Ketamine for Depression: Yay or Neigh?

Venn diagram of psychoactive drugs [click for larger image]

NOTE: This post is part of a Nature Blog Focus on hallucinogenic drugs in medicine and mental health, inspired by a recent Nature Reviews Neuroscience paper, The neurobiology of psychedelic drugs: implications for the treatment of mood disorders, by Franz Vollenweider & Michael Kometer. This article will be freely available, with registration, until September 23. For more information on this Blog Focus, see the Table of Contents.

The secret history of psychedelic psychiatry is discussed over at Neurophilosophy. Neuroskeptic covers Serotonin, Psychedelics and Depression while Mind Hacks provides a personal look at yagé in Visions of a psychedelic future.


Veterinary Anesthetic, Club Drug, or Antidepressant?

Club drug "Special K" (aka ketamine) is stepping out of the laser light into the broad daylight of mainstream psychiatry with the publication of a new review article by Vollenweider and Kometer (2010). Long used to anesthetize animals (and children), ketamine was classified as a "dissociative anesthetic" by Domino et al. (1965) for its combined effects of sedation/analgesia and hallucinations. Domino (2010) recently revisited his classic paper, which reported on a study in 20 volunteers incarcerated at the Jackson Prison in Michigan:

The first human was given ketamine in an intravenous subanesthetic dose on August 3, 1964. Guenter [Corssen, M.D.] and I gradually increased the dose from no effect, to conscious but “spaced out,” and finally to enough for general anesthesia. Our findings were remarkable! The overall incidence of side effects was about one out of three volunteers. Frank emergence delirium was minimal. Most of our subjects described strange experiences like a feeling of floating in outer space and having no feeling in their arms or legs.

The ego death of the "K hole" can be a terrifying experience for some ("I ceased to exist") or transformative for others ("I witnessed myself as a part of the universal collective of strange energy")¹. In their Nature Reviews Neuroscience opinion piece, Vollenweider and Kometer considered ketamine a psychedelic, along with the traditional hallucinogens such as LSD, psilocybin, and mescaline. They noted that both classes of drugs may have psychotherapeutic effects through actions on the excitatory glutamate neurotransmitter system.

Ketamine is an antagonist of the glutamate NMDA receptor and is thought to work by blocking NMDA receptors on inhibitory GABA-containing interneurons, ultimately promoting glutamate release. In a scientific tour de force, Li and colleagues (2010) demonstrated that the mTOR (mammalian target of rapamycin) protein kinase pathway is rapidly activated by ketamine. This sets off a cascade of events including the formation of new synapses on dendritic spines. Using a combination of cellular, molecular, electrophysiological, behavioral, and phamacological techniques, ketamine was shown to exhibit antidepressant properties in animal models of depression and anxiety, perhaps via rapid induction of synaptic plasticity in the medial prefrontal cortex (PFC). Regions of the medial PFC in humans, particularly the ventral anterior cingulate cortex, have been implicated in the pathophysiology of major depression.

Human clinical trials of ketamine as a rapidly acting antidepressant aren't especially new. A randomized, double-blind study in 2000 involved administration of saline or a single subanesthetic dose of ketamine (0.5 mg/kg intraveneously) to nine depressed patients, seven of whom completed the trial (Berman et al., 2000). Within 72 hrs, amelioration of depressive symptoms was observed. Half of the treated patients showed a 50% or greater improvement in depression scores. However, these therapeutic effects weren't very long-lasting, returning to baseline levels in 1-2 weeks. In a larger study, 18 patients with major depression participated in a similar double-blind cross-over design where they received the 0.5 mg/kg dose of ketamine and placebo one week apart (Zarate et al., 2006). The patients were rated at baseline and at 40, 80, 110, and 230 minutes and 1, 2, 3, and 7 days post-infusion on a number of clinical scales, including the Hamilton Depression Rating Scale (HDRS), the Brief Psychiatric Rating Scale (BPRS) positive symptoms subscale, and the Young Mania Rating Scale (YMRS).

The primary outcome measure was change in HDRS score, shown in Figure 2 below (top graph). Significant improvements began at the 110 min time point. Scores declined further from 1-3 days and remained below placebo levels for 7 days. However, unusual experiences were noted at 40 min, with substantial increases in scores for psychosis-like and mania-like symptoms. Other adverse events associated with ketamine included...

...perceptual disturbances, confusion, elevations in blood pressure, euphoria, dizziness, and increased libido. ... The majority of these adverse effects ceased within 80 minutes after the infusion. In no case did euphoria [YMRS] or derealization/depersonalization [BPRS] persist beyond 110 minutes (Figure 2, middle and bottom graphs).

Figure 2 (Zarate et al., 2006). Change in the 21-item HDRS, BPRS positive symptoms subscale, and YMRS scores over 1 week (n=18). Values are expressed as generalized least squares means and standard errors for the completer analysis. * indicates P<.05; †, P<.01; ‡, P<.001.

So here we have several research groups that say yay! to ketamine as an antidepressant. Are there any naysayers?

Although the immediate onset of symptom amelioration gives ketamine a substantial advantage over traditional antidepressants (which take 4-6 weeks to work), there are definite limitations (Tsai, 2007). Drawbacks include the possibility of ketamine-induced psychosis (Javitt, 2010), limited duration of effectiveness (aan het Rot et al., 2010), potential long-term deleterious effects such as white matter abnormalities (Liao et al., 2010), and an inability to truly blind the ketamine condition due to obvious dissociative effects in many participants.

At present, what are the most promising uses for ketamine as a fast-acting antidepressant? Given the disadvantages discussed above, short-term use for immediate relief of life-threatening or end-of-life depressive symptoms seem to be the best indications.


Suicidal Ideation

Acute ketamine treatment in suicidal patients presenting at the ER has the potential to provide immediate changes in the risk that a patient will harm herself when released, when accompanied by proper followup and appropriate long-term treatment. An open label study in 33 patients with refractory depression involved infusion of 0.5 mg/kg ketamine over a period of 40 min (DiazGranados et al., 2010). Those with high scores on the Scale for Suicide Ideation showed significant improvements at 40 min that were maintained for the 230 min duration of the study. Obviously, one would like to follow actively suicidal patients for a longer period of time than 4 hrs, and future clinical trials should take this into account.


Palliative Care

Watching a terminally ill loved one suffer from unbearably excruciating pain is one of the most emotionally wrenching experiences you'll ever have. Anything, and I mean anything², that will relieve this sort of suffering should be freely administered without reservation or stigma. As discussed in The secret history of psychedelic psychiatry, psilocybin has been shown to alleviate anxiety and pain in cancer patients. Reports of psychedelic psychotherapy in the 60s and 70s suggested that many patients overcame their fear of death through LSD-facilitated sessions. More recently, an open label study in two hospice patients, each with a prognosis of only weeks or months to live, showed beneficial effects of ketamine in the treatment of anxiety and depression (Irwin & Iglewicz, 2010). A single oral dose produced rapid improvement of symptoms and improved end of life quality. To disentangle the pain relieving and antidepressant effects of ketamine, the authors emphasized the importance of conducting clinical trials for this particular indication.


Better Drugs for a Brighter Tomorrow

Newer NMDA antagonist drugs with fewer dissociative side effects (e.g., more selective antagonists such as NR2B receptor blocker EVT 101) are undergoing testing and development. Personalized medicine and pharmacogenomics may ultimately shift psychedelic experiences out of the realm of hippies and into the doctor's arsenal.


ADDENDUM: Moheb Costandi summarizes all four posts in this article for The Guardian, and there's more coverage at The Great Beyond, 3 Quarks Daily, The Atlantic, and Boing Boing.



Footnotes

¹ Personal communication and Erowid Experience Vault.

² Heroin.


References

aan het Rot M, Collins KA, Murrough JW, Perez AM, Reich DL, Charney DS, Mathew SJ. (2010). Safety and efficacy of repeated-dose intravenous ketamine for treatment-resistant depression. Biol Psychiatry 67:139-45.

Berman RM, Cappiello A, Anand A, Oren DA, Heninger GR, Charney DS, Krystal JH. (2000). Antidepressant effects of ketamine in depressed patients. Biol Psychiatry 47:351-4.

DiazGranados N, Ibrahim LA, Brutsche NE, Ameli R, Henter ID, Luckenbaugh DA, Machado-Vieira R, Zarate CA Jr. (2010). Rapid resolution of suicidal ideation after a single infusion of an N-methyl-D-aspartate antagonist in patients with treatment-resistant major depressive disorder. J Clin Psychiatry. Jul 13. [Epub ahead of print]

Domino EF. (2010). Taming the ketamine tiger. Anesthesiology 113:678-84.

Domino EF, Chodoff P, Corssen G. (1965). Pharmacologic Effects of CI-581, a New Dissociative Anesthetic, in Man. Clin Pharmacol Ther. 6:279-91.

Irwin SA, Iglewicz A. (2010). Oral ketamine for the rapid treatment of depression and anxiety in patients receiving hospice care. J Palliat Med. 13:903-8.

Javitt DC. (2010). Glutamatergic theories of schizophrenia. Isr J Psychiatry Relat Sci. 47:4-16.

Li N, Lee B, Liu RJ, Banasr M, Dwyer JM, Iwata M, Li XY, Aghajanian G, Duman RS. (2010). mTOR-dependent synapse formation underlies the rapid antidepressant effects of NMDA antagonists. Science 329(5994):959-64.

Liao Y, Tang J, Ma M, Wu Z, Yang M, Wang X, Liu T, Chen X, Fletcher PC, Hao W. (2010). Frontal white matter abnormalities following chronic ketamine use: a diffusion tensor imaging study. Brain 133:2115-22.

Tsai GE. (2007). Searching for rational anti N-methyl-D-aspartate treatment for depression. Arch Gen Psychiatry 64:1099-100; author reply 1100-1.

Vollenweider, F., & Kometer, M. (2010). The neurobiology of psychedelic drugs: implications for the treatment of mood disorders Nature Reviews Neuroscience, 11 (9), 642-651 DOI: 10.1038/nrn2884

Zarate CA Jr, Singh JB, Carlson PJ, Brutsche NE, Ameli R, Luckenbaugh DA, Charney DS, Manji HK. (2006). A randomized trial of an N-methyl-D-aspartate antagonist in treatment-resistant major depression. Arch Gen Psychiatry 63:856-64.

Dedication:

For my father.

Lou Gehrig Probably Died of Lou Gehrig's Disease

OR: Why news embargoes are bad for science.

In an example of mainstream reporting that is aptly described as a "jumbled ball of confusion", the New York Times claimed that baseball player Lou Gehrig (who died in 1941 and whose remains were cremated) might not have had Lou Gehrig's disease:

A peer-reviewed paper to be published Wednesday in a leading journal of neuropathology, however, suggests that the demise of athletes like Gehrig and soldiers given a diagnosis of amyotrophic lateral sclerosis, commonly known as Lou Gehrig’s disease, might have been catalyzed by injuries only now becoming understood: concussions and other brain trauma.

Although the paper does not discuss Gehrig specifically, its authors in interviews acknowledged the clear implication: Lou Gehrig might not have had Lou Gehrig’s disease.

Amyotrophic lateral sclerosis (ALS) is a horrible progressive disease that causes the degeneration of motor neurons that control the muscles. Patients with ALS gradually lose the ability to walk, eat, and breathe on their own. This can happen in a relatively short amount of time (Mitchell & Borasio, 2007):

The clinical features of amyotrophic lateral sclerosis are indicative of the loss of neurons at all levels of the motor system—from the cortex to the anterior horn of the spinal cord. Physical signs of this disorder thus encompass both upper motor neuron and lower motor neuron findings. Objective sensory findings are incompatible with a diagnosis of amyotrophic lateral sclerosis unless they can be accounted for by neurological comorbidity. The course of the disorder is inexorably progressive, with 50% of patients dying within 3 years of onset.

Gehrig died two years after his diagnosis.

What is the evidence that Gehrig might have died from brain trauma and not ALS? According to the New York Times, the forthcoming paper in the Journal of Neuropathology & Experimental Neurology presents postmortem findings from three patients:

...markings in the spinal cords of two players and one boxer who also received a diagnosis of A.L.S. indicated that those men did not have A.L.S. at all. They had a different fatal disease, doctors said, caused by concussionlike trauma, that erodes the central nervous system in similar ways.

From that limited evidence we see extrapolation to a dead sports hero who suffered a number of concussions during his playing career. Gary Schwitzer's HealthNewsReview Blog provides an excellent summary of what was wrong with this coverage, and I suggest you read beyond the excerpt below:

NYT's unfounded leap: Lou Gehrig might not have had Lou Gehrig's disease

This was one time when the headline was OK, but the story that followed had our heads spinning. "Study Says Brain Trauma Can Mimic Lou Gehrig's Disease" is a story that was troubling on a number of fronts. It reported on a study which at the time had not yet been published suggesting that some "athletes and soldiers given a diagnosis of amyotrophic lateral sclerosis...might have been catalyzed by injuries only now becoming understood: concussions and other brain trauma."

To be clear - and please don't anyone miss or miscontrue this point - this is an important and fascinating area of research.

But the story did not exhibit the best of health/medical/science journalism.

Why is it bad that the study has not yet been published? Because experts in the field are not able to read the article and report on what it actually showed. Because the news coverage gets worse, much worse. As in this outright lie printed by The Guardian:

Lou Gehrig killed by baseball not Lou Gehrig's disease, study finds

Player who gave his name to a type of motor neurone disease more probably died due to brain trauma

On the other hand, here's the more modest press release from the journal publisher:

Head Trauma in Pro Athletes Linked to Motor Neuron Disease

Released: 8/17/2010 11:50 AM EDT
Source: Wolters Kluwer Health: Lippincott Williams & Wilkins

Football Players and Boxers with ALS-Like Condition Show Specific Patterns of Protein Deposits in Brain

Newswise — Professional athletes with repetitive head trauma—and possibly others with a history of head injuries many years previously—may be prone the development of a motor neuron disease similar to amyotrophic lateral sclerosis (ALS or "Lou Gehrig's disease"), reports a study in the September Journal of Neuropathology & Experimental Neurology, official journal of the American Association of Neuropathologists, Inc...

"This is the first pathological evidence that repetitive head trauma experienced in collision sports might be associated with the development of a motor neuron disease," according to the study by Dr. Ann C. McKee of Boston University School of Medicine and colleagues.

Specific Brain Abnormalities Linked to Motor Neuron Disease in Athletes with Head Trauma
The researchers used sophisticated neuropathology techniques to study specific proteins, called tau and TDP-43, in brains obtained at autopsy from twelve former athletes. Eleven of the athletes had been professional football players or boxers; one was a hockey player.

The study actually included neuropathological findings from 12 brains {all 12 had chronic traumatic encephalopathy, but only 3 had ALS}. The embargoed paper is likely to be very good research on an important topic. In addition, there is good evidence that mild traumatic brain injury IS a risk factor for neurodegeneration, as shown by the same group of investigators (Gavett et al., 2010).

The overblown and downright erroneous claims propagated by the press are unfortunate. Will more people read, click, and buy [and fund research] if the name of a historical baseball figure is invoked? I guess so. Some of the blame must be shared by the senior author of the paper, Dr. Ann McKee, who offered up the following quotes in an interview:

“Here he is, the face of his disease, and he may have had a different disease as a result of his athletic experience.”

. . .

“If we can create this in laboratory mice, which are easily genetically altered and breed quickly, we can learn about the pathogenesis of this disorder, and then provide treatment,” Dr. McKee said.

Three postmortem cases --> genetically altered mice --> treatment.

Uh, aren't we jumping the gun just a bit? Even though the chronic traumatic encephalopathy (CTE) variant of ALS-like disease may have a different etiology, drug development will not be easy. According to the ALS Association:

Present treatment of ALS includes one drug, riluzole (Rilutek©) and is aimed at symptomatic relief, prevention of complications and maintenance of maximum optimal function and optimal quality of life. Most of this, in the later stages, requires substantial physical caregiving. Click here for more information on Rilutek.

For information on drug development and clinical trials, click here.

Riluzole slows the progression of ALS but is not a cure. Neurodegenerative diseases exact a terrible toll on patients and their families. Sufficient funding for the development of effective treatments is of critical importance. But do we have to warp the news coverage to obtain such funding? Such is the sorry state of scientific research today.

References

Gavett BE, Stern RA, Cantu RC, Nowinski CJ, McKee AC. (2010). Mild traumatic brain injury: a risk factor for neurodegeneration. Alzheimers Res Ther. 2:18.

Mitchell JD, Borasio GD. (2007). Amyotrophic lateral sclerosis. Lancet 369:2031-41. Review.

Airplane Headache

Cartoon Reenactment of JetBlue Flight Attendant’s Dramatic Exit

No, the term "airplane headache" does not refer to disgruntled JetBlue flight attendant Steven Slater (or to being a passenger on that flight). Instead, it refers to a recently characterized type of headache that occurs during take-off and landing (Atkonson & Lee, 2004). The pain appears to be unique to plane travel and not associated with other conditions. Neurological exam and brain imaging results in all published cases (n=14) have been normal. A new case study of a man with airplane headaches has been reported by Domitrz (2010). Clinical details are as follows:

A 29-year-old healthy man, who works as a psychologist, reported that during his last airplane journey, he developed a very severe and sudden jabbing headache located in the left frontal region with radiation into the left eye. It started during take-off, diminished during the 2-h flight, a very mild pain was present during the flight and increased during plane’s descent and lasted until a few minutes after landing. Then, the pain completely and spontaneously subsided. The same situation took place 3 days later when the patient was returning. He remembers that he had similar, but milder headaches during previous flights. However, they occurred only during airplane flights and did not develop during jumbo jet flights. Similar headache did not appear in other altitude variation moments, e.g. in mountain trips. The pain was always located in the left frontal region with radiation into the left eye without any autonomic symptoms and neurological focal problems. He could not move until the headache disappeared. The patient has no medical history of sinus problems and using any medications. The family history has shown only tension type headache in patient’s 4 years older sister. General (including blood pressure and heart rate), neurological, otolaryngological and ophthalmological examinations were normal. Brain magnetic resonance imaging also with angiography excluded any structural lesions and arterial malformations.

Domitrz (2010) further notes that most reported cases have been in young males, as is her patient. She is also puzzled by why he gets these headaches only on airplanes that are not jumbo jets -- perhaps it is connected with differences in air pressure, she speculates. What causes this specific type of headache? One view is that barotrauma is involved, with pressure changes affecting the trigeminovascular system (Berilgen & Müngen, 2006):

We think that barotrauma caused by pressure changes in the cabin during take-off and landing could affect ethmoidal nerves (branching from the ophthalmic branch of the trigeminal nerve) that carry the senses of the mucosa on the inner surface of the paranasal sinuses, and/or nociceptors in ethmoidal arteries, thereby activating the trigeminovascular system and leading to headache.

It's enough to make someone attempt an emergency exit! ADDENDUM (added July 24, 2011): A new paper found that triptan drugs (used to treat migraines and cluster headaches) may be effective in preventing airplane headaches (Ipekdal et al., 2011). The abstract is reprinted below.

Ipekdal HI, Karadaş O, Oz O, Ulaş UH. Can triptans safely be used for airplane headache? Neurol Sci. 2011 May 10. [Epub ahead of print]. A few cases of airplane headache (AH) have been reported in the literature. Treatment strategies of AHs are also controversial. We followed-up five patients with AH. They were symptom-free during the daytime. Their physical, neurological, and ear-nose-throat examinations were all normal. Blood chemistries, cerebral magnetic resonance imaging, cerebral magnetic resonance imaging angiography, and paranasal sinus tomography studies of the patients were also normal. We preferred triptans because of the possible effect on the mechanism of AH. Patients were recommended to use single-dose of their drugs half an hour prior to flights. All of the patients had a good response to single dose triptan treatment and became headache-free during flights. This is the first study which puts forward the usefulness of the triptans as a safe treatment choice for airplane AH.

References Atkonson V, Lee L. (2004). An unusual case of an airplane headache. Headache 44:438–439 Berilgen MS, Müngen B. (2006). Headache associated with airplane travel: report of six cases. Cephalalgia 26:707-11. Domitrz, I. (2010). Airplane headache: a further case report of a young man. The Journal of Headache and Pain DOI: 10.1007/s10194-010-0245-9

A Concise Critique of the Methods Used in the Personality Genetics Paper

The previous post, Bad News for the Genetics of Personality, discussed a genome-wide association study that searched for common genetic variants associated with personality ratings from Cloninger's temperament scales. None were found:

Participants' scores on Harm Avoidance, Novelty Seeking, Reward Dependence, and Persistence were tested for association with 1,252,387 genetic markers. We also performed gene-based association tests and biological pathway analyses. No genetic variants that significantly contribute to personality variation were identified, while our sample provides over 90% power to detect variants that explain only 1% of the trait variance. This indicates that individual common genetic variants of this size or greater do not contribute to personality trait variation, which has important implications regarding the genetic architecture of personality and the evolutionary mechanisms by which heritable variation is maintained.

The post discussed possible problems with the Tridimensional Personality Questionnaire but remained agnostic on the GWA aspects of the paper:

[Those technical and statistical methods are beyond the scope of this blog, so I will leave it to someone else to describe and critique the genotyping aspects of the paper.]

A comment at Gene Expression on Heritability, personality, and genomics by Princeton Professor Lee M. Silver criticized the methods used by Verweij et al. (2010):

20. LeeMSilver Says:
August 10th, 2010 at 8:04 am

If you read the original article describing the research, you’ll find numerous serious problems with the way the study was conducted. The GWAS approach is designed to work with a sample of unrelated individuals. But the sample set used by Wray and colleagues consisted of 5117 subjects, who only came from 2567 families. The sample set also included 1702 monozygotic twins (797 pairs), and it also included an entire cohort of people diagnosed with bipolar disorder. All of this substructure can muddy the waters, which seems to be perfectly fine to Wray and colleagues whose language gives away their bias against GWAS.

However, the really fundamental problem is the subjective complexity of all the traditional scales for measuring personality. For thousands of years, breeders tried to find patterns in heredity, with no success. Mendel succeeded not by stuffing multiple measurements into individual traits but by eliminating all the variables except one or two in each experiment. This won’t get you the genes for “harm avoidance” (which has no objective meaning) but it could uncover loci that influence the response to one important question in the harm avoidance panel, before investigating the next.

ADDENDUM: Authors Karin Verweij and Brendan Zietsch have replied to Lee Silver in the comments. Briefly, they pointed out that their analysis did take into account relatedness between family members, including monozygotic twins. They also noted that the small subsample with high vs. low depression scores was treated appropriately in the analysis. Furthermore, these high depression individuals were not diagnosed with bipolar disorder.

Besides his critique that the population was not suitable for GWAS, Professor Silver also raised a good point on reducing traits or temperaments to their constituent elements. For starters, Harm Avoidance has four subscales:

1. Anticipatory worry (HA1)
2. Fear of uncertainty (HA2)
3. Shyness/Shyness with strangers (HA3)
4. Fatigability/Fatigability and asthenia (HA4)

The same is true for Novelty Seeking, except the subscales seem even more diverse:

1. Exploratory excitability (NS1)
2. Impulsiveness (NS2)
3. Extravagance (NS3)
4. Disorderliness (NS4)

LMK made similar points in a comment on The Neurocritic's previous post. There are a number of other interesting observations, including a link to Kevin Mitchell on Nature, Nurture, and Noise. And we also have Genomes Unzipped Setting the record straight on Genetic Heterogeneity of Human Disease. So head over there and keep the conversation going. As for me, I'm still 8 comments behind...

Reference

Verweij KJ, Zietsch BP, Medland SE, Gordon SD, Benyamin B, Nyholt DR, McEvoy BP, Sullivan PF, Heath AC, Madden PA, Henders AK, Montgomery GW, Martin NG, Wray NR. (2010). A genome-wide association study of Cloninger's Temperament scales: Implications for the evolutionary genetics of personality. Biol Psychol. Aug 3. [Epub ahead of print].

Bad News for the Genetics of Personality

CREDIT: RYAN SNOOK (from Holden, 2008).


The latest search for genetic variants that underlie differences in personality traits has drawn a blank (Verweij et al., 2010). The researchers conducted a genome-wide association study using personality ratings from Cloninger's temperament scales in a population of 5,117 Australian individuals:

Participants' scores on Harm Avoidance, Novelty Seeking, Reward Dependence, and Persistence were tested for association with 1,252,387 genetic markers. We also performed gene-based association tests and biological pathway analyses. No genetic variants that significantly contribute to personality variation were identified, while our sample provides over 90% power to detect variants that explain only 1% of the trait variance. This indicates that individual common genetic variants of this size or greater do not contribute to personality trait variation, which has important implications regarding the genetic architecture of personality and the evolutionary mechanisms by which heritable variation is maintained.

But it's still fun and popular for some science writers to assert that personality traits are "hard wired" into our brains, like there's really A Brain Circuit for Bungee Jumping? [thanks for the exciting new info, ScienceNOW.] In reality, some of the major early findings in personality genetics, such as an association between Novelty Seeking and the Dopamine D4 Receptor gene (Benjamin et al., 1996; Ebstein et al., 1996), have failed to replicate (Gelernter et al., 1997; Paterson et al. 1999; Strobel et al., 2002). Fortunately, others writers have pointed out the increasingly obvious difficulties of this endeavor, as did Constance Holden in Parsing the Genetics of Behavior:

For some of us, it's satisfying to attribute social awkwardness to anxiety genes or to think that the driver who cuts off other cars as he zips across lanes is pumped up by the "warrior" gene. Was it a bad dopamine receptor gene that made author Ernest Hemingway prone to depression? Can variations in a vasopressin receptor gene--a key to monogamy in voles--help explain adulterous behavior?

But as scientists are discovering, nailing down the genes that underlie our unique personalities has proven exceedingly difficult. That genes strongly influence how we act is beyond question. Several decades of twin, family, and adoption studies have demonstrated that roughly half of the variation in most behavioral traits can be chalked up to genetics. But identifying the causal chain in single-gene disorders such as Huntington's disease is child's play compared with the challenges of tracking genes contributing to, say, verbal fluency, outgoingness, or spiritual leanings. In fact, says Wendy Johnson, a psychologist at the University of Edinburgh, U.K., understanding genetic mechanisms for personality traits "is one of the biggest mysteries facing the behavioral sciences."

Nonetheless, unscrupulous businesses like My Gene Profile (which offers the "Inborn Talent Genetic Test" for the low low price of $1,397) have capitalized on the public's desire for simple explanations. Now you can find out whether your child has the Split Personality Gene! The Propensity for Teenage Romance Gene! The Self Detoxifying Gene!

Returning to the current study, the authors cast a genome-wide net to find genetic variants related to the four dimensions of temperament identified by Cloninger in his Temperament and Character Inventory (TCI), a 240 item self-report questionnaire. As described by Verweij et al., (2010):

Novelty Seeking reflects the tendency to respond strongly to novelty and cues for reward as well as relief from punishment, and is thought to play a role in the activation or initiation of behaviours. Harm Avoidance reflects the tendency to respond strongly to aversive stimuli, which leads to learned inhibition of behaviour, and is thought to play a role in the inhibition or ceasing of behaviours. Reward Dependence reflects the tendency to react strongly to rewards and to maintain behaviours previously associated with reward or relief of punishment, and is thought to play a role in the maintenance or continuation of behaviour. Persistence reflects the tendency to persevere despite frustration and fatigue.

The participants completed a short form of Cloninger's (1986) original Tridimensional Personality Questionnaire (TPQ).¹ The fourth dimension of temperament -- Persistence -- was constructed using a small subset of the Reward Dependence questions. The 1986 version of Cloninger's biosocial theory of personality associated Novelty Seeking with low dopamine activity, Harm Avoidance with high serotonin activity, and Reward Dependence with low noradrenaline activity. These were thought to be independent and heritable aspects of personality that influence responses to reward, punishment, and novelty. The TPQ was later revised to include Persistence and also three character dimensions (Self-Directedness, Cooperativeness, and Self-Transcendence) to form the basis of the TCI (Cloninger et al., 1993).

Cloninger's theory of personality is not without its critics. In 2008, Farmer and Goldberg challenged the psychometric validity of the TCI in a target article and in a wonderfully titled reply to Cloninger. A trenchant quote from the latter (Farmer & Goldberg, 2008) is below:

Overall, several core theoretical assumptions and predictions associated with the psychobiological model and TCI-R assessment are either non-falsifiable, in conflict with each other, or not supported by empirical evidence.

So the question arises, are we dealing with a flawed set of personality constructs to begin with? No matter. The scales are widely used, so we'll go on.

For genotyping, single nucleotide polymorphisms (SNPs) across the entire genome were tested for association with each of the four traits. The Illumina and Affymetrix platforms were used. [Those technical and statistical methods are beyond the scope of this blog, so I will leave it to someone else to describe and critique the genotyping aspects of the paper.] Stated succinctly, the results showed that:

No SNPs reached genome wide significance (α = 7.2*10-8) and the SNP with the lowest p-value for each personality scale explains less than 0.5% of the total variance.

None of the previously identified candidate genes (e.g., serotonin receptor gene, D4 receptor gene) were close to showing a significant relationship with any trait, nor were any of the SNPs with the lowest p value for each trait "in or close to a gene of known relevant function." The authors conclude that "common genetic variants do not contribute substantively to variation in personality." How can this be the case, when 30-60% of the variance in personality should be explained by genetics?

This raises the question of "missing heritability"... Missing heritability has been observed to a large extent in almost all complex traits. Proposed explanations focus on: many variants of very small effect that are yet to be found; rare variants that are poorly detected by available genotyping arrays that focus on variants present in at least 5% of the population; structural variants poorly captured by existing arrays, such as copy number variations; and low power to detect epistasis (interaction between genes). Newer technologies (e.g. whole genome sequencing) and novel statistical approaches combined with larger samples and meta-analyses will contribute to our understanding of the genetic architecture of complex traits.

So don't rush out and spend $1,397 on the Inborn Talent Genetic Test just yet...

Footnote

¹ Note that the participants did not complete the full TCI. Did that make a difference? Perhaps not, since two previous GWAS failed to find anything for Eysenck's Neuroticism scale or for the Big Five personality traits.

References

Benjamin J, Li L, Patterson C, Greenberg BD, Murphy DL, Hamer DH. (1996). Population and familial association between the D4 dopamine receptor gene and measures of Novelty Seeking. Nat Genet. 12:81-4.

Cloninger CR. (1986). A unified biosocial theory of personality and its role in the development of anxiety states. Psychiatr Dev. 4:167-226.

Cloninger CR, Svrakic DM, Przybeck TR. (1993). A psychobiological model of temperament and character. Arch Gen Psychiatry 50:975-90.

Ebstein RP, Novick O, Umansky R, Priel B, Osher Y, Blaine D, Bennett ER, Nemanov L, Katz M, Belmaker RH. (1996). Dopamine D4 receptor (D4DR) exon III polymorphism associated with the human personality trait of Novelty Seeking. Nat Genet. 12:78-80.

Gelernter J, Kranzler H, Coccaro E, Siever L, New A, Mulgrew CL. (1997). D4 dopamine-receptor (DRD4) alleles and novelty seeking in substance-dependent, personality-disorder, and control subjects. Am J Hum Genet. 61:1144-52.

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Acrylic Brain

Acrylic Brain, by Dwight Song

Dwight Song recently received a Masters in Architecture from the University of Michigan College of Architecture and Urban Design. His first run Acrylic Brain sold on Etsy last month, but fortunately a second run is under production.

Description from the artist:

This is a lasercut and etched model of the brain made up of 32 laser etched sections layered together on top of a white acrylic base to form a whole, reconstituted brain. Inspired by MRI images, this was originally designed and made as part of my thesis project in graduate architecture and is hand assembled.

A great gift for that special neuroscientist in your life!