The present open-label study is the first clinical trial to evaluate the efficacy and safety of pioglitazone in patients with MDD and co-occurring abdominal obesity. The results indicate significant improvement in depressive symptoms following pioglitazone treatment over an acute 12-week period. For patients continuing on pioglitazone over 24 weeks, a consistent antidepressant effect was maintained according to both clinician- and patient-rated assessments of depression severity. Moreover, efficacy results were similar in patients treated with monotherapy pioglitazone or when administered as an adjunctive therapy with a conventional antidepressant(s).
A protocol defined response (≥ 50% decrease in IDS total score) occurred in 65% (n=15) of the sample, and 22% (n=5) of patients met criteria for remission. These outcomes are comparable to the STAR*D trial, in which response and remission rates were 49% and 37%, respectively (Rush et al., 2006
). Representing the first large-scale trial to compare the effectiveness of different antidepressant strategies for patients who did not become symptom free after initial treatment with citalopram, STAR*D suggests that lower remission rates should be expected when additional treatment steps are required. As 52% (n=12) of patients enrolled in the present trial had failed 2 or more antidepressant treatments during the current episode, the observed response and remission rates are striking, but may be inflated as an inadequate response to past antidepressant trials was not observed prospectively.
Approximately 57% (n=13) had a lifetime co-occurring generalized anxiety disorder. Among all patients the mean SIGH-A scores at study entry were approximately 23, indicating the presence of a moderate level of anxiety severity. The significant improvement in symptoms of anxiety with pioglitazone suggests that therapeutic benefit may extend beyond a potential ability to acutely relieve depressive symptoms.
Overall pioglitazone was very well tolerated, with no serious adverse events reported. None of the patients discontinued prematurely due to an adverse event during the acute 12-week phase. Consistent with pioglitazone’s side effect profile in type-2 diabetes, a non-significant mean weight gain was observed (Shah and Mudaliar, 2010
). The increase in body weight was presumably due to an increase in subcutaneous as opposed to visceral adiposity, given that measurements of waist circumference decreased significantly. Pioglitazone has been observed to remodel abdominal fat tissue, differentiating preadipocytes into small fat cells within subcutaneous depots and redistributing large fat cells from visceral into subcutaneous fat depots (Miyazaki et al., 2002
). These changes are accompanied by improved glycemic control and improved hepatic and peripheral tissue sensitivity to insulin.
In this study, pioglitazone also produced improvement on measures of glucose homeostasis and dyslipidemia. In type-2 diabetes, pioglitazone has well documented effects for reducing HbA1c and has been shown to reduce all-cause mortality, non-fatal myocardial infarction, and stroke in patients at high risk for macrovascular events (Dormandy et al., 2005
). In the present study, treatment with pioglitazone significantly improved the atherogenic profile of patients with abdominal obesity or metabolic syndrome. Significant improvements occurred in LDL-C and HDL-C levels, while a trend occurred for a decrease in triglycerides and total cholesterol. These findings are in concert with long-term results of pioglitazone therapy in patients with diabetic dyslipidemia, where durable improvements in triglyceride and high-density lipoprotein cholesterol levels occurred independent of baseline statin therapy (Spanheimer et al., 2009
). Pioglitazone was also associated with a significant reduction in levels of highly sensitive C-reactive protein, a biomarker of inflammation implicated in the risk of both first incident and recurrent cardiovascular events (Zacho et al., 2008
Converging lines of clinical and pre-clinical research support the rationale for studying thiazolidinediones in the treatment of depressive disorders. Not only can depression precipitate the occurrence of insulin resistance and states of increased cardiometabolic risk, but the metabolic syndrome (Koponen et al., 2008
), type-2 diabetes (Pan et al., 2010
), and abdominal obesity (Vogelzangs et al., 2010
) have all been identified as risk factors for the development of depression. Population-based studies have found that men and women with metabolic syndrome are twice as likely to develop depressive symptoms as compared to individuals without metabolic syndrome at baseline (Koponen et al., 2008
). Similarly, in a large cohort of community-based older men aged 65–84 years old, metabolic syndrome at the time of recruitment was associated with a 137% increase in the adjusted risk of incident depression (Almeida et al., 2009
). These findings suggest that reducing the prevalence of metabolic syndrome could potentially lead to a decline in the prevalence of depression.
Alterations in insulin signaling pathways may also represent part of the underlying pathophysiology of mood disorders. For instance, insulin signaling has been shown to regulate dopamine-mediated neurotransmission in animal models (Williams et al., 2010
). By depleting insulin levels, amphetamine-induced dopamine release can be severely attenuated. Related lines of research suggest that circulating levels of insulin can influence the function of the norepinephrine and serotonin transporter, and in turn, extracellular levels of norepinephrine and serotonin (Daws et al., 2009
). In animal models, pioglitazone has been shown to reduce the numbers of activated microglia and may mitigate the inflammation associated with chronic and acute neurological insults (Kapadia et al., 2008
). Activation of inflammatory cytokines is known to stimulate indoleamine-2,3-dioxygenase. Stimulation of the indoleamine-2,3-dioxygenase enzyme promotes the formation of kynurenine and quinolinic acid, which have been correlated with depressive symptoms (Raison et al., 2010
). In animals, PPAR-gamma activation by pioglitazone has been shown to attenuate quinolinic acid induced neurotoxicity (Kalonia et al., 2010
A small pilot study involving the drug rosiglitazone, another member of the thiazolidinedione class, has recently been reported to reduce depression severity in 12 patients with MDD and insulin resistance (Rasgon et al., 2010
). In that trial, patients showed a mean 39% reduction in Hamilton Depression Rating Scale scores, with 50% (n=4) of study completers showing ≥ 50% reduction in severity. Although insulin resistance improved significantly, no correlations were observed between change in depression severity and change in insulin resistance. In contrast, change in insulin resistance in the present trial was significantly correlated with change in depression severity, such that patients with greater improvement in insulin sensitivity also experienced the greatest reductions in depressive symptoms. Positive correlations between insulin resistance and severity of depressive symptoms have been identified in cross-sectional studies of adults and adolescents (Shomaker et al., 2010
; Timonen et al., 2005
), but whether insulin-resistant states lead to depressed mood or vice versa is unclear. For the first time, we prospectively show that intervention with a thiazolidinedione intended to reduce insulin resistance was correlated with clinically meaningful reductions in depression severity. Although causality cannot be determined, the finding does suggest that insulin sensitivity may be one biological mediator of depression, and that efforts to increase insulin sensitivity through any number of mechanisms (e.g. medications, exercise, diet) may generate sustainable antidepressant effects.
Strengths of the present study include the use of objective and validated measures of depressive symptomatology and use of a structured clinical interview to diagnose MDD. The patient population was broadly representative and did not exclude patients with comorbid anxiety disorders, substance abuse, or a variety of concurrent medical illnesses. The 12-week duration was longer than several antidepressant trials which typically last only 6 to 8 weeks, serving to limit the potential for the observed improvement to be only a transient phenomenon.
The results of this study should also be interpreted in the context of several limitations. These data are uncontrolled and open-label. Response rates in open-label studies are typically higher than those observed in studies employing a placebo-controlled design (Adam et al., 2005
). The sample size was small and may have led to underestimation of potential side effects that could emerge when pioglitazone is administered to a population with major depression. Some patients received pioglitazone as augmentation to existing psychotropic medications, potentially obscuring the full effect of the drug. Use of the HOMA-IR technique to measure insulin resistance is not ideal because the model assumes that insulin sensitivity values from hepatic and peripheral sources are equivalent. Future studies may benefit from a more precise measure of approximating whole-body insulin sensitivity, such as the Matsuda Index as derived from an oral glucose tolerance test (Matsuda et al., 1999
). The results reported for this prospective pilot study of pioglitazone are encouraging, but are not definitive. These data support the conduct of larger, placebo-controlled trials to fully delineate the role of pioglitazone in the treatment of patients with depression and metabolic risk factors.
Metabolic abnormalities in patients with mood disorders present clinicians with a challenging situation, as several medications newly approved for the adjunctive treatment of acute major depressive episodes (i.e. aripiprazole and quetiapine extended-release) are associated with an increased risk for weight gain, hyperglycemia and dyslipidemia (Chen et al., 2011
; Fava et al., 2009
; Weisler et al., 2009
). At present, pioglitazone and potentially other agents that promote insulin sensitivity appear worthy of further study as they may reduce depressive symptoms and address the cardiometabolic risks associated with mood disorders. The preliminary research findings suggest that by treating underlying metabolic defects, both the core mood symptoms and cardiometabolic abnormalities may improve.