Mirtazapine for treatment resistant depression

Plain English Summary

Background and study aims
Depression is common and most depressed patients are treated by their general practitioner (GP). Antidepressants are very widely prescribed, but a substantial proportion of those who take them do not get better. There is very little evidence to guide GPs when this happens, and most are unsure what to do when their patients do not respond to the medication. Many patients remain in a depressed state for long periods of time, despite taking antidepressant treatment. We are looking for other ways to help those whose depression does not respond to initial treatment, and we think that it might be useful to use combinations of antidepressant drugs. Combination treatments are used in many areas of medicine, including other common conditions such as hypertension and diabetes. Most of the antidepressants prescribed in the UK as first line treatment are Selective Serotinin Reuptake Inhibitors (SSRIs) like Fluoxetine (Prozac). However, there is another well-established antidepressant called Mirtazapine, that works in a different way from SSRIs and the related noradrenaline reuptake inhibitors (SNRIs). We propose a large study in general practice, where most depression is treated, to examine the effectiveness and cost-effectiveness of the combination of mirtazapine and an SSRI or SNRI.

Who can participate?
Patients from primary care who are depressed and have taken an SSRI or SNRI antidepressant for at least six weeks without substantial benefit. They must be aged between 18 and 75 and must not be suffering from a psychotic disorder or be dependent on drugs and alcohol. They must not be pregnant.

What does the study involve?
Participants who agree will be randomly allocated to receive either mirtazapine treatment or a dummy drug (placebo) that appears identical. Neither the participant, GP, or study investigator will know whether the participant is taking mirtazapine or placebo. They will continue to take their SSRI antidepressant and be treated by their GP in the usual way.

What are the possible benefits and risks of participating?
If it proves effective, this combination has the potential to rapidly make a difference for people with depression that does not respond to usual first line antidepressant treatment. Mirtazapine has been licensed in the UK for the treatment of depression since 1994, and its adverse effect profile is well known. Its principal effects are increase in appetite, weight gain and drowsiness. Mirtazapine continues to be used in psychiatric settings in combination with other antidepressants without the reporting to date of any unexpected or new adverse events.

Where is the study run from?
Bristol University. The other participating centres are the Universities of Exeter, Manchester and York.

When is study starting and how long is it expected to run for?
The study begins in January 2013 and will run for 42 months

Who is funding the study?
NIHR Health Technology Assessment Programme (HTA)

Who is the main contact?
Dr David Kessler
david.kessler@bristol.ac.uk

Study website

Type

Scientific

Contact name

Dr David Kessler

ORCID ID

http://orcid.org/0000-0001-5333-132X

Contact details

University of Bristol
School of Social & Community Medicine
Oakfield House
Oakfield Grove
Bristol
BS8 2BN
United Kingdom
-
david.kessler@bristol.ac.uk

EudraCT/CTIS number

IRAS number

ClinicalTrials.gov number

Protocol/serial number

HTA 11/129/76

Scientific title

A double blind placebo-controlled randomised trial of the addition of mirtazapine for patients with depression in primary care who have not responded to at least 6 weeks of treatment with a selective serotonin reuptake inhibitor or serotonin and noradrenaline reuptake inhibitor.

Acronym

MIR

Study hypothesis

That the addition of mirtazapine will improve outcome in depressed patients from primary care who have not responded to an SSRI antidepressant after at least 6 weeks of treatment.

Ethics approval(s)

South East Wales Research Ethics Committee C, 25/01/2013, ref: 12/WA/0353

Study design

A two parallel group multi-centre pragmatic placebo-controlled randomised trial with allocation
at the level of the individual

Primary study design

Interventional

Secondary study design

Randomised controlled trial

Study setting(s)

Hospital

Study type

Treatment

Patient information sheet

Not available in web format, please use the contact details to request a patient information sheet

Condition

Depression

Intervention

The addition of Mirtazapine to SSRI antidepressants

Added 27/07/2017:
To investigate whether combining mirtazapine with Serotonin-Noradrenaline Reuptake Inhibitor (SNRI) or Selective Serotonin Reuptake Inhibitor (SSRI) antidepressants results in better patient outcomes and more efficient NHS care than SNRI or SSRI therapy alone in Treatment Resistant Depression (TRD).
Design: MIR is a two-parallel group, multi-centre, pragmatic, placebo controlled, randomised trial with allocation at the level of the individual.
Interventions: Participants are randomised to receive either oral mirtazapine or matched placebo, starting at 15mg daily for two weeks and increasing to 30mg daily thereafter, for up to 12 months to be taken in addition to their usual antidepressant.

Intervention type

Drug

Pharmaceutical study type(s)

Phase

Not Applicable

Drug/device/biological/vaccine name(s)

Mirtazapine

Primary outcome measure

Change in Beck Depression Inventory score at 12 weeks (added 27/07/2017: measured using the BDI-I) measured as a continuous variable

Secondary outcome measures

Current secondary outcome measures:
The following are measured at 12, 24, and 52 weeks:
1. Response
2. Remission of depression symptoms
3. Changes in anxiety symptoms
4. Adverse Effects
5. Quality of life
6. Adherence to antidepressant medication
7. Health and social care use
8. Time off work
9. Cost effectiveness
All outcomes are analysed on an intention to treat basis.

Previous secondary outcome measures:
1. 50% improvement in BDI score (remission)
2. A measure of anxiety (GAD7)
3. Quality of life (EQ-5D-5L)
4. Health care utilisation

Overall study start date

01/01/2013

Overall study end date

30/06/2016

Reason abandoned (if study stopped)

Participant inclusion criteria

1. Aged 18-75 years
2. Currently taking any of the following SSRI or SNRI antidepressants, for at least 6 weeks at recommended (BNF) doses:
2.1. Fluoxetine
2.2. Sertraline
2.3. Citalopram
2.4. Escitalopram
2.5. Fluvoxamine
2.6. Paroxetine
2.7. Duloxetine
2.8. Venlafaxine and who have done so for at least 6 weeks at
3. Patients who score 14 or more on the Beck Depression Inventory (BDI)
4. Patients who have adhered to their medication and meet ICD-10 criteria for depression (assessed using the Computerised Interview Schedule – Revised version (CIS-R))

Participant type(s)

Patient

Age group

Adult

Lower age limit

18 Years

Upper age limit

75 Years

Sex

Both

Target number of participants

400

Participant exclusion criteria

GPs will be asked to exclude patients who have bipolar disorder, psychosis or alcohol/substance abuse/dependence or who are pregnant. In addition, we will exclude patients who: are not able to complete the study questionnaires or have a past history of an adverse reaction to mirtazapine.

Recruitment start date

01/01/2013

Recruitment end date

30/06/2016

Countries of recruitment

England, United Kingdom

Study participating centre

University of Bristol
Bristol
BS8 2BN
United Kingdom

Study participating centre

University Of Exeter Medical School
St Lukes Campus
Magdalen Road
Exeter
EX1 2LU
United Kingdom

Study participating centre

Keele University
Primary Care And Health Sciences
Keele
ST5 5BG
United Kingdom

Study participating centre

Hull York Medical School
Cottingham Road
Hull
HU6 7RX
United Kingdom

Organisation

University of Bristol (UK)

Sponsor details

c/o Dr Birgit Whitman
Research Governance and Compliance Manager
Research and Enterprise Development
Senate House
Tyndall Avenue
Bristol
BS8 1TH
England
United Kingdom
-
Birgit.Whitman@bristol.ac.uk

Sponsor type

University/education

Website

http://www.bris.ac.uk/

ROR

https://ror.org/0524sp257

Funder type

Government

Funder name

Health Technology Assessment Programme

Alternative name(s)

NIHR Health Technology Assessment Programme, HTA

Funding Body Type

government organisation

Funding Body Subtype

National government

Location

United Kingdom

Publication and dissemination plan

Planned publication in a high-impact peer reviewed journal.

Intention to publish date

Individual participant data (IPD) sharing plan

The current data sharing plans for the current study are unknown and will be made available at a later date

IPD sharing plan summary

Data sharing statement to be made available at a later date

Study outputs