Neurology Center

Recently, I wrote about diurnal mood variation: the way in which depression often waxes and wanes over the course of the day. Mornings are generally the worst.

A related phenomenon is late insomnia, or "early morning waking".

But this phrase is rather an understatement. Everyone's woken up early. Maybe you had a flight to catch. Or you were drunk and threw up. Or you just needed a pee. That's early morning waking, but not the depressive kind. When you're depressed, the waking up is the least of your problems.

Suddenly, you are awake, more awake than you've ever been. And you know something terrible has happened, or is about to happen, or that you've done something terribly wrong. It feels like a Eureka moment. You can be a level-headed person, not given to jumping to conclusions, but you will be convinced of this.

In a panic attack, you think you're going to die. Your heart is beating too fast, your breathing's too deep: your body is exploding, you can feel it too closely. With this, With this, you think you should die or even, in some sense, already have. It feels cold: you can no longer feel the warmth of your own body.

The moment passes; the terrible truth that you were so certain of five minutes ago becomes a little doubtful. Maybe it's not quite so bad. At this point, the wakefulness goes too, and you become, well, as tired as you ought to be at 3 am. You try to go back to sleep. If you're lucky, you succeed. If not, you lie awake until morning in a state of miserable contemplation.

While it's happening, you think that you're going to feel this way forever; bizarrely, you think you always have felt this way. In fact, this is the darkest hour.

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Why does this happen? There has been almost no research on early morning waking. Presumably, because it's so hard to study. To observe it, you would have to get your depressed patients to spend all night in your brain scanner (or, if you prefer, on your analyst's couch), and even then, it doesn't happen every night.

But here's my theory: the key is the biology of sleep. There are many stages of sleep; at a very rough approximation there's dreaming REM, and dreamless slow-wave. Now, REM sleep tends to happen during the second half of the night - the early morning.

During REM sleep, the brain is, in many respects, awake. This is presumably what allows us to have concious dreams. Whereas in slow wave sleep, the brain really is offline; slow waves are also seen in the brain of people in comas, or under deep anaesthesia.

When we're awake, the brain is awash with modulatory neurotransmitters, such as serotonin, norepinephrine, and acetylcholine. During REM, acetylcholine is present, while in slow-wave sleep it's not; indeed acetylcholine may well be what stops slow waves and "wakes up" the cortex.

But unlike during waking, serotonin and norepinephrine neurons are entirely inactive during REM sleep - and only during REM sleep. This fact is surprisingly little-known, but it seems to me that it explains an awful lot.

For one thing, it explains why drugs which increase serotonin levels, such as SSRI antidepressants, inhibit REM sleep. Indeed, high doses of MAOi antidepressants prevent REM entirely (without any noticeable ill-effects, suggesting REM is dispensable). SSRIs only partially suppress it.

Ironically, SSRIs can make dreams more vivid and colourful. I've been told by sleep scientists that this is because they delay the onset of REM so the dreams are "shifted" later into the night making you more likely to remember them when you wake up. But there could be more to it than that.

The fact that REM is a serotonin-free zone also explains wet dreams. Serotonin is well known to suppresses ejaculation; that's why SSRIs delay orgasm, one of their least popular side effects, although it's useful to treat premature ejaculation: every cloud has a silver lining.

So, having said all that: could this also explain the terror of early-morning waking? Suppose that, for whatever reason, you woke up during REM sleep, but your serotonin cells didn't wake up quick enough, leaving you awake, but with no serotonin (a situation which never normally occurs, remember). How would that feel?

Using a technique called acute tryptophan depletion (ATD), you can lower someone's serotonin levels. In most people, this doesn't do very much, but in some people with a history of depression, it causes them to relapse. Here's what happened to one patient after ATD:

[her] previous episodes of clinical depression were associated with the loss of important friendships had, while depressed, been preoccupied with fears that she would never be able to sustain a relationship. She had not had such fears since then.

She had been fully recovered and had not taken any medication for over a year. About 2 h after drinking the tryptophan-free mixture she experienced a sudden onset of sadness, despair, and uncontrollable crying. She feared that a current important relationship would end.

We don't know why tryptophan depletion does this to some people, or why it doesn't affect everyone the same way, and it's pure speculation that early morning waking has anything to do with this. But having said that, the pieces do seem to fit.

One of the difficulties doctors face when prescribing antidepressants is that they're unpredictable.

One person might do well on a certain drug, but the next person might get no benefit from the exact same pills. Finding the right drug for each patient is often a matter of trying different ones until one works.

So a genetic test to work out whether a certain drug will help a particular person would be really useful. Not to mention really profitable for whoever patented it. Three recent papers, published in three major journals, all claim to have found genes that predict antidepressant response. Great! The problem is, they were different genes.

First up, American team Binder et al looked at about 200 variants in 10 genes involved in the corticosteroid stress response pathway. They found one, in a gene called CRHBP, that was significantly associated with poor response to the popular SSRI antidepressant citalopram (Celexa), using the large STAR*D project data set. But this was only true of African-Americans and Latinos, not whites.

Garriock et al used the exact same dataset, but they did a genome-wide association study (GWAS), which looks at variants across the whole genome, unlike Binder et al who focussed on a small number of specific candidate genes. Sadly no variants were statistically significantly correlated with response to citalopram, although in a GWAS, the threshold for genome-wide significance is very high due to multiple comparisons correction. Some were close to being significant, but they weren't obviously related to CRHBP, and most weren't anything to do with the brain.

Uher et al did another GWAS of response to escitalopram and nortriptyline in a different sample, the European GENDEP study. Escitalopram is extremely similar to citalopram, the drug in the STAR*D studies; nortriptyline however is very different. They found one genome-wide significant hit. A variant in a gene called UST was associated with response to nortriptyline, but not escitalopram. No variants were associated with response to escitalopram, although one in the gene IL11 was close. There were some other nearly-significant results, but they didn't overlap with either of the STAR*D studies.

Finally, one of the STAR*D studies found a variant significantly linked to tolerability (side effects) of citalopram. GENDEP didn't look at this.

Via Dormivigilia, I came across a fascinating paper about a man who suffered from a severe lack of monoamine neurotransmitters (dopamine, serotonin etc.) as a result of a genetic mutation: Sleep and Rhythm Consequences of a Genetically Induced Loss of Serotonin


Neuroskeptic readers will be familiar with monoamines. They're psychiatrists' favourite neurotransmitters, and are hence very popular amongst psych drug manufacturers. In particular, it's widely believed that serotonin is the brain's "happy chemical" and that clinical depression is caused by low serotonin while antidepressants work by boosting it.

Critics charge that there is no evidence for any of this. My own opinion is that it's complicated, but that while there's certainly no simple relation between serotonin, antidepressants and mood, they are linked in some way. It's all rather mysterious, but then, the functions of serotonin in general are; despite 50 years of research, it's probably the least understood neurotransmitter.

The new paper adds to the mystery, but also provides some important new data. Leu-Semenescu et al report on the case of a 28 year old man, with consanguineous parents, who suffers from a rare genetic disorder, sepiapterin reductase deficiency (SRD). SRD patients lack an enzyme which is involved, indirectly, in the production of the monoamines serotonin and dopamine, and also melatonin and noradrenaline which are produced from these two. SRD causes a severe (but not total) deficiency of these neurotransmitters.

The most obvious symptoms of SRD are related to the lack of dopamine, and include poor coordination and weakness, very similar to Parkinson's Disease. An interesting feature of SRD is that these symptoms are mild in the morning, worsen during the day, and improve with sleep. Such diurnal variation is also a hallmark of severe depression, although in depression it's usually the other way around (better in the evening).

The patient reported on in this paper suffered Parkinsonian symptoms from birth, until he was diagnosed with dystonia at age 5 and started on L-dopa to boost his dopamine levels. This immediately and dramatically reversed the problems.

But his serotonin synthesis was still impaired, although doctors didn't realize this until age 27. As a result, Leu-Semenescu et al say, he suffered from a range of other, non-dopamine-related symptoms. These included increased appetite - he ate constantly, and was moderately obese - mild cognitive impairment, and disrupted sleep:

The patient reported sleep problems since childhood. He would sleep 1 or 2 times every day since childhood and was awake during more than 2 hours most nights since adolescence. At the time of the first interview, the night sleep was irregular with a sleep onset at 22:00 and offset between 02:00 and 03:00. He often needed 1 or 2 spontaneous, long (2- to 5-h) naps during the daytime.

One of the limitations of antidepressants is that they don't always work. Worse, they don't work in an unpredictable way. Some people benefit from some drugs, and others don't, but there's no way of knowing in advance what will happen in any particular case - or of telling which pill is right for which person.

As a result, drug treatment for depression generally involves starting with a cheap medication with relatively mild side-effects, and if that fails, moving onto a series of other drugs until one helps. But since it can take several weeks for any new drug to work, this can be a frustrating process for patients and doctors alike.

Some means of predicting the antidepressant response would thus be very useful. Many have been proposed, but none have entered widespread clinical use. Now, a pair of papers(1,2) from UCLA's Andrew Leuchter et al make the case for prediction using quantitative EEG (QEEG).

EEG, electroencephalography, is a crude but effective way of recording electrical activity in the brain via electrodes attached to the head. "Quantitative" EEG just means using EEG to precisely measure the level of certain kinds of activity in the brain.

Leuchter et al's system is straightforward: it uses six electrodes on the front of the head. The patient simply relaxes with their eyes closed for a few minutes while neural activity is recorded.

This procedure is performed twice, once just before antidepressant treatment begins and then again a week later. The claim is that by examining the changes in the EEG signal after one week of drug treatment, the eventual benefit of the drug can be predicted. It's not an implausible idea, and if it did work, it would be rather helpful. But does it?

Leuchter et al say: yes! The first paper reports that in 73 depressed patients who were given the antidepressant escitalopram 10mg/day, QEEG changes after one week predicted clinical improvement six weeks later. Specifically, people who got substantially better at seven weeks had a higher "Antidepressant Treatment Response Index" (ATR) at one week than people who didn't: 59.0 ± 10.2 vs 49.8 ± 7.8, which is highly significant (p less than 0.001).

In the companion paper, the authors examined patients who started on escitalopram and then either kept taking it or switched to a different antidepressant, bupropion. They found that patients who had a high ATR after a week of escitalopram tended to do well if they stayed on it, while patients who had a low ATR to escitalopram did better when they switched to the other drug.

These are interesting results, and they follow from ten years of previous work (mostly, but not exclusively, from the same group) on the topic. Because the current study didn't include a placebo group, we can't say that the QEEG predicts antidepressant response as such, only that it predicts improvement in depression symptoms. But even this is pretty exciting, if it really works.

In order to verify that it does, other researchers need to replicate this experiment. But they may find this a little difficult. What is the Antidepressant Treatment Response Index use in this study? It's derived from an analysis of the EEG signal, and we're told that you get it from this formula:

Some of the terms here are common parameters that any EEG expert will understand. But "A", "B", and "C" are not. They're constants, which are not given in the paper. They're secret numbers. Without knowing what those numbers are, no-one can calculate the "ATR" even if they have an EEG machine.

Why keep them secret? Well...

"Financial support of this project was provided by Aspect Medical Systems. Aspect participated in the design and conduct of the study; collection, management, analysis, and interpretation of the data; and preparation and review of the manuscript."

"To facilitate independent replication of the work reported here, Aspect intends to make available a limited number of investigational systems for academic researchers. Please contact Scott Greenwald, Ph.D... for further information."

[BPSDB]

Leuchter AF, Cook IA, Gilmer WS, Marangell LB, Burgoyne KS, Howland RH, Trivedi MH, Zisook S, Jain R, Fava M, Iosifescu D, & Greenwald S (2009). Effectiveness of a quantitative electroencephalographic biomarker for predicting differential response or remission with escitalopram and bupropion in major depressive disorder. Psychiatry research PMID: 19709754

Leuchter AF, Cook IA, Marangell LB, Gilmer WS, Burgoyne KS, Howland RH, Trivedi MH, Zisook S, Jain R, McCracken JT, Fava M, Iosifescu D, & Greenwald S (2009). Comparative effectiveness of biomarkers and clinical indicators for predicting outcomes of SSRI treatment in Major Depressive Disorder: Results of the BRITE-MD study. Psychiatry research PMID: 19712979

The herb St John's Wort is as effective as antidepressants while having milder side effects, according to a recent Cochrane review, St John's wort for major depression.

Professor Edzard Ernst, a well-known enemy of complementary and alternative medicine, wrote a favorable review of this study in which he comments that given the questions around the safety and effectiveness of antidepressants, it is a mystery why St John's Wort is not used more widely.

When Edzard Ernst says a herb works, you should take notice. But is St John's Wort (Hypericum perforatum) really the perfect antidepressant? Curiously, it seems to depend whether you're German or not.

The Cochrane review included 29 randomized, double-blind trials with a total of 5500 patients. The authors only included trials where all patients met DSM-IV or ICD-10 criteria for "major depression". 18 trials compared St John's Wort extract to placebo pills, and 19 compared it conventional antidepressants. (Some trials did both).

The analysis concluded that overall, St John's Wort was significantly more effective than placebo. The magnitude of the benefit was similar to that seen with conventional antidepressants in other trials (around 3 HAMD points). However, this was only true when studies from German-speaking countries were examined.

Out of the 11 Germanic trials, 8 found that St John's Wort was significantly better than placebo and the other 3 were all very close. None of the 8 non-Germanic trials found it to be effective and only one was close.


Edzard Ernst, by the way, is German. So were the authors of this review. I'm not.

The picture was a bit more clear when St John's Wort was directly compared to conventional antidepressants: it was almost exactly as effective. It was only significantly worse in one small study. This was true in both Germanic and non-Germanic studies, and was true when either older tricyclics or newer SSRIs were considered.

Perhaps the most convincing result was that St John's Wort was well tolerated. Patients did not drop out of the trials because of side-effects any more often than when they were taking placebo (OR=0.92), and were much less likely to drop out versus patients given antidepressants (OR=0.41). Reported side effects were also very few. (It can be dangerous when combined with certain antidepressants and other medications however.)

So, what does this mean? If you look at it optimistically, it's wonderful news. St John's Wort, a natural plant product, is as good as any antidepressant against depression, and has much fewer side effects, maybe no side effects at all. It should be the first-line treatment for depression, especially because it's cheap (no patents).

But from another perspective this review raises more questions than answers. Why did St John's Wort perform so differently in German vs. non-German studies? The authors admit that:

Our finding that studies from German-speaking countries yielded more favourable results than trials performed elsewhere is difficult to interpret. ... However, the consistency and extent of the observed association suggest that there are important differences in trials performed in different countries.

We cannot rule out, but doubt, that selective publication of overoptimistic results in small trials strongly influences our findings.

Who's more likely to start digging prematurely: one guy with a metal-detector looking for an old nail, or a field full of people with metal-detectors searching for buried treasure?

In any area of science, there will be some things which are more popular than others - maybe a certain gene, a protein, or a part of the brain. It's only natural and proper that some things get of lot of attention if they seem to be scientifically important. But Thomas Pfeiffer and Robert Hoffmann warn in a PLoS One paper that popularity can lead to inaccuracy - Large-Scale Assessment of the Effect of Popularity on the Reliability of Research.

They note two reasons for this. Firstly, popular topics tend to attract interest and money. This means that scientists have much to gain by publishing "positive results" as this allows them to get in on the action -

The second effect results from multiple independent testing of the same hypotheses by competing research groups. The more often a hypothesis is tested, the more likely a positive result is obtained and published even if the hypothesis is false. ... We refer to this mechanism as “multiple testing effect”.

Saturday saw the Guardian on fine form with a classic piece of bad neuro-journalism which made it all the way onto the front page:

The fact that our genotype groups were matched on a range of self-report measures, including neuroticism can be seen as a major strength.

Update: See also Lessons from the Video Game Brain



The Journal of Neuroscience has published a Swedish study which, according to New Scientist (and the rest) is something of a breakthrough:

First 'Placebo Gene' Discovered

PET data: whole-brain analyses

Exploratory analyses did not reveal significantly different treatment-induced patterns of change in responders versus nonresponders. Significant within-group alterations outside the amygdala region were noted only in nonresponders, who had increased (pre < post) rCBF in the right cerebellum ... and in a cluster encompassing the right primary motor and somatosensory cortices...

In a logistic regression analysis, the TPH2 polymorphism emerged as the only significant variable that could reliably predict clinical placebo response (CGI-I) on day 56, homozygosity for the G allele being associated with better outcome. Eight of the nine placebo responders (89%), for whom TPH2 gene data were available, were GG homozygotes.

Patients were taken from two previously unpublished RCTs that evaluated changes in regional cerebral blood flow after 56 d of pharmacological treatment by means of positron emission tomography. ... The clinical PET trials ... included a total of 108 patients with SAD. There were three treatment arms in the first study and six arms in the second. ... Only the pooled placebo data are included herein, whereas additional data on psychoactive drug treatment will be reported separately.