The FIRSTS: Lack of happy events in depression (2003)

My last post focused on depression and it reminded me of something that I keep telling my students and they all react with disbelief. Well, I tell them a lot of things to which they react with disbelief, to be sure, but this one I keep thinking it should not generate such disbelief. The thing is: depressed people perceive the same amount of negative events happening to them as healthy people, but far fewer positive ones. This seems to be counter-intuitive to non-professionals, who believe depressed people are sadder than normal and only see the half-empty side of the glass of life.

So I dug out the original paper who found this… finding. It’s not as old as you might think. Peeters et al. (2003) paid $30/capita to 86 people, 46 of which were diagnosed with Major Depressive Disorder and seeking treatment in a community mental health center or outpatient clinic (this is in Netherlands). None were taking antidepressants or any other drugs, except low-level anxiolytics. Each participant was given a wristwatch that beeped 10 times a day at semi-random intervals of approximately 90 min. When the watch beeped, the subjects had to complete a form within maximum 25 min answering questions about their mood, currents events, and their appraisal of those events. The experiment took 6 days, including weekend.

The results? Contrary to popular belief, people with depression “did not report more frequent negative events, although they did report fewer positive events and appraised both types of events as more stressful” (p. 208). In other words, depressed people are not seeing half-empty glasses all the time; instead, they don’t see the half-full glasses. Note that they regarded both negative and positive events as stressful. We circle back to the ‘stress is the root of all evil‘ thing.

I would have liked to see if the decrease in positive affect and perceived happy events correlates with increased sadness. The authors say that “negative events were appraised as more unpleasant, more important, and more stressful by the depressed than by the healthy participants ” (p. 206), but, curiously, the  mood was assessed with ratings on the feeling anxious, irritated, restless, tense, guilty, irritable, easily distracted, and agitate, and not a single item on depression-iconic feelings: sad, empty, hopeless, worthless.

Nevertheless, it’s a good psychological study with in depth statistical analyses. I also found thought-provoking this paragraph: “The literature on mood changes in daily life is dominated by studies of daily hassles. The current results indicate that daily uplifts are also important determinants of mood, in both depressed and healthy people” (p. 209).

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REFERENCE: Peeters F, Nicolson NA, Berkhof J, Delespaul P, & deVries M. (May 2003). Effects of daily events on mood states in major depressive disorder. Journal of Abnormal Psychology, 112(2):203-11. PMID: 12784829, DOI: 10.1037/0021-843X.112.2.203. ARTICLE

By Neuronicus, 4 May 2019

Epigenetics of BDNF in depression

Depression is the leading cause of disability worldwide, says the World Health Organization. The. The. I knew it was bad, but… ‘the’? More than 300 million people suffer from it worldwide and in many places fewer than 10% of these receive treatment. Lack of treatment is due to many things, from lack of access to healthcare to lack of proper diagnosis; and not in the least due to social stigma.

To complicate matters, the etiology of depression is still not fully elucidated, despite hundreds of thousand of experimental articles published out-there. Perhaps millions. But, because hundreds of thousands of experimental articles perhaps millions have been published, we know a helluva a lot about it than, say, 50 years ago. The enormous puzzle is being painstakingly assembled as we speak by scientists all over the world. I daresay we have a lot of pieces already, if not all at least 3 out of 4 corners, so we managed to build a not so foggy view of the general picture on the box lid. Here is one of the hottest pieces of the puzzle, one of those central pieces that bring the rabbit into focus.

Before I get to the rabbit, let me tell you about the corners. In the fifties people thought that depression is due to having too little neurotransmitters from the monoamine class in the brain. This thought did not arise willy-nilly, but from the observation that drugs that increase monoamine levels in the brain alleviate depression symptoms, and, correspondingly, drugs which deplete monoamines induce depression symptoms. A bit later on, the monoamine most culpable was found to be serotonin. All well and good, plenty of evidence, observational, correlational, causational, and mechanistic supporting the monoamine hypothesis of depression. But two more pieces of evidence kept nagging the researchers. The first one was that the monoamine enhancing drugs take days to weeks to start working. So, if low on serotonin is the case, then a selective serotonin reuptake inhibitor (SSRI) should elevate serotonin levels within maximum an hour of ingestion and lower symptom severity, so how come it takes weeks? The second was even more eyebrow raising: these monoamine-enhancing drugs work in about 50 % of the cases. Why not all? Or, more pragmatically put, why not most of all if the underlying cause is the same?

It took decades to address these problems. The problem of having to wait weeks until some beneficial effects of antidepressants show up has been explained away, at least partly, by issues in the serotonin regulation in the brain (e.g. autoreceptors senzitization, serotonin transporter abnormalities). As for the second problem, the most parsimonious answer is that that archeological site called DSM (Diagnostic and Statistical Manual of Mental Disorders), which psychologists, psychiatrists, and scientists all over the world have to use to make a diagnosis is nothing but a garbage bag of last century relics with little to no resemblance of this century’s understanding of the brain and its disorders. In other words, what DSM calls major depressive disorder (MDD) may as well be more than one disorder and then no wonder the antidepressants work only in half of the people diagnosed with it. As Goldberg put it in 2011, “the DSM diagnosis of major depression is made when a patient has any 5 out of 9 symptoms, several of which are opposites [emphasis added]”! He was referring to DSM-4, not that the 5 is much different. I mean, paraphrasing Goldberg, you really don’t need much of a degree other than some basic intro class in the physiology of whatever, anything really, to suspect that someone who’s sleeping a lot, gains weight, has increased appetite, appears tired or slow to others, and feels worthless might have a different cause for these symptoms than someone who has daily insomnias, lost weight recently, has decreased appetite, is hyperagitated, irritable, and feels excessive guilt. Imagine how much more understanding we would have about depression if scientists didn’t use the DSM for research. No wonder that there’s a lot of head scratching when your hypothesis, which is logically correct, paradigmatically coherent, internally consistent, flawlessly tested, turns out to be correct only sometimes because you’re ‘depressed’ subjects are as a homogeneous group as a pack of Trail Mix.

I got sidetracked again. This time ranting against DSM. No matter, I’m back on track. So. The good thing about the work done trying to figure out how antidepressants work and psychiatrists’ minds work (DSM is written overwhelmingly by psychiatrists), scientists uncovered other things about depression. Some of the findings became clumped under the name ‘the neurotrophic hypothesis of depression’ in the early naughts. It stems from the finding that some chemicals needed by neurons for their cellular happiness are in low amount in depression. Almost two decades later, the hypothesis became mainstream theory as it explains away some other findings in depression, and is not incompatible with the monoamines’ behavior. Another piece of the puzzle found.

One of these neurotrophins is called brain-derived neurotrophic factor (BDNF), which promotes cell survival and growth. Crucially, it also regulates synaptic plasticity, without which there would be no learning and no memory. The idea is that exposure to adverse events generates stress. Stress is differently managed by different people, largely due to genetic factors. In those not so lucky at the genetic lottery (how hard they take a stressor, how they deal with it), and in those lucky enough at genetics but not so lucky in life (intense and/or many stressors hit the organism hard regardless how well you take it or how good you are at it), stress kills a lot of neurons, literally, prevents new ones from being born, and prevents the remaining ones from learning well. Including learning on how to deal with the stressors, present and future, so the next time an adverse event happens, even if it is a minor stressor, the person is way more drastically affected. in other words, stress makes you more vulnerable to stressors. One of the ways stress is doing all these is by suppressing BDNF synthesis. Without BDNF, the individual exposed to stress that is exacerbated either by genes or environment ends up unable to self-regulate mood successfully. The more that mood is not regulated, the worse the brain becomes at self-regulating because the elements required for self-regulation, which include learning from experience, are busted. And so the vicious circle continues.

Maintaining this vicious circle is the ability of stressors to change the patterns of DNA expression and, not surprisingly, one of the most common findings is that the BDNF gene is hypermethylated in depression. Hypermethylation is an epigenetic change (a change around the DNA, not in the DNA itself), meaning that the gene in question is less expressed. This means lower amounts of BDNF are produced in depression.

After this long introduction, the today’s paper is a systematic review of one of epigenetic changes in depression: methylation. The 67 articles that investigated the role of methylation in depression were too heterogeneous to make a meta-analysis out of them, so Li et al. (2019) made a systematic review.

The main finding was that, overall, depression is associated with DNA methylation modifications. Two genes stood out as being hypermethylated: our friend BDNF and SLC6A4, a gene involved in the serotonin cycle. Now the question is who causes who: is stress methylating your DNA or does your methylated DNA make you more vulnerable to stress? There’s evidence both ways. Vicious circle, as I said. I doubt that for the sufferer it matters who started it first, but for the researchers it does.

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A little disclaimer: the picture I painted above offers a non-exclusive view on the causes of depression(s). There’s more. There’s always more. Gut microbes are in the picture too. And circulatory problems. And more. But the picture is more than half done, I daresay. Continuing my puzzle metaphor, we got the rabbit by the ears. Now what to do with it…

Well, one thing we can do with it, even with only half-rabbit done, is shout loud and clear that depression is a physical disease. And those who claim it can be cured by a positive attitude and blame the sufferers for not ‘trying hard enough’ or not ‘smiling more’ or not ‘being more positive’ can bloody well shut up and crawl back in the medieval cave they came from.

REFERENCES:

1. Li M, D’Arcy C, Li X, Zhang T, Joober R, & Meng X (4 Feb 2019). What do DNA methylation studies tell us about depression? A systematic review. Translational Psychiatry, 9(1):68. PMID: 30718449, PMCID: PMC6362194, DOI: 10.1038/s41398-019-0412-y. ARTICLE | FREE FULLTEXT PDF

2. Goldberg D (Oct 2011). The heterogeneity of “major depression”. World Psychiatry, 10(3):226-8. PMID: 21991283, PMCID: PMC3188778. ARTICLE | FREE FULLTEXT PDF

3. World Health Organization Depression Fact Sheet

By Neuronicus, 23 April 2019

Locus Coeruleus in mania

From all the mental disorders, bipolar disorder, a.k.a. manic-depressive disorder, has the highest risk for suicide attempt and completion. If the thought of suicide crosses your mind, stop reading this, it’s not that important; what’s important is for you to call the toll-free National Suicide Prevention Lifeline at 1-800-273-TALK (8255).

The bipolar disorder is defined by alternating manic episodes of elevated mood, activity, excitation, and energy with episodes of depression characterized by feelings of deep sadness, hopelessness, worthlessness, low energy, and decreased activity. It is also a more common disease than people usually expect, affecting about 1% or more of the world population. That means almost 80 million people! Therefore, it’s imperative to find out what’s causing it so we can treat it.

Unfortunately, the disease is very complex, with many brain parts, brain chemicals, and genes involved in its pathology. We don’t even fully comprehend how the best medication we have to lower the risk of suicide, lithium, works. The good news is the neuroscientists haven’t given up, they are grinding at it, and with every study we get closer to subduing this monster.

One such study freshly published last month, Cao et al. (2018), looked at a semi-obscure membrane protein, ErbB4. The protein is a tyrosine kinase receptor, which is a bit unfortunate because this means is involved in ubiquitous cellular signaling, making it harder to find its exact role in a specific disorder. Indeed, ErbB4 has been found to play a role in neural development, schizophrenia, epilepsy, even ALS (Lou Gehrig’s disease).

Given that ErbB4 is found in some neurons that are involved in bipolar and mutations in its gene are also found in some people with bipolar, Cao et al. (2018) sought to find out more about it.

First, they produced mice that lacked the gene coding for ErbB4 in neurons from locus coeruleus, the part of the brain that produces norepinephrine out of dopamine, better known for the European audience as nor-adrenaline. The mutant mice had a lot more norepinephrine and dopamine in their brains, which correlated with mania-like behaviors. You might have noticed that the term used was ‘manic-like’ and not ‘manic’ because we don’t know for sure how the mice feel; instead, we can see how they behave and from that infer how they feel. So the researchers put the mice thorough a battery of behavioral tests and observed that the mutant mice were hyperactive, showed less anxious and depressed behaviors, and they liked their sugary drink more than their normal counterparts, which, taken together, are indices of mania.

Next, through a series of electrophysiological experiments, the scientists found that the mechanism through which the absence of ErbB4 leads to mania is making another receptor, called NMDA, in that brain region more active. When this receptor is hyperactive, it causes neurons to fire, releasing their norepinephrine. But if given lithium, the mutant mice behaved like normal mice. Correspondingly, they also had a normal-behaving NMDA receptor, which led to normal firing of the noradrenergic neurons.

So the mechanism looks like this (Jargon alert!):

No ErbB4 –> ↑ NR2B NMDAR subunit –> hyperactive NMDAR –> ↑ neuron firing –> ↑ catecholamines –> mania.

In conclusion, another piece of the bipolar puzzle has been uncovered. The next obvious step will be for the researchers to figure out a medicine that targets ErbB4 and see if it could treat bipolar disorder. Good paper!

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P.S. If you’re not familiar with the journal eLife, go and check it out. The journal offers for every study a half-page summary of the findings destined for the lay audience, called eLife digest. I’ve seen this practice in other journals, but this one is generally very well written and truly for the lay audience and the non-specialist. Something of what I try to do here, minus the personal remarks and in parenthesis metacognitions that you’ll find in most of my posts. In short, the eLife digest is masterly done. As my continuous struggles on this blog show, it is tremendously difficult for a scientist to write concisely, precisely, and jargonless at the same time. But eLife is doing it. Check it out. Plus, if you care to take a look on how science is done and published, eLife publishes all the editor’s rejection notes, all the reviewers’ comments, and all the author responses for a particular paper. Reading those is truly a teaching moment.

REFERENCE: Cao SX, Zhang Y, Hu XY, Hong B, Sun P, He HY, Geng HY, Bao AM, Duan SM, Yang JM, Gao TM, Lian H, Li XM (4 Sept 2018). ErbB4 deletion in noradrenergic neurons in the locus coeruleus induces mania-like behavior via elevated catecholamines. Elife, 7. pii: e39907. doi: 10.7554/eLife.39907. PMID: 30179154 ARTICLE | FREE FULLTEXT PDF

By Neuronicus, 14 October 2018

The FIRSTS: The roots of depressive realism (1979)

There is a rumor stating that depressed people see the world more realistically and the rest of us are – to put it bluntly – deluded optimists. A friend of mine asked me if this is true. It took me a while to find the origins of this claim, but after I found it and figured out that the literature has a term for the phenomenon (‘depressive realism’), I realized that there is a whole plethora of studies on the subject. So the next following posts will be centered, more or less, on the idea of self-deception.

It was 1979 when Alloy & Abramson published a paper who’s title contained the phrase ‘Sadder but Wiser’, even if it was followed by a question mark. The experiments they conducted are simple, but the theoretical implications are large.

The authors divided several dozens of male and female undergraduate students into a depressed group and a non-depressed group based on their Beck Depression Inventory scores (a widely used and validated questionnaire for self-assessing depression). Each subject “made one of two possible responses (pressing a button or not pressing a button) and received one of two possible outcomes (a green light or no green light)” (p. 447). Various conditions presented the subjects with various degrees of control over what the button does, from 0 to 100%. After the experiments, the subjects were asked to estimate their control over the green light, how many times the light came on regardless of their behavior, what’s the percentage of trials on which the green light came on when they pressed or didn’t press the button, respectively, and how did they feel. In some experiments, the subjects were wining or losing money when the green light came on.

Verbatim, the findings were that:

“Depressed students’ judgments of contingency were surprisingly accurate in all four experiments. Nondepressed students, on the other hand, overestimated the degree of contingency between their responses and outcomes when noncontingent outcomes were frequent and/or desired and underestimated the degree of contingency when contingent outcomes were undesired” (p. 441).

In plain English, it means that if you are not depressed, when you have some control and bad things are happening, you believe you have no control. And when you have no control but good things are happening, then you believe you have control. If you are depressed, it does not matter, you judge your level of control accurately, regardless of the valence of the outcome.

Such illusion of control is a defensive mechanism that surely must have adaptive value by, for example, allowing the non-depressed to bypass a sense of guilt when things don’t work out and increase self-esteem when they do. This is fascinating, particularly since it is corroborated by findings that people receiving gambling wins or life successes like landing a good job, rewards that at least in one case are demonstrably attributable to chance, believe, nonetheless, that it is due to some personal attributes that make them special, that makes them deserving of such rewards. (I don’t remember the reference of this one so don’t quote me on it. If I find it, I’ll post it, it’s something about self-entitlement, I think). That is not to say that life successes are not largely attributable to the individual; they are. But, statistically speaking, there must be some that are due to chance alone, and yet most people feel like they are the direct agents for changes in luck.

Another interesting point is that Alloy & Abramson also tried to figure out how exactly their subjects reasoned when they asserted their level of control through some clever post-experiment questioners. Long story short (the paper is 45 pages long), the illusion of control shown by nondepressed subjects in the no control condition was the result of incorrect logic, that is, faulty reasoning.

In summary, the distilled down version of depressive realism that non-depressed people see the world through rose-colored glasses is correct only in certain circumstances. Because only in particular conditions this illusion of control applies and that is overestimation of control only when good things are happening and underestimation of control when bad things are happening. But, by and large, it does seem that depression clears the fog a bit.

Of course, it has been over 40 years since the publication of this paper and of course it has its flaws. Many replications and replications with caveats and meta-analyses and reviews and opinions and alternative hypotheses have been confirmed and infirmed and then confirmed again with alterations, so there is still a debate out there about the causes/ functions/ ubiquity/ circumstantiality of the depressive realism effect. One thing seems to be constant though: the effect exists.

I will leave you with the ponders of Alloy & Abramson (1979):

“A crucial question is whether depression itself leads people to be “realistic” or whether realistic people are more vulnerable to depression than other people” (p. 480).

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REFERENCE: Alloy LB, & Abramson LY (Dec. 1979). Judgment of contingency in depressed and nondepressed students: sadder but wiser? Journal of Experimental Psychology: General, 108(4): 441-485. PMID: 528910. http://dx.doi.org/10.1037/0096-3445.108.4.441. ARTICLE | FULLTEXT PDF via ResearchGate

By Neuronicus, 30 November 2017

Video games and depression

There’s a lot of talk these days about the harm or benefit of playing video games, a lot of time ignoring the issue of what kind of video games we’re talking about.

Merry et al. (2012) designed a game for helping adolescents with depression. The game is called SPARX (Smart, Positive, Active, Realistic, X-factor thoughts) and is based on the cognitive behavioral therapy (CBT) principles.

CBT has been proven to be more efficacious that other forms of therapy, like psychoanalysis, psychodynamic, transpersonal and so on in treating (or at least alleviating) a variety of mental disorders, from depression to anxiety, form substance abuse to eating disorders. Its aim is to identify maladaptive thoughts (the ‘cognitive’ bit) and behaviors (the ‘behavior’ bit), change those thoughts and behaviors in order to feel better. It is more active and more focused than other therapies, in the sense that during the course of a CBT session, the patient and therapist discuss one problem and tackle it.

SPARX is a simple interactive fantasy game with 7 levels (Cave, Ice, Volcano, Mountain, Swamp, Bridgeland, Canyon) and the purpose is to fight the GNATs (Gloomy Negative Automatic Thoughts) by mastering several techniques, like breathing and progressive relaxation and acquiring skills, like scheduling and problem solving. You can customize your avatar and you get a guide throughout the game that also assess your progress and gives you real-life quests, a. k. a. therapeutic homework. If the player does not show the expected improvements after each level, s/he is directed to seek help from a real-life therapist. Luckily, the researchers also employed the help of true game designers, so the game looks at least half-decent and engaging, not a lame-worst-graphic-ever-bleah sort of thing I was kind of expecting.

To see if their game helps with depression, Merry et al. (2012) enrolled in an intervention program 187 adolescents (aged between 12-19 years) that sought help for depression; half of the subjects played the game for about 4 – 7 weeks, and the other half did traditional CBT with a qualified therapist for the same amount of time.  The patients have been assessed for depression at regular intervals before, during and after the therapy, up to 3 months post therapy. The conclusion?

SPARX “was at least as good as treatment as usual in primary healthcare sites in New Zealand” (p. 8)

Not bad for an RPG! The remission rates were higher for the SPARX group that in treatment as usual group. Also, the majority of participants liked the game and would recommend it. Additionally, SPARX was more effective than CBT for people who were less depressed than the ones who scored higher on the depression scales.

And now, coming back to my intro point, the fact that this game seems to be beneficial does not mean all of them are. There are studies that show that some games have deleterious effects on the developing brain. In the same vein, the fact that some shoddy company sells games that are supposed to boost your brain function (I always wandered which function…) that doesn’t mean they are actually good for you. Without the research to back up the claims, anybody can say anything and it becomes a “Buyer Beware!” game. They may call it cognitive enhancement, memory boosters or some other brainy catch phrase, but without the research to back up the claims, it’s nothing but placebo in the best case scenario. So it gives me hope – and great pleasure – that some real psychologists at a real university are developing a video game and then do the necessary research to validate it as a helping tool before marketing it.

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Oh, an afterthought: this paper is 4 years old so I wondered what happened in the meantime, is it on the market or what? On the research databases I couldn’t find much, except that it was tested this year on Dutch population with pretty much similar results. But Wikipedia tells us that is was released in 2013 and is free online for New Zealanders! The game’s website says it may become available to other countries as well.

Reference: Merry SN, Stasiak K, Shepherd M, Frampton C, Fleming T, & Lucassen MF. (18 Apr 2012). The effectiveness of SPARX, a computerised self help intervention for adolescents seeking help for depression: randomised controlled non-inferiority trial. The British Medical Journal, 344:e2598. doi: 10.1136/bmj.e2598. PMID: 22517917, PMCID: PMC3330131. ARTICLE | FREE FULLTEXT PDF  | Wikipedia page | Watch the authors talk about the game

By Neuronicus, 15 October 2016

Tryptophan-rich foods and happiness

angry-woman public domainThe paper I feature today is not an experimental study, but an editorial written as a short review (5 pages). A not very good one, I’m afraid.

Neurochemical imbalances are to be found in virtual any brain disorder. Probably the most known is the serotonin depletion associated to depression, which is the main reason why SSRIs (selective serotonin reuptake inhibitors) are so widely prescribed for the disorder. With the caveats that serotonin is but one player, that it has many receptors involved in different aspects of the disease and “depression” is an umbrella term for a host of behaviors, this editorial focuses on non-pharmacological ways to address the depletion of serotonin. Noble goal, poor execution.

In a nutshell, Young (2007) argues that there are 4 ways to increase serotonin availability in the brain:
1) effortful focusing on positive things, either via psychotherapy, talk, social interactions, mediation or just mental exercises to consciously improve mood. I’m sure that the thought of trying to focus on the positive thoughts never crossed the minds of depressed people! Of course that this is how healthy people regulate their moods, everybody is sad or suffers loss at some point in their life and a lot of people snap out of it by engaging in those suggested behaviors, but the trouble with depression is that it persists despite efforts to be positive. The author should know that crying “Cheer up!” to a depressed person never works, but chances are they would feel even more alienated because they’ve tried that already!
2) exposure to bright light (3000 lux). No contention here. Light therapy is successful in treating seasonal depression. We should all get more light.
3) exercise. It’s unclear which kind, aerobic or to fatigue, but probably either would work.
4) eating tryptophan-rich foods (like meat, cheeses or eggs). Why tryptophan? Because the brain can make serotonin out of tryptophan, but serotonin itself is too big of a molecule to enter the brain (i.e. doesn’t cross the brain blood barrier). But the author admits that “although purified tryptophan increases brain serotonin, foods containing tryptophan do not” (p. 396) soooo,… then eating tryptophan-rich foods will NOT increase the serotonin. But then he goes on saying that drinking milk or eating nixtamalized corn increases serotonin (verbatim: “Acute ingestion of alpha-lactalbumin by humans can improve mood and cognition in some circumstances, presumably owing to increased serotonin” and “Breeding corn with a higher tryptophan content was shown in the 1980s to prevent pellagra; presumably, it also raised brain serotonin” p. 396-397). Utterly confusing and self-contradictory.

I also want to make a big note here:
a) there is no reliable evidence that eating tryptophan-rich foods increases the brain serotonin. Otherwise, instead of paying for Prozac, you would buy a huge bottle of tryptophan pills from the nearest dietary supplements store. Which brings me to my second point:
b) why don’t we give tryptophan supplements instead of SSRIs? Tryptophan is sold in USA as a dietary supplement which I think is a tremendously dangerous thing to allow (in most EU countries is considered a drug, so you can’t buy it from the shoddy dietary supplements stores). Because its efficacy in depression is inconclusive at best, i.e. most studies did not find significant improvements, while others showed improvement only in a subpopulation of depression sufferers. But it can induce nausea, sleepiness, confusion, depression, and even dementia symptoms and death. And interacts badly with other drugs or even with carbohydrate-rich foods, like pizza or pasta.

This is definitely not among the best papers I have read. It has many speculations supported by un-replicated studies. Or, when such studies are sparse, the reasoning relies on evolutionary speculations elevated to the rank of causal explanations (e.g. we spend so much time indoors, therefore depression is on the rise; conversely, our ancestors spent more time outside, therefore they were happier). Although I agree with Young that we should invest more research into non-pharmacological ways to improve brain dysfunctions, we need to do so in a more pragmatical manner that just telling people to think positive. Ok, rant over.

Reference: Young SN (Nov 2007). How to increase serotonin in the human brain without drugs. Journal of Psychiatry and Neuroscience, 32(6):394-399. PMID:18043762, PMCID:PMC2077351. Article | FREE FULLTEXT PDF

By Neuronicus, 3 December 2015

Putative mechanism for decreased spermatogenesis following SSRI

fishThe SSRIs (selective serotonin reuptake inhibitors) are the most commonly prescribed antidepressants around the world. Whether is Prozac, Zoloft or Celexa, chances are that 1 in 4 Americans (or 1 in 10, depending on the study) will be making a decision during their lifetime to start an antidepressant course or not. And yet adherence to treatment is significantly low, as many people get off the SSRI due to their side effects, one of the main complains being sexual dysfunction in the form of low libido and pleasure.

Now a new study finds a mechanism for an even more worrisome effect of citalopram, (Celexa), an SSRI: the reduction of spermatogenesis. Prasad et al. (2015) used male zebrafish as a model and exposed them to citalopram in 3 different doses for 2- or 4-weeks period. They found out that the expression in the brain of the serotonin-related genes (trp2 and sert) and gonadotropin genes (lhb, sdhb, gnrh2, and gnrh3) were differently affected depending on the dose and durations of treatment. In the testes, the “long-term medium- and high-dose citalopram treatments displayed a drastic decrease in the developmental stages of spermatogenesis as well as in the matured sperm cell count” (p. 5). The authors also looked at how the neurons are organized and they found out that the serotonin fibers are associated with the fibers of the neurons that release gonadotropin-releasing hormone 3 (GnRH3) in preoptic area, a brain region in the hypothalamus heavily involved in sexual and parental behavior in both humans and fish.

Shortly put, in the brain, the citalopram affects gene expression profiles and fiber density of the serotonin neurons, which in turn decreases the production of GnRH3, which may account for the sexual dysfunctions that follow citalopram. In the testes, citalopram may act directly by binding to the local serotonin receptors and decrease spermatogenesis.

Reference: Prasad P, Ogawa S, & Parhar IS. (Oct 2015, Epub 8 Jul 2015). Serotonin Reuptake Inhibitor Citalopram Inhibits GnRH Synthesis and Spermatogenesis in the Male Zebrafish. Biololy of Reproduction. 93(4):102, 1-10. doi: 10.1095/biolreprod.115.129965. Article | FREE FULLTEXT PDF

By Neuronicus, 11 November 2015

Giving up? Your parvalbumin neurons may have something to do with it

Cartoon from http://i393.photobucket.com/albums/pp20/saisi24/dontgivedup.jpg, licensing unknown
Cartoon from Photobucket, licensing unknown.

One of the most ecologically-valid rodent models of depression is the learned helplessness paradigm. You get a rat or a mouse and you confine it in a cage with an electrified grid. Then you apply mild foot shocks at random intervals and of random duration for an hour (which is one session). The mouse initially tries to escape, but there is no escape; the whole floor is electrified. After a couple of sessions, the mouse doesn’t try to escape anymore; it gives up. Even when you put the mouse in a cage with an open door, so it can flee to no-pain freedom, it doesn’t attempt to do so. The interpretation is that the mouse has learned that it cannot control the environment, no matter what he does, he’s helpless, so why bother? Hence the name of the behavioral paradigm: learned helplessness.

All antidepressants on the market have been tested at one point or another against this paradigm; if the drug got the mouse to try to escape more, then the drug passed the test.

Just like in the higher vertebrate realm, there are a few animals who keep trying to escape longer than the others, before they too finally give up; we call these resilient.

Perova, Delevich, & Li (2015) looked at a type of neuron that may have something to do with the capacity of some of the mice to be resilient; the parvalbumin interneurons (PAI) from the medial prefrontal cortex (mPFC). These neurons produce GABA, the major inhibitory neurotransmitter in the brain, and modulates the activity of the nearby neurons. Thanks to the ability to genetically engineer mice to have a certain kind of cell fluoresce, the researchers were able to identify and subsequently record from and manipulate the function of the PAIs. These PAIs’ response to stimulation was weaker in helpless animals compared to resilient or controls. Also, inactivation of the PAI via a designer virus promotes helplessness.

Reference: Perova Z, Delevich K, & Li B (18 Feb 2015). Depression of Excitatory Synapses onto Parvalbumin Interneurons in the Medial Prefrontal Cortex in Susceptibility to Stress. The Journal of Neuroscience, 35(7):3201–3206. doi: 10.1523/JNEUROSCI.2670-14.2015. Article | FREE FULLTEXT PDF

By Neuronicus, 21 October 2015

Cell phones give you hallucinations

A young businessman in a suit screaming at a cell phone. By: Benjamin Miller. License FSP Standard FreeStockPhotos.biz
Photo by Benjamin Miller. License: FSP Standard FreeStockPhotos.biz

Medical doctors (MD) are overworked, particularly when they are hatchlings (i.e. Medical School students) and fledglings (interns and residents). So overworked, that in many countries is routine to have 80-hour weeks and 30-hour shifts as residents and interns. This is a concern as it has been shown that sleep deprivation impairs learning (which is the whole point of residency) and increases the number of medical mistakes (the lack of which is the whole point of their profession).

Lin et al. (2013) show that it can do more than that. Couple internship and cell phones and you get… hallucinations. That’s right. The authors asked 73 medical interns to complete some tests before their internship, then every third, sixth, and twelfth months of their internship, and after the internship. The questionnaires were on anxiety, depression, personality, and cell phone habits and hallucinations. That is: the sensation that your cell phone is vibrating or ringing when, in fact, it is not (which fully corresponds to the definition of hallucination). And here is what they found:

 Before internship, 78% of MDs experienced phantom vibration and 27% experienced phantom ringing.
 During their 1-year internship, about 85 to 95% of MDs experienced phantom vibration and phantom ringing.
 After the internship when the MDs did no work for two weeks, 50% still had these hallucinations.

Composite figure from Lin et al. (2015) showing the interns' depression (above) and anxiety (below) scores before, during, and after internship. The differences are statistically significant.
Fig. 1. Composite figure from Lin et al. (2015) showing the interns’ depression (above) and anxiety (below) scores before, during, and after internship. The differences are statistically significant.

The MDs’ depression and anxiety were also elevated more during the internship than before or after (see Fig. 1), but there was no correlation between the hallucinations and the depression and anxiety scores.

These findings are disturbing on so many levels… Should we be worried that prolonged exposure to cell phones can produce hallucinations? Or that o good portion of the MDs have hallucinations before going to internship? Or that 90% the people in charge with your life or your child’s life are so overworked that are hallucinating on a regular basis? Fine, fine, believing that your phone is ringing or vibrating may not be such a big deal of a hallucination, compared with, let’s say, “the voices told me to give you a lethal dose of morphine”, but as a neuroscientist I beg the question: is there a common mechanism between these two types of hallucinations and, if so, what ELSE is the MD hallucinating about while reassuring you that your CAT scan is normal? Or, forget about the hallucinations, should we worry that your MD is probably more depressed and anxious than you? Or, the “good” news, that the medical interns provide “a model of stress-induced psychotic symptoms” better that previous models, as the authors put it (p. 5)? I really wish there was more research on positive things (… that was a pun; hallucinations are a positive schizophrenic symptom, look it up 🙂 ).

Reference: Lin YH, Lin SH, Li P, Huang WL, & Chen CY. (10 June 2013). Prevalent hallucinations during medical internships: phantom vibration and ringing syndromes. PLoS One, 8(6): e65152. doi: 10.1371/journal.pone.0065152. Article | FREE PDF | First time the phenomenon was documented in press

By Neuronicus, 14 October 2015

Stressed out? Blame your amygdalae

amygdala
Clipart: Royalty free from http://www.cliparthut.com. Text: Neuronicus.

Sooner or later, everyone is exposed to high amounts of stress, whether it is in the form losing someone dear, financial insecurity, or health problems and so on. Most of us manage to bounce right up and continue with our lives, but there is a considerable segment of the population who do not and develop all sorts of problems, from autoimmune disorders to severe depression and anxiety. What makes those people more susceptible to stress? And, more importantly, can we do something about it (yeah, besides making the world a less stressful place)?

Swartz et al. (2015) scanned the brain of 753 healthy young adults (18-22 yrs) while performing a widely used paradigm that elicits amygdalar activation (brain structure, see pic): the subjects had to match a face appearing in the upper part of the screen with one of the faces in the lower part of the screen. The faces looked fearful, angry, surprised, or neutral and amygdalae are robustly activated when matching the fearful face. Then the authors had the participants fill out questionnaires regarding their life events and perceived stress level every 3 months over a period of 2 years (they say 4 years everywhere else in the paper minus Methods & Results, which are the sections that count if one wants to replicate; maybe this is only half of the study and they intend to follow-up to 4 years?).

The higher your baseline amygdalar activation, the higher the risk to develop anxiety disorders later on if expossed to life stressors. Yellow = amygdala. Photo credit: https://www.youtube.com/watch?v=JD44PbAOTy8, presumably copyrighted to Duke University.
The higher your baseline amygdalar activation, the higher the risk to develop anxiety disorders later on if expossed to life stressors. Yellow = amygdala. Photo credit: https://www.youtube.com/watch?v=JD44PbAOTy8, presumably copyrighted to Duke University.

The finding of the study is this: baseline amygdalar activation can predict who will develop anxiety later on. In other words, if your natural, healthy, non-stressed self has a an overactive amygdala, you will develop some anxiety disorder later on if exposed to stressors (and who isn’t?). The good news is that knowing this, the owner of the super-sensitive amygdalae, even if s/he may not be able to protect her/himself from stressors, at least can engage in some preventative therapy or counseling to be better equipped with adaptive coping mechanisms when the bad things come. Probably we could all benefit from being “better equipped with adaptive coping mechanisms”, feisty amygdalae or not. Oh, well…

Reference: Swartz, J.R., Knodt, A.R., Radtke, S.R., & Hariri, A.R. (2015). A neural biomarker of psychological vulnerability to future life stress. Neuron, 85, 505-511. doi: 10.1016/j.neuron.2014.12.055. Article | PDF | Video

By Neuronicus, 12 October 2015