VIENNA – Psychiatrists have received a welcome gift in the form of CEQUEL, a randomized trial that offers much needed guidance on how to proceed when quetiapine for bipolar depression isn’t achieving sufficient response, Eduard Vieta, MD, said at the annual congress of the European College of Neuropsychopharmacology.
The answer provided by CEQUEL is to add lamotrigine.
“Quetiapine is indicated for treatment of symptoms of bipolar depression, but many clinicians – including myself – are a bit underwhelmed about the practical results. In the clinical trials, quetiapine looks great, but when we use it in practice we’re not so happy with the results. The trials are consistently positive with a large effect size, whereas in clinical practice many patients respond only partially to quetiapine. The question has been what to do next,” observed Dr. Vieta, professor of psychiatry and head of the bipolar disorders program at the University of Barcelona.
Dr. Eduard Vieta
Increasing the dose of quetiapine (Seroquel) above the recommended 300 mg/day in an effort to boost efficacy is problematic. Patients become extremely sedated. The CEQUEL (Comparative Evaluation of Quetiapine plus Lamotrigine) investigators decided to examine combination therapy with two drugs having completely different mechanisms of action.
A total of 202 patients with bipolar depression at 27 U.K. sites were placed on quetiapine and randomized double-blind to lamotrigine or placebo. Lamotrigine (Lamictal) was started at 25 mg/day and gradually increased to 200 mg daily. Because there is some limited evidence that folic acid is effective in unipolar depression, the investigators employed a 2x2 factorial design, further randomizing participants to 500 mcg/day of folic acid or placebo.
The primary endpoint was improvement in depressive symptoms at 12 weeks, with 52-week outcomes as a secondary endpoint. The group on combination therapy with quetiapine and lamotrigine showed significantly greater improvement both on mean depressive symptoms as measured with the Quick Inventory of Depressive Symptomatology-self report version 16 (QIDS-SR16), and on rates of remission at 12 and 52 weeks, compared with patients on quetiapine and placebo. The combination also reduced the risk of relapse in patients with bipolar I disorder with predominantly depressive symptoms.
Folic acid proved to be not only ineffective, it actually interfered with lamotrigine’s effectiveness. The mean reduction from baseline to 12 weeks on the QIDS-SR16 was 4.4 points in patients who received lamotrigine without folic acid, compared with a 0.12-point increase in those receiving lamotrigine plus folic acid (Lancet Psychiatry. 2016 Jan;3[1]:31-9).
Dr. Vieta wasn’t involved in CEQUEL, but he considers the study one of the highlights of the year in the field of affective disorders and urged his colleagues to consider lamotrigine/quetiapine combination therapy for bipolar depression.
“Quetiapine and lamotrigine are both now generic drugs. CEQUEL showed both are superior to quetiapine alone. It’s good news – a not-expensive treatment combining quetiapine with a drug, lamotrigine, that’s quite well tolerated,” he said.
CEQUEL was funded by the Medical Research Council. Dr. Vieta reported having no financial conflicts of interest.