Serotonin-induced hyperactivity in SSRI-resistant major depressive disorder patient-derived neurons

Vadodaria, Krishna C.; Skime, Michelle; Paquola, Apuã C.M.; Nelson, T. J. N.; Hall‐Flavin, Daniel K.; Fredlender, Callie; Heard, Kelly J.; Deng, Yalin; Le, Amy; Dave, Sonia; Fung, Lianna; Marchetto, Maria C.; Weinshilboum, Richard M.; Gage, Fred H.

doi:10.1038/s41380-019-0363-y

Cited by 69 publications

(55 citation statements)

References 35 publications

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“…There was no significant difference between the three groups at baseline, however after 5-Hydroxytryptamine (= serotonin, 5-HT) in vitro treatment non-responder forebrain neurons displayed significantly higher activity compared to responder and healthy controls. After further analysis, it was found that SSRI-nonresponder neurons displayed 5-HT-induced hyperactivity via upregulated 5-HT2A and 5-HT7 receptors (Vadodaria et al 2019a). In contrast, serotonergic neurons from three SSRI-responders and three non-responders did not demonstrate significant differences in 5-HT release/reuptake, or in genes related to 5-HT signaling.…”

Section: Major Depressive Disordermentioning

confidence: 91%

Mental health dished up—the use of iPSC models in neuropsychiatric research

et al. 2020

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Genetic and molecular mechanisms that play a causal role in mental illnesses are challenging to elucidate, particularly as there is a lack of relevant in vitro and in vivo models. However, the advent of induced pluripotent stem cell (iPSC) technology has provided researchers with a novel toolbox. We conducted a systematic review using the PRISMA statement. A PubMed and Web of Science online search was performed (studies published between 2006–2020) using the following search strategy: hiPSC OR iPSC OR iPS OR stem cells AND schizophrenia disorder OR personality disorder OR antisocial personality disorder OR psychopathy OR bipolar disorder OR major depressive disorder OR obsessive compulsive disorder OR anxiety disorder OR substance use disorder OR alcohol use disorder OR nicotine use disorder OR opioid use disorder OR eating disorder OR anorexia nervosa OR attention-deficit/hyperactivity disorder OR gaming disorder. Using the above search criteria, a total of 3515 studies were found. After screening, a final total of 56 studies were deemed eligible for inclusion in our study. Using iPSC technology, psychiatric disease can be studied in the context of a patient’s own unique genetic background. This has allowed great strides to be made into uncovering the etiology of psychiatric disease, as well as providing a unique paradigm for drug testing. However, there is a lack of data for certain psychiatric disorders and several limitations to present iPSC-based studies, leading us to discuss how this field may progress in the next years to increase its utility in the battle to understand psychiatric disease.

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Section: Major Depressive Disordermentioning

confidence: 91%

Mental health dished up—the use of iPSC models in neuropsychiatric research

et al. 2020

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“…To maximize our ability to detect the effects of treatment outcomes, we plotted the mean trajectories of the metabolites among the CBT remitters ( N = 12) and the treatment failures ( N = 7), leaving out the patients with intermediate outcomes, consistent with the approach used in other biomarker studies (Dunlop et al, 2017b; Vadodaria et al, 2019). There were interesting trends among the metabolites in the purple, yellow, and green-yellow modules.…”

Section: Resultsmentioning

confidence: 99%

Pilot Study of Metabolomic Clusters as State Markers of Major Depression and Outcomes to CBT Treatment

et al. 2019

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Major depressive disorder (MDD) is a common and disabling syndrome with multiple etiologies that is defined by clinically elicited signs and symptoms. In hopes of developing a list of candidate biological measures that reflect and relate closely to the severity of depressive symptoms, so-called “state-dependent” biomarkers of depression, this pilot study explored the biochemical underpinnings of treatment response to cognitive behavior therapy (CBT) in medication-free MDD outpatients. Plasma samples were collected at baseline and week 12 from a subset of MDD patients (N = 26) who completed a course of CBT treatment as part of the Predictors of Remission in Depression to Individual and Combined Treatments (PReDICT) study. Targeted metabolomic profiling using the AbsoluteIDQ® p180 Kit and LC-MS identified eight “co-expressed” metabolomic modules. Of these eight, three were significantly associated with change in depressive symptoms over the course of the 12-weeks. Metabolites found to be most strongly correlated with change in depressive symptoms were branched chain amino acids, acylcarnitines, methionine sulfoxide, and α-aminoadipic acid (negative correlations with symptom change) as well as several lipids, particularly the phosphatidlylcholines (positive correlation). These results implicate disturbed bioenergetics as an important state marker in the pathobiology of MDD. Exploratory analyses contrasting remitters to CBT versus those who failed the treatment further suggest these metabolites may serve as mediators of recovery during CBT treatment. Larger studies examining metabolomic change patterns in patients treated with pharmacotherapy or psychotherapy will be necessary to elucidate the biological underpinnings of MDD and the -specific biologies of treatment response.

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“…One fascinating and potentially major step forward in our understanding the mechanism that contributes to the SSRI's treatment‐resistance observed in approximately 30% of MDD patients and may greatly aid patient stratification, was recently published by Fred Gage's group. This group studied serotonergic transmission in patient forebrain iPSC neurons in vitro and observed that nonremitter patient‐derived neurons displayed serotonin‐induced hyperactivity downstream of upregulated excitatory serotonergic receptors, in contrast to what is seen in healthy and remitter patient‐derived neurons . These findings suggest that postsynaptic forebrain hyperactivity downstream of SSRI treatment may play a role in SSRI resistance in MDD.…”

Section: Current Treatment and Drug Classificationmentioning

confidence: 99%

Depressive disorders: Treatment failures and poor prognosis over the last 50 years

Blackburn

2019

Pharmacology Res & Perspec

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Depression like many diseases is pleiotropic but unlike cancer and Alzheimer's disease for example, is still largely stigmatized and falls into the dark shadows of human illness. The failure of depression to be in the spotlight for successful treatment options is inherent in the complexity of the disease(s), flawed clinical diagnosis, overgeneralization of the illness, inadequate and biased clinical trial design, restrictive and biased inclusion/exclusion criteria, lack of approved/robust biomarkers, expensive imaging technology along with few advances in neurobiological hypotheses in decades. Clinical trial studies summitted to the regulatory agencies ( FDA / EMA ) for approval, have continually failed to show significant differences between active and placebo. For decades, we have acknowledged this failure, despite vigorous debated by all stakeholders to provide adequate answers to this escalating problem, with only a few new antidepressants approved in the last 20 years with equivocal efficacy, little improvement in side effects or onset of efficacy. It is also clear that funding and initiatives for mental illness lags far behind other life‐treating diseases. Thus, it is no surprise we have not achieved much success in the last 50 years in treating depression, but we are accountable for the many failures and suboptimal treatment. This review will therefore critically address where we have failed and how future advances in medical science offers a glimmer of light for the patient and aid our future understanding of the neurobiology and pathophysiology of the disease, enabling transformative therapies for the treatment of depressive disorders.

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Serotonin-induced hyperactivity in SSRI-resistant major depressive disorder patient-derived neurons

Cited by 69 publications

References 35 publications

Mental health dished up—the use of iPSC models in neuropsychiatric research

Mental health dished up—the use of iPSC models in neuropsychiatric research

Pilot Study of Metabolomic Clusters as State Markers of Major Depression and Outcomes to CBT Treatment

Depressive disorders: Treatment failures and poor prognosis over the last 50 years

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