RU2540491C1 - Method for assessing severity of current depressive episode in patients with recurrent depressive disorder - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: method is implemented by evaluating the relation of GSK-3β/β-actin, calculating a composite score on SIGH-SAD scale. If observing an increase of the relation of GSK-3β/β-actin in blood mononuclear cells of the patients with depressive disorders of more than 0.70, and the total score on SIGH-SAD scale of more than 30, a severe current depressive episode accompanying a recurrent type of depressive disorder is predicted.

EFFECT: by evaluating the biological value, the method enables assessing the depression severity, holding the targeted rehabilitation psychotherapeutic and pharmacological measures.

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Description

The invention relates to medicine, namely to psychiatry, and can be used to assess the severity of depression in patients with recurrent depressive disorder.

This method is aimed at studying the biological factor involved in the formation of depressive symptoms and causing their severity.

A known method for predicting the course of depressive reactions, which indicates that in the presence of concomitant pathology and a decrease in the content of natural killers to 8% or less and phagocytic activity of leukocytes to 60% or less, a prolonged course of depressive reactions is predicted (3), as well as methods for diagnosing affective disorders based on electroencephalographic and neuropsychological studies (1, 2).

An adequate prototype of the present invention, allowing to evaluate the severity of depression in recurrent depression, was not found in the analyzed literature.

The objective of the invention is to develop a method for assessing the severity of the current depressive episode in patients with recurrent depressive disorder.

The problem is solved by assessing the content of total kinase glycogen synthase 3β (GSK-3β) in blood mononuclear cells through the calculation of the ratio GSK-3β / β-actin. There is a high positive correlation of this indicator with the total score on the SIGH-SAD scale in patients with a current depressive episode who have recurrent depressive disorder.

New in the proposed method is the use of the determination of the GSK-3β / β-actin ratio as a biological parameter reflecting the severity of depressive symptoms, together with the correlation of this indicator with the total score on the SIGH-SAD scale, and with an increase in the value of the GSK-3β / β ratio β-actin in blood mononuclear cells of patients with depressive disorders above 0.70 and a total score of SIGH-SAD above 30 points predict a severe degree of current depressive episode in a recurrent type of depressive disorder.

Intracellular protein kinase glycogen synthase 3β (GSK-3β) is a regulatory multifunctional enzyme that plays an important role in the functioning of nervous tissue. GSK-3β regulates the processes of neurogenesis, circadian rhythms, and also takes part in serotonin and dopamine neurotransmission (16). Animal models have shown that GSK-3β is involved in the formation of depressive and manic symptoms, and is also a target for a number of antidepressants and normotimics (8). A number of studies have demonstrated that in patients with affective disorders, an increase in this protein is observed with a decrease in its inactive phosphorylated forms, which indicates the participation of GSK-3β in the pathogenesis of this pathology (9, 10, 13). The cytoskeleton protein β-actin is widely represented in the cell. He is responsible for maintaining the cellular structure and is a protein of the “household”, i.e. contained in all tissues at a relatively constant level. In biochemical methods, β-actin is used as a reference indicator reflecting the total protein content in the cell (14).

In this regard, the determination of the intracellular level of GSK-3β has prognostic and diagnostic value.

An assessment of the severity of a depressive episode taking into account typical and atypical depressive symptoms and the possibility of its recurrence (recurrence), objectified by biological indicators, is an urgent clinical problem of high practical importance, since the choice and basic antidepressant therapy depends on the correctness and timeliness of this type of assessment (in phase stopping or acute treatment of a severe depressive episode in comparison with a mild to moderate depressive episode requires higher starting doses of antidepressants, the use of double-acting antidepressants: selective serotonin and norepinephrine reuptake inhibitors, with good tolerance and no contraindications - tricyclic antidepressants, the starting use of combination therapy: for example, SSRIs and small doses of atypical antipsychotics, etc.), and the need for supportive (contraindicated ) therapy (for example, according to the recommendations of WHO (1989), if with a mild depressive episode, ongoing antidepressant therapy can t last an average of 6 months from the gradual withdrawal of the base of the antidepressant, the long-term preventive treatment is recommended even for those patients who have had 1 or more major depressive episodes). In addition, a greater severity of the current depressive episode is associated with a higher risk of recurrence of depressive disorder and a higher risk of resistance to therapy (4, 6, 7).

When assessing the severity of the current depressive episode, it is important to consider not only typical, but also atypical depressive symptoms, the presence of which indicates a high probability of inversion of the depressive phase and the risk of the subsequent formation of a bipolar course of affective disorder, which in practical terms justifies the use of normotimics in the treatment of the current depressive episode (3 , 12).

Clinical criteria for the severity of a depressive episode in routine clinical practice may be underestimated, and unambiguous reliable biological markers of the severity of the current depressive episode have not yet been found (11).

New features have shown new properties that are not explicitly derived from the prior art in this field and are not obvious to a specialist. No identical features were found in the patent medical literature. The proposed method can be used in practical health care to improve the accuracy of diagnosis and the selection of adequate treatment.

Based on the foregoing, the present invention should be considered relevant to the conditions of patentability: "Novelty", "Inventive step", "Industrial applicability".

The invention will be clear from the following description.

The proposed criterion (the ratio of GSK-3β / β-actin) was obtained as a result of a clinical and biological examination of patients with depressive disorders who underwent treatment in the Department of Affective Conditions of Clinics of FSBI NIIPZ SB RAMS.

We examined 24 patients diagnosed with a depressive episode (F32, 12 people) and recurrent depressive disorder (F33, 12 people). As a control group, 19 mentally and somatically healthy individuals were examined.

In patients with depressive disorders, blood for biological research was taken from the cubital vein, in the morning, on an empty stomach, in test tubes with the EDTA anticoagulant. Blood sampling was performed at the initial admission before pharmacotherapy. Next, a fraction of mononuclear cells was isolated from the obtained blood on a ficoll gradient. Cells were lysed, lysates were used to determine total GSK-3β. The intracellular content of total GSK-3β and β-actin was determined by immunoblotting with chromatographic detection. Using a gel documentation system, the signal intensity for each protein was calculated, and then the GSK-3β / β-actin ratio was calculated. A psychometric assessment of the severity of typical and atypical depressive symptoms was performed using the SIGH-SAD scale (Structured Interview Guide For The Hamilton Depression Rating Scale, Seasonal Affective Disorders Version), which contains 21 points of the Hamilton scale and 8 atypical symptoms (social withdrawal, increased appetite, weight gain, increase in the amount of food consumed, preference for carbohydrate foods, hypersomnia, a feeling of fatigue in the morning, the reverse circadian rhythm of mood: deterioration of mood in the evening) (17).

Statistical data processing was performed using the SPSS 20.0 application software package. Verification of the normality of the distribution of quantitative indicators was carried out according to the Kolmogorov-Smirnov criterion. For each sample, the median, the first and third quartiles were calculated. Comparison of the studied parameters was carried out using the nonparametric Mann-Whitney test. To assess the relationship between the level of total GSK-3β and the total score on the SIGH-SAD scale, a correlation analysis was used using the Spearman rank correlation coefficient. Differences were considered significant at a significance level of p <0.05.

When determining the ratio of GSK-3β / β-actin in blood mononuclear cells of patients with depressive disorders, an increase in this indicator was found in the group of patients with recurrent depression (0.80 (0.67-0.95)) compared with patients with a primary depressive episode ( 0.66 (0.57-0.78)) (p = 0.050) and the control group (0.62 (0.48-0.66)) (p = 0.001). There were no differences between the group of healthy donors and patients with a primary depressive episode (p = 0.071). The total score on the SIGH-SAD scale did not differ between groups of patients with depressive disorders (p = 0.160) (Table 1).

In the group of patients with recurrent depressive disorder, there was a statistically significant positive relationship between the average strength of the GSK-3β / β-actin ratio and the total score on the SIGH-SAD scale, the correlation coefficient was 0.601 (p = 0.039). No statistically significant correlation was found in the group of patients with primary depressive episode (Table 1).

Thus, in patients with recurrent depressive disorder, a positive correlation is observed between the ratio of GSK-3β / β-actin in blood mononuclear cells and the total score on the SIGH-SAD scale.

Clinical examples are provided as an illustration.

Example 1 (mild depressive episode).

Patient E., b. 1984 (27 years).

Anamnesis: Patient's mother, 51 years old, suffering from degenerative degenerative disease of the brain, group I disabled person. She became ill almost immediately after the birth of her daughter (at 23), she was treated many times in various neurological hospitals of the country, but an exact diagnosis was never made, the disease is constantly progressing.

The patient's father died at the age of 49 from a repeated myocardial infarction. He worked as an electrician, by nature he was kind, trouble-free, silent, closed. The patient is the only child in the family. From the age of 5-6 months she was brought up by grandparents, as the patient’s mother was seriously ill and could not take care of the child. Grandmother - 76 years old, a teacher by profession, demanding, tough, domineering by nature, loves discipline, she was mainly engaged in the education of her granddaughter. Grandfather is 75 years old, kind and sympathetic.

The patient grew and developed according to her age, in the village of her grandparents along her mother's side. She visited kindergartens, where she always liked. She was cheerful, sociable in nature, and was friends with her peers. I went to school from the age of 7. I liked studying, it was easy, I was an excellent pupil. She preferred the humanities, participated in olympiads in the Russian language and literature, won prizes, and reached the regional level. I did not really like chemistry, although it notes that there were no unloved objects. She actively participated in the public life of the school, was engaged in amateur performances (sang), in sports sections (volleyball, tennis), organized extra-curricular activities, and was the host of various events. She participated in the “Student of the Year” exit competition, where she also won a prize. She always came to visit her parents on vacation, or they came to visit her in the village. Menses from 13 years old, the cycle established immediately, a little painful in the early days. Graduated 11 classes with a gold medal. I always dreamed of being a doctor, I entered the Siberian State Medical University. She also studied well there. When I entered the university, I moved to my parents in Tomsk, saw their life “from the inside”. I tried to help my father in the care and housework, family relations were warm, trusting. After the second year, she met her future husband, got married after graduation, began to live separately in her own apartment. He works as a doctor in the hospital.

At the age of 25, she became pregnant, the child was planned, desired. In July 2010, the patient’s child died, having lived only 16 days, the cause of death is a congenital heart disease. I was very worried about what had happened, cried for a long time, was depressed, apathetic, “I didn’t want anything, I didn’t want to see anyone, to talk.” I constantly had thoughts “why this could happen”, felt guilty, could not concentrate on work.

2 months after the death of the child, the patient’s father suddenly dies of myocardial infarction. I was also very worried, the previous condition was aggravated, was depressed, apathetic. A psychiatrist at the place of work recommended fevarin, but the patient did not take it. After a few weeks, the condition spontaneously improved.

02/11/2012, it was necessary to terminate the second pregnancy for a period of 22-23 weeks due to the suspicion of the presence of a congenital heart defect in the fetus. The patient was very worried about this, cried for a long time. Apathy reappeared, reluctance to do anything, even decided to quit work, but management recommended contacting a psychiatrist. She independently applied to the clinics of NIIPZ, was hospitalized in the department of affective conditions.

Mental state at admission: The patient looks according to age, asthenic physique. It looks neat, but is dressed somewhat casually, does not use decorative cosmetics. The gait is somewhat slow. In the conversation is passive, answers strictly to the question posed, without particularly detailing the story. It is somewhat inhibited, sits in a uniform pose, rarely changes the position of the body, shoulders are lowered, arms folded into the lock are held between the knees. Visual contact with the interlocutor supports. The face is sad, hypomimic. Complains of low mood, depression, apathy, weakness. Efficiency decreased, because He works in the hospital, sees healthy newborns, which constantly reminds him of his grief, in connection with which at some point the decision to quit has matured. The ability to concentrate is reduced, cannot concentrate on the activity being performed, and self-esteem has decreased. He feels guilty, believes that she could change something or not have an abortion, constantly thinks that these tests are “for something”. Appetite is reduced, eating because it is necessary. Sleep is disturbed in the form of difficulty falling asleep, early awakenings. She feels much worse in the morning, I don’t feel like waking up in the morning. Denies suicidal thoughts, although sometimes the question arises: "why live?". No productive symptoms have been identified. Intelligence corresponds to the education and lifestyle. Mental status is characterized by depressive syndrome.

Psychometric assessment of the severity of typical and atypical depressive symptoms using the SIGH-SAD scale: before treatment, the total score was 25 (19 for typical symptoms and 6 for atypical), on the 14th day of therapy - 13 (10 for typical symptoms and 3 for atypical )

Laboratory examination: the value of the ratio of GSK-3β / β-actin in blood mononuclear cells is 0.72.

Mental state at discharge. During the treatment, the mood was leveled, sleep, appetite normalized, she became more active, copes with household chores, makes positive plans for the future. It is discharged with improvement. Recommended: Valdoxan 25 mg for 6–9 months.

Justification of the diagnosis. The current depressive episode, which began in February 2012 after terminating a pregnancy for medical reasons, meets the criteria for a moderate depressive episode with somatic symptoms (according to ICD-10). From the anamnesis it is known that a similar condition was noted after the death of the first child and the death of the father and lasted about 3 months, spontaneously reducing without antidepressant treatment.

Example 2 (severe depressive episode).

Patient K., b. 1967 (45 years).

Anamnesis. The patient's father abused alcohol, the mother of the patient at the age of 40 was treated in the NIIPZ clinics due to her depressed mood. Grew restrained, calm. She was born in a complete family as the second child of four children (older sister, two younger brothers), lived in the village. According to the patient, the relationship with her mother was cold, she never experienced any manifestations of love on her part. Mother often punished, beat the patient for the mischief of her younger brothers. I did not attend preschool institutions. By nature, in childhood was closed, shy. She studied well, she was uncommunicative with classmates. Monthly from 14 years old, established immediately, painless. After the 7th grade, my family and I moved to the city. She finished school well, entered a teacher training college, liked to study, preferred the Russian language, literature, actively participated in amateur performances, sports events. Notes that in these years has become more sociable. With many former classmates still maintains a relationship.

After graduating from college, she worked as a teacher in a kindergarten for 5 years, then was fired to reduce staff, worked as a hostess in OKB, and as a postal operator. Relations with the team have always been good, friendly.

At the age of 19, she began dating a man, gave birth to a daughter from him, but family life did not work out (a year later the man became ill with tuberculosis and left for another city). Currently, communication with this man does not support. She lived with her child with her parents, and worked at that time as a teacher in a kindergarten.

Officially married since the age of 24, he describes his spouse as stubborn, prone to cruelty, alcohol abuse, several times there have been cases of physical violence on his part.

In 1993, his sibling suffered a serious head injury, in connection with which he underwent two neurosurgical operations, the patient took care of him. She was forced to identify her brother in the house of the disabled, where he died. The patient was worried about the death of her brother, because of what happened vinyl on everything.

In 1989 and 2002 underwent surgery for congenital stricture of the ureter, hydronephrosis. Since 2003, “stomach pains” began to bother, was repeatedly examined on this subject, and in 2006 the diagnosis was established: a hiatal hernia, in connection with which the operation was performed, but the pain continues to be disturbed. In 2008 - appendectomy, in 2011 - surgery for uterine fibroids.

In 2008, the patient’s mother died of a heart attack, whose death was very worried, "squeezed grief in her chest", persistent insomnia appeared, asthenia gradually increased. She experienced a breakdown, decreased appetite, and a constantly reduced mood was noted. This condition lasted several months.

Since 2010, against the backdrop of a constant conflict with her husband who is drinking, his mood again decreased, and pronounced drowsiness and fatigue appeared. Significant deterioration has been noted since the beginning of April 2010, when there was a markedly decreased mood, drops in blood pressure, interruptions in the pulse, “hot flashes” of heat and cold worried, intense pain in the umbilical region, any load caused deterioration, there was no strength even to climb the steps of the stairs. On this occasion, a therapist was examined, a diagnosis of coronary heart disease was made. In May 2010, there were pulling chest pains that were first provoked by scandals with her husband, and then became permanent, after the examination the therapist was diagnosed with "Thoracic osteochondrosis", for which she received treatment on an outpatient basis. However, no improvement was noted. The patient was disturbed by shortness of breath while walking, "during an excited" state. The clinic doctor was recommended to consult a psychiatrist.

From June 24 to August 19, 2010 she was treated at the Tomsk Clinical Psychiatric Hospital, followed by treatment in a day hospital of a neuropsychiatric clinic with a diagnosis of Hypochondriacal disorder (F.45.2). Upon admission, the mental status was characterized as follows: it looks neat on the surface, and light makeup on the face. In a clear mind. The mood is lowered. While speaking, he sighs heavily, pronouncing the final sound of a word, sighs as if there was a lack of air. Reports that shortness of breath appears with excitement, sometimes when walking. Describes in detail, emotionally, his complaints about weakness, loss of strength, disturbed sleep. Complains of "pulling pains" in the chest, hands shows their localization. Reports that there was a "fear" to go out alone, because afraid that suffocation will occur or pressure will rise. Reports that she began to scare the sharp sounds. He calls himself suspicious, "if that gets sick, it seems to me that this is a cancer", explains that she wanted to be examined at the Research Institute of Oncology. She claims that over the past 2 weeks she lost 12 kg, because practically didn’t eat anything. He actively asks for help: "I'm tired, because they can’t help me anywhere." She notes that against the background of this condition, irritability appeared, she began to get tired of talking with others, there was no desire to do anything. She reports that now she is tired, asks to continue the conversation another day.

Psychological examination (07/06/2010): mood decline, hypochondriacal fixation, dominance of psychasthenic, astheno-neurotic features; difficulty distributing and shifting attention; slowing the pace of mental processes, fatigue.

She received the following treatment: intravenous and intramuscular injections with seduxen up to 30 mg / day, eglonil 300 mg / day, cipralex 10 mg / day, then transferred to oral administration of eglonil 400 mg / day, teraligen 10 mg / day, paxila up to 40 mg / day. In addition, she received symptomatic treatment with phenazepam, motherwort, ultop, betalok, trimectal, cardiomagnyl, motilium, bellataminal, mexidol, piracetam, cetrin, and vitamin therapy.

Mental status in dynamics: she was fixed on her painful state, anxious, often asked to take drugs at her discretion, or suggested that doctors prescribe her her own treatment. Gradually, the patient's mood level leveled off, pain was reduced, the patient began to actively communicate with patients, and used the home leave regimen.

Was discharged with the recommendation of a psychiatrist's advisory supervision as necessary; Paxil 40 mg × 1 time per day (morning) - 3 months, followed by a transition to a dose of 20 mg / day (3 months); eglonil 400 mg / day.

After discharge, she did not take the recommended drugs, did not bother for some time, but then resumed, in December 2010 she was forced to leave her job (“asked to leave, because she was often on a sick leave”).

She noted a noticeable deterioration in condition since September 2011: abdominal pain intensified, her mood decreased, she became absent-minded, irritable, tearful, felt anxiety for her health, reluctance to do anything, communicate with anyone, stopped leaving the house. In the morning, the patient's condition was noticeably worse than in the evening. At the insistence of the psychiatrist, she turned to the NIIPZ clinics, was hospitalized in the 3rd department.

Mental status upon admission. She is dressed neatly, her expression is pained, she looks tired. The mood is reduced, in the conversation often cries, fixed on somatic sensations, complains of poor sleep, appetite, weight loss of 10 kg, fatigue, irritability, pain of a pulling nature in the chest, abdomen, back, loss of interest and pleasure from usually pleasant activities , feeling of weakness, weakness, anxiety for one’s health, apathy, decreased energy, distraction. Attention is unstable, in the conversation it is quickly depleted, pessimistic about its prospects. The presence of suicidal thoughts denies. No psychotic symptoms were detected.

Psychometric assessment of the severity of typical and atypical depressive symptoms using the SIGH-SAD scale: before treatment, the total score was 44 (29 for typical symptoms and 15 for atypical), on the 14th day of therapy - 31 (19 for typical symptoms and 12 for atypical )

Laboratory examination: the ratio of GSK-3β / β-actin in blood mononuclear cells is 0.96.

The rationale for the diagnosis: anamnestic data, a clinical and dynamic assessment of the current disorder suggest the presence of repeated depressive episodes in the anamnesis. The first distinct depressive episode (of moderate severity with somatic symptoms) was noted after the death of the mother and was accompanied by vital manifestations of depression. The second depressive episode (April - August 2010) was also associated with stressful circumstances of a family nature and was accompanied by polymorphic symptoms with the presence of algic equivalents of depression, anxiety-phobic symptoms, psycho-vegetative dysfunction, and hypochondria fixation. The third depressive episode (since September 2011) was characterized by an increase in depressive symptoms: the presence of decreased mood, anhedonia, fatigue, sleep disturbance, decreased appetite, 10 kg body weight, distraction, difficulty concentrating, pessimistic assessment of one's prospects, unpleasant somatoalgic sensations. In the morning, the patient's condition was noticeably worse than in the evening. Symptoms of the psychotic register were not detected. The presence of the above symptoms meets the diagnostic criteria for a severe depressive episode without psychotic symptoms. Given the presence of depressive episodes in the past and the symptoms of the current depressive episode, the diagnosis is justified: Recurrent depressive disorder, current severe depressive episode without psychotic symptoms (F 33.2).

The method has been tested in 24 patients, is simple to implement, and based on the determination of the GSK-3β / β-actin ratio, it is possible to assess the severity of the current depressive episode in patients with recurrent depressive disorder, and to purposefully carry out rehabilitation psychotherapeutic and pharmacological measures.

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Claims (1)

A method for assessing the severity of the current depressive episode in patients with recurrent depressive disorder based on the determination of the GSK-3β / β-actin ratio as a biological parameter reflecting the severity of depressive symptoms, together with the correlation of this indicator with the total score on the SIGH-SAD scale, and increasing the ratio of GSK-3β / β-actin in blood mononuclear cells of patients with depressive disorders above 0.70 and the value of the total score on the SIGH-SAD scale above 30 assess the severe degree of the current depressive episode with recurrent course of depressive disorder.