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Association of Depressive Symptoms and Heart Rate Variability in Vietnam War–Era Twins: A Longitudinal Twin Difference Study | JAMA Psychiatry | JAMA Network

The association between depression and autonomic dysregulation, indexed by HRV, is bidirectional, with stronger evidence suggesting that autonomic function affects depression risk rather than vice versa.

The immune system and the pathogenesis of depression

There is bidirectional communication between the HPA axis and the immune system. Cytokines activate the HPA axis and thus lead to the release of cortisol, the stress hormone, which ordinarily suppresses the immune response. Cortisol also inhibits its own release and thus the body is able to maintain a stable immune response through a tightly regulated feedback inhibition system. This regulation mechanism seems to be dysfunctional in depressive disorders and is thought to occur because of cytokine mediated receptor resistance to cortisol, thus impairing feedback inhibition. This essentially means that cytokines make cortisol unable to act on the receptors that would inhibit its release. Long story short — the HPA axis is hyperactive because of cytokines, leading to a chronic stress response because cytokines impair the body’s ability to regulate it — thus leading to depressive symptoms.

Ketamine Acts Fast to Treat Depression and Its Effects Last, But How? - Neuroscience News

Ketamine produces rapid and robust antidepressant effects in depressed patients within hours of administration, often when traditional antidepressant compounds have failed to alleviate symptoms. We hypothesized that ketamine would translocate Gαs from lipid rafts to non-raft microdomains, similarly to other antidepressants but with a distinct, abbreviated treatment duration. C6 glioma cells were treated with 10 µM ketamine for 15 min, which translocated Gαs from lipid raft domains to non-raft domains. Other NMDA antagonist did not translocate Gαs from lipid raft to non-raft domains. The ketamine-induced Gαs plasma membrane redistribution allows increased functional coupling of Gαs and adenylyl cyclase to increase intracellular cyclic adenosine monophosphate (cAMP). Moreover, increased intracellular cAMP increased phosphorylation of cAMP response element-binding protein (CREB), which, in turn, increased BDNF expression. The ketamine-induced increase in intracellular cAMP persisted after knocking out the NMDA receptor indicating an NMDA receptor-independent effect. Furthermore, 10 µM of the ketamine metabolite (2R,6R)-hydroxynorketamine (HNK) also induced Gαs redistribution and increased cAMP. These results reveal a novel antidepressant mechanism mediated by acute ketamine treatment that may contribute to ketamine’s powerful antidepressant effect. They also suggest that the translocation of Gαs from lipid rafts is a reliable hallmark of antidepressant action that might be exploited for diagnosis or drug development.

Antidepressants don't work, or depression doesn't exist (as a meaningful category)

The real truth isn't found within the published paper but rather within a busy table on page 142 of the online appendix. It is here where the authors report what we want: the actual difference between drugs and placebo, before and after treatment, on the depression rating scales. Here we see that the Cohen's d standardized mean difference effect sizes range from a low of 0.19 to a high of 0.62 with amitriptyline. Thus, amitriptyline exceeds the clinically meaningful threshold of 0.50, with a traditional meta-analytic method. No other drug does so, with the closest second place being fluvoxamine, with a Cohen's d value of 0.44. Looking at all of the agents, 10 drugs have Cohen's d values less than 0.30, which is very small and clinically meaningless, whereas four have effect sizes from 0.30 to 0.34. Thus, 74% (14/19) of antidepressants clearly have little or no clinically important benefit in this analysis (for some reason, no data are provided in this table with two of the drugs). Four drugs have effect sizes of 0.37-0.44, and as noted, one agent exceeds the 0.50 threshold (amitriptyline). Perhaps a clearer conclusion than anything else is the well-proven fact that the tricyclic antidepressants are more effective than newer agents (there were no monoamine oxidase inhibitors in this meta-analysis).

Lessons learned from placebo groups in antidepressant trials

The analysis of ‘nocebo effects’, e.g. adverse effects in placebo groups of antidepressant trials also confirms the impact of expectations: nocebo symptoms reflected the typical side-effect patterns expected in the drug group, with higher symptoms rates in the placebo groups of tricyclic antidepressant trials compared with placebo groups of trials testing selective serotonin reuptake inhibitors.

Antidepressants and bladder medicines linked to dementia in landmark study -- ScienceDaily

"We studied patients with a new dementia diagnosis and looked at what anticholinergic medication they were prescribed between four and 20 years prior to being diagnosed. "We found that people who had been diagnosed with dementia were up to 30 per cent more likely to have been prescribed specific classes of anticholinergic medications. And the association with dementia increases with greater exposure to these types of medication. "What we don't know for sure is whether the medication is the cause. It could be that these medications are being prescribed for very early symptoms indicating the onset of dementia.

Antidepressant withdrawal

About half (54%) met their goal of completely discontinuing one or more medications; 46% reported another outcome (use was reduced, use increased, or use stayed the same). Concerns about medications’ effects (for example, long-term effects and side effects) prompted the decision to discontinue for 74% of respondents. They used various strategies to cope with withdrawal symptoms, which 54% rated as severe. Self-education and contact with friends and with others who had discontinued or reduced medications were most frequently cited as helpful. Although more than half rated the initial medication decision with prescribers as largely collaborative, only 45% rated prescribers as helpful during discontinuation. Of respondents who completely discontinued, 82% were satisfied with their decision.

Men and women have opposite genetic alterations in depression: A study examines the sex-specific molecular changes in major depressive disorder -- ScienceDaily

Most of the genes that had altered expression were changed in only men or only women. However, genes that were altered in both men and women were changed in opposite directions. Women had increased expression of genes affecting synapse function, whereas men had decreased expression of the same genes. Women had decreases in genes affecting immune function, whereas men had increased expression of these genes. Additionally, the researchers applied their methods to data from a different set of subjects and replicated the opposing changes.

Psychiatric Medications Kill More Americans than Heroin

According to data from the MEPS (Medical Expenditure Panel Survey) database, the number of prescriptions for psychiatric medications (i. e. sedatives, antidepressants, psychostimulants, and antipsychotics) increased 117% between 1999 and 2013, from 197,247,557 prescriptions in 1999 to 427,837,506 prescriptions in 2013. Meanwhile, death rates from psychiatric medication overdose climbed a whopping 240% over the same time period, from 1.31 deaths per 100,000 in 1999 to 4.46 deaths per 100,000 in 2013 (we are excluding the CDC death rate data from 2014 since the MEPS 2014 data has not yet been published).

2008 -- long term use of antidepressants

More than 60% of Americans taking antidepressant medication have taken it for 2 years or longer, with 14% having taken the medication for 10 years or more.

Heart attack patients prescribed antidepressants have worse one-year survival -- ScienceDaily

After adjusting for baseline characteristics the researchers found that the rates of stroke and subsequent heart attacks were similar between the two groups, but patients prescribed antidepressants had significantly worse survival. The rate of all-cause mortality at one-year after discharge was 7.4% in patients prescribed antidepressants compared to 3.4% for those not prescribed antidepressants (p<0.001). Antidepressant prescription was an independent predictor for mortality, and increased the odds by 66% (odds ratio: 1.66; 95% confidence interval: 1.16 to 2.39).