The aim of this study is to evaluate the efficacy of N-acetylcysteine (NAC) add-on to antidepressant medication in treating patients who do not relieve during standard antidepressant treatment for 6 weeks at least. Meanwhile, secondary outcomes will include changes in some biomarkers and on specifically local brain activity (functional Magnetic Resonance Imaging, fMRI) and white matter integrity (Diffusion Tensor Imaging, DTI). The hypothesis of this study is that NAC has positive effects on refractory major depressive disorder patients with increased inflammatory activity.

It's a double-blind randomised placebo controlled antidepressant augmentation study with 12-week treatment and 8-week follow up. Its purpose is to investigate antidepressant efficacy and safety of NAC in patients with treatment resistant depression (TRD) defined as insufficient response to 1 or more antidepressants given for at least 6 weeks and in an adequate dose, displaying increased peripheral inflammatory activity and moderate to severe depression. Apart from studying the effects of NAC on depression severity, the secondary outcomes are to examine a range of biomarkers related to potentially important underlying mechanisms such as oxidative stress and inflammatory activity and to evaluate the effects on brain functioning (fMRI) and on white matter integrity (DTI). Scale assessments are performed in the week preceding initiation of treatment, during the treatment period, at the end of the treatment period and at 8-week follow up. Neuro-imaging is performed before the treatment starts and in week 12, before the study medication is terminated. Collection of blood and morning urine only takes place at three time points, in the week preceding initiation of treatment, closely before tapering off the study medication and at the end of 8-week follow up. This study is hoped to show that NAC perform positive effects on those aspects mentioned above.

Inclusion Criteria:

• a current episode of MDD diagnosed according to Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV-TR) diagnosed with SCID
• an age between 18 and 65 years
• a total score of HAMD-17 ≥ 17
• a CRP level between 0.85 and 10 mg/L (The CRP range is based on literature values for mild to moderate chronic inflammation, while values > 10 mg/L point at acute inflammation. A pilot study at the Tianjin Hospital (n=62) indicated that approximately one third of all patients with MDD will have CRP values within this range). insufficient response to 1 or more antidepressants given for at least 6 weeks and in an adequate dose during the current episode
• stable dose of the current antidepressant drug for at least 2 weeks prior to initiation of the study
• Patients are allowed to use benzodiazepines (BZD) to relieve anxiety during the first phase of antidepressant treatment (Anding Hospital protocol). Benzodiazepines may also be prescribed because of sleeping problems during the trial. BZD use will be recorded at all assessments during the trial and after follow-up.
• Patients are compliant with treatment according to the judgement of the treating clinician.
• Female subjects will be eligible to participate in the study if they are of non-childbearing potential or of child-bearing potential and willing to practice appropriate birth control methods during the study. Clinical patients always get a pregnancy test before start of treatment.
• Participant or guardian has to sign informed consent. The patients' guardians will sign the informed consent on behalf of the participants when the capacity of participants to consent is compromised.

Exclusion Criteria:

• A history of manic episode
• Use of mood stabilizer
• Use of antipsychotic medication with more than half of the maximum dosage suggested in the instruction
• History of substance abuse or dependence
• An allergic reaction to NAC or any component of the preparation
• Severe somatic diseases that might interfere with regular antidepressant treatment including conditions such as kidney and liver failure, uncontrolled hypertension, cardiovascular, cerebrovascular and pulmonary disease, thyroid disease, diabetes, epilepsy and asthma.
• Use of anti-inflammatory medication for longer than 7 days in the last two months preceding the trial
• Use of immunosuppressive medication such as oral steroid hormones
• History of chronic infection, such as Tuberculosis, AIDS, hepatitis
• CRP value > 10 mg/L
• Women in pregnancy or lactation period