Here are the most popular of the 65 posts I’ve made so far in 2018, starting from the earliest:
This 2018 Polish review subject was the relationship between melatonin and depression:
“Although melatonin has been known about and referred to for almost 50 years, the relationship between melatonin and depression is still not clear. In this review, we summarize current knowledge about the genetic and epigenetic regulation of enzymes involved in melatonin synthesis and metabolism as potential features of depression pathophysiology and treatment.
Melatonin has an antidepressant effect by:
- Maintaining the body’s circadian rhythm,
- Regulating the pattern of expression of the clock genes in the suprachiasmatic nucleus (SCN) and
- Modifying the key genes of serotoninergic neurotransmission that are linked with a depressive mood.
Light input causes the release of γ-aminobutyric acid (GABA) by the SCN, and the inhibitory signal is transmitted to the pineal gland to inhibit melatonin production.
Melatonin is produced via the metabolism of serotonin in two steps which are catalyzed by serotonin N-acetyltransferase (SNAT) and acetylserotonin-O-methyltransferase (ASMT). Serotonin, SNAT, and ASMT are key melatonin level regulation factors.
Both melatonin and serotonin are synthesized from the same amino acid, tryptophan. People on a high tryptophan diet (>10 mg/kg body weight per day) have a significantly lower level of depressive symptoms, irritation, and anxiety than people on a low tryptophan diet (<5 mg/kg body weight per day).
To our knowledge, there are only 2 studies in the literature that characterize mRNA expression of ASMT in the peripheral blood of recurrent DD [depressive disorders]. [They] have demonstrated the reduced mRNA expression of ASMT in patients with depression and cognitive impairment. Surprisingly, these studies, despite promising results, have not been replicated. Moreover, no analysis of other melatonin related-genes as potential biomarkers of depression has been provided.
The main monoamine hypothesis of the pathophysiology of depression indicates that depression is induced by a change in the level of ≥1 monoamines such as serotonin, noradrenaline, and dopamine. The evidence for the serotonergic theory is an observation that antidepressants such as tricyclic antidepressants, selective serotonin reuptake inhibitors, and noradrenaline reuptake inhibitors increase the level of serotonin in the brain.
We focus on serotonin as a neurotransmitter which is a precursor of melatonin synthesis. In a depressed patient, serotonin synthesis is impaired and the poor precursor availability may prevent the formation of an adequate amount of melatonin. However, only a few studies have analyzed the relationship between serotonin and melatonin levels and the correlation with the blood serum.”
At eight cents a day ($.04 for women) melatonin is a cheap and effective supplement.
I hadn’t considered possible antidepressant effects until reading this review. More human studies are needed.
https://www.karger.com/Article/Pdf/489470 “Pathophysiology of Depression: Molecular Regulation of Melatonin Homeostasis – Current Status” (not freely available)
This 2018 French/Italian/Swiss rodent study used the prenatally restraint stressed (PRS) model to create problems that could be resolved by various chemicals:
“S 47445 is a positive modulator of glutamate AMPA-type receptors, possessing neurotrophic and enhancing synaptic plasticity effects as well as pro-cognitive and anti-stress properties.
Most of studies examining the antidepressant effects of new molecules are carried out using behavioral tests performed in unstressed animals.
Corticosterone-treated mice and rats exposed to chronic stress are models that do not recapitulate the early programming of stress-related disorders, which likely originates in the perinatal period. The PRS rat model is characterized by a prolonged corticosterone response to stress and by abnormal behavior.
All the behavioral alterations induced by PRS..were corrected by chronic S 47445 administration at both doses.”
The paper included a section comparing S 47445 to ketamine:
“Ketamine, however, causes severe cognitive impairment and psychotomimetic [mimics the symptoms of psychosis, reference not freely available] effects that are direct consequences of the prolonged inhibition of NMDA receptors in cortical and hippocampal interneurons, and seriously limit the chronic administration of the drug in the clinical setting. [reference not freely available]
S 47445 by inducing a direct activation of AMPARs displayed an antidepressant activity without the adverse effect of ketamine. Indeed, contrary to ketamine, S 47445 presented no psychotomimetic effects and induced no occurrence of spontaneous epileptic seizures. [reference freely available] Moreover, S 47445 also presented pro-cognitive properties.”
Compare the above with this April 2018 Chicago Tribune story that had opinions with no linked references:
“..ketamine, an anesthetic used to sedate both people and animals before surgery. It’s also a notorious street drug, abused by clubgoers seeking a trancelike, hallucinatory high. But in recent years, numerous studies have found that ketamine can be an effective and speedy treatment for people with depression.”
Which coverage better informed us?
Treating prenatal stress-related disorders with an oxytocin receptor agonist was performed by several of this paper’s coauthors. One of this paper’s references to it was:
“We have already reported that depolarization-evoked glutamate release in the ventral hippocampus is negatively correlated with risk-taking behavior of PRS rats, and that such correlation can be corrected by chronic treatment with monoaminergic/melatoninergic antidepressants or oxytocin receptor agonist. Thus, an impairment of glutamatergic transmission in the ventral hippocampus lies at the core of the pathological phenotype of PRS rats.”
Looking at the above graphic of the experimental design, I’m not sure why the term perinatal (occurring during or pertaining to the phase surrounding the time of birth) was used in the paper’s title and content to describe the stress period. The pregnant females were stressed three times every day during the second half of pregnancy up until delivery, so the prenatal (previous to birth) term was more applicable.
So, how does this study help humans?
One takeaway is to avoid stressing pregnant mothers-to-be if her children will be expected to become adults without cognitive, emotional, and behavioral problems.
The study demonstrated one way prenatal events cause lifelong effects. The PRS model provides another example of why it’s useless to ask adult humans to self-report the causes of epigenetic problems in their lives when these originated before birth, during infancy, or in early childhood well before humans develop the cognitive capability to recognize such situations. It’s incomprehensible that this unreliable paradigm is still given significant weight in stress studies, especially when the experimental designs:
“..do not recapitulate the early programming of stress-related disorders, which likely originates in the perinatal period.”
Also, the relevant difference between humans and PRS rats is that we can ourselves individually change our responses to experiential causes of ongoing adverse effects. Standard methodologies can only apply external treatments such as those mentioned above.
https://www.sciencedirect.com/science/article/pii/S0028390818301291 “The reduction in glutamate release is predictive of cognitive and emotional alterations that are corrected by the positive modulator of AMPA receptors S 47445 in perinatal stressed rats” (not freely available) Thanks to coauthors Stefania Maccari and Dr. Jerome Mairesse for providing a copy.
This 2018 Italy/UK meta-analysis subject was the use of dietary supplement acetyl-L-carnitine to treat depression symptoms:
“Deficiency of acetyl-L-carnitine (ALC) appears to play a role in the risk of developing depression, indicating dysregulation of fatty acids transport across the inner membrane of mitochondria. However, the data regarding ALC supplementation in humans are limited. We thus conducted a systematic review and meta-analysis investigating the effect of ALC on depressive symptoms across randomized controlled trials (RCTs).
Pooled data across nine RCTs (231 treated with ALC versus 216 treated with placebo and 20 no intervention) showed that ALC significantly reduced depressive symptoms.
In three RCTs comparing ALC versus antidepressants (162 for each group), ALC demonstrated similar effectiveness compared with established antidepressants [fluoxetine (Prozac), duloxetine (Cymbalta), amisulpride (Solian) respectively below] in reducing depressive symptoms. In these latter RCTs, the incidence of adverse effects was significantly lower in the ALC group [79%] than in the antidepressant group.
From the Study selection subsection:
“Studies were excluded if:
- did not include humans;
- did not include a control group;
- did not use validated scales for assessing depression;
- did not report data at follow-up evaluation regarding tests assessing depression;
- included the use of ALC with another agent vs. placebo/no intervention.”
The Discussion section was informative regarding possible mechanisms of ALC affecting depression, pain, and linked symptoms. Several citations were of a review rather than of the original studies, however.
Research needs to proceed on to investigate therapies that address ultimate causes for depression and pain. Researchers and sponsors shouldn’t stop at just symptoms and symptom relief, notwithstanding the requirement from a statistical point of view for “future large scale trials.”
Here are other acetyl-L-carnitine topics I’ve curated:
- A common dietary supplement that has rapid and lasting antidepressant effects
- Familiar stress opens up an epigenetic window of neural plasticity
- A gaping hole in a review of nutritional psychiatry
https://journals.lww.com/psychosomaticmedicine/Citation/2018/02000/Acetyl_L_Carnitine_Supplementation_and_the.4.aspx “Acetyl-L-Carnitine Supplementation and the Treatment of Depressive Symptoms: A Systematic Review and Meta-Analysis” (not freely available)
This post has somehow become a target for spammers, and I’ve disabled comments. Readers can comment on other posts and indicate that they want their comment to apply here, and I’ll re-enable comments.
Consider this post a reblog of Neuroskeptic’s informative About that New Antidepressant Study.
“Here’s why the new study doesn’t tell us much new. The authors..conclude that “all antidepressants were more effective than placebo,” but the benefits compared to placebo were “mostly modest.” Using the Standardized Mean Difference (SMD) measure of effect size, Cipriani et al. found an effect of 0.30, on a scale where 0.2 is considered ‘small’ and 0.5 ‘medium.’
The thing is, “effective but only modestly” has been the established view on antidepressants for at least 10 years. Just to mention one prior study, the Turner et al. (2008) meta-analysis found the overall effect size of antidepressants to be a modest SMD=0.31 – almost exactly the same as the new estimate.”
“I put his data in a Forest plot and ALL of the positive effect[s] by CBT [cognitive behavior therapy] could be explained by publication bias.
Paroxetine was developed in 1975 and FDA approved for MDD in 1992. It was 2017 before we discovered the true data behind suicides in these trials. That is 25 years. The order of SSRI approval is fluoxetine-> sertraline-> paroxetine-> citalopram-> escitalopram. We know from court cases and other efforts that the suicide data for the first three are false.
PhRMA never got serious about studying clinically meaningful subtypes of “depression” so most data in the meta-analysis just bear on a weak construct called “major depression.”
The reality is these drugs do not help depression much (if any) at all – their effect is to numb the emotions in most people.
The only thing worse than Paxil is Paxil withdrawal.”
Another review of the study, Rewarding the Companies That Cheated the Most in Antidepressant Trials, from which this post is titled, had these comments:
“Patients who take part in these drug trials have been on an antidepressant before the trial. They are then put on placebo for 10 days, a so-called washout. Then half the group, now in cold turkey wit[h]drawal, is now put back on a similar drug to what they had 10 days earlier, and the other group gets to continue their Cold turkey withdrawal.
The fact that these studies are just testing relief from abstinence symptoms by taking a similar drug, could explain why there is no effect in children and young adults.
Most people don’t realize that we are talking about statistical significance, and not clinical significance..The so-called significant difference between drug and placebo is approximately two points on the Hamilton depression scale. The difference has to be at least three for either patient or therapist to notice a difference.
According to this study (https://www.ncbi.nlm.nih.gov/pubmed/23357658), changes of three points or less on the HAM-D correspond to ratings of “no change” on clinician‐rated global symptom severity.
What this study has confirmed is that antidepressants can create a totally insignificant difference compared to a placebo pill. The placebo pill is often combined with attention and close follow up with a professional, and this has a very positive effect.”
This 2018 Hungary/UK study used Bayesian analysis to better understand gene-environment interactions that produce depression:
“Most genetic studies do not consider the effect of stressors which may be one reason for the lack of replicable results in candidate gene studies, GWAS [genome-wide association studies] and between human studies and animal models..Animal models of depression usually imply environmental factors, such as chronic unpredictable stress or learned helplessness.
Relevance of functional polymorphisms in seven candidate genes previously implicated in animal and human studies on a depression-related phenotype given various recent stress exposure levels was assessed with Bayesian relevance analysis in 1682 subjects.
Our data support the strong causative role of the environment modified by genetic factors, similar to animal models.”
“In order to identify recent negative life events (RLE) we used the List of Threatening Experiences questionnaire which queried problems related to illnesses/injuries, financial difficulties, problems related to intimate relationships, and social network occurring in the last year. Based on corresponding items the number of RLEs was counted for each subject, and categorized (low = 0–1, moderate = 2, high = 3/more).”
One item from the findings, and two from the cited references were:
“5-HTTLPR [serotonin transporter], the most extensively investigated polymorphism with respect to interaction with life events, showed only very low relevance.
Compared to heritability which accounts for 37–42% in the variance in general population samples, influence of environmental effects is estimated at 63% in depression.
Etiologically relevant distal and proximal stressors are relatively common, and while frequency of severe life events is estimated to be one in every 3–4 years, depression is triggered in only about one fifth of those with acute stress exposure.”
The methods of this study bypassed problems with GWAS and provided evidence for the lasting effects of “Etiologically relevant distal..stressors.” This was another way of saying that traumatic experiences beginning from the earliest parts of our lives still affect our biology and behavior.
As mentioned in Changing an individual’s future behavior even before they’re born, GWAS:
“Focuses on the average effect of alternative alleles averaged in a population.”
What this methodology often missed was:
“When phenotypic variation results from alleles that modify phenotypic variance rather than the mean, this link between genotype and phenotype will not be detected.”
The problems found in GWAS may also be found in epigenome-wide association studies. Researchers conducting DNA methylation analyses in particular may benefit from changing their approach if what they’re doing follows the GWAS paradigm.
Using twins to estimate the extent of epigenetic effects summarized three studies’ methods that showed:
“The epigenetic effects of each of our unique experiences of our non-shared environment predominately determine our individual physiology.”
This study’s approach should be considered, given the almost 2:1 relative impacts of environmental over genetic factors in influencing our biology and behavior. It’s especially indicated when human studies don’t replicate animal studies’ findings from strictly controlled experimental environments.
It wasn’t the study’s purpose to evaluate effective treatments for depression. Yet the abstract ended with:
“Galanin-2 receptor, BDNF and X-type purin-7 receptor could be drug targets for new antidepressants.”
The researchers were very careful to document the benefits of using a different approach to a problem. I hope that in the future, they will maintain their carefulness and independence in their approach to solutions, and not be influenced by:
“Consultancy, speaking engagements and research for Bristol-Myers Squibb, AstraZeneca, Eli Lilly, Schering Plough, Janssen-Cilag and Servier..share options in P1vital..consultancy fees from Alkermes, Lundbeck-Otsuka Ltd., Janssen-Cilag Ltd and fees for speaking from Lundbeck.”
https://www.nature.com/articles/s41598-018-22221-z “Significance of risk polymorphisms for depression depends on stress exposure”
Most of the spam I get on this blog comes in as ersatz comments on The hypothalamus couples with the brainstem to cause migraines. I don’t know what it is about the post that attracts internet bots.
The unwanted attention is too bad because the post represents a good personal illustration of “changes in the neural response to painful stimuli.” Last year I experienced three three-day migraines in one month as did the study’s subject. This led to me cycling through a half-dozen medications in an effort to address the migraine causes.
None of the medications proved to be effective at treating the causes. I found one that interrupted the progress of migraines – sumatriptan, a serotonin receptor agonist. I’ve used it when symptoms start, and the medication has kept me from having a full-blown migraine episode in the past year.
1. It may be argued that migraine headache tendencies are genetically inherited. Supporting personal evidence is that both my mother and younger sister have migraine problems. My father, older sister, and younger brother didn’t have migraine problems. Familial genetic inheritance usually isn’t the whole story of diseases, though.
2. Migraine headaches may be an example of diseases that are results of how humans have evolved. From Genetic imprinting, sleep, and parent-offspring conflict:
“..evolutionary theory predicts: that which evolves is not necessarily that which is healthy.
Why should pregnancy not be more efficient and more robust than other physiological systems, rather than less? Crucial checks, balances and feedback controls are lacking in the shared physiology of the maternal–fetal unit.“
Both migraine causes and effects may be traced back to natural lacks of feedback loops. These lacks demonstrate that such physiological feedback wasn’t evolutionarily necessary in order for humans to survive and reproduce.
3. Examples of other processes occurring during prenatal development that also lack feedback loops, and their subsequent diseases, are:
A. Hypoxic conditions per Lack of oxygen’s epigenetic effects are causes of the fetus later developing:
- “age-related macular degeneration
- cancer progression
- chronic kidney disease
- adipose tissue fibrosis
- detrimental effects which are linked to epigenetic changes.”
B. Stressing pregnant dams per Treating prenatal stress-related disorders with an oxytocin receptor agonist caused fetuses to develop a:
- “defect in glutamate release,
- anxiety- and depressive-like behavior,
1. What would be a treatment that could cure genetic causes for migraines?
I don’t know of any gene therapies.
2. What treatments could cure migraines caused by an evolved lack of feedback mechanisms?
We humans are who we have become, unless and until we can change original causes. Can we deal with “changes in the neural response to painful stimuli” without developing hopes for therapies or technologies per Differing approaches to a life wasted on beliefs?
3. What treatments could cure prenatal epigenetic causes for migraines?
The only effective solution I know of that’s been studied in humans is to prevent adverse conditions like hypoxia from taking place during pregnancy. The critical periods of our physical development are over once we’re adults, and we can’t unbake a cake.
Maybe science will offer other possibilities. Maybe it will be necessary for scientists to do more than their funding sponsors expect?
BTW, comments are turned off for the above-mentioned post. Readers can comment on this post instead.