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Initial Severity and Antidepressant Benefits: A Meta-Analysis of Data Submitted to the Food and Drug Administration

Drug–placebo differences in antidepressant efficacy increase as a function of baseline severity, but are relatively small even for severely depressed patients. The relationship between initial severity and antidepressant efficacy is attributable to decreased responsiveness to placebo among very severely depressed patients, rather than to increased responsiveness to medication.

Mice Genetically Depleted of Brain Serotonin Do Not Display a Depression-like Behavioral Phenotype - ACS Chemical Neuroscience (ACS Publications)

Reductions in function within the serotonin (5HT) neuronal system have long been proposed as etiological factors in depression. Selective serotonin reuptake inhibitors (SSRIs) are the most common treatment for depression, and their therapeutic effect is generally attributed to their ability to increase the synaptic levels of 5HT. Tryptophan hydroxylase 2 (TPH2) is the initial and rate-limiting enzyme in the biosynthetic pathway of 5HT in the CNS, and losses in its catalytic activity lead to reductions in 5HT production and release. The time differential between the onset of 5HT reuptake inhibition by SSRIs (minutes) and onset of their antidepressant efficacy (weeks to months), when considered with their overall poor therapeutic effectiveness, has cast some doubt on the role of 5HT in depression. Mice lacking the gene for TPH2 are genetically depleted of brain 5HT and were tested for a depression-like behavioral phenotype using a battery of valid tests for affective-like disorders in animals. The behavior of TPH2–/– mice on the sucrose preference test, tail suspension test, and forced swim test and their responses in the unpredictable chronic mild stress and learned helplessness paradigms was the same as wild-type controls. While TPH2–/– mice as a group were not responsive to SSRIs, a subset responded to treatment with SSRIs in the same manner as wild-type controls with significant reductions in immobility time on the tail suspension test, indicative of antidepressant drug effects. The behavioral phenotype of the TPH2–/– mouse questions the role of 5HT in depression. Furthermore, the TPH2–/– mouse may serve as a useful model in the search for new medications that have therapeutic targets for depression that are outside of the 5HT neuronal system.

Is serotonin an upper or a downer? The evolution of the serotonergic system and its role in depression and the antidepressant response - ScienceDirect

The role of serotonin in depression and antidepressant treatment remains unresolved despite decades of research. In this paper, we make three major claims. First, serotonin transmission is elevated in multiple depressive phenotypes, including melancholia, a subtype associated with sustained cognition. The primary challenge to this first claim is that the direct pharmacological effect of most symptom-reducing medications, such as the selective serotonin reuptake inhibitors (SSRIs), is to increase synaptic serotonin. The second claim, which is crucial to resolving this paradox, is that the serotonergic system evolved to regulate energy. By increasing extracellular serotonin, SSRIs disrupt energy homeostasis and often worsen symptoms during acute treatment. Our third claim is that symptom reduction is not achieved by the direct pharmacological properties of SSRIs, but by the brain's compensatory responses that attempt to restore energy homeostasis. These responses take several weeks to develop, which explains why SSRIs have a therapeutic delay. We demonstrate the utility of our claims by examining what happens in animal models of melancholia and during acute and chronic SSRI treatment.

Is the dark really making me sad? | Ars Technica

the leading theory is the ‘phase-shift hypothesis’: the idea that shortened days cause the timing of our circadian rhythms to fall out of sync with the actual time of day, because of a delay in the release of melatonin. Levels of this hormone usually rise at night in response to darkness, helping us to feel sleepy, and are suppressed by the bright light of morning. “If someone’s biological clock is running slow and that melatonin rhythm hasn’t fallen, then their clock is telling them to keep on sleeping even though their alarm may be going off and life is demanding that they wake up,” says Kelly Rohan, a professor of psychology at the University of Vermont. Precisely why this should trigger feelings of depression is still unclear. One idea is that this tiredness could then have unhealthy knock-on effects. If you’re having negative thoughts about how tired you are, this could trigger a sad mood, loss of interest in food, and other symptoms that could cascade on top of that. However, recent insights into how birds and small mammals respond to changes in day length have prompted an alternative explanation. According to Daniel Kripke, an emeritus professor of psychiatry at the University of California, San Diego, when melatonin strikes a region of the brain called the hypothalamus, this alters the synthesis of another hormone—active thyroid hormone—that regulates all sorts of behaviours and bodily processes. When dawn comes later in the winter, the end of melatonin secretion drifts later, says Kripke. From animal studies, it appears that high melatonin levels just after the time an animal wakes up strongly suppress the making of active thyroid hormone—and lowering thyroid levels in the brain can cause changes in mood, appetite, and energy. For instance, thyroid hormone is known to influence serotonin, a neurotransmitter that regulates mood. Several studies have shown that levels of brain serotonin in humans are at their lowest in the winter and highest in the summer. In 2016, scientists in Canada discovered that people with severe SAD show greater seasonal changes in a protein that terminates the action of serotonin than others with no or less severe symptoms, suggesting that the condition and the neurotransmitter are linked.

Exercise boosts tryptophan, a mild hypnotic and serotonin precursor

The largest body of work in humans looking at the effect of exercise on tryptophan availability to the brain is concerned with the hypothesis that fatigue during exercise is associated with elevated brain tryptophan and serotonin synthesis. A large body of evidence supports the idea that exercise, including exercise to fatigue, is associated with an increase in plasma tryptophan and a decrease in the plasma level of the branched chain amino acids (BCAAs) leucine, isoleucine and valine (see64,65 for reviews). The BCAAs inhibit tryptophan transport into the brain.66 Because of the increase in plasma tryptophan and decrease in BCAA, there is a substantial increase in tryptophan availability to the brain. Tryptophan is an effective mild hypnotic,67 a fact that stimulated the hypothesis that it may be involved in fatigue. A full discussion of this topic is not within the scope of this editorial; however, it is notable that several clinical trials of BCAA investigated whether it was possible to counter fatigue by lowering brain tryptophan, with results that provided little support for the hypothesis. Further, exercise results in an increase in the plasma ratio of tryptophan to the BCAAs before the onset of fatigue.64,65

Overview of exercise and serotonin

A third strategy that may raise brain serotonin is exercise. A comprehensive review of the relation between exercise and mood concluded that antidepressant and anxiolytic effects have been clearly demonstrated.53 In the United Kingdom the National Institute for Health and Clinical Excellence, which works on behalf of the National Health Service and makes recommendations on treatments according to the best available evidence, has published a guide on the treatment of depression.54 The guide recommends treating mild clinical depression with various strategies, including exercise rather than antidepressants, because the risk–benefit ratio is poor for antidepressant use in patients with mild depression. Exercise improves mood in subclinical populations as well as in patients. The most consistent effect is seen when regular exercisers undertake aerobic exercise at a level with which they are familiar.53 However, some skepticism remains about the antidepressant effect of exercise, and the National Institute of Mental Health in the United States is currently funding a clinical trial of the antidepressant effect of exercise that is designed to overcome sources of potential bias and threats to internal and external validity that have limited previous research.55

Light boosts serotonin

Exposure to bright light is a second possible approach to increasing serotonin without drugs. Bright light is, of course, a standard treatment for seasonal depression, but a few studies also suggest that it is an effective treatment for nonseasonal depression38 and also reduces depressed mood in women with premenstrual dysphoric disorder39 and in pregnant women suffering from depression.40 The evidence relating these effects to serotonin is indirect. In human postmortem brain, serotonin levels are higher in those who died in summer than in those who died in winter.41 A similar conclusion came from a study on healthy volunteers, in which serotonin synthesis was assessed by measurements of the serotonin metabolite 5-hydroxyindoleacetic acid (5-HIAA) in the venous outflow from the brain.42 There was also a positive correlation between serotonin synthesis and the hours of sunlight on the day the measurements were made, independent of season. In rats, serotonin is highest during the light part of the light–dark cycle, and this state is driven by the photic cycle rather than the circadian rhythm.43,44 The existence of a retinoraphe tract may help explain why, in experimental animals, neuronal firing rates, c-fos expression and the serotonin content in the raphe nuclei are responsive to retinal light exposure.44–48 In humans, there is certainly an interaction between bright light and the serotonin system. The mood-lowering effect of acute tryptophan depletion in healthy women is completely blocked by carrying out the study in bright light (3000 lux) instead of dim light.49

The Serotonin Surprise |

Glenmullen has long suspected that drugs that alter serotonin metabolism cause profound changes in the brain. He bases his suspicion on a body of research during the last 20 years by scientists investigating another class of drugs that includes MDMA (Ecstasy) as well as fenfluramine, the diet drug recently removed from the market because of its association with heart valve problems. These drugs do more than just block serotonin reuptake; they primarily stimulate the release of large quantities of serotonin from nerve endings into the brain. The resulting flood is thought to cause the mind-altering effects of MDMA. And that flood, some scientists argue, leaves brain damage in its wake. When monkeys and rats are given high doses of serotonin releasers--up to 40 times the dose that people generally take--the microscopic architecture of their brains looks different from normal brains. The nerve fibers (axons) that carry serotonin to the target cells seem to change their shape and diminish in number--effects some scientists claim are properly understood as brain damage.