Rebooting pyschiatry: time for a new set of disorders

I can't remember when I first decided that the psychiatric classifications I'd learned in medical school had outlived their usefulness. It was probably a gradual process, but by 2005 I wrote to a colleague "DSM IV was great in its day, but new knowledge is breaking down the simplistic classifications of the 1960s and 1970s. Schizophrenia, autism, etc -- bah, humbug. Those labels are better than nothing, but humans tend to confuse labels with reality …".

A few months later I took my rants public and went on for about 30 posts or so.  Soon I learned I wasn't alone, and by 2010 victory was in sight. I was a solitary crank no more.

After a bit of a hiatus the end came quickly, first with a frontal attack by the director of the National Institutes of Mental Health, then, amazingly, a NYT editorial. I mean, really, an editorial?

It's been one heck of a ride over the past 8 years. This rebellion must have been brewing for much longer in the research community, but I've been following this area pretty closely and it was cool to see it grow from nowhere to become a consensus. (I may be a crank, but I'm not crazy. I know my posts had no effect on this transformation.)

Okay, science has won. So now what ….

*cough*

Well, for now, we keep on using our legacy classifications -- either DSM IV or V, they're equally valid and equally invalid. Terms like "autism" [1], "schizophrenia", "depression",  OCD, ADHD, and "bipolar disorder" will remain guides to initial pharmaceutical therapy. Even more importantly, they will be the basis of reimbursement, regulation, disability support, and legal process for years (decades?) to come.

At the same time researchers will be using new terms to group people who seem to share common biology, including genetic programs and common protein expression. Those groups will cross traditional boundaries like childhood schizophrenia and autism; they will include some atypical minds that may be highly functional or advantageous in certain environments -- but that share traits with persons who live with disability. 

From new classifications will come better prognosis, better guides to treatment, and better outcomes. Our best guide to what lies ahead is to look back to the early 20th century, when people like William Osler and his colleagues rewrote the medical textbooks. In those days terms like "dropsy" were used to describe patients with heart failure, renal failure, lymphatic obstruction and venous valve failure. Four very different biological processes were assigned the same label and similar treatments. Reclassifying those patients was a first step towards scientific medicine.

Psychiatry, powered by the neuroscience renaissance of the past thirty years, is now taking the same journey.

[1] Aspergers', traditionally considered an autism variant, was dropped in the revised classification of disorders called DSM V. I understand the logic, but I actually think Aspergers was a relatively useful label. Ironic that we lost that one first.

Update 5/18/13 - my favorite psychiatrist blogger summed up our past and future worlds in two short posts:

• New Efforts to Overhaul Psychiatric Diagnoses Spurred by DSM Turmoil | Follow Me Here...
• Suicidal behaviour is a disease, psychiatrists argue | Follow Me Here...; An impulse disorder?

Special needs and psychosis: living with uncertainty

A NYT story of psychosis following developmental delay recalls Andrew's story (emphases mine)...

Providing Comfort When a Cure Is Out of Reach - Tara Ebrahimi - NYTimes.com

... Although Takkin had been found to have development delay and fairly severe A.D.H.D. at a young age, he had managed to lead a “normal” life well into his teenage years. He stayed in the school system for as long as he could, participating in work and life-skills programs. He was doing data entry at the airport and held a steady part-time job as a greeter at Trader Joe’s.

His situation was complex, as is often the case for people who fall into the gray space between severe intellectual disability and borderline development delay. He knew he was different from others in their early 20s, recognized that he didn’t really have any friends and that he would never go to college as his two older siblings had. He wanted nothing more than to get his driver’s license. But he was happy at times, especially when he was socializing.

Then he had the dental surgeries, and it was as if a switch in him had been flipped. After a series of root-canal procedures and teeth extractions, he woke up from his final round of procedures and anesthesia, and was never the same...

... we began seeking psychiatric help for what eventually would be referred to as Takkin’s “psychosis” and “delusional thinking.”...

... he was already in the social services system, which in our state consisted of a labyrinthine series of hoops and hurdles and bureaucratic insanity that not even the most educated and competent can easily navigate...

... I came up with a plan of action. And then another when the first plan failed. And another when the second plan failed...

... I drove to the emergency room, where we waited eight hours for him to be admitted to the psychiatric ward...

... it was time for Takkin to leave the psychiatric ward for an outpatient home ... I called a dozen times a day and could never get a response on the status of his anticipated stay, so he never went....

... he was released from the psychiatric ward into my custody, I was unable to reach his case manager at the hospital despite my constant phone calls, e-mails and voice messages, which were alternately kind, threatening and pleading...

Tara tells a story of psychosis developing after low IQ/ADHD cognitive disorder, Andrew's story tells of psychosis developing after Asperger's/autism. Adam's story may add to this tragic set. We have no idea how often this happens; that's just one of the failures of modern mental health research [1].

Tara also describes the disaster of American mental health care. That story has been told before. Recently some have suggested taxing bullets to drive a renaissance in mental health care. We could hardly do worse than we do now.

For us these stories are  personal. Our #1 son resembles the young Takkin. He lives in the "gray space", -- he has severe ADHD, cognitive disabilities, and the usual range of essential but near meaningless diagnostic labels. Will he, like Takkin and Andrew, develop a psychotic disorder over the next seven years? Does he, in a sense, have only a few relatively good years left?

We look at him, and we see features of an unnamed syndrome that continues to play out. We see uncoordinated growth, as though his cells were a mosaic of developmental clocks. Small feet, short legs, persistent  mandibular growth after maxillary has stopped. He too will need dental surgery.

There is something we cannot name that is ongoing. We assume the same process will continue to affect his brain development over at least the next decade.

How do we live with this? How do other parents of children with short lifespans or degenerative neurologic disorders live?

We live in the moment and in the past. We take photographs of good times. We spend our time and our money to have good experiences for him now, because his future is grimmer than most. Not hopeless, but not particularly hopeful.

We don't spend our time looking for a fix or a cure. We are decades from being able to fix this type of problem. Maybe centuries. Better to spend the time we have building memories.

Being the best we can be.

- fn -

[1] While we known almost nothing of natural history or epidemiology of psychosis with developmental disorders, we have hints like this preprint.

Emphases mine, the research community suspects that our definitions of "autism" and "schizophrenia" are at best incomplete, at worst completely misleading. This knowledge has not made its way into the general psychiatric community.

Expression of autism spectrum and schizophreni... [Schizophr Res. 2012] - PubMed - NCBI

Copy number variants (CNVs) associated with neuropsychiatric disorders are increasingly being identified. While the initial reports were relatively specific, i.e. implicating vulnerability for a particular neuropsychiatric disorder, subsequent studies suggested that most of these CNVs can increase the risk for more than one neuropsychiatric disorder. Possibly, the different neuropsychiatric phenotypes associated with a single genetic variant are really distinct phenomena, indicating pleiotropy. Alternatively, seemingly different disorders could represent the same phenotype observed at different developmental stages or the same underlying pathogenesis with different phenotypic expressions.

... ASD and schizophrenia associated with 22q11.2DS should be regarded as two unrelated, distinct phenotypic manifestations, consistent with true neuropsychiatric pleiotropy...

In this particular small study with a particular autism-spectrum-related genotype, the incidence of psychosis resembled the general population.

I have created an RSS Feed to track research on the relationship between developmental disorders and psychosis.

The twilight of "schizophrenia"

Neurologic disorders, alas, are not going away. The concept of "schizophrenia", however, is shuffling off the stage.

Today's obit comes from Kwang-Soo Kim, a stem-cell scientist at McLean Hospital in Belmont, Massachusetts:  "These disorders are not really disorders. There's no such thing as schizophrenia. It's a syndrome. It's a collection of things psychiatrists have grouped together."[1]

Just like autism. Autism is a collection of "things" psychiatrists have grouped together, sustained by law, regulation, tradition -- and the current lack of a better alternative.

[1] Schizophrenia 'in a Dish': Scientific American 4/13/2011

See also:

• Victory: The war against 20th century psychiatric diagnoses is all but won

Schizoprhenia and a suspicious retrovirus

Researchers have long looked for an infectious cause of schizophrenia, especially because of a relationship between a child's birth month and the later development of schizophrenia. The focus though has been on a maternal infection.

Now there is interest in an endogenous retrovirus as a contributing factor in the development of schizophrenia. This virus is present in the DNA of most of us, though there might be secondary infections triggers that would activate a quiescent retrovirus. It's quite speculative, but noteworthy.

Naturally everyone who wasn't already looking for an endogenous retrovirus in autism will redouble their efforts.

As always, there's a large caveat about this type of research. Autism and schizophrenia are labels we place on a variety of cognitive disorders that likely have diverse causes, courses, and therapies. Even if this early work bears fruit, not all of what we currently label "schizophrenia" will be related to a retroviral infection.

Understanding a different mind: memory organization and receptive language

I wrote about my son's memory and processing disabilities two days ago. Today I read a Zimmer article on the routers in our brains, and how consciousness goes offline during even simple decision making tasks. I think we'll hear more about this "router" dysfunction hypothesis, particularly in the context of autism, schizophrenia and other disorders of cognition and consciousness.

The "offline when making decisions" model is something I'll be watching for in him.

Suspect with little evidence: The action of psych meds on injured brains is unpredictable

Another in a series of things I suspect but cannot prove ...

I suspect that the actions of psychiatric meds on injured brains cannot be predicted.

If this were true, it would not be surprising. It's hard to predict how psych meds affect even intact brains. In the injured brains of autism, mental retardation, and (presumably) schizophrenia we expect to find unusual neurotransmitter distributions, injured connections with recovery bypass routes, and areas of atypically high and low activity corresponding to injury and compensation.

If this were true, it would not mean we should avoid these meds. It would mean that we should look for unexpected side-effects, and perhaps be cautious about how we interpret response and failure. It would also mean that medications might be unexpectedly effective in atypical contexts.

Anyone know of any research on this? I doubt any research exists, there's unlikely to be funding for it.

Schizophrenia and autism: the connectopathies?

For the past few years we've been thinking about developmental disorders of cognition, such as "schizophrenia" and "autism", as being fundamentally wiring disorders.

So very different conditions, but both arising from disordered development of neuronal connectivity.

It's not exactly a new idea. I recall the insult "wired wrong" from 40 years ago. It may turn out to be quite wrong, and it's unlikely to have clinical implications for years, but it's still worth tracking (emphases mine) ...

Finding out how the brain is wired | Wired | The Economist

.... Dr Lichtman’s work is the most famous example of the emerging science of connectomics. But it is not the only one. For, just as every organism has a genome (the complete set of its genes, as encoded in its DNA), every organism with a nervous system has a connectome (the complete set of its nerve cells and the connections between them). In practice, of course, a connectome will change over the course of time as new connections form and old ones die. But that does not stop people like Dr Lichtman dreaming of a Human Connectome Project inspired by the success of the Human Genome Project....

...The cerebral cortex—the part of a mammal’s brain that thinks—is composed of 2mm-long units called cortical columns. Winfried Denk of the Max Planck Institute for Medical Research in Heidelberg, Germany, estimates that it would take a graduate student (the workhorse of all academic laboratories) about 130,000 years to reconstruct the circuitry of such a column. But efforts to automate the process are gaining ground.

... The result of all this effort, it is hoped, will be precise circuit-diagrams of brains. The first brains to be mapped will probably have belonged to mice. Besides being cheap and disposable, a mouse brain weighs half a gram and packs a mere 16m neurons. Human brains (1.4kg and 100 billion neurons) will come later, when all the wrinkles have been ironed out in rodents, and proper methods devised to analyse the results. But come they will. And when they do, the most complicated object in the known universe will begin to give up the secrets of how it really works.

Controlling nerve cell connectivity - more developments

A day or two ago my post on Fragile X and autism research included a discussion of a general theme in current autism research ...

... Bear and other scientists have also identified several drugs that seem to correct the problem. The drugs don't replace the missing brakes in the brain. Instead, they limit acceleration by reducing the activity of a group of receptors on brain cells known as mGluR5 receptors.

The drugs have reversed most of the effects of Fragile X in mice. They are now being tried in humans. And at least one small study found that a single dose of a drug had an effect....

The idea is that neuronal connectivity is a delicate, dynamic, balance. Too much connectivity, or too little, can both prevent cognition from working correctly.

So now there's research on modulating neuronal interconnectivity. If they worked safely these drugs would inevitably be used on "normal" brains, probably illegally, but they could be of enormous benefit to persons with impaired cognition.

Note in this review the implication that autism and schizophrenia may be, in a simplistic sense, two sides of one coin.

A Switch to Turn Off Autism?: Scientific American

Scientists say they have pinpointed a gene in the brain that can calm nerve cells that become too jumpy, potentially paving the way for new therapies to treat autism and other neurological disorders...

... The brain is continually trying to strike a balance between too much and too little nerve cell activity. Neurologists believe that when the balance tips, disorders such as autism and schizophrenia may occur. They are not sure why neurons (nerve cells) go berserk. But Greenberg says he and his colleagues located a gene in mice and rats that helps keep neural activity in check—and may one day be manipulated to prevent or reverse neurological problems.

Researchers report in Nature that they discovered a gene called Npas4 churns out a protein that keeps neurons from becoming overexcited when they fire (communicate with one another through connections known as synapses). When scientists blocked the protein, the nerve cells fired or sent out more signals than normal; when they beefed up production, the neurons quieted down...

As scientists learn more about how brain cells stay balanced, Greenberg says they will be able to identify people who are genetically at risk for neurological disorders and develop new drugs to prevent and treat them. He notes that some of the other genes that Npas4 affects also have been linked to autism...

Drugs to treat these disorders are years away from common use -- if ever. In the near term understanding the protein products of these genes may help us better classify and organize brain disorders, though we can also expect that prenatal testing will lead to more abortions.

These developments may also increase the value of doing genetic testing on persons with cognitive disorders, so that if appropriate trials are available one might, very carefully, consider enrolling.

Schizophrenia revelations - implications for autism

Following close on the heels of findings that major gene scramblings are common in "normal" brains comes more startling news about brain disorders:

Gene-Hunters Find Hope and Hurdles in Schizophrenia Studies - NYTimes.com

... The variants discovered by the two groups, one led by Dr. Kari Stefansson of Decode Genetics in Iceland and the other by Dr. Pamela Sklar of Massachusetts General Hospital, are rare. They substantially increase the risk of schizophrenia but account for a tiny fraction of the total number of cases.

This finding, coupled with the general lack of success so far in finding common variants for schizophrenia, raises the possibility that the genetic component of the disease is due to a large number of variants, each of which is very rare, rather than to a handful of common variants...

... The new focus on rare mutations suggests that natural selection is highly efficient at removing schizophrenia-causing genes from the population. Despite selection against the disease, according to this new idea, schizophrenia continues to appear because it is driven by a spate of new mutations that occur all the time in the population....

“This may be the case in other brain diseases, too,” Dr. Goldstein said, “because successful cognitive functioning is a highly complex system and there are many independent ways to take it down.”

The search for common variants in schizophrenia, however, has not been very successful so far, though not for want of trying. There have been more than a thousand studies, implicating 3,608 genetic variants.

But when all the data are pooled, only 24 of those variants turn out to be statistically significant, according to an analysis in the current issue of Nature Genetics by a group led by Dr. Lars Bertram of Massachusetts General Hospital...

I read this as consistent with recent literature telling us that the human brain has been undergoing rapid evolution for a few thousand years, perhaps with an unusually accelerated mutation rage and high selection pressures.

Rapidly evolving organs are often fragile things -- like a car slapped together in a rush. Thousands of thousands of things can go wrong. Some are manageable, others produce schizophrenia and perhaps autism.

The bad news is we were hoping gene studies would identify common genetic mechanisms; we could then use these to characterize disease subtypes, better evaluate therapies, and identify new drug targets. Now that door seems to have shut. We have to look further up the bioinformatics chain for common functions that meds could act on, and we may fear that they'll be hard to find.