Depression is a universal, timeless and age-independent disease that affects humans. It is called the plague of the XNUMXst century.
Depression is tricky, complicated, and very difficult to diagnose and treat. The exact causes of depression are unknown. It is known that they can be psychological as well as biological. That is why this ailment is often called the disease of the soul, because, like it, it is difficult to grasp and diagnose.
Depression is a recurrent disease that threatens life and the proper functioning of society, and carries enormous costs in terms of treatment, welfare and incapacity for work. It is estimated that in Europe (6 European countries; Belgium, France, Spain, the Netherlands, Germany, Great Britain), about 17 percent. adult people suffer from one of the forms of depression, and the suicide rate in this group is approximately 15-25%. Intensive research, both clinical and experimental, is aimed at understanding the mechanisms responsible for the development of this disease, which have not been satisfactorily explained so far, in order to create more effective therapies with no side effects.
Taking into account the variety of factors contributing to the development of depression (genetic predisposition, environmental conditions: stress, traumatic experiences, viral infections) and the multitude of symptoms, often coexisting in each patient, depression cannot be treated as a single disease, but rather as a set of symptoms of various origins and pathophysiology.
Common symptoms of depression include:
- Irritability, irritability
- Poor self-esteem
- Irrational sense of worthlessness and guilt, helplessness
- Reduced ability to concentrate and think
- Reduced or increased appetite
- Weight gain or weight loss
- Insomnia or hypersomnia
- Decreased energy, feeling tired, weary or over-excited
- Decreased interest in normally enjoyable activities
- Repetitive thoughts of death and suicide
Depression is diagnosed when a certain number of the above symptoms are observed for more than two weeks, and when these symptoms disrupt normal social and professional functioning.
- Do the test and see if you are depressed
Depression as a disease has existed for as long as the human species. Reading the Old Testament, we can say that King Saul probably suffered from depression and committed suicide under its influence. Job’s confession in the Old Testament: “The soul melts in tears, days of trouble have troubled me, why did I not die after leaving the womb, did I not come out of my bowels to die? Why did my knees take me, and my breasts gave me food? … I know neither peace nor silence, before I rest, the turmoil comes, at night my bones are like a furnace, my suffering does not stop. I thought: I will rest on my bed, a bed is my trustee. But you scare me with dreams, you scare me with visions ”- they are even a model example of symptoms characteristic of a person suffering from severe depression (violent desire to die, psychosomatic pain, severe sleep disturbance).
Historians are sure that the problem of depression was known to the Sumerians around 2600 BC and to the ancient Egyptians. They probably perceived depression and other mental illnesses as being possessed by an evil spirit, some researchers claim that the trepanation of the skull performed in antiquity was intended to cure mental illnesses by creating an exit for the demons inhabiting the patient’s head. Throughout its history, mankind has repeatedly reverted to the idea of mental illness as a result of being possessed by “evil powers”.
In ancient Greece, an attempt was made to scientifically explain the causes of depression for the first time. Depression was defined as a disease by the Greek physician Hippocrates (460-377 BC), the founder of the foundations of medicine and humoral pathophysiology. 2400 years ago, Hippocrates developed the theory of the 4 fluids in the human body. These fluids are: phlegm (mucus), yellow bile, blood, and black bile. On the basis of this theory, Hippocrates then designated 4 types of human temperament: phlegmatic (predominance of phlegm), choleric (predominant yellow bile), sanguine (predominant blood) and melancholic (predominant black bile). According to Hippocrates, when the balance between the fluids was disturbed and black bile gained the advantage, a person developed melancholy, i.e. mental depression – apathy, sadness, depression and aversion to life appeared. Thus, the treatment of melancholy consisted, among other things, in removing excess dark bile from the body through the use of laxatives and bloodshed, or by moisturizing.
The Arabs took over the entire intellectual heritage of late antiquity. Abu Ali al Hussein ibn Sinie, known as Avicenna (980–1037) in the Canon of Medicine, which was a comprehensive lecture of medical knowledge at the time, considered mental disorders as a result of various disturbances in the patient’s body, especially in the brain. Avicenna believed that mood disorders arise as a result of disturbances in the work of the brain, as well as as a result of disturbances in the work of other systems that are important for the functioning of the body, and that it is possible that the primary pathology affects the brain, and then pathological processes leading to mood disorders take place outside him. Like Hippocrates, Avicenna believed that changes in the brains of people with depression are caused by an excess of dark bile. Interestingly, Avicenna considered unhappy love a mental illness – a kind of melancholy. As part of her treatment, he recommended bathing in a bathhouse and sending ugly and filthy old ladies in love, who would make him dislike of women. The humoral theory and the methods of treatment proposed in it (ie enema, bleeding and moistening with warm baths), having the status of officially recognized and promoted by the academic community, survived until the XNUMXth century.
In the XNUMXth century, Quesnay François, the court physician of the French King Louis XV, recommended the administration of chicken broth to treat the symptoms of melancholy. In turn, in the nineteenth century, attempts were made to solve the problem of depression using hydrotherapy – the melancholy depressed with life were sent to seaside spas, where the mineral-rich waters were supposed to remove their sorrows with potassium and iodine.
The turn of the nineteenth and twentieth centuries brought psychoanalysis, which also tried to fight depression. One of the first theoretical models of depression in the psychoanalytical approach was presented by Sigmund Freud. Freud believed that unmet emotional needs from childhood played a key role in the development of depression. According to him, the quality of the relationship between mother and child was decisive in determining whether an individual would be prone to depression in the future. Freud argued that if the feelings of anger and fear in a relationship with the mother are stronger than the experienced feeling of love, the child directs on himself (rather than at the right object) anger resulting from a sense of failure in a relationship with such an important person as the mother. This leads to a loss of self-respect and guilt later in life. As you can see, in psychoanalysis it is believed that depression (as well as other disorders) has its source in an unresolved conflict from the past in the patient’s subconscious. Treatment of depression by the method of psychoanalysis and psychotherapy would consist mainly in examining the psyche by analyzing free associations, fantasies, dreams, thoughts, feelings and behaviors in order to consciously recognize the problem existing in the psyche. When looking for a general term for psychotherapy, one can use a historical definition derived from one of the precursors of psychotherapy, Pierre Janet (1859-1947). He believed that psychotherapy is the name of all methods of treatment that act on both the body and the psyche by means of agents acting via the psyche. Thus, psychotherapy is clearly distinguishable from pharmacological and other biological treatments. He uses what is generally referred to as “psychological”. These include, first of all, discourse (conversation) and therapeutic reflection with an analysis of the life situation with an emphasis on reaching and experiencing repressed emotions and reacting them.
The history of biological therapy for depression begins with the introduction of electroconvulsive therapy in the 30s. For a long time, this therapy was considered the only effective therapeutic tool in the treatment of most mental disorders. Rather than being confined to strictly defined cases, electroshock was in common use until the mid-XNUMXs. Their abuse and incorrect conditions of use have created an image of almost barbaric therapy in societies. Currently, it is used only when the patient’s condition is particularly severe, when drugs are ineffective or inadvisable. The conditions in which the procedure is performed have also changed completely – modern electroconvulsive therapy is performed under anesthesia and muscle relaxation.
Another important step in treating depression was the discovery made in the late 50s. Hydrazine derivatives were introduced in the treatment of tuberculosis in the early 5s. It has been accidentally observed that they improve the mood of patients. Thus, the first antidepressant drug (LPD) – iproniazid – was discovered. Further studies showed that by inhibiting the breakdown of the neurotransmitter substance in the brain – serotonin (1954-HT), it increases its concentration in the brain. Serotonin is involved in the regulation of anxiety, mood, emotional states, impulsivity, sleep, appetite, circadian cycles, the reward system, and thus the functions of the body, disorders of which are a common symptom of depression. As early as 15, Wolley and Shaw suggested a link between serotonin and mental disorders. 5 years later, the first serotonin hypothesis of depression was formulated. Namely, substances used as antidepressants such as imipramine and monoamine oxidase inhibitors have been found to increase the level of 5-HT in the brain. Based on clinical trials, it has been hypothesized that XNUMX-HT system insufficiency is a factor that increases the likelihood of depression. This was the birth of the neurochemical model of the pathophysiology of depression. According to this theory, depression may be caused by a deficiency of certain biogenic amines (amino acid derivatives, neurochemicals responsible for the transmission of nerve impulses at synapses between neurons) in the brain. Excessive reduction in the level of these biogenic amines causes motivation deficits. The hypothesis on the neurochemical basis of depression concerns mainly a decrease in the levels of norepinephrine and / or dopamine (the so-called catecholamines – catecholamine hypothesis) and serotonin (serotonin hypothesis). Antidepressants would work by reversing the decline in norepinephrine and serotonin levels. These hypotheses met with great interest from pharmaceutical companies, which resulted in the synthesis of many drugs acting on the principle of norepinephrine and / or serotonin reuptake inhibition.
Taking into account the mechanism of action, we distinguish the following groups of antidepressants:
- MAO inhibitors – delay the chemical breakdown of biogenic amines by inhibiting monoaminoxidase, the enzyme responsible for this breakdown – e.g. moclobemide,
- drugs that inhibit the non-selective reuptake of biogenic amines – they retain the available norepinephrine and serotonin in the synapse by blocking reabsorption – e.g. amitriptyline, imipramine,
- medicines that selectively inhibit serotonin uptake, e.g. fluvoxamine, fluoxetine or paroxetine.
- drugs that mainly act on the receptor – mianserin. Mianserin blocks the norepinephrine and serotonin receptors, which causes their increased secretion in various parts of the brain,
- atypical antidepressants, e.g. tianeptine – in contrast to the above, tianeptine paradoxically increases the neuronal reuptake of serotonin by neurons, but does not directly affect dopamine, noradrenaline and monoamine oxidase.
Modern treatment of depression it is bipolar. It is psychotherapy on the one hand and pharmacological treatment on the other.
Pharmacotherapy treats acute symptoms of the disease, and when used chronically, it helps to prevent relapses. Whereas psychotherapy its purpose is to understand the disease and to cope with it. Being aware of the existence of traumatic experiences allows the patient to reduce their impact on his thinking and behavior patterns. At the same time, the constant contact of the patient with the psychotherapist allows to assess the effectiveness of the antidepressant medication used by the doctor and to monitor the effects of long-term drug therapy. Unfortunately, despite the use of drugs from different groups, showing a different profile and different mechanism of action of 50 chemical substances (a total of several hundred preparations manufactured by different companies), the cure rate of depression remains at the level of 50-70%. Worse, the medications used have a number of adverse side effects. The most undesirable symptoms associated with taking antidepressants include, among others: cholinolytic effects, e.g. drying of the oral mucosa and respiratory tract, visual acuity disturbances, adrenergic effects, e.g. cardiac disturbances, as well as lowering blood pressure. Other symptoms associated with taking antidepressants are fatigue, anxiety, anxiety, sleep and concentration disorders, sexual drive disorders, stuttering or symptoms of drug-induced parkinsonism. Currently used therapies show an antidepressant effect only after a few weeks of use. This means that the increase in serotonergic and / or noradrenergic transmission per se is not responsible, as originally thought, for the clinical effects of these drugs. It is likely that adaptive changes that occur at the level of receptors, secondary cell transmitters or gene expression are the factor behind the antidepressant effects. Unfortunately, these changes are often ambiguous, depend on the drug used, or occur selectively in some structures. Thus, new substances that could replace current treatments are constantly being sought.
Returning to the pathomechanism of depression, the monoamine theory discussed above dominated for a long time, suggesting disorders within one of the three transmission systems: serotonergic, noradrenergic or dopaminergic. Recently, however, more and more attention has been paid to the role of glutamate in the context of depression. Glutamate transmission is estimated to account for approximately 90% of total brain transmission. Increased levels of glutamate in the cerebrospinal fluid are observed in people diagnosed with depression. Another premise linking glutamate transmission disorders with depression are the results of studies on cortical fragments taken from suicides in which the number of NMDA receptors (ionotropic receptors for glutamic acid) measured in the frontal cortex has decreased. Accordingly, new LPDs are sought for, inter alia, compounds that are ligands for glutamic acid receptors.
The first report on the connection of the glutamatergic system with the pathomechanism of depression was included in the works of Trullas and Skolnick (1990), who described the antidepressant properties of NMDA receptor antagonists in mice. The antidepressant effect of NMDA antagonists, demonstrated in preclinical experiments, was confirmed in preliminary clinical studies. The first described clinical experiment to test the antidepressant effect of the NMDA antagonist ketamine was performed in patients with severe drug-resistant depression who did not improve after long-term use of conventional antidepressants. The intravenous administration of ketamine resulted in a significant improvement in the mood of patients within several dozen minutes after the administration of the drug. The initial optimism related to this new direction of research was cooled down by the results of preclinical tests of compounds acting on ionotropic receptors for glutamic acid, indicating that side effects such as psychosis, memory impairment and neurodegeneration or movement disorders constitute a serious problem in the application of this type of therapy. Currently, high hopes are associated with compounds that are non-competitive antagonists with low affinity for the NMDA receptor and antagonists for metabotropic glutamic acid receptors.
Krzysztof Tokarski, MD, PhD – employee of the Institute of Pharmacology of the Polish Academy of Sciences in Krakow
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