Lights

Psychiatry is a fascinating field.

I find psychiatry to be one of the most fascinating things in the entire world—I’ll use this piece to share some thoughts about it. Keep in mind—as you read this piece—that I’m a complete layperson. You should definitely take everything I say—about psychiatry—with a grain of salt, since I’m about as far from an expert as you can get.

Trajectories and Outcomes

I’ve had a whole rainbow of psychiatric issues throughout my life—I’ve been diagnosed with bipolar disorder, OCD, ADHD, and autism. I think that ADHD has—throughout my life—been my main problem. I always had a lot of skepticism about the autism diagnosis—for example, ADHD and autism seems to me to be conceptually inseparable in the domain of social difficulties. Edmund Sonuga-Barke and others write in an 11 October 2022 article: “overlap and ambiguity is common across the symptoms that define different diagnostic categories”; this “creates problems, especially in research that relies on questionnaires or highly structured interviews, which may incorrectly assign symptoms”; “there may also be shared neuropsychological mediators” between distinct diagnostic categories; executive-function deficiencies—“common in ADHD”—are also seen in autism, depression, and anxiety; and these deficiencies seem to drive ADHD’s co-occurrence with depression particularly and also autism.

I took guanfacine in 2018—it was a major event in my life, since the treatment effect was so dramatic. I could function—it was life-changing. I could see—and hold—things in my mind, including things that I’d never visualized in my life and that I hadn’t witnessed since childhood. My Vividness of Visual Imagery Questionnaire score went way up. And I went—socially and work-wise—from being completely dysfunctional to being effortlessly competent. There’s tons more to say about my 2018 experience—it was quite something for me to go through that mental rearrangement. I lost the treatment effect after only a week, but regained it—again on guanfacine—five years later in 2023. I don’t know what level of consistent treatment effect I’ll be able to get from guanfacine, but I’m hopeful about the situation.

I’m sure that it’s common for people to have some negative emotions when a psychiatric medication works extremely effectively—how can one not worry about losing the treatment effect? What about the emotions that arise when you imagine how radically different your life trajectory and life outcomes would’ve been had you been diagnosed and treated at the age of 10 instead of at the age of 20, 30, or 40? Sandra Kooij writes in the 2022 book Adult ADHD: the “diagnosis of ADHD has a lot of impacts”; for “some patients, the diagnosis is a huge relief”; the “problems appear to be related to a disorder that they have had all their lives”; at “that moment, or a little later, sadness and anger arise over everything that has gone wrong in their lives”; the “process of diagnosis causes a patient to examine his or her life retrospectively”; this “can be confronting, as patients have often had to deal with failure”; diagnosis “and treatment lead to a better perspective, so that patients get an overview of the repetitive nature of their problems”; the “pieces of the puzzle begin to fall into place”; it “takes time to process things and give them a place”; “this also applies to acceptance”; one’s “whole life may be viewed from a different perspective because of the diagnosis”; for “many patients, everything changes at the same time”; and it’s “important to make it clear to a patient that the acceptance process can be accompanied by strong feelings (sadness, anger, shame, fear, perhaps relief) and that these reactions are normal”.

The State of the Broader System

I see psychiatry through my keyhole—I have no idea whether my experience reflects the actual state of the broader system. I want to know how often ADHD is properly diagnosed and treated—to what extent does proper diagnosis and treatment happen for the general public as opposed to just for wealthy people? It seems to me that it’s essential that an ADHD sufferer sees a psychiatrist who really, really, really: (1) knows what they’re doing in terms of both diagnosis and treatment; (2) understands the latest literature on diagnosis and treatment; (3) knows how to approach a situation where a patient has been a “moving target” symptomatically; (4) knows how to avoid various harmful—or even tragic—blunders; and (5) approaches psychiatry with humility. Regarding (5), I’ve witnessed various times a certain rigid, arrogant, and dogmatic approach in psychiatry—I can imagine that that approach is the scourge of medicine in general.

A 2022 Pharmacology and Therapeutics article says: ADHD’s “prevalence lies at approximately 5% in children and adolescents and at approximately 2.5% in adults”; the “disorder follows a multifactorial etiology and shows a high heritability”; patients “show a high interindividual and intraindividual variability of symptoms, with executive deficits in several cognitive domains”; “ADHD is associated with high rates of psychiatric comorbidities”; regarding ADHD, “insufficient treatment is linked to adverse long-term outcomes”; patients “with ADHD show executive deficits in several cognitive domains, e.g., visuospatial and verbal working memory, inhibitory control, vigilance, planning and reward regulation”; ADHD symptoms “show a high variability on the interindividual and intraindividual level and need to be viewed within the context of a chronic neurodevelopmental disorder”; “making a diagnosis is challenging”; the “diagnostic process is aided by assessment tools (rating scales, semi-/structured interviews) and guided by classification systems (e.g., DSM-5 or ICD-10), but relies mainly on the classical skills of psychiatrists”, namely “a careful and comprehensive clinical interview and behavioral observation of the patient and respective family members/caregivers as well as an observation of their interactions”; since “(insufficiently treated) ADHD negatively affects many long-term outcomes (e.g., academic achievement, employment status, traffic accidents), timely and adequate treatment is crucial”; ADHD causes “substantial functional impairment”; and ADHD “leads to a serious societal burden”. I think that it’s important to highlight a painful truth regarding ADHD—proper treatment at age 10 will yield very different life outcomes from proper treatment at age 30. It’s a race to diagnose and treat the ADHD sufferer as soon as possible, since the goal is to minimize the avoidable damage—I just quoted an article that says (1) “timely and adequate treatment is crucial” and (2) “insufficient treatment is linked to adverse long-term outcomes”.

Optimization and Effectiveness

I have no idea—in terms of statistics—what psychiatrists actually do when they treat ADHD. At what frequency do psychiatrists actually follow the 2021 guide “A clinician’s guide for navigating the world of attention deficit hyperactivity disorder medications”? The guide talks about layering doses, combining formulations, and combining molecules. And it says: the “rule of thumb is to titrate until there are no breakthrough symptoms or residual functional difficulties or one encounters a dose-limiting side effect or has reached the maximum dose”; one “should then consider trying an alternative molecule” that “may address breakthrough symptoms at the beginning, the middle, or the end of the day”; a “patient can be “partially better but not well”; clinicians and patients “may be tempted to be satisfied with 30% improvement, even though the evidence is clear that such minimal improvement almost inevitably means continued functional impairment”; for “most patients, further improvement is possible”; and long-term “trials demonstrate that nearly 75% to 80% of patients can achieve >50% symptom reduction and achieve symptomatic remission”. I wonder (A) how many ADHD sufferers take medication but are far from optimization, (B) how clinical trials ensure that everyone in the trial is genuinely and truly optimized, and (C) whether optimizing ADHD medication actually yields stunningly good outcomes at a stunningly high rate.

The guide says “no breakthrough symptoms or residual functional difficulties”. And “achieve >50% symptom reduction and achieve symptomatic remission”. And “normalized”. I would find it very informative to see interviews with—and documentaries about—ADHD patients who illustrate what different levels of symptom reduction might look like. And who illustrate what “symptomatic remission”—and lack of “residual functional difficulties”—might look like. ADHD medications have been in use for a long time—how many people are out there whose stories might help to illustrate these medications’ effectiveness? My own story might turn out to be a success story—in a way—if I can figure out my medications. It’s 2023, though—there should be 1000s and 1000s of these stories at this point, so it’s more than a little bit strange that the stories aren’t abundant and prominent.

Big, Active, Lively!

I really wish that there were some big, active, and lively forum where experts would answer psychiatry questions—it feels lonely, demoralizing, and bleak when no such forum exists. I’ll share some of my burning questions—I’ve already asked a couple above—about psychiatry.

First, suppose you get a great short-lived effect from a medication like escitalopram. How often will that effect ever return—and “stick”—if you raise the dose enough? Will pursuing that great effect inevitably lead to more tolerance and disappointment?

Second, how often do patients have a “breakthrough” with one medication that then causes their other medications to work differently? Suppose a patient has totally failed guanfacine and Adderall XR. They increase their dose of escitalopram, feel a lot better right away, find that the guanfacine suddenly works extremely well, and find that the Adderall XR—thanks to what the guanfacine is now doing—suddenly works extremely well too. It’s like one medication “lays a foundation” for another one that previously didn’t work whatsoever. And can’t this “breakthrough” phenomenon lead to a situation where the patient has to titrate the same medications—including ones that the patient isn’t even taking any longer—over and over? It’s like this phenomenon yields a “circular” process instead of a “linear” one.

Third, I always want to read all about the patients who are—for a given medication—in the 99th percentile in terms of how good their response is. Where’s the literature on these special responders, though? I don’t just want to see how they performed on one or another test—I want to read their descriptions of what it felt like to respond in the way that they did, what their life was previously like, and what their life is like post-response. I always want to start out my investigation of a drug with the question “What can this drug do at its very best?”. But you never seem to hear about these 99th-percentile people.

Fourth, where’s the literature on the issue of patients who need—and can tolerate—high doses of medications? I personally regard this as a very disturbing problem—is it possible to estimate how big this group of patients is? Consider that patients have gone their whole lives—maybe even committed suicide—without ever discovering that they just needed an unusually high dose of one or more medications in order to get a life-changing treatment effect. Or have been—without knowing it—a single dose increase away from discovering that a life-changing treatment effect was possible with a given medication. It’s remarkable to think about the stakes, the serendipity, and the injustice. I can’t say how accurate Scott Alexander’s 31 March 2021 piece is—there’s criticism in the comment section—but I highly recommend the piece, which makes one think about how the FDA determines what a safe maximum dose of a given drug is. We know that some patients need high doses of medications—can’t we run careful tests in order to ensure the patient’s safety as we go above a given threshold? We know that there will—with every drug out there—be small numbers who respond to very tiny doses as well as small numbers who need very large doses. Would it be helpful to look more closely at the physiologic effects on the individual and not worry so much about how many milligrams it took to get there?

Fifth, how effective is nefazodone really? Has it really been an incredible and life-changing medication for people with treatment-resistant mental illness, how interesting is its mechanism of action, and could future drugs be designed to work in a similar way? And does Scott Alexander make a strong point in his 25 April 2015 piece when he writes that “drugs with rare but spectacular side effects get consistently underprescribed relative to drugs with common but merely annoying side effects, or drugs that have more side effects but manage to hide them better”? I didn’t fact-check the piece—I found the argument interesting, though. He writes: “SSRIs, the class which includes most currently used antidepressants, are very safe in the traditional sense of ‘unlikely to kill you’”; on “the other hand, there’s increasing awareness of very common side effects which, while not disabling, can be pretty unpleasant”; about “50% of users report decreased sexual abilities, sometimes to the point of total loss of libido or anorgasmia”; “something like 25% of users experience ‘emotional blunting’ and the loss of ability to feel feelings normally”; nefazodone “is an equally good (and maybe better) antidepressant that does not have these side effects”; on “the other hand, every year, one in every 300,000 people using nefazodone will go into ‘fulminant hepatic failure’, which means their liver suddenly and spectacularly stops working and they need a liver transplant or else they die”; “nefazodone is practically never used”; it’s “actually illegal in most countries”; there “are something like thirty million people in the US on antidepressants”; if “we put them all on nefazodone, that’s about a hundred cooked livers per year”; if “we put them all on SSRIs, at least ten million of them will get sexual side effects, plus some emotional blunting”; the “same doctors who would never dare give nefazodone, consider Seroquel a perfectly acceptable second-line treatment for depression”; “if my calculations are right, low-dose Seroquel causes an extra cardiac death once per every 20,000 patient-years”; that’s “ten times as often as nefazodone causes an extra liver death”; when “treatment with an SSRI fails, nefazodone and Seroquel naively seem to be equally good alternatives”; “nefazodone has a death rate of 1/300,000 patient years, and Seroquel 1/20,000 patient years”; “I conclude either doctors are terrible at thinking about risk, or else maybe a little too good at thinking about risk”; doctors “want to do what’s best for their patients”; “they also want to do what’s best for themselves, which means not getting sued”; no “one has ever sued their doctor because they got a sexual side effect from SSRIs, but if somebody dies because they’re the lucky 1/300,000 who gets liver failure from nefazodone, you can bet their family’s going to sue”; “it’s a matter of comparing zero percent chance of lawsuit with non-zero percent chance of lawsuit”; “if a doctor has 100 patients at a time on antidepressants, and works for 30 years, then if she uses” nefazodone “as her go-to antidepressant, she’s risking a 1% chance of getting the liver failure side effect once in her career”; that’s “small, but since a single bad lawsuit can bankrupt a doctor, it’s worth taking seriously”; a nefazodone lawsuit “would be a tough lawsuit to fight”; when “someone dies of nefazodone toxicity, everyone knows”; and “the same facet of nefazodone that makes it exciting for the media makes it exciting for lawsuits”. I want to highlight the fact that people will say that nefazodone is the sole medication that allows them to be free from mental illness—consider the stakes and the injustice. How often does liver damage ever occur after special protocols are put in place? Is there no way to be vigilant enough so that no liver damage ever occurs?

Sixth, have researchers made any effort to respond—both at a basic level and in a thorough and detailed way—to the various harsh criticisms of psychiatry? I have in mind a 1 April 2019 New Yorker piece, then a 2023 Deutsche Welle documentary about antidepressants, then a 2020 Psychiatric Times conversation, and then a 2020 article that asks whether “antidepressant drugs worsen the conditions they are supposed to treat”. I get the impression that researchers don’t want to engage with these criticisms, but that expert silence could—if it’s the case that specious criticisms are getting a lot of traction with people—result in significant damage to both individuals and society. I myself would love to know what the basic—as well as the thorough and detailed—response would be to the various criticisms. Lee McIntyre writes in a 2021 article: “in a pathbreaking new study by Philipp Schmid and Cornelia Betsch, we now have the first experimental evidence that it is possible to break the grip of resistance on scientific topics”; in “their study, Schmid and Betsch ran six online experiments with 1,773 subjects in the United States and Germany on topics such as climate change and vaccine denial”; “what they found was astonishing”; fighting “back against science deniers not only had a positive effect on changing their beliefs, but also the effect was greatest for subgroups who had the most conservative ideologies”; in “the course of their work, Schmid and Betsch tested four possible ways of responding to subjects who had been exposed to scientific misinformation”, namely “no response, ‘topic’ rebuttal, ‘technique’ rebuttal, and both kinds of rebuttal”; topic “rebuttal consisted of providing subjects with factual information to correct the bogus content of a message they had just heard”; “‘technique’ rebuttal” borrows “a page from the finding that virtually all science deniers engage in a common form of reasoning”; this “consisted of pointing out the dangerous manipulative techniques—cherry-picking, reliance on conspiracy theories, use of fake experts, illogical reasoning, or use of impossible standards—to mitigate the impact of the science denier’s misinformation”; the “clear result of this study was that providing no response to misinformation was the worst thing one could do”; “researchers found that it was possible to mitigate the effects of scientific misinformation, either by using content rebuttal or technique rebuttal, and indeed that both were equally effective”; there “was, however, no additive advantage when both content and technique rebuttal were used together”, so one “does not have to be an expert on the content of science to push back against science denial”; “in light of both the experimental and anecdotal evidence, perhaps it is worthwhile to try to convince scientists that they should become more engaged in the effort to make science deniers change their beliefs”; regarding engagement with science denial, the “experimental evidence has shown that it can have an effect and indeed that choosing not to intervene leads to the worst possible outcome”; “Schmid and Betsch’s work has shown that there is more than one way to fight against science denial”; there’s “a crucial role for scientists to play in these efforts”, though; “‘technique rebuttal’ can be quite effective”, but there’s “an equal role for ‘topic rebuttal,’ where scientists can bring their expert knowledge to the forefront and explain not just the findings but also the process of science”; and if “one will not engage with people who are ignorant or willfully ignorant, then misinformation will rule the day”.

I think there needs to be an online place where people can actually get high-quality expert answers to their questions about (1) psychiatry in general and (2) their own treatment. The rift between the experts and the public couldn’t expand any wider—it’s disheartening, tragic, and unnecessary.

Turning on the Lights

I should add a huge question to the ones that I’ve asked so far in this piece—how can we create a situation where we see a steady flow of life-changing drugs that dramatically reduce the burden of ADHD, depression, anxiety, and other mental illnesses? I suppose that the two big issues are (A) where the money should come from and (B) where the funds should be directed.

I was—regarding (A)—disturbed to read a 2013 International Journal of Neuropsychopharmacology article that says: in “the past few years, several high profile pharmaceutical companies, based worldwide, have decided to shut down major research activities within the neuroscience area”; the “withdrawal of pharmaceutical companies from neuroscience research is a serious concern to the whole community, including researchers, clinicians, patients and scientific organizations”; and “major concerns arise from the knowledge that leading world pharmaceutical companies are not as much focused on these areas as in previous years, dashing the hopes of millions of patients for new and more effective drugs in the near future”. Dean Baker writes in his 2015 book Rigged: “patent-supported research is particularly ill-suited for the pharmaceutical sector, as well as for the medical equipment sector”; it’s “likely that a system of directly funded research, paid for by the government, would be considerably more efficient for the development of new drugs and medical equipment”; there’s “no way to determine in advance the effectiveness of an alternative funding mechanism to replace patents and copyrights”; there “are good reasons for believing that an alternative would be at least as effective, especially in the case of patents”; and the “prospect of having fully open research, where the incentive is for dissemination rather than secrecy, would almost certainly lead to more rapid progress than the current patent system”. And Steven Johnson writes in his 2010 book Where Good Ideas Come From: the “premise that innovation prospers when ideas can serendipitously connect and recombine with other ideas, when hunches can stumble across other hunches that successfully fill in their blanks, may seem like an obvious truth, but the strange fact is that a great deal of the past two centuries of legal and folk wisdom about innovation has pursued the exact opposite argument, building walls between ideas, keeping them from the kind of random, serendipitous connections that exist in dreams and in the organic compounds of life”; ironically, “those walls have been erected with the explicit aim of encouraging innovation”; the walls have many names—“patents, digital rights management, intellectual property, trade secrets, proprietary technology”; the “problem with these closed environments is that they inhibit serendipity and reduce the overall network of minds that can potentially engage with a problem”; traditionally, “organizations that have a strong demand for innovation have created a kind of closed playpen for hunches”; ironically, “R&D labs have historically functioned as a kind of idea lockbox”; “the hunches evolving in those labs tended to be the most heavily guarded secrets in the entire organization”; allowing “these early product ideas to circulate more widely would allow rival firms to copy or exploit them”; that secrecy “comes with great cost”; and protecting “ideas from copycats and competitors also protects them from other ideas that might improve them, might transform them from hints and hunches to true innovations”. I think that innovation will—regarding drugs for mental illness—probably accelerate significantly if research becomes open and freely shared.

I wonder—regarding (B)—how much debate there is over which hurdles are slowing drug innovation the most. The 2013 International Journal of Neuropsychopharmacology article says: the “lack of translation from animal models to clinical efficacy makes it difficult to generate human models of psychiatric disease that provide a good concept for expensive clinical trials in patients”; it’s “often observed that molecules work very well in animal models, but when transferring to patients, they do not”; “most of the model tests lack the precision and sophistication required to model complex behavioural disorders such as, for example, depression and schizophrenia”; and “what is needed is to develop animal models that more closely mimic specific dimensions of psychopathology”. And a 2023 Molecular Psychiatry article says: “we argue that there is a need for a paradigm shift in the methodologies used to measure animal behavior in laboratory settings”; the “stagnation in developing remedies for mental illnesses seems puzzling in light of the outstanding technological advances that have been made in brain research over the last three decades”; “for translational psychiatry, the gap between bench and bedside has remained as wide and deep as a few decades ago”; there’s “a general understanding that this gap is partly due to a limited relevance of the behavioral assays in animals to the human disease”; the “primary unmet objective in basic psychiatric research is to translate biological measures and findings in the laboratory to the symptom-based categorization as defined in the existing disease-diagnostic systems”; the “Research Domain Criteria (RDoC) initiative addresses this challenge with a framework that provides a taxonomy for mental illnesses that is based on genetics, behavioral neuroscience, and psychological measures”; and “we believe that the evolving RDoC framework together with utilization of various rodent species models in a dynamic but controlled semi-natural setup could be the Rosetta Stone for revealing neuronal mechanisms of emotions in humans”.

A 2019 Proceedings of the National Academy of Sciences piece says: all “of science depends on basic research, research that has the goal of understanding a system rather than the goal of fixing or building it”; anyone “who has close experience with a brain disease knows that current medicine is mostly groping in the dark with these disorders”; and it’s “the job of basic science to turn on some lights”. I find it absolutely fascinating to read what Amy Arnsten has to say about the illuminations that might give us therapeutic breakthroughs—she has an excellent 2015 talk titled “Prefrontal Cortical Circuits in Schizophrenia”:

She comments in the Q&A section: “I’ve been very sad to see how many drug companies have given up on neuroscience because it’s so complicated.”

Arnsten writes in a 2022 Neuroscience and Biobehavioral Reviews article: our “experience of ourselves, and the world around us, can be altered by changes in our brains caused by exposure to uncontrollable stress”; under “healthy conditions we are able to process events with appropriate ‘top-down’ regulation and optimism governed by the prefrontal cortex (PFC)”; “with exposure to uncontrollable stress, the orchestration of brain circuit connections shifts such that we can lose perspective and experience our universe through an ‘Aversive Lens’”; this “can be seen most clearly in patients with major depressive disorder, who focus on negative events, even experiencing a neutral stimulus as sad”; these patients “lose pleasure in rewarding events, a condition known as anhedonia”; recent “research in nonhuman primates has begun to illuminate the neural bases for this phenomenon, where activation of Brodmann Area 25 (BA25), a major output of the PFC to the subcortical structures that mediate emotion, increases responses to threat and induces anhedonia”; these “data are consistent with the over-activation of BA25 in patients with depression, and the relief of symptoms when BA25 activity is normalized”; research in monkeys has discovered (1) “the PFC circuits that normally provide ‘top-down’ regulation of BA25” and (2) “how these circuits are weakened by stress exposure”; we “have learned a great deal about the neural circuits involved in PFC top-down regulation of emotion and their vulnerability to stress exposure”; we’re “beginning to understand how BA25 can activate visceral, somatic and emotional responses through its connections to subcortical structures”; and we “still have insufficient knowledge”—regarding “the molecular regulation of these circuits”—relative to what’s “needed to develop superior treatments”.

Roshan Cools and Amy Arnsten write in a 2021 Neuropsychopharmacology article: the “primate prefrontal cortex (PFC) subserves our highest order cognitive operations”; it “generates our mental arena, and subserves our highest order functions, such as abstract reasoning, working memory, high-order decision making, planning, and organization, providing top-down control of attention, actions, and emotions”; “understanding neuromodulatory influences on PFC circuits can help to explain why these circuits are so often impaired in mental disorders”; the PFC “is tremendously dependent on a precise neurochemical environment for proper functioning”; depletion “of noradrenaline and dopamine, or of acetylcholine from the dorsolateral PFC (dlPFC), is as devastating as removing the cortex itself”; “serotonergic influences are also critical to proper functioning of the orbital and medial PFC”; most “neuromodulators have a narrow inverted U dose response”; studies “in monkeys have revealed the molecular signaling mechanisms that govern the generation and modulation of mental representations by the dlPFC, allowing dynamic regulation of network strength, a process that requires tight regulation to prevent toxic actions”; research “in monkeys has already led to new treatments for cognitive disorders in humans, encouraging future research in this important field”; “there are large arenas where little or no research has been performed in this field”; there “are many outstanding questions in this field”; and “the power of neuromodulatory influences on the primate PFC” means that we must understand the relevant mechanisms if we want to (A) know what causes many disorders and (B) have “superior therapeutics”.

A 2019 ACS Chemical Neuroscience article says: the “prefrontal cortex is essential for both executive function and emotional regulation”; there’s increasing recognition of (1) the “interrelationships among these behavioral domains” and (2) these domains’ “sensitivity to serotonin (5-hydroxytryptamine, 5-HT)”; prefrontal “cortex receives serotonergic inputs from the dorsal and median raphe nuclei and is modulated by multiple subtypes of 5-HT receptor across its layers and cell types”; extremes “of serotonergic modulation alter mood regulation in vulnerable individuals”; “the impact of serotonin under more typical physiological parameters remains unclear”; optogenetic “and chemogenetic manipulations of dorsal raphe 5-HT neurons reveal that serotonin has a greater impact on executive function than previously appreciated”; domains “that appear sensitive to fluctuations in 5-HT neuronal excitability include patience and cognitive flexibility”; a “growing literature suggests 5-HT modulation of these prefrontal circuits is unexpectedly flexible to alteration during development by genetic, behavioral, environmental or pharmacological manipulations, with lasting repercussions for cognition and emotional regulation”; here “we review the cellular and circuit mechanisms of prefrontal serotonergic modulation, investigate recent research into the cognitive consequences of the serotonergic system, and probe the lasting consequences of developmental perturbations”; early “stress significantly increases individual vulnerability to adult psychopathology”; early “life stress has been shown to alter prefrontal 5-HT receptors”; “differential regulation of 5-HT receptor expression during development tightly controls the activity and the establishment of the local circuitry within the prefrontal cortex”; disruption “to the 5-HT system at a critical time window during development leads to alterations in serotonergic modulation of prefrontal cortex and results in impaired cognitive and emotional behaviors in adulthood”; and “exposure to stress during development affects expression and function of 5-HT receptors in the prefrontal cortex and is likely to alter cognitive behavior that depends on serotonergic modulation of prefrontal cortex”.

A 2022 Neuroscience and Biobehavioral Reviews article says: the “regulation of energy metabolism represents a major challenge for the nervous system”; it’s “estimated that the energetic needs of the adult human brain account for approximately 20% of the body’s oxygen consumption, although the brain represents just 2% of total body’s weight”, while “the metabolic cost in the developing brain is even higher”; this “is mainly due to the complexity of neuronal morphology and the highly energetic processes required to sustain and regulate neuronal transmission and synaptic plasticity”; stress “and higher cognitive functions underlying complex behaviours further increase cerebral energy demands in terms of glucose oxidation and oxygen consumption”; overall, “the energetic cost of brain activities must be efficiently covered by mitochondrial respiration”; it’s “not surprising that even small alterations in metabolic processes may severely affect neural functions, thereby increasing vulnerability for brain disorders”; cellular “energy metabolism is regulated mainly by mitochondria which are the cells’ powerhouse for producing ATP but also acknowledged as key regulators of a variety of processes, including reactive oxygen species (ROS) production, calcium buffering, apoptosis, lipid biogenesis and hormones biosynthesis”; over “the last decade, emerging studies have highlighted a bidirectional interplay between mitochondria bioenergetics and psychosocial stress”; chronic “stress has been considered as a key factor for the development and progression of many neuropsychiatric conditions, including anxiety and mood disorders, currently affecting millions of individuals worldwide”; these “mental disorders represent a major personal, societal, and economic burden”; “there is an urgent need to understand the biological mechanisms underlying these conditions and find novel therapeutic strategies”; strong “evidence has linked the role of mitochondria and oxidative stress to anxiety and depression”; regarding “generalized anxiety disorder, the role of mitochondria appears to be more complex”; “results indicate a complex relationship between mitochondrial activity and stress-related psychopathologies, although the causality of mitochondrial functions in the generation of these diseases still needs to be shown”; in addition to the “role in stress and anxiety, mitochondrial dysfunctions may also contribute to the etiopathogenesis of other major mental conditions, such as mood disorders and schizophrenia”; in “support of a possible mitochondrial dysfunction hypothesis of bipolar disorder, Kasahara et al. observed altered day-night rhythms in a transgenic mouse line for a human mitochondrial disorder, called chronic progressive external ophthalmoplegia”; this “mouse line carried a neuron-specific accumulation of partially deleted” mitochondrial DNA “that caused a behavioural phenotype resembling bipolar disorder”; over “the last years, increasing data have suggested a mitochondrial aetiology of autism spectrum disorder (ASD)”; it’s “reasonable to hypothesise that stress-induced changes in mitochondrial functions could effectively alter neuronal transmission and synaptic plasticity”; stressful “experiences such as reductions in maternal care, changes in diet and exposure to aversive stimuli” are “known to lead to long lasting epigenetic modifications in the degree of DNA methylation/demethylation or histone post-translational modifications such as acetylation”; evidence suggests two things; first, “that alterations in mitochondrial function do impact” cognitive processes; second, that these alternations may be causatively “linked to the onset of psychiatric disorders”; and understanding “the connections between mitochondria and cognitive functions could pave the way to” next-generation approaches that target “mitochondria to alleviate neuropsychiatric conditions”.

A 2020 Annual Review of Clinical Psychology article says: convincing “evidence across various fields of inquiry has reliably demonstrated over the past two decades that adversity in childhood is associated with increased risk for both psychopathology and chronic health problems throughout the lifespan”; the “psychological and biophysical sequelae of stress exposure originate in evolutionary mechanisms designed to enable an individual to respond to an environmental threat”; “acutely these may be adaptive”; “in excess, these processes produce broad systemic physiologic and psychological disruption”; the “mitochondrion, well-known for its role in cellular energy production, represents a critical nexus of biological, psychological, and social factors that underlie the mechanisms and consequences of the stress response”; psychosocial “factors impact biological processes through physiological systems that are highly integrated with mitochondrial functioning”; mitochondria “are subcellular organelles with broad functions in energetics, cell-signaling, and hormone production”; mitochondrial “structure and function are exquisitely responsive to the environment and serve as both a target and mediator of the stress response”; there’s “a profound impact of mitochondrial dysfunction on psychological processes, with increasing evidence demonstrating associations of stress-related mitochondrial dysfunction and psychopathology”; “findings indicate that mitochondria may play a critical role in neuronal integrity and synaptic transmission”; “mitochondria may provide the biological link between psychosocial stress and psychiatric outcomes”; accumulating “evidence from animal models and recent human studies has identified mitochondria as a critical intersection point for psychosocial factors and stress physiology”; “many questions remain” despite “improved understanding of the wide-ranging roles for this organelle in regulating key stress-related processes”; the “mechanisms that underlie these processes are highly complex”; “the relationship between stress, mitochondria, and psychiatric disorders is non-linear, with bidirectional interaction among multiple interwoven physiological systems”; allostasis “is a complex collection of physiological functions, which allows an organism to adapt and maintain stability in a dynamic environment”; in excess, allostatic “processes are overextended, leading to maladaptive, pathological functioning”; there’s “emerging evidence indicating that chronic stress generates maladaptive alterations in mitochondria, which contribute to allostatic processes, ultimately promoting aging and disease”; research “provides a foundation for the opportunity to expand our understanding of risk and resilience and identify therapeutic interventions targeting these biological mechanisms”; further “studies are needed that seek to elucidate how mitochondria contribute to neuronal circuits”; and continued “efforts across relevant fields should be focused on translating this emerging area of research into clinical applications”.

Amy Arnsten, Min Wang, and Constantinos Paspalas write in a 2012 Neuron article: the “highly evolved neuronal networks of the dorsolateral prefrontal cortex (dlPFC) subserve working memory, our ‘mental sketch pad,’ by representing information in the absence of sensory stimulation”; the “dlPFC expands greatly over evolution, with no exact counterpart in rodents, and an enormous extension from nonhuman to human primates”; comparisons “of dendritic complexity in human versus animal cortices have shown that the basal dendrites of dlPFC deep layer III pyramidal cells are the ones most increased in primate evolution, with increases in both dendritic complexity and the number of spines”; the “dlPFC representational machinery interacts extensively with posterior cortices, providing top-down regulation, for example, to suppress irrelevant operations or enhance the processing and storage of a nonsalient but relevant stimulus and to reactivate long-term memories onto the mental sketch pad as a key part of memory retrieval and recall”; the “representational properties of the dlPFC arise from extensive neural connections that have greatly expanded in human evolution”; these “circuits engage in an ever-changing, intricate pattern of network activation that underlies the contents of thought and provides top-down regulation of attention, action, and emotion”; multiple “neuromodulatory arousal systems project to the dlPFC, and we are now learning that neuromodulation plays an essential role in shaping the contents of our ‘mental sketch pad,’ thus coordinating arousal state with cognitive state”; “physiological research has shown that neuromodulators can rapidly alter the strength of dlPFC network firing on a timescale of seconds, through powerful influences on the open states of ion channels residing near network synapses, a process called dynamic network connectivity (DNC)”; this “work has shown that the highly evolved circuits of dlPFC are often modulated in a fundamentally different manner than are sensory/motor or subcortical circuits, providing great flexibility in the pattern and strength of network connections”; these “neuromodulatory processes allow moment-by-moment changes in synaptic strength without alterations in underlying architecture and can bring circuits ‘on-line’ or ‘off-line’ based on arousal state, thus coordinating the neural systems in control of behavior, thought, and emotion”; “this extraordinary flexibility also confers great vulnerability”; “errors in this process likely contribute to cognitive deficits in disorders”; “genetic and environmental insults to DNC contribute to cognitive deficits in mental illness and in advancing age”; and understanding “and respecting these actions will be key for the development of effective treatments for higher cognitive disorders in humans”.

Data “indicate that there are ionic mechanisms that can cause rapid losses of dlPFC network excitation while maintaining the architectural integrity of the immensely complex networks needed for mental representation”; “there can be a momentary weakness in dlPFC function (e.g., a potential stressor that takes dlPFC ‘off-line’ and switches control of behavior to more habitual, subcortical mechanisms), quickly followed by a return to more thoughtful, top-down dlPFC regulation when safety is assured”; the “recurrent excitatory working memory microcircuits in deep layer III of dlPFC interconnect on dendritic spines”; these “spines are predominately long and thin”; increases “in calcium-cAMP signaling open ion channels in” these spines; opening these ion channels gates network connections; generalized “increases in calcium-cAMP signaling during fatigue or stress disengage dlPFC recurrent circuits, reduce firing and impair top-down cognition”; inhibition “of calcium-cAMP signaling by stimulating α2A-adrenoceptors on spines strengthens synaptic efficacy and increases network firing”; “optimal stimulation of dopamine D1 receptors sculpts network inputs to refine mental representation”; guanfacine stimulates α2A-adrenoceptors; “infusion of guanfacine directly into dlPFC improves working memory”; “systemic administration of guanfacine improves a variety” of “cognitive functions, including spatial working memory, behavioral inhibition, top-down regulation of attention, and rapid associative learning”; a “recent study has shown that guanfacine improves impulse control by inhibiting responses to an immediate, small reward in order to wait over a delay for a larger reward”; all “of these tasks require behavior to be guided by mental representation”; guanfacine “strengthens the efficacy of dlPFC microcircuit connections, enhancing mental representation and top-down regulation of behavior”; “guanfacine is now being used to treat a variety” of “disorders in human patients, including attention deficit hyperactivity disorder”; research “on the primate dlPFC has revealed that the highly evolved microcircuits underlying representational knowledge are modulated in a unique manner, different from sensory/motor and subcortical circuits”; these “differences must be respected if we are to understand the neurobiology underlying higher cognitive disorders and thus create effective treatments”; guanfacine’s success shows “that understanding the unique modulation of higher cortical circuits can lead to effective treatments for humans”; and it’s necessary to (1) “understand how genetic and environmental alterations in higher cognitive circuits impact their physiological integrity” and (2) learn how to identify function-restoring targets.

Arnsten and Wang write in a 2016 Annual Review of Pharmacology and Toxicology article: medications “to treat cognitive disorders are increasingly needed, yet researchers have had few successes in this challenging arena”; coupling “our knowledge of higher primate circuits with the powerful methods now available in drug design will help create effective treatments for cognitive disorders”; “guanfacine serves as an example of successful translation from research in animals to cognitive disorders in humans”; several “factors facilitated guanfacine's translation from animals to humans”; first, extensive “guanfacine dose/response curves were available from both young and aged monkeys that allowed identification of a potential dose range”; second, guanfacine “had also been approved for use in humans as an antihypertensive, thus allowing open-label explorations of effective doses in patients”; “this type of exploration is not possible with new compounds”, though “more extensive Phase II testing might achieve similar goals”; third, “research in monkeys and open-label trials also helped to identify the most appropriate methods for easing side effects”; this “knowledge facilitated the success of the more expensive Phase III trials”; many “hurdles must be overcome in the successful development of cognitive enhancers”; “a major challenge in translating cognition-enhancing drug actions from animals to humans is identifying the appropriate dose range”; this “is complicated both by narrow, inverted, U-shaped dose response curves, in which there is loss of efficacy when the dose is a little too high, and by the typical variability in optimal dosages between individuals, such as because of variations in levels of the endogenous transmitter”; the “use of monkeys to identify an approximate dose range prior to Phase II testing in humans may be helpful in facilitating this process”; “monkey research is expensive”; “human research is more so, so it may actually be considered a cost-effective approach”; and “expanding dose-finding in Phase II (especially for low doses) and creating experimental designs that allow optimal individual dosing may facilitate success in this complex space”.

Many “key areas for future research on the primate cortex would facilitate the development of informed treatments for mental disorders”; “although we have learned a lot about the molecular needs of the” dorsolateral prefrontal cortex, “investigators have conducted no or very little research on the needs of other cortical areas that may be modulated in unique ways”; “the gap between molecular biology and studies of the primate cortex is growing, as studies of the primate cortex are generally performed by researchers who have little background or interest in pharmacology or molecular biology, whereas molecular biology is focused on mouse models and cell cultures for which genetic tools can be used”; “scientists know almost nothing about the modulation of most of the primate cortex”; research “on other cortical areas that have immediate clinical relevance will be especially important, e.g., the subgenual cortex (Brodmann area 25) in regard to depression, the orbital” prefrontal cortex “in regard to disorders such as OCD, and the entorhinal cortex and parietal cortices that are afflicted in” Alzheimer’s disease; “most of the cortex remains unexplored”; it “would be particularly interesting to examine the molecular regulation of the primate subgenual cortex (Brodmann area 25), given its enriched serotonin innervation, role as a visceromotor center, and immediate relevance to depression”; a “major need for future research is to learn what causes the neurodegeneration of higher cortical circuits in schizophrenia” and in Alzheimer’s disease; “researchers do not know how stress signaling events might interact with the molecular mechanisms involved in healthy spine pruning that begins in teen years, nor how all these events interact with the genetics of schizophrenia”; our “growing understanding of the unique regulation of higher cortical pyramidal cells may also help us understand the origins of degeneration in” Alzheimer’s disease; regarding Alzheimer’s disease and schizophrenia, “we must understand what is causing these degenerative processes”; research “in monkeys may be helpful in viewing the molecular processes that weaken association cortical circuits”; as the dorsolateral prefrontal cortex “has built-in mechanisms to take its circuits offline, dysregulation of these events may contribute to their susceptibility to degeneration”; and recognizing “the unique regulation and vulnerabilities of the primate association cortices may help guide future research in protecting higher cognitive functions”.

I view my life in a very positive light—I’m in a great place mentally. I’ve been through a lot of tough times, but I look at it all through a scientific lens—I look at the pain of the past and see hope for the future. I hope to attain my incredible guanfacine effect permanently. And I think that it would be—right now at least—too overwhelming to imagine places even higher than what guanfacine has awakened for me. The “dlPFC representational machinery interacts extensively with posterior cortices, providing top-down regulation, for example, to suppress irrelevant operations or enhance the processing and storage of a nonsalient but relevant stimulus and to reactivate long-term memories onto the mental sketch pad as a key part of memory retrieval and recall”—that quote from the 2012 Neuron article speaks to me on an extremely deep level, since the words capture so well what my 2023 guanfacine experience was all about. It was all about “top-down regulation”. And suppressing “irrelevant operations”. And processing and storing “nonsalient but relevant” things. And reactivating “long-term memories onto the mental sketch pad”. Lots of questions come to mind—where had all those memories that rushed onto my mental sketchpad been residing, how could I see so vividly things that I’d never visualized in my life and that I hadn’t witnessed since childhood, how was my brain—which grouped my long-term memories in such an interesting fashion—able to organize all of my long-term memories in such a useful and logical way, and how did these systems in my brain spring to life if they’d never been online? I can’t be the only one to have had a response like this to guanfacine or some other ADHD medication—I hope to read similar stories from others. I think that the future is bright—we just have to turn the lights on.