A randomised, placebo-controlled 52-week trial of continued quetiapine treatment in recently depressed patients with bipolar I and bipolar II disorder

Abstract

Objectives. To examine the longer-term efficacy of quetiapine monotherapy in bipolar depression in a preplanned pooling of data from the EMBOLDEN I and II studies. Methods. Patients (N = 584) with bipolar I or II disorder (most recent episode: depressed) who achieved remission after 8 weeks of treatment with quetiapine (300 or 600 mg/day) were randomised to the same quetiapine dose or placebo for 26–52 weeks or until mood event recurrence. Results. The risk for recurrence of a mood event was significantly lower with quetiapine than placebo (HR 0.51 (95% CI: 0.38–0.69); P < 0.001). Quetiapine was associated with a lower risk for recurrence of depressive events (HR 0.43 (95% CI: 0.30–0.62); P < 0.001) but recurrence of manic/hypomanic events was not significantly reduced (HR 0.75 (95% CI: 0.45–1.24; P = 0.263). There was a lower risk of recurrence of mood events in bipolar I (HR 0.58 (95% CI: 0.41–0.82), P = 0.002) and bipolar II patients (HR 0.33 (95% CI: 0.18–0.60), P < 0.001). Discontinuation rates due to adverse events were 4.3, 4.0 and 1.7% for quetiapine 300 mg/day, 600 mg/day and placebo, respectively. Safety data, including changes in lipid and glucose parameters, were consistent with the recognized profile of quetiapine. Conclusions. The efficacy of quetiapine monotherapy in bipolar depression is maintained during continued treatment for 26–52 weeks. Quetiapine was generally well tolerated.

Key words::

• Antipsychotics
• bipolar I disorder
• bipolar II disorder
• depression
• quetiapine

Acknowledgements

We thank AstraZeneca for statistical analysis, and Eleanor Bull, from PAREXEL, who provided medical writing support funded by AstraZeneca.

Statement of Interest

The studies D1447C00001 and D1447C00134 were supported by AstraZeneca Pharmaceuticals. Dr Young has received honoraria from pharmaceutical companies, including AstraZeneca Pharmaceuticals LP, for lecturing on this topic. Dr Young has also received grant support from AstraZeneca for an investigator-initiated study. Dr McElroy is a consultant to or member of the scientific advisory boards of Alkermes, AstraZeneca Pharmaceuticals LP, Eli Lilly and Company, Schering Plough, and Shire. Dr McElroy is a principal or co- investigator on studies sponsored by Abbott Laboratories, Agency for Healthcare Research & Quality (AHRQ), Alkermes, AstraZeneca Pharmaceuticals LP, Bristol-Myers Squibb, Cephalon, Eli Lilly and Company, Forest Labs, GlaxoSmithKline, Jazz Pharmaceuticals, Marriott Foundation, National Institute of Mental Health, OREXIGEN Therapeutics, Inc., Pfizer, Shire, Takeda Pharmaceutical Company Ltd, and Transcept Pharmaceuticals, Inc. Dr McElroy is also an inventor on United States Patent No. 6,323,236 B2, Use of Sulfamate Derivatives for Treating Impulse Control Disorders, and, along with the patient's assignee, University of Cincinnati, Cincinnati, OH, has received payments from Johnson & Johnson Pharmaceutical Research & Development, LLC, which has exclusive rights under the patent. Dr Olausson and Dr Paulsson are employees of AstraZeneca, Södertälje, Sweden.

Appendix

EMBOLDEN I (Trial 001) Study Investigators

Angelo Fallu, Clinique Woodward, Sherbrooke, Québec, Canada; Jean-Guy Gagnon, Edwards Building, Sudbury, Ontario, Canada; Carlos Galarraga-Carrero, ERB Center, Waterloo, Ontario, Canada; Paul Latimer, Kelowna, British Columbia, Canada; Serge Lassard, Introspect Clinic, Orleans, Ontario, Canada; Nabil Philips, Credit Valley Medical Arts, Mississauga, Ontario, Canada; Francisco Pinero-Medina, Sherbrooke, Québec, Canada; Javed Ali, Global Psychiatric Research, Sydney, Nova Scotia, Canada; Rustom Sethna, Markham-Stouffville Health Centre, Markham, Ontario, Canada; Smadar Tourjman, Centre Medical Rene Laennac, Montreal, Québec, Canada; Vera Folnegovic-Smalc and Bacic Davor, Psychiatric Hospital Vrapce, Zagreb, Croatia; Pavo Filakovic, University Hospital Osijek, Osijek, Croatia; Goran Dodig, Psychiatric Hospital Split, Split, Croatia; Neven Henigsberg, Policlinic Neuron, Zagreb, Croatia; Miro Jakovljevic, Clinical Hospital Centre Rebro, Zagreb, Croatia; Dragica Kozaric-Kovacic, University Hospital Dubravna, Zagreb, Croatia; Branka Restek Petrovic, Psychiatric Hospital Jankomir, Zagreb, Croatia; Gilic Ante, Department of Psychiatry, Zadar, Croatia; Georgi Belotserkovski, Ahtme Mental Hospital, Kohtle-Jarve, Estonia; Kairi Magi, Tartu University Clinics, Tartu Estonia; Katrin Noorkoiv and Petra Poolamets, North-Estonia Regional Hospital, Tallinn, Estonia; Michael Bauer, University Clinic for Psychiatry and Psychotherapy, Berlin, Germany; Martin Klein, Medical Studycentra, Würzburg, Germany; Alexander Schulze, Praxis Dr Schulze, Berlin, Germany; Jana Thomsen, Praxis Dr Jana Thomsen, Berlin, Germany; Jürgen Ribbschlaeger, Praxis Dr Margit and Jürgen Ribbschlaeger, Berlin, Germany; Nurmiati Amir, Dr Cipto Mangunkusumo General Hospital, Jakarta, Indonesia; H. Aris Sudiyanto, Surakarta Mental Health Hospital, Solo, Indonesia; M.A. Widyastuti Darmohusodo, Dr Radjiman W State Mental Hospital, Lawang, Indonesia; Biruta Kupca, Mental Health State Agency, Riga, Latvia; Ilona Paegle, Outpatient Clinic, Riga, Latvia; Olga Sokolova, Daugavpils Psychoneurologica, Daugavpils, Latvia; Valentinas Maciulis, Republican Psychiatric Hospital, Vilnuis, Lithuania; Gintautas Daubaras, Antakalnio Psychiatric Consultation Centre, Vilnuis, Lithuania; Petras Janulionis, Vilnuis Mental Health Centre, Vilnuis, Lithuania; Daiva Deltuviene, Medical Centre Neuromeda, Kaunas, Lithuania; Eugenijus Mikaliunnas, Sauliai Mental Hospital, Sauliai, Lithuania; Sonata Rudzianskiene, Kaunas Silainiai Outpatient Clinic, Kaunas, Lithuania; Laisve Dembinskiene, Vilnuis, Lithuania; Ahmad Sulaiman, University Malaya Medical Centre, Petaling Jaya, Malaysia; Teck Hoe Yen, Chinese Maternity Hospital, Kuala Lumpur, Malaysia; Abdul Kadir Abu Bakar, Hospital Sentosa, Kuching, Malaysia; Paul Stronegger, Hospital Østfold HF Division, Mysen, Norway; Erik Øfjord, Centre for Clinical Studies, Paraida, Norway; Ole Johan Høyberg, Doctors Office Brattvåg, Brattvåg, Norway; Hans Jørgan Nyrerød, Drammen Psychiatric Centre, Drammen, Norway; Dag Norum, Dag Norum, Fredrikstad, Norway; Efren Reyes and Juan Villacorta, National Center for Mental Health, Mandaluyong City, Philippines; Victor Amantillo, West Visayas State University Medical Centre, Iloilo City, Philippines; Agnes Padilla, Davao Mental Hospital, Davao City, Philippines; Michal Kujawski and Agata Szulc, Unpublic Centre of Health Care, Zabrze, Poland; Aleksander Araszkiewicz, Cathedral and Psychiatric Clinic of Medical Academy, Bydgoszcz, Poland; Piotr Baranowski, Medical Psychiatric Outpatient Clinic, Wroclaw, Poland; Wlodzimierz Chrzanowski, Private Medical Offices Promedicus, Bialystok, Poland; Leszek Bidzan, Unpublic Centre of Health Care, Gdynia, Poland; Zbigniew Wawrzyniak, Specialist Psychiatric Complex of Health Care, Lodz, Poland; Przemyslaw Bogacki, Private Medical Office, Skorzewo, Poland; Jaroslaw Bialek, Complex of Psychiatric Clinics, Wloclawek, Poland; Magdelena Kielkiewicz, Unpublic Centre of Health Care, Leszno, Poland; Won-Myong Bahk, Catholic University of St. Mary's Hospital, Seoul, Republic of Korea; Yeon-Ho Joo, Asian Medical Centre Psychiatry, Seoul, Republic of Korea; Kyoo-Soeb Ha, Seoul National University Bundang, Gyeonggi-do, Republic of Korea; Yakhin Kausar, City Psychoneurological Clinical Hospital, Kazan, Republic of Russia; Pavel Sidorov, Arkhangelsk Regional Psychoneurological Dispensary, Arkhangelsk, Republic of Russia; Alexander Okhapkin, Regional Clinical Hospital, Smolensk, Republic of Russia; Lala Kasimova, City Psychiatric Clinical Hospital, Republic of Russia; Andrey Gribanov, Lipetsk Regional Psychiatric and Neurologic Hospital #1 Dispensary, Lipetsk, Republic of Russia; Igor Boyev, Clinic of Borderline Mental Disorders, Stavropol, Republic of Russia; Elena Grigorieva, Yaroslavl Regional Psychiatry Clinical Hospital, Yaroslavl, Republic of Russia; Felix Torubarov, Clinical Hospital #6, Moscow, Republic of Russia; Galina Panteleeva, Mental Health Research Centre, Moscow, Republic of Russia; Yuri Suchkov, City Psychiatric Clinical Hospital #1, Nizhyny Novgorod, Republic of Russia; Alexander Bukhanovsky, Rehabilitology Scientific Center, Rostov-on-Don, Republic of Russia; Nikolay Ivanets, Korsakov Psychiatric Clinic, Moscow, Republic of Russia; Mikhail Burdukovsky, 4-th Psychiatric Hospital, Saint Petersburg, Republic of Russia; Nikolay Neznanov, Krestovsky Island Medical Institute, Saint Petersburg, Republic of Russia; Valentina Rasnuk, City Clinical Hospital #2, Saratov, Republic of Russia; Natalia Maxsimova, Regional Psychoneurological Hospital, Tver, Republic of Russia; Vitaly Tadtaev, Psychoneuropatology Dispensary #10, Saint Petersburg, Republic of Russia; Maria Andrusenko, Clinic Mental Health, Moscow, Republic of Russia; Vladimir Paunovic, Clinical Centre of Serbia Institute for Psychiatry, Belgrade, Serbia and Montenegro; Ivana Timotijevic, Institute for Mental Health, Belgrade, Serbia and Montenegro; Goran Mihajlovic, Clinical Hospital Centre Kragujevac, Kragujevac, Serbia and Montenegro; Vladimir Diligensk, Clinical Centre Dedinje, Belgrade, Serbia and Montenegro; Jelena Martinović, Clinical Centre Zvezdara, Belgrade, Serbia and Montenegro; Željko Špirić, Military Medical Academy Clinic for Psychiatry, Belgrade, Serbia and Montenegro; Grozdanko Grbeša, Clinical Hospital Centre Niš, Niš, Serbia and Montenegro; Tomislav Gajić, Health Centre Valjevo Psychiatric Service, Valjevo, Serbia and Montenegro; Mirjana Šojić, Health Centre Dr Dragiša Mišović, Čačak, Serbia and Montenegro; Milanka Cvetković, Health Counselling for Neuro Disorders, Belgrade, Serbia and Montenegro; Tung-Ping Su, Tapei Veterans General Hospital, Tapei, Taiwan; Nan-Ying Chin, Changhau Christain Hospital, Changau, Taiwan; Chih-Jen Ho and Shen-Ing Liu, Mackay Memorial Hospital, Tapei, Taiwan; Bohdan Suvalo, Lviv Regional State Clinical Psychiatric Hospital, Lviv, Ukraine; Petro Vlasovych Voloshyn, Institute of Neurology Psychiatry and Narcology of the Academy of Medical Sciences of Ukraine, Kharkiv, Ukraine; Oleksandr Konstyantynovych Napryeyenko, Kiev City Clinical Psychoneurologic Hospital No 1, Kiev, Ukraine; Oleh Sozontovych Chaban, Scientific Research Institute of Forensic, Social Psychiatry and Narcology, Kiev, Ukraine; Gennadiy Vasliovych Zilberblat, Kiev Regional Specialized Psycho-Narcological Medical Centre, Glevaha, Ukraine; Natallya Grygoruivna Pshuk, Regional Clinical Psycho-Neurological Hospital, Vinnytsya, Ukraine; Ellina Vitalyivna Melnyk, Odessa Regional Psychiatry Hospital No 1, Odessa, Ukraine; Vladyslav Andriyovych Demchenko, Psychoneurologic Hospital No 2, Kiev, Ukraine; Anatoliy Ipatov, Ukrainian Research Institute of Disability Problems, Dnipropetrovsk, Ukraine; Irina Dmitriyevna Spirina, Dnipropetrovsk Regional Clinical Psychiatric Hospital, Dnipropetrovsk, Ukraine; Tetyana Leonidovna Ryapolova, Donetsk Medical Psycho-Neurological Centre, Donetsk, Ukraine; Valeriy N Kuznetsov, Kiev City Clinical Psychiatric and Neurological Hospital No 1, Kiev, Ukraine; Svitlana Yehv Kazakova, Lugansk State Medical University, Lugansk, Ukraine; Svitlana Moroz, Dnipropetrovsk Regional Clinical Hospital, Dnipropetrovsk, Ukraine; Vitaliy Pischel, Ukrainian Scientific Institute of Social and Forensic Psychiatry and Drug Abuse, Kiev, Ukraine; Viktoriya Verbenko and Mykola Verbenko, Crimea Republic Clinical Hospital, Simferopol, Ukraine.

EMBOLDEN II (Trial 134) Study Investigators

Nevin Taylor, Gold Coast Hospital, Southport, Australia; Michael Theodoros, Brisbane, Australia; Thomas George, North West Specialist Centre, Queensland, Australia; Russell D’Souza, The Northern Hospital, Epping, Australia; Peter Farnbach, Neurotherapy Victoria, Malen, Australia; Sergio Gloger, Psico Medica Research Group, Santiago, Chile; Marco Gonzalez, Psychological Medical Center Phillips, Santiago, Chile; Miguel Burmester, Medical and Mental Center Apoquindo, Santiago, Chile; Veronica Larach, Clinical Pedro Mont, Santiago, Chile; Rodrigo Cordoba Rojas, UIC Campo Abierto-CISNE, Bogota, Colombia; Jose Daniel Toledo Arenas, Bogota, Colombia; Carlos Alberto Lopez Jaramillo, Conciencia Ltda, Medellin, Colombia; Mario Alberto Pena Garcia, Bogota, Colombia; Camilo Umana Valdivieso, Clinic ISNOR, Bucaramanga, Colombia; Andrea Mesén Fainardi, Costa Rican Neuropsychiatric Studies, Costa Rica, Calle 37; José Luis Salas Jerez, Montserrat Medical Center, San Jose, Costa Rica; Panagiotis Panagoutsos, Psychiatric Hospital of Tripoli, Tripoli, Greece; Athanassios Vidalis, Hippokratio Hospital of Thessaloniki, Thessaloniki, Greece; Anastassios Kanistras, Psychiatric Hospital of Thessaloniki, Thessaloniki, Greece; Lefteris Lykouras, Attikon General University Hospital, Athens, Greece; Humberto Nicolini, Group Medical Carracci, Carracci, Mexico; Miguel Angel Viveros Erosa, Hospital Psychiatric Yucatan, Yucatan, Mexico; Aitor Castillo, Specialized Institute of Mental Health, Lima, Peru; Hernan Zavalaga, Central Hospital Luis N Saenz, Lima, Peru; Juan Francisco Rivera Feijoo, Virgen de las Mercedes Clinic, Lima, Peru; Felipe Ramos Neyra, Integra Medical Services, Lima, Peru; Pedro Alipazaga, Center of Mental Health and Psychiatry, Chiclayo, Peru; Victor Ramos Patino, Office Victor Ramos Patino, Lima, Peru; Carlos Mendoza Angulo, Private Office Intihuatana, Lima, Peru; Alejandro Villanueva Ruska, Lima, Peru; Carlos Alvarado Vargas, Psychiatry Clinic and Psychotherapy of the Clinical Saint Lucas, Lima, Peru; Zoila Pacheco Armas, Lima, Peru; Jorge Pizarro Sanchez, Limatambo Clinic, Republic of Panama, Lima, Peru; Hector Chue Pinche, Psicosalud SAC, Lima, Peru; Petru Biosteanu and Ana Maria Grigorescu, IASI, Psychiatric Hospital SOCOLA, Romania; Lidia Maria Nica Udangiu, Obregia Psychiatric Hospital, Bucharest, Romania; Adrian Ionescu, Buzau, Psychiatric Nifon, Magura, Romania; Eufrosina Cotoranu, County Hospital Galati, Galati, Romania; Mirela Manea, Clinic Hospital Alexandru Orbregia, Bucharest, Romania; Elena Gherman, Clinic Hospital Al Obregia, Bucharest, Romania; George Hart, Sandton Medi Clinic, Bryanston, South Africa; Yao Mfodwo, Karibu Specalist Clinic, Benoni, South Africa; Lynette Nel, New Muckleneuk, Pretoria, South Africa; Annemarie Potgieter, Amy's Research Unit, Brooklyn, Pretoria, South Africa; Gert Jacobus Venter, Vista Clinic, Centurion, Pretoria, South Africa; Catherine Maud, Westville Hospital, Durban, South Africa; Vasavan Agambaram, Entabeni Hospital Suites 10, Durban, South Africa; Hilda Russouw, Somerset West Clinical Research, Somerset West, South Africa; Kaan Kora, Marmara University Medical Faculty, Istanbul, Turkey; Oguz Karamustafalioglu, Sisli Etfa Research & Education Hospital, Istanbul, Turkey; Omer Aydemir, Celal Bayar University Medical Faulty, Manisa, Turkey; Haluk Asuman Savas, Gaziantep University Medicine Faculty, Gaziantep, Turkey; Mohammed Alam, American Medical Research, Oak Brook, Illinois, USA; Mohammed Bari, Synergy Clinical Research, National City, California, USA; Louise Beckett, IPS Research CO, Oklahoma City, Oklahoma, USA; Michal Biunno, Louisiana Research Associates, New Orleans, Louisiana, USA; Gary J. Booker, Shreveport, Louisiana, USA; David Brown, Community Clinical Research, Austin, Texas, USA; John Carman, Carman Research, Smyrna, Georgia, USA; Jeffrey Danziger, CORE Research Inc. Maitland, Florida, USA; Bernadette D’Souza, Midwest Clinical Research Center, Dayton, Ohio, USA: Steven Eisen, CNS Research Institute, Philadelphia, Pennsylvania, USA; Donald J. Garcia, Future Search Trials, Austin, Texas, USA; Howard Hassman, CNS Research Institute, Clementon, New Jersey, USA; Richard Jaffe, Belmont Behavioral Health, Philadelphia, Pennsylvania, USA; Susan L. McElroy, Psychiatric Professional Service, Cincinnati, Ohio, USA; Airfulla Khan, Northwest Clinical Research Center, Bellevue, Washington, USA; Maryann Knesevich, University Hills Clinical Research, Irving, Texas, USA; James Knutson, Eastside Therapeutic Resource, South Kirkland, Washington, USA; Henry Lahmeyer, Northshore Clinical Trials, Northfield, Illinois, USA; Mohd Malik (Azfar M. Malik), Psych Care Consultants Research, St. Louis, Missouri, USA; Charles Meredith, Affiliated Research Institute, San Diego, California, USA; Franco Sicuro, Millennium Psychiatric Associates, St Louis, Missouri, USA; Trisha Suppes, University of Texas, Dallas, Texas, USA; Richard Weisler, Richard H. Weisler MD & Assoc., Raleigh, North Carolina, USA; John Gilliam, International Clinical Research, Richmond, Virginia, USA; Barbara Harris, PsyPharma Clinical Research, Phoenix, Arizona, USA; Alfredo Rivera, Community Clinical Research, Cincinnati, Ohio, USA; Lawrence Adler, Clinical Insights, Glen Burnie, Maryland, USA; Brad Diner, Arkansas Psychiatric Clinic, Little Rock, Arkansas, USA; Robert Riesenberg, Atlanta Center for Medical Research, Atlanta, Georgia, USA; Nicholas Vatakis, Social Psychiatry Research Institute, New York, New York, USA; Irving Kolin, Kolin Research Group, Winter Park, Florida, USA; Surendra Chagani, Med Clin Research Inc, St. Louis, Missouri, USA: Michael Downing, Future Search Trials, Dallas, Texas, USA.

Notes

^aIncluding sedation, lethargy and sluggishness.

^bIncluding akathisia, akinesia, athetosis, bradykinesia, buccoglossal syndrome, chorea, choreoathetosis, cogwheel rigidity, drooling, dyskinesia, dyskinesia oesophageal, dystonia, extrapyramidal disorder, freezing phenomenon, grimacing, hyperkinesia, hypertonia, hypokinesia, masked facies, micrographia, movement disorder, muscle contractions involuntary, muscle rigidity, nuchal rigidity, oculogyration, opisthotonus, parkinsonian gait, parkinsonism, pleurothotonus, posturing, psychomotor hyperactivity, restlessness, tardive dyskinesia, torticollis and tremor.

^cIncluding anti-insulin antibody increased, anti-insulin antibody positive, blood glucose abnormal, blood glucose fluctuation, blood glucose increased, blood insulin abnormal, blood insulin decreased, blood proinsulin increased, blood insulin increased, blood proinsulin abnormal, blood proinsulin decreased, dawn phenomenon, diabetes mellitus, diabetes mellitus inadequate control, diabetes mellitus insulin dependent, diabetes mellitus non insulin dependent, diabetes with hyperosmolarity, diabetic coma, diabetic complication, diabetic hyperglycaemic coma, diabetic hyperosmolar coma, diabetic ketoacidosis, diabetic ketoacidic hyperglycaemic coma, glucose tolerance decreased, glucose tolerance impaired, glucose tolerance test abnormal, glucose urine present, glycosylated haemoglobin increased, hyperglycaemia, hyperglycaemic hyperosmolar nonketotic syndrome, hyperinsulinaemia, hyperinsulinism, hyperphagia, impaired fasting glucose, impaired insulin secretion, increased insulin requirement, insulin C-peptide abnormal, insulin C-peptide decreased, insulin C-peptide increased, insulin resistance, insulin resistance syndrome, insulin-resistant diabetes, insulin-requiring type II diabetes mellitus, insulin tolerance test abnormal, metabolic disorder, Somogyi phenomenon, polydipsia, polyuria, thirst, blood ketone body present, blood ketone body increased, neonatal diabetes mellitus, glycosuria during pregnancy, gestational diabetes, glucose tolerance impaired in pregnancy and diabetes complicating pregnancy.