I have some psychiatric problems—my diagnoses are ADHD, OCD, and bipolar. I’m curious about various topics regarding psychiatry—I’ll mention two of them. First, I’ve found that guanfacine—though only temporarily—has been able to wipe away all of my mental illness. I wonder (A) how commonly people experience a remarkable transdiagnostic effect from a drug and (B) what the phenomenon might mean. Second, I experience what I’d call a “fractured consciousness”—I’m always moving from one novel and unprecedented consciousness state into another. There’s no quiet, calm, or stability—something seems to be fluctuating inside my brain in an unhealthy way. The fluctuations happen from one day to the next or even—it seems—from one hour to the next. I suspect that my consciousness will—finally—stabilize once I find the right psychiatric medication. How abnormal is such an experience? Is there research on this topic? What mechanisms might underlie such an experience?
Regarding the guanfacine and “fractured consciousness” topics, I’ve gotten nowhere—maybe there are no answers. I have—additionally—made no progress regarding other psychiatry topics that I’m curious about. But despite the brick walls that I keep running into, I’m constantly impressed with how much researchers are learning about mental illness—the scientific progress gives me hope even though we obviously need to accelerate the pursuit of effective treatments. I’ll use this piece to talk about the mental-illness research that excites me.
I do think—regarding my own situation—that I’ll be able to fix my brain and live a fulfilling life. There are a lot of drugs that I haven’t tried yet. I do feel the urgency—I need to fix my brain problems soon.
Vulnerabilities
We try to treat mental disorders. It would—of course—be world-changing if we could prevent them instead. Apparently a great deal of mental illness occurs because of perinatal disruption to the intricate and delicate process of neurodevelopment. Under what circumstances could a human being be exposed to enormous perinatal disruption and yet end up not suffering from mental illness? And under what circumstances could a human being be exposed to zero perinatal disruption and yet end up suffering from mental illness? I’m curious about both those thought-experiment questions.
A 2019 Annual Review of Clinical Psychology article talks about “the impact of pregnant women’s distress” on “fetal and infant brain–behavior development”. And the authors define distress to include: perceived stress; life events; depression; and anxiety. The article says: “maternal distress affects fetal and child brain–behavior development and increases the risk for child psychopathology”; the “effects of prenatal distress have been documented as early as the fetal stage and are related to increased risks for a host of psychopathologies”; “maternal prenatal distress may be a third pathway for the familial inheritance of risk for psychiatric illness beyond shared genes and the quality of parental care”; there are studies “probing the biological, mechanistic pathways through which maternal distress ‘gets under fetal skin’ as an intermediate phenotype of altered child outcomes”; regarding the potential pathways through which this happens, there are maternal (hypothalamic–pituitary–adrenal-axis regulation, immune activation), placental (epigenetic effects, mitochondrial dysfunction), and fetal (brain programming) pathways; “distress during pregnancy is typically a modifiable factor”; “interventions with distressed pregnant women can help women and may positively affect their children as well”; and it “would be a grave perversion of science if research into prenatal maternal distress were interpreted as blaming women for their child’s development”. A 2016 Neuropsychopharmacology article says: “the early postnatal brain is far from maturity and continues to undergo significant developmental processes”; the perinatal period “represents a critical stage of development, rendering the brain particularly vulnerable to organizing (and disorganizing) environmental influences”; “when stress is experienced during this critical early-life period, its impact on brain function can be long-lasting or even permanent, compared with the typically transient effects of stress on the adult brain”; developmental “stress may have long-lasting consequences for the structure and function of several brain networks, ultimately modulating the output of multiple emotional, social, and cognitive behaviors”; it’s “clear that the ultimate outcome of early-life stress depends on several aspects of the ‘stressful’ experience”—“its timing, quality, severity, and duration”; “the developing brain responds to age-specific stress in an age-specific manner, with profound, enduring consequences”; “within the early postnatal period, the type and magnitude of stress-induced changes can vary markedly according to precisely when the stress occurs”; during “stress, synapses in several brain regions are impacted by a cocktail of stress mediators with distinct and concerted actions and mechanisms”; regarding the “individual and concerted actions of these mediators during” vulnerable postnatal periods, these actions should be investigated; the focus of investigation should be these mediators’ effects on (A) individual genes, (B) individual neurons, (C) gene networks, and (D) brain networks; “early-life adversity is a powerful determinant of subsequent vulnerabilities to emotional and cognitive pathologies”; and “understanding the underlying processes will have profound implications for the world’s current and future children”. A 2019 Neurotoxicology and Teratology article says: “brain maturation throughout adolescence occurs” against “a backdrop of genetic and environmental interactions”; these interactions begin before conception and continue “throughout gestation and postnatal life”; it’s now known “that experience during childhood and adolescence can modify the trajectory of the structural and functional changes”—“induced by environment and experience”—“that occur during the rest of life”; during “childhood and adolescence, the brain exhibits sensitive periods when experience can greatly alter its functional and structural characteristics”; these “sensitive periods occur in different brain regions at different times of development and may even occur in different layers of the same cortical region at different times”; “childhood includes the sensitive periods for the development of the sensory and motor systems”; “adolescence includes sensitive periods for social, emotional”, and cognitive development; during adolescence, “the networks subserving these domains are undergoing plasticity based on the experiences of the individual”; regarding sensitive periods, experiences “that occur before or after the sensitive period will have less effect on the maturation of” a neural circuit, “but some plasticity can still occur”; and there is—during the adolescent maturation of complex behaviors—“a vulnerability to exogenous influence and the increased possibility that functional and structural maturation can become abnormal and” that “psychopathology can ensue”.
A 2012 Cerebrum article says: “environmental influences during fetal development are especially potent in the brain”; “the brain’s plasticity during gestation confers both increased vulnerability to environmental exposures and opportunities for therapeutic interventions”; scientists “have found that the consequences of maternal stress depend on the cause, timing, duration, and intensity of the stress, as well as maternal stress reactivity and the genetic susceptibility of the fetus”; overgeneralized “assertions, such as ‘Stress is bad for you and your baby,’ may inadvertently contribute to anxiety and worry among pregnant women”; “issues critical to determining whether prenatal stress exposure has beneficial or deleterious consequences relate to the nature, magnitude, chronicity, and timing of stress”; and regarding what these critical issues relate to, it’s relevant what the pregnant mother’s biological response is to stress, what the pregnant mother’s psychological response is to stress, and what the pregnant mother’s sense of control is over the stressor. A 2018 Nature Neuroscience article says: executive “function (EF) is a broad term, which describes a set of cognitive processes that support” goal-directed behavior; working “memory, specifically, is a resource-limited executive function that relates to the ability to temporarily hold items in mind for manipulation”; findings “highlight the association of maternal inflammation during pregnancy with” (A) the brain’s developing functional architecture and (B) emerging EF; cytokines “(inflammatory markers) and their receptors are expressed throughout the fetal brain and play a role in typical neurodevelopmental processes”; the pro-inflammatory cytokine Interleukin 6 (IL-6) “has been indicated as a mediating factor in processes leading from maternal inflammation to alterations in fetal brain development and subsequent risk for psychopathology”; functional “connectivity within and between multiple neonatal brain networks can be modeled to estimate maternal IL-6 concentrations during pregnancy”; “regions heavily weighted in these models overlap significantly with those” that—in a meta-analysis—support working memory; and maternal IL-6 “directly accounts for a portion of the variance of working memory at” age two. And a 2020 Brain, Behavior, and Immunity article says: increased “cytokines in the intrauterine environment and fetal brain can shape or perturb brain development”; this study provides evidence that (1) “maternal cytokines during pregnancy predict ADHD in early childhood” and (2) “maternal prenatal inflammation is one mechanism through which prenatal risks such as maternal distress influence child psychopathology”; “maternal prenatal inflammation appears to be a promising marker of risk for child ADHD symptoms”; if confirmed, this study’s results “would hold promise that maternal prenatal cytokine concentrations may be an easily obtained, low-cost marker of ADHD risk in offspring”; and if confirmed, this study’s results “would begin to set the stage for trials to reduce risk in susceptible individuals”.
Glutamate
I think that this video—where Dr. Rakesh Jain talks about glutamate—is entertaining and interesting:
Jain talks—in the video—about how powerful and important glutamate is. And indeed, I can say that glutamate seems to be right at the center of every psychiatric disorder. Just consider my own diagnoses—OCD, bipolar, and ADHD.
Regarding OCD, a 2021 Current Topics in Behavioral Neurosciences article points out: the “evidence-based algorithm for the pharmacological treatment of OCD is distressingly limited”; regarding OCD, much “recent work has focused on the hypothesis that” (1) “glutamate imbalance contributes to OCD” and (2) “glutamate modulators may have therapeutic utility in treatment of” disease that’s otherwise refractory; “these two claims are not equivalent”; “glutamate modulators may be of therapeutic benefit even if glutamate dysregulation is not central to pathophysiology”; “glutamate abnormalities might contribute causally to the development of OCD” even if glutamate modulators aren’t therapeutically effective; several “lines of evidence suggest that glutamate dysregulation may contribute to the pathophysiology of OCD”; glutamate “is the primary excitatory neurotransmitter in the mammalian brain”; glutamate is “involved in virtually everything the brain does”; and “pathological activity of virtually any circuit in the brain could be reflected in a local disruption of glutamate levels”. And the 2022 book Glutamate and Neuropsychiatric Disorders says in Chapter 19: it’s known that stress can trigger psychiatric illnesses; “prolonged and constant exposure to stressful events leads to chronic stress that leads to persistent functional changes”; “stress is one of the relevant factors underlying OCD and other anxiety disorders”; the hypothalamic–pituitary–adrenal axis (HPA axis) is activated in response to stressful events; early-life “stress presents a developmental and complex interference in the HPA axis, with changes throughout life that impact the triggering and severity of anxiety disorders and OCD in adulthood”; the “glutamatergic pathway is involved in the mechanism of resilience to stress”; regarding anxiety disorders and regarding OCD, these disorders “have in common the involvement of glutamatergic neurotransmission”; “research suggests that deregulations in glutamatergic activity are critical in OCD”; regarding OCD’s genetic etiology, “genes related to glutamatergic transmission are strong candidates”; and “evidence suggests that glutamatergic hyperactivity may” underlie anxiety disorders.
Regarding bipolar, the 2022 book says in Chapter 8: bipolar disorder (BD) “is a relatively common psychiatric disorder that affects millions of people worldwide”; the “relationship between glutamatergic dysfunction and the pathophysiology of depression either unipolar or bipolar has been documented over the past 20 years”; the glutamate hypothesis of mood-disorder etiology “is expected to complement and improve the prevailing monoamine hypothesis and may indicate novel therapeutic targets”; several glutamatergic-system genes “have been found to be involved in the etiology of bipolar disorder”; both “preclinical and clinical studies have implicated glutamatergic dysfunction in the pathophysiology of mood disorders”; it’s fundamentally important—regarding the effort to discover innovative therapies for BD—that the combination of cellular interactions and molecular mechanisms that’s responsible for BD is understood; NMDA receptors are glutamate receptors; recent “findings from research into the treatment of bipolar disorder suggest” that “effects on NMDA receptors may need to be combined with other cellular and/or molecular effects to provide effective therapeutic responses”; and research “to date justifies the optimism that new pharmaceutical agents targeting the glutamatergic system may play an important role in the treatment of bipolar disorder”.
Regarding ADHD, a 2013 Neuroscience and Biobehavioral Reviews article says: a “number of strands of evidence are converging on energy insufficiency as a prominent factor in ADHD”; there’s work hypothesizing that ADHD symptoms may arise due to (1) astrocytes’ impaired lactate production being “insufficient to meet energy demands” and (2) the “supply of adenosine triphosphate (ATP)” therefore being “inadequate to maintain ion gradients across neuronal membranes”; “the behavioral Neuroenergetics Theory (NeT) predicts the results of many neuropsychological tasks involving individuals with ADHD and kindred dysfunctions”; NeT’s “central thesis is that neurons may not be adequately resupplied with the energetic resources—lactate—that they require for prolonged, precisely timed firing”; there are “energetic pools associated with all cerebral actions, and these consist of the ATP immediately available to the neurons, backed up by astrocytic glycogen, and by the astrocytes’ ability to convert that into lactate to provide the long-term energy required by sustained neuronal firing”; there are—regarding action potentials, postsynaptic potentials, ion-gradient resetting, and glutamate clearance—“energy-demanding processes critical for high rates of information transmission”; the “singular premise that one or more of these processes is disordered in ADHD constitutes our theory, NeT”; there’s a neuron-powering supply chain that involves glutamate, glucose uptake, glycogenolysis, lactate production, the conversion of glutamate to glutamine, astrocytes shuttling the glutamine “to the neurons to restore their pools of neurotransmitters”, and norepinephrine release; failure “of this supply chain at any one of the reactions can undermine functionality of the neuron”; all “pharmacotherapies for ADHD facilitate catecholamine function”; regarding ADHD pharmacotherapies, “what they have in common is their ability to stimulate the release of lactate from astrocytes”; therapeutic “agents such as amphetamine that block the monoamine transporters maintain high extracellular concentrations of norepinephrine”; these high concentrations of norepinephrine stimulate the production—in astrocytes—of cyclic adenosine monophosphate and of lactate; these high concentrations “can help compensate for any of several potential energetic bottlenecks”; dopamine “insufficiency plays no role in ADHD”; and norepinephrine “is an effective therapeutic agent because of its ability to stimulate astrocytes to release lactate”. And the 2022 book says in Chapter 16: regarding ADHD treatment, studies have suggested that “targeting the glutamate system with pharmacological agents may” alleviate ADHD symptoms; regarding memantine, it’s “theorized that memantine’s ability to decrease glutamate signaling is a possible reason for its therapeutic value in ADHD”; “some research has shown that lactate hypo-function in the brain can cause aberrant neuronal firing”, promoting ADHD symptoms; there’s “overwhelming evidence for a relationship between” (A) energy dynamics, (B) glutamate, and (C) ADHD; “the neurotransmitter imbalances seen in ADHD could be due to issues with how the brain obtains energy”; regarding future ADHD-drug targets, there could be benefit in targeting (1) the glutamate system and (2) “systems that can increase energy flow to the brain”; it’s “easy to imagine a situation where lack of brain energy eventually causes catecholamine hypo-function because not enough energy is available to sustain normal neuronal firing”; this “catecholamine hypo-function then promotes an increase in glutamatergic firing, which then puts more energy stress on a” system that’s already vulnerable; this “could create a feed-forward pathological situation that may lead to the symptoms seen in ADHD”; atomoxetine is a current ADHD treatment that “works on the norepinephrine, dopamine, and glutamate pathways”; regarding ADHD-drug development, drugs that—like atomoxetine—both decrease glutamate signaling and increase catecholamine signaling “may help to increase the energy supply to the brain and directly act on the neurotransmitter systems dysregulated”; and “both effects should normalize brain physiology and meliorate the symptoms of ADHD”.
A 2018 Cerebral Cortex article talks about glutamate—I think the article’s images are excellent. The article says: the “newly evolved circuits in layer III of primate dorsolateral prefrontal cortex (dlPFC) generate the neural representations that subserve working memory”; regarding the group II metabotropic glutamate receptors mGluR2 and mGluR3, this “study is the first dissection of mGluR2 versus mGluR3 mechanisms in the higher cognitive circuits of primate dlPFC that generate the mental representations underlying working memory”; the authors “have discovered that, in addition to their astrocytic expression, mGluR3 is concentrated postsynaptically in spine synapses of layer III dlPFC, positioned to strengthen connectivity”; in “contrast, mGluR2 is principally presynaptic as expected, with only a minor postsynaptic component”; “data illuminate why insults to mGluR3 would erode cognitive abilities”; and data “support mGluR3 as a novel therapeutic target for higher cognitive disorders”.
Treating ADHD
I found very interesting the following 2022 commentary that appears as a chapter in a 2022 book about ADHD:
The commentary says: it’s “widely accepted that ADHD drugs reduce its core symptoms by potentiating catecholaminergic signalling in the prefrontal cortex”; the “intervening decade since we wrote our last review on the pharmacotherapy of ADHD has produced no evidence to question the hypothesis that ADHD is a catecholaminergic disorder which responds to drugs that potentiate noradrenergic and/or dopaminergic signalling in the brain”; attempts “to treat this disorder successfully through neurotransmitter systems that modulate catecholaminergic function or with cognitive enhancers all failed in clinical trials”; and all “of the recently approved drugs and those currently in late-stage clinical development broadly remain within the same pharmacological confines as existing medications”. I wonder whether glutmatergic ADHD drugs will be successful. And will break the “pharmacological confines” that the authors refer to.
I recommend this 2021 CNS Drugs article that talks about how to approach stimulant-refractory ADHD:
The article says: with “appropriate optimization strategies, the vast majority of patients with ADHD will have a significant reduction in the severity of ADHD with stimulants”; practitioners should check “that the lack of response is not due to alternative explanations”, then consider “augmenting with guanfacine XR or clonidine XR”, and then consider “moving to second- or third-line pharmacological options”; “the choice of medications is currently based on a trial-and-error process”; and it’s “hoped that advances in precision psychiatry will allow more personalized, tailored, and efficient management of patients with ADHD”. I’m not sure whether any of the ADHD drugs that the 2021 article talks about will be winners for me—time will tell. I might—in the end—need at least two drugs to turn out to be winners.
I’m interested in agomelatine—it’s a drug that apparently does all sorts of positive things in the brain. A 2023 Brain Sciences article says that agomelatine (AGM): “increases the availability of norepinephrine and dopamine in the prefrontal cortex”; has “an antidepressant and nootropic effect”; increases a particular protein’s expression and thus (A) optimizes learning, (B) optimizes consolidation of long-term memory, and (C) improves neuron survival; “has been shown to modulate glutamatergic neurotransmission in regions associated with mood and cognition”; “reduces the stress-induced release of glutamate in the prefrontal and frontal cortex”; “is involved in the resynchronization of interrupted circadian rhythms”; and has “beneficial effects on sleep patterns”. And I think that memantine is interesting—it’s one of many glutamatergic medications that I’m interested in, though. A 2020 Expert Opinion on Emerging Drugs article says: memantine “is a noncompetitive antagonist of NMDA receptors”; memantine was tested on ADHD-diagnosed adults; there was a large therapeutic effect; 56% of “participants were clinically negative at the endpoint”; memantine was also tested on ADHD-diagnosed adults in another study; memantine was “much superior to placebo in the reduction of ADHD symptoms”; and memantine “was effective in reducing ADHD symptoms but in our opinion the” drop-out rate suggested issues regarding tolerability.
I’m excited about genetic analysis—precision and personalization are the future of psychiatry, though we must make sure that that future arrives sooner rather than later. A 2015 Therapeutic Innovation and Regulatory Science article says: GRM genes encode for metabotropic glutamate receptors (mGluRs); the mGluR network includes “genes in the signaling pathway of GRM genes”; the authors “have identified a small molecule compound, NFC-1, which previously underwent extensive clinical testing and was shown to have stimulatory activity towards mGluR pathways”; the “drug was originally developed in the late 1980s for treating dementia-related cognitive impairment, but was eventually abandoned during Phase III trials in dementia”; “NFC-1, which exhibits stimulatory activity for all three groups of mGluRs, has been shown to improve cognitive functions in animal models”; and “we aim to reposition NFC-1 for use as a targeted therapy for ADHD in patients who are ‘biomarker positive’ for the mGluR/GRM gene network”. And a 2018 Nature Communications article says: “NFC-1 (fasoracetam monohydrate) is a small synthetic molecule and” an mGluR activator; NFC-1 “may have the potential to restore normal glutamatergic activity in ADHD patients with glutamatergic hypofunction due to mutations in” mGluR-network genes; this study’s objectives were to explore—in ADHD-diagnosed adolescents with “disruptive mutations in genes impacting the mGluR network”—the safety, pharmacokinetic parameters, and potential efficacy of NFC-1; and “NFC-1 treatment resulted in significant improvement”.
Great article. There’s still so little we know about the various causes of mental illness and how best to treat them. Hopefully, some real progress can be made in the near future.