This is a multi-center, double blind, randomized, placebo-controlled, parallel group, flexible dose titration study conducted in centers in the USA and India. Following a washout period, subject will be treated with citalopram 20 mg once daily for 4 weeks, then with 40 mg once daily for 4 weeks. Subjects who tolerate 40 mg citalopram, but whose MADRS score is < 50% from baseline, but no lower than 17, will be considered partial or non-responders and will be randomized to receive either placebo or TC-5214 as add-on therapy. TC-5214 or placebo will be started at 2 mg daily (BID dosing), and be titrated based on tolerability and therapeutic response up to 8 mg daily. Approximately 560 subjects will enter the Open Label Phase and approximately 220 will enter the double blind phase of the study.

This is a multi-center, double blind, randomized, placebo-controlled, parallel group, flexible dose titration study conducted in centers in the USA and India.

Following a washout period, subject will be treated with citalopram 20 mg once daily for 4 weeks, then with 40 mg once daily for 4 weeks. Subjects who tolerate 40 mg citalopram, but whose MADRS score is reduced 50% from baseline, but no lower than 17, will be considered partial or non-responders and will be randomized to receive either placebo or TC-5214 as Add:-on therapy.

TC-5214 or placebo will be started at 2 mg daily (1mg BID dosing). After 2 weeks treatment, medication can be increased to 4 mg (2mg BID) or continued unchanged. Dose escalation will depend on good tolerability and inadequate therapeutic response. After a further 2 weeks, medication can be increased to 8 mg (4mg BID) if felt appropriate by the investigator. Again, dose escalation will depend on good tolerability and inadequate therapeutic response. At any time during the double blind phase of the study, placebo or TC-5214 can be reduced to the last previous dose level following the emergence of unacceptable adverse event(s).

If a subject is prematurely discontinued from the study between Week 8 and Week 16 for any reason, the investigator will make every effort to perform all evaluations as per protocol, assuming the subject had reached the end of the double blind Add:-on treatment phase. These evaluations are to be made as soon as possible but within 2 weeks of discontinuation.

For the subjects completing the double blind phase of the study, there will be a follow-up visit 2-3 weeks after the last dose of trial medication. At this follow-up, any signs or symptoms of relapse will be evaluated.

Inclusion Criteria:

1. Diagnosis of major depressive disorder (MDD) according to DSM-IV and confirmed via MINI diagnostic scale
2. No more than 1 prior antidepressant course of treatment before trial entry.
3. Able to give written informed consent.
4. MADRS score greater than 27.
5. CGI-S score greater than or equal to 4.
6. No clinically significant abnormality on physical examination, vital signs, ECG or laboratory tests at screening.
7. Women of child bearing potential must: a) have a negative urine pregnancy test, b) not be nursing, and c) be willing to use acceptable methods of contraception throughout the study period.

Exclusion Criteria:

1. Any co morbid psychiatric illness confirmed by MINI diagnostic scale, especially bipolar disorder, schizophrenia, dementia, or PTSD
2. Subjects with significant suicidal risk upon clinical assessment utilizing the M.I.N.I.
3. History of alcohol or drug abuse over the last 6 months
4. History of seizures or seizure disorders
5. Any other severe progressive and uncontrolled medical condition
6. For other controlled medical conditions, medication to be unchanged over the 2 months preceding screening, or else the subject will be excluded
7. Subjects with Glaucoma, Kidney Disease or Heart Disease
8. Known hypersensitivity to mecamylamine
9. Other investigational drug in previous 30 days
10. Screening QTcB or QTcF > 450 msec
11. Current or prior citalopram treatment