Adjuvant pioglitazone for unremitted depression: Clinical correlates of treatment response

doi:10.1016/j.psychres.2015.10.013

Psychiatry Research

Volume 230, Issue 3, 30 December 2015, Pages 846-852

https://doi.org/10.1016/j.psychres.2015.10.013 Get rights and content

Highlights

•
This study assessed a PPARγ-agonist, pioglitazone, as an adjuvant treatment for depression.
•
Subjects (N=37) with received 90 days of pioglitazone in addition to treatment as usual.
•
Improvement in depression associated with improvement in glucose metabolism in IR subjects.
I
•
Response to pioglitazone was stronger in younger patients.

Abstract

Previous studies suggest that insulin-sensitizing agents could play a significant role in the treatment of major depression, particularly depression in patients with documented insulin resistance or those who are resistant to standard psychopharmacological approaches. This study aimed to assess the effects on depressive symptoms with adjuvant treatment with the PPARγ-agonist pioglitazone. Patients (N=37) with non-psychotic, non-remitting depression receiving standard psychiatric regimens for depression were randomized across an insulin sensitivity spectrum in a 12-week double blind, randomized controlled trial of pioglitazone or placebo. Improvement in depression was associated with improvement in glucose metabolism but only in patients with insulin resistance. An age effect was also shown in that response to pioglitazone was more beneficial in younger aged patients. Study findings suggest differential improvement in depression severity according to both glucose metabolic status and level of depression at baseline. A greater understanding of the reciprocal links between depression and IR may lead to a dramatic shift in the way in which depression is conceptualized and treated, with a greater focus on treating and/or preventing metabolic dysfunction.

Introduction

While the association between insulin resistance (IR) and depressive symptoms is well documented (Gold et al., 2005), causal aspects of the relationship are incompletely documented and likely bidirectional. As the current prevalence rates of DM2 and related diseases grow worldwide and its associated metabolic consequences become more salient, it is increasingly critical to understand the role of IR in depressive disorders.

We previously proposed that treatment of depressive disorders results in reversal of IR (Rasgon et al., 2010) and recently reported pilot work demonstrating significant improvement in depression severity upon open-label add-on of a PPAR-gamma-agonist to treatment as usual (TAU) (Rasgon et al., 2010). There are two main potential mechanisms by which PPAR-γ agonizts may improve depressive symptoms: insulin-sensitization (Rasgon et al., 2010) and anti-inflammation (Kemp et al., 2014).

A greater understanding of the reciprocal links between depression and IR may lead to a dramatic shift in the way in which depression is conceptualized and treated, with a greater focus on treating and/or preventing metabolic dysfunction. To date, studies evaluating IR in patients with depressive disorders before and after treatment have reported a decrease in IR upon improvement in mood (Heninger, et al., 1975). These studies reported that IR normalizes in patients who respond to antidepressant treatment compared to non-responders who show no significant improvement in IR (Nathan et al., 1981, Boyd et al., 1985, Okamura et al., 2000a). Specifically, selective serotonin reuptake inhibitors (SSRIs) appear to improve insulin sensitivity (Goodnick, 2001), with improvement in glucose tolerance generally observed in treatment responders compared with non-responders.

While only a few studies explored the potential mood-modifying effects of insulin-sensitizing agents, all showed improvement in depressive symptoms (Rasgon et al., 2010a, Rasgon et al., 2010b, Sepanjnia et al., 2012). This suggests that insulin-sensitizing agents could play a significant role in the treatment of major depression, particularly depression in patients with documented IR or those who are resistant to standard psychopharmacological approaches.

Insulin has been shown to alter central nervous system (CNS) concentrations of neurotransmitters such as dopamine (Lozovsky et al., 1981) and norepinephrine (Boyd et al., 1985), by a variety of mechanisms, as well as to have direct electrophysiological effects on neuronal activity (Boyd et al., 1985). Additionally, induced IR in the CNS has been shown to result in cognitive and behavioral alterations in animal models (Kovacs and Hajnal, 2009).

Accordingly, when depression manifests as a sequela of metabolic disorders such as obesity and DM2, it is hypothesized to be associated with resistance of CNS structures to the effects of insulin, which may derive from genetic polymorphisms, as well as from long-term exposure to excess amounts of circulating insulin due to peripheral IR (Okamura et al., 2000b). Thus, “overcoming” central IR,” for example by pharmacological interventions, could be an attractive strategy in the treatment and prevention of these disorders.

This study aimed to assess mood effects in a 12-week double-blind, randomized-controlled trial of adjuvant treatment with the PPARγ-agonist pioglitazone, an insulin-sensitizing agent, compared with treatment with placebo, in participants with non-psychotic, non-remitting depression receiving standard psychiatric regimens for unipolar or bipolar depression. Pioglitazone is an FDA-approved, insulin-sensitizing treatment for DM2 and has particularly beneficial effects on lipid profile (Goldberg et al., 2005) and rate of cardiovascular events (Lincoff et al., 2007) in this population. Furthermore, in assessing the utility of an additive insulin-sensitizing agent on mood outcomes in both insulin sensitive and insulin resistant patients, this study attempted to disentangle the role of insulin-sensitizing and anti-inflammatory mechanisms.

In an a prior manner, this study's aims were twofold: (1) to assess whether treatment with pioglitazone would result in significantly greater mood improvement compared to treatment with placebo among patients with unremitted depression despite treatment as usual (TAU) and (2) to examine mechanisms of proposed effects of a PPARγ-agonist on mood outcomes by comparing treatment outcomes based on surrogate markers of glucose metabolic status (hereafter referred to IR and IS) between IR and insulin sensitive (IS) participants.

Section snippets

Methods and materials

The Stanford University Institutional Review Board approved the current study in its entirety. All participants provided informed consent prior to study enrollment after they received detailed information regarding all study procedures, potential side effects of study medication, risks and benefits of participation, and contact personnel in case of questions or concerns. Study were participants were recruited on an rolling basis from November 2011 to April 2014 through collaboration with

Results

Forty-two subjects were enrolled and 37 participants (8 males and 29 females) completed the study. Five participants withdrew from the study; 2 moved, 1 withdrew due to a side effect (edema) of treatment with Pioglitazone, and 2 did not specify a reason for withdrawal.

Significant baseline differences between treatment groups were found in HDRS-21 scores and OGTT (Table 1). No significant baseline differences were found in BMI, HOMA, FPG or FPI between treatment and placebo groups. No

Discussion

Our main findings showed that improvement in glucose metabolism was associated with improvement in depression. Additionally, treatment with pioglitazone was effective in improving mood but only when IR was present, particularly with younger aged individuals.

Insulin resistance (IR) occurs in approximately one third of otherwise apparently healthy individuals to such an extent that it significantly increases risk for cardiovascular disease (CVD) (Yip et al., 1998) and type 2 diabetes (DM2) and is

Disclosures

Ms. Watson Lin, Dr. Wroolie and Dr. Robakis have no biomedical financial interests, potential conflicts of interest or funding to report. Dr. Rasgon has been a consultant for the following companies: Shire Pharmaceuticals, and Sunovion Pharmaceuticals. She has received research support from the following companies: Magceutics, Inc., ADA (American Diabetes Association), and Corcept Pharmaceuticals.

Acknowledgments

Funding was provided by the National Institutes of Health Grant number R21 MH093948-01A1. The authors thank Norma Costello and Abigail Faisal for technical assistance.

References (39)

F.T. Boyd et al.
Insulin receptors and insulin modulation of norepinephrine uptake in neuronal cultures from rat brain
J. Biol. Chem.
(1985)
S. Davis et al.
Evidence that the brain of the conscious dog is insulin sensitive
J. Clin. Investig.
(1995)
A.A. Eissa et al.
Antidepressant-like effects of rosiglitazone, a PPARgamma agonist, in the rat forced swim and mouse tail suspension tests
Behav. Pharmacol.
(2009)
M.B. First et al.
Structured Clinical Interview for DSM-IV-TR Axis I Disorders-Patient Edition (SCID-I/P, 2/2001 revision)
(1997)
M.F. Folstein et al.
Mini-mental state. A practical method for grading the cognitive state of patients for the clinician
J. Psychiatr. Res.
(1975)
Gold, P.W., Martinez, P., Haim, A., Eskandari, F., Cizza, G., Alesci, S., Kling, M., Quon, M., 2005. Decreased insulin...
R.B. Goldberg et al.
A comparison of lipid and glycemic effects of pioglitazone and rosiglitazone in patients with type 2 diabetes and dyslipidemia
Diabetes Care
(2005)
P. Goodnick
Use of antidepressants in treatment of comorbid diabetes mellitus and depression as well as in diabetic neuropathy
Ann. Clin. Psychiatry
(2001)
M. Hamilton
A rating scale for depression
J. Neurol. Neurosurg. Psychiatry
(1960)
G. Heninger et al.
Depressive symptoms and the glucose tolerance test and insulin tolerance test
J. Nerv. Ment. Dis.
(1975)

L. Kashani et al.

Does pioglitazone improve depression through insulin-sensitization? Results of a randomized double-blind metformin-controlled trial in patients with polycystic ovarian syndrome and comorbid depression

Psychoneuroendocrinology

(2013)

D.E. Kemp et al.

Use of insulin sensitizers for the treatment of major depressive disorder: a pilot study of pioglitazone for major depression accompanied by abdominal obesity

J. Affect. Disord.

(2012)

D.E. Kemp et al.

PPAR – gamma agonism as a modulator of mood: proof-of-concept for pioglitazone in bipolar depression

CNS Drugs

(2014)

H. Kenna et al.

Insulin resistance link between depressive disorders and cognitive dysfunction

D. Kerr et al.

Symmetry of cerebral blood flow and cognitive responses to hypoglycemia in humans

Diabetologia

(1993)

P. Kovacs et al.

In vivo electrophysiological effects of insulin in the rat brain

Neuropeptides

(2009)

S. Lanquillon et al.

Cytokine production and treatment response in major depressive disorder

Neuropsychopharmacology

(2000)

A.M. Lincoff et al.

Pioglitazone and risk of cardiovascular events in patients with type 2 diabetes mellitus: a meta-analysis of randomized trials

J. Am. Med. Assoc.

(2007)

D. Lozovsky et al.

Dopamine receptor binding is increased in diabetic rats

Science

(1981)

Cited by (66)

Toward a Precision Treatment Approach for Metabolic Depression: Integrating Epidemiology, Neuroscience, and Psychiatry
2023, Biological Psychiatry Global Open Science
Individuals with comorbid major depressive disorder and type 2 diabetes represent an important subgroup of patients for whom conventional treatment may be insufficient. A precision treatment approach that addresses insulin resistance with an outcome of a positive response to antidepressants may prove beneficial.
This study utilized an emulated target trial on a large dataset from the Optum Clinformatics Data Mart Database. We evaluated the effect of adjuvant pioglitazone, an insulin-sensitizing drug, on antidepressant response among 4696 people with type 2 diabetes, comparing it with DPP4 (dipeptidyl peptidase-4) inhibitors (non–insulin-sensitizing). An additional analysis involving 6518 participants was conducted to assess the efficacy of pioglitazone versus sulfonylureas.
The instrumental variable analysis indicated that the initiation of an antidepressant with pioglitazone was superior to DPP4 inhibitors in terms of antidepressant response, with fewer treatment shifts and/or additions of new antidepressant or antipsychotic over a 1-year period. This result was consistent when pioglitazone was compared with sulfonylureas in a supplemental analysis.
Our findings suggest that pioglitazone may be more effective than DPP4 inhibitors or sulfonylureas in enhancing antidepressant response among people with comorbid major depressive disorder and type 2 diabetes. This provides a strong case for the use of pioglitazone in patients with these conditions, emphasizing the potential of precision medicine strategies. The results should be interpreted with caution due to inherent limitations associated with observational data.
Brain insulin signaling as a potential mediator of early life adversity effects on physical and mental health
2023, Neuroscience and Biobehavioral Reviews
In numerous brain structures, insulin signaling modulates the homeostatic processes, sensitivity to reward pathways, executive function, memory, and cognition. Through human studies and animal models, mounting evidence implicates central insulin signaling in the metabolic, physiological, and psychological consequences of early life adversity. In this review, we describe the consequences of early life adversity in the brain where insulin signaling is a key factor and how insulin may moderate the effects of adversity on psychiatric and cardio-metabolic health outcomes. Further understanding of how early life adversity and insulin signaling impact specific brain regions and mental and physical health outcomes will assist in prevention, diagnosis, and potential intervention following early life adversity.
Impact of insulin and insulin resistance on brain dopamine signalling and reward processing – An underexplored mechanism in the pathophysiology of depression?
2023, Neuroscience and Biobehavioral Reviews
Type 2 diabetes and major depressive disorder (MDD) are the leading causes of disability worldwide and have a high comorbidity rate with fatal outcomes. Despite the long-established association between these conditions, the underlying molecular mechanisms remain unknown.
Since the discovery of insulin receptors in the brain and the brain’s reward system, evidence has accumulated indicating that insulin modulates dopaminergic (DA) signalling and reward behaviour. Here, we review the evidence from rodent and human studies, that insulin resistance directly alters central DA pathways, which may result in motivational deficits and depressive symptoms. Specifically, we first elaborate on the differential effects of insulin on DA signalling in the ventral tegmental area (VTA) - the primary DA source region in the midbrain - and the striatum as well as its effects on behaviour. We then focus on the alterations induced by insulin deficiency and resistance. Finally, we review the impact of insulin resistance in DA pathways in promoting depressive symptoms and anhedonia on a molecular and epidemiological level and discuss its relevance for stratified treatment strategies.
Hyperlipidic diets and depression
2022, Cahiers de Nutrition et de Dietetique
La dépression majeure (DM) est une pathologie psychiatrique reposant sur différents mécanismes neurobiologiques. Parmi ces mécanismes, on trouve une hypersensibilité de l’axe hypothalamo-hypophyso-surrénalien et des modifications de différents processus de type inflammation et stress oxydatif. Différents arguments suggèrent que ces mécanismes conduisent à un déficit de neurotransmission monoaminergique. En particulier, la dépression majeure résulterait d’un manque de sérotonine (5-HT) dans le cerveau. Des données de plus en plus nombreuses montrent que les patients atteints de diabète de type 1 ou de type 2 sont plus prompts à développer des troubles de l’humeur que les patients non diabétiques. Ces données épidémiologiques sont confortées par des travaux menés dans différents modèles animaux présentant un défaut de signalisation de l’insuline (exposition à des substances cytotoxiques sur les cellules pancréatiques ou à des régimes hyperlipidiques) à l’origine d'états pseudo-dépressifs. Cet article récapitule les évidences démontrant le lien entre les troubles métaboliques et psychiatriques. Il présente les différentes hypothèses mécanistiques pouvant expliquer cette comorbidité. Enfin, il ouvre la voie à de nouvelles pistes thérapeutiques qui consisteraient à utiliser les antidiabétiques oraux seuls ou en association avec les antidépresseurs pour une prise en charge optimale de la DM.
Major depression (MD) is a psychiatric pathology based on different neurobiological mechanisms. Among these mechanisms, there is a hypersensitivity of the hypothalamic-pituitary-adrenal axis and modifications of various processes such as inflammation and oxidative stress. Various arguments suggest that these mechanisms lead to a deficit in monoaminergic neurotransmission. In particular, major depression is thought to result from an attenuation of serotonin (5-HT) levels in the brain. There is increasing evidence that patients with type 1 and type 2 diabetes are more likely to develop mood disorders than patients without diabetes. These epidemiological data are supported by studies conducted in different animal models displaying deficit in insulin signaling (exposure to cytotoxic compounds to the insulin-producing beta cell or hyperlipidic diets) leads to depressive-like states. This article summarizes the evidence linking metabolic and psychiatric disorders. It then presents the different mechanistic hypotheses that may explain this comorbidity. Finally, it opens the way to new therapeutic avenues that would consist in using oral antidiabetic drugs alone or in combination with antidepressants for an optimal management of MD.
Family history of diabetes moderates metabolic depression endophenotypes in overweight/obese adults
2022, Journal of Psychiatric Research
Citation Excerpt :
Our group recently reported that indirect measures of IR are positively associated with depression severity among individuals with current major depressive disorder (MDD) (Watson et al., 2020). A few studies have provided evidence that the use of adjunctive insulin-sensitizing agents in patients with MDD may improve depressive symptoms (Lin et al., 2015; Rasgon et al., 2010a,b; Sepanjnia et al., 2012). Furthermore, IR modifying therapies may be particularly beneficial in treating depressed individuals who concurrently have IR (Watson et al., 2018).
Insulin resistance (IR) is linked to depressive disorders, and there is growing evidence that targeting IR may be beneficial in treating them. We examine the association between depressive symptoms and a direct measure of IR, and whether family history of type 2 diabetes (FHx-T2DM) or major depressive disorder (FHx-MDD) moderate this relationship.
Cross-sectional data were collected from 96 primarily overweight/obese adults ages 25–50 without diabetes or clinical depression. Multiple regression and correlation analyses were used to assess the association between depressive symptoms and a direct measure of IR (steady-state plasma glucose) as well as moderating effects of FHx-T2DM or FHx-MDD.
In the total sample, elevated depressive symptoms were positively associated with IR (p = 0.005). IR was associated with depressive symptoms in subjects with FHx-T2DM (p = 0.002) or FHx-MDD (p = 0.009) whereas BMI was associated with depressive symptoms in subjects without FHx-T2DM (p = 0.049) or FHx-MDD (p = 0.029). The odds of being in the top tertile of IR increased with elevated depressive symptoms alone (OR, 4.22; 95%CI, 1.15 to 17.33), presence of FHx-T2DM alone (OR, 3.42; 95%CI, 1.26 to 10.00), and presence of both FHx-T2DM and elevated depressive symptoms (OR, 10.08; 95%CI, 1.94 to 96.96).
Our findings indicate that depressive symptoms are positively associated with a direct measure of IR in overweight/obese individuals without diabetes or clinical depression. This association is moderated by FHx-T2DM. Early identification of groups vulnerable to IR related to depressive symptomatology may be useful for determining personalized interventions that have the potential to reduce morbidity in later years.
Insulin resistance as a marker for the immune-metabolic subtype of depression
2021, Journal of Affective Disorders
Citation Excerpt :
Possibly, hypofunction of the reward circuitry plays a role in depression in higher IR individuals, while it does not in lower IR individuals. This may also explain why previous studies reported the placebo effect of antidepressant treatment to be absent in higher IR individuals – while present in more insulin sensitive individuals – (Lin et al., 2015; Brouwer et al., 2019), as the placebo response appears to rely in the expectation of reward, which requires intact reward circuitry (Holmes et al., 2016). The previously mentioned study in youngsters reported that IR and anhedonia were accompanied by smaller anterior cingulate cortex and hippocampal volumes, structures that are part of the motivational neural circuit (Singh et al., 2019).
Insulin resistance (IR), a marker of metabolic dysregulation and pro-inflammatory state, moderates the antidepressant treatment effect in patients with type 2 diabetes (T2D) and is therefore a potential marker for personalized treatment. Based on data from a light therapy trial (NTR4942), we aimed to evaluate whether 1) depression symptoms differ according to the level of IR, and 2) improvement of specific depression symptoms drive the positive effects of light therapy in those with higher IR.
This secondary analysis in 59 individuals with depression and T2D explored differences in depressive symptom profile (30-item Inventory of Depressive Symptomatology (IDS)) at baseline and in response to light therapy (versus placebo), between lower and higher IR individuals, using Likelihood Ratio tests and Linear-by-linear association. IR was measured using the gold standard, a hyperinsulinemic-euglycaemic clamp.
At baseline, higher IR individuals reported more symptoms of irritability (p=0.024) anhedonia (no interest in people and activities: p=0.011; absence of pleasure and enjoyment: p=0.021), fatigue (fatigue: p=0.036; physical fatigue: p=0.035) and hypersomnia (p=0.029) relative to persons with lower IR, who reported more insomnia (nightly awakening: p=0.041; early morning awakening: p=0.012). Light therapy led to an improvement across IDS symptoms in higher IR individuals, while in lower IR individuals, light therapy improved early morning awakening (p=0.005) and interest in people and activities (p=0.015), but worsened mood (feeling sad: p=0.001; feeling irritable: p=0.002; interpersonal sensitivity: p=0.014).
Results add to the hypothesis of an immune-metabolic subtype of depression, and suggest that IR might be a promising focus for precision medicine.

View all citing articles on Scopus

^☆: Clinical registry name: Pioglitazone in patients with mood disorders. URL: https://clinicaltrials.gov/ct2/show/NCT01559857. Registration number: NCT01559857.

View full text

Adjuvant pioglitazone for unremitted depression: Clinical correlates of treatment response☆

Highlights

Abstract

Introduction

Section snippets

Methods and materials

Results

Discussion

Disclosures

Acknowledgments

Insulin receptors and insulin modulation of norepinephrine uptake in neuronal cultures from rat brain

J. Biol. Chem.

Evidence that the brain of the conscious dog is insulin sensitive

J. Clin. Investig.

Antidepressant-like effects of rosiglitazone, a PPARgamma agonist, in the rat forced swim and mouse tail suspension tests

Behav. Pharmacol.

Structured Clinical Interview for DSM-IV-TR Axis I Disorders-Patient Edition (SCID-I/P, 2/2001 revision)

Mini-mental state. A practical method for grading the cognitive state of patients for the clinician

J. Psychiatr. Res.

A comparison of lipid and glycemic effects of pioglitazone and rosiglitazone in patients with type 2 diabetes and dyslipidemia

Diabetes Care

Use of antidepressants in treatment of comorbid diabetes mellitus and depression as well as in diabetic neuropathy

Ann. Clin. Psychiatry

A rating scale for depression

J. Neurol. Neurosurg. Psychiatry

Depressive symptoms and the glucose tolerance test and insulin tolerance test

J. Nerv. Ment. Dis.