Pipamperone/Citalopram (PNB01) Versus Citalopram (CIT) and Versus Pipamperone (PIP) in Major Depressive Disorder (MDD)
Pipamperone/Citalopram (PNB01) Versus Citalopram (CIT) and Versus Pipamperone (PIP) in Major Depressive Disorder (MDD)
The overall objective of this trial is to demonstrate clinically relevant superior
 antidepressant efficacy of the fixed dose combination PNB01 (low dose pipamperone and
 citalopram) over reference antidepressant treatment with citalopram alone, and a low dose of
 psychoactive pipamperone alone in patients with moderate to severe Major Depressive Disorder.

 This study was specifically designed to assess patient related outcome (PRO) parameters using
 an Interactive Voice Response System (IVRS) via telephone.
This is an international, double-blind, centrally randomized (stratified), multicenter study
 in 555 patients suffering from moderate to severe MDD in up to 40 sites in the USA, Germany
 and Canada. Eligible out-patients will be treated once daily (QD) with a fixed dose of either
 PNB01 (PIP 15 mg / CIT 20 mg (Week 1) - PIP 15 mg / CIT 40 mg (Week 2-10)), CIT alone (CIT 20
 mg (Week 1) - CIT 40 mg (Week 2-10) or PIP 15 mg alone (Week 1-10) in a 1:1:1 ratio in a
 double-blind fashion for 10 weeks. Study visits will be conducted 1, 2, 3, 4, 6, 8 and 10
 weeks after study treatment initiation. Possible withdrawal effects will be assessed 1 week
 after study treatment withdrawal.

 A blood sample for pharmacokinetic analysis will be collected when drawing blood for routine
 biochemistry. Patients who provided written informed consent to participate to the study will
 be asked to provide their consent to participate also to the non-mandatory pharmacogenetic
 study.

 Patient related outcomes will be collected electronically (ePRO) at study visits prior to
 visiting the investigator by using an Interactive Voice Response System (IVRS) via telephone.
 Patients wishing or choosing to discontinue the study treatment prematurely will be
 encouraged to continue to provide their scores, safety data and medications taken, up to the
 scheduled study end, by telephone.
Inclusion Criteria:

 1. Patient is informed and given ample time and opportunity to think about her/his
 participation and has given her/his written informed consent.

 2. Patient understands the investigational nature of the trial and is willing and able to
 comply with the trial requirements.

 3. Patient is male or female, aged ≥ 18 years.

 4. Patient has MDD according to the DSM IV-R criteria with an existence of depressed mood
 (DSM-IV-R Crit. A1) and loss of interest/anhedonia (DSM-IV-R Crit. A2) as confirmed by
 the MINI, lasting for at least 4 weeks and no longer than 18 months (78 weeks) for the
 current episode, and causing significant functional impairment (DSM-IV-R MDD C-
 criterion).

 5. CGI-S rating of at least 4 and a minimum MADRS total score of 26 using IVRS ePRO at
 Baseline.

 Exclusion Criteria:

 1. Patient is pregnant, nursing, or is a woman of child-bearing potential who is not
 surgically sterile, 2 years postmenopausal, or who does not consistently use 2
 combined effective methods of contraception (including at least 1 barrier method),
 unless sexually abstinent.

 2. Existence of Mood Disorder with psychotic features and/or high suicidality risk, as
 confirmed by MINI.

 3. Concomitant diagnosis of any additional primary Axis I disorder and presence of any of
 the following co-morbid disorders: (Hypo)manic episode, Panic Disorder (limited
 symptom attacks allowed), Obsessive Compulsive Disorder, Post-traumatic Stress
 Disorder, Alcohol dependence, any other Substance abuse and/or dependence, Psychotic
 Disorder, Eating Disorder, or General Anxiety Disorder, as confirmed by MINI.

 4. Concomitant diagnosis of any primary Axis II disorder.

 5. Patient is hospitalized.

 6. Patient has a clinically relevant renal dysfunction (e.g. GFR <60mL/min).

 7. Patient has hepatic dysfunction (total bilirubin >2.0mg/dL or alanine aminotransferase
 (ALT) and/or aspartate aminotransferase (AST) greater than 2 times the upper limit of
 the reference range).

 8. Patient has a malignant neoplastic disease, a documented history of epilepsy (juvenile
 convulsions excepted) or a documented, in the opinion of the investigator, clinically
 relevant risk of bleeding (eg. severe bleeding disorder, treatment with warfarin, …).

 9. Patient with a documented history or concomitant diagnosis or significant risk of
 cardiac arrhythmia or dysrhythmia, including a QTc interval of ≥500 ms at Baseline.

 10. Patient has any other medical or psychiatric condition, which in the opinion of the
 investigator, can jeopardize or would compromise the patient's ability to participate
 in this trial or that would interfere with trial assessments.

 11. Patient with documented alcohol or drug abuse, or having a positive standard screen
 for alcohol or drugs (including benzodiazepines and opioids).

 12. Patient received, in the past 7 days treatment with any psychoactive drug prior to
 randomization, including typical and atypical antipsychotics, hypnotics,
 antidepressants, anxiolytic drugs, anticonvulsive therapy, opioids, monoamine oxidase
 (MAO) inhibitors, sedative antihistamines, psychostimulants or amphetamines, dopamine
 D2 receptor antagonists, butyrophenones, metoclopramide, lithium, anticonvulsants,
 benzodiazepines, or barbiturates. If patient has received such therapy, a washout
 period of at least 7 days prior to baseline is required before inclusion in this trial
 (except fluoxetine: 4 weeks, and St John's Wort or MAO inhibitors: within 2 weeks).

 13. Concomitant treatment with diuretics, QT prolongation drugs, or dopamine agonists.

 14. Resistant depression defined as having failed to respond to either: a/ 2 previous
 antidepressants at an adequate dose administered for at least 4 weeks during the
 current episode; b/ augmentation therapy with any atypical antipsychotic drug

 15. Electroconvulsive therapy (ECT) or repetitive Transcranial Magnetic Stimulation
 therapy (rTMS) within the last 6 months; Vagus Nerve Stimulation (VNS) or Deep Brain
 Stimulation (DBS) ever.

 16. Formal psychotherapy or alternative treatment for 1 week prior to or during the study.

 17. Patient has participated in another trial of an investigational agent (including
 medical device) within the last 3 months prior to baseline or is currently
 participating in another trial of an investigational drug.

 18. Known hypersensitivity to any of the study drugs