New Study of Studies / Male to Female Ratio ASD

JAACAPJournal of the American Academy of Child and Adolescent Psychiatry

What Is the Male-to-Female Ratio in Autism Spectrum Disorder? A Systematic Review and Meta-Analysis

University College, London UK



To derive the first systematically calculated estimate of the relative proportion of boys and girls with autism spectrum disorder (ASD) through a meta-analysis of prevalence studies conducted since the introduction of the DSM-IV and the –International Classification of Diseases, Tenth Revision. (Thus – conclusions can only be as “accurate” as the data in the original studies) (Since DSM-V did away with Asperger’s as a diagnosis, how does this “deletion” affect this study?)


Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were followed. The Medline, Embase, and PsycINFO databases were searched, and study quality was rated using a risk-of-bias tool. Random-effects meta-analysis was used. The pooled outcome measurement was the male-to-female odds ratio (MFOR), namely the odds of being male in the group with ASD compared with the non-ASD group. In effect, this is the ASD male-to-female ratio, controlling for the male-to-female ratio among participants without ASD.


Fifty-four studies were analyzed, with 13,784,284 participants, of whom 53,712 had ASD (43,972 boys and 9,740 girls). The overall pooled MFOR was 4.20 (95% CI 3.84–4.60), but there was very substantial between-study variability (I2 = 90.9%). High-quality studies had a lower MFOR (3.32; 95% CI 2.88–3.84). Studies that screened the general population to identify participants regardless of whether they already had an ASD diagnosis showed a lower MFOR (3.25; 95% CI 2.93–3.62) than studies that only ascertained participants with a pre-existing ASD diagnosis (MFOR 4.56; 95% CI 4.10–5.07).


Of children meeting criteria for ASD, the true male-to-female ratio is not 4:1, as is often assumed; rather, it is closer to 3:1. There appears to be a diagnostic gender bias, meaning that girls who meet criteria for ASD are at disproportionate risk of not receiving a clinical diagnosis.

Hate to be snippy – but with the all the manipulation going on, is the “new” ratio of male / female ASD any more informative than a “good guess”? At least this group acknowledges the bias against clinical diagnoses of ASD in girls.


…And we are still expected to join the other inmates in the pink and purple social prison that confines female H. sapiens to low status.


The Childish Blame Game / Excuses


Human beings have expended great time and effort in the fashioning of moral and ethical systems, but beyond the common sense admonition, “Treat other people as you wish to be treated,” which is fundamental to cultures and religions worldwide and throughout history, not much has come of it. Maybe we could forget “the rest” of the instructions, and work on this one sufficient behavior.

Do any of these excuses made by school children for incidents of bullying sound familiar?

He started it. (The universal revenge response.)

He hit me first. (The universal violent revenge response.)

I only stole $10.00; Suzy took her iPhone. (“I’m not as bad as she is” blame shift)

I thought he was going to hit me, so I hit him first. (The preemptive strike rationalization)

She took my notebook so I had to punch her. (The out-of-proportion retaliation)

She’s a retard; she’s too stupid to even know that we tricked her. (Vulnerable people are fair game)

So I lied; big deal. I got what I wanted. (Narcissism – I’m the center of the universe.)

Everybody does it. (Spread the blame; normalize bad behavior)

He wouldn’t give me his laptop so I beat him up. (If people don’t do what I want, I have the right to hurt them.)

I didn’t do it anything. (The simple lie / bluff protest.)

My (Dad, Mom, teacher, the principal, boss) said I could do it. (The appeal to protection by an authority figure.)

How many adults get beyond this “excuse” stage of development? Social groups? Corporations? Nations?

Our leaders never do.


But… You may find yourself at the top of the social pyramid $$$ in government, business, the military, Big Pharma, the “helping, caring, fixing industry” or in law enforcement, advertising-media-entertainment and of course politics and the banking-financial industry.

I googled “kids draw bullies” but liked these better!








The Magic Word Syndrome / Psychology Re-Post


People come up with persuasive words and phrases to introduce concepts; words control the message as it makes its way into common usage. As a result, we now have more word-concepts than anyone actually knows what to do with. There’s a catch to human language: words are not things.  Words are tools of language that vary from culture to culture. Chien in French refers to a Dog; no one can claim that either word is correct. A person can examine a dog, photograph a dog, or do an autopsy on a dog, but never will the word Chien or Dog or any other word description be found in or on that animal. Even if you could convince everyone on earth to use the generic English label “Dog” you would not be able to find a generic dog; there are only individual dogs.

There is a glitch in the human language system: it’s as if the brain is confused by its ability to use language, as if we experience the words as a message from a dimension outside reality – a supernatural dimension. Language creates ideas (the supernatural dimension) and manipulates thought: modern humans believe that words create reality. So strong is this illusion, that people make decisions based on utterly insubstantial and incorrect social, economic, religious, nutritional, political and health concepts. This has serious and devastating real world consequences.

Water in a bottle: Bottled water; water that comes from a regular tap, inside a building, in a city. This water is the same as that which is dispensed in kitchens around the city, but once packaged in a plastic bottle and falsely labeled spring water, natural water, or pure water, with a clean-looking graphic, consumers will believe the words on the label and argue that the water comes from a pure cold spring in a virgin wilderness, uncontaminated in any way by humans.

Even when people are confronted by the absurdity of the assumptions and are shown photographs of “Holy water” being filled inside a bottling plant, people will claim that it can’t be so: bottled water “tastes better” than the water at home. This self-delusion that tap water, once it is contained in a plastic bottle with a pretty label, magically becomes health-promoting is not benign: the Earth’s oceans and vast landfills are clogged by plastic bottles and other devastating trash.

This is not a woman strangling a cat.

This is not a woman strangling a cat.

This illusion that words create reality applies to things that are not things: to nonexistent properties, such as empathy: Just what are we talking about? Empathy is a name for…..what? An imaginary aspect of human behavior that all humans must display in order to be labeled as fully human? Psychologists are already deep into the supernatural dimension with the assumption that the word Normal describes a majority of human beings, when the condition Normal is a subjectively constructed concept that they themselves have invented, and which changes from culture to culture and over time.

Like wizards and priests that practiced conceptual labeling before them, psychologists claim to “see” into the brains of individuals (using the magic power of technology) and to “see” a label that says “normal human brain” or “subhuman human brain” stamped into blood flow, electrical activity and eye movement – socially imposed “symptoms” (subjective defects) that have been elevated to scientific fact by deceptive manipulation of bad data and the promotion of the attitude that human beings are objects that can be sorted and categorized into acceptable and defective bins.

But what is normal? Normal is an idea that requires massive manipulation of information; it is an artificial construct. Where does information come from? In the case of psychology, from a very small sample of select individuals (college students) who fill out surveys that rely heavily on self-reporting. Tests (another word concept) that test psychological assumptions about human behavior, are designed to prove those assumptions. Normal parameters are in fact nonexistent; only individuals exist. In nature, there are only individuals and that is true of the human animal. Psychology regard human beings as OBJECTS that can be arranged by supernatural concepts. In other words, the foundational concepts of psychology lack empathy.

Normal behavior, as conceived by psychologists, is a clever substitute for acceptable or required behavior. Normal sounds scientific and objective, as if each infant arrives with the same package of instructions, which coincidentally match a list of (religious, supernatural) behaviors, which appear to come from an all-powerful but invisible entity that created and possesses the BLUEPRINT of the universe, and who has handed down the details of this blueprint to psychologist – priests. The idea today (pseudoscientific update from superstition) is that certain children and adults fail to live up to nature’s standard template, but the standards used by psychologists are socially constructed and are never found in nature. It’s the same old religious routine: condemnation of people who are different and ‘refuse’ to obey. Ideas about acceptable human behavior have their origin in human concepts that are attributed to an absolute and permanent supernatural template that is in fact a socially acceptable hallucination.

Humans were prey animals for most of our existence; once we dealt effectively with predators, we became predators, that is, males became hunters. Pregnant women, women responsible for children, and young children, are unlikely hunters. Females underwent sexual selection for early puberty and the retention of childlike physical and psychological traits into adulthood (if they lived to adulthood), an early step in domestication. That is, women remain prey animals.

Predators, then and now.

Sabre-toothed cats2014-01-500-awesomest-pp-pieces

Modern humans have been changed by 10,000+ years of domestication. Children born into a predator class will be raised to be predators. In American culture, money confers behavioral leeway, so a license to exploit others can be earned, even if a child begins life humbly. It’s the American Dream. People at the bottom are supposed to stay put, which is why obstacles are put in the way of people at the bottom. Predatory behavior is criminal behavior if you live at the bottom; it’s the key to success at the top of the pyramid, which is why activities at the top are left unregulated and top predators rarely pay for their profitable predation.

This then, is why Asperger individuals are so reviled; the taboo of disobedience to the social hierarchy is a very big taboo: a No-No, a travesty, an attack on authority, God, and corporate profits. In the case of Asperger individuals, this is utterly ridiculous. We aren’t even on the pyramid! We inhabit a separate Flatland of equality in which all things and all people simply exist. In order to be fulfilled, we require honesty from other people and justice for everyone.

We are unhappy because our values will never be more than empty words in the social universe. 

Ironically, courtesy of men like Thomas Jefferson, our values are supposed to inform the ‘democratic’ principles that are the foundation of our country. How abused are the notions of equality and liberty, of diversity and happiness!

One couldn’t even organize a cocktail party of Asperger’s types, let alone a political party, and yet we are characterized in the media as dangerous, cunning and aggressive. Mostly, we are told that we need fixed, as if wings ought to be clipped from birds because deer aren’t supposed to fly. It’s bizarre.

Asperger people are not modern social humans, nor can we be socialized. Our brains function more like so-called primitive people (Wild Humans) who inhabited pre-hypersocial environments. Asperger females are unlike modern social females; we often lack “domesticated” behavior, and prefer animals to people. When in the presence of social humans we are mystified – gob smacked by demands that make no sense to our concrete, and decidedly non-supernatural brains.

Brain development and Neoteny / Neuroscience

J Psychiatry Neurosci. 2011 Nov;36(6):412-21. doi: 10.1503/jpn.100138.

Can Asperger syndrome be distinguished from autism? An anatomic likelihood meta-analysis of MRI studies.

Yu KK1, Cheung C, Chua SE, McAlonan GM

Whereas grey matter differences in people with Asperger syndrome compared with controls are sparser than those reported in studies of people with autism, the distribution and direction of differences in each category are distinctive.


In development, timing is of the utmost importance, and the timing of developmental processes often changes as organisms evolve. In human evolution, developmental retardation, or neoteny, has been proposed as a possible mechanism that contributed to the rise of many human-specific features, including an increase in brain size and the emergence of human-specific cognitive traits. We analyzed mRNA expression in the prefrontal cortex of humans, chimpanzees, and rhesus macaques to determine whether human-specific neotenic changes are present at the gene expression level. We show that the brain transcriptome (transcriptome includes all mRNA transcripts in the cell; it reflects the genes that are being actively expressed at any given time, with the exception of mRNA degradation phenomena such as transcriptional attenuation.) is dramatically remodeled during postnatal development and that developmental changes in the human brain are indeed delayed relative to other primates. This delay is not uniform across the human transcriptome but affects a specific subset of genes that play a potential role in neural development.


By comparing the gene expression profiles in human, chimpanzee, and rhesus macaque prefrontal cortices throughout postnatal development, we have found that there is no uniform shift in the developmental timing between humans and other primates. We find instead a significant excess of genes showing neotenic expression in humans. This result is in line with the neoteny hypothesis of human evolution (6) and provides insight into the possible functional role of neoteny in human brain development. Specifically, we show that at least in one of the 2 cortical regions studied, the neotenic shift is most pronounced at the time when humans approach sexual maturity, (body matures; brain does not) a process known to be delayed in humans relative to chimpanzees or other primates (6, 24). Furthermore, the neotenic shift particularly affects a group of genes preferentially expressed in gray matter. Intriguingly, the timing of the shift also corresponds to a period of substantial cortical reorganization characterized by a decrease in gray-matter volume, which is thought to be related to synaptic elimination (21, 25, 26). The developmental pace of changes in gray-matter volume has been associated with the development of cognitive skills among humans (e.g., linguistic skills) (27) as well as with the development of disorders (e.g., attention-deficit/hyperactivity disorder) (28).

Although the precise causes and consequences of the human neotenic shift remain unknown, together these observations suggest that ontogenetic timing differences between the human and the chimpanzee prefrontal cortex transcriptomes may reflect differences in sexual and cognitive maturation between the 2 species. According to this logic, delayed gray-matter maturation in the human prefrontal cortex may extend the period of neuronal plasticity associated with active learning, thus providing humans with additional time to acquire knowledge and skills.



Things to think about:

Maturation of gray matter in the human prefrontal cortex is delayed by neotenic shifts. Developmental delay is neotenic. There is a “fuzzy boundary” (?) between too much / too little grey matter volume for the brain to function well; there also seem to be 2 types of brain organization: social navigation vs. factual and problem-solving. (See today’s Temple Grandin post.) These are probably not ‘separate’ paths, but are developmental stages. (Social is juvenile; factual is adult.)

The gray matter volume in any specific human brain may vary between mature and neotenic states. Humans vary in degrees of neoteny. It might be more accurate to dump “Autism Spectrum” for an inclusive classification “The Neoteny Spectrum” which includes all contemporary homo sapiens.

How do we know which human brains (volume of grey matter) are mature and which are neotenic? What volume of grey matter is the reference for maturity vs. neoteny? We can begin with behavior.

Some changes in grey matter volume occur during puberty: therefore it would be useful to compare the pre-puberty and post-puberty states of grey matter in individuals, especially those diagnosed with a “brain disorder” in early childhood. Mixing data from before and after stages of brain reorganization may be completely misleading do to variations in timing.

Grey matter differences in individuals reflects maturity vs. neoteny (a spectrum of rates of development) and not fundamental developmental disability; if one is ONLY interested in “The Social Brain,” and designates this juvenile stage of development as the ONLY legitimate human brain, then the “problem” of Asperger’s is the product of inattentional blindness and ignorance. Bad science!

CASE IN POINT: It is said that Asperger’s have “less than normal” volumes of gray matter, but if this conclusion has been derived from pre-puberty testing, then it is entirely possible that Asperger children, in terms of specific brain development, (intellect, language, concrete – visual thinking, facts and problem-solving) simply MATURE FASTER – and gray matter volume is reduced to a more effective and efficient volume well before their peers.

Social brains are neotenic; the neurotypical neotenic brain never fully matures. Which means that the social orientation (obsession) of modern social humans is the product of extreme neoteny.   Neoteny is evident in a lack of logic, rationality, analytical thinking and effective problem-solving, which are absent in everyday life and most seriously, in our political leaders.

“Juvenile” neotenic behavior is evident in the inability to recognize that facts and physical reality exist. Instead, emotions are paramount; self absorption is rampant, magical thinking prevails, action is missing, narcissitic orientation is “normal”, and “worship of” childlike celebrities is a substitute for adult models and personal development. Adult children never leave home but remain dependent on parental support. Violence is characteristic of juvenile males; violent behavior usually decreases as males age, but today “frivolous” violence is the perpetual activity of neotenic males and is encouraged by popular culture.


Cerebral Asymmetry / Asperger Brain Differences

Philosophical Transactions of the Royal Society / Biological sciences

The evolution and genetics of cerebral asymmetry

Michael C Corballis

Fake “Nature” documentaries defended as better than “Reality”

How Nature Documentaries are Fake: A Filmmaker’s Perspective

Simon Cade is an English Filmmaker and Director who owns and runs the YouTube Channel, DSLRguide in which he teaches both aspiring and weathered Filmmakers the art of making movies. Cade is 19 years old, a “director” and teaches filmmaking. Jeez! His casual attitude about “reality” reveals a common, neotenic inability to distinguish “lies” from scientifically established facts, which is A-OK in the modern social “value” system.

American Criminal Hypocrisy / E-Waste, Prison Labor, Modern Slavery

Uh-oh! Warning! Asperger defect! 

This Asperger’s insistence on using the same old PC, year in, year out, because it works just fine, is “proof” of the ridged habits and fear of change for which people like me are slammed by psychologists and the Autism Industry. Refusing to “try out” every new gizmo, in pink, purple, and red; overpriced designer toys intended to be “socially obsolete” in a few weeks is a “developmental defect” of profound “social” importance. High-tech innovation is disguised as neotenic novelties, just like designer handbags and faddish foods, and is meant to be discarded – and inevitably to pollute the cities of the world. Products are dumped out-of-sight “overseas” to be “recycled” by children; primitive “disposal” that poisons air, land and water and the brains and bodies of scavenging humans. To refuse to participate in these superior social behaviors is an “official” NO-NO!

How defective can a subhuman Asperger “weirdo” get?

Yes. Asperger’s are “weird”. We are likely to use products that satisfy a need, but have no “status” attached, and prefer function over fashion. My lifelong policy of purchasing good, used objects at thrift stores and yard sales is sure proof of subhuman behavior. How dare an individual threaten the careless and wasteful socio-economic order!

From Electronics Take Back Coalition

E-Waste Problem Overview

The Problem with Electronics and E-Waste

Products Are Quickly Obsolete and Discarded

In the US, we scrap about 400 million units per year of consumer electronics, according to recycling industry experts. Rapid advances in technology mean that electronic products are becoming obsolete more quickly. (Wow! How irrational, irresponsible and environmentally destructive can “smart” industry get?) This, coupled with explosive sales in consumer electronics, means that more products are being disposed, even if they still work. (It’s the “throw out your shoes and buy a new pair because the shoe laces are out of style” effect.) More on how products become quickly obsolete

Electronics are Difficult To Recycle

Recycling electronics isn’t like recycling cardboard. These products are not easy to recycle. Proper and safe recycling often costs more money than the materials are worth. Why?

Electronics are not designed for recycling

Materials used and physical designs make recycling challenging. While companies claim to offer “green electronics,” we are a far way from truly green products. More on not designed for recycling.

Electronics contain many toxic materials

Monitors and televisions made with tubes (not flat panels) have between 4 and 8 pounds of lead in them. Most of the flat panel monitors and TV’s being recycled now contain less lead, but more mercury, from their mercury lamps. About 40% of the heavy metals, including lead, mercury and cadmium, in landfills come from electronic equipment discards. More on toxics in electronics.

Discarded Electronics Are Managed Badly

Most e-waste still goes in the landfill. The EPA estimates that in 2011, the US generated nearly 3.4 million TONS of e-waste. But only about 25% of that was collected for recycling. The other 75% went to landfills and incinerators, despite the fact that hazardous chemicals in them can leach out of landfills into groundwater and streams, or that burning the plastics in electronics can emit dioxin.  More on e-waste in the landfill.

Most Recyclers Don’t Recycle, They Export

And what about the 25% that is supposedly recycled? Most recycling firms take the low road, exporting instead of recycling.  A large amount of e-waste that is collected for recycling is shipped overseas for dismantling under horrific conditions, poisoning the people, land, air, and water in China, other Asian nations and to Ghana and Nigeria in western Africa.  More info on global e-waste dumping.

Prison Recycling: High Tech Chain Gang

Electronic recycling operations are increasingly active within America’s prison systems. Inmate laborers are not automatically afforded the same degree of worker health and safety protections as are people employed on the outside, nor are they paid comparable wages. Moreover, reliance on high tech chain gangs may frustrate development of the free market infrastructure necessary to safely manage our mountains of e-waste.  More on prison recycling

For list of corporations that exploit prison inmate labor and how they do it: How Prison Labor is the New American Slavery and Most of Us Unknowingly Support it

“If you buy products or services from any of the 50 companies listed below (and you likely do), you are supporting modern American slavery”
Video link: 13th Amenment abolished slavery EXCEPT AS A PUNISHMENT FOR CRIME. How U.S. Prisons “sell” inmate labor to corporations.

Any question as to why DRUGS remain illegal? Non-violent “drug possession laws” keep the prison population at all-time highs, and provide “cheap labor” to Corporate America.







Success Story / Asperger Females Disguised as Neurotypicals

From the Daily Mail:

They are successful career women in loving relationships – and they all live with an affliction that will surprise you!

by Jill Foster for the Daily Mail, August 2012 Check out a slew of “articles” directed at female readers!

Looking Back on Bipolar / Seasonal Transitions and Disruptions

See also related Circadian Rhythm posts –

I used to be bipolar; diagnosed long ago, before Asperger’s was a recognized “thing” (1994) and not considered applicable to females. Looking back, I think this was a mistake – the “bipolar” symptoms I experienced can logically be seen as evidence for “Asperger-ness” as a brain type that processes the environment in a distinct and even radically different way than the overwhelming majority of Modern Social Humans – neurotypicals. One notable problem for me, was and is, a response to seasonal change; lack of sunlight and outdoor activity in winter produce a direct physical effect: extreme restlessness (anxiety) and a longing for the world to “come back” – to revive, to be washed in sunlight and present a landscape wide open to movement. This is not an uncommon condition for many people! The experience can be grossly represented as  claustrophobia. Winter is a time, that once adjusted to, can be very productive; a time of internal focus, mental activity and concentration.

The transition into summer, while eagerly embraced, can be disruptive, unsettling, and “mind-blowing” – Where I live, it’s a long process; inter-leaving of days of increasing sunlight that fool fragile plant life into attempts to emerge, but which are discouraged by snow storms and overnight freezes. The energy gained by extended sunlight at high altitude (6,000-7,000 feet) hits a certain point – and suddenly, our tan and brown,  heavily dissected desert is GREEN. It’s “shocking” to the eye; strange and brief. The sagebrush steppe is covered in prickly shrubs and myriad bunch grasses, which  must reproduce in the short window of mid May through June, and then pack away their chlorophyll for another year, leaving only yellow leaves and seeds to be dispersed by the famous Wyoming wind.  A palette of rich yellows, pale earth, and dusty gray green returns; a much more interesting landscape for sunlight to change in appearance, from moment to moment, throughout the day and evening. A “light show” transforms our two-part landscape of land and sky – a daily cycle of color and shadow that passes into cool night.

I don’t know if this experience of reality is common to Asperger individuals; that is  – the direct influence of the environment on mood, emotion and energy. This responsiveness to the land is not exclusive to Asperger’s types.

This desert has no “social” uses; agriculture is futile. Few people can live here, and without resource extraction for “dollars” and importation of food, even fewer could, or would stay. There is something extremely luxurious about a landscape that can’t be “socialized” – unitized, divided, owned and exploited by human agriculture, trade, commerce – made useful or productive. There’s something extremely luxurious about a life that grows to fit this type of land. I was made for this place: finding it meant “letting go of things not meant for me.” The Bhudda.


Original post about transitioning from summer into winter:

This is my 65th transition from summer into fall. Of course I don’t remember most of these changes. Fall is a bit of a drive-through season; the way we get to winter. It says so on the calendar: First Day of Fall, but for me it’s a long drawn out state of confusion, instability, moodiness: doom. What has disrupted my normal, careful, mostly peaceful days? Normal for me: my “writer’s routine” of coffee, computer and coming awake. Sometimes writing is easier while I’m still a bit stupefied by sleep.

Anticipation: that’s my experience of Fall, as if something momentous is about to happen, but it never does. One morning the garden plants have frozen, cells bursting; really physically dead; mush with frost rimming the remains. Light snow that melts quickly, the rocks damp and shiny, their colors deep and revealing.

It’s not that I don’t like winter, but some innocent intuitive organ believes that the earth is dying, and me with it. These experiences are so strong and consistent year after year, that I’m sure that being bipolar has something to do with ancient humans -tropical creatures who pushed too far north for their mental health. People whose brains and bodies were extensions of the seasons: work like mad in Spring and Summer and semi-hibernate in winter. Expend the least energy possible obtaining food and water; curl up like most of nature and sleep and dream an alternate existence filled with giants, heroes and mortal powers.




Circadian Rhythm Disturbances / Bipolar – Asperger Syndrome

Bipolar Disorder is thought to be co-morbid to Asperger Syndrome. I want to introduce material from Circadian Rhythm studies.

Circadian Rhythm

Social cues help set sleep patterns

Social cues help set sleep patterns

© 2002 Psychiatric Times. All rights reserved. Circadian Rhythms Factor in Rapid-Cycling Bipolar Disorder by Ellen Leibenluft, M.D. Psychiatric Times May 1996 Vol. XIII Issue 5

The nervous systems of people with bipolar disorder frequently make specific types of regulatory errors. Many of those errors involve the body’s internal clock, which controls the phenomena known as circadian rhythms. These are the regular rhythmic changes in waking and sleeping, activity levels, and sensations of hunger and thirst.

Phototherapy and melatonin, two interventions that manipulate the circadian system, are being used widely for seasonal affective disorder, jet lag and some forms of insomnia. Scientists continue to make tremendous strides in understanding the regulation of the circadian system in humans and animals. We now know that the body’s clock is located in the suprachiasmatic nucleus (SCN) of the hypothalamus, and that the SCN regulates the pineal gland’s secretion of the hormone melatonin (Klein and colleagues). In humans as well as animals, light suppresses melatonin secretion; recent evidence shows that even ordinary room light can have this effect. Because light suppresses melatonin secretion, the hormone is typically secreted at night. Furthermore, the SCN can “remember” the day-length to which it has been recently exposed, so the timing of nocturnal melatonin secretion is determined by the “lights on” and “lights off” times of the preceding days. In 1994, scientists cloned genes regulating circadian rhythms in mice, making the circadian system the first complex behavioral system whose genetic underpinnings could begin to be unraveled in mammals (Vitaterna and coworkers).

In mood disorder research, interest in circadian rhythms is not new. For at least 50 years, investigators have questioned whether abnormalities in circadian rhythm regulation might be involved in the pathogenesis of mood disorders, including rapid-cycling bipolar disorder. These questions were motivated by three clinical observations. The first of these was that the sleep duration of patients often changes dramatically as they cycle between mania and depression; bipolar depression is typically associated with hypersomnia, while mania is characterized by extreme and sometimes total insomnia.

The second observation was that approximately 60 percent of depressed patients experience remission after a night of total or partial sleep deprivation (SD). In bipolar patients, sleep deprivation (SD) may actually cause a switch into hypomania or mania. However, this “upward” switch usually lasts only until the patient undergoes recovery sleep, leading to the formulation that SD, or extended wakefulness, is antidepressant, (or manicogenic), while sleep is depressogenic, (Wehr). The antidepressant effects of SD are conceptually important because they show that changes in sleep duration are more than just symptoms of the illness, and also play a pathogenic role.

Using a longitudinal analysis of mood and sleep in a sample of patients with rapid-cycling bipolar disorder, we recently demonstrated that decreased sleep duration precedes, rather than simply follows, a switch into hypomania or mania (Leibenluft and coworkers, in press). Furthermore, in this sample, decreased sleep duration was more consistently associated with a shift to an earlier wake-up time than it was with a shift to a later bedtime. Pharmacologically, it is easier to manipulate the time a patient goes to sleep than to change the time he or she wakes up; perhaps for this reason, clinicians have generally attended less to wake-up time than to sleep-onset time. However, these data indicate that interventions designed to shift patients’ wake-up time may deserve further study.

The third observation implicating abnormal circadian rhythms in the pathogenesis of mood disorders concerns diurnal variation. In its classic, typical form, diurnal variation is defined as a gradual improvement in the patient’s depressed mood as the day wears on. Like sleep deprivation, typical diurnal variation demonstrates that extended wakefulness is associated with an antidepressant response. We recently extended the concept of diurnal variation to bipolar patients with data demonstrating that rapid-cycling patients are more likely to switch “up” (i.e., from depression or euthymia into hypomania) during the day, and to switch “down” (from hypomania or euthymia into depression) overnight, while they sleep (Susana Feldman-Naim, M.D., and coworkers, unpublished data). Thus, once again, extended wakefulness is associated with an antidepressant response, while sleep appears to be depressogenic.

Specific theories have been advanced as to how circadian rhythm dysfunction might lead to rapid-cycling bipolar disorder. In 1968, Halberg suggested that some, but not all, circadian rhythms in such patients were not synchronized with the 24-hour day-night cycle (Halberg). According to Halberg’s hypothesis, the interaction between the unsynchronized, “free-running” rhythms and the normally synchronized (entrained) rhythms causes switches back and forth between mania and depression.

Kripke and colleagues then presented data demonstrating what appeared to be a free-running temperature rhythm in five of seven rapid-cycling patients. In these patients, the period (time taken to complete one cycle) was abnormally short, in essence showing that patients with rapid mood cycles had rapid physiological cycles. However, subsequent investigators have not generally found either free-running or unusually fast circadian rhythms in patients with rapid-cycling bipolar disorder.

In the 1970s and ’80s Wehr and collaborators, working at the National Institute of Mental Health, continued to study biological rhythms in this patient population. Using both cross-sectional and longitudinal designs, they showed that the phase (timing) of patients’ sleep, temperature and motor activity rhythms varied systematically as they cycled between hypomania or mania and depression. Specifically, the timing of these rhythms appeared to be earlier in manic than in depressed patients, and earlier in depressed patients than in controls (Wehr and colleagues 1980). We now have preliminary data indicating a similar pattern in the time of onset of nocturnal melatonin secretion. These new data show that, in rapid-cycling bipolar patients, the time of nocturnal melatonin onset may be approximately 90 minutes earlier when they are hypomanic, compared to when they are depressed (Leibenluft and colleagues 1993). It is as if rapid-cycling patients might have an endogenous form of jet lag, internally traveling back and forth over one or two time zones as they cycle between hypomania and depression. Indeed, several studies show that bipolar patients are at risk to develop an affective episode when they travel across time zones (Young).

What might cause these shifts in the phase (time) of onset of nocturnal melatonin secretion? It is possible that phase shifts.i.phase shifts; in nocturnal melatonin secretion precede the patients’ mood switches and play a pathogenic role in mood cycling. However, it is also possible that the phase shifts are epiphenomena caused by the patient’s symptoms. Specifically, the phase shifts may be secondary to the changes in the sleep-wake cycle.i.sleep-wake cycle; that occur with mood cycling. The phase of circadian rhythms is determined by zeitgebers (“time-givers”).

While light is the most potent zeitgeber, physical activity, eating and social routines can probably also affect the timing of circadian rhythms. The timing of all these zeitgebers is often different when a patient is hypomanic, compared to when he or she is depressed, and shifts in the timing of zeitgebers would cause phase shifts in circadian rhythms.

However, a third possibility also exists. We suggest that phase shifts in melatonin secretion and other circadian rhythms are not the primary cause of mood cycling, but they are also not irrelevant epiphenomena. We hypothesize that phase shifts in melatonin secretion are secondary to the patient’s symptoms or to more fundamental causes of bipolar illness, but they nonetheless have pathogenic significance and contribute to the development of a full-blown affective episode.

This formulation is analogous to that of Wehr and coworkers (1987) in describing the contribution of sleep deprivation to the development of manic episodes. These authors suggested that insomnia, which is itself a symptom of mania, contributes to the development of a manic episode because it causes sleep deprivation. In other words, insomnia is both a symptom and a cause of mania. If one treats the insomnia early and aggressively, one can truncate an episode, or prevent mild or moderate symptoms from snowballing into a severe and destructive episode. Similarly, it is possible that the shifts in circadian rhythms, while not the initial cause of a mood switch, contribute to the severity and duration of an episode, and thus play a role in determining the course of illness.

We are currently testing this hypothesis by determining whether interventions designed to prevent phase shifts in nocturnal melatonin secretion have therapeutic effects in rapid-cycling bipolar patients. One such experimental treatment involves the use of phototherapy. Data indicate that midday bright light may increase the amplitude of nocturnal melatonin secretion. Since increasing the amplitude of a rhythm makes it more resistant to phase shifts, midday light might be expected to stabilize the time of nocturnal melatonin secretion. In other words, midday phototherapy administered to these patients might prevent the shifts in timing of nocturnal melatonin secretion that we believe have pathogenic significance. After encouraging results with a small number of patients, we are now conducting a formal, controlled trial of this intervention. Interestingly, morning bright light, which shifts patients’ circadian rhythms, may have caused several of our rapid-cycling bipolar patients to cycle more dramatically.

Thus, even if circadian abnormalities are neither the sole nor the primary cause of bipolar illness, it is possible that circadian interventions can have therapeutic utility. Compared to psychotropic medications, circadian interventions are relatively flexible therapeutic modalities; they have a rapid onset and offset of action, and their clinical effects may be altered by changing the time that they are administered. This flexibility may be particularly useful in rapid-cycling bipolar patients, whose frequent mood cycles may require rapid alterations in their therapeutic regimen. Further research will indicate what, if any, role circadian dysfunction plays in the pathogenesis of rapid-cycling bipolar disorder, and whether circadian interventions can be helpful to these often treatment-resistant patients.

Ellen Leibenluft, M.D., is chief, Unit on Rapid-Cycling Bipolar Disorder, Clinical Psychobiology Branch, National Institute of Mental Health.