PPAR-γ agonism as a modulator of mood: proof-of-concept for pioglitazone in bipolar depression.
BACKGROUND
Insulin resistance and other cardio-metabolic risk factors predict increased risk of depression and decreased response to antidepressant and mood stabilizer treatments. This proof-of-concept study tested whether administration of an insulin-sensitizing peroxisome proliferator-activated receptor (PPAR)-γ agonist could reduce bipolar depression symptom severity. A secondary objective was to determine whether levels of highly sensitive C-reactive protein and interleukin (IL)-6 predicted treatment outcome.


METHODS
Patients (n = 34) with bipolar disorder (I, II, or not otherwise specified) and metabolic syndrome/insulin resistance who were currently depressed (Quick Inventory of Depressive Symptoms [QIDS] total score ≥11) despite an adequate trial of a mood stabilizer received open-label, adjunctive treatment with the PPAR-γ agonist pioglitazone (15-30 mg/day) for 8 weeks. The majority of participants (76 %, n = 26) were experiencing treatment-resistant bipolar depression, having already failed two mood stabilizers or the combination of a mood stabilizer and a conventional antidepressant.


RESULTS
Supporting an association between insulin sensitization and depression severity, pioglitazone treatment was associated with a decrease in the total Inventory of Depressive Symptomatology (IDS-C30) score from 38.7 ± 8.2 at baseline to 21.2 ± 9.2 at week 8 (p < 0.001). Self-reported depressive symptom severity and clinician-rated anxiety symptom severity significantly improved over 8 weeks as measured by the QIDS (p < 0.001) and Structured Interview Guide for the Hamilton Anxiety Scale (p < 0.001), respectively. Functional improvement also occurred as measured by the change in total score on the Sheehan Disability Scale (-17.9 ± 3.6; p < 0.001). Insulin sensitivity increased from baseline to week 8 as measured by the Insulin Sensitivity Index derived from an oral glucose tolerance test (0.98 ± 0.3; p < 0.001). Higher baseline levels of IL-6 were associated with greater decrease in depression severity (parameter estimate β = -3.89, standard error [SE] = 1.47, p = 0.015). A positive correlation was observed between improvement in IDS-C30 score and change in IL-6 (r = 0.44, p < 0.01).


CONCLUSIONS
Open-label administration of the PPAR-γ agonist pioglitazone was associated with improvement in depressive symptoms and reduced cardio-metabolic risk. Reduction in inflammation may represent a novel mechanism by which pioglitazone modulates mood. (ClinicalTrials.gov Identifier: NCT00835120).
University Hospitals Case Medical Center, Case Western Reserve University, 10524 Euclid Ave., 12th Floor, Cleveland, OH, 44106, USA, kemp.david@gmail.com.
David E
DE
Kemp
Martha
M
Schinagle
Keming
K
Gao
Carla
C
Conroy
Stephen J
SJ
Ganocy
Faramarz
F
Ismail-Beigi
Joseph R
JR
Calabrese
D000293:Adolescent; D000328:Adult; D000339:Affect / Q000187:drug effects*; D000368:Aged; D001714:Bipolar Disorder / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism / Q000523:psychology; D001786:Blood Glucose / Q000378:metabolism; D002097:C-Reactive Protein / Q000032:analysis; D005260:Female; D006801:Humans; D007333:Insulin Resistance; D015850:Interleukin-6 / Q000097:blood; D008297:Male; D024821:Metabolic Syndrome / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism / Q000523:psychology; D008875:Middle Aged; D009483:Neuropsychological Tests; D047495:PPAR gamma / Q000819:agonists*; D000077205:Pioglitazone; D011237:Predictive Value of Tests; D045162:Thiazolidinediones / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D016896:Treatment Outcome; D055815:Young Adult
D001786:Blood Glucose; C508600:IL6 protein, human; D015850:Interleukin-6; D047495:PPAR gamma; D045162:Thiazolidinediones; D002097:C-Reactive Protein; D000077205:Pioglitazone