Immunosuppression using the mammalian target of rapamycin (mTOR) inhibitor everolimus: pilot study shows significant cognitive and affective improvement.
Immunosuppression using calcineurin inhibitors (CNIs) is accompanied by neuropsychiatric side effects, which counteract longevity and quality of life benefits in 10% to 28% of patients. Following the availability of the mammalian target of rapamycin (mTOR) inhibitors, it became possible to replace CNI without increasing the risk of acute graft rejection. mTOR, a member of the phosphatidyl inositol 3' kinase family, is a downstream target of brain-derived neurotrophic factor, which has been implicated in the pathophysiology and treatment of several psychiatric disorders. Preclinical evidence has implicated the mTOR pathway in synaptic plasticity and fear memory consolidation and reconsolidation.


METHODS
In the present study we prospectively evaluated the psychiatric outcomes of CNI-free immunosuppression in adult maintenance heart transplant recipients (n = 9; age: 66.1 +/- 6.1) using the Wechsler Memory Scale-Revised (WMS-R), Symptom Checklist-90-Revised (SCL-90-R), Beck Depression Inventory (BDI), Trail Making Tests A and B, Digit Span (DS), and Hamilton Depression Scale (HAMD).


RESULTS
Four weeks after switching to CNI-free immunosuppression using everolimus, BDI (Z = -1.14; P = .048), Trail Making tests A and B (Z = -2.52; P = .012), WMS-R (Z = 2.37; P = .018), and SCL-90-R (Z = -2.37; P = .018) were all significantly improved while DS (Z = -1.18; P = .236) and HAMD (Z = -0.595; P = .552) remained unchanged.


CONCLUSIONS
This report describes favorable psychiatric outcome variables using everolimus in maintenance heart transplant recipients. CNI-free immunosuppression with everolimus might provide significant improvement in memory, concentration, and overall psychiatric symptoms among heart transplant recipients.
Lang
U E
UE
Department of Psychiatry and Psychotherapy, Charité--University Medicine Berlin, Campus Mitte, Chariteplatz 1, 10117 Berlin, Germany. undine.lang@charite.de
Heger
J
J
Willbring
M
M
Domula
M
M
Matschke
K
K
Tugtekin
S M
SM
D000328:Adult; D000339:Affect; D065095:Calcineurin Inhibitors; D003071:Cognition / Q000187:drug effects*; D003863:Depression / Q000517:prevention & control; D000068338:Everolimus; D016027:Heart Transplantation / Q000276:immunology* / Q000523:psychology*; D006801:Humans; D007165:Immunosuppression Therapy / Q000009:adverse effects / Q000379:methods; D007166:Immunosuppressive Agents / Q000009:adverse effects / Q000627:therapeutic use*; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D011581:Psychological Tests; D020123:Sirolimus / Q000031:analogs & derivatives* / Q000627:therapeutic use; D058570:TOR Serine-Threonine Kinases
D065095:Calcineurin Inhibitors; D007166:Immunosuppressive Agents; D047908:Intracellular Signaling Peptides and Proteins; D000068338:Everolimus; C546842:MTOR protein, human; D017346:Protein Serine-Threonine Kinases; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus