https://www.youtube.com/watch?v=AKV5slCDYs8

Mood swing is the cardinal clinical feature of bipolar disorder of the present or manic depression of the past. This common disorder of mood swing, has been recognized from the age of antiquity. Hippocrates, the father of medicine, has described the mania, that without it, bipolar disorder or manic depression could not be diagnosed, as a state of high energy and euphoria. He appreciated the importance of the brain to be the site of all these mood changes and not the heart: “Men ought to know that from the brain and from the brain only arrives our pleasures, joys, laughter and jests, as well as our sorrow, pains, grieves and tears…wherefore, I assert, the brain is the interpreter of the consciousness.” (1, 2)

 The differentiating fact between the unipolar disorder or depression and bipolar disorder or manic depression, known well in the ancient world, was buried in history until in mid-nineteen century when in 1854, the French psychiatrist, Falret, brought it back to recognition under the term “La folie circulaire”. (3) But it was not until Emil Kraeplin (4) in 1919 popularized the disorder under the term of “manic-depressive insanity” in his historical text-book, elaborating on all his predecessors including Karl Kahlbaum’s concept of “cyclothymia” (5)

 Clinically bipolar disorder or manic depression, is characterized by mood swings at different rates and severity, and on that basis is classified to classical or type I, with long cycles of severe elevation and depression of mood, of at least a few months each. Milder form of the disorder or mood swings has been classified as type II, with less severe depressive and high mood (called “hypomania”). Shorter cycles of these mood swings, form days to weeks are classified as rapid cycling and within day, as ultra cycling bipolar disorder or mood swings. The high mood state that could manifest as elation or agitation and aggression, is accompanied with elation in many mood and cortical functions, such as thought racing, pressured speech, self-esteem elevation, high physical and mental energy, shopping spree, risk taking behavior, hypersexuality, less need for sleep, etc. The depressive cycle is similar to unipolar or usual depression with an inversion of almost all the mood and mental states to the low side. It seems that the higher the mood elevation, the more severe the downfall of depression would be, such as the higher risk of suicide in bipolar depression than the unipolar or major depression (26-6% vs. 17.8% suicide attempts) (6).    

 The story of microbes of different kinds causing insanity or mental illness, including mood swings, manic depression of the past or bipolar disorder of the modern time, is not something new, but perhaps under-recognized. Julius Wagner-Jauregg (1857-1940) (7) an Austrian physician who won the noble prize in medicine for his discovery of malaria inoculation for the treatment of dementia paralytica or general paresis of insane (GPI) caused by neurosyphlilis, was one of the first who believed in such association. He thought and practiced induction of high fever (pyrotherapy) to cure psychoses including manic depression, initially by inoculation of tuberculin and later on plasmodium vivax, the microbe of malaria. (8)

 The first recorded association of infection with psychoses and probably manic depression or bipolar disorder, per PubMed search is an article by Muchnik in the Russian Psychiatric journal of “Zhurnal nevropatologii i psikhiatrii imeni Korsakova” in 1970. (9) Interestingly the journal has been named after the eminent Russian neuro-psychiatrist of 19^th century, Sergie Korsakoff who was one of the frontiers of searching and demonstrating the organic origin of psychoses, leading him to discovery of Krosakoff Syndrome, a type of alcoholic psychosis due to thiamine deficiency. Muchnik in his prominent research over 12 years period, rare for the time and even now, studied the emergence of psychoses in 150 of patients in age range of 16-45 years old, “closely coincident in time with exacerbations of focal suppurative or rheumatic infections” He truly suggested that psychoses due to infections occur upon hereditary predispositions, although he wrongly called it of “allergic origin”. He also suggested “mental diseases diagnosed as periodic schizophrenia, atypical manic-depressive psychosis, organic brain lesion pursuing a periodic course, etc., are undoubtedly psychoses of infectious origin.”

 Soon after in the western society, Steinberg et al. (10) in the British Journal of Psychiatry, described a patient who in the course of a febrile illness during an influenza epidemic, “showed symptoms of an acute confusional state which then developed into a manic psychosis of prolonged duration.” This patient during the entire period of her psychiatric illness had unusually high levels of Influenza A antibody titer at the extreme range compared to other influenza patients, and moreover her titers remained abnormally high for an unusual period of time as compared to other influenza patients. These researchers based on this case, challenged the concept of `functional’ affective psychosis of the time.

 Krauthammer & Klerman in 1978 (11) in a review in the prominent journal of Archives of General Psychiatry, warned clinicians that many seemingly primary manias could in fact be secondary to other medical causes including infections: “mania occurs secondary to drugs, infection, neoplasm, epilepsy, and metabolic disturbances. These cases are best considered secondary manias. They suggest that mania–like, for example, hypertension–is a syndrome with multiple causes and that with further research many manic syndromes currently considered primary will be shifted into the secondary category. Furthermore, the concept of secondary mania casts doubt on any unitary or single-agent hypothesis of the etiology of mania and supports the notion of a continuum of psychopathologic syndromes. Clinicians are alerted to the existence of this syndrome and are urged to screen for it when conditions warrant.”

Case reports such as “a 45-year-old physician with bipolar disorder presented with an acute organic psychosis, fever, and hematologic and serologic findings of a primary Epstein-Barr virus infection.” (12) prompted the prominent British psychiatrist, Timothy Crow to cast doubt on the primary etiology of schizophrenia and bipolar disorder to be of viral or viral-genetic interaction. (13) This soon led to the seasonal birth hypothesis of schizophrenia and bipolar disorder. (e.g. 14) A very good example of the link between infection and bipolar disorder, could be seen in AIDS patients where cases of mania and bipolar disorder have been many times reported. (e.g.15-16) AIDS due to its immunodeficiency could lead to many infections in the subjects including CNS infections (e.g. meningitis, encephalopathy) with psychiatric manifestations, such as mania or mood swings.

Borna virus that is a neurotropic infectious agent with a predilection for neurons and astrocytes in the limbic system and cerebrum of infected hosts, have also been reported causing encephalitis with mood disorders manifestations, specially mood swings and bipolar disorder symptoms. Fu et al. (17) have reported Borna virus-specific antibodies in the sera of 4.5% of 138 affectively ill patients, with the highest titers in bipolar patients. A similar finding has also been reported by Amesterdam et al. (18) in 265 unipolar and bipolar patients with the same prevalence of 4.5% detection of antibody against Borna virus in the sera of their sample. Similar findings have been reported by others researchers. (e.g. 19-20)  

 Several other infections, e.g. Lyme disease (21), Epstein-Barr virus (22-23), skin and nail infections (24), maternal influenza in the first and second-trimester (e.g. 25-27), West Nile Virus infection (28), dengue infection (29), adeno-associated virus 2 and parvovirus B19 (30-1), toxoplasma gondii (32-6), cytomegalovirus (37-9) and inflammatory bowel inflammations and infections (40) have been reported in link with bipolar disorder. On the other side, while the above infecting agents could be causal in bipolar disorder, some infections, e.g. HIV and hepatitis-B &-C could cause secondary mania, precipitating mania or carry higher risks of these infections in Bipolar patients. (41-9) For example it has been reported treatment with interferon alpha2b in patients with hepatitis could trigger mania. (46), or combination therapy with interferon and citalopram (47), manic traits induction with interferon therapy in depressed hepatitis C subjects (48), or a cascade of psychiatric symptoms including mania in hepatitis infected patients going under interferon treatment. (49)

 The infectious agents could directly invade and infect the brain and stall its development in the fetuses of infected pregnant mothers (18, 19,30,33,35) or and could cause a cascade of immune reactions in the human subjects, leading to a central nervous functional disorder such as bipolar disorder. (25, 29-31, 50) These microbial immune activation, as I have detailed elsewhere in the case of other neurodevelopmental disorders such as schizophrenia and autistic spectrum disorders (51-2), seem to only harm the vulnerable developing brain of the fetus and not the developed adult brains, e.g. the maternal brains. (53) The footsteps of such disturbed immune system of the off springs have led many experts to interpret the neuro-developmental disorders as autoimmune conditions (e.g. 54).  For example, Severance et al. (40) have found seroactive markers for inflammatory bowel disease in reaction to food derived proteins such as wheat gluten and bovine milk caseins in adult bipolar disorder subjects. In another study Stich and colleagues (50) have reported increased polysepcific anti-bodies in the CSF (central spinal fluid) of bipolar patients against not one but several viral and parasitic infections, suggestive of ongoing chronic inflammatory conditions in the brains of these individuals. There are also evidences pointing to the long-term destructive impact of the microbial invasion to our genetic make-ups. Avramopoulos et al. (55) like some others in the genome-wide association studies have reported the maternal and fetal infections causing gene mutations by creating schizophrenia and bipolar-associated SNPs (single nucleotide polymorphism) in the HLA (Human Leukocyte Antigens) regions of chromosomes. This fact has even been proven on animal infection models in-vitro, by causing infections to the maternal mouse models to detect the inflammatory consequences in the off springs. Such experiments have shown long-term alterations in GSK3β signaling of brain dopaminergic pathway that are critically implicated in schizophrenia and bipolar disorder. (56)

 Moreover it seems that the impact of a remote infection in the mothers of inflicted off springs, is not only limited to causing neurodevelopmental disorders such as bipolar disorder, and life-long sufferings. But the enduring even low grade inflammation in the immune system of the individuals seem to cause premature cell senescence and aging by shortening the telomeres of immune cells, e.g. T-lymphocytes. (57) The proinflammatory biomarkers such as cytokines, e.g. TNF(Tumor Necrosis Factor)-alpha seem to be specifically related to the manic or hypomanic (elevated mood states) than the depressive mood states in bipolar disorder (55), making this disorder closer to a neurodevelopmental and infectious origin compared to unipolar depression that could be otherwise. Interestingly the therapeutic effect of Lithium as perhaps the most effective mood stabilizer in bipolar disorder has been shown to be related to its anti-inflammatory and potential anti-oxidative properties. Albayrak and colleagues (58) have proven this hypothetical effect of lithium in an animal experiment through the inhibiting pro-inflammatory cytokine effect of lithium and the generation of reactive oxygen species (ROS) after induction of sepsis in lab rats. Also some anti-psychotic medications that are effective in the treatment of bipolar disorder, specially the manic phase of the disease have shown to have anti-toxoplasmic effect. (36)      

 While mood stabilizers such as Lithium and anti-psychotics could have anti-inflammatory and anti-oxidant effects, first of all as it is well known, they cannot be preventive and curative, meaning that they cannot reverse the pathological process in bipolar disorder. The other interesting fact is that antibiotics not only have no efficacy in this disorder, but could have triggering effects! One wonders the reason if infection is considered in the pathophysiological mechanism of disease causation. As explained elsewhere in the case of schizophrenia (51), first of all the infecting machinery, acts long earlier on the fetus through gestational infestations, leaving only their impact and damages on the off springs years after, hence causing a neurodevelopmental disorder, interrupting the normal brain development, as in case of schizophrenia and ASD. (52, 59) As it was briefly explained above and detailed elsewhere in the case of other neurodevelopmental disorders (51-2), only the footsteps of the early gestational infections could be traced through the evidence of inflammation in the afflicted individuals, but none of infections or the infecting agents! That is why antibiotics are not only effective but could be triggering through dampening the immune system, precipitating or facilitating the disease processes.

Since 1963 there have been reports of linking antibiotics precipitating mania in susceptible individuals as early as age 3. (60-5) The case report of Kane and Taylor in 1963 of mania associated with the use of cocaine and I.N.H. (Isoniazid, used in the treatment of Tuberculosis), was the first such alarming sign. A review of the published and unpublished literature on the link between treatment with antibiotics and triggering mania in 2002 by Abouesh et al. (61) reported 21 total published cases, 6 caused by clarithromycin, 13 by isoniazid, and 1 case each by erythromycin and amoxicillin. The authors contacted WHO for unpublished cases, found 82 reports, 27.6% caused by clarithromycin, 14.4% by ciprofloxacin, 12% by ofloxacin , and Cotrimoxazole, metronidazole, and erythromycin altogether responsible for 15 reported manic episodes. Cases reported by the FDA showed clarithromycin and ciprofloxacin to be the most frequently associated with the development of mania. (61) Interestingly these authors elected to name this syndrome “antibiomania.” A recent search of the literature at the time of writing these lines, through Pubmed of the NIH (National Institute of health) in US resulted in 17 published cases only for Clarithromycin, 12 of them occurred after the review by Abouesh, including three cases alone in 2014, two in elderly and two in children, the extremes of life span where immunity is the most fragile.

 Conclusion:

Mania or hypomania which is the elevation of mood in a pathological manner, so steering away the individual out of touch with reality, even in the absence of psychosis, into an ecstatic state of mind, seems to have been initiated by the microbial world long before the person has even been born. The inflicted patient may be happy about such mood elevation and its consequences, thought racing, pressured speech, high energy, inflated self-esteem, acting flamboyantly, risk taking, substance abuse and hyper-sexuality. But such individuals are not aware that such fast and abnormal mood elevation, will result in a consequential mood downfall of severe depression that suicide could be eminent. It may take a long effort of the clinicians and the family of such individuals to help him or her to recognize that these mood swings are actually pathological, so the person finally after years of swaying around by the wind of incontrollable emotions, be convinced of having a disorder and stick to the treatment. But the available treatment is far from stabilizing these mood swings, lest curing the condition. The reason is perhaps in the lack of our full knowledge and appreciation of the pathophysiology of the bipolar disorder and other neurodevelopmental conditions, caused long time before the onset of these disorders by microbial invasions. In fact the world should know that these are the microbes, seemingly of different kinds, behind the curtain, make the inflicted persons to dance like puppets!

Dr.Mostafa Showraki, MD, FRCPC                                                               Lecturer, University of Toronto,School of Medicine,Author: “ADHD:Revisited” Book “adhdrevisited.com”/”medicinerevisited.com”

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