Clinical trial NCT01197846: Efficacy of Quetiapine XR Versus Placebo as Concomitant Treatment to Mood Stabilizers in the Control of Subsyndromal Symptoms of Bipolar Disorder
Official title: Efficacy of Quetiapine XR vs. Placebo as Concomitant Treatment to Mood Stabilizers in the Control of Subsyndromal Symptoms of Bipolar Disorder
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Bipolar Disorder
Lead sponsor: Centro de Investigación Biomédica en Red de Salud Mental
Sponsor class: NETWORK
First posted: 2010-09-09
Enrollment: 28
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: Pilot multicentric, prospective, placebo controlled, randomized double blinded, study of 12 weeks follow-up Adult patients diagnosed of bipolar disorder I or II, in previous treatment with no more than two concomitant mood stabilizers at stable doses and current subsyndromal symptoms, defined as YMRS ≤14 and/ or MADRS≥8 and ≤14 would be included Sub-acute phases would be excluded (at least 8 weeks from last exacerbation would be required for inclusion).

Detailed description: Remission of acute episodes usually doesn't correlate with symptomatic or functional recovery in occupational and social domains after (McQueen et al, 2001; Tohen et al, 2000) Ongoing depressive symptoms are the strongest predictor of functional deficits in persons with bipolar disorder (Bauer et al, 2001; Judd et al, 2005). Depressive subsyndromal symptoms are associated to functional impairment in bipolar disorder (Vojta et al, 2001; Altshuler et al, 2002; Yatham et al, 2004) The addition of olanzapine to valproate or lithium provided superior efficacy to valproate or lithium plus placebo in non completely remitted manic and mixed bipolar episodes, mainly through a control of depressive symptoms (Tohen et al, 2002) Quetiapine has demonstrated to be efficacious in the control of depressive symptoms in Bipolar Disorder (BOLDER, EMBOLDEN studies) and in the prevention of recurrences, maintaining the patient in YMRS and MADRS scores under the cut-off point between asymptomatic and subsyndromal states (Studies 126, 127 and 144) Thus it's expectable that adding quetiapine to previous mood stabilizers in bipolar patients with subsyndromal symptoms probably would improve their symptoms, mainly depressive, to levels not only of syndromic but of symptomatic remission, driving to a better functional status Quetiapine extended release would be used because its advantages on quetiapine immediate release regarding an easier and comfortable posology and potential better adherence

Eligibility criteria: Inclusion Criteria:

1. Informed Consent signature
2. At least 18 years old
3. Diagnoses of bipolar disorder I or II (as DSM-IV-TR 4ª Ed codes)
4. Previous treatment with a mood stabilizer (lithium, valproate or lamotrigine) at stable and optimum doses for at least six weeks prior to the start of the trial (i.e., on the same dose and serum levels within the therapeutic ranges: 0.6-1.2 mEq/l of lithium or 50-100 ug/ml of valproate)
5. Presenting subsyndromal symptoms at enrolment and randomization point, defined as YMRS ≤ 14 and/ or MADRS ≥ 8 and ≤14
6. At least one manic, mixed, or depressed episode in the last 5 years
7. Being able to understand and meet the study requirements

Exclusion Criteria:

1. Pregnant or nursing women
2. Mental retardation.
3. Current active diagnoses of any axis I or II DSM-IV-TR diagnoses different from bipolar disorder I or II. This doesn't apply to nicotine nor caffeine abuse-dependence. Punctual alcohol and/or substances use not constitutive of a diagnoses of abuse or dependence following DSM-IV-TR criteria wouldn't suppose the exclusion of the patient from the study. Anxiety in levels not constitutive of any anxiety disorder within those codified in DSM-IV-TR wouldn't either suppose the exclusion of the patient from the study
4. Having suffered any acute episode (depressive, manic, or mixed) within the 8 weeks prior to enrolment, as defined in DSM-IV-TR
5. Patients that, in the investigator's opinion, are at a high risk of suicide or mean a risk of aggression to others.
6. Having been treated with any antidepressant at randomization.
7. Having been treated with any mood stabilizer other than lithium/valproate/lamotrigine at randomization.
8. Having been treated with any oral antipsychotic drug at randomization. Administration of a depot antipsychotic medication within one dosing interval prior to randomization (e.g. Long acting Risperidone 2 weeks; Zuclopenthixol 4 weeks; Pipotiazine 4 weeks; Flufenazine 6 weeks)
9. Having been treated with any of the following P450-3A4 cytochrome inhibitors in the 14 days prior to inclusion, including: ketoconazole, itraconazole, fluconazole, erythromycin, clarithromycin, fluvoxamine, indinavir, nelfinavir, ritonavir and saquinavir.
10. Having been treated with any of the following P450-3A4 cytochrome inducers in the 14 days prior to inclusion, including: phenytoin, carbamazepine, barbiturates, rifampicin, St. John's wart, and glucocorticoids.
11. Any contraindication to the use of quetiapine fumarate in the investigator's opinion (including lack of response to it in previous treatment attempts)
12. Suffering any medical condition that can effect the absorption, distribution, metabolism or excretion of the study treatment(s).
13. Suffering any medical condition in decompensation or not receiving inappropriate treatment for it in the investigator's opinion (e.g., hyperthyroidism, angina pectoris, hypertension...)
14. Suffering unstable diabetes at enrolment or randomization
15. Absolute neutrophil count ≤ 1.5 x 109 per litre at randomization
16. Non-compliance with the study plan.
17. Participation in another clinical trial in the four weeks prior to randomization

Primary outcomes:
measure: To assess the efficacy of quetiapine extended release (QTP XR) vs. placebo in the control of bipolar subsyndromal symptoms when added to previous mood stabilizer treatment (lithium/ valproate/lamotrigine)
timeFrame: Study of 12 weeks follow-up
Secondary outcomes:
measure: To assess the efficacy of QTP XR vs. placebo when added to previous mood stabilizer treatment (lithium/ valproate/lamotrigine) in functional level of bipolar patients with subsyndromal symptoms
timeFrame: Study of 12 weeks follow-up
Other outcomes:
Locations:
city: Barcelona
country: Spain
facility: Hospital Santa Creu I Sant Pau
city: Barcelona
country: Spain
facility: Hospital Clinic I Provincial
city: Barcelona
country: Spain
facility: Hosptial Benito Menni
city: Barcelona
country: Spain
facility: Hospital Universitari de Bellvitge
city: Barcelona
country: Spain
facility: Parc Sanitari Sant Joan de Deu
city: Madrid
country: Spain
facility: Hospital General Universitario Gregorio Marañon
city: Madrid
country: Spain
facility: Hospital Universitario Ramon Y Cajal
city: Oviedo
country: Spain
facility: Centro de Salud Menta II
city: Valencia
country: Spain
facility: Hosptial Clinico Valencia/ CSM Foios
city: Vitoria
country: Spain
facility: Hospital Santiago Apostol
Study officials:
affiliation: Hospital Clinic I Provincial. Barcelona. Spain
name: Eduard Vieta, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Hospital Santiago Apostol. Vitoria. Spain
name: Ana Gonzalez Pinto
role: PRINCIPAL_INVESTIGATOR
affiliation: Hospital Benito Menni. Barcelona. Spain
name: Benedikt Amann
role: PRINCIPAL_INVESTIGATOR
affiliation: Hospital General Universitario Gregorio Marañon. Madrid. Spain
name: Celso Arango
role: PRINCIPAL_INVESTIGATOR
affiliation: Hospital Universitari de Bellvitge. Barcelona. Spain
name: Jose Manuel Crespo
role: PRINCIPAL_INVESTIGATOR
affiliation: Centro de Salud Mental II. Oviedo. Spain
name: Julio Bobes
role: PRINCIPAL_INVESTIGATOR
affiliation: Hospital Santa Creu I Sant Pau. Barcelona. Spain
name: Josefina Perez
role: PRINCIPAL_INVESTIGATOR
affiliation: Hospital Clinico de Valencia/ CSM Foios. Valencia. Spain
name: Gabriel Selva
role: PRINCIPAL_INVESTIGATOR
affiliation: Parc Sanitari Sant Joan de Deu. Barcelona. Spain
name: Belen Arranz
role: PRINCIPAL_INVESTIGATOR
affiliation: Hospital Universitario Ramon y Cajal. Madrid. Spain
name: Jeronimo Saiz
role: PRINCIPAL_INVESTIGATOR
References: