, the average weight gain of 3.3 kg over 12 months was substantial; however, these patients started with an average BMI of 32, and many of them were taking concomitant medication. Further, the weight gain was far less than that seen in McIntyre and others’ trial measuring the antidepressive effects of risperidone and olanzapine over a 6-month period (2). Patients in both groups experienced significant weight gain with a mean weight gain of 5.9 kg in risperidone and 11.3 kg in olanzapine. This study pointed out that patients with BD may be at higher risk of significant weight gain with some novel antipsychotics, so a treatment that reduces this risk might aid in the prevention of weight gain and its side effects (2). EPSEs, including tardive dyskinesia, are an unwanted side effect of antipsychotic drugs. Compared with typical antipsychotics such as haloperidol, those generally considered atypical have a relatively low risk of EPSE induction. Atypical antipsychotics, however, do vary considerably in their pharmacology and neurologic effects. According to Tarsy and others, the atypical antipsychotics can be tentatively ranked by EPSE risk (excluding akathisia and neuroleptic malignant syndrome): clozapine < quetiapine < olanzapine = ziprasidone (9). The decreased risk of EPSEs makes quetiapine a safe treatment option for both patients at increased risk of EPSEs and the general population (10). Although the risk of EPSEs is relatively small, it is a risk about which patients must be informed, and it must be monitored during treatment with quetiapine. To better understand the effects of quetiapine, we preformed an item analysis of the HDRS scores. We observed major improvements reflected by reductions in “depressed mood,” “insomnia,” and “anxiety” scores. The reduction in the “insomnia” score was significant because patients suffering from insomnia were taking several sedative medications (that is, 8 patients during the study and 4 patients prior to the study) but were refractory to treatment. The “insomnia, early” score (Item 6) of 0.95 fell to 0.29 (LOCF) and 0.14 (observed cases). This substantial drop in score can be attributed to the sedative properties of quetiapine. Quetiapine may be a promising treatment for insomnia associated with BD. We also found, however, that patients who did not experience somnolent effects from quetiapine had a slightly better response to treatment (that is 60.9%, compared with 50.2%) and were twice as likely to meet remission criteria. Perhaps the somnolence associated with quetiapine is an adverse effect for some patients, negatively impacting their improvement. Measures of anxiety (HDRS Items 15, “psychic anxiety,” and 16, “somatic anxiety”) also showed improvement with the addition of quetiapine. The psychic anxiety score fell from 2.05, SD 0.9, to 0.88, SD 1.1, (LOCF) and 0.43, SD 0.5, (observed cases); reductions of 57.1% and 79.0%, respectively. Prior to the trial, 7 patients were taking benzodiazapines and 5 patients were taking them during the trial. BD is often comorbid with an anxiety disorder. In this study, 13 patients had an additional diagnosis of anxiety disorder. Quetiapine shows promising reductions of potentially incapacitating anxiety levels. Interestingly, we found that there was no statistically significant response to the “work and activities” item of the HDRS, indicating that the some patients still had trouble with their ability to work and with their interest in activities of daily living. Similarly, the mean scores of the Severity scale of the CGI also missed the response criteria, which indicates that the manifestations of the disease pervade the subjects’ daily lives. The small sample size, however, does not allow us to draw firm conclusions. “Irritability” scores were also high, compared with the other measures. They account for 58.8% of the itemized score at baseline. The reductions of “irritability” scores were 42.2% (observed cases) and 53.2% (LOCF). This was not as significant a decrease as the other measures. This is consistent with Deckersbach and others’ finding that a significant number of patients with BD who met criteria for a DSM-IV major depressive episode also experienced substantial irritability in the absence of associated symptoms of mania (11). Quetiapine did reduce this irritability. The average length of a bipolar depression is generally considered about 3 months (12). A major concern of this trial was to determine whether the response to treatment was owing to spontaneous remission or whether the medication had some effect.The patients in this trial had refractory bipolar depression. Within the first 8 weeks, however, there was a marked improvement in HDRS scores from an average of 27.2, SD 4.5, to an average of 11.9, SD 6.8. This significant drop cannot be attributed to a placebo effect or to spontaneous remission. Further, of the 13 patients who displayed a 50% response to quetiapine, only 4 patients displayed a return to depression levels over 18 during the 12-month study. This indicates that quetiapine has some mood-stabilizing properties. ConclusionsResults from this preliminary 12-month, open-label trial indicate that quetiapine added to the usual treatment of patients with BD may be helpful in treating acute bipolar depressive symptoms, may prevent future depressive symptoms, and does not seem to induce manic or hypomanic episodes. The generalizability of these findings must be determined though randomized controlled studies with larger numbers of patients. AcknowledgementsWe would like to acknowledge Teresa Garrah for her help with organizing and making possible this study and Marianne McGuire for her assistance in preparing this manuscript. Funding and SupportFunding for the study was provided from a seeding grant from Queen’s University to Roumen Milev. References1. Woods SW. The economic burden of bipolar disease. J Clin Psychiatry 2000;61(Supp 13):38–41. 2. McIntyre RS, Mancini DA, Srinivasan J, McCann S, Konarski JZ, Kennedy SH. The antidepressant effects of risperidone and olanzapine in bipolar disorder. Can J Clin Pharmacol 2004;11:e218–e226. 3. Yatham LN, Calabrese J, Kusumaker V. Bipolar depression: criteria for treatment selection, definition of refractoriness, and treatment options. Bipolar Disord 2003;5:85–97. 4. Sachs G. Treatment-resistant bipolar depression. Psychiatr Clinic North Am 1996;19:215–36. 5. Levine J, Chengappa KN, Brar JS, Gershon S, Yablonsky E, Stapf D, and others. Psychotrophic drug prescription patterns among patients with bipolar I disorder. Bipolar Disord 2000;2:120–30. 6. Calabrese JR, Keck PE Jr, Macfadden W, Minkwitz M, Ketter TA, Weisler RH, and others. A randomized, double-blind, placebo-controlled trial of quetiapine in the treatment of bipolar I or II depression. Am J Psychiatry 2005;162:1351–60. 7. Tohen M, Vieta E, Calabrese J, Ketter TA, Sachs G, Bowden C, and others. Efficacy of olanzapine and olanzapine-fluoxetine combination in the treatment of bipolar I depression. Arch Gen Psychiatry. 2003;60:1079–88. 8. Nasrallah H. A review of the effect of atypical antipsychotics on weight. Psychoneuroendocrinology 2003;28(Suppl 1):83–96. 9. Tarsy D, Baldessarini RJ, Tarazi FI. Effects of newer antipsychotics on extrapyramidal function. CNS Drugs 2002;16:23–45. 10. Sussman, N. Choosing an atypical antipsychotic. Int Clin Psychopharmacol 2002;17(Suppl 3):S29–S33. 11. Deckersbach T, Perlis RH, Frankle WG, Gray SM, Grandin L, Dougherty DD, and others. Prescence of irritability during depressive episodes in bipolar disorder. CNS Spectrums 2004;9:227–31. 12. Frankle WG, Perlis RH, Deckersbach T, Grandin L, Gray SM, Sachs G, and others. Bipolar depression: relationship between episode length and antidepressant treatment. Psychol Med 2002;32:1417–23. Author(s)Manuscript received September 2005, revised, and accepted February 2006. 1. Associate Professor and Chair, Division of Adult Treatment and Rehabilitation Psychiatry, Department of Psychiatry, Queen’s University, Kingston, Ontario; Clinical Program Director, Adult Treatment and Rehabilitation Services, Providence Continuing Care Centre, Mental Health Services, Kingston, Ontario. 2. Assistant Professor, Department of Psychiatry, University of Toronto, Toronto Ontario; Chief, Mood and Anxiety Unit-Inpatient, Centre for Addiction and Mental Health, Toronto, Ontario. 3. Medical Student, Queen’s University, Kingston, Ontario. Address for correspondence: Dr R Milev, Providence Continuing Care Centre, Mental Health Services, 752 King Street West, Kingston; ON K7L 4X3 e-mail: milevr@pccchealth.org
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