SAMe as an epigenetic treatment of depression in people with childhood trauma, a double blind placebo-controlled trial

The global burden of depression is increasing and progress in treatment
discovery is disappointing. It is therefore important to capitalize on the
recent insight that epigenetic mechanisms play a role in the increased risk to
depression after childhood trauma. We have evidence for a consistent epigenetic
maladaptation to childhood trauma in bipolar disorder and therefore propose to
target these epigenetic abnormalities for treatment
of depression in patients with high levels of childhood trauma. To this end, we
will use S-Adenyl-Methionine (SAMe) that influences DNA methylation. We have
shown that SAMe changes a prominent DNA methylation mark of childhood trauma in
vitro, and previous studies have shown efficacy in depression and cancer
treatments. We investigate whether the epigenetic changes that are related to
childhood trauma provide a treatment target for successful treatment of
depression with SAMe.

Primary objective is to compare changes in depression ratings in patients with
childhood trauma receiving SAMe with patients receiving a placebo over a 12
week follow-up period. A number of secondary objectives will be investigated:
1. Comparing the treatment group with the placebo group regarding changes in
continuous and long-term depression scores, measured weekly over a 12 week
period and at 6 month follow-up.
2. Comparing the treatment group with the placebo group assessing changes in
DNA methylation on a genome-wide scale, including the KITLG gene.
3. Investigate the relation between changes in plasma levels of SAMe and
treatment response as well as DNA methylation (pertaining to the question
whether there is a dose response relation of SAMe with methylation changes as
well as treatment response)
4. To collect and store RNA, serum, plasma and sorted cells in order to measure
SAMe plasma and serum levels and validate the DNA methylation changes in
separate cell types and whole blood expression for better understanding of
their biological relevance of identified methylation marks.
5. Comparing the treatment group with the placebo group regarding changes in
stress resilience (changed symptom response on stressors).

12-week double-blind randomized placebo controlled add-on clinical trial with 6
months follow up. SAMe or placebo is added to trauma therapy and medication.

For 12 weeks, 50 patients receive once daily 3 x 400mg of SAMe and 50 patients
receive daily three placebo capsules which is added to 12 weekly individual
sessions of trauma therapy.

Using SAMe carries a risk of rare side effects, the most common of which
gastrointestinal symptoms and headaches. Manic switching in patients with
bipolar disorder has been reported in case studies with the use of intravenous
administration (but rates were not compared to switch rates in untreated
patients not using SAMe). In this proposal we use oral administration of SAMe
and do not expect an increased rate of manic switching. However (as part of
good clinical practice) we will monitor participants closely for signs of
elation and (hypo)manic symptoms. There is no additional risk associated with
the study procedures. The pragmatic study design intends to minimize additional
time investment from participating subjects. Permission to collect laboratory
and medication history from available databases including their pharmacy and
laboratory will be requested. Potential individual benefits are substantial: a
decline of depressive symptoms and better adjustment to stressful experiences.