Mixed states are by definition extreme states in the three dimensions throught, Action, Mood. Research unfortunately does not use instruments along these 3 dimensions. Antidepressants also map to these three dimensions which are correlated with neurochemistry of NA, SER, and ACH. Since mast cells are at the center of bipolar disorders their pharmacology ist also central to teh problem. Some rapid cyclers get better if you treat their periungueal infections with e.g. thymian oil.

Mixed depression is, in fact, the association of non-cured signs of depression with cured signs .

In fact, many depressed people are ill before puberty and never enjoyed good health.

So, when some signs improve at a better level than ever, physician think that it is mania.

Hower, the patient sleeps well (or better) and finishes that he (or she) starts.

The solution is not to "pull the carpet under his feets" but to carry on the treatment under all the signs have dissappeard!

Dear Gottfried,

Thank your for your punctual remark. Indeed, the acknowledgment of the involvement of the immune system in the pathophysiology of BD in not a novel theme.

There is a huge literature focusing on the matter. But there are even some controversial issues. I will just recall some aspects about the cytokines involved in BD...

In physiological conditions, cytokines are beneficial, but in the context of excessive and/or prolonged activation, these substances can promote several abnormalities that are increasingly thought to be relevant to the pathophysiology of BD itself.

These include diminished neurotrophic support, decreased neurogenesis, increased glutamatergic activation, oxidative stress, induction of apoptosis in relevant cell

types (eg, astrocytes and oligodendrocytes), and deregulation of glial/neuronal interactions. TNF-alpha, for example, has been shown to be produced in response to physiological activity in neuronal circuits. This cytokine stimulates receptors in neurons linked to the activation of the transcription factor Nuclear Factor-kappa B. Also, signaling pathway can modulate neuronal excitability and vulnerability to excitotoxicity, suggesting that this pathway may be important for synaptic plasticity and neuroprotection, mainly in the hippocampus. Moreover, when the release of TNF-alpha is prolonged or excessively intense, it will induce neuronal and glial apoptosis by a cascade which results in caspases activation and cell degradation.

So, just focusing on the "promising avenue" of cytokines modulations in the treatment of BD, we need to shed further light on the matter... even if I'm one of the strongest supporters of this avenue in general.

I'm also attaching a reference here for your convenience.

Take care, Michele.

By the way Gottfried, please have a look also at the attached PDF by DR. MATTEO MARTINO.

Article Immunomodulation Mechanism of Antidepressants: Interactions ...

Hi Bernard,

I agree with you, in some cases, mixed states are the results of an attempt to "treat" mood, especially, depressive/ruminative contents, actually disregarding volition/motricity and the flow of thought, which are invariably "lifted up" by antidepressants, especially if prescribed as monotherapy. So, yes, what you are going to "cure" (?) may also determine a iatrogenic effect in not therapeutically balanced.

You state that most people is healthy before adulthood.... Well, at least some of them have not yet been exposed to improper prescriptions resulting in drug-induced rapid-cycling or mixed states or mania (the newly introduced DSM-V criteria now allow the diagnosis of a manic episode even if induced by medication/substance or general disease).

About your statement "when some signs improve at a better level than ever, physician think that it is mania"... It is a quite strong one. The issue of overdiagnosis in BD is one of the most controversial theme nowadays. While there is no doubt the under- or mis- diagnosed BD may result in worsening of the course of the disorder (either the natural or drug-induced courses) and increased burden, social cost and more... it is also important to avoid patients unnecessary prescriptions, which may likewise be harmful. I will attach a concise selection of some papers you may find interesting on the matter (considering both the evidence in support and against broadening of BD and the need for differential criteria for the diagnosis of mania).

The need for a complete recovery in BD is also a primary goal of the therapy. The consequences of incomplete remission or recovery are also of primary relevance, including higher risk for recurrence, emerging cognitive impairments and loss of trust towards the prescribing clinicians, which may further mine the already weak therapeutic compliance most BD patients have towards their medications, especially when it takes to mixed states... I'll try to attach some essential references for your convenience.

Thank you for your kind attention on this post.

Michele Fornaro, MD, PhD.

P.S. I don't know why RG doesn't allow me to attach multiple PDFs at once...

Bernard, please find attached the following additional papers...

I can provide you more if you need.

MF.

For Bernard:

As I mentioned, I don't why RG allows just one PDF attached at once...

Dear Michele

I am going to read your attached files.

I can also direct you on my site http://bmaroy.free.fr In the chapter DepressionF&E, you can read the english version of the abstract of my book La dépression et son traitement : aspects méconus published in french L'Harmattan Paris 2005 and 2011.

I have had the opportunity to start with depression on a alcohologic, then gastroenterologic vision, thirty years ago.

Therefore, I have the conviction that many conceptions of depression are wrong, just because people think that it is a psychic disease. In fact, it is a neuro-biochemical disease with multisystemic, frequently but not always psychic, features.

So, I have developped a somatic-based system of diagnosis, associated with a personnal, very efficient way of treatment. In thirty years and thousands of patients treated, I have NEVER encoutered a single case of manic change of mood and very rare bipolar diseases. In my opinion, usual fluctuations of monopolar depression are mistaken for bipolar state.

I am going to write you later, after having red your papers.

Have a good day

http://bmaroy.free.fr

Dear Bernard,

Thank you very much for your kind remark. I will read your book carefully. I agree with you: the somatic-immune background of manic-depressive illness is indisputable. About the prevalence, please consider that in some specific settings, including non psychiatric outpatients facilities or wards, a possible under-appreciation of the actual prevalence of the disorder may occur. Conversely, an over-estimation may occur in too much "specialized" clinics.

What is sure, it the involvement of the immune system and the vulnerability some manic-depressive patients have towards mania in case of severe somatic disturbances.

Thank you once more for your book!

Michele.

DIco la mia stasera ... :-)%%%

I find the clinical experience of Dr Bernard Maroy – a gut-doctor interested in affective dirsorders beyond alcohol dependence - highly exciting as gut-trouble is emerging as a source of midbrain and basal ganglia trouble e.g. Mb. Parkinson often preceded by non-movment problems, and because it nicely fits my “real biological” (!!) model of neuropsychiatric disorders being driven by lymphatic inflammations, often from the nail folds – veritable immuno-antennas with quarantaine function, and “bad” defence – but from all other GALT, MALT, eyeALT etc., with roles for mast cells at every step.

Clinically I’m not surprised but highly delighted to find In Dr Maroy’s list the same indicators I encounter – tenderness at RE “prostatitis”, pruritus ani, fugace proctalgia to coccygodynia, vaginism and sexual problems,, bladder trouble, pelvic pain or anxiogenic pelvic cross-talk, duodenalgia, pancreas irritation, obstipation, gastroparesis, GERD with secondary laryngitis, gingivitis, rhinitis, tinnitus, and secondary GERD via inner ear irritation, IBD, strange strictures, diverticulosis/litis, duodenalgia, pancreas irritation, but also hypaesthesia, fibromyalgia, or other pains follwing the “unanatomical” LYMPHATIC patterns, AND secondarily the neurological patterns.

Bipolars run to the doctors twice as often of more since childhood and these medical problems have to be central to a new wave of early diagnosis!

The pathomechanism of these somato-neuro-psychic, I’m convinced, is immuno (micro and nano-)mechanic.

The plethora of “fluid Psychoneuroimmunology” data – so beautifully put into perspective by Dr. Fornaro et al. in the papers he just attached to the discussion, cannot explain the anatomical patterns, but they will show clear patterns once the mechanical conduits are accepted (and established scientifically: here tremendous hidden progress has been made in many fileds recently).

I may be quite wrong in the details, but to me they explain what I have to explain… In short I propose that the lymphatics under distal (nerval) germ challenge open up (in order to sieve water and thereby hasten the signal transport to the lymph nodes). Hereby mast cells are activated which are able to liberate granules with 50 pellets with cytokines and alike (Kundera 2009) – much like cutting-edge nano-galenics. These can easily open up tight junctions and enter other vessels. As far as neurospychaitry is concerned these migrate from the distal end of the “strange upper curve” the thoracic ducts make to the vasa vasorum of the carotid wall – as I have shown at the IRBD 2012. This distributes to the entire arterial tree of the brain and the properties of the mast cells, activating again the genesis and behaior of further mast cells up to the BBBS. This mechanism is highly speculative, but also highly supported by the UNBELIEVABLY HOMOGENOUS localized lesions, lateralized stages clinically informed neuropsychiatric imaging keeps producing since a decade or more, and the broad somatic pathologies my few patients show – and there responses to “proximal real biologic treatment.”. Fair enough, we could discuss this at IRBD (now …: IRPD) 2014 in Athens 25-28.May.

To OBTAIN the welfare of the patient and his surrounds obviously comes equal to optimize his APPROACH curves – which is central to my thinking:

In my view (which I showed at IRBD 2005 ff. and in the last version at the WPA facets of psychiatry congress in Athens nov. 2012) temperament and “mood disorders” map to the Thought-Action-Mood-phase space in which – following an illustrative intuition of Emil Kraepelin in “Fig. 228” – a process is cycling which I came to identify in the “appropriation curve” of which some, very few, models of APPROACH have been predecessors.

In practical terms I therefore think, should we (?) ever treat mood, or rather the approach curve – where it not for the quality of life and “unreflected” motivation of the patients (or ourselves)…

The Thought-Action-Mood dimensions map precisely to the 3 psychiatric Cortico-subcortico-Thalamic Loops of Anderson, and especially at the thalamus were they approximate for some hidden reason they encounter many “psychosocially” migrating tissue mast cells, which have about 100 receptors … (GT IRBD Nice 2012, Seville 2013) and these care, but not too much, and mostly through partners, for bioamines.

Antidepressants mainly act through the bioamines serotonine and noradrenaline. While the first seems to have some mood-stabilizing effect (perhaps mainly in people in inflammatoy IDO-trouble, sometimes taking up 40 mg Cipralex without any side-effect) one meta-analysis showed that all the antidepressant trial effects in BPAD were due to the noradrenergic component, which is active on the immune system. Both interact with dopamine systems.

There is no doubt, that most of the pathomechanics of bipolar depression "is unipolar." But some special tracks make up bipolarity, maybe in the above way: and these lift "mood", and equally accelerate and protect processes akin to other comorbid or ANTI-comorbid processes - as mast cells do e.g. in MS.

As to Zimmermann 2008: nobody really said “SCID-BPAD” had expanded; if they don’t like the severe part of the spectrum to be considered as “bipolarity” that’s a choice to be evaluated. A trial of pills is very little cost in relation to these disturbances of lifes and health connected with “soft bipolarity” and can’t really compensate for the rest of care – but they help avoiding the all too common unsuccess of care.

The Yutzy et al. paper 2012 – heavily influenced by Frances and Paris - doesn’t really take up the question wether they deny a multifactoral psycho-biological “bipolarity” dimension or, if not, what they think appropriate to do with the patients beneath the highly improvised thresholds on which Jules Angst and friends (and Kraepelin and others) have cast doubt on, and the question is allowed, what their very personal, therapeutically motivating problems with especially mixed (!) soft bipolarity or affective temperament are.

It's a long way to Tipperary, but now it's downhill and winter is APPROACHing.

Gottfried

OUTSTANDING reply Gottfried! Really IMPRESSIVE: I'll read it again and will go further in search of the material you mentioned.

Glad to learn so much from you!

Michele.

Grazie caro, molto appreso in Italia.