Hippocampal Volume in Young Patients With Major Depression Before and After Combined Antidepressive Therapy
Condition: Depressive Disorder, Major
MeSH terms: Depression; Depressive Disorder; Depressive Disorder, Major
Study type: Interventional
Phase: Phase 4

Summary: 
      The proposed study is a randomized, placebo-controlled, double-blind trial to evaluate the
      safety and efficacy of antidepressant combination for the treatment of depression.

      Depressive disorder is one of the most common human diseases with a high burden for every
      patient, her/his family, health care system and society as a whole. Actual treatment concepts
      of depressive disorders include pharmacologic, biologic (e.g. electroconvulsive therapy,
      light therapy) and psychologic therapy. Even though effective therapeutic options are at
      hand, therapy needs time. It is often not possible to reach full remission of the disease and
      10-25% of patients suffering from depression are regarded as "treatment-resistant". In
      treatment resistant depression, the use of a combination of antidepressive drugs is
      considered safe and effective. However, at present no data exist concerning the use of drug
      combination as primary therapeutic option. The aim of the study is to examine the hypothesis,
      that significantly more patients achieve full remission of depressive symptoms when treated
      with the combination of two antidepressants and as a secondary hypothesis, that patients
      receiving a drug combination will achieve remission faster than patients treated with
      monotherapy. To test these hypotheses, a two group parallel design is used comparing the
      efficacy and safety of mirtazapine in combination with venlafaxine or placebo.
    

Detailed description: 
      Background Information

      Combining antidepressants is a well-established medical procedure for the treatment of
      therapy refractory depression, that may also be applied successfully under non-refractory
      conditions. The goal of the study is to test this hypothesis. All participants are to be
      treated with Remergil Soltab®, a sedative antidepressant containing mirtazapine. In a
      double-blind, parallel-group design, all participants are treated with either Trevilor®
      retard, an antidepressant of the selective-serotonin-norepinephrine-reuptake-inhibitor class
      containing venlafaxine or placebo.

      Especially in the treatment of therapy-resistant depression augmentation- and combination
      strategies are widely used (Demling and Frieling 2004).

      Only limited data exist on the efficacy and safety of combination of antidepressants:
      Carpenter et al. have shown, that adjunctive use of mirtazapine added to the prior used
      antidepressant (mostly SSRIs) was more effective than placebo (Carpenter et al 2002).
      Devarajan and Dursun report a more effective antidepressive therapy with the combination of
      citalopram and reboxetine (Devarajan and Dursun 2000). Rubio et al. found the combination of
      reboxetine, SSRI or venlafaxine and mirtazapine effective (Rubio et al 2004). Smith et al.
      report less side effects of venlafaxine use when combined with mirtazapine.

      All mentioned studies were conducted in treatment-resistant depression. Only the study by
      Carpenter et al. was done in a randomized, controlled, double-blind design. No data exist on
      the efficacy and safety of combined antidepressant use as primary therapy of depression.

      Pallanti et al. were able to show, that combination of SSRI and mirtazapine leads to an
      earlier onset of therapeutic effects in OCD (Pallanti et al 2004).

      There exists little evidence on the benefits of combined antidepressant use in depression.
      However, combination of antidepressants proved to be effective and safe in
      treatment-resistant depression. All used antidepressants have side-effects (see
      "Fachinformation" for further details). Drug-drug interactions have not been described for
      the drugs used in the trial. A risk-potentiation therefore seems unlikely.

      Route of administration:

      Venlafaxine and placebo are administered orally, the usual mode of administration for
      antidepressive drugs. Only Remergil Soltab®is administered using an orodispersible tablet.
      This way of administering mirtazapine has proven to be effective.

      Dosage:

      All participants are to be treated with Remergil Soltab® 45mg, the highest dosage of its
      license in Germany.

      Trevilor® retard will be used 300mg/d. It is licensed for 375mg/d, but for practicability
      reasons, especially blinding procedures, the modestly lower dosage will be entertained.

      Dosage regimen:

      Remergil® medication starts with 15mg for two days after randomization. On day 3 and 4, 30mg
      are used. From day 5 on, 45mg are used.

      In the Trevilor® group, treatment starts with 150mg for the first three days, afterwards
      300mg are used.

      Beginning with day 4, both groups are treated with two capsules of the blinded study
      medication.

      Treatment period:

      All patients are treated for 12 weeks in a double-blind fashion.

      The trial will be conducted in compliance with this protocol, the guidelines for good
      clinical practice (CPMP/ICH/135/95) and the applicable regulatory requirements, namely the
      German law on drugs (AMG).

      Participants:

      160 participants, both female and male are to be recruited when admitted to the open wards of
      the Department of Psychiatry and Psychotherapy, Universitätsklinikum Erlangen. Participants
      have to suffer from depressive disorder and need to be 18-65 years old.

      Treatment of Subjects

      After screening and inclusion into the trial, all prior psychopharmacological medication is
      stopped and washed out. How dose reduction and cessation is done will be decided
      individually. The wash-out phase should not exceed 5-7 days. The use of irreversible
      inhibitors of monoamine oxidase (MAOI) during 14 days prior to screening is an exclusion
      criterion, as a wash-out period of 14 days is not suitable for the trial. After the wash-out,
      patients are randomized into two groups:

        1. VENLA - Participants receiving Trevilor®retard 150mg in a blinded capsule. For three
           days, one capsule is administered, afterwards two capsules are administered,
           representing a dosage of 300mg/d.

        2. CONT - Participants receiving placebo capsules. For three days, one capsule is
           administered, afterwards two capsules are administered.

      All participants are receiving Remergil Soltab® starting with 15mg for two days, 30mg for
      days 3 and 4 and 45mg beginning with day 5

      Medication permitted during the trial: all non-psychiatric medication, lorazepam and
      pipamperon.

      Medication not permitted: Antidepressants other than the study medication, neuroleptics other
      than pipamperon, sedative other than lorazepam. Medication with known interactions with the
      study medication (according to the SPC).

      All medication is allowed before the wash-out period of the trial with the exception of
      irreversible MAO inhibitors (MAOI).

      Medication permitted after the trial: All medication is allowed after the trial. The use of
      MAOI and other monoaminergic substances should not be started earlier than 14 days after the
      end of intake of study medication.

      Assessment of Efficacy

      Efficacy is assessed using different psychometric scales either filled out by the participant
      or the investigator. Scales to be used are BDI, BAI, BSI, PSQuI as questionaires filled by
      the participant and CGI, MADR-S, HAM-D and HAM-A as rating scales filled out by the
      investigator. During the first week and week 13, a cranial magnetic resonance image is
      obtained, to assess morphologic changes of the brain.

      During the weekly visits, BDI, BAI, CGI, HAM-D, HAM-A and MADR-S are entertained. BSI and
      PSQuI are entertained at screening, visit 4, visit 8, visit 12 and visit 13. (please see also
      the attached flow chart and 16 Supplement A for further details).
    

Intervention name(s): Mirtazapine; Venlafaxine
Intervention type(s): Drug; Drug
Intervention description(s): Patients receive mirtazapine 45mg and placebo.; Patients receive mirtazapine 45mg and venlafaxine 300mg.
Other intervention name(s): Remergil SolTab (R); Remergil SolTab (R); Trevilor retard (R)
Intervention MeSH terms: Mirtazapine; Venlafaxine Hydrochloride
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Treatment
Keywords: Depressive Disorder, Major; Venlafaxine; Mirtazapine; Double-blind RCT; Magnetic resonance imaging; Hippocampal volume