Quetiapine Prolong, Escitalopram and Hypothalamic-pituitary-adrenocortical (HPA) Axis Activity in Depressed Patients

Ludwig Maximilian University of Munich

Status and phase

Completed

Phase 3

Conditions

Major Depression

Treatments

Drug: escitalopram

Drug: quetiapine

Study type

Interventional

Funder types

Other

Identifiers

NCT00953108

QUE/09

Details and patient eligibility

About

In former studies of the investigators research group the investigators could also demonstrate acute inhibitory effects of the antidepressant mirtazapine on ACTH and cortisol release in normal controls (Schüle et al. 2002), most likely mediated via antagonism at central 5-HT2- and H1-receptors. In contrast to mirtazapine, serotonin or norepinephrine reuptake inhibiting antidepressants acutely stimulate ACTH and cortisol secretion (Schüle 2007). The investigators also performed a study in depressed patients who were treated either with mirtazapine or with reboxetine using serial dexamethasone/CRH tests (week 0, 1, and 5) as a parameter for HPA axis activity. Mirtazapine, but not the norepinephrine reuptake inhibitor reboxetine was able to significantly reduce HPA axis activity already within one week (Schüle et al. 2006). Mirtazapine is known to have an earlier onset of antidepressant action than do SSRIs such as sertraline (Behnke et al. 2003) or antidepressants with dual mechanism of action such as venlafaxine (Benkert et al. 2006), possibly due to its rapid inhibition of HPA axis activity in unipolar depressed patients.

Since mirtazapine and quetiapine have similar effects on the HPA system in healthy male volunteers (i.e. inhibition of ACTH and cortisol secretion), a rapid attenuation of HPA axis activity is also expected during quetiapine XR treatment in depressed patients.

Therefore, in the present study the investigators goal is to investigate whether quetiapine fumarate XR at a dosage of 300 mg per day has an impact on HPA axis activity in unipolar depressed patients, as measured by serial dexamethasone/CRH tests (week 0, 1, and 5) and salivary cortisol profiles and whether putative effects of quetiapine XR on the HPA system are related to its antidepressant efficacy.

Enrollment

60 patients

Sex

All

Ages

18+ years old

Volunteers

No Healthy Volunteers

Inclusion criteria

For inclusion in the study patients must fulfil all of the following criteria:

Inpatients (the admission to hospital occurs independently from study participation)
Provision of written informed consent
A diagnosis of major depression by Diagnostic and Statistical Manual of Mental Disorders- Fourth Edition (DSM-IV) (unipolar depression: 296.2, 296.3)
Female and male patients aged 18 to 65 years
Female patients of childbearing potential must have a negative serum human chorionic gonadotropin (hCG) pregnancy test at enrolment and e willing to use a reliable method of birth control (i.e. barrier method, oral contraceptive, implant, dermal contraception, long-term injectable contraceptive, intrauterine device, or tubal litigation) during the study.
Able to understand and comply with the requirements of the study as judged by the investigator.
A sum score of at least 18 on the 21-item version of the Hamilton Depression Rating Scale (21-HAMD)

Exclusion criteria

Any of the following is regarded as a criterion for exclusion from the study:

Pregnancy or lactation
Any DSM-IV Axis I disorder not defined in the inclusion criteria
Patients who, in the opinion of the investigator, pose an imminent risk of suicide or a danger to self or others
Known intolerance or lack of response to quetiapine fumarate and/or escitalopram, as judged by the investigator
Use of any of the following cytochrome P450 3A4 inhibitors in the 14 days preceding enrolment including but not limited to: ketoconazole, itraconazole, fluconazole, erythromycin, clarithromycin, troleandomycin, indinavir, nelfinavir, ritonavir, fluvoxamine and saquinavir
Use of any of the following cytochrome P450 3A4 inducers in the 14 days preceding enrolment including but not limited to: phenytoin, carbamazepine, barbiturates, rifampin, St. John's Wort, and glucocorticoids
Use of monoamine oxidase inhibitors (MAOIs) or other serotonergic drugs (e.g. triptans) in the 14 days preceding enrolment
Use of oral anticoagulants in the 14 days preceding enrolment
History of bleeding disorders.
Use of drugs which are mainly metabolized by cytochrome P450 2D6 having a low therapeutic index (e.g. flecainide, propafenone, metoprolol) in the 14 days preceding enrolment
Administration of a depot antipsychotic injection within one dosing interval (for the depot) before randomisation
Substance or alcohol dependence at enrolment (except dependence in full remission, and except for caffeine or nicotine dependence), as defined by DSM-IV criteria
Opiates, amphetamine, barbiturate, cocaine, cannabis, or hallucinogen abuse by DSM-IV criteria within 4 weeks prior to enrolment
Medical conditions that would affect absorption, distribution, metabolism, or excretion of study treatment
Unstable or inadequately treated medical illness (e.g. congestive heart failure, angina pectoris, hypertension) as judged by the investigator
Involvement in the planning and conduct of the study
Previous enrolment or randomisation of treatment in the present study.
Participation in another drug trial within 4 weeks prior enrolment into this study or longer in accordance with local requirements
A patient with Diabetes Mellitus (DM) fulfilling one of the following criteria:
- Unstable DM defined as enrolment glycosylated hemoglobin (HbA1c) >8.5%.
- Admitted to hospital for treatment of DM or DM related illness in past 12 weeks.
- Not under physician care for DM
- Physician responsible for patient's DM care has not indicated that patient's DM is controlled.
- Physician responsible for patient's DM care has not approved patient's participation in the study
- Has not been on the same dose of oral hypoglycaemic drug(s) and/or diet for the 4 weeks prior to randomisation. For thiazolidinediones (glitazones) this period should not be less than 8 Weeks.
- Taking insulin whose daily dose on one occasion in the past 4 weeks has been more than 10% above or below their mean dose in the preceding 4 weeks Note: If a diabetic patient meets one of these criteria, the patient is to be excluded even if the treating physician believes that the patient is stable and can participate in the study.
An absolute neutrophil count (ANC) of 1.5 x 109 per liter
Abnormal laboratory parameters of clinical relevance before enrolment
Abnormal blood pressure, abnormal electrocardiogram, and/or abnormal electroencephalogram with clinical relevance before enrolment
Psychotropic drugs within 3 days before and throughout the study with the exception of zopiclon (up to 7.5 mg per day) in case of sleep difficulties and lorazepam (up to 2 mg per day) in case of inner tension and anxiety