Quetiapine as add-on treatment for bipolar I disorder: efficacy in preventing relapse of depressive episodes

1745-0179-3-17 1745-0179 Research Quetiapine as add-on treatment for bipolar I disorder: efficacy in preventing relapse of depressive episodes Hardoy Carolina Maria mgcarta@tiscali.it Garofalo Alessandra alessandra.garofalo@gmail.com Mellino Gisa gismel@tiscali.it Tuligi Francesco ftuligi@tiscali.it Cadeddu Mariangela mariangelacadeddu@aliceposta.it Carta Giovanni Mauro mgcarta@tiscali.it

Center for Epidemiology and Clinical Practice in Mental Health ASL 7 Iglesias, Italy and Department of Public Health, University of Cagliari, Italy

AUSL, Lanusei, Italy

Clinical Practice and Epidemiology in Mental Health 1745-0179 2007 3 1 17 http://www.cpementalhealth.com/content/3/1/17 1789254810.1186/1745-0179-3-17 19 12 2006 24 9 2007 24 9 2007 2007 Hardoy et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Objective

To assess the long-term response to add-on quetiapine therapy in patients with bipolar I disorder who were not adequately responding to standard medications.

Methods

Outpatients with bipolar I disorder (DSM-IV-TR) responding inadequately to standard treatment were observed before and after the addition of quetiapine. Symptom severity was evaluated using the Clinical Global Impressions scale for Bipolar Disorder (CGI-BP) each month. Relapses included hospitalization, treatment in a day hospital or clinic, scores ≥ 1 point higher than previous CGI-BP scores and/or upward titration of quetiapine or other medications.

Results

Sixty-one patients (age range of 18–68 years) were observed prospectively for an average of 7.5 months (range 3–18 months) prior to addition of quetiapine and subsequently followed for an average of 15.7 months (range 6–42 months). The final mean quetiapine dose was 537.1 ± 91.7 mg/d. Prior to quetiapine addition, an annual relapse rate of 2.09 episodes was recorded, relating to 0.94 depressive and 1.15 manic or mixed episodes. Following quetiapine addition, annual relapse rates were reduced to 0.61 episodes, representing 0.14 depressive and 0.46 manic or mixed episodes. Compared with the period of add-on quetiapine treatment, the relative risk of relapse prior to quetiapine therapy was 3.4 for all episodes (χ²= 24.8, P < 0.001), 6.7 for depressive episodes (χ²= 24.7, P < 0.001), and 2.5 for manic or mixed episodes (χ²= 9.0, P < 0.05).

Conclusion

This naturalistic follow-up study provides preliminary evidence for the efficacy of long-term add-on quetiapine treatment in the prevention of relapses of manic or mixed and depressive episodes of bipolar I disorder, and particularly in the prevention of depressive episodes.

Background

Bipolar I disorder is a severe and chronic illness characterized by episodes of mania and depression 1. Two major challenges of treating bipolar I disorder are the high percentage of patients who do not respond to therapy and the high percentage of patients who relapse after initially responding. To address these challenges, patients are often given long-term treatment with combinations of drugs from different classes 2. Quetiapine is an atypical antipsychotic with a superior tolerability profile to conventional antipsychotics. Large, placebo-controlled studies have shown the efficacy of quetiapine for treating both acute manic episodes (as monotherapy and combination therapy) and acute depressive episodes (as monotherapy) associated with bipolar disorder 3456.

Objective

To assess the long-term response to add-on quetiapine therapy in patients with bipolar I disorder who were not adequately responding to standard medications.

Methods

Study design

An open-label study of patients with bipolar I disorder inadequately responsive to ongoing medications who were prospectively observed for 3–18 months before receiving add-on quetiapine treatment for 6–42 months.

Study population

Adult outpatients with bipolar I disorder (based on DSM-IV-TR) 7 who had responded inadequately to prior standard treatment. Inadequate response to prior treatment was defined as a Clinical Global Impressions scale for Bipolar Disorder (CGI-BP) 8 score ≥ 3 with no improvement in score after 3 months of therapy. Patients who were pregnant or breastfeeding, or had a recent history of alcohol or drug abuse, were excluded. Written consent for the study was obtained after giving patients a complete description of the study.

Study medication

Quetiapine was added to ongoing medication at an initial dose of 25 mg/d for the first 2 days, increased to 50 mg/d for the next 2 days, and then increased by 50 mg increments every 2 days until a clinical response was observed (up to a maximum dose of 800 mg/d). This dose was then maintained throughout the remainder of the study.

Assessments

Prospective evaluations were made at least once every 2 months and no fewer than 8 times per year. Clinical response was evaluated using the CGI-BP scale 8. The relative risk of relapse, defined as the number of relapse events per patient-year of treatment, was determined for the period before initiating quetiapine. Relapse events included hospitalization, treatment in a day hospital or clinic, or an increase of ≥ 1 in CGI-BP 8 score accompanied by a change in therapy.

Statistical methods

Mean CGI-BP scores were compared by one-way analysis of variance (ANOVA) for repeated measures. Confidence intervals for comparing the relative risks of relapse were calculated using the simplified method of Miettinen 9.

Results

Patient and treatment characteristics

Of the 61 patients, 41% were male (mean age 41.4 ± 8.2 years) and 59% were female (mean age 47.2 ± 16.9 years). Patients were prospectively observed for 3–18 months (average 7.5 months) before quetiapine therapy was added. Patients' ongoing medications are listed in Table 1. Add-on quetiapine therapy was maintained for 6–42 months (average 15.7 months) until study termination. Fourteen patients received quetiapine add-on therapy for ≥ 24 months. The final mean quetiapine dose was 537.1 ± 91.7 mg/day. Four patients discontinued the study: 1 due to adverse effects (hypotension and drowsiness) and 3 due to non-adherence after the first evaluation at 6 months.

Table 1

Ongoing medications*

Medication

Number of patients

Carbamazepine

Chlorpromazine

Oxcarbazepine

Gabapentin

Haloperidol

Lithium

Olanzapine

Risperidone

Sodium valproate

*Some patients were treated with more than 1 of the listed medications.

Efficacy

Risk of relapse

The overall relapse rate decreased following the addition of quetiapine (Table 2, Figure 1). When analyzed by episode type, the relapse rates of depressive and manic/mixed episodes also decreased after adding quetiapine compared with the period before adding quetiapine (Table 2, Figure 1). Relative risks of relapse for all episodes, manic episodes, and depressive episodes prior to quetiapine treatment are shown in Table 2.

Table 2

Relapse rates and relative risks of relapse before and after the addition of quetiapine to ongoing therapy

Before add-on quetiapine

After add-on quetiapine

Observation period (in months)

Average

7.5

15.7

Range

3–18

6–42

Relapse rate (episodes/year)

Any episode

2.09

0.61

Manic/mixed episodes

1.15

0.46

Depressive episodes

0.94

0.14

Relative risk of relapse before add-on quetiapine

Any episode

3.4 (χ²= 24.8, 95% CI 2.1–5.5; P < 0.001)

Manic/mixed episodes

2.5 (χ²= 9.0, 95% CI 1.4–4.5; P < 0.05)

Depressive episodes

6.7 (χ²= 24.7, 95% CI 3.7–14.0; P < 0.001)

Figure 1

Annual relapse rates before and after add-on quetiapine treatment

Annual relapse rates before and after add-on quetiapine treatment.

Symptom improvement

Mean change in CGI-BP score showed a significant improvement in symptoms from baseline at 6, 12, 18, and 24 months (P < 0.001; Table 3).

Table 3

Mean CGI-BP scores before and after addition of quetiapine

CGI-BP Score (Mean ± SD)

Observation period

Baseline*

During observation

F-ratio

P-value ^†

3 months before quetiapine

4.5 ± 1.1

4.3 ± 1.4

6 months after quetiapine

4.5 ± 1.1

3.4 ± 1.1

30.5

<0.001

12 months after quetiapine

4.7 ± 1.0

3.3 ± 1.3

34.3

<0.001

18 months after quetiapine

4.8 ± 0.9

3.6 ± 1.0

19.1

<0.001

24 months after quetiapine

4.4 ± 0.9

3.0 ± 0.9

16.9

<0.001

*Represents the start of quetiapine treatment except for the observation period at 3 months before the start of quetiapine treatment

^†Observation period versus baseline

Tolerability

Side effects during quetiapine combination therapy (Table 4) were generally mild or moderate. Mild extrapyramidal symptoms (EPS) were reported by 4 patients (6.5%), all of whom were taking lithium or divalproex. No tardive dyskinesia was reported.

Table 4

Side effects during add-on quetiapine treatment

Adverse event

Patients, n (%)

Weight gain (> 7% of baseline body weight)

21 (34.4%)

Sedation

15 (24.6)

Asthenia

7 (11.4)

Insomnia

7 (11.4)

Dry mouth

5 (8.2)

Transient drowsiness

4 (6.5)

Headache

4 (6.5)

Constipation

3 (4.9)

EPS

4 (6.5)

Conclusion

In patients with bipolar I disorder who had shown inadequate responses to prior standard therapy, relapse rates and symptoms were significantly improved with 6 months of add-on quetiapine therapy. These improvements were maintained in 14 patients treated for 24 months. Add-on quetiapine therapy was well tolerated, with no incidences of tardive dyskinesia reported following addition of quetiapine and only 4 patients reporting mild EPS. This naturalistic follow-up study demonstrates the efficacy of quetiapine in the prevention of relapses of manic and depressive episodes of bipolar I disorder in the long term, and particularly in the prevention of depressive episodes, which is consistent with our earlier findings 10 and with other follow-up studies concerning bipolar depression 11, bipolar depression and rapid cycling disease course 12, rapid cycling bipolar disorders 13. These results warrant confirmation in large, randomized, placebo-controlled studies.

Epidemiological and clinical aspects of bipolar disorders: controversies or a common need to redefine the aims and methodological aspects of surveys Carta MG Angst J Clin Pract Epidemol Ment Health 2005 1 4 1151596 15967053 10.1186/1745-0179-1-4 Practice guideline for the treatment of patients with bipolar disorder (revision) American Psychiatric Association Am J Psychiatry 2002 159 1 50 10.1176/appi.ajp.159.1.1 Quetiapine monotherapy for mania associated with bipolar disorder: combined analysis of two international, double-blind, randomized, placebo-controlled studies Vieta E Mullen J Brecher M Paulsson B Jones M Curr Med Res Opin 2005 21 923 934 10.1185/030079905X46340 15969892 Quetiapine with lithium or divalproex for the treatment of bipolar mania: a randomized, double-blind, placebo-controlled study Sachs G Chengappa K Suppes T Bipolar Disord 2004 6 213 223 10.1111/j.1399-5618.2004.00115.x 15117400 A randomized, double-blind, placebo-controlled trial of quetiapine in the treatment of bipolar I or II depression Calabrese JR Keck PE Jr Macfadden W Am J Psychiatry 2005 162 1351 1360 10.1176/appi.ajp.162.7.1351 15994719 Quetiapine versus placebo in combination with lithium or divalproex for the treatment of bipolar mania Yatham LN Paulsson B Mullen J Vågerö M J Clin Psychopharmacol 2004 24 599 606 10.1097/01.jcp.0000144887.66319.2f 15538120 American Psychiatric Association Diagnostic and Statistical Manual of Mental Disorders, 4th edn, text revision (DSM-IV-TR) Washington, DC: American Psychiatric Association 2000 Modification of the Clinical Global Impression (CGI) Scale for use in bipolar illness (BP): the CGI-BP Spearing MK Post RM Leverich GS Brandt D Nolen W Psychiatry Res 1997 73 159 171 10.1016/S0165-1781(97)00123-6 9481807 Confounding and effect-modification Miettinen O Am J Epidemiol 1974 100 350 353 4423258 Combination quetiapine therapy in the long-term treatment of patients with bipolar I disorder Hardoy MC Garofalo A Carpiniello B Calabrese JR Carta MG Clin Pract Epidemiol Ment Health 2005 1 7 10.1186/1745-0179-1-7 Add-on quetiapine for bipolar depression: a 12-month open-label trial Milev R Abraham G Zaheer J Can J Psychiatry 2006 51 8 523 30 16933589 Quetiapine monotherapy in the treatment of patients with bipolar I or II depression and a rapid-cycling disease course: a randomized, double-blind, placebo-controlled study Vieta E Calabrese JR Goikolea JM Raines S Macfadden W BOLDER Study Group Bipolar Disord 2007 9 4 413 25 10.1111/j.1399-5618.2007.00479.x 17547587 Effectiveness of quetiapine in rapid cycling bipolar disorder: A preliminary study Goldberg JF Kelley ME Rosenquist KJ Hsu DJ Filkowski MM Nassir Ghaemi SJ J Affect Disord 2007 4