I think this observation mirrors a similar finding in bipolar disorders, where cognitive function (particularly executive functions) does not appear to return to "normal" after the onset of illness. Importantly the nature of the depressive disorder is critically relevant (melancholic/psychotic forms particularly) and has made research in this area more difficult to interpret. From my clinical experience, recovery from melancholic depression takes many months to achieve remission and research in this area confirms this impression. The prognosis is also highly modified by the extent of remission, as opposed to recovery. I suspect you are right that there is a significant similarity between this cognitive deficit (in the melancholic group of depressions) and the cognitive and negative features of schizophrenia. I hope you are researching this phenomenon, it would seem to be of critical importance.

Precaution, this answer may change you view on depression.

According to the publications of Michael Maes, many cases of Stress-induced depression are an interaction of cortisol, LPS from the gut, free chemical radicals and chronic inflammation in the brain. Confirmed in an animal model by Gárate et al. In a recently paper we describe the underlying molecular process of chronic inflammation, the TRL Radical Cycle.

To answer your question, most psychotropic drugs act only on the symptoms, but not on the cause of depression. With a causative strategy it is possible to treat all symptoms effective. Not only depression but also cognitive impairments.

To my experience molecular hydrogen is the strongest ROS-scavenger known today. See the paper of Ohno et al. 2011. It is very helpful in stress-induced depression. But this could only be understood, accepting inflammation as cause of depression, what today definitively is not common sense.

http://www.ncbi.nlm.nih.gov/pubmed/21407167

http://www.ncbi.nlm.nih.gov/pubmed/23436141

http://www.ncbi.nlm.nih.gov/pubmed/22053929

http://www.ncbi.nlm.nih.gov/pubmed/22720117

As a long term depression sufferer, I am interested in this new approach to depression what gram negative antibiotics are available?

Thank you everyone for your astute answers. I will most certainly follow those links Kurt, it sounds fascinating and may be of value in what I am trying to ascertain, and I have seen studies that suggest inflammation in very specific brain regions ( I do not know where they are in my library, my titles for some reason disappeared on the database!). The possibility of reduced cognitive impairment/deficits - are there any particular ones that you are focussing on? Darryl, in all the literature I have gone through, I simply cannot find any correlational studies that have significant results which indicate a link between cognitive impairment and cognitive processing, so I tried cross referencing to Schizophrenia and Bipolar Disorder. The information you provided Darryl is of great interest. I have a hypothesis that there is no link between cognitive impairment and cognitive processing, except that cognitive processing abilities may help to develop strategies to work around the cognitive deficits being experienced. Graeme, have you found that you experience deficits, but that you use executive functioning to overcome them? I would be extremely interested in your answer, if you feel that it is not too personal a question. I know people who have suffered chronic disorders such as these and the fact that you are able to mention it is exceptional and it is incredible that you have managed it so well for such a long period of time! Most of the correlational research I have come across with regards to MDD seems to agree with regards to two main cognitive deficits, those of slowed reactions to tasks and memory deficits. Other deficits seem to be open to debate. With the DSM IV - TR the main factors are related to symptomology such as anhedonia, etc - the 5 main criteria. When there is an improvement in these symptoms which tend to be based on observable behaviour ( hopefully the suggested inclusion on aspects such as cognitive processing will appear in the DSM - V), the improvement of these symptoms would suggest cognitive inhibition/control processes being activated, which would require the use of meta-cognitive processes and self awareness in the regulation of emotional states and the long process of adjusting well established schemas, however I have not seen it mentioned anywhere that cognitive processing has improved cognitive deficit, or that improvements in cognitive deficit have resulted in improved cognitive processing.

I would be very interested in everyone's comments.

Look at Ca++ in brain. It has been supposed that the Ca++ in the brain and the blood can prevent the HOST human from dying of Tuberculosis--a selection advantage. Kathleen Baggs

Thanks Kathleen, this is worthy of investigation!

Dear all,

I did not understood if Cheryl's question about cognitive impairment refers to first episodes of depression or to patients with a previous history of treatment with antidepressants and/or other drugs?

You can get some unexpected answers to this question in an excellent book, which raises relevant issues about cognitive impairment during long term treatment with antidepressant or antipsychotic drugs. The book is "Anatomy od an Epidemic", by Robert Whitaker. In the references section, you can find useful hints about cognitive impairment in depression, bipolar disorders and schizophrenia.

Thank you Giuseppe, I am referring to Major Depressive Disorder and also Treatment resistant Depression, where at least two episodes have occurred. A previous history of Depression with treatment would be correct as well. Thank you so much for referral to this book, I will try to source it in my country if it is possible. Your input is much appreciated!

@cheryl

It's hard to say which cognitive imparements are related to long term depression, but I note that I was originally treated for Major Depression, and only recently have been treated as schizophrenic. I would say that my imparements were to some extent masked by my high executive function, but over time there has been an appreciable deterioration in the quality of my life. Among other things I have been considered unable to work now for 15 years.

Guys! When the neurons (neuropeptides are the pearls with information running through our bodies; aptly named because the discoverers Candace Pert, et. al. saw them) are not firing because the Ca++ is too high in the brain, then what you say as cognitive impairment is a given. Most Ca++ is stored in the muscle cells. What if the muscles didn't get enough Ca++? Tell me where I'm assuming or being assumptive. Kathleen

@ Kathleen

You are absolutely right, enhanced concentration Ca++ is a problem in depression. But it may be a consequence and not the cause. Let me put the things in the order of occurrence for stress-induced depression.

Permanent stress led to the release of cortisol. Cortisol, the stress hormone has several effects. One is, it weakens the tight junctions of the gut. Lipopolysaccharide (LPS) can now cross the barrier of the gut and gets into the bloodstream. LPS can cross the blood brain barrier. In the brain LPS triggers TLR4, an inflammation results. On the lowest level, TLR4 activated cells release interleukins, e.g. IL-6. IL-6 triggers the release of reactive oxygen species (ROS) and NOS. The radicals modify body own substances. Hyaluronan is degraded, HMGB1 get in an active form, lipids are oxidized etc. Resulting in several DAMPs. These DAMPs trigger TLR4, the circle closes. On a higher lever the NLRP3 inflammasome gets involved. This enhances the concentration of Ca++ and has impact on further ion concentration like K+. Finally the neurotransmitters are affected, due to the change in ion-concentration. The result is impairments of the brain, showing up as depression, and many other symptoms, like chronic fatigue.

To treat this form of depression the stress must be taken away from the patient. But the processes are already autonomous. To stop the chronic inflammation TLR4 antagonists and strong ROS scavengers are useful. Natural TLR4 antagonist are find in green tea, ginger, curcuma, cinnamon and several other plants of the Traditional Chinese Medicine. Strong ROS scavengers are Resveratrol, N-Acetylcysteine and the best of all is molecular hydrogen.

I have developed a proprietary method to provide hydrogen-enriched water. Seeking for co-operation in a clinical trial. So far I only have results for hydrogen in a single case of stress-induced depression, the effect was overwhelming. Chronic fatigue disappeared within 4 weeks, depression after 6 weeks.

Dear all,

An amazing question indeed! MDD seems to be, at least in part, a neuroprogressive disorder, similar to bipolar disorder. This means that relapses and chronicity over the course of illness are associated with deterioration in terms of psychosocial functioning, quality of life, and neurocognitive functioning that manifest independently of clinical remission or euthymia (your question). In other words, the accumulation of illness burden (for instance, more episodes or comorbidities) translate into functional deficitis beyond the presence of acute clinical states. Reseachers such as Michael Maes and Michael Berk have put forward hypothetical models to explain these clinical observations. In short, they suggest that the major players seem to be increased oxidative stress and inflammation, and decreased neuroprotection (the BDNF story), as already mentioned here by other colleagues. This is related with the key concept of allostatic load, originally developed by Bruce McEwen, and later applied by Flavio Kapczinski to bipolar disorder (please search in PubMed). For example, there is a vicious circle among stress, cell endangerment, tisular damage in key areas (PFC, hyppocampus), reduced BDNF (neuronal resistance to stress, neuroplasticity, and memory/learning), and more likelihood for subsequent relapses, even without stress (illness has taken an autonomous evolution). This echoes Bob Post´s contribution with the kindling model. Allostatic load is the toll paid to regain or at least try to mantain homeostasis (equilibrium after each episode) in molecular terms. This wear and tear process accumulates (allostatic load, AL) in the body even though mood symptoms have disappeared with medications. AL seems to explain or at least links three major domains in bipolar - neurocognitive dysfunction, psychiatric comorbidities, and medical comorbidities.

One step further is the development of models of clinical Staging for mood disorders, such as those by Kapczinski and Berk. The combined use of biomarkers, neurocognitive and daily functioning data, in addition to markers of illness burden (presence of comorbidities, number of episodes) will hopefully lead to better classification of BD (also MDD) patients in different stages of the illness, then address the right interventions at each stage to arrest the neuroprogressive process (ideally reverse this process) and ultimately improve patients´ qualty of life and social-occupational functioning.

Hope this helps.

Also, be careful in assuming that depression causes cognitive impairment. I believe this to be more a myth than a reality and have published several articles demonstrating such. I believe that depression cause complaints of dysfunction of all types (cognition, health, social skills, occupational skills, etc.) and the complaints are not synonymous with dysfunction. Depression puts dark colored glasses on a person and colors their self-perception so that they believe they stink at everything, which is not always true. Compliants of dysfunction are more highly correlated with scores on depression and anxiety instruments (Beck Depression Inventory, HRSD, etc) than they are related to objective scores on cognitive instruments (IQ, memory, executive functioning). Furthermore, if the research you are reading has not included measures of performance validity (often referred to in the past as symptom validity tests, SVTs, ore measures of effort), then the results are essentially useless from my perspective. Secondary gain is a huge problem in studies of depression and individuals who are seeking or receiving compensation (SSDI, SSI, VA benefits, workers comp, civil litigation, etc.) will intentionally perform poorly and you will misattribute low cognitive test scores to depression rather than to feigning or malingering. My own research, as well as that of many others, has shown that by excluding individuals who fail PVTs the effect of depression or PTSD on cognition is ZERO.

Demakis, G., Gervais, R. O., & Rohling, M. L. (2008). The effect of failure on cognitive and psychological symptom validity tests in litigants with symptoms of posttraumatic stress disorder. The Clinical Neuropsychologist, 22, 879-895.

Rohling, M. L., Allen, L. M., & Green, P. (2002). Who is exaggerating cognitive impairment and who is not? CNS Spectrum, 7, 387-395.

Rohling, M. L., Green, P., Allen, L. M., & Iverson, G. L. (2002). Depressive symptoms and neurocognitive test scores in patients passing symptom validity tests. Archives of Clinical Neuropsychology, 17, 205-222.

Green, P., Rohling, M. L., Lees-Haley, P., & Allen, L. M. (2001). Effort accounts for more neuropsychological test variance then does ability in litigant sample. Brain Injury, 15, 1045-1060.

Binder, L., & Rohling, M. L. (1996). Money matters: A meta-analysis of the effect of financial incentives on recovery from closed-head injury. American Journal of Psychiatry, 153, 7-10.

Rohling, M. L., Binder, L., & Langhinrichsen-Rohling, J. (1995). Money matters: A meta-analysis of the association between of financial compensation and the experience and treatment of chronic pain. Health Psychology, 14, 537-547.

Rohling, M. L., & Scogin, F. (1993). Automatic and effortful memory processes in depressed persons. The Journals of Gerontology: Psychological Sciences, 48, P87-P95.

Rohling, M. L., Ellis, N. R., & Scogin, F. (1991). Automatic and effortful memory processes in elderly persons with organic brain pathology. The Journals of Gerontology: Psychological Sciences, 46, P137-P143.

Scogin, F., & Rohling, M. L. (1989). Cognitive processes, self-reports of memory functioning, and mental health status in older adults. Journal of Aging and Health, 4, 507-520.

It also depends on the nature of "treatment". One might expect some differential outcomes of affect vs. cognitive improvement with drugs that effect relatively more serotonin reuptake vs. norepinephrine reuptake. For example treatment outcome of SSRIs vs.SNRIs. In addition, there is mounting evidence that antidepressants may not be effective for persons with mild to moderate MDD and that Cognitive Behavior Therapy is more effective and also works toward behavior activation which is probably the active ingrediant of that form of treatment for beneficial outcome of depression.

Dear Graeme. I thnk that what you say about your executive functions masking cognitive impairment is of great importance, as it has been found that those with higher intellectual abilities and higher levels of education tend to have more neuroplasticity (possibly because they developed specific pathways, and additional pathways) and are thus able to develop and adapt to compensate for impairments. Thank you so much for providing me with your personal experience in this, it is greatly appreciated. The other thing you mention which I find of great interest is that you have developed Schizophrenia and it is now believed that tauopathy plays a role in Scizophrenia and one of my previous questions, was whether MDD was perhaps linked to tauopathy. This was an unexpected insight, for which I am grateful you have provided, as it has occurred to me that certain forms of MDD/ Treatment resistant Depression may not be a "normal" form of Depression. You have given me a great deal to think about in the search for answers and treatments for MDD!

Martin, thank you for such an excellent response! I have read some of your studies during my Masters year, and found them to be in agreement with what I hypothesize with regards to cognitive impairment. The self report by Depressed patients of deficits are most certainly often exaggerated ( as found in somatic symptoms of cardiovascular patients with MDD), or reported in such a way as to make it nigh impossible to separate actual impairment from perceived impairment. The studies I found indicated that mainly memory and processing speed seemed to be impacted, with conflicting results for other cognitive deficits. I am wandering now whether cognitive processing (such as rumination) is then linked more to depressive symptomology rather than to cognitive deficit - I have kept an open mind on this, as I believe that if memory and processing speed is impacted, this would affect the ability of someone with MDD to activate meta cognitive processes in time to counterbalance the feeling of sadness, hence resulting in activating rumination before other processes such as self awareness are able to kick in.

Vincent - I am delighted you brought up allostatic load as I investigated it in relation to MDD in cardiovascular patients, who demonstrated higher levels for instance, of hospital visits, higher mortality levels and higher rates of sceondary non fatal mycocardial infarction. Allostatic load as you say maintains the cycle on a physiological basis, from the correlational studies I have viewed. I have seen studies which indicate that this has an impact on cognitive processing, but I have not seen any that indicate cognitive deficit. Please let me know where I can find any of these studies, as I would be very interested in going through them. A brilliant response Vincent and much appreciated!

Hi Kurt and Kathleen:

Kurt I agree, I think ca++ is a consequence. Your outlining of the process is excellent. The following physiological factors have been identified in Depressed Individuals, as well as those with cardiovascular disease; low heart rate variability, high levels of platelet reactivity, abnormally high cortisol levels and high levels of inflammatory cytokines. These physiological factors also cause or contribute to the development of Endothelial Vascular injury, Thrombosis, Ventricular Arrhythmias and sudden death. Would cognitive impairment still continue if the factors above were treated and no longer occurred?

Kathleen I would be very interested in your comment on the above. Also cytokines are implicated in diseases such as Rheumatoid arthritis. They are also play a role from what I can gather in muscle contraction abilities, arrythmias, hyperparathyroidism, and decreased neuromuscular excitabilty.

Milan ( a member or Research gate has mentioned that "Many of these mental illnesses and diseases seem to be caused by disfunction of postsynaptic density proteins (i.e., MAGUK scaffold proteins)", which could be of further interest to some of you.

You are welcome, Cheryl. Thanks for your kind comments.

I don´t remember studies on the likely connection between the molecular mediators of AL and cognitive deficits in MDD. Apart from the quite obvious link between BDNF and memory dysfunction. Clearly, a promising area of research!!

Dear all,

Regardless the discrepancies about the nature and origin of neurocognitive dysfunction in MDD that arose in this debate, the functional consequences is probably the most critical issue for patients and mental health providers. See this recent review:

http://www.ncbi.nlm.nih.gov/pubmed/23468126

So neurocognitive deficits are major players of functional outcomes in severe disorders, such as schizophrenia, bipolar and MDD. This may represent another non-specific, core dimension of illness, cutting across DSM / ICD nosological boundaries. Differences among categories would be mostly quantitative (degree) rather than qualitative. This is consistent with my practice.

Persistent neurocognitive dysfunction associated with recurrent MDD represents an unmet need with available medications. As raised by Alan, not all antidepressants share the same neurocognitive profile. Clearly, the worst part of it is compounded by tricyclic antidepressants (overall speaking, agents with anticholinergic and anti-histaminergic properties carry an extra burden on cognition). We and others have recently reviewed the relationship between neucognition and medications (both negative side-effects and potential enhancing properties) in bipolar disorder, including some pharmacological agents used in MDD:

http://www.ncbi.nlm.nih.gov/pubmed/19836378

http://www.ncbi.nlm.nih.gov/pubmed/22881296

Finally, I would favour the expanding use of neurocognitive training (remediation) in mood disorders when necessary:

http://www.ncbi.nlm.nih.gov/pubmed/22678229

Thank you Vicent, I agree with your comments, the differences among categories would mostly certainly be degrees of weighting on a quantitative scale. I think that neurocognitive training should be a critical consideration in mood disorders as well.

Darryl, having read through everyone's input so far, I have been delighted with the expertise and input and it comes full circle back to the notion that perhaps Bipolar, Schizophrenia and MDD may be on some type of continuum which is related to physiological factors, and may be a form of neuroprogressive disorder. Vicent has mentioned that there is a connection between BDNF and memory dysfunction. Perhaps the physiological chain of events trigger cognitive deficits via allostatic load and though symptomology may remit partially or fully. I then hypothesize that perhaps cognitive processes such as rumination selective attention etc which the 'remitted' patient, has altered may be involved in subconscious maintainance of mood homeostasis This possibly may be adding to the continuance of cognitive deficit, as the brain may be using its resources for modd maintenance rather than for the improvement of cognitive deficit. What do you think, do you think that this is a viable idea?

This is very interesting, the discussion now returns to a very upper level.

You could view a disease in many ways.

The basic level is the molecules involved.

Then the level of cells and cell interaction follows

Next different organs interact

Complete subsystems are the next level, e.g. nervous system in interaction with the immune system.

Then you can view on the whole body, next would be personality, spirit, mind etc.

On the highest level you can regard the interaction between different persons, the social aspects.

To be honest, my expertise is primary on the molecular level. Definitely an integrated view on all level is necessary to fully understood depression and others disorders. Anyhow, drugs work on the molecular level and it makes a big different whether you target neurotransmitters, ion concentrations or an inflammatory process.

That is very interesting Kurt, I think you have put it quite precisely, I am very interested in what you say about targeting neurotransmitters, ion concentrations, inflammation process. Based on this (I am not knowledgeable on the actions of specific drugs in general), which drugs target these different areas and do you have any idea what their different rates of success are? This would be invaluable information!

Neurotransmitter: Here most of all usually prescribed psychotropic drugs are more or less active. Either receptors are blocked; Enzymes are blocked, retarded re-uptake etc.

Ions, I do have no detailed knowledge whether the ion concentration can be changed. But drugs acting on ion channels play a major role.

My topic is inflammation. Different possibilities are available. Substances acting as TLR4 antagonist are under development e.g. Eritoran. Natural TLR4 antagonist one can find in green tea, ginger, curcuma and many other herbs of Traditional Chinese Medicine. I myself was suffering from a chemical hypersensitivity, what basically has the same inflammation process in the background. What I did was, I suppressed the expression of MyD88. This molecule is the second messenger of all TLR and several other receptors, e.g. IL-1 receptor. Suppressing MyD88 means massive suppression of the innate immune system. After one week, my hypersensitivity was gone, after two weeks I stopped the self-experiment. What did I use? A pharmaceutical cinnamon extract in high dose. Cinnamon is available from two different plants Ceylon Cinnamon, which is o.k. and Cassia Cinnamon, which comes along with high amounts of coumarin, which is very toxic and destroys the liver within a few days. A sure source of Cinnamon is the product from MAROS, Germany. There is no experience on high dose Cinnamon use in human in the literature. I did on my own risk and I was very lucky, no side effects occurred.

The other approach is to eliminate the radicals. Here Resveratrol is helpful; stronger is N-Acetylcysteine (NAC, the very well-known expectorant). Best is molecular hydrogen.

Dealing with inflammation further Omega 3 fatty acids is essential. The resolution of the inflammosome can only be archived with Omega 3 fatty acids. Having fish three times the week may be sufficient. Ibuprofen, Diclophenac and Paracetamol block COX enzymes. Therefore the resolution of inflammation seems not to be possible with these painkillers. Aspirin probably may work, no painkiller would be best.

Moderate exercises are helpful, but excessive exercises are counterproductive, worsening inflammation.

Avoiding the inhalation of Ozone, nanoparticles, metals, volatile organic compounds (all four in the emissions of laser printer and photocopier), pesticides, wood protection and radiation (X-ray, radioactivity and high dose UV) is recommended.

Hyperthermia seems to reduce inflammation, too. Perhaps a vacation in a warm area or a stay in a sauna can help to improve. And clearly stress must be avoided, since it is also leading to inflammation.

Here the paper which summarizes the possibilities.

@ Martin

Think you made a good point. Many extraordinary results in science and technology were achieved by persons in a depressive mood. Cruel, but it may help to focus on one topic, so my own experience.

Absolutely Kurt! Not to mention the arts, above all music and literature :)

Kurt, the information is fascinating! Kurt, Vicent, Darryl and all (If anyone is interested) Shrikant (also from Research Gate) and I are considering a collaboration in a study with regards to looking at physiological markers and cognitive processing markers that may help in predicting which patients with MDD/ Seasonal Depression etc respond better to different forms of medication. Please let me know if you are interested, as we could make this an inter continental study.

Cheryl sound very good, I would like to join!

That sounds super Kurt, I will message Shrikant later and let him know.

There is some very interesting comment in all these discussions. Thanks for the offer to join in a research project, Cheryl, but I am current preoccupied with research into autonomic dysregulation and cortisol levels in bipolar disorders and recurrent depression, not to mention clinical work, and will not be able to participate at present. However, here are a few thoughts.

The cognitive deficits in mood disorders appear to be associated with changes in both regional metabolic changes and structural changes in size, in various brain regions associated with those functions. The physiological disruptions would seem critically important and include (broadly), changes in frontolimbic interaction, the cortical autonomic network and white matter pathways in several areas. The molecular level changes are very complex and interact extensively with each other. Many of these have already been mentioned and I would add alterations in GSK-3 beta, to the long list. I have always conceptualized the significance of the cogntive processesing level to reflect these functions as a "total" organism: the Bio-psycho-social-cultural model. In the brain (uniquely), the interaction between levels is two-way and hence your novel idea Cheryl, about shifts in energy utilization in different psychological states. I rather think that the distribution of energy demand can be managed on that "psychological" level but the consequences of certain patterns of neural networking associated with certain highly "significant" (previously created under circumstances of emotional importance) thoughts and memories, can evoke disruptions in physiological functions on many levels. For example, certain polymorphisms of the serotonin transporter carry a higher risk of depressive disorder following stress. As the serotonin system is a major element of our physiological response to stress, a "faulty switch" here could leave a person vulnerable when certain emotionally potent networks are activated. Persistent and/or recurrent adverse activation can then lead to a variety of noxious events depending upon genetic history, life experience, and so on. In broad terms, noxious processes such as excessive intracellular calcium (eg from excessive NMDA glutamate activity), an imbalance of proinflammatory cytokines and anti-inflammatory cytokines, excessive ROS and NOS, etc, can follow such repeated insults to the brain from a psychological level of disruption.

We already know that the hippocampus is highly sensitive to these and other "stress related" problems, I wonder what other areas of cognitive relevance are affected.

Cheryl, i think your proposals are fundamentally important, we must approach these questions from all levels simultaneously, or we will be left guessing.

Incidentally Cheryl, you asked about my thoughts regarding a "transdiagnostic" approach to mood disorders and schizophrenia. I think the evidence is drawing us toward a notion that many mental disorders have more in common than in difference. This extends from genetics to elements of clinical symptoms and daily function. However signfiicant differences still exist and are important. My suspicion is that the cogntivie deficits you are considering are probably related to a common process, which varies in severity rather than form. It would be interesting to compare such changes with those seen in other, non-mental disorders such as closed head injury or various neurological disorders.

A rambling answer but I hope it is of some use :).

Darryl I am pleased to find that my thinking on certain aspects is also that of others. Your comments are great use, and to try and discuss issues as complex as this is very difficult to do in short form. Your input is invaluable! I hope that once you have finished your research on autonomic dysregulation and costisol levels in bipolar disorder and recurrent Depression that you will post it to Research Gate. It will be of great interest to me. I think that there is a commonality underlying cognitive deficits that varies in severity and that there is some type of continuum. Thank you Darryl, for sharing your expertise!

@ Darryl

Many thanks for that input! Your comments about enegy production made me remind of another major player- mitochondria. Relatively unexplored so far in MDD, to my knowledge.

I totally agree on your perspective of transdiagnostic issues. In this regard, your project about MDD and BD sounds fascinating. We do need that kind of comparative studies in psychiatry. Best of luck and keep us posted with your findings!!

@ Cheryl

If I understood well, your proposal is about the identification of physilogical and cognitve (I guess neuropsychological and cognitive styles?) predictors of therapeutic response to different medications (only antidepressants? if so, which? in monotherapy?) in subjects with MDD.

Many thanks for your kind offer Cheryl. I´d be potentially interested in such an inter-continental study but I´d love to discuss the details before considering a definitve participation.

In my experience, failure of one treatment node, just means another one gets tried.

Any prediction of outcomes must depend on new tests and protocols being established, and there is little at the medical level to indicate why one treatment mode works for one person and not for another.

My first question for your collaboration to think about, is what tests can be developed that indicate cognitive deficits in depressive individuals? Once you have some tests, it becomes easier to evaluate outcomes, because you can show whether or not the outcomes involve just mood or improved function. (Most anti-depressants work on the flood the brain with Neuro-transmitter model, to improve mood, and ignore cognitive deficits). The only tests that seem available are mood related tests, which don't even recognize cognitive functions as important.

If you want to explore cognitive deficits, it makes sense to develop some instruments that indicate specific cognitive deficits and then use those indications to evaluate treatment plans, and evaluate patients for outcomes.

To add to the confusion, I have a question, which came first the cognitive deficit or the depression? Or can it be that a cognitive deficit triggers depression, which makes the deficit worse?

Dear Vicent, From the physiological side, Shrikant will most likely provide details. At this stage the common sense route would most likely be to look at the most utilised forms of pharmacotherapeutic treatments. At this stage we have not concluded whether we should also include psychotherapy, this still needs to be discussed. On the psychological markers side, I am proposing the following theoretical basis, along with the cognitive tests that are used to assess it.

It is the Self-regulatory Executive function model (S-REF) of affective disorder. This model (Wells & Matthews, 1996) is based on the importance of Meta-cognition in determining cognitions. Metacognitions appraise, control, and monitor both the processes and outputs of cognition. The S-REF Model allows for the investigation of distributed networks and the holistic inclusion of all cognitive processes thought to be involved in affective disorders. “Existing cognitive theories of emotional disorder tend to consider only limited elements of cognition, and they often neglect broader aspects such as attention, regulation of cognition, levels of control processing and interactions between varieties of processing” (Wells & Matthews, 1996, p.881)

In the case of affective disorder this model proposes a specific configuration of cognitive processes which is termed Cognitive Attentional Syndrome (CAS) by Wells, and Matthews (1996). The key Meta - cognitive processes of procedural beliefs, plans and strategies in combination with schemas may generate positive beliefs with regards to the use of types of perseverative cognition, such as rumination. Critical dysfunctionalities in cognitive processes have been identified as “heightened self-focused attention, reduced efficiency of cognitive functioning, activation of self-beliefs and self-appraisal, attentional bias and capacity limitations”, (Wells & Matthews, 1996, p. 883) with rumination being considered the most critical disruption of the S-REF system, due to its heavy utilisation of cognitive resources to maintain dysfunctional meta-cognitive directives.

Symptomologies are reduced and cognitive processing altered in effective treatments, according to data found. If we were able to isolate which cognitive processes (tested before medications are started) had improved/not improved with the use of treatments (also indicates which parts of the brain are effected), and were able to find significant correlations, between these, symptomologies and different types of treatment, we may be able to determine via assessing cognitive processing combinations in relation to CAS, which patients would respond better to certain types of treatment. I am not sure as yet, which physiological markers Shrikant wishes to consider as we are at the beginning of our discussions. Your input would be invaluable in all areas. The tests I am proposing from a cognitive and symptomology perspective exclude cognitive deficits, as I am for now considering this as an independent syndrome. The tests that I am considering all take on average 15 - 30 minutes to administer. For instance the two metacognitive processing tests (such as the MCQ) developed by Dr Wells, in combination with symptomology tests such as the BDI-II, SCL-90 etc and a clinical interview like the SCID. I hope that this is not too much of a ramble, but it may give you some idea of what is being considered at this stage and I would be delighted to discuss it further. Monotherapy would most likley be the best way to simplify it, to gain an understanding of the effectiveness of different types of therapies. Co-morbid disorders, physiological or psychological would need to be considered very carefully, for instance Depression with anxiety has a different impact on cognitive processing and on therapies provided. Hope I am making sense Vicent, and I look forward to hearing from you further.

Graeme, that is a very very interesting question! It could be that cognitive deficit is part of the progression of a disorder. Neuropsychological tests are the best way to test cognitive deficit, but the issue is separating the impact of symptomology from cognitive deficit. This is the whole reason I brought the subject up, as there is a physiological base for the deficits but why do they appear to act independently from the reduction in symptomology. These are crucial questions you are asking and they deserve detailed study.

Thank you Vincent and Cheryl for your supportive comments. I have a few comments to make about the recent discussions. First, the assessment of depressive disorders needs to be addressed by several different methods to be fully meaningful. Questionnaires such as the BDI are "cognitively" biased, while the HDRS is more biased toward "physical" signs and symptoms. The MADRS includes more symptoms of anhedonia and subjective cogntive dysfunction, but also allows psychomotor function to be assessed. Neuropscyhological tools address many different elements of cogntiive function (including metacognition). A careful mix is preferable but never complete. Secondly, isolating pharmacotherapy without psychotherapy is poor practice, although attractive for researchers. Having done some research into psychotherapies, I suggest combinations of medications with well defined psychotherapies. The research methodology becomes more challenging, but the results more meaningful. Thirdly, there are many forms of "depression" and the elements of the disorder being studies needs to be defined. Finally, the usual subjects for reaearch into depressive disorders tend to be rather unrepresentative of the clinical population for a variety of reasons. This disorts the results markedly and is an issue which is often ignored.

I am very tenpted to join your study, Cheryl, as it sounds very exciting and novel. In any case I do wish you all well and expect some very exciting results in due course. Have fun!

Thnaks Darryl. I quite agree, with regards to tests and what they measure, I have studied them in length and found that weightings for and different types of symptomologies are measured in some tests, in different combinations in others and some are left out in others. It is tempting to leave out CBT, Psychodynamic therapies just to get an understanding of whether cognitive processes are altered by pharmacotherapy drugs, but this is is generally not feasible. Your points are extremely relevant. By the way, the National Institutes of Health - USA found the most effective treatment for MDD was a combination of Psychotherapy and Pharmacotherapy, which I am in complete agreement with. Just how much Pharmacotherapy alters cognitive processes with therapy is not well understood, but is well understood on a physiological level. Your advice is of great use and simply wonderful and will be considered seriously as we go forward. Thank you so much Darryl, for taking the time to provide your input, it is greatly appreciated.

Thank you all, I think this is a wonderful project so I will be delighted to collaborate with you Cheryl

Thank you so much Vicent, I will come back to you when Shrikant has assessed the outlines etc, so it may take a little while. Your input will be greatly appreciated!

Michael S Lidow,

Department of Biomedical Sciences and Program of Neuroscience, University of Maryland, Room 5-A-12, HHH, 666 W. Baltimore Street, Baltimore, MD 21201, USA

Tel.: +1-410-706-4435; fax: +1-410-706-0865.

Accepted 3 June 2003Available online 16 July 2003

http://dx.doi.org/10.1016/S0165-0173(03)00203-0, How to Cite or Link Using DOIPermissions & ReprintsView full text1. Introduction2. Historical notes3. Proteins altered in schizophrenia as they relate to Ca2+ signaling4. Major molecular hypothesis of schizophrenia and Ca2+ signaling5. Ability of altered Ca2+ signaling to generate structural and functional abnormalities observed in schizophrenic patients6. Ca2+ signaling and antipsychotic medications7. Concluding remarksAcknowledgementsReferences

Referred to byMichael S. Lidow

Corrigendum to “Calcium signaling dysfunction in schizophrenia: a unifying approach” [Brain Research Reviews 43 (2003) 70–84]

Brain Research Reviews, Volume 43, Issue 3, December 2003, Page 285

PDF (51 K)

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Abstract

The present paper demonstrates a remarkable pervasiveness of underlying Ca2+ signaling motifs among the available biochemical findings in schizophrenic patients and among the major molecular hypotheses of this disease. In addition, the paper reviews the findings suggesting that Ca2+ is capable of inducing structural and cognitive deficits seen in schizophrenia. The evidence of the ability of antipsychotic drugs to affect Ca2+ signaling is also presented. Based on these data, it is proposed that altered Ca2+ signaling may constitute the central unifying molecular pathology in schizophrenia. According to this hypothesis schizophrenia can result from alterations in multiple proteins and other molecules as long as these alterations lead to abnormalities in certain key aspects of intracellular Ca2+ signaling cascades.

@ Kathleen

Ca2+ signaling surely is an issue. Changes in neurotransmitter definitively are another issue. But what is cause and what consequence? There must be a reason, why Ca2+ changes. Altered pattern in neurotransmitter can be cause by Ca2+. What alters Ca2+?

To my opinion the initial step is inflammation in many cases of depression. Cytokines and Hormones involved in inflammation do have the ability to affect also calcium channels.

Hi Kurt and Kathleen, Cytokines and hormones are most certainly involved and their is a significant correlation between inflammation and Depression, especially in MDD and treatment resistant Depression. These do affect Ca2 levels, so I think that there is a combination of different systems that impact on each other causing interactions which could become cyclical

My theory is that mental illness is a result of a Selection Advantage. I support it by the fact that the last stages of tuberculosis (when the Bacterium is in the blood and permeates the Brain Barrier) mirrors mental illness. Selection Advantages such as low iron in the blood as an advantage against malarial parasite appears in different ways--Alpha-thalessemia, Beta-thallasemia, Sickly Cell Anemia, etc. This keeps the HOST alive to reproduce.

But, a defense by the body such as this would not work in the colder parts of the work. Look at European weather and the spread of tuberculosis as people moved into congested cities. So, we have Ca++ in the serum and blood to limit the growth of the Tuberculosis Bacterium.

I suggest growin tuberculosis bacterium in a petri dish full of blood that is high in calcium (Ca++). I've been told that there are eight ways that Ca++ can manifest itself--manic-depressive, schizophrenia, schizoactive disorder, depressive disorder, autism. Often, sufferers have found to have been born to a mother that has had a cold during pregnancy.

Recently, meta-studies have suggested that the one trait that mental illness have in common is increased Ca++. And, meta-studies have also suggested that mental illness is similar to what Selection Advantages do when protecting the Host from parasitic infection--inflammation--and bacterium.

OK, so what I am hearing is that the mother having a cold during pregnancy may result in the babies body reacting by flooding the blood with ca2+ ions, but that there might also be a genetic tendency to run with high ca2+ levels as a defense against certain diseases.

This defense must operate by reducing ca2+ levels in the neurons by inhibiting calcium influx, which because calcium is required for vessicle binding to the cellular membrane and therefore for release of neurotransmitter reduces the level of neurotransmitters being released depressing the subject.

This is somehow linked to gram-negative bacteria in the gut, by a chemical produced as a result of activity of gram-negative bacteria, in combination with cortisol, which in turn increases the inflamation in the rest of the body, resulting in an increase in the inflamation side effects, and possibly increasing antibody activity which eventually begins to attack the body in what is known as an autoimmune disorder. Along with this comes histamine production which increases reactions to external irritants in the form of allergies. We are looking at a reason why psychological diseases might be comorbid with allergies and autoimmune diseases like arthuritus.

What we need to turn this theory into a real diagnostic criteria, is a mechanism by which ca2+ activity is reduced, and tests that will allow us to determine whether such a mechanism is involved without resorting to soft diagnostic techniques. I suspect that serum levels of ca2+ are not enough by themselves to indicate this mechanism is working, since they might although regulated by the parathyroid be different just as a matter of personal variation.

Hi Kathleen, perhaps this may be interesting for supporting your statement.

Arch Gen Psychiatry. 2012 Nov;69(11):1123-30.

Toxoplasma gondii infection and self-directed violence in mothers.

Pedersen MG, Mortensen PB, Norgaard-Pedersen B, Postolache TT.

http://www.ncbi.nlm.nih.gov/pubmed/22752117

T gondii–infected mothers had a relative risk of self-directed violence of 1.53 compared with noninfected mothers. Regarded was a cohort of 45 788 women in Danmark.

Graeme, I think your deduction is correct, the mechanisms for interaction need to be investigated. Super answer!

Kathleen, it is a fascinating theory and deserves proper investigation. Your hypothesis is extremely interesting I hope you are going to research it and I would love to see your research!

Out of interest, I have provided below the listings of disorders which are believed to cause Depression in some way. In looking at Ca 2, and cytokines etc this may be of interest. These listings are from: Treatment-Resistant Depression - July 15, 2009 - American Family Physician http://www.aafp.org/afp/2009/0715/p167.: Table 1 Adapted with permission from Loosen PT, Shelton RC. Mood disorders. In: Ebert MH. Current Diagnosis and Treatment Psychiatry . 2nd ed. New York, NY: McGraw-Hill Medical; 2008:312–313. Table 2 :Adapted with permission from Rouchell AM, Pounds R, Tierney JG. Depression. In: Textbook of Consultation-

Liaison Psychiatry . Rundell JR, Wise MG, eds. Washington, DC: American Psychiatric Press; 1996:315.

TABLE 1

Selected Organic Causes of Depression

Cardiovascular conditions

Chronic heart failure

Hypoxia

Post-myocardial infarction or -coronary artery bypass graft

Collagen-vascular conditions

Giant cell arteritis

Rheumatoid arthritis

Systemic lupus erythematosus

Commonly abused substances

Alcohol

Amphetamine (withdrawal)

Cocaine (withdrawal)

Opiates

Infectious disease

Brucellosis

Encephalitis

Human immunodeficiency virus

Infectious endocarditis

Infectious hepatitis

Influenza

Lyme disease

Mononucleosis

Syphilis

Tuberculosis

Medications

Analgesics (e.g., indomethacin [formerly Indocin], opiates)

Antibiotics and antiinfectives (e.g., interferon)

Antihypertensive agents with catecholamine effects (e.g., clonidine [Catapres], methyldopa [formerly

Aldomet], propranolol [formerly Inderal], reserpine)

Antineoplastic agents (e.g., amphotericin B [Amphocin], cycloserine [formerly Seromycin], interferon,

procarbazine [Matulane], vinblastine [formerly Velban], vincristine [formerly Oncovin])

Corticosteroids

Gastrointestinal motility drugs (e.g., metoclopramide [Reglan])

Heavy metals (e.g., mercury, lead)

Histamine2 receptor antagonists (e.g., cimetidine [Tagamet], ranitidine [Zantac])

Insecticides (e.g., organophosphates)

Levodopa (formerly Larodopa)

Oral contraceptives

Sedative-hypnotics (e.g., barbiturates, benzodiazepines)

Metabolic and endocrine disorders

Addison disease

Anemia

Apathetic hyperthyroidism

Cushing disease

Diabetes mellitus

Hepatic disease

Hypokalemia

Hyponatremia

Hypoparathyroidism

Hypopituitarism

Hypothyroidism

Porphyria

Thiamine, B12, and folate deficiencies

Uremia

Neoplasm

Bronchogenic carcinoma

Central nervous system tumors

Disseminated carcinomatosis

Lymphoma

Pancreatic cancer

Neurologic disease

Chronic subdural hematoma

Dementia

Huntington disease

Migraine

Multiple sclerosis

Normal pressure hydrocephalus

Parkinson disease

Stroke

Temporal lobe epilepsy

Wilson disease

Other conditions

Chronic pyelonephritis

Pancreatitis

Postpartum depression

TABLE 2

Likelihood of Developing Major Depression Following Diagnosis of a

Specific Medical Condition

Condition Likelihood of developing depression (%)

Cushing syndrome 67

Epilepsy 55

Huntington disease 41

Hypothyroidism 40

Hyperthyroidism 31

Human immunodeficiency virus infection 30

Stroke 27

Diabetes mellitus 24

Parkinson disease 21

Chronic pain 21 to 32

Cancer 20 to 38

Chronic fatigue syndrome 17 to 47

Coronary artery disease 16 to 19

Dementia 11

Hemodialysis 7

Multiple sclerosis 6 to 57

New study shows possibility of blood test for MDD. For your interest I have attached the Abstract!

Early-onset major depressive disorder (MDD) is a serious

and prevalent psychiatric illness in adolescents and young

adults. Current treatments are not optimally effective.

Biological markers of early-onset MDD could increase

diagnostic specificity, but no such biomarker exists. Our

innovative approach to biomarker discovery for early-onset

MDD combined results from genome-wide transcriptomic

profiles in the blood of two animal models of depression,

representing the genetic and the environmental, stressrelated,

etiology of MDD. We carried out unbiased analyses

of this combined set of 26 candidate blood transcriptomicmarkers in a sample of 15–19-year-old subjects with MDD

(N=14) and subjects with no disorder (ND, N=14). A panel

of 11 blood markers differentiated participants with earlyonset

MDD from the ND group. Additionally, a separate but

partially overlapping panel of 18 transcripts distinguished

subjects with MDD with or without comorbid anxiety. Four

transcripts, discovered from the chronic stress animal

model, correlated with maltreatment scores in youths.

These pilot data suggest that our approach can lead to

clinically valid diagnostic panels of blood transcripts for

early-onset MDD, which could reduce diagnostic

heterogeneity in this population and has the potential to

advance individualized treatment strategies" (Citation: Translational Psychiatry (2012) 2, e101; doi:10.1038/tp.2012.26 Published online 17 April 2012. Discovery of blood transcriptomic markers for depression in animal models and pilot validation in subjects with early-onset major depression K Pajer1,5, B M Andrus2,5, W Gardner1,3, A Lourie3, B Strange3, J Campo3, J Bridge3, K Blizinsky2, K Dennis2, P Vedell4, G A Churchill4 and E E Redei2,5"

Pathophysiology of bacterial infection of the central nervous system and its putative role in the pathogenesis of behavioral changes

See link:

http://www.scielo.br/scielo.php?pid=S1516-44462013000100015&script=sci_arttext

Thanks Kurt, this is very interesting!

I have been considering the role of cognitive deficits further. In some studies cognitive deficits in general are presumed to be different forms of memory and attention, the physical abilty to shift, for instance one's attention, the ability to inhibit cognitions, control cognitions or present with cognitive flexibility. However, some consider , for instance attention and memory to also be information processing. The Executive functions are considered to be a form of information processing. When considering this what presented itself was the possibility that cognitive deficits could be low lying forms of attention (i.e., states of consciousness that are automatic), or memory systems that are automated (implicit), whereas effortful memory, such as working, or explicit memory, or the active control of attention are higher levels of the same systems, but are actually related to information processing. If this is the case, active attention and explicit memory functions may be governed by a different physiological system, which could be a basis for why Depression can improve (involving for instance executive functions, working memory and active attention). Thus my hypothesis is that there are essentially two governing systems. The cognitive deficits seen could be linked to low lying systems, whilst the improvement in Depression may be linked to higher lying systems. If this is the case low lying cognitive systems could be related to 'damage' , or pathophysiology in transmission systems. Naturally the systems interact, but due to the fact that cognitive deficits generally do not improve, but in some cases people are able to develop strategies to overcome them could indicate that there are certain points of interaction between the two systems, rather like a manual override,but this overide may not be available in certain systems (on a physiological level), which could explain the ability of patients to overcome schemas (in implicit memory), but not be able to 'remember' other events or occurrences (forgetfulness). In cases where the deficits occur, it is may be possible that this cannot be reversed as it is physiologcally based, whilst in other cases it can be partially reversed as there may only be subtle damage to a specici physiological location, area, or chemical system. I could be off course on this, but I looked at research on TBI and often it is dificult to make very refined assessments of a deficit in one particular system, and thus establish which part of a system has been impacted on a subtle level. I look forward to your comments on this idea.

Hi again Cheryl and all,

First of all, I´m glad to see you have further considered the key role of neurocognition in mood disorders, namely MDD. Because, as said before, these neurocognitive (neuropsychological) deficits may persist into periods of clinical remission (euthymia) and, more importantly, are major determinants of patients´ functional outcomes, as in schizophrenia and bipolar disorder. Thus they are increasingly regarded as trait markers in a significant proportion of individuals with MDD, and therapeutic targets (an unmet need with current pharmacotherapies, so we need neurocognitive enhancers), respectively. And in the case of SZ and BD they are seen as endophenotypes (intermediate phenotypes) fulfilling most if not all criteria for candidate endophenotypes (e.g. those by Gottesman and Gould).

Second, I´d like to share some thoughts about this topic with you. The heterogeneity of neurocognition in mood disorders is important, much higher than in schizophrenia where dysfunction is the rule rather than the exception. In the case of MDD, I wouldn´t say neurocognitive impairment is the rule at all, but in clinical practice you do find some patients who are cognitively impaired to a significant clinical degree (daily functional impairment).

How could we explain this picture in MDD? Clinical features (comorbidities; illness severity indexed by number of episodes, chronicity or psychotic symptoms to name a few) are thought to play a key role to explain those inter-individual differences. We need to consider also the side-effects of antidepressants and other medications, as well as likely protective factors such as high premorbid intelligence and premorbid social adjustment. And genetic background, family history of mood disorder, age at onset, and all the usual suspects.

Now some words about our ´technology´ to detect such deficits. As you all know, one of the major problems with standard neuropsychological evaluation applied to major psychiatric disorders is that historically it comes from a different tradition, that of adquired brain damage, TBI, stroke, and so on, which are mostly characterized by ´focal´ deficits, in most cases discernible or dissociable deficits which allowed clinicians to localize the ´lesion´ in the brain before the advent of neuroimage. But the ´lesion´ in psychotic and mood disorders is not at that ´macroscopic´ level, but instead at the cytoarchitecture, synaptic plasticity, intracellular events, and so on. So let´s admit that this pencil-and-paper tests we use to assess subjects´ neurocognitive status is definitely not the best, fine-ground technology to that end. Clearly, we need more sensitive and specific tests to tackle the (in most cases) subtle neurocognitive deficits associated with psychiatric ailments. In this regard, you have for instance the CNTRICS initiative for schizophrenia.

And, on the other hand, neuroimage techniques have evolved in the last 3 decades at an uncredible level to localize the pathophysiology. So what´s the utility of neuropsych today? Well, we turn back to functional outcomes again and close the full circle. Because neuroimaging is amazing, but it does not really tell you anything about patients´ ability to funcion in daily life. Conversely, a thorough neuropscyh assessment may be more informative to that end. In my opinion, this is the major advantage of neuropsychology today. Well, this and a proper, qualified validation´ of sufferers´ subjective complaints of memory, attention or executive deficits.

Thanks Vicent, you are quite right! The issues around testing via neurospychological tests for refined system architecture does not have the refinement we need. On a functional level they provide excellent information re - Depressive cognitive deficit symptoms. but cognitive deficits are naturally common across many disorders, so the utilisation of these to provide an aspect of an endophenotype is difficult and made more so by the heterogenity of cognitive disorders in MDD patients. We may be able to distinguish MDD patients from others by assessing information processing instead. Here we may be able to weight for instance the level of rumination.

Thanks Cheryl, I agree with your comment about the non-specific nature of neurocognitive deficits. That is clearly one of the drawbacks to isolate viable endophenotypes in psychiatric disorders. Nevertheless, there are many other examples, from the genome to the phenome, of overlapping, trans-diagnostic features.

On the other hand, Information processing may include both neurocognitive processes (from the low-level, pre-attentional level to the high-order, executive functioning) and cognitive styles or related issues, such as rumination. Do you plan to study only the latter or both?

On the adjustability to adapt for cognitive deficits. Recently there has been some work on "Familiarity" as opposed to "retreival" based memory access. Evidence supports the idea that there are strategic pathways in the brain that determine whether a strategy of primary use of familiarity or retrieval will be used, and it is assumed that aging tends to favor a strategy of familiarity over retrieval due to the cognitive deficits of aged brains. There has actually been work on determining where the strategy is set up in the brain. Adaptation to failure of retrieval might cause a change of strategy to more "Familiarity" based memory access.

My current treatment seems to be trying to force me away from a strategy of familiarity based memory as a possible way of reducing my schizophrenia like symptoms.

Hi Vicent,

I am in the middle of determining which processes and impairments to utilise. I found some very interesting evidence which I have not found an answer to yet. It may also be of interest to you Graeme. Explicit memory is effortful (episodic memory, working memory etc), whereas recall is an automatic process. A study on electrophysiological signals showed that reduced capacity in working memory was related more to the contents of what was in working memory, indicating that for some reason less effective control of working memory was behind memory impairment in explicit memory. This indicates Executive dysfunction in cognitive control/inhibition. If drugs such as SSRI's and SRNI's work on the lower levels by increasing activations of the lower brain and decrease activity in the prefrontal lobes, this means that any dysfunctional control processes should essentially be reduced, freeing up explicit memory processes and capacity to absorb and use memory for information that is not self-focused in a mood disorder. CBT works from the top down and decreases activity in the prefrontal lobes whilst increasing activity in the hypothalamic-pituitary adrenocortical system, increases blood flow and metabolic activity in the hippocampus and dorsal cingulate Theoretically then, working memory and episodic memory should improve, as the usage of high activity in the hypothalamic-pituitary-adrenocortical systems becomes more effective. As a result I am thinking that norepinephrine (stress hormone) involved in the fight/flight syndrome may be increasing arousal and alertness, but may be causing attentional shifts which are inappropriate and therefore this may be involved in the continuation of cognitive impairments in working and episodic memory. The decrease in control factors in the prefrontal cortex could mean that cognitive control mechanisms may still be dysfunctional, and as a result control functions which can direct attention to effortful tasks, such as explicit memory tasks may then contribute to the continuance of cognitive impairment. The other thought I have on this is that cognitive impairments may be continuing due to allostatic load. For example if you have the met variant gene of the BDNF there is diffuse activation along the sides of the hippocampus, instead of more focused activation (in memory and learning). As a result higher levels of activation are required to complete a difficult memory task, this in combination with decreased or dysfunctional cognitive control, depleted levels of serotonin etc, (short alleles of 5HT receptor) may result in higher than acceptable levels of cognitive vulnerability and as a result the brain's resources may be attempting to compensate for these vulnerabilities and be directing resources to these areas. As a result resources for cognitive processing may be dramatically reduced with those requiring explicit processes being the most sensitive to resource limitations.

Let me know your thoughts!

Vicent and Kurt, Shrikant wishes to conduct a pilot study first, to assess whether the study will yield significant results and to assess if anything needs to be adapted in the study . He would be very happy to do an international collaboration once the pilot study has been conducted, as this would prove beneficial to all of us. We are still working on the rough draft of the study which will take a great deal of time still, possibly another month. After that it will be put forward for funding etc. The idea of an international collaboration is exciting and we hope to have good results from the pilot study. Thank you so much for showing an interest and I am looking forward to being able to turn this into an international collaboration!

A quick note - In reference to the post above, I have reached the hypothesis that control/inhibition may be the interaction point between the higher and lower lying systems with regards to the continuance of cognitive impairments.

correction - the quality or effectiveness of cognitive control/inhibition may be one of the interaction points. Sorry about that, could not work out how to edit the post.

To edit a post highlight the posting, a down caret will appear in the top Right corner of the post, if you click on this, a menu with edit and delete appears that allows you to edit the post or delete it. FYI (This only works on your own postings)

Thanks so much Graeme !

Hi Cheryl,

I am delighted to collaborate in such international project to test your nice hypotheses. Good luck with the pilot study, Please keep me posted.

Will do Vicent - thank you so much!!

On TED there was recently a talk by a neurologist that implants deep brain stimulation probes in the brain. He mentioned that when they interfered with the "Sadness" center that previously subdued areas of the brain "Lit up again" He suggested that this might be a useful treatment for untreatable depression. It begs the question of why the sadness center would have such a deleterious effect on other areas of the brain, and what these cognitive deficits so caused are recovering from.

I am currently reading a book on "Networks of the brain" that suggests that some mental disorders are caused by network imbalances where one type of information flow overflows and another is unable to compete. Perhaps the flow of "Sadness" keeps the flow of "Gladness" from flowing, and that reduces the function of some of the other networks that depend on "Gladness" for their operation. For cup half empty people like me, the loss of Gladness might be pathological.

Current treatments because they don't actually affect the sadness center may not be effective at relighting the gladness centers.

Graeme this may interest you then. There is a form of cognitive functioning that essentially locks in all other forms of functioning (ie., emotional), and this involves a network across many different brain regions, which has biological correlates. I have attached an interesting article by Aaron Beck which gives a basic explanation of how this happens and how this relates to physiological processes. You may find it very interesting.

The article is called The evolution of the cognitive model of Depression

Nice article. It brings together the HPA, the hyperactive amygdala, genetic vulnerability, and even cortisolaemia without quite explaining how they all fit together. It is all so tentative.

But it is early days yet. I think the important point that the neurologist made was that despite amygdala hyperactivity cognitive deficits were reversed when deep brain stimulation regulated the amygdala (although they didn't call the center that)

What this seems to suggest is that amygdala hyper-reactivity is a symptom of many of the depressive patients. Hyper-activity fits in with my three NT model, suggesting that the third NT, the Modulator NT such as tonic inhibition modulation has failed for some reason and this presets the neurons to be hyperactive.

The short form of the Serotonin Transporter might be one reason why, especially if it is more prevalent in the function of the amygdala than in other organs.

This might explain why some people do not respond as well to antidepressants, if they have other reasons for depression than serotonin supply raising the supply might not help.

I agree Graeme, what I find of interest is that in a few studies they found that though medications worked, they did not seem to reactivate the pre frontal areas. With the knowledge that there are few dopamine receptors in the pre frontal areas, the role of norepinephrine as a co transporter of dopamine, I would have thought that SNRI's may have worked better, by assisting with additional dopamine in the pre frontal areas, BUT this does not seem to work any better than SSRI's. However, if they use CBT, this somehow re activates areas in the pre frontal region and some people get better. What I found interesting is that in a few studies they have concluded that by activating the pre frontal area, the mechanisms of cognitive processing begin to work, but what they hypothesize is that the content (your actual cognitions, for instance I can't do this) may still be an important factor in cases where there are relapses, as they may keep reactivating the HPA axis. However, it does not seem that anyone actually knows what the neurobiological mechanism/s are that operate in those areas specificcally. I have found a few studies that indicate that micro lesions in areas in the pre frontal lesions may actually be disrupting pathways in those areas, which leads me to the hypothesis that perhaps those with major depressive disorder may actually have micro lesions, which impact on their cognitive processing in thsoe areas. This would make a great deal of sense to me, as the outcomes are extremely varied in treatment, and though cognitive content may still be negative, some people are able to overcome it and continue struggling with great effort against the disorder for many years. Hence, I think that possibly MDD is a form of neuroprogressive disorder which could also be linked to the early phases of other illnesses, such as dementia, schizophrenia etc. The other thought is that naturally if you have an underlying endogenous cause, if the endogenous cause is not treated successfully, that Major Depressive Disorder is likely to not clear up, but some people are able to develop coping techniques to keep it at bay based on combinations of biological factors as well as psychological ones.

Another important point is that your prefrontal areas are hypotonic in MDD, which means that they are unable to down regulate activity in the HPA Axis, but if you are able to use cognitive control executive functions you are able to lessen activity in the HPA axis, rediucing symptoms, but cognitive deficits may or may not remain. This led me to the conclusion that your prefrontal areas, all your explicit processes are under severe duress, so all available resources on a conscious and subconscious level are diverted to maintaining a form of homestasis, which may not allow other processes to occur normally, such as memory functions. Also, speed of processing is actually an indication of underlying damage to the brain, which is a feature of many disorders, so, my hypothesis is that with MDD this may indicate that there is underlying damage, whilst cognitive deficits are a victim of the attempt of the pre frontal lobes to exert control and maintain homeostasis. I would love to know more about your NT theory!

Essentially a 3 NT neuron is one that has an excitory NT, an Inhibitory NT, and a Modulatory NT. The idea is that the cell is normally excited the modulatory NT brings it back into range and the signal comes in on the inhibitory NT in a negative logic manner.

When you lose the modulatory NT for any reason, the inhibitory signal is too weak to keep the cell in range and it becomes hyperactive. It explains the nature of parkinsons disease as a loss of modulation in Dopamine Modulated Neurons. Of course many cells are now known to have more than 3 NT's but tonic inhibition is rare, possibly because of how badly things go wrong when modulation is lost.

It's all part of a theory I was working on years ago.

I think this theory is extremely viable, and this would definitely explain some of the aberrant outcomes seen!

Can you be more specific regarding the specific cognitive impairments and how they are measured? Cognition covers a great deal of territory. Some types of cognitive skill such as reading recognition are very resistant to many kinds of psychological or neuropsychological insults, while others such as processing speed are much more vulnerable. We are also seeing what appears to be negative symptoms in older individuals with autism spectrum disorder, but without a history of positive symptoms. Its more than anxiety or social avoidance. I would be interested to hear more details.

Alan

As a person with negative symptoms and some autism possible I am interested in this characteristic pattern. Please tell me more about older autistic types, and their negative symptoms.

Dear Alan, thank you for your response. Some of the research I have perused is by Maya, Gupta, Joorman etc. The types of impairments in different subtypes of Depression appear to vary across the type, age, gender etc. They apear to be slowed processing speed, cognitive inhibition/control, working memory, and various aspects of long term memory (such as recall, versus recognition) and attentional processes such as alerting and orienting. Most of the studies are conducted utilising standard cognitive or neurospyschological batteries. In some cases these are conducted in conjuntion with imaging during cognitive tests. In all cases tests that determine depressive symptomology, such as the BDI-II, Hamilton Depression Scale etc are conducted, however in many cases a clinical interview to verify the type of depression etc has not been conducted. Some studies have small sample populations, whilst others are sufficient. In some cases underlying processes such as rumination may play a role in the cognitive tests outcomes, such as in the case of free recall memory tasks, where impiarments are found , whereas if the memory task is structured the result does not indicate memory impairment. The continuance of depressive symptomology and cognitive impairments may be linked to relapse or the re occurance of Depression sub-types.

I have not been focusing on autism, but I think Kathleen has.

I have a simpler theory than some other answers; this study was done related to shorter term hospital stays, likely with people with more severe impairment. At discharge, medications may have affected serotonin levels but may not have had enough time to stimulate neurogenesis in the hippocampus to improve cognitive functioning. There may also not have been enough impact on dopamine to improve executive functions, and not enough psychotherapy to reorganize thinking which had long been organized around depression. It may be true that there is a cognitive deficit syndrome that runs in parallel with other aspects of depression; for future study, I'd like to see them add psychotherapy for some patients, add dopaminergic meds for some, and wait longer for all of them.

Thanks James, in that particular study I most certainly agree, and I also completely agree with your position on the length of treatment etc.. Possibly SSRNI's which increase the transportation of dopamine to the frontal lobes in conjunction with intensive psychotherapy is possibly the best treatment method I am aware of. What has come up recently is that morphological findings in depressed patients who have comitted suicide is the atrophy of cells, particularly in the hippocampal regions. Stimulation of neurogenesis by for instance SSRI's and SSRNI' s does work, but perhaps not as well as we like. BDNF may increase but from some of the case studies I have seen recently related to brain injury a combined treatment of GH (dosages that differentiate neuronal cells, not proliferation) and Melatonin, seems to resolve cognitive impairments far more rapidly and effectively. I have been looking into this recently and would need to establish this through a convergence of evidence properly, but if this is done in conjunction with psychotherapy, the ability to couple new events with emotions improve executive functions, and allow cognitive resources to be redirected to other processes other than rumination, we may be able to provide more effective treatments. Your expert opinion on this would be greatly appreciated.

James and Cheryl, how interesting. I am currently investigating the reason behind the cognitive decline in a person who has situational depression that is on-going due to familial issues. If that were the case and they decided to not take their medication halfway through the assessment process how might I predict a fairly accurate outcome? I am not a prescriber of medication but I know some medications have half lives and do not. How long must we wait for the medication to have an impact on cognitive functioning? I am seeing cognitive decline with or without medication. Maybe an anomaly with the person. You have me thinking so will start tracking! Thanks for the thought provoking "conversation."

Dear Carla, I have dealt with similar situations as a Psychometrist. Depending on the type of assessment, the results can be confounded to some degree by the taking of medication. Depending on the type of medication, and whether it has a cumulative effect or not, one can then determine whether it is prudent to have the patient on medication or not during assessment. I know that in cases where the medication will not mask the disorder to a large degree and it is cumulative, that the patient is assessed whilst on medication. If the medication is not cumulative, it can be requested that the patient not have their medication before assessment, but takes it afterwards. However, if there is inconsistency in the use of medication during assessment periods this may impact on the results, i.e., they may be more labile in one assessment and far more emotional in another. Depending on the disorder, the risks to the patient of taking or not taking medications before assessments needs to be carefully considered, you may or may not be aware for instance that there is an underlying psychosis , which, can be triggered by the use of unstructured protocols, hence weighing the type of medication being utilised, in relation to the possible severity of the disorder is important. Naturally there are other factors to be considered, such as suicidal tendencies etc before making a decision with regards to determining whether medication should be disallowed for assessment purposes. This is not the entire picture, but just an aspect of it. I hope it helps!

Carley,sorry i forgot to add some information. With regards to cognitive deficits, there is no correlational evidence that indicates that when depressive symptomologies improve, so do cognitive deficits. Also there does not appear to be a set timeline in which deficits improve. These can take a long time to improve, but utilising for instance psychotherapy in conjunction with attentional training techniques and cognitive rehabilitation may be plausible methods of treatment. There are other forms of treatment in psychotherapy that also work, but the ones I have just mentioned are ones that I know of that work. If executive functions begin to work efficiently there should ideally be a reduction in cognitive deficits, but this does not always occur, nor do deficits always dissipate entirely.

I agree with Carla about the issue of antidepressants and their impact on cognitive functioning. I suggest to assess cognitive improvement or decline in two, or three, different groups: those under antidepressants and those without drugs (the third option are those under antidepressants, before and after a successful withdrawal from these drugs).

I attach a paper written by Andrews et al. published by Frontiers of Psychology. Their approach is radical, but it is worth reading it. In the area of cognitive assessment of depressive patients, it is time to realize that harms and goods of antidepressants should be properly addressed (above all in the long term)

Dear Cheryl, I try to answer your question in an oversimplified way. Cause of Major Depressive Disorder is in many cases a chronic inflammatory process (see Papers of Michael Maes), which is based on a vicious circle of Toll-like Receptor activation, cytokine release, ROS & NO Release from innate immune cell, generation of DAMPs, which again trigger TLR4 (and TLR2) [Published under doi: 10.1007/s12035-013-8425-7].

Cognitive impairments may result from disturbed TLR2 and TLR4 expression, both regulate the proliferation of hippocampal stem cells [Rolls et al, Nat Cell Biol 9(9):1081–8.] This could impair learning and mind.

Most antidepressants fight the consequence (disturbances of neurotransmitter) but not the cause of Major Depressive Disorder. With TLR-antagonist, cytokine as well with ROS scavengers it should be possible to improve both depression and cognitive impairments.

Years ago Hudson and Pope considered MDD to be part of Affective Spectrum Disorder where it seemed to share some pathology with multiple other brain conditions:

http://archpsyc.jamanetwork.com/article.aspx?articleid=207153

We now believe that in fact this disorder is likely driven by long term exposure to certain dietary elements in processed food. We have changed the name to Carbohydrate Associated Reversible Brain syndrome or CARB syndrome.

Classic MDD has always been associated with loss of appetite and weight loss. Today many patients with depression have an increased appetite and weight gain. In our opinion this is CARB syndrome, not true MDD. Patients with CARB syndrome often have significant cognitive impairment whereas those with classic (weight loss) depression usually do not, creating significant confusion among clinicians and researchers.

You have to be careful about making weight gain part of your diagnosis, if only because many anti-depressants cause weight gain.

There has recently been some work on T-H-17 cells that points out that they cause inflamation when exposed to nonstandard light schedules. Since they happen to be sited in the Gut, it makes sense that many people assume a dietary problem when treating gut based inflamation.

Dear Kurt, a very interesting answer, as I have been looking at the morphological evidence of patients with depression who have committed suicide and though there appears to be atrophy resulting in loss of volume in some regions, the most striking to me was a general 19% reduction in the left hippocampus and some reduction in the right hippocampus. This led to further questions for me with regards to possible treatment which could increase the role of cell differentiation of stem cells and thereby reduce in the occurrence of cognitive impairments. Dr Devesa has had success in the reduction of cognitive impairments, with a reduction in motor impairments (which takes slightly longer) in cases of brain injury, which has led to me further hypothesizing that perhaps some of our pharmacological agents increase stem cell proliferation, but not differentiation, which may be part of the reason why we do not see a significant reduction in cognitive impairment in general. These are very broad sweeps so to speak, but it does indicate where my thinking is heading about cognitive impairment in MDD sub types and treatment resistant depression. I would love your opinion on this idea.

Dear William, I find what you are saying fascinating. If I am correct, there may be a specific part of the population who have increased weight gain and increased appetite symptomology and possibly other symptoms which mimic MDD (... a specific sub type, or across sub-types?) that is in fact diagnosed in error as an MDD sub-type, but though symptomologies are shared to some degree and physiological pathways are shared, possibly with common gene expressions, that the possible contributing factor is long term nutritional factors. Inflammation is at the base of many different disorders, is inflammation a major factor in CARB? Please let me know if I have understood all of this correctly. I would love to hear more about this, as I would like to establish if this may have influences on a number of factors such as stem cell proliferation/differentiation etc. Thank you for this valuable information!!

Dear Graeme, it is so good to see you on the discussion. As always your contributions are valuable! It is critical to determine which other variables, or mediating variables have contributed to outcomes and I perfectly agree with the need to look into information further to gain more insight into extraneous, or contributing variables. Definitely, current treatments and their impact need to be considered in trials. I have asked William for more information on the studies, as I think the possibility of CARB may in fact be of great value in establishing possible differential diagnoses, which will allow us to establish how to target treatments for individuals. Lovely to hear from you Graeme!!!!