Providing straightforward information pertaining to drugs, drug use & drug policy. The Grey Pages promotes drug-related literacy and advocates a system of viable and tolerant drug policies. This is my personal collection of commentaries, essays, tid-bits, and other such writings on everything ranging from drug use, drug policy and drug-myths, to drug-science, addiction, human behavior, and the workings of the human brain. I started this blog with a particular focus on opioids, and over the past year have found my interest gravitate toward the intriguing, ever-changing world of designer intoxicants (i.e. "research chemicals" or "designer drugs").

Monday, March 7, 2011

A Progressive Approach to Depression

The Monamine Theory of Depression Must Be Challenged 

Depression and Anxiety related illness may have a vast variety of underlying pathology. The mainstream approach is in fran terms, a "One size fits all" approach - a simple solution to a complex issue, which is touted as absolute 'fact'.

Our approaches must be expanded to reflect the intricate nature of the human brain.

As pharmacological science & the medical establishment advances, our understanding of the pathological nature of mental illness has progressed. Research has shown a complex degree of biological elements underlying depressive states; which frankly go far beyond the simple monoamine hypothesis to depression. Mainstream drug companies such as Pfizer market a cookie cutter series of SSRI's and SNRI's, each new drug with the same effect as the last - With advertisements presenting a simplistic and outdated 'monoamine chemical imbalnce' theory as absolute fact. This theory upon which big-pharma continue to fixate is becoming less credible over time, and at best, questionable.

Along with a continuing open minded approach to revisiting the MANY elements of mood and emotion, an important element to focus upon is the endogenous opioid system:

Focusing in part on the endogenous opioid neurotransmitter system can be seen as a single key component which can serve as a building block to a modern, more progressive understanding of depression. Based on the general understanding of the body's endogenous opioid system, we can conclude that new treatments for depressive conditions may start with some of the following opioidergic based therapies.

ERI's or Enkephalinase Inhibitors: Inhibit enzymes responsible for the metabolism of enkephalin. Enkephalins are naturally occuring opioid peptides which act as agonists at primarily delta opioid receptors, in addition to mu receptors, and produce antidepressive effects. An enkephalinase inhibitor works in an analogous way to popular serotonergic antidepressants; essentially by inhibiting the (metabolic) reuptake of these neurotransmitters, allowing higher synaptic levels of the peptide to remain active.

KOR Antagonists: Reverse the effects of endogenous/exogenous kappa agonists; Although certain selective kappa activity may play a role in supraspinal analgesia, agonist activation of the kappa receptor is implicated in profoundly dysphoric and often hallucinogenic effects. In addition, kappa activation is believed to reverse many effects of mu receptor activation; thereby acting as a negative feedback system to mu opioid effects. Therefore, antagonist activity at the KOR (kappa receptor) and neutralization thereof will prevent this negative feedback, as well as enhance positive mu-opioid mediated effects. The opioid buprenorphine in addition to partial mu-activity, is an antagonist at the kappa receptor; this is believed to play a role in buprenorphine's antidepressant properties. Another kappa antagonist, simply known as JDTic is being studied for its antidepressant-anxiolytic (anti-anxiety) effects - JDTic is highly selective to the kappa receptor, and produces its antagonist effects without affecting mu or delta receptors.

DOR Agonists: Agonists of the delta receptor produce modest analgesia, and are believed to possess antidepressive effects. This may be associated in part by increasing production of BDNF, or 'brain derived neurotrophic factor' - BDNF promotes nerve cell growth, and has been shown to play a role in modulating depression in mammals; studies have shown that stress induced downregulation of BDNF leads to eventual atrophy of the hippocampus, a trait which is common among subjects suffering chronic depression. Delta agonists have been observed to stimulate respiratory function in low doses, while producing occasional respiratory depression in ultra-high doses. Delta activity plays a small role in the analgesic properties of some opioids.

MOR Agonists: The ability of opioids to produce analgesia and an emotional state of well being is primarily mediated by agonist activity at mu opioid receptors. Opium derivatives were historically used to treat depression and anxiety related disorders, and were widely prescribed by Physicians for this purpose. Mu opioid receptors modulate our cortical perception of pain, both physical and emotional - Both manifest as through the same states of suffering, which is reduced with MOR agonists. The body's natural opioid peptide endomorphin, is our most potent natural painkiller and antidepressant, and is selective for mu opioid receptors. MOR agonism enhances dopaminergic release within the nucleus accumbens, leading to increased motivation and a state of well being. Antagonists of the kappa receptor essentially accomplishes the same goal; increased mu opioid activity - through a different mechanism. Regularly administered alongside supplemental agents such as NMDA and/or cholecystokinin antagonists, mu selective opioid agonists can succesfully control depression/anxiety without the rapid development of tolerance; the key destructive element behind opioid dependence.

Furthermore, three known variants or subtypes of the mu opioid receptors exist: mu-1, mu-2, and mu-3. The profoundly pleasurable and pain relieving properties of a mu agonist are heavily mediated through the mu-1 subtype. Activation of pre-synaptic mu-1 receptors within the lymbic area of the brain blocks the inhibitory effect of GABA, thus allowing increased cell firing of dopamine within the nucleus accumbens; this is experienced as extremely pleasurable. Mu-opioid agonists selective for the mu-1 receptor subtype allows the beneficial effects of an opioid, with lesser likelihood of the problematic respiratory depression mediated by the mu-2 subtype. Currently, no opioids are available which selectively target the mu-1 receptor type. However their development is likely to offer smarter & cleaner opioids with a superior safety and side effect profile.

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