Inclusion criteria

• Adult male and female patients with a diagnosis of a major depressive episode (unipolar or bipolar disorder) according to DSM-IV Diagnosis Criteria.

• Age requirements: 18 to 70 years of age in D-01; 18 to 80 years of age in D-02, D-03, and D-04; and > 18 years of age in D-21 and D-23.

• Patient has a history of chronic (≥2 years) or recurrent (at least 4 episodes for D-01, D-02, D-03, and D-04; at least 2 episodes for D-21 and D-23) major depression.

• An inadequate response to antidepressant treatments from at least 2 different treatment categories. Inadequate response was defined as follows:

○ D-01, D-02, D-03, and D-04 only: antidepressant resistance rating ≥ 3 for at least 2 treatments.

○ D-21 and D-23 only: resistant to ≥4-adequate antidepressant treatments.

• Patient is able to comply with all testing and visit requirements per protocol.

• D-02, D-03, and D-04 only: a score ≥ 20 on the 24-Item Hamilton Rating Scale for Depression (HRSD).

• D-01 only: A score ≥ 20 on the 28-item HRSD.

• D-01, D-02, and D-03 only: patient is a male or non-pregnant female adequately protected from conception.

• D-21 only: a minimum baseline score of 24 on the Montgomery-Asberg Depression Rating Scale (MADRS) and no greater than a 25% decrease in the MADRS score between the prestudy and baseline visits.

• D-23 only: a Clinical global Impression (CGI) severity of illness score of moderately ill (score of $4).

• D-01 only: patient has a score ≤ 50 on the global Assessment of function.

• D-01, D-02, and D-03 only: stable on current antidepressant medication regimen for ≥ 4 weeks prior to visit 1 or not taking antidepressant medications.

• D-21 only: on stable anti-depressant for >4 weeks.

• D-01, D-02, D-03, D-04, and D-21 only: patient with a bipolar disorder has demonstrated a resistance to lithium treatment or has a medical contraindication to treatment with lithium or is known to be intolerant to lithium.

• D-01, D-02, D-03, and D-04 only: patient has an intelligence quotient (IQ) ≥ 70 based on the investigator’s judgement

• D-02 only: if currently taking atypical antipsychotics, stable medications for .4 weeks.

• D-03 only: patient has a history of psychotherapy treatment that did not result in clinical improvement.

• D-21 only: patient with a current diagnosis of bipolar disorder must be receiving a mood stabilizer.

Exclusion criteria

• A history of schizophrenia, schizoaffective disorder, any other psychotic disorder, or a current major depressive episode that includes psychotic features; or is currently psychotic.

• Other exclusion criteria included simultaneous enrollment in another investigational trial, previously received Vagus Nerve Stimulation therapy, presence of other cognitive disorders (such as delirium or dementia), other neurological problems (such as central nervous system disease or injury), current alcohol or substance abuse, clinically significant suicidal intent, and cardiac or pulmonary disorders (such as history of myocardial infarction or cardiac arrest).

• D-02, D-03, D-04, D-21, and D-23 only: a history of rapid cycling bipolar disorder.

• D-01, D-02, D-03, D-21 only: has had a vagotomy.

• D-01, D-02, D-03, and D-21 only: patient requires a whole body MRI subsequent to VNS implantation.

• D-01, D-02, and D-21 only: a history of ulcers including gastric and duodenal, vasovagal syncope, or swallowing difficulties.

• D-21 only: a history of borderline personality disorder.