RU2530635C1 - Method for prediction of clinical effectiveness in depressive episode - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: method is implemented as follows: patients' blood serum is examined for pre-therapeutic cortisol, dihydroepiandrosterone (DHEA) and serotonin, and if the cortisol concentration is more than 650 nmole/l, the DHEA concentration is less than 7.8 mg/ml, and the serotonin concentration is more than 115 ng/ml, the high clinical effectiveness of the drug therapy is predicted.

EFFECT: method is easy to implement and enables the pre-therapeutic prediction of the efficacy of the drug therapy of a depressive episode by determining a number of neurohumoral values and provides adequate rehabilitation pharmacological actions.

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Description

The invention relates to medicine, namely to psychiatry, and can be used to predict the effectiveness of pharmacotherapy of affective disorders.

This method is aimed at studying biological indicators characterizing the stress-realizing and stress-limiting systems of the body, the mobilization of the body in affective disorders and causing the clinical effectiveness of pharmacotherapy.

A known method for predicting the effectiveness of treatment of depressive disorders with coaxil based on determining the level of activity of serum amino oxidase before treatment [1]. Methods for predicting the efficacy of treatment for depressed disorders with zoloft include determining the effective and total serum albumin concentration [2] and platelet monoamine oxidase activity in blood plasma before and after 2 weeks of treatment [3]. There is a method for predicting the effectiveness of treatment of residual schizophrenia with atypical antipsychotics before treatment based on determining the concentration of dehydroepiandrosterone sulfate (DHEAS) and cortisol and neutrophil apoptosis rate [4]. The efficacy of ladasten therapy for organic asthenic disorders is predicted by the serum cortisol and dehydroepianrosterone sulfate levels before therapy [5].

An adequate prototype of the proposed invention, allowing prior to treatment to determine the effectiveness of pharmacotherapy of the current depressive episode, was not found in the analyzed literature.

The task of the invention is to improve the accuracy of predicting the effectiveness of pharmacotherapy of a depressive episode before treatment.

The problem is solved by determining the neurohumoral blood parameters: the concentration of the hormone cortisol, the neurosteroid dehydroepiandrosterone (DHEA) and the neurotransmitter serotonin in patients prior to pharmacotherapy. With a high concentration of cortisol (above 650 nmol / L), a reduced content of dehydroepiandrosterone (below 7.8 ng / ml) and an increased concentration of serotonin (above 115 ng / ml), high efficacy of pharmacotherapy for the current depressive episode is predicted.

New in the proposed method are the use of determining the concentrations of cortisol and DHEA in combination with determining the serotonin content of blood serum as biological predictors of effective pharmacotherapy of the current depressive episode.

The study of the level of hormones of the pituitary-adrenal system (in particular, cortisol), neurosteroids (dehydroepiandrosterone) and neurotransmitters (serotonin) was chosen because these indicators, characterizing the state of stress-realizing and stress-limiting body systems, play an important role in etiopathogenesis of affective disorders and dynamically change during treatment.

Currently, it is considered the most justified that the key pathogenetic mechanisms of depressive disorders are associated with disorders of a number of neurochemical systems, including dysregulation of the serotonergic system. Depressive disorders are accompanied by a decrease in the activity of the serotonergic system, as well as interactions of polymorphic loci of the genes of serotonin metabolism, which determine the predisposition to the development of affective disorders [6]. One of the most common explanations for impaired neuronal plasticity in depression is hyperactivity of the hypothalamic-pituitary-adrenal axis and, accordingly, hyperactivity of the corticotropin releasing factor (CTRF), adrenocorticotropic hormone (ACTH) and cortisol [7]. Protecting hippocampal neurons from the harmful effects of increased secretion of cortisol and regulating glucocorticoid activity in the brain, DHEA has a neuroprotective and stress-protective effect [8].

New features showed in the claimed combination of new properties that are not explicitly derived from the prior art in this field and are not obvious to a specialist. An identical set of features was not found in the patent medical literature. The proposed method can be used in medical practice to predict the response to antidepressant pharmacotherapy in patients with a current depressive episode.

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 criteria (the content of cortisol, DHEA and serotonin in the blood serum) for predicting a highly effective response to pharmacotherapy were obtained as a result of a clinical and biological examination of patients with a current depressive episode of varying severity who underwent a course of treatment in the Department of Affective Conditions of the Federal State Budget Scientific Research Scientific Research Institute of Medical Sciences.

The study involved 46 patients with affective disorders who underwent treatment in clinics of the Federal State Budget Scientific Institution "Scientific Research Institute of Applied Microbiology" of the Russian Academy of Medical Sciences. Diagnostic assessment and clinical verification were carried out by psychiatrists, the diagnosis of the disorders was carried out under the headings F32-F33 according to ICD-10 (single depressive episode, recurrent depressive disorder). The average age of the patients was 56 ± 7.6 years. The study was conducted in accordance with the ethical principles of conducting human research in accordance with the protocol approved by the Committee on Biomedical Ethics of the Federal State Budget Scientific Institution NIIPZ SB RAMS. Clinical symptoms were assessed using the 17-point Hamilton Depression Scale (HDRS-17), and pharmacotherapy efficacy was assessed using the General Clinical Impression Scale (subscale that measures improvement dynamics — CGI-I, The Clinical Global Impression-Improvement scale).

For laboratory examinations in patients in the morning (between 8 and 9 hours), on an empty stomach, before starting drug therapy, blood was taken from the ulnar vein into Vakuteyner tubes with a blood coagulation activator (inert silicone particles - SiO2 deposited on the inner walls of the tube). The concentrations of cortisol, dehydroepiandrosterone (DHEA) and serotonin were determined in blood serum. To obtain serum, a test tube with venous blood was centrifuged at 1500 rpm for 20 minutes. After centrifugation, the resulting serum was collected using a pipette.

Determination of the concentration of steroid hormones and serotonin was carried out by enzyme-linked immunosorbent assay in accordance with the instructions for the use of reagent kits for enzyme-linked immunosorbent assay of the studied metabolites in blood serum (CJSC Alkor Bio, St. Petersburg, Diagnostics Biochem, Canada and IBL HAMBURG, Germany). The reaction was carried out according to the instructions attached to the kits with the mandatory control of the standard positive and negative sera that are part of the test system. ELISA results were evaluated on an automatic microplate spectrophotometer Epoch BioTek Instruments (USA) at a wavelength of 450 nm. The final results were expressed in units recommended by manufacturers for constructing calibration graphs from standard batches of the substances to be determined (cortisol — nmol / l, DHEA — ng / ml, serotonin — ng / ml).

In accordance with the dynamics of improvement during treatment, which was recorded using the 17-point Hamilton Depression Scale (HDRS-17) and the General Clinical Impression Scale (CGI-I subscale), the patients were divided into 2 groups: responder group 1 ( 38 people, 82.6%); 2nd group non-correspondents (8 people, 17.4%). The criteria for a therapeutic response (response) were: reduction in the course of pharmacotherapy of the starting total score for HDRS-17 ≥50%, 1-2 points for CGI-I ("significant" or "significant" improvement).

Estimating neurohumoral parameters statistically and by an expert method before treatment, predictors of pharmacotherapy effectiveness were determined in the study population. The results of an enzyme-linked immunosorbent assay of neurohumoral factors in patients upon admission to the clinic amid severe clinical symptoms are presented in table 1.

Table 1 Neurohumoral indicators of patients with a current depressive episode upon admission to the clinic before the appointment of pharmacotherapy in the groups of responders and non-responders Indicators Responders N = 38 Non-correspondents N = 8 R Cortisol nmol / L 719.35 ± 30.73 575.63 ± 35.24 0,046 Serotonin ng / ml 136.2 ± 9.27 89.3 ± 12.97 0,03 DHEA ng / ml 6.75 ± 0.4 8.6 ± 0.29 0.04 Note: P is the significance of differences between the group of responders and non-correspondents according to the Mann-Whitney criterion.

The study of neurohumoral signs in blood serum showed that the level of cortisol concentration in the group of responders was 719.35 nmol / ml. The concentration of serotonin in patients with a significant improvement in mental state was 136.2 ng / ml. The DHEA content in the group of responders was 6.75 ng / ml.

In the group of patients with a slight improvement in their mental state, the concentration of cortisol was 575.63 nmol / L, which is lower than the level of this indicator in the first group (p = 0.04). The content of serotonin in nonresponders differs from the concentration of the neurotransmitter in the group of responders (p = 0.03). The level of DHEA in the group of non-correspondents is significantly lower than the corresponding indicator of responders (p = 0.04; 8.6 ng / ml).

Determination of the serum content of the hormone cortisol, the neurosteroid dehydroepiandrosterone (DHEA) and the neurotransmitter serotonin before the start of therapy allows predicting the effectiveness of pharmacotherapy for the current depressive episode.

We give clinical examples as an illustration.

Example 1

Patient K.T.P., born in 1945 (medical history No. 1516)

Diagnosis: Recurrent depressive disorder, current mild depressive episode F33.0; Other organic personality disorder due to cerebrovascular disease of vascular origin F07.8

Complaints about unstable mood (lowered), melancholy, apathy, increased anxiety, shallow sleep, sometimes reduced interest in the environment and tearfulness, as well as unstable blood pressure, meteosensitivity, noise in the head, memory impairment.

Anamnesis: Heredity is weighed down by alcohol dependence and epilepsy (brother), father suffered from cardiovascular disease.

The patient was born the oldest child in a complete family. Grew a healthy child, developed in accordance with age. Has a secondary special education, an accountancy profession. Married since 19 years. Relations with the husband are even friendly. In marriage, she gave birth to healthy son and daughter. Children live separately from their parents with their families. There are 5 medical abortions in the obstetric history. Menopause since 54 years, proceeded without pronounced vegetative manifestations.

For the first time it came to the attention of psychiatrists in the fall of 2006. In the past, she repeatedly suffered depressive episodes of mild to moderate severity, for which she was treated by psychiatrists. This admission to the clinics of FSBI “NIIPZ” SB RAMS is the fifth in a row, repeated this year.

Mental status at admission: Outwardly, she looks neat, well-groomed, but somewhat tired. He enters the conversation willingly. Mimic reactions are poor, inexpressive. Sits in a closed position, rarely gestures. A voice of sufficient volume, speech at an average pace. Slowly, he talks about his condition, often with a stuck on insignificant details. Complaints of mood swings with a predominance of lowered mood, periodic increase in anxiety, a decrease in interest in the environment, a feeling of longing, tearfulness, and superficial sleep. Appetite is rated as normal or slightly elevated. The mood background is reduced, but periods of even good mood may be present during the day. Denies suicidal thoughts. Notes unstable blood pressure, with a tendency to increased, weather sensitivity, sometimes a noise in the head. The leading syndrome is anxiety-depressive.

Table 2 shows the dynamics of indicators for HDRS-17 and CGI-I.

table 2 Dynamics of indicators for HDRS-17 and CGI-I during antidepressant therapy 0 day 14 day 28 day CGI-I - 2 (significant improvement) 2 (significant improvement) HDRS-17 14 (mild expression of depression) 7 (no depression) 5 (no depression)

Treatment: Lerivon 60 mg / day, eglonil 100 mg / m, then eglonil 300 mg / day by oral administration. Concor, diroton, aspirin, B1 vitamins, vinpocetine iv drip, piracetam \ m, Fezam.

Mental state at discharge: Against the background of treatment, the emotional state leveled off, the feeling of anxiety was reduced, sleep was restored, blood pressure stabilized. Weakness, lethargy disappeared. It is discharged from the department with improvement.

Laboratory examination: cortisol 690.38 nmol / l, serotonin 156.08 ng / ml, DHEA 7.03 ng / ml.

Due to the fact that neurohumoral indicators meet the criteria for a highly effective response to pharmacotherapy (the concentration of cortisol in the patient’s blood serum is above 650 nmol / l, the level of serotonin is above 115 ng / ml and contain DHEA below 7.8 ng / ml), we predict this patient high clinical efficacy of pharmacotherapy.

Example 2

Patient B.A.V., b. 1974 (medical history No. 724)

Diagnosis: Depressive episode of moderate severity with somatic symptoms (F 32.11); Dysthymia (F 34.1); Other mixed anxiety disorders (F 41.3).

Complaints of depressed mood, frequent tearfulness, reluctance to communicate, decreased appetite, shallow sleep with a lack of a sense of relaxation, as well as bouts of anxiety, fear arising at night with a fast heartbeat and a feeling of lack of air, express distrust of doctors.

Anamnesis: Heredity burdened by suicidal behavior and affective disorders: mother's cousin committed suicide at a young age; the patient’s mother suffers from recurrent depressive disorder, mixed anxiety disorder, was treated in the clinics of NIIPZ, observed in connection with hypertension; the mother’s aunt suffered from a mental disorder (the diagnosis is not known), was strange in behavior, “talked to herself.”

The patient was born from a second pregnancy, second birth, the youngest of two sisters in the family. Early development according to age, often suffered from acute respiratory infections. I went to school on time, managed to "excellent". By nature she was calm, stubborn, striving for perfection. After graduating from high school, she entered the Pedagogical Institute at the Faculty of Foreign Languages.

At the age of 19, after a brief acquaintance, she got married. From marriage she gave birth to a son; pregnancy proceeded physiologically. From 23 years old, the patient began to live with her parents. At 25, she successfully defended her thesis. At 27, she filed for official divorce. She was engaged in scientific and teaching activities, often went on business trips, including abroad.

In 2004, the patient’s father revealed hepatitis “B” and “C”, on the recommendation all family members were examined, hepatitis “B” was detected in the patient’s mother and hepatitis “C” in the patient herself. In March 2006, the patient’s father died of liver failure. This event extremely traumatized her: she felt anxiety, fear of death. Immediately after his death, she began antiviral treatment, which she stopped in January 2007. Against the background of treatment, she was depressed, tearful, and lost 12 kg, while still maintaining hope for a cure. For several years after these events, a somewhat depressed, irritable mood persists. There were difficulties in communicating with a son who has reached puberty. A child from childhood grew excitable, hyperactive, until 11 years old suffered from enuresis; after the death of his grandfather became uncontrollable, quick-tempered. Currently, the child lives with his father, from time to time he meets with his mother, relations with him are aligned. In March 2010, she experienced a stressful situation at work, the degree of depressed mood was further aggravated, anxiety attacks at night with a feeling of shortness of breath, palpitations, increased blood pressure began to disturb, caused the ambulance team twice, between the attacks I was disturbed by the feeling of “constant spilled anxiety. " She sought counseling at the clinics of the Siberian State Medical University; treatment at the clinics of the Scientific Research Institute of Mental Health was recommended.

Mental state at admission: Looks according to the passport age. Tidy. Moderately uses decorative cosmetics. The expression is bleak, the gaze is directed to one point directly in front of you, sometimes it looks somewhat defiantly into the interlocutor’s eyes. He speaks in a low voice. The pace of speech is slow, carefully selects words. Mimic reactions are smoothed out. In conversation, the patient is tense, depressed. It is fixed on the state of health, convinced that “life does not last long,” “he is interested in doctors (infectious disease specialists, therapists) for the duration of his remaining life”. The vision of the future is pessimistic. It expresses fears that they can learn about the disease at work, and then the attitude towards it will change. It is burdened by loneliness, inability to share their experiences. The pace of mental processes is slowed down. The memory functions are not disturbed. The leading syndrome is anxiety-depressive.

Table 3 shows the dynamics of indicators for HDRS-17 and CGI-I.

Table 3 Dynamics of indicators for HDRS-17 and CGI-I during antidepressant therapy 0 day 14 day 28 day CGI-I - 3 (slight improvement) 3 (slight improvement) HDRS-17 24 (mild depression) 19 (mild depression) 13 (mild depression)

Treatment: stimulotone 100 mg / day, fluanxol 1 mg / day, relanium 10 mg / day, heptral, folic acid, suprastin.

Mental state at discharge: Against the background of therapy, my mood improved slightly, I became somewhat calmer, and fixation on a traumatic situation decreased. Sleep, appetite sufficient.

Laboratory examination: cortisol 617.02 nmol / l, serotonin 67.7 ng / ml, DHEA 9.34 ng / ml.

Thus, as a result of a clinical and biological examination, it was determined that the concentration of cortisol in the patient’s blood serum is below 650 nmol / l, the serotonin content is below 115 ng / ml and the DHEA level is above 7.8 ng / ml, in connection with which we predict this patient low clinical efficacy of pharmacotherapy.

The method is simple to implement and based on the determination of a number of neurohumoral indicators, it is possible to predict the effectiveness of pharmacotherapy of a depressive episode before treatment and to conduct targeted pharmacological rehabilitation measures.

Information sources

1. Pat. 2176087 Russian Federation, IPC G01N 33. A method for predicting the effectiveness of treatment with coaxil for depressive disorders / Maksimova N.M., Misionzhnik E.Yu., Vertogradova O.P., Uzbekov M.G., Karpachevskaya I.K. - application number 2000110694/14; declared 04/28/2000; publ. 11/20/2001, Bull. Number 32. - 3 p.: Ill.

2. Pat. 2002120296 Russian Federation, IPC G01N 33. A method for predicting the effectiveness of treatment with depressed conditions / Maximova N.M., Misionzhnik E.Yu., Vertogradova OP, Uzbekov MG - application number 2002120296/15; declared 07/31/2002; publ. March 20, 2004, Bull. Number 35. - 3 p.: Ill.

3. Pat.2235330 Russian Federation, IPC G01N 33. A method for assessing the effectiveness of treatment with depressed conditions / Maximova N.M., Misionzhnik E.Yu., Vertogradova O.P., Uzbekov MG - application number 2002120295/15; declared 07/31/2002; publ. March 20, 2004, Bull. Number 34. - 3 p.: Ill.

4. Pat. 2319155 Russian Federation, IPC G01N 33. A method for predicting the effectiveness of treatment of residual schizophrenia with atypical antipsychotics / Ivanova SA, Semke AV, Rakitina NM, Kornetova EG, Fedorenko O.Yu., Private L. A., Gutkevich E.V. - application number 2006108350/15; declared 03/16/2006; publ. 03/10/2008, Bull. Number 7. - 9 p.: Ill.

5. Pat. 2459208 Russian Federation, IPC G01N 33. A method for predicting the effectiveness of therapy with organic asthenic Ladasten / Levchuk LA, Ivanova SA, Semke V.Ya., Aksenov MM - application number 2011121539/15; declared 05/27/2011; publ. 08/20/2012, Bull. Number 23. - 8 p.: Ill.

6. Levchuk L.A., Shmigol M.V., Ivanova S.A. Serotonergic system in the pathogenesis and therapy of depressive disorders (literature review) // Siberian Bulletin of Psychiatry and Addiction. - 2012. - No. 2. - S. 75-79.

7. Sapolsky R.M. The possibility of neurotoxicity in the hippocampus in major depression: a primer on neuron death // Biol. Psychiatry. - 2000. - V.48. - P.755-765.

8. Goncharov N.P. Dehydroepiandrosterone and brain functions / N.P. Goncharov, G.V. Katsiya, A.N. Nizhnik // Bulletin of the Russian Academy of Medical Sciences. - No. 8. - 2005. - P.37-43.

Claims (1)

A method for predicting the effectiveness of pharmacotherapy for a depressive episode, characterized in that the content of cortisol, dehydroepiandrosterone (DHEA) and serotonin in the blood serum of patients is determined before treatment and at a cortisol concentration above 650 nmol / L, a DHEA content below 7.8 ng / ml and a serotonin concentration above 115 ng / ml predict high clinical efficacy of pharmacotherapy.