Mood

The Thought Spectrum - Thinking Up A Storm

What do hypersomnia, lack of concentration, and neurotrophic malfunction have in common? A mood disorder that may be lurking around the next neuron.

by John McManamy

Is there a different way of thinking about mood disorders? Clinical observation and brain studies are turning up convincing evidence of persistent cognitive impairments in a good many people with depression and bipolar disorder, even in symptom-free states. At the 2004 American Psychiatric Association annual meeting, Deborah Yurgelun-Todd PhD of Harvard argued that cognitive deficits should be regarded as a core feature of bipolar disorder.

Can we take this argument one step farther? Might bipolar, at least in some cases, be regarded as a thought disorder with a mood component? If there is a mood spectrum, might there also be a thought spectrum?

The obvious first place to investigate is schizophrenia. Only 10 percent of individuals with schizophrenia work full time, but bipolar is no picnic, either, with only 34.5 percent of us fully-employed, according to early STEP-BD findings. Granted, when it comes to schizophrenia, practically all of us tend to be thankful we only have bipolar, but might we share some of the same underlying brain circuitry?

In Part I, we examined some of the areas where thought difficulties may bleed over into both bipolar and schizophrenia, with an emphasis on glutamate dysregulation affecting working memory. Antipsychotics, which block dopamine, may clear up mania and psychosis, but may actually worsen cognitive processes. The good news is there are new meds in the development pipeline aimed at different targets. In the meantime, you and your psychiatrist may be able to come up with off-label work-arounds.

This article considers the thought spectrum in the context of where depression intersects with hypersomnia, alertness, and memory. Parts I and II are based on my listening to experts at various symposia and lectures at the 2007 APA annual meeting, held in late May in San Diego. No attempt is made here to be comprehensive – that would require several books. The object, instead, is to simply open up the conversation …

Sleep and Alertness

At an industry-sponsored symposium, "Still Sleepy After All These Years: Hypersomnia in Psychiatry," Stephen Stahl MD, PhD of the University of California, San Diego pointed out that the neurotransmitters of arousal are also the neurotransmitters of concentration. These include norepinephrine, dopamine, acetylcholine, and histamine.

Serotonin, he said is like an "anti-dopamine or anti-norepinephrine." Those talking SSRIs, he said, may feel flat.

Impairments in concentration can lead to poor judgment and impulsive decisions, apathy and lack of motivation, and often inappropriate fixation on one solution. Sleep-deprived individuals require more brain activation in order to process mental tasks. Brain scans reveal little activity in the dorsolateral prefrontal cortex until subjects are able to "kick it up a notch."

Mood disorders, hypersomnia, fatigue, and lack of concentration go hand in hand. Significantly, hypersomnia can also be found on what Dr Stahl refers to as the same arousal-concentration or hypersomnia-cognitive spectrum as depression, anxiety, sleep deprivation, numerous sleep disorders, ADD and even schizophrenia, often traveling along the same brain circuits, suggesting treatment with the same drug.

"There are very few pathways for the brain to get symptoms out of," Dr Stahl advised his audience, which raises the whole question of the relevance of a diagnosis in the first place. Dr Stahl confessed, with probably only slight hyperbole, to writing in a diagnosis "in order to get paid." Then, "I forget about it."

Dr Stahl was speaking in the context of off-label uses of Provigil (modafanil) and other meds. Provigil is FDA-indicated to improve wakefulness in patients with narcolepsy, obstructive sleep apnea, and shift work sleep disorder. (The drug’s manufacturer, Cephalon, sponsored the symposium, and Dr Stahl declared his financial interest as a paid consultant.)

The FDA, Dr Stahl advised, does not regulate the practice of medicine. Rather, it regulates "the sale of medicine."

"WE regulate the practice of medicine," Dr Stahl reminded his audience.

The Depression Connection

Almost anything that disrupts normal sleep contributes to hypersomnia, a number of speakers at the same symposium pointed out. These include medical problems, psychiatric problems, medications and substances, work schedules, sleep deprivation, and sleep disorders (such as obstructive sleep apnea, narcolepsy, restless legs syndrome, and delayed sleep phase).

Hypersomnia is different than fatigue. You will recover from fatigue from lying down, but not from hypersomnia. And the only treatment for sleep deprivation is sleep.

Christopher Drake PhD of Wayne State University cited a 2002 National Sleep Foundation poll that found that more than one-third of Americans are so sleepy it interferes with their daily activities. Despite this, the same poll found that only 29 percent of physicians ask their patients about their sleep habits.

A 2005 study found that pediatric residents performed various cognitive tasks seven percent slower and committed 40 percent more errors after a heavy call rotation than a light call rotation.

Dr Drake explained that a sleep loss of four hours equates to five to six beers, or blood alcohol of 0.095, over the legal limit. The overworked residents in the 2005 study experienced impairment associated with a 0.04 to 0.05 alcohol level. Meanwhile, a 2003 study found that the mostly A students in a middle school population were more awake than C students.

According to an NIMH catchment study, 46.5 percent of patients with hypersomnia had a psychiatric disorder. Another study found that 29 percent of individuals with hypersomnia or excessive sleepiness had major depression. A 1999 study of patients with their depression in remission found the most common residual symptoms were sleep disturbances (44 percent) and fatigue (26 percent). Another study found that these residual symptoms were predictive of depressive relapse.

Fighting Off Sleep

At the same symposium, Leslie Lundt MD of Idaho State University hosted a coming out party for the neurotransmitter orexin, also known as hypocretin. Orexin/hypocretin was discovered in 1998 and originally thought to regulate appetite, but was soon found to be the main culprit in narcolepsy, and later to play a wider role in promoting sleep/wake.

Cortical arousal originates in the lower brain, with midbrain regions such as the hypothalamus acting as relay stations. Orexin-active neurons are located in the hypothalamus, from whence they interact with other neurotransmitter systems throughout the brain.

Other relevant neurotransmitters, besides the ones mentioned by Dr Stahl, include glutamate (wake), histamine (wake), GABA (sleep), and adenosine (sleep). Chardonnay, Dr Lundt said, is a GABA med.

Adenosine, by contrast, is why "people would be stupid enough to pay four dollars for a cup of coffee." Caffeine binds to adenosine receptors. The catch is that when the caffeine wears off the adenosine, which is still in the system, attaches to the naked receptors and the result is a crash. People who drink coffee regularly, Dr Lundt advised, develop a tolerance. If using caffeine as a drug, one should only use it on an as-needed basis.

Although NIDA has no position on the topic, Dr Lundt asserted, "I have seen patients addicted to caffeine."

As for meds treatments (and abuses): Amphetamines block the reuptake of dopamine, so much so that dopamine flows out of the neuron’s transporter rather than being sucked up. Methylphenidates such as Ritalin simply block dopamine uptake. Provigil has a "wimpy binding" to the dopamine transporter.

Non-meds treatments include strategic napping and managing light and dark.

Meanwhile, Over in the Hippocampus

It has long been assumed that we are stuck with the brain cells we are born with. Then, in 1998, Fred Gage PhD of the Salk Institute in La Jolla, CA, found evidence of neural stem cells in the hippocampus that matured in 28 days into adult neurons, a process called neurogenesis. The mature cells then formed connections with other cells.

Intriguingly, new neurons need to displace old neurons to make connections, suggesting a brain constantly at work in renewing itself.

Dr Gage has received the Charles Dana Award for Pioneering Achievement, plus other awards, and has been cited by Time magazine as one of the top 100 innovators of the 21st century.

At a packed lecture at the APA meeting, entitled, "New Neurons in the Adult Brain," Dr Gage explained that the hippocampus is the "seat of the acquisition of new memories," and is part of a critical circuit for affective behaviors. The hippocampus, he said, binds different experiences into a single unit and sends it to the cortex.

Acute stress blocks neurogenesis transiently while chronic stress results in long-lasting suppression of neurogenesis. By contrast, exercise and environmental enrichment encourages neurogenesis and promotes memory.

At another lecture filled to overflowing, "A Neurotrophic Hypothesis for Depression and Antidepressant Response," Ronald Duman PhD expounded on similar work conducted by his team at Yale, which has helped give rise to the above-named hypothesis.

Dr Duman is the recipient of numerous prestigious awards, including the Anna-Monika Prize. "Depression, in part," he explained, "results from loss of neurotrophic support." In other words there is more to depression and its treatment than just serotonin. Embattled and weakened neurons drop out of neural networks. With no replacement neurons, these networks are severely compromised.

But the process can be reversed. In 2000, Dr Duman discovered that antidepressants induced hippocampal neurogenesis in rats, which undid the destructive effects of stress. But that is not the end of the story. What is likely happening downstream (and upstream) of serotonin is a host of chemical actions inside the neuron responsible for cell maintenance, plasticity, growth, and programmed cell death. Current research is investigating a number of the molecules in these signaling pathways as potential direct targets for a new generation of meds. One leading candidate molecule is BDNF, which (fittingly), stands for brain derived neurotrophic factor.

Diagnosis: Everything

There we have it. We droop on the Stroop, get bad reporting on the Card Sorting, fail taking the Trail Making, and really annoy on the Tower of Hanoi. Our dopamine is less than keen, our glutamate is strictly cut-rate, our dorsolateral has no collateral, and there ain’t no amp in the hippocamp.

But if bipolar disorder is one defined by polar opposites, and this applies with equal force to thinking as it does to mood. Imagine a chronic physical illness that has you bedridden one week and running a sub-four-minute mile the next. The DSM in its criteria for mania refers to "flight of ideas or subjective experience that thoughts are racing." Believe me, there is nothing subjective about these racing thoughts. The only reason that the word, subjective, made it into the DSM is that science has no way to objectify the phenomenon.

Researchers only have the capability to get us into a room and put us through tests that make us look stupid. These are the parts of our brains that function like busted laptops. Yes, we may droop on the Stroop.

What the experts have yet to figure out is how to set up an experiment that can record the birth of a creative thought or take a snapshot of a breakthrough idea. These are the parts of our brains that run like Cray supercomputers. We rule in this school.

Our minds are literally processing data so fast that we make the type of connections and associations that lead to Eureka! moments, often at a rate that astounds people who do not share our illness. If there is anything subjective about our thinking, it is only after our brains have delivered the mental goods, when a solution miraculously reveals itself or a revelation floors us.

Society has benefited enormously from this aspect of our illness, from Newtonian physics to the Sistine Chapel. A good case can be made that we would all still be living in caves were it not for our supercomputers. In Darwinian terms, this would explain why our illness - terrible as it is - is seen as a positive trait worth passing down to the next generation.

Like our cognitive deficits, one need not be in an episode to experience racing thoughts. For this writer, they are a constant in my life. Since these thoughts are often running in the background as I am performing other tasks and at speeds usually quicker than the conscious mind can capture, one might call the process subconscious. Ideas literally pop out of the brain.

Paradoxically, my brain can run like a supercomputer and a clapped out laptop at the same time. I can go to Google to follow up on a brilliant thought only to forget momentarily why I am on the page. Since I am not a math whiz, my supercomputer is not going to outperform Stephen Hawking. It is only as good as what I put into it, from the books I read to the people I meet to the problems I focus on.

Racing thoughts can be a liability. The mouth can find itself articulating an errant thought before the rest of the brain has had a chance to process it. The intoxication of a latest revelation can distract one from current projects, ironically ones initiated by previous moments of inspiration. And many bright ideas turn out to be plain stupid ones. Our rational minds can usually protect us here, but in a state of mania we are not thinking rationally. It is one thing to come up with a brilliant idea for dog mascara, for instance, but it is another to quit your day job and sink your entire 401(k) in pursuit of such a venture.

No doubt, a future Business Week cover will feature the entrepreneurial genius who succeeded in convincing millions of dog owners that they were abusing their pooches by neglecting their mutts' eyelashes. That person could well be you, but only if you possess the skills to marry reason and persistence to inspiration and enthusiasm. Be advised: Our supercomputer is both a rare gift and potentially devastating liability. Act wisely.

February 10, 2008