Thiazolidinediones: novel treatments for cognitive deficits in mood disorders?

Treatment resistant depression (TRD) is defined as the failure to respond to two adequate antidepressant trials. TRD patients have high levels of psychosocial distress, poor levels of functioning and are at increased risk for suicide. Novel treatment approaches are being developed to address TRD involving both pharmacological and neuromodulation interventions. In this symposium, leaders in the field will outline three strategies for treating depression which has not responded to conventional therapy and contrast the efficacy of these strategies in younger vs. older patients. William McDonald MD (JB Fuqua Professor of Late -Life Depression, Emory University, Atlanta, GA) will provide a brief overview of TRD and moderate the discussion. George Petrides MD (Director of Clinical Trials Operation and Division of ECT, Zucker Hillside Hospital, New York, NY) will discuss recent data from the National Institute of Mental Health sponsored Consortium on ECT Research (CORE) outlining the response of older patients to ultrabrief right unilateral ECT in TRD. He will contrast the response to ECT in older vs, younger patients from the CORE database accumulated over the last 15 years. Collin Reiff MD (Addiction Psychiatrist, New York University Langone Health Center, NY, NY) will discuss his recent review in the American Journal of Psychiatry on Psychedelic and Psychedelic Assisted Psychotherapy and the implications on the treatment of medication resistant depression, including late life mood disorders. The FDA’s breakthrough designation of MDMA for the treatment of PTSD and psilocybin for the treatment of depression reflects the drugs’ potential to treat resistant psychiatric disorders. Psychedelic assisted therapy may play a unique role in late life mood disorders. Finally, Patricio Riva Posse MD (Director of the TRD and Ketamine Clinic, Emory University, Atlanta, GA) will discuss ketamine treatment in resistant depression including a comparison of response rates and safety data on ketamine treatment in older vs. younger patients. He has recently published the largest compilation of safety data for ketamine infusions and he will review a new tool to monitor safety in clinical practice. Dr. Riva Posse is medical director of the Emory TRD program and has enrolled over 1000 patients (100 in his IV ketamine clinic and about half over the age of 60 years) and followed patients through several novel treatments including transcranial magnetic stimulation, ketamine infusion therapy and ECT to start to look at differential response rates.

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New Therapeutic Targets for Mood Disorders

The Scientific World JOURNAL ◽

10.1100/tsw.2010.65 ◽

2010 ◽

Vol 10 ◽

pp. 713-726 ◽

Cited By ~ 36

Author(s):

Rodrigo Machado-Vieira ◽

Giacomo Salvadore ◽

Nancy DiazGranados ◽

Lobna Ibrahim ◽

David Latov ◽

...

Keyword(s):

Mood Disorders ◽

Histone Deacetylases ◽

Glycogen Synthase ◽

Pharmacological Treatments ◽

Novel Treatments ◽

Kinase C ◽

Targeted Treatments ◽

Antidepressant Effects ◽

Preclinical Animal Models ◽

New Compounds

Existing pharmacological treatments for bipolar disorder (BPD) and major depressive disorder (MDD) are often insufficient for many patients. Here we describe a number of targets/compounds that clinical and preclinical studies suggest could result in putative novel treatments for mood disorders. These include: (1) glycogen synthase kinase-3 (GSK-3) and protein kinase C (PKC), (2) the purinergic system, (3) histone deacetylases (HDACs), (4) the melatonergic system, (5) the tachykinin neuropeptides system, (6) the glutamatergic system, and (7) oxidative stress and bioenergetics. The paper reviews data on new compounds that have shown antimanic or antidepressant effects in subjects with mood disorders, or similar effects in preclinical animal models. Overall, an improved understanding of the neurobiological underpinnings of mood disorders is critical in order to develop targeted treatments that are more effective, act more rapidly, and are better tolerated than currently available therapies.

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Factors Influencing Mood Disorders and Health Related Quality of Life in Adults With Glioma: A Longitudinal Study

Frontiers in Oncology ◽

10.3389/fonc.2021.662039 ◽

2021 ◽

Vol 11 ◽

Author(s):

Antonella Leonetti ◽

Guglielmo Puglisi ◽

Marco Rossi ◽

Luca Viganò ◽

Marco Conti Nibali ◽

...

Keyword(s):

Quality Of Life ◽

Mood Disorders ◽

Cognitive Deficits ◽

Bivariate Analysis ◽

Health Related Quality ◽

Factors Associated ◽

The Third ◽

Related Quality ◽

Health Related

ObjectiveAt present, it is not clear whether Mood Disorders (MD) and poor Health Related Quality of Life (HRQoL) in the glioma population correlate with features of the tumor, or rather with secondary symptoms associated with treatment. The aim of this study was to assess the prevalence of MD and decline in HRQoL in glioma patients, and to determine the main factors associated with these two variables.Methods80 patients affected by lower-grade gliomas (LGGs) and 65 affected by high-grade gliomas (HGGs) were evaluated, from admission up to 12 months after surgery, for MD, HRQoL, clinical characteristics, and cognitive functions. Independent factors associated with MD and low HRQoL were identified by using bivariate analysis.ResultsData showed that prevalence of low HRQoL was comparable in both groups during all the time points assessed (pre, 1, 3, 6 and 12 months after surgery). In contrast at 6 months following surgery, HGGs showed a higher prevalence of MD compared to LGGs;. Bivariate analysis revealed that factors associated with MD and HRQoL in LGGs and HGGs were different over the course of the disease. In LGGs, from the pre-operative period to one year post surgery, MD and low HRQOL were associated with the occurrence of cognitive deficits and, from the third month after surgery onward, they were also associated with the effect exerted by adjuvant treatments. In HGGs, MD were associated with cognitive deficits at 3 and 6 months after surgery, along with older age (65-75 years); HRQoL, in its Physical component in particular, was associated with older age only from 6 months after surgery.ConclusionFactors associated with MD and low HRQoL were different in LGGs and HGGs over the course of the disease. In LGGs the effect of adjuvant treatments was prominent in determining the prevalence of both MD and poor HRQoL from the third month after surgery onward. In HGGs, MD and HRQoL were associated with age, at 3 and 6 months after surgery. In both, the occurrence of cognitive deficits was significantly associated with MD.

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A Mechanistic Rationale for PDE-4 Inhibitors to Treat Residual Cognitive Deficits in Acquired Brain Injury

Current Neuropharmacology ◽

10.2174/1570159x17666191010103044 ◽

2020 ◽

Vol 18 (3) ◽

pp. 188-201 ◽

Cited By ~ 1

Author(s):

Rudy Schreiber ◽

Romain Hollands ◽

Arjan Blokland

Keyword(s):

Brain Injury ◽

Cognitive Deficits ◽

Treatment Options ◽

Cyclic Adenosine Monophosphate ◽

Acquired Brain Injury ◽

Adenosine Monophosphate ◽

Intracellular Camp ◽

Residual Symptoms ◽

Novel Treatments ◽

Creb Pathway

Patients with acquired brain injury (ABI) suffer from cognitive deficits that interfere significantly with their daily lives. These deficits are long-lasting and no treatment options are available. A better understanding of the mechanistic basis for these cognitive deficits is needed to develop novel treatments. Intracellular cyclic adenosine monophosphate (cAMP) levels are decreased in ABI. Herein, we focus on augmentation of cAMP by PDE4 inhibitors and the potentially synergistic mechanisms in traumatic brain injury. A major acute pathophysiological event in ABI is the breakdown of the blood-brain-barrier (BBB). Intracellular cAMP pathways are involved in the subsequent emergence of edema, inflammation and hyperexcitability. We propose that PDE4 inhibitors such as roflumilast can improve cognition by modulation of the activity in the cAMPPhosphokinase A-Ras-related C3 botulinum toxin substrate (RAC1) inflammation pathway. In addition, PDE4 inhibitors can also directly enhance network plasticity and attenuate degenerative processes and cognitive dysfunction by increasing activity of the canonical cAMP/phosphokinase- A/cAMP Responsive Element Binding protein (cAMP/PKA/CREB) plasticity pathway. Doublecourtin and microtubule-associated protein 2 are generated following activation of the cAMP/PKA/CREB pathway and are decreased or even absent after injury. Both proteins are involved in neuronal plasticity and may consist of viable markers to track these processes. It is concluded that PDE4 inhibitors may consist of a novel class of drugs for the treatment of residual symptoms in ABI attenuating the pathophysiological consequences of a BBB breakdown by their anti-inflammatory actions via the cAMP/PKA/RAC1 pathway and by increasing synaptic plasticity via the cAMP/PKA/CREB pathway. Roflumilast improves cognition in young and elderly humans and would be an excellent candidate for a proof of concept study in ABI patients.

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Developing novel treatments for mood disorders: accelerating discovery

Biological Psychiatry ◽

10.1016/s0006-3223(02)01470-1 ◽

2002 ◽

Vol 52 (6) ◽

pp. 589-609 ◽

Cited By ~ 46

Author(s):

Carol A Tamminga ◽

Charles B Nemeroff ◽

Randy D Blakely ◽

Linda Brady ◽

Cameron S Carter ◽

...

Keyword(s):

Mood Disorders ◽

Novel Treatments

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Targeting Metabolic Dysfunction for the Treatment of Mood Disorders: Review of the Evidence

Life ◽

10.3390/life11080819 ◽

2021 ◽

Vol 11 (8) ◽

pp. 819

Author(s):

Brett D. M. Jones ◽

Salman Farooqui ◽

Stefan Kloiber ◽

Muhammad Omair Husain ◽

Benoit H. Mulsant ◽

...

Keyword(s):

Mood Disorders ◽

Structural Changes ◽

Current Knowledge ◽

Lipid Lowering ◽

Current Evidence ◽

Metabolic Dysfunction ◽

Specific Symptom ◽

Novel Treatments ◽

Lipid Lowering Agents ◽

The Impact

Major depressive disorder (MDD) and bipolar disorder (BD) are often chronic with many patients not responding to available treatments. As these mood disorders are frequently associated with metabolic dysfunction, there has been increased interest in novel treatments that would target metabolic pathways. The objectives of this scoping review were to synthesize evidence on the impact on mood symptoms of lipid lowering agents and anti-diabetics drugs, while also reviewing current knowledge on the association between mood disorders and dyslipidemia or hyperglycemia. We propose that metabolic dysfunction is prevalent in both MDD and BD and it may contribute to the development of these disorders through a variety of pathophysiological processes including inflammation, brain structural changes, hormonal alterations, neurotransmitter disruptions, alteration on brain cholesterol, central insulin resistance, and changes in gut microbiota. Current evidence is conflicting on the use of statins, polyunsaturated fatty acids, thiazolidinediones, glucagon-like peptide agonists, metformin, or insulin for the treatment of MDD and BD. Given the paucity of high-quality randomized controlled trials, additional studies are needed before any of these medications can be repurposed in routine clinical practice. Future trials need to enrich patient recruitment, include evaluations of mechanism of action, and explore differential effects on specific symptom domains such as anhedonia, suicidality, and cognition.

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