Quetiapine versus placebo as augmentation strategy in treatment resistent depression
Augmentation strategies are particularly helpful in managing treatment-resistant depressive patients. These strategies allow the patient to maintain the improvement already achieved with an given antidepressant and positive effects may appear rapidly. Over the past few decades, besides the typical augmentation strategies with Lithium and thyroid hormones, numerous compounds have been used as augmentation agents. Of the newer strategies the augmentation with atypical antipsychotics seems promising. Thus far, case reports and a small number of clinical trials have suggested that olanzapine, risperidone, ziprasidone and in particular quetiapine may be effective. However, the quality of clinical evidence available varies dramatically. The only published double-blind, placebo-controlled study in major depressive disorder to date is with olanzapine.
The main aim of this study is to compare the effects of the augmentation of the antidepressant venlafaxine with quetiapine or placebo in patients with “difficult to treat depression”. Secondary aims are to investigate the effects of venlafaxine with quetiapine or placebo on cognitive functions, the hypothalamic- pituitary-adrenal-axis and the tolerability of the combination strategies. Additionally, the influence of the genetic profil on different therapeutic outcomes and the effects of drug treatment on RNA expression and on protein level is analysed.
Our monocentric, double blind study is performed in depressed in-patients of the Max Planck Institute of Psychiatry in Munich. At first, all patients will be treated with venlafaxine up to 375mg over 28 days. After this time period, those patients who had a reduction in Hamilton Depression Rating Scale (HAMD) less than 45% are included in a second study phase and treated additionally with quetiapine (up to 200mg/day) or placebo under double blind conditions for further 28 days. The patients with a reduction in HAMD over 45% are expected as responders on a monotherapy with venlafaxine and are further openly treated with venlafaxine.
The participants will be assessed at selection, and once a week during the open treatment with venlafaxine and the double-blind phase between day 29 and day 56. The HAMD, the Montgomery Asperg Depression Rating Scale (MADRS), the Clinical Global Impression Scale (CGI), the Beck Depression Inventory (BDI), Spielberger’s State-Trait Anxiety Inventory (STAI) and the Epworth Sleepiness Scale (ESS) are used as efficacy measures. Test of cognitive functions with the main focus on aspects of attention, memory and executive functions will be done before the start of treatment with venlafaxine, before beginning the double-blind study phase (day 28) and at the end of the study (day 56). Prior to inclusion in the study, the patients will have a cerebral NMR-examination and a lumbar puncture will be performed, if the patients agree with this voluntary part of the study. A dexamethasone-CRH test will be done at the beginning of the study, on day 28 and day 56, a blood account for the assessment of DNA and RNA will be performed at the beginning of the study.
The plasma levels of venlafaxine and quetiapine are performed weekly. As safety parameters all patients will undergo a comprehensive medical examination, with physical examination, medical history, weight, blood pressure, heart rate, laboratory parameters with hematology and biochemistry, EEG and ECG. Some of these examinations are repeated during the study. To document the evolution of somatic complaints of the patient and to search for adverse events the Somatic Scale for the Assessment of Psychopathology (AMDP5) is used.
Research groups involved:
RG Susanne Lucae: Sonja Horstmann
RG Michael Czisch: Philipp Sämann
RG Günter Stalla: Ludwig Schaaf