The study aims to evaluate or to assess:

• An improvement in the peripheral inflammatory levels in depressed patients after 8 weeks of treatment with Minocycline in addition to their current antidepressant treatment;
• Any improvements in depressive symptoms after 8 weeks of treatment with Minocycline given as adjuvant to the current antidepressant treatment;
• Changes in the inflammatory status in the brain (in terms of microglia activation with 11C PK PET) after 8 weeks of treatment with Minocycline in addition to the current patient's treatment;
• Possible structural and functional brain changes evaluated by MRI after 8 weeks of treatment with Minocycline given as adjuvant to the current patient's treatment;
• Whether changes in MRI, in microglia activation, and peripheral inflammation correlate with the improvement in depressive symptoms.

In order to achieve these, a total of 60 patients, male and female, aged 25-45, who have not responded to their pharmacological treatment and who have medium-high levels of inflammation (with CRP> 2 mg/L) will be included in the study.

Enrolled patients will receive, in addition to their current antidepressant treatment, Minocycline (200 mg/day as total dosage) for 8 weeks.

Patients will be subjected to blood collection and clinical evaluations at baseline and after 8 weeks of treatment with Minocycline.

A subgroup of patients will be subjected to MRI and 11C PK PET assessment at baseline and after 8 weeks of treatment with Minocycline.

Inclusion Criteria:

1. Being male or female depressed patients (aged 25-45);
2. Having a current DSM-V diagnosis of non-psychotic major depressive disorder confirmed by SCID;
3. Being non-responder to a current SSRI for at least 8 weeks, and historically to one other SSRI;
4. Being in stable antidepressant therapy for at least 8 weeks;
5. Being tolerant to the current SSRI;
6. Accepting Minocycline treatment;
7. Having CPR level> 2 mg/L;
8. Having signed and dated an informed consent to participate in the study;
9. Having no contraindications to receive treatment with Minocycline;
10. Having no contraindications to undergo the 11C-PK PET scan.

Exclusion Criteria:

1. Having active suicidal ideation;

2. Having a primary diagnosis of bipolar disorder, obsessive-compulsive disorder, eating disorder, PTSD;

3. Having a history of substance/alcohol abuse;

4. Having received tetracycline therapy within the previous 2 months;

5. Having a history of sensitivity to this class of drugs;

6. Having acute infections or an autoimmune or inflammatory disorder;

7. Having CRP>20 mg/L, as indicates acute infection or other major pathology;

8. Being sensitive to Minocycline;

9. Having a history of severe allergy or hypersensitivity to drugs;

10. Being hypersensitive to the active substance, to other tetracyclines or to any of the excipients;

11. Having severe renal failure;

12. Having hepatic dysfunction;

13. Being pregnant and in lactation;

14. (for MRI) Having pacemakers, electromechanical devices, ferromagnetic vascular clips, cochlear implants, stapedial prostheses, ferromagnetic foreign bodies, sickle cell anemia;

    EXCLUSION CRITERIA (FOR ONLY THOSE PATIENTS WHO WILL PERFORM 11C PK PET)

15. Having undergone imaging or treatment procedures using radiopharmaceuticals 7 days prior to the imaging session of this study;

16. Being unable to complete the 11C PK PET session, according to the clinician;

17. Being in current or previous (last two months) treatment with neuroactive drugs (benzodiazepines, barbiturates, picrotoxin and muscimol);

18. Being women of childbearing potential who are not surgically sterile and who do not guarantee to abstain from sexual activity for the 24 hours following the administration of 11C PK PET.