Adjunctive Allogeneic Mesenchymal Stem Cells for Treatment-resistant Bipolar Depression

This clinical trial is a randomized, double-blind, placebo-controlled study aiming to study
the efficacy and side effects of BMMNCs adjunctive to TAU compared to a normal saline
solution in patients with TRBD. A flow chart of the study design is shown in Fig. 1. Relevant
patients with bipolar depression will be addressed in order to establish whether they are
willing to be screened for the study. The patients must be assigned a patient number and sign
the consent form after receiving oral and written information about the study prior to
undergoing any study procedures.

BMMNCs will be infused as a single dose up to one week after the inclusion of the patient.
The treatment trial lasts eight weeks. Of note, we will assess patients also at week 26 with
a neurocognitive and clinical battery. It will not be allowed changes in psychiatric
medication during this period. If a patient or the treating clinician decides that the
patient could receive better treatment outside of the study, the patient may leave the study
at all times, as specified in the informed consent. Patients were not allowed to take
nonsteroidal or steroidal anti-inflammatory medications during the study. Medications for
hypertension, diabetes, hypothyroidism, allergies, infections, or other medical conditions
were allowed as dictated by the patients' treating physicians. We defined refractory bipolar
depression as depression that failed to respond to two trials (during lifetime) with
antidepressants and/or mood stabilizer with proven efficacy in bipolar depression (lithium,
lamotrigine, quetiapine, lurasidone, olanzapine) in adequate doses for at least 6 weeks or
until cessation of treatment due to side effects (Schoeyen et al., 2015).

After the initial injection, patients will continue maintenance treatment with their current
psychiatrist. During this time, they will not receive additional injections but will receive
treatment as usual per their clinician's choice. We will ask patients to remain on stable
psychiatric medications during this period. If patients need to change medications, they will
be removed from the study protocol.

Inclusion criteria:

1. Diagnosis of DSM-IV-TR of Bipolar I or Bipolar II disorder as verified by the
semi-structured diagnostic interviews SCID. The diagnosis may be supported by
information from significant others, and from hospital records.

2. Age: 18-65 years

3. Severity: meet DSM-IV-TR criteria of depressive episode and MADRS of 25 or above

4. Treatment resistance: None response to two trials (during lifetime) with mood
stabilizers with proven efficacy in bipolar depression (lithium, lamotrigine,
quetiapine, olanzapine) and/or antidepressants.

a A trial is defined as at least 6 weeks in adequate or tolerated dose as reported by
the patient, or patients that have been unable to comply with 6 weeks trials of mood
stabilizer or an antidepressant.

b None response: Less than 50% reduction in MADRS values or still meet DSM-IV-TR
criteria of depressive episode

5. CRP concentration greater than 5 mg/L

6. Female subjects whom are not pregnant, not breastfeeding, and not planning on becoming
pregnant during the study. Female patients of childbearing potential must be using a
reliable method of contraception.

7. Patient competent to give informed consent according to the judgment of the clinician

8. Written informed consent

9. Patient sufficiently fluent in English language to ensure valid responses to
psychometric testing (needed for validated neurocognitive outcomes testing)

Exclusion criteria:

1. MSCs transplant within the last six months

2. Inability to comply with study protocol

3. Patient at high suicidal risk according to clinicians' judgement

4. History of previous brain injury; neurologic impairment and/or deficit; seizure
disorder requiring anti-convulsant therapy; renal disease or altered renal function as
defined by serum creatinine 2x ULN at admission; hepatic disease or altered liver
function as defined by SGPT > 2 x ULN (non-contusion related), and/or T. Bilirubin 1.5
x ULN at admission; immunosuppression as defined by WBC<3,000 cells/ml at admission;
HIV, splenectomy or cancer

5. Unstable serious medical conditions, including clinically relevant laboratory
abnormalities. Conditions that affect neuropsychological assessment such as
Parkinson's Disease, Multiple sclerosis, stroke, alcohol and substance abuse or
dependence (according to SCID or DSM-IV-TR). Other serious medical illness that is not
adequately controlled and, in the investigator's opinion, would not permit the subject
to be managed according to the protocol.

6. Hemodinamic instability at the time of MSCs infusion.

7. Positive pregnancy test (at screening or baseline visits).