Vitamin B12 plays an important role in DNA synthesis and neurological function. Its
deficiency is associated with hematological, neurological and psychiatric manifestations of
which the latter include irritability, personality change, depression, dementia and rarely,
psychosis. Recent literature has seen links between this vitamin and depression. High B12
levels in serum are associated with good treatment response, high homocysteine levels are
common in folate / B12 deficiency and in those suffering from depression.
Hyperhomocysteinemia may have direct effects on neurotransmitters implicated in depression.
Randomized trials have shown folate and other nutritional supplementations are strategies of
atleast significant effect in treating treatment-resistant depression. Folate deficiency has
also been linked with delay in treatment response as well as relapse.
To date no trial from Pakistan compares anti-depressant monotherapy with B12 augmentation in
a population showing poor or partial response to first drug trial. The investigators aim to
compare clinical response of SSRI-monotherapy with that of B12-augmentation in a sample of
depressed patients.
Objective
To compare reduction in depression of patients with low normal B12 levels on SSRI monotherapy
with patients on a combination of SSRI and Vitamin B12 supplementation.
Hypothesis There will be higher response rate among patients who will be treated with
combined SSRI therapy and B12 supplementation as compared to those who will be treated with
SSRI alone.
Operational Definitions Depression: Patients scoring ≥ 16 on the 17-item Hamilton Rating
Scale for Depression-Urdu version (HAM-D) 24, 25 Low B12 level : (<300 pg/ml)
Design open label Trial
Setting of the Study Out patient clinics of the department of Psychiatry at Aga Khan
University Hospital, Karachi Pakistan.
Duration 12 months after approval of protocol
Sample Size Calculation A total of 232 patients equally divided into two groups will achieve
90 percent power, 5 percent level of significance using one sided hypothesis and an
anticipated difference in the response rate of 20 percent in the two groups with 30 percent
response rate among SSRI group and atleast 50% in the combination treatment group.
Considering 15 percent drop out in each group an additional sample of 36 patients equally
divided into two groups will be recruited to make a total required sample of 268 patients.
Therefore sample size required for each arm would be 134.
Sampling Technique
268 consecutive patients - who fulfill the inclusion criteria given below - presenting to
physicians at the PAMH Clinic will be recruited after informed consent. Consequently, 134
would be randomized to SSRI-monotherapy group and B12 augmentation group each
Method
Patients will be recruited at outpatient clinic of AKUH from among those who have received a
diagnosis of major depressive disorder by a qualified psychiatrist there. After this they
will be explained the research study in a simple language and will be registered after the
informed consent. At this point a unique ID will be assigned to them which will be in the
form of an alpha numeric code and attached to each of these ID will be a computer number
which is obtained from a number series used for similar trials The research officer then will
administer an Urdu version of the HAM-D scale. A blood sample of each participant will be
drawn by a phlebotomist at Aga Khan University Hospital clinical laboratory. Cold chain will
be maintained throughout. Those who will be fulfilling the eligibility criteria will then be
recruited to the study. After recruitment these numbers will be randomized to the two arms of
the study by the computer itself. The procedure will be performed by a data entry operator
who will have no affiliation with the research team and will be hired on per diem basis for
this purpose only. Final recruitment may take place in the next visit after the B12 levels
are back. The entire process will be monitored by the research officer who will be supervised
by a consultant psychiatrist at AKUH clinic who is also principal investigators. The research
officer as well as the supervisor will be blind to the arm allocation and will know only
codes such as Arms A and B. Participants in the monotherapy arm will only receive the SSRI.
Those in B12 arm will concomitantly be administered B12 intramuscular injectable as 1000 mcg
every week for 06 weeks . HAM-D scoring will be monitored at baseline and 12 weeks after the
baseline.
The investigators will also be blind to the group assignment but will not be blind to the
outcome assessment.The injectables will be picked up by the research officer or the patient
from the main pharmacy AKUH or any designated pharmacy outlet within AKUH campus.
Any adverse effects on oral medications and injections (B12 or placebo) will be monitored and
documented on a progress sheet in patient folder and treated according to the guidelines and
standard of care. In case of an unfortunate rare event such as anaphylactic shock the patient
will be managed according to the AKUH protocol. A crash cart will be available at the clinic
all the time. The registered nurse is always present at the clinic who is ACLS certified
Instruments
Hamilton Depression Rating Scale (HAM-D) 24, 25 is a 21-item, multiple-choice questionnaire
that screens for severity of depression. Available in several languages, Urdu version has
been translated but not clinically validated25. Therefore a pilot study will be conducted on
10% of sample size in the target population and compared with diagnosis on psychiatric
interview along DSM-IV criteria for depression (gold standard).
The items comprise of cardinal and biological symptoms of depression in the first 17 items,
with 3 further questions to rule out paranoia and obsessions. A score of ≥ 16 on the first
17-items correlates with clinical depression.