Pain killers interfere with antidepressants:

http://www.healthcentral.com/depression/treatment-579181-5.html

In two studies, scientists found that taking antidepressants raises levels of cytokines in a person’s body. These cytokines then boost the levels of a protein called p11. This protein makes more serotonin receptors on the surface of cells. Having more of these receptors makes it easier for them to interact with serotonin. Serotonin is the primary brain chemical that SSRIs are designed to affect. Increasing serotonin usually reduces depression.

painkillers interfered with the production of these cytokines. This reduced the levels of p11 protein, which then reduced serotonin receptors on cells.  Thus, there were fewer serotonin receptors for the brain chemical to work on, and this kept the SSRI antidepressants from working at full strength.

scientists found evidence that non-steroidal anti-inflammatory drugs (NSAIDs) significantly reduce the effectiveness of selective serotonin reuptake inhibitor antidepressants (SSRIs) In fact, NSAIDs were associated with a 10 percent drop in depression remission rates, from 55 percent to 45 percent.What this means is that if you take NSAIDs and SSRI antidepressants together, there’s a 10 percent greater chance you’ll still suffer from depression, even if you’re taking a medication to treat it.

People who suffer from chronic pain could be prescribed other kinds of antidepressants such as tricyclic antidepressants or buproprion (Wellbutrin), which work on neurotransmitters in the brain, but not in the same way.  Or, people with depression could be given other types of medications to treat their pain.

http://www.pnas.org/content/early/2011/04/20/1104836108.abstract

In contrast to the levels detected in serum, we found that frontal cortical levels of certain cytokines (e.g., TNFα and IFNγ) were increased by serotonergic antidepressants and that these effects were inhibited by antiinflammatory agents. The antagonistic effect of antiinflammatory agents on antidepressant-induced behaviors was confirmed by analysis of a dataset from a large-scale real-world human study, “sequenced treatment alternatives to relieve depression” (STAR*D), underscoring the clinical significance of our findings. Our data indicate that clinicians should carefully balance the therapeutic benefits of antiinflammatory agents versus the potentially negative consequences of antagonizing the therapeutic efficacy of antidepressant agents in patients suffering from depression.

Scan of the Insula Predicts Whether CBT or SSRI's Will Best Lift Depression

Scan Predicts Whether Therapy or Meds Will Best Lift Depression
http://www.sciencedaily.com/releases/2013/06/130612162358.htm

Currently, determining whether a particular patient with depression would best respond to psychotherapy or medication is based on trial and error. In the absence of any objective guidance that could predict improvement, clinicians typically try a treatment that they, or the patient, prefer for a month or two to see if it works. Consequently, only about 40 percent of patients achieve remission following initial treatment. This is costly in terms of human suffering as well as health care spending.

one specific brain area emerged as a pivotal predictor of outcomes from two standard forms of depression treatment: cognitive behavior therapy (CBT) or escitalopram, a serotonin specific reuptake inhibitor (SSRI) antidepressant. If a patient's pre-treatment resting brain activity was low in the front part of an area called the insula, on the right side of the brain, it signaled a significantly higher likelihood of remission with CBT and a poor response to escitalopram. Conversely, hyperactivity in the insula predicted remission with escitalopram and a poor response to CBT.


What I find most intersting about this, is that one is a hyperreactivity and the other a hyporeactivity, it almost suggests two inverse conditions. One which CBT talk therapy will help, and another where drug treatment with an SSRI and probable increases in seretonin or BDNF will help?! Most of us would predict them to work on similar pathways, not for distinct conditions! Indeed, I was always under the impression that CBT WITH and SSRI would be most efficacious, this suggests otherwise, and that both together would be pointless for most people, with people's treatment choice depending on their insula reactivity.


Among several sites of brain activity related to outcome, activity in the anterior insula best predicted response and non-response to both treatments. The anterior insula is known to be important in regulating emotional states, self-awareness, decision-making and other thinking tasks. Changes in insula activity have been observed in studies of various depression treatments, including medication, mindfulness training, vagal nerve stimulation and deep brain stimulation.

"If these findings are confirmed in follow-up replication studies, scans of anterior insula activity could become clinically useful to guide more effective initial treatment decisions, offering a first step towards personalized medicine measures in the treatment of major depression" said Mayberg.

Ketamine and ketamines "cousin" GLYX-13 = suitable candidates for countering acute suicidality in affective disorders

http://www.sciencedaily.com/releases/2013/05/130530170052.htm

Keatmines “cousin” [GLYX-13] rapidly lifts depression without side effects:
“Human clinical studies demonstrated that ketamine can ward off major and bipolar depressive symptoms within 2 hours of administration and last for several days. Ketamine is fraught with serious side effects including excessive sleepiness, hallucinations, and substance abuse behavior.”
"Our drug, GLYX-13, is very different. It does not block the receptor ion channel, which may account for why it doesn't have the same side effects."

“Previous electrophysiological and conditioning studies had suggested that GLYX-13, unlike ketamine, enhanced memory and learning in rats, particularly in the brain's memory hub or hippocampus. GLYX-13 also produced analgesic effects.”

“GLYX-13 and ketamine produced rapid acting (1 hour) and long-lasting (24 hour) antidepressant-like effects in the rats. Fluoxetine, an SSRI that typically takes from 2-4 weeks to show efficacy in humans, did not produce a rapid antidepressant effect in this study.”

“These results are consistent with data from a recent Phase 2 clinical trial, in which a single administration of GLYX-13 produced statistically significant reductions in depression scores in patients who had failed treatment with current antidepressants. The reductions were evident within 24 hours and persisted for an average of 7 days. After a single dose of GLYX-13, the drug's antidepressant efficacy nearly doubled that seen with most conventional antidepressants after 4-6 weeks of dosing. GLYX-13 was well tolerated and it did not produce any of the schizophrenia-like effects associated with other NMDA receptor modulating agents.”

“Moskal speculates that GLYX-13 either directly binds to the glycine site on the NMDA receptor or indirectly modulates how glycine works with the receptor. Resulting activation of more NMDA and AMPA receptors leads to an increase in memory, learning -- and antidepressant effects. By contrast, ketamine only blocks the NMDA receptor, but also increases the activity of the AMPA receptor. Knowledge of these mechanisms could lead to the development of more effective antidepressants.”

This reminds me of how SSRI’s are speculated to possibly work through their effects on increasing brain derived neuro factor (BDNF) which may in turn make one hypersusceptible to new learning, in turn allowing someone in a rut to quickly learn a way out of it…

People are always suprised when I say Ketamine, horse tranquiliser, or special K as it is known in drug circles has beneficial properties. It was also shown in another study to have neuroregenerative effects:
http://www.sciencedaily.com/releases/2012/10/121004141747.htm
"In their research, Duman and others show that in a series of steps ketamine triggers release of neurotransmitter glutamate, which in turn stimulates growth of synapses. Research at Yale has shown that damage of these synaptic connections caused by chronic stress is rapidly reversed by a single dose of ketamine."

Though I've never used it, so I can't attest to this personally, but i'm all for the open study of drugs and there effects, both positive and negative.

Sapolsky on chronic stress and hippocampal damage:
 http://www.ncbi.nlm.nih.gov/pmc/articles/PMC60045/

Chronic stress causes prolonged Cortisol release from the adrenals, which in turn feeds back to the hypothalamus and has a negative feedback on the cortisol release, as one would expect. However, there is more to this than a simple negative feedback loop. The hippocampus seems to have a negative influence upon the hypothalamic release of CRH, in turn lowering cortisol levels. Unfortunately, the sustained levels of cortisol, if an organism is chronically stressed, seem to inhibit the hippocampus through 3 possible mecahnisms described by sapolsky:
1)Temporary (reversible) retraction of hippocampal dendritic connections
2)Ihnibition of neurogenesis in the hippocampus
3)Hippocampal neurotoxicity = a loss of preexisting hippocampal neurons

This explains the loss of hippocampal volume that is common in severly depressed patients that express high cortisol levels, and might explain the permanency of various functional/mood/ learning losses as a result of depression working through permanent hippocampal damage.




The potentially good news is that anti depressants (Tianeptine - and SSRE [enhancer]) - and possibly other (SSRI's) [despite the seeming incongruity] increase BDNF, which in turn inhibits the effect of cortisol upon the hippocampus thereby preserving its integrity.
"Although the best known of these are the specific serotonin reuptake inhibitors such as Prozac, other efficacious drugs also block the reuptake of norepinephrine and/or dopamine. Nicely commensurate with the involvement of serotonin, there is some evidence that increased serotonin availability can stimulate cell proliferation in the hippocampus However, tianeptine is a distinctly atypical antidepressant (with, reputedly, only limited clinical efficacy), which increases serotonin reuptake. Thus, it decreases synaptic serotonin concentrations, rather than enhancing them."



It may well be then, that antidepressants not only help the patient now, but if they can both lower stress now, and lower the deleterious effects of stress upon the hippocampus, that the patient is less likely to have lasting permanent damage to the hippocampus, and with it permanent damage to learning and mood centres!

It is worth mentioning that a few still think some sort of neurogenesis issue in the hippocampus could lead to depression, not the other way around, but they are a minority and evidence appears scarce.

I will leave you with the great man's words himself:
"Obviously, more research is needed. It would be a boon to biological psychiatry if any antidepressants can prevent some of the neurobiological correlates of depression, in addition to alleviating the affective symptoms. But findings such as these also support the frequent uphill battle for those who study depression, or suffer from it, namely convincing others that this is a real biological disorder, rather than some sort of failure of fortitude or spirit."