While most antidepressants block monoamines uptake, it is not clear at all which is the role of this blockade on antidepressants pharmacological activity. In fact, AD exert such effect after the first dose but antidepressant effect requires two or three weeks of continuous treatment. Several other theories have been proposed to explain antidepressant action: downregulation of adrenergic or serotonergic receptors, increments in the synthesis of BDNF and neurotrophic response, promotion of adult neurogenesis in hippocampus, epigenetic mechanisms as well.

On the other hand, you are right: antidepressants act not only on the brain but also in nerve terminals in the body. However, measuring monoamine leves after administrating a potentially antidepressant drug is not a validated method to assess antidepressant-like effect. Activity in experimental models of depression (forced swimming test, learned helplessness, etc.) are much better.

I have long held that the monoamine hypothesis/depression theory is a weak one, and dangerous from the standpoint that it presupposes that seratonin's main role is mood control. In fact, less than 5% of seratonin is in the brain, at least 65% in the gut of the body where its main role is involved in food to nutrition synthesis and various functions of the pancreas. The remainder is in the other cells of the body and appears to have a key role in relieving hypoxia wherever it occurs. In our work with video otoscopy, we began noticing about 20 years ago, when the SSRI bandwagon was getting artificially promoted not from patient responses but from slick marketing of a concept that was tenuous at best, that synaptic dilation was occuring in many cases of SSRI patients. This dilation seemed to slow both the reuptake and secretion of hormones, including seatonin, and those were the patients who would plunge into deep clinical depression. Now, as we look over the landscape of patient histories, we have to ask ourselves if it would be better to get at the root causes of the depression or to stay on the path of addressing symptoms only and allowing the underlying causes to fester on. Long-term effects are the key and in our findings getting to the causes are the only viable long-term model for treatment.

The best treatment, of course, is getting to the underlying cause. For instance, we see more and more long-standing keratosis obturans in the ear canals of patients (most often mistaken by physicians as impacted cerumen, when instead it is a slowly developing mass of septic debris with keratin wrapped around it)..a phenomenon that seems to track the falling cellular pH of the US population, especially the diabetic trends that are in epidemic proportions today. We are currently gathering file information to see if the trend is strong enough to warrant a study on this very topic, which heretofore seems to have completely eluded the attention of the medical and scientific community. But the most pronounced feature (see attached monologue) is the presence of inflammation when these occur--could be from a septic infection in a tooth, an infection in the jaw, ingrown toenail, inflamed prosthesis, or just the development of diabetes mellitus type 2, etc. But the thing that always surprises us is these people are nearly always taking an SSRI/SNRI antidepressant, have severe digestive problems, taking steroids and NSAIs, and some have a chronic cough (via Arnold's reflex of the EAC). By taking care of the tooth, jaw, toe, prosthetic, diabetes, etc. and removal of the obturans--all the other problems seem to miraculously evaporate. Then, all they have to contend with is the side/interaction/withdrawal effects of polypharmacy their physicians so unwittingly gave them to cover a multitude of symptoms. These cascade of health behaviors are not rare by a long shot. So, while the pharmaceutical community marches on looking for the magic antidepressant that exhibits fewer side/withdrawal effects, the medical community should be vigorously exploring how to raise the cellular pH of the population (without medication), and to being treating causes instead of superficial symptoms. I have offered but one example--there are many more, and all trace back to similar underlying causes--nutritional deficiencies, dehydration, heavy metal toxicities, food sensitivities, etc.

Max, have you ever considered psychological factors as the main cause of most depressions? To mention a number of them: loss, long-lasting frustration, solitude, suppressed anger and non-assertiveness, rejection, disproportionately small thanks for one's pains, chronic deprivation of existential necessities, being side-tracked in the family, company, society, and so on.

Yes, have taught entire courses on that, Peter. But for such I say again that underlying causes (psychological, physiological, etc.) should be addressed before we prescribe side/interaction/withdrawal effects-laden antidepressants. But in the majority of clinical depression cases, physiological factors have been implicated, as well. Inflammation of the cortex is a major cause of physical depression (which of course manifests as psychological depression). My contention for many years now is that there are no shortcuts, no bypasses, no excuses for us to not search for and address all REAL causes by reaching for the script pad that only ignores and deprives patients of ever truly healing. Incidentally, in the seven underlying causes of all chronic disease, unresolved psychological figures most prominently in the model from which we work in our practice. Mind/body and body/mind effects are the totality of where all medicine should be concerned, in my opinion.

I do not claim to be the expert of the matter under discussion but would like to share my ramble reflections on the issue raised and discussed here.

I think that there is a need to be careful in making distinction between cause and correlates of any psychological disorder including depression.

In my view we are from the exact cause of depression and this is reflected in the failure of various treatment options of depression and also from the frequent relapse of depression after discontinuation of treatment for a long time.

I do agree with many of the earlier posts of the esteemed members that certain psychological factors as well as neurological/neurochemical factors are linked with depression but I hesitate in concluding that they are the cause of depression in true sense. For instance, I do agree that certain psychological factors such as stress, loss, long-lasting frustration, solitude etc. have been found to be associated with onset of depression. However, we cannot be sure (with evidences for such link) that these psychological factors directly trigger depression. These factors somehow may lead to some changes at psycho-biological level (that in my view is still not well known) that may be the direct cause of depression.

If we believe in the notion that there is always some cause of certain event or phenomenon then definitely there would be a cause for depression also. But what is that is still not known. The best that we can infer is that there are some potential psychological, social, and biological factors that alone or together bring some changes ( that is still not well known) that leads to depression. In other words, the bio-psycho-social factors lead to depression by influencing the unknown (or little known) causal agent of depression.

The specific networking and interaction of the bio-psycho-social factors and the resultant outcome of it in relation to depression need to be discovered yet. If the exact causal mechanism will be known then it is likely that all the cause (or correlates) of depression discovered so far would converge.

For instance, diverse biological correlates depression, such as reduced nerogenesis in the hippocampus, lower level of serotonin, the change in the density of serotonin receptor, and the changes in the level of dopamine have been reported in the literature. The most recent addition is the glutamatergic N-methyl-D-aspartate (NMDA) receptor based hypothesis of depression based on the quick antidepressant effect of "ketamine" . However, there is no theory or model that attempts to explain how these diverse biological changes observed in depression can occur together. These changes are likely to be linked to some third variable and this third variable may be the cause of depression as well as the factor for convergence of such diverse biological changes in depression.

Monoamine Oxidase is a mitochondrial born enzyme, therefore inherited from mother to son, just like mitochondrial DNA. The activity of the enzyme is the same for any cell in the host's body. Conveniently, blood platelet MAO is relatively easily harvested and assays have been standardized for many years. The clinical correlation between low activity levels of MAO and symptoms of weight and sleep disturbances are statistically significant. Associated reports of feeling hopeless, helpless, worthless with high statistical significance have also been reported. These results have been replicated several times since the original report by Schildkraut, Schatzberg, Cole, and Rohde in the mid 1970s. The relative distribution of catecholamine secreting neurons in brain areas associated with mood control shows that norepinephrine (NE) neurons are the most abundant, followed by serotonin(5HT) and then dopamine (DA). A simple picture of what happens when reuptake of catechols fails is that the concentration of NE available for nerve signal transport across the synaptic cleft depletes first, resulting in a loss of "energy" that supports vital regulatory functions like sleep and appetite. If the balance isn't restored by exercise, diet, or what have you, then the 5HT production increases to boost mood and maintain "emotional" well being until the NE concentration is endogenously corrected. Eventually, 5HT production may also fail, and this results in the loss of well-being that we associate with the usual presentation of "I feel depressed." If the NE-5HT concentrations are not restored, then the only other catecholamine available, dopamine (DA) will become dominant. Unlike NE and 5HT, DA neurons are also active in other parts of the brain that support interpretative cognition. so the end state of catechol depletion is a brain with no energy to support vital functions, failed capacity to maintain well-being and flooded with DA, which presents the classic picture of psychosis. Unlike the DA flooding seen in schizophrenia, end stage depression is usually manifested according to affect consonant somatic delusions of smelling bad, believing that something is rotten inside. The catastrophic crash of the 5HTsystem leads to profound suicidal ideation, which is generally not seen in schizophrenia unless there is an affective component. Constructing an heuristic model only awaits the perseverance to map critical "causative" factors like defective MAO activity which appear to be hereditary, and defective membrane reuptake and receptor site sensitivity that can be up or down regulated by other mechanisms like dietary precursor intake, enhanced feed back loop capacity from higher cortical levels usually mediated by glutamic acid. MAO being only one of the potential feedback controls for catechol production. Underactive MAO would cause a buildup of catecholamines and increased electrical activity leading to a global sleep disturbance, exaggerated feels of well-being and affect-consonant delusions of grandeur a syndrome we call mania. Eventually both endogenous and cognitive feedbacks will damp and even stop the over production, leading to the "crash" of depression that follows a manic episode. These fluctuations can be monitored by serial measurements of urinary catecholamine metabolites such as nor-metanephrine and methyl-hydroxyl-phenyl-glycol (MHPG), The major take home lesson is that these are all biofeedback mechanisms that the human brain has been genetically programmed to enable correctively. Without exact biological measures of precisely how much and what kinds of catechols have been depleted, or restored, we have no rational basis for recommending one exogenous intervention versus another.

William this is a superb review of the role of the various hormonal components that have been implicated, in theory and practice, in contributing to abnormal human behaviors. One phenomena we observe when patients are given an SSRI/SNRI anti-depressant irrespective of any intelligent reason for giving it other than a complaint of "feeling depressed" is, in time, synaptic dilation sets in at some point in time and the hormones neither secrete or come back into the system, but are held at bay, causing the patient to plunge into a deeper, more serious depression. We find this particularly with young people who are also taking in high levels of beverage caffeine (a very common thing today) and coupled with the adrenal depletion wrought by caffeine toxicity are far often misdiagnosed as bipolar. Remove both the caffeine and medication, and affording a good diet and re-established circadian cycle, and the "bipolar behaviors" nearly always seem to resolve. There is so much overlay in these modern dietary and polypharmaceurtical trends that it is difficult to parse out causal from relational factors. Thank you for your thoughtful and thorough review.

Thank you Dr. Chartrand. Caffeine's principal action is to stimulate the production of second messenger RNA - to increase synthesis of new protein or enzymes that are already in production - which is why you can't get a primary pressor effect with caffeine alone, caffeine is not a sympathomimetic. The reason that SSRIs increase the concentration of 5HT within the synaptic cleft is that is what they are supposed to do. How would that blockage of re-uptake also block the release of neurotransmitter from the pre-synaptic neuron?

Our observation is that it is only under dilated synapses state that cell signaling mechanisms are interrupted and release slowed...by what precise cascade I cannot explain. Your comment on the 5HTP vs dopamine deprivation is surely relevant to this, and we might have been confusing chemistry with behavior. I raise this issue here, because SSRIs/SNRIs appear routinely to be prescribed by the vast majority of prescribing physicians without ANY clinical evidence that they are even needed (mourning is not clinical depression, but one would think so by what we see in everyday medical practice) or effective for the patient (measures are rarely used in the PCP practice that we can see to determine that anything has been improved), so in pain clinics like ours are seen the end-result: patients that plunge into the side/interaction/withdrawal effects occurring in statistically much higher numbers than the literature would suggest. In adolescent patients we routinely find among those on SSRIs/SNRIs also heavy caffeine intake. Caffeine may not be a sympathomimetric, but combined with anti-depressants, and especially when overlayed with other psychstimulants, the withdrawal crash sure appears sympathomimetric. Perhaps you have some observations or knowledge on this that would help those of us on the front lines who have to tangle with these questions. I cannot and do not make prescription, but am deeply and perennially concerned about the indiscriminate practice of those who can in overprescribing these medications in medicine today.

Of course, it bears worth repeating that by getting to and resolving the physical cause(s) (which produce the proinflammatory states of the cortex) that the vast majority of clinical depression cases will be resolved without need for medication. Only in a world where we leave these underlying factors untouched do we need the universe of anti-depressants of pharmacopia.