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The Anatomy of Melancholy
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I am not neurotic, but I occasionally worry that dreadful things will happen, caused by a lamentable oversight on my part, such as an un-returned Christmas greeting provoking justifiable depression in a former acquaintance who then turns to drink, and crashes his car into a pedestrian who happens to be the only person capable of saving us from a world-wide bird-flu pandemic, thus leading to the end of humanity.

Now an explanation for my slight tendency to worry arrives in the form of a mammoth study on the genetics of neuroticism. Has my affliction been tracked down, and is it attributable to my genes, rather than the slings and arrows of outrageous fortune? Let us see.

The status quo ante was that a nervous disposition, mostly concerned with worry and guilt, was associated with 11 genetic loci. Now the Deary gang have crunched the genetic data on 329,821 Biobank participants, and in a GWAS identified 116 significant independent loci related to neuroticism, an order of magnitude increase in our understanding of the genetic basis of the condition. 15 of these loci replicated at P < 0.00045 in an unrelated cohort (N = 122,867). In fact, it is a bit better than that, as 111 out of 116 were found in the replication cohort, with 51 nominally significant, and only 15 after Bonferroni correction. As one might expect, the genetic signals of neuroticism correlated with the genetic signals of depressive symptoms (0.82) major depressive disorder (0.69) and subjective well-being (-0.68).

Association analysis in over 329,000 individuals identifies 116 independent variants influencing neuroticism. Nature Genetics.

Far from being a random collection of signals that happen to have got through even the most rigorous controls for multiple comparisons, this bunch make sense in terms of their molecular function, biological process and protein class. There are some demonstrated links with anxiety and depression, and psychiatric disorder generally. Among the 15 replicated SNPs 9 were associated with significant regulation of 60 genes expressed in a variety of tissues. Of the 30 brain expression associations, half were in the cerebellum, with 4 SNPs regulating 10 genes. Notably, magnetic resonance imaging (MRI) studies have shown associations between cerebellar volume and neuroticism as well as cerebellar blood flow in response to negative emotional cues.

Yes, the effect sizes are still small, and other studies will be required to confirm these findings, and to extend them.

In the current climate of genetic research, this will be correctly seen as a big advance in understanding the causes of personality differences. However, earlier in the 20th Century, this would have been dynamite, because the prevailing ideology, fuelled by psycho-analytic theory, was that variously, trauma, seduction and repressed sexuality were the root causes of neuroticism. With rather more evidence, and far less impact on popular culture, Pavlov was on the right track when he surmised that a different balance of excitation and inhibition in the nervous system was what determined the resilience of dogs under stress. Dogs have temperaments, and Pavlov noticed that. Hans Eysenck and Jeffrey Gray extended those insights.

The authors conclude:

There was also support for neuroticism having causal effects on socioeconomic markers. These discoveries promise paths to understanding the mechanisms whereby some people become depressed and broader human differences in happiness, and they are a resource for those seeking novel drug targets for major depression.

After millennia in which scholars and researchers have sought the sources of individual differences in proneness to dysphoria, the present study adds to explanations of the (genetic) anatomy of melancholy.

I wonder if these sorts of research results might one day bring about a cultural change, in which it is accepted that while some people experience more negative events than others, people also differ in their sensitivity to emotional issues.

• Category: Science 
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  1. FKA Max says: • Website

    Just commented on this issue over in another Unz Review comments thread, Mr. Thompson, and how these emotional and genetic differences can even affect IQ test scores, etc., since stress-susceptibility is quite a significant moderating/confounding factor when it comes to stressful test taking conditions, in my opinion.

    23andMe blog summarizes the alleles at this SNP as

    rs4680(A) = Worrier. Met, more exploratory, lower COMT enzymatic activity, therefore higher dopamine levels; lower pain threshold, enhanced vulnerability to stress, yet also more efficient at processing information under most conditions
    rs4680(G) = Warrior. Val, less exploratory, higher COMT enzymatic activity, therefore lower dopamine levels; higher pain threshold, better stress resiliency, albeit with a modest reduction in executive cognition performance under most conditions

    East Asians and Africans, on average, have a competitive advantage under stressful test taking conditions over Caucasians and Mexicans, etc. due to this, in my opinion.

    Distribution of the Val108/158Met polymorphism of the COMT gene in healthy Mexican population

    We observed that Met was the most common allele, ranging from 57% (Tabasco) to 85% (Mexico City). In addition, we analyzed the frequency of Val108/158Met polymorphism of Caucasian (54% Met allele), Asian (29% Met allele) and African (34% Met allele) populations separately and also in comparison with Mexican (63% Met allele) population.
    The pooled results of Caucasian populations showed that the Met allele had a frequency of 54% and Val allele frequency of 46%; the Asian population exhibited a frequency of 29% for the Met allele and 71% for the Val allele, and the African population presented a frequency of 34% for the Met allele and 67% for the Val allele.

    Mr. Kirkegaard thinks that these are “More failed candidate gene ideas.”, but I believe he is jumping to premature conclusion, due to the reasons I stated above:

    There were no substantial COMT Val¹⁵⁸Met effects on cognitive abilities, showing that either the true effect is zero or too small to be uncovered due to insufficient power of the analysis.
    I am not quite convinced that this is another failed candidate gene idea, but rather that this could be more evidence that IQ tests don’t fully test and assess cognitive abilities; I have commented on this before
    IQ tests seem to measure and predict certain things very accurately, e.g., better cognitive performance/functioning under pressure/stress, educational attainment, income, possibly testosterone and dopamine levels, etc., but they do ironically/paradoxically only seem to test “intelligence” to a limited extent

    Performance Under Stress: Are you a Strategist, a Warrior, or a hybrid of the two?


    In case Mr. Kirkegaard is reading this comment; it would be great to get your feedback, sir. Since I don’t have a Twitter account, I was not able to comment on and reply back to your Twitter message that you posted a few days ago on this topic.

    • Replies: @FKA Max
    , @FKA Max
  2. FKA Max says: • Website
    @FKA Max

    Typo: … but I believe he is jumping to premature *conclusions*

    COMT (Catechol-O-Methyltransferase) – What’s The Big Deal?

    In this video, the person interviewed claims/estimates that “worriers/strategists” have a 10 IQ point advantage over “warriors” in non-stressful situations/environments.

    Is your child a worrier or warrior?

    It’s in your child’s genes, says bestselling author Po Bronson. Learn more about the COMT gene and your child’s biological response to stress.

  3. As one might expect, the genetic signals of neuroticism correlated with the genetic signals of depressive symptoms (0.82) major depressive disorder (0.69) and subjective well-being (-0.68).

    And psychosis?

  4. dearieme says:

    “a cultural change, in which it is accepted that … people also differ in their sensitivity to emotional issues”: do you mean that our culture doesn’t accept that at the moment? Really? Am I alone? What about everyone else who believes “it takes all sorts …”?

    Anent different sorts of stresses: I know that long ago I reacted poorly to the stress of having an appalling boss. On the other hand the stress of examinations suited me, and I refer to proper, old-fashioned, taxing British examinations, not superficial tick-boxery. I could speedily demolish problems that would merely have bored or irked me in a tutorial.

    I worked for a spell in the petrochemicals biz: when the alarms sounded I automatically ran towards the source of the trouble, not away. This was not affected manliness, or a result of screwing up my courage, or because I’d thought it out beforehand; it was simply a spontaneous reaction. If I had to rationalise it I’d probably say “because that’s where the interesting stuff was”.

    Funny old world, eh?

    • Replies: @James Thompson
  5. JackOH says:

    I recall reading that depression was a perfectly normal response to an environment that presented overwhelming, irremediable challenges. Something about conserving psychological resources. Can’t recall any details, but it seemed sort of persuasive to this non-expert. I’m sort of sure it was written by a psychiatrist or psychologist.

    dearieme–thanks for that “anent”. A small but real pleasure of Unz Review is reading words that are new to me, or words that I’ve read only rarely. I’m not sure “tick-boxery” or its variants are popular in the UK, but its meaning is immediately clear to me, and it has good punch. I expect to use it if the opportunity comes up.

    • Replies: @dearieme
  6. @dearieme

    There may have been a moiety of exaggeration.

    As to running towards industrial accidents, research on a paint factory fire in Norway showed that trained workers experienced less stress after the explosion. They had some emergency skills, and thus had a coping mechanism, which in some way was also a distraction. That said, stress reactions fell off sharply with distance. My work on the King’ Cross Fire partly confirmed that finding, in that the correlation between stress and exposure (composite of where they were, and how long they were at risk, and whether they saw bodies) was 0.3 but the correlation with neuroticism was also 0.3

  7. dearieme says:

    “tick-boxery”: as far as I know you’ve just seen its launch into the English language. I look forward to the translation into German and French.

    • Replies: @JackOH
  8. In Spanish it would be “garrapata-caja-ismo” from tick (an insect which grabs feet) and box -ism.

    More boringly, it would be “marca de aprobación-caja-trampa (a mark of approbation)-box-trickery

  9. “I wonder if these sorts of research results might one day bring about a cultural change, in which it is accepted that while some people experience more negative events than others, people also differ in their sensitivity to emotional issues.”

    Really? Do we need to send time and money for research on what, for many, is already in the realm of common sense?

  10. JackOH says:

    First attestation is right here! Life is good.:)

    “Sam really doesn’t know much. He just tick-boxed his way to the party chairmanship.”

    Or, I suppose, alternately, it could have a Janus meaning and refer to substantively fulfilling some requirement.

    “The competition for district manager was fierce, but Sue tick-boxed all the mandatory and optional job requirements.”

  11. FKA Max says: • Website
    @FKA Max

    I found some other highly interesting, new research on melancholy, etc:

    Is serotonin an upper or a downer? The evolution of the serotonergic system and its role in depression and the antidepressant response

    The role of serotonin in depression and antidepressant treatment remains unresolved despite decades of research. In this paper, we make three major claims. First, serotonin transmission is elevated in multiple depressive phenotypes, including melancholia, a subtype associated with sustained cognition. The primary challenge to this first claim is that the direct pharmacological effect of most symptom-reducing medications, such as the selective serotonin reuptake inhibitors (SSRIs), is to increase synaptic serotonin. The second claim, which is crucial to resolving this paradox, is that the serotonergic system evolved to regulate energy. By increasing extracellular serotonin, SSRIs disrupt energy homeostasis and often worsen symptoms during acute treatment. Our third claim is that symptom reduction is not achieved by the direct pharmacological properties of SSRIs, but by the brain’s compensatory responses that attempt to restore energy homeostasis. These responses take several weeks to develop, which explains why SSRIs have a therapeutic delay. We demonstrate the utility of our claims by examining what happens in animal models of melancholia and during acute and chronic SSRI treatment.

    Depression: It’s Not Your Serotonin

    by Kelly Brogan, MD

    Andrews goes further to include this interpretation in a long list of arguments against the role of low serotonin in depression (Box 1[see below]).

    So if we cannot confirm the role of serotonin in mood and we have good reason to believe that antidepressant effect is largely based on belief, then why are we trying to “boost serotonin”?

    There are times in our evolution as a cultural species that we need to unlearn what we think we know. We have to move out of the comfort of certainty and into the freeing light of uncertainty.


    Serotonin, genetic variability, behaviour, and psychiatric disorders – a review

    The serotonin transporter polymorphism (5HTTLPR) and the monoamine oxidase A polymorphism (MAOA-LPR) have been implicated in conditions and behaviours such as depression, anxiety, aggression, alcoholism, autism, suicidality, and impulsiveness (9–15).
    A consensus finding from association studies seems to hold that the low-expressing variants of these genes are risk factors for vulnerability to develop psychiatric disorders, conditions associated with reduced serotonergic activity, despite the fact that the low-expressing variants of 5HTTLPR and MAOA-LPR should intuitively promote increased serotonergic activity by keeping extracellular levels of serotonin high. This contradictory relation is further discussed below.

    Serotonin depletion induces ‘waiting impulsivity’ on the human four-choice serial reaction time task: cross-species translational significance.

    Here, serotonin depletion was induced by the dietary tryptophan depletion procedure (TD) in healthy volunteers to examine the role of serotonin in impulsive action and impulsive choice.
    There was no effect of TD on impulsive choice as indexed by the reward delay-discounting questionnaire.
    TD also improved the accuracy of performance and speeded responding, possibly indicating enhanced attention and reward processing.

    High-activity MAO-A breaks down dopamine, serotonin, etc.
    Low-activity COMT means higher dopamine levels, but not higher serotonin levels.
    The most ideal combination, in my opinion, for non-insane genius is high-activity MAO-A and low-activity COMT, high dopamine levels but low serotonin levels, European-derived populations have the highest frequency of this combination:

    Northern Europeans are the group with the highest percentage of “worrier pacifists” (35.75%), followed by Ashkenazi Jews (20%), and Africans and East Asians have the lowest percentage (13.5%) of “worrier pacifists” in their populations.

  12. FKA Max says: • Website
    @FKA Max

    The bright side of being blue: Depression as an adaptation for analyzing complex problems

    Anti-depressants likely do more harm than good, researchers find

    Paul Andrews, assistant professor of psychology, neuroscience & behaviour, is the lead author of a new journal article that describes why anti-depressant medication appears to do more harm than good.

    What doesn’t kill you makes you stronger – it’s just that some things kill you

    Lecture by Paul W. Andrews, PhD, JD (McMaster University).

    Introduction by J. Anderson Thomson, Jr., MD (University of Virginia, Author of “Why We Believe in Gods”) Website:

    Recorded at McMaster University on January 22, 2016 as part of the Discover Psychology lecture series.

    I was trained in behavioral ecology at the University of New Mexico (UNM), Department of Biology, but I am somewhat unusual in that I worked on human behavior and psychology as part of my PhD dissertation. So I may call myself a behavioral ecologist, an evolutionary biologist, or an evolutionary psychologist, depending on the situation.

    My primary research interest is understanding the evolution of depression. Andy Thomson and I published a paper in Psychological Review that argues depression is an evolved emotional response to complex problems, and its function is to promote changes in body systems that promote analysis of those problems.

  13. Anon • Disclaimer says:

    I wonder if these sorts of research results might one day bring about a cultural change, in which it is accepted that while some people experience more negative events than others, people also differ in their sensitivity to emotional issues.

    Like there is an IQ, there is a S(ensitivity) Quotient.
    One only needs be not too low on it to know that it is there.

    As for this reality being accepted by society and mainstream culture, it will when and if it will turn useful towards wider interests and aims of society and mainstream culture. Not in a short time, if ever.

  14. I’ll have a go at the Danish translation…

    “ikke overfladisk fluebeneri”, perhaps.

    Checkmark = flueben (flea’s leg). “Ikke” = not, “overfladisk” = superficial. “-eri” turns the noun into a verb.

    It has the benefit of sounding a bit like “flueknepperi” (flea fucking), a word for wasting a lot of time and effort on minor and irrelevant things.

  15. @FKA Max

    Depression is not melancholy.

    Melancholy is a pre-state or heterogeneously emotional state of depression, in my view.

    Melancholy is more related with ”existential depression” than with more-personally-related-depression.

    Creativity and psychotic spectrum are both also related with ”global brain hyperconnectivity” [and autism with localized hyperconnectivity, based on what i read in ”The Imprinted Brain section” on Psychological Today.

  16. @FKA Max

    Depression itself, conceptually speaking, is not a adaptation, it’s a over or a sub-adaptation, when certain set of traits in-combination surpass their functioning [ in the case of depression over-worrying].

    Depression//neuroticism related-traits in balanced functioning [itself above average in intensity] it’s logically likely to become useful to survive, even as a intellectual tool [for example, fear of massified immigration improving the capacity to understand related-issues].

    Depression is the asynchrony between intensity and quality or functioning. The intensity is too high to its functioning = mental disturbance.

  17. FKA Max says: • Website
    @FKA Max

    These discoveries promise paths to understanding the mechanisms whereby some people become depressed and broader human differences in happiness, and they are a resource for those seeking novel drug targets for major depression.

    Study found via Unsilenced Science‘s Twitter account: His comment “Maybe scientists should not study only SNPs. Maybe they should complete their research on repeat polymorphisms of neurotransmitter genes, like #MAOA.”

    Childhood behaviour problems show the greatest gap between DNA-based and twin heritability

    We estimated twin and SNP heritabilities for diverse domains of childhood behaviour problems as rated by parents, teachers, and children themselves at ages 12 and 16 in a large UK-representative sample. We found surprisingly low SNP heritability estimates (average 6%) in comparison to twin heritabilities (average 52%). This is particularly striking given that SNP-based estimates were half those of twin-based estimates for anthropomorphic and cognitive measures.


    Speaking of pharmaceutical companies. I just posted a comment on another potential contributor to this negative trend mentioned in this article on one of Mr. Thompson’s other articles. Maybe “Big Pharma” is causing the rot?

    These serotonin level-increasing ( SSRI ) antidepressants produce “warrior gene”/psychopathic societies

    This might be a better way forward?

    Why ‘big pharma’ stopped searching for the next Prozac

    In terms of advances that have the potential to significantly change treatment, there is a new wave of “fast-acting” drugs for depression, and all eyes are on ketamine. Although it is an old drug, recent research with ketamine has shown it to have powerful antidepressant effects. Early studies found patients with depression who had tried multiple antidepressants without success saw quick, positive effects from ketamine. A number of firms including Johnson & Johnson are in late-stage trials for ketamine-based medicines.

    Assessment of Ketamine Binding of the Serotonin Transporter in Humans with Positron Emission Tomography

    Measurable occupancy of the serotonin transporter was not detectable after administration of an antidepressant dose of ketamine. This might suggest that ketamine binding of the serotonin transporter is unlikely to be a primary antidepressant mechanism at routine antidepressant doses, as substances that facilitate antidepressant effects via serotonin transporter binding (e.g., selective serotonin reuptake inhibitors) show 70% to 80% occupancy.

    • Replies: @Santoculto
    , @Santoculto
  18. @FKA Max

    Maybe because people with developmental issues tend to come from phenotypically [high familial mutational load] diverse families.

  19. “an un-returned Christmas greeting provoking justifiable depression in a former acquaintance who then turns to drink, and crashes his car into a pedestrian who happens to be the only person capable of saving us from a world-wide bird-flu pandemic, thus leading to the end of humanity.”

    I was really hoping that twitter thread would be a litany of similar “what if” examples.

    • Replies: @James Thompson
  20. @FKA Max

    Depression is a dead end of introspection specially existential depression. Melancholy and introspection are strongly related one each other.

  21. Melancholy and introspection are strongly related one each other.

    The most clear-sighted Germans I know of – knew a lot about depression and/ or melancholia.
    A bug and a feature, I’d hold.

    Oh, those two men: The painters Caspar David Friedrich and Albrecht Dürer.

    cf. Dürer’s “Melancholia” and his famous quote:”Perfection is not within reach for our dumb consciousness.”

    Here’ a decent reproduction of Dürer’s “Melancholia” engraving:

    • Replies: @Santoculto
  22. @Dieter Kief

    I often believe that melancholy//introspection is a state between too-much-domestication [ignorance is a bliss] and too-much-instinctive-mode, a kind of ”real or original state of self-aware mind”.


    Off topic

    It can be translated to English

    My comment as well

    Final verdict: “Japanese cultural values” are “superior” than ” ‘iberian’ ones”…

  24. @James Thompson

    I think your original “what if” example may have scared off competitors with its intensity.

    Sure someone could go even more apocalyptic but there are 5 billion or so people connected to the internet, right?, and why would anyone want to top your scenario?

    So – (science) I could have married that clever girl with the bad haircut but I married the cuter girl with a good haircut, we had a couple kids, but me and the clever girl with the bad haircut would have had the kid who figured out how to save this universe (this universe which will not be here, a generation or two from now, because of my romantic choices) by decoding the informational insurrection by another confrontational universe that was hidden to everybody else in the places only he (our hypothetical child, the child of me and the girl with the bad haircut, for which I did not date her and consequently did not marry her) would have known about and understood … knew about and understood … would have known about and understood …

    So – (philosophy) the ultimate project of German Romantic Philosophy was not ultimately achieved (Good!) because I talked my college roommate into changing his double major from Philosophy and Slavic Literature and Linguistics, to a single major in Anthropology (he is now an accomplished Talk Radio figure), and he never met that cute chick in Philosophy 301 (Hegel and his Influence) whose kid (with him as the father) would have completed the Kant-Hegel continuum, to all our sorrow (Good!)

    So – (religion) You know that chapter in the Apocalypse where (x) does (y) and (x) would never have been born if (The narrator) had gotten too excited, in the moment, to write down the right phone number of the woman who would have been the eventual mother of (x), clubbing one night, a generation before that …. Had he written down that phone number, the world would end in, let us say, 2278. He did not, and the world will not end until long long after the heat death of the universe, not that it makes much difference, when you look at it that way … 2278, on the one hand, the heat death of all the universe, after all those trillions of years – there is not all that much difference, from the point of view of all of us who were created by God, who laughs at the trillions of years, and laughs at the heat death of the universe, the way a child laughs at the state fair, watching the cotton candy being spun out, knowing that soon all that pink and orange goodness, that which is so wished for, will be, as we learn in Proverbs 8, (will be) evident, and more than evident. I remember, and if I don’t (but I do) I wish I remembered.

    • Replies: @James Thompson
  25. @middle aged vet . . .

    Great comment. If only you had found a literary agent much sooner, then……….

  26. Thanks for the compliment, it is particularly appreciated since I have been interested in your view of the world from long before your Unz days.
    I actually did find a helpful literary agent when I was in my 30s, and I had a novel ready to go, but, like a lot of people who now post on the internet, I wanted to say whatever I wanted to say to people who could talk back. Cor ad cor loquitur, and all that. I did not send in the novel.
    The pool of really good writers my age is just about the same size now as it would have been if I had tried to join it. Also, I did not want my friends to think of me as a ‘writer’. I had a near death experience in 1986 and after that I had different ambitions. I would have lost, in a way, a few friends if I had become even an ‘obscure writer’ and I did not want to do that.
    No regrets.

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