The first scientific work on bipolar disorder was published in 1850 by the French physician Jean-Pierre Falre. He described a state of “folie circulaire”, a cyclical insanity characterized by a change of two extremes — manic excitement and depressed mood. In 1854, another doctor, Jules Bayarge, gave a lecture on “folie à double forme”, insanity in two forms. Falre said that he was the first to describe this condition, Bayarge did not agree, and a dispute broke out on the topic of plagiarism.
Falre was closer to the modern concept of bipolar disorder. Unlike Bayarea, he stressed the importance of intervals, the cyclic movement from one phase to another.
Most doctors of the time held the theory of a single mental disorder, which manifests itself differently in different people. Falre, on the other hand, believed that psychiatrists, like other doctors, deal with various diseases. Diseases need to be distinguished by their clinical manifestations and prognosis. “Folie circulaire”, according to Falre, is the first mental illness that has received a clear description. As for the forecast, and False, and Bayarea wrote about the complete lack of hope for improvement in these patients.
In the 1880s, the concept of “cyclical insanity” was adopted in Germany and other countries. But the decisive event in the history of research on this disease occurred in 1899, when a new reissue of the textbook written by Kraepelin was published.
The founding father of modern psychiatry, Kraepelin, built his system on the principle that Falre advocated: there are several mental illnesses, not just one. According to Kraepelin, there are two diseases: premature dementia (dementia praecox, later called ” schizophrenia») and manic-depressive insanity (manisch-depressiven Irresein), or manic-depressive psychosis. Kraepelin, in contrast to the French psychiatrists, believed that the prognosis for manic-depressive illness is better than for dementia praecox.
The essence of the disease is that the mental state of a person fluctuates between two poles: from a catastrophic decrease in mood, slowing mental and physical activity to euphoria, acceleration of mental and physical activity, and then back down to depression.
Plus, there are also mixed States. In 70 % of patients with manic symptoms, symptoms of depression are also observed. Observations of such mixed States suggest that bipolar disorder is not a disease in which the two polar States — manic and depressive-are clearly separated.
The presence of depressive symptoms in the manic phase was noted at the beginning of the XIX century. “Mischungen” (mixtures) — so they were called by German scientists in the first quarter of the XIX century. Griesinger  in 1845 wrote about “Mittelformen” (middle forms). At the end of depression and the beginning of mania, transitional States were observed in which the symptoms of mania and depression were mixed.
Kraepelin’s description of mixed States starts from the fact that between pure mania and pure depression there are subtypes in which the features of depression and mania are combined in different combinations. Kraepelin allowed this situation: depression is noticeable, but the manic episode passes unnoticed, and Vice versa, mania is noticeable, and the depressive episode is unnoticeable. This complicates the diagnosis, because then the framework of manic-depressive illness should include depression with barely noticeable signs of mania. Now this disease is called bipolar disorder type II. It is believed that if the manic phase does not require treatment in a hospital, it is a mild mania or hypomania, and then you can make a diagnosis of “bipolar disorder type II”.
Kraepelin’s textbook of 1899 was the starting point in the development of modern classification of mental disorders. Manic-depressive disorder is a separate diagnostic category. However, the features of Kraepelin’s categorical approach slowed down the research search a little. Kraepelin had all his affective disorders in one basket. Strictly speaking, in the Kraepelin system, mood, well-being, and emotionality do not have the significance that this sphere deserves. Old-school psychiatrists focused on cognitive functions, seeing the weakening of the mind as the main damage from the disease. The difference between manic-depressive illness and “premature dementia” is not that these disorders unfold in two planes: one hits the mind, the other — on the emotional balance. According to Kraepelin, the main difference is in the forecast and trajectory. If dementia praecox fatally cripples the mind, then manic-depressive disease moves along a sinusoid whose coordinates sometimes coincide with the boundaries of the norm.
Over time, psychiatry has gotten rid of this ancient bias toward cognitive impairment. The symbol of this was the renaming of manic-depressive psychosis into bipolar affective disorder and the development of a new nosological class — mood disorders.
Kraepelin’s system began to be adjusted during his lifetime, which, by the way, He did not resist at all, admitting that he might have missed something fundamentally important. In the early twentieth century, German scientists Karl Wernicke and Karl Kleist pointed out that depression is sometimes experienced without the subsequent transition to a manic state. There are unipolar affective States, and there are bipolar States. “Folie circulaire” is a bipolar disorder. It is necessary to separate unipolar States from it: “pure mania” and “pure melancholy”.
Until the 1960s, the idea that depression can be unipolar and bipolar, i.e. part of manic-depressive insanity, remained almost unheeded. Several publications in the 1960s changed the situation. Unipolar depression has been shown to differ from bipolar depression in many aspects. At the same time, the concept of unipolar mania has not been confirmed.
Bipolar depression is more dependent on heredity than unipolar depression. Unipolar is more common in women, and bipolar is equally common in men and women. Bipolar begins at an earlier age than unipolar. The duration of an episode of unipolar depression reaches twelve months, bipolar-six months. With bipolar, sleepiness is more often observed, with unipolar — insomnia. Finally, antidepressants for bipolar depression only make things worse — they cause mania or mixed States.
In the early 1980s, the concept of a bipolar spectrum was formed, including States of varying severity, as well as variants of the so-called “norm”. The image of a spectrum with a smooth gradation of colors arose due to the fact that diseases in the form in which they are described in textbooks and diagnostic classifications are rarely found in practice. What classification is called the atypical variant, in fact, is a typical option. The uncertainty of the borders of symptoms is a natural phenomenon.
In the 1990s, psychiatrists tried to understand what could and could not be attributed to the bipolar spectrum. On the one hand, the rejection of the strictness of the categorical approach gives more freedom to the researcher and the doctor. On the other hand, the broader the understanding of the spectrum, the more difficult it is to make any definite diagnosis. The idea that a sick person’s condition jumps between two extremes is a thing of the past. The current science of bipolar disorder speaks of a mood disorder with two aspects.
The search for the biological causes of this disorder followed the same pattern as with other mental illnesses-from larger systems to smaller ones. The assumption that bipolar disorder develops due to anatomical abnormalities of the brain was based on the fact that people with brain tumors and head injuries sometimes show symptoms of mania. However, a more detailed study of the issue has shown that physical brain defects are more likely to cause depression, rather than mania. But in the course of searching for the anatomical substrate of bipolar disorder, the brain regions that cause damage to mania were identified: the frontal and temporal lobes, the head of the caudate nucleus and the thalamus.
For some time, there was a theory that people suffer from mania because of a defect in the right frontotemporal region, and depression-because of a defect in the left frontal lobe. Under the weight of a huge number of exceptions, this theory collapsed.
Before the development of neuroimaging technology, the neurobiology of bipolar disorder was a field of speculation and speculation. To build a more or less stable theory on the basis of post-mortem studies did not work — such studies of patients with a confirmed diagnosis of “bipolar disorder” (or, as they used to say, “manic-depressive psychosis”) was not enough.
CT and MRI confirmed that the structure of the brain in bipolar disorder differs slightly from the norm. Based on CT scans in the 1980s, it was assumed that bipolar disorder was associated with an increase in the lateral ventricles of the brain (the same feature is observed in patients with schizophrenia). An increase in the ventricles indicates a decrease in the number of brain cells, as in Alzheimer’s disease or a violation of the development of neurons. But the number of neurons can be reduced due to a passion for alcoholic beverages. Given that alcohol problems are quite common in patients with bipolar disorder, the anatomical features found cannot be interpreted unambiguously.
In the 1990s, attention was drawn to another feature: bipolar and unipolar depression are associated with a decrease in the volume of the prefrontal cortex, but in bipolar depression, the volume of the basal ganglia and thalamus is also increased. This is an interesting observation, but as with other identified structural features of the brain, it is not clear what to do with this information. Structural changes can occur under the influence of various factors, and they are often unstable.
Research with MRI in the mid-1990s showed that in bipolar disorder, hyperactivity is detected in certain parts of the brain. So-called unidentified luminous objects in white matter were found in 5-50 % of patients with bipolar disorder (in the group of healthy people — in 3 %). Hyperactivity is found where there are connections between the frontal and temporal lobes. Thus, the long-standing assumption about problems in these parts of the brain has received new confirmation.
An interesting observation was made at the turn of the 1990s-2000s. The result of MRI in bipolar disorder is similar to the result of MRI in CADASIL disease — so called hereditary disease (damage to blood vessels in the brain), which begins with migraines, and ends with stroke and dementia. However, this pattern is only found in a small subset of people with bipolar disorder.
The most up-to-date MRI studies, based on thousands and thousands of images of patients with bipolar disorder, show a decrease in gray matter in the frontal, temporal and parietal areas of both hemispheres. There is also a link between the duration of the disease and a decrease in the thickness of the cortex in the frontal, medial parietal and occipital regions.
The conclusion from such studies of the structure of the brain is one-Yes, there is something wrong with the brain anatomy of people with bipolar disorder. But what role the observed deviations in the development of the disease play, and what is primary and what is secondary, is still unclear.
In the early 2000s, a new technology-functional MRI-showed reduced cortical metabolism compared to normal and unipolar depression. These results could not be replicated, but there were other studies that indicated a metabolic disorder in the brain: not in the cortex, but in the caudate nucleus and subgenual prefrontal cortex. They also found changes in metabolism in the dorsolateral prefrontal cortex, although the same changes occur in unipolar depression, schizophrenia, and in General in many mental disorders in which attention and working memory are impaired.
The transition to the next stage of studying bipolar disorder coincided with the development of functional MRI, a promising new method of neuroimaging. Hence the high expectations and, as a result, the frustration due to the lack of revolutionary breakthroughs. Over time, it became clear that it was pointless to look for local abnormalities, because depression and mania are pathological processes that are not limited to one isolated area of the brain. In these conditions, global changes occur in the brain, in different places and at different levels — from the anatomical to the molecular.
Another area of research is neuroendocrine changes. This topic has been of interest since the beginning of the study of mood disorders. Even complete Amateurs in the field of endocrinology have heard something about how hormones affect a person’s mood. It is logical to assume that the pathological emotional imbalance is somehow related to hormones. Since the 1960s, in parallel with the study of neurochemical disorders in bipolar disorder, the role of the hypothalamic-pituitary-adrenal axis, which plays a major role in the development of stress reactions of the body, has been studied. In the early 1990s. published works on increasing the level of cortisol and corticoliberin (“conductor” of stress) with depression, which indicates increased activity of the body’s stress systems. But again, this change is not specific to bipolar disorder, and the same is true for unipolar depression.
The most recent work has revealed one notable feature — the increased activity of the body’s stress systems is not typical for all patients with bipolar disorder. In the 1990s, the first high-quality scientific papers began to appear with evidence that depression is heterogeneous, and bipolar disorder is more characterized by the development of so-called atypical depressions. The main clinical difference between atypical depression and “classic” unipolar depression is the presence of the former, in addition to depression, a reactive mood (i.e., a negative mood). a person in response to a strong stimulus can still get pleasure), as well as increased appetite, increased sleep duration (up to 16-18 hours) and pronounced fatigue with heaviness in the arms and legs (with “classic” depression, on the contrary, there is a decrease in appetite and insomnia). In atypical depression, the activity of stress systems is the same as in healthy people, or even lower.
To neurochemical side of the issue have gotten only the beginning of the 2000s it Was discovered changed the ratio of choline/creatine in the basal ganglia. This is also a non-specific change for bipolar disorder, as it happens with depression and many anxiety disorders.
The problem with studying the neurochemistry of bipolar disorder is that the traditional model that links depression to abnormal levels of neurotransmitters — serotonin and norepinephrine — does not work well in this case. It would seem that the breakdown should be looked for in the same place as in the case of depression. Emotions and mood are regulated in the limbic system, where these neurotransmitters are abundant. But antidepressants that effectively treat depression in bipolar disorder do not improve the condition, but change one form of the disease to another.
For this reason, the main medication for patients with bipolar disorder since the 1950s is not antidepressants, but lithium, which effectively stabilizes the mood. As in the case of schizophrenia, first there was a drug, and then researchers followed the traces of this substance in search of knowledge about the disease. Lithium penetrates the cell and changes its susceptibility to neurotransmitters. It is assumed that it affects several biological systems at once, protects neurons from death, and helps new neurons appear.
The wonderful effect of lithium was discovered by the Australian psychiatrist John Cade (1912-1980). In an unused storeroom at the Bandura psychiatric hospital in suburban Melbourne, he collected urine samples from patients with depression, mania and schizophrenia. Cade intended to identify a substance released in the urine that might correlate with symptoms. With no theoretical Foundation and no access to sophisticated chemical analysis methods, Cade guilelessly injected urine into the bellies of Guinea pigs, increasing the dose to the point of death. The urine of people with delusions was particularly toxic to animals.
In further experiments, Cade found that lithium carbonate, which has been used since the nineteenth century to treat gout, reduces the toxicity of patients ‘ urine. Cade also noticed that a high dose of the drug calmed Guinea pigs, and wondered if lithium could have the same tranquilizing effect on his patients. After testing the drug on himself to establish a safe dose, Cade began treating ten patients with mania. In September 1949, he published a report of rapid and significant improvement in the condition of all his patients. Most of these patients have been permanently hospitalized in a psychiatric hospital for many years. Now, five of them have improved so much that they have been able to return home to their families.
The drug that initiated the psychopharmacological revolution of the 1950s was a stunning success. But it was developed in an old storeroom, and the patients ‘ urine samples were stored in Cade’s home refrigerator. In addition, looking back, we can assume that the discovery of lithium is partly due to an erroneous interpretation of the experiments by Cade himself. The “tranquilized” Guinea pigs most likely had the first symptoms of lithium poisoning: lethargy is still a sign of overdose. And the transition from Guinea pigs to humans, neatly referred to as a “conceptual leap,” is hardly well-grounded in theory. A modern researcher would certainly not have been allowed to perform experiments similar to Cade’s. Moreover, Cade’s discovery could easily have gone unnoticed if the American researcher John Talbott had not continued to develop the topic raised in his 1949 paper.
In addition to lithium and other mood stabilizers, patients with bipolar disorder are prescribed antipsychotics to treat manic episodes. The task of antipsychotics is to prevent dopamine from contacting its receptors.
For the past four decades, the dopamine theory has dominated all neurotransmitter theories of bipolar disorder. Recent results from pharmacological and neuroimaging studies support the idea that increased dopamine activity, specifically increased availability of dopamine receptors and hyperactivity of the reward system, is at the root of the symptoms of mania. In laboratory mice, manic behavior can be triggered by activation of dopamine neurons.
The latest neuroimaging studies of bipolar depression show an increase in the level of the dopamine Transporter in the striatum — an area of the brain critical to the reward system. This leads to a decrease in dopamine function, which is characteristic of depression. It is the lack of dopamine that causes one of the main symptoms of depression — anhedonia, a condition in which a person is not able to enjoy.
The “reward” system is one of the most important inventions of evolution. This system regulates behavior through positive responses to environmental actions and stimuli. According to the theory of ” reward hypersensitivity “in people with bipolar disorder (or people at risk of developing bipolar disorder), the” reward ” system is extremely sensitive. Therefore, motivating motives cause a very strong affect, which leads to the appearance of hypomanic/manic symptoms.
At the same time, hypersensitivity can lead to a weakening of affect in response to failure to achieve goals and not receiving remuneration. The hypersensitive person thus overreacts to success and failure. The cause is believed to be a defect in the dopamine system.
Modern basic research has focused on studying what happens in brain cells (neurons, astrocytes, etc.) and, in particular, what happens between them. It turned out that in mental diseases, the places of contact between neurons — synapses-change. Certain features of synapses in people with bipolar disorder are found in such areas of the brain as the prefrontal cortex, hippocampus, amygdala, and other structures of the limbic system involved in the regulation of emotions. In bipolar disorder, various cellular and molecular changes are observed that can affect neural connections (neuroinflammation, oxidative stress, apoptosis, mitochondrial dysfunction, etc.). Since this line of research is still at an early stage, it is not yet known how these disorders are associated with the development of bipolar disorder.
Confirmed the fact of neuroprogression of bipolar disorder, which was first described by Kraepelin. Progression refers to a reduction in the” light ” interval between episodes over time and a decrease in the likelihood of a response to treatment in some patients with bipolar disorder.
Several versions have been proposed to explain the progression of bipolar disorders. For example, the “kindling” hypothesis suggests that with each new episode, changes occur in the brain, increasing vulnerability to stressors and leading to repeated exacerbations. Over time, the influence of pathological neurobiological processes can only increase. There comes a time when the development of a new affective episode no longer requires stressful events, the disease worsens in an “Autonomous” mode.
Neuroprogression is associated with clinical and cognitive impairment in people with bipolar disorder. This is primarily due to the toxic effect of cortisol on certain areas of the brain, which leads to neurodegenerative processes — the death of neurons. Taking mood stabilizers can reduce the duration and depth of depressive and manic (including mixed) phases, which clearly improves the prognosis and, consequently, the social functioning of people with bipolar disorder.
By the early 2010s, molecular geneticists were actively engaged in bipolar disorder. First, this was facilitated by technological progress, which allowed reading the entire human genome. Since the introduction of such technologies, scientists with good funding (full — genome research is very expensive) did not need to guess at the coffee grounds and look for “candidate genes” to blame for any disease. Now you can read the entire genome of patients with bipolar disorder at once and compare it with the conditional norm, trying to find the differences responsible for mood swings.
Second, since the mid-twentieth century, psychiatrists have been well aware that bipolar disorder tends to accumulate in families among blood relatives. The first family studies published before 1960 did not distinguish between unipolar and bipolar disorders. Despite this disadvantage, 13 studies that appeared before 1960 found an increased risk of serious affective disorders among relatives of people who were ill. A little later, higher-quality scientific research showed an almost 18-fold increase in the risk of developing bipolar disorder among relatives of patients compared to the control group.
Clinical studies of families at high risk of developing bipolar disorder also confirmed the fact of heritability. In the second half of the XX century. it was proved that in people with family burden of bipolar disorder, this disease manifests at an earlier age (from 5 to 18 years) 15 times more often than in people without a family history of bipolar disorder. In addition, there is currently evidence that bipolar disorder, which develops in early childhood, may be a separate form of” family ” disorder, which is genetically closely related to attention deficit hyperactivity disorder.
Although the presence of blood relatives with the same disorder confirms the genetic influence on its development, family studies cannot quantify the contribution of genetic factors and separate their effects from environmental influences. This, as we wrote in the previous Chapter, can only be handled by twin studies. According to the latest data from twin studies, the heritability of bipolar disorder reaches 85%, i.e. more than in schizophrenia, autism and Alzheimer’s disease.
However, the manifest and course of bipolar disorder are significantly influenced by environmental factors. These risk factors include influenza infection in the mother during pregnancy, caesarean section, late age of the father, traumatic events in childhood, and the use of cannabis and other drugs. In addition, various endocrinological, immune or vascular diseases, the use of medications (antidepressants, corticosteroids, androgens) and electroconvulsive therapy can trigger the first exacerbation of bipolar disorder.
To date, significant genetic associations with bipolar disorder have been found in 19 regions of the genome. Genes associated with bipolar disorder determine the work and growth of neurons, the building of neuronal connections, the work of the body’s stress systems, and so on.Several gene polymorphisms have also been associated with schizophrenia. This coincidence with schizophrenia is not surprising — mental disorders overlap with each other at the genetic level (we will discuss this later).
Despite the data obtained, currently genetic variants associated with bipolar disorder cannot be used to predict individual risk of the disease, its clinical course, and the effectiveness of medication. We will need to conduct a more thorough analysis of the data obtained, and only then will it be possible to transfer the achievements of genetics to the routine practice of a psychiatrist.
Today, bipolar disorder attracts more and more attention from society. Leading foreign and domestic media write about it with varying frequency, patients are less and less afraid to tell their family and friends about their illness, and popular rappers dedicate entire songs to “bipolar” and perform them at crowded stadiums.
On the one hand, it helps to destigmatize and draw attention to a problem that has long needed to be solved. On the other hand, excessive romanticizing of bipolar disorder leads to underestimating the severity of the disease. Bipolar disorder remains one of the most disabling diseases not only in psychiatry, but in all of medicine. The high risk of suicide makes this disorder one of the most difficult to control. Because of the increased interest in studying schizophrenia, all other mental disorders, including bipolar disorder, have long been relegated to the background. The high biological determinism of bipolar disorder gives hope that with the development of new technologies, we will learn more about the nature of this disease and be able to treat it more effectively.