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Psychosomatic Medicine and General Practice The effectiveness of selank in the treatment of adjustment disorder

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Psychosomatic Medicine and General Practice The effectiveness of selank in the treatment of adjustment disorder
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  PsychosomaticMedicineandGeneralPractice DOI:10.26766/pmgp.v3i1.86 Theeffectivenessofselankinthetreatmentofadjustment disorder Verbenko G. 1 and Verbenko V. 11 Ukrainian Scientiic Research Institute of Neurology and Psychiatry  Abstract  Background.  Adjustment disorder (AD) is one of the most common mental disorders. Considering the social and eco-nomic situation in Ukraine at present, in almost 50% of the population, there are non-psychotic mental health disorders,and this number tends to increase. Individual risk factors that are particularly important for the AD development includethe experience of signiicant stress in childhood, problems with mental health in the past, dificult life circumstances, etc.At the same time, pathogenetically approaches to AD therapy are not fully understood. Pathogenetically oriented therapyofADshouldbebasedonneurotransmittercausesandsystemictherapeuticapproach. Theneurometabolic,anxiolytic,andpsycho-stimulatingactionoftheregulatorypeptideallowsittobeusedinthetherapyofpsychogenicadaptationdisorders. Methods.  ClinicalmanifestationsoftheADwerestudiedindifferentagegroups-21-34years(n=153),35-50years(n=257),51-65 years (n=167) using the Patient Health Questionnaire (PHQ) and Questionnaire of Stress Resistance (QSR). For thestudy on the effectiveness of the selank (a synthetic analogue of the immunomodulatory peptide tuftsin) were included 30patients with the AD. Main (experimental group) received selank for two weeks; the control group didn’t receive any treat-ment (wait list). Patients were monitored for additional two weeks after the treatment with an assessment at the end of follow-up. Results.  According to the study results, selank signiicantly reduced PHQ score in patients with AD compared to controlgroup. PHQ scores in the selank group after 2 weeks of follow-up were signiicantly lower for somatic symptoms (meanscore 1.2 vs. 3.6; p<0.05), nutritional problems (0.1 vs. 3.4; p<0.05), and alcohol misuses (0.3 vs. 1.5; p<0.05) Conclusion.  The use of the synthetic analogue of the immunomodulatory peptide tuftsin has a therapeutic effect on thesomatic and mental symptoms of the adjustment disorder. Keywords:  adjustment disorder , diagnostics , therapy , regulatory peptides 1 Introduction 1.1 ADprevalenceanddiagnosticcriteria Adjustment disorder (AD) is one of the most commonmental disorders. Considering the social and economic situ-ationinUkraineatpresent,almost50%ofthepopulationhassymptomsofmentalhealthdisorders,andthisnumbertendsto increase [1]. Personally signiicant stressful life events,even short-term, affect both the mental and physical healthof the individual. Individual risk factors are particularly im-portant for the development of the AD, including the experi-enceofsigniicantstressinchildhood,problemswithmentalhealth in the past, and challenging life circumstances.1  Psychosomatic Medicine and GeneralPractice •  February 2018  •  V. 3, I. 1  •  030186The most signiicant combination of factors is the pres-ence of provoking agents (individually substantial types of stressful life events) combined with an individual response(stress vulnerability) and constant personal dificulties incombinationwithotheraversivesocialandpsychosocialfac-torsofvulnerability(lowself-esteem,self-blame,pessimism)[2],[3]. Itshouldbenotedthatthefuzzyseparationbetweendifferent manifestations of the AD and normal adaptive re-sponses is dificult to diagnose [3],[4] Therefore, the diagno-sis and treatment of adjustment disorder is extremely rele-vant.TheICD-10indicatesthatapredispositionorindividualvulnerability plays the more signiicant role in the onset of theADthaninotherdisordersofthesamecluster(F43). Thisassociationimpliesakindof”stress-vulnerabilitysyndrome”thatusuallydeclinessocialorprofessionalfunctioning,evenif it doesn’tcorrespond to the diagnostic group.IntheDiagnosticandStatisticalManualoftheAmericanPsychiatric Association (DSM-5) [5], the chapter ”Traumaand Stress Disorder Disorders” combines anxiety disorderspreceded by an anxiety or traumatic event and clearly iden-tiies the criteria for a traumatic event. Special attention ispaid to sexual violence. Adaptive disorders are redeined asan array of stress response syndromes that occur after con-tact with an alarm event.AccordingtoDSM-5criteria,forADdiagnosisemotionalorbehavioralsymptomsshoulddevelopwithinthreemonthsafteridentiiablestresshadtakenplace(A).Symptomsorbe-havior are clinically signiicant, as evidenced by one or bothof the following (B):1. A pronounced disorder that does not correspond to theseverity or intensity of the stressor, even with an exter-nalcontextandculturalfactorsthatmayaffectthesever-ity of the symptoms and presentation.2. Signiicant deterioration in social, professional or otherields of functioning.A stress-related disorder does not meet the criteria of another mental disorder and is not simply an aggravation of a pre-existing mental disorder (C). Symptoms do not repre-sent a normal bereavement (D). After the termination of thestressor (or its consequences), the symptoms persist for nomore than 6 additional months (D) [5], [6].Symptoms may include: a feeling of sadness, hopeless-nessorlackofenjoymentwiththethingsyouused;frequent crying;feelingofanxiety,nervousness,stress;problemswithsleep; lack of appetite, concentration of attention; a sense of congestion;dificultiesindailyactivities;asenseoflackofso-cialsupport;avoidanceofimportantthings(suchasworkorpaying bills); suicidal thoughts or behavior. The persistent or chronic AD can last more than 6 months, especially if thestressor continues, for example, in case of unemployment.Many publications note that AD is most often (up to 37%)observedinprimaryhealthcarefacilitiesandoutpatientpsy-chiatric practice [7],[8]. The AD has high co-morbidity withdepression, anxiety, mixed anxiety-depressive states, behav-ioral disorders, substance abuse. 1.2 Pathophysiologicalmechanismsofadjust-mentdisorder AD occurs when the need for adaptation exceeds theability of a person to maintain a psychological or physio-logical balance. Adaptation at the physiological level is as-sociated with the activity of monoamine neurotransmitters,hormones(e.g.,glucocorticoids)andotherneuromodulatorsthat affect several areas of the brain and various organ sys-tems [9]. Excessively high or low levels of glucocorticoidslead to neuronal atrophy, especially in the hippocampus,amygdala and prefrontal cortex (PFC), negatively affectingthe grey matter volume in this regions. The disturbance inthe PFC activation causes a deicit in the prefrontal corti-cal function and anomalies in the metabolism of mesocor-tical dopamine (DA), which leads to hyperactivation of theamygdala, hippocampus, and locus coeruleus. Such changescan provoke hypothalamic–pituitary–adrenal axis hyperacti-vation,disruptthemetabolismofserotonin,enkephalins,glu-tamate,etc.,andpromotethedevelopmentofmentalandbe-havioral disorders [10]. At the same time, a decrease in theeffect of PFC on subcortical reactions potentiates the devel-opmentof newstressreactions,affects the speciic behavioroftheindividual,includingsleep,impulsivityorisolation,au-tonomic responses, movements and sensitivity to pain. Anyof these symptoms may be due to an uncontrolled or exces-sivereactiontostress. Forexample,lossofcontroloversuici-dal impulses may be associated with a decrease in the avail-abilityofserotoninandanincreaseinserotonin-2Areceptoractivity [11]. Serum levels of protein carbonyl groups andnitrosylated proteins, which are biological markers of oxida-tive stress, have been studied [12]. Biomarkers have beenidentiied,suggestingthedirectroleofoxidativestressinreg-2  Psychosomatic Medicine and GeneralPractice •  February 2018  •  V. 3, I. 1  •  030186ulatory disorders.At the same time, pathogenetically approaches to ADtherapyarenotfullyunderstood[9],[13]. ThestudiesonADtreatmenthaverevealedanexcessiveuseofdifferentclassesof antidepressants without taking into account the concept of time-limited AD [9],[13]. A retrospective analysis aimedatevaluatingtheeffectivenessofantidepressantsinpatientswith AD did not show any difference in the clinical responseto any particular antidepressant. The primary statistical dif-ference consisted in the frequency of responses when pa-tients diagnosed with AD were twice as likely to respond tostandard antidepressant treatment (approximately 70% of cases)thanpatientsdiagnosedwithdepression. Itwasfoundthat all antidepressant are equally effective and more efi-cient than other agents in the treatment of AD, while drugscombinations can increase the risk of possible side effects[14]. The presence of suicidal risk in patients with a this di-agnosis requires the choice of the safesttreatment.ModernpathogeneticallyorientedtherapyofADshouldbe targeted on neurotransmitter causes and use systemictherapeutic approach, taking into account, irst of all, thesafety of the drugs. In this aspect, in our opinion, the use of newclasses ofregulatorymedicationslookspromising. Reg-ulatory peptides have a wide spectrum of biological activity,which is of great importance in coordination of body func-tions, because of neuroendocrine, immunological, cellularand molecular interactions [15]. Regulatory peptides are re-latedtotheendogenousbodycompoundsthatbindthebasicbiochemical systems of the body and mediate the reactivityoftheorganismtovariousexternalfactors. Exposuretoneg-ativeenvironmentalfactorscanincreasetheeffectsofregula-torypeptides[16]. Theadvantageofpeptidepreparationsistheextremelylowprobabilityoftoxicitywhenadministeredeven in large doses, since the products of their metabolismare natural amino acids that perform mainly homeostaticfunctions, which signiicantly reduces the likelihood of sideeffects. Selank(synthesizedanalogueoftheendogenousreg-ulator of immunity – taftcin) is one of the promising regula-tory peptides in the AD treatment. Since it has an srcinalmechanism of neurospeciic action on the central nervoussystem,itaffectstheexchangeofmonoaminesintheemotio-genic structures of the brain (hypothalamus, limbic system)and the activity of brain enzymes tyrosine and tryptophanhydroxylase [17]. Anxiolytic and antidepressant action of “Selank” is associated with regulation at the genome level of the synthesis and metabolism of norepinephrine, serotonin,and enkephalins in the emotional zones of the brain. “Se-lank” stabilizes the processes of excitation and inhibition inthe brain and increases the stability of neurons of the cere-bral cortex to functional loads of high intensity [18]. Thus,the complex action of the regulatory peptide, including neu-rometabolic, anxiolytic, psycho-stimulating effects, reducingasthenic symptoms and normalizing mental activity [19], al-lows it to be used in the therapy of AD. 2 Materials and methods of the re-search In the study were included individuals aged 21 to 65years, which were admitted to hospital for routine exami-nation. The survey was conducted using the Health Ques-tionnaire (PHQ) and Express Diagnostics of the Stress Level(BCS) (K. Schreiner, 1993) [20], [21]. Participants in the sur-vey were divided into age categories 21-34 (n=153), 35-50(n=257), and 51-65 years old (n=167). In the trial on the ef-fectiveness of a regulatory peptide drug participated 30 pa-tients, which met inclusion and didn’t met exclusion crite-ria. The main (MG, n=15) and control group (CG, n=15) in-cluded patients with the diagnosed AD. The most prevalent complaints were a feeling of anxiety, nervousness, or stressrelated to work or family problems; problems with sleep;a sense of congestion; dificulties in daily activities. Eachpatient was informed of the study’s purpose and objectives,medication’scharacteristics,possiblesideeffectsandsignedinformed consent. The patients from the control group (CG)didn’t receive any medication. The groups were compara-ble in the all of the studied parameters. Psychotherapy, diet therapy,othermedicamentandnon-drugtherapieswerenot used.Clinical examination included assessment of objectivephysical and mental status and measurement of physiologi-calparameters. Toclarifythenatureandseverityofpsychoe-motional status alteration, a PHQ health questionnaire wasused[21]. Expressdiagnosticsofthestresslevelwascarriedout according to the DSS questionnaire (K. Schreiner, 1993).Performance parameters were evaluated at an interimand inal visit compared to the initial state. Evaluation of the safety of therapy was conducted on the basis of registra-tion of adverse events, analysis of complaints and subjectivesymptoms,theirseverity. Statisticalprocessingoftheresults3  Psychosomatic Medicine and GeneralPractice •  February 2018  •  V. 3, I. 1  •  030186was carried out using MS Exceland Statistic 6 software. 3 Resultsanddiscussion The results of the screening revealed the following fea-tures in different age groups. The low level of regulationin stressful situations was detected in 31.4% of participantsfrom the age group 21-34 years, 44.0% of participants aged35-50 years and in 50.9% from the age group 51-65 years,which demonstrates decrease in stress resistance with age(Table 1).AsshowninTable1,ahighlevelofstressresistancealsotended to decrease in the older age group.The analysis of the clinical examination, including dataregarding psychoemotional state and the PHQ, made it pos-sible to assess the presence of somatic symptoms, nutritioncharacteristics,andattitudestowardsalcoholuseinthestud-iedagegroups. TheresultsofthescreeningaccordingtothePHQ health status questionnaire are presented in Table 2.Despite the absence of complaints at the time of thesurvey, according to the questionnaire, during the last threeweeks, 31.4% of participants in the 21-34 age group, 23.3%ofparticipantsaged35-50yearsand50.9%oftheagegroupthegroupof51-65yearsnotedthepresenceofsomatic(pre-dominantly algic) pain with a frequency corresponding tohigh severity. In the studied sample, 34.6% of participantsfrom the 21-34 age group, 34.2% of participants aged 35-50years and 27.5% in the age group 51-65 years consumed al-cohol more than twice a week. Among frequent reasons of alcohol consumption was to relieve tension and anxiety. Ab-normaleatinghabitswereabsentin34.6%ofparticipantsinthe21-34agegroup,22.2%ofparticipantsaged35-50yearsand 27.5% in the 51-65 age group. The rest noted that theyhad episodes of diet misuses.The results of the screening study demonstrated theprevalence of a decrease in stress resistance and subjectivedeterioration in all age groups with an increase to 50.9% inthe age group 51-65 years. The data obtained are compara-ble with international studies [3], [7], [8], [22], [23]. Thesestudiesemphasizetheimportanceofassessingtheconditionof patients with the AD and choosing the safesttherapy.Astudywasmadeoftheeficacyofthesynthesizedana-logue of the endogenous peptide taftcin (Thr-Lys-Pro-Arg-Pro-Gly-Pro)inthetreatmentofsymptomsofadaptationdis-orders. The results of the study are presented in Table3.AsshowninTable3,thegroupswerecomparableintheoriginalparameters. IntheMGgroup,attheendofthetreat-ment, in the MG group symptoms improved statistically sig-niicant (p<0.05) compared to baseline. AD symptoms im-proved more signiicantly in the MG group, compared to CGgroup (p<0.05). In the CG, in turn, during the observation,not only the preservation of the initial symptomatology wasnoted, but there was a tendency to overeating and weight gain.TheaveragescoreofalcoholconsumptioninCGwas1.3 ± 0.4. After2weeksoffollow-up(28thdayofthestudy),thenumber of alcohol users did not change, but the frequencyof alcohol consumption increased, and the average score onthis subscale increased to 1.5  ±  0.4 (Table 3). Two weeksafter cessation of therapy with the regulatory peptide (ana-logue of the endogenous peptide taftcin), its positive effectswith respect to the correction of the AD symptoms in MG re-mained signiicant (Table 3).According to the analysis, the regulatory peptide hada signiicant positive effect on the emotion regulation andAD symptoms; moreover, medication had pronounced post-therapeutic effect. The study conirmed that “Selank” (syn-thesized analogue of the endogenous peptide taftcin) can beused for the treatment of AD. It signiicantly improves so-matic symptoms, helps to reduce alcohol consumption andcorrecteating habits in patients with this diagnosis. 4 Conclusion 1. Thepharmacologicalandtherapeuticeffectsoftheregu-latory peptides, such as synthesized analogue of the en-dogenouspeptidetaftcin,isdeterminedbythepresenceofanormalizingeffectontheactivityoftheprimaryneu-rotransmitter systems of the brain.2. The use of analogue regulatory peptides has a positiveeffect on the somatic and mental symptoms in patientswith AD.3. One of the therapeutic effects of the “Selank” is thepreservation of psychoemotional health, which prede-terminesits rolenotonlyfortreatmentbutalso forpre-vention of stress-related disorders.4  Psychosomatic Medicine and GeneralPractice •  February 2018  •  V. 3, I. 1  •  030186 5 Additionalinformation 5.1 Competinginterests The authors have no conlicts of interestto declare.Table 1: The indicators of stress-resistance in different age groups according to the data of rapid diagnostics of the state of stress (DSS).Parameters/groups 21-34 years, N = 153 35-50 years, N = 257 51-65 years, N = 167Mild regulation in stressfulsituations 48 (31.4%) 113 (44.0%) 85 (50.9%)Moderate regulation in stressfulsituations 53 (34.6%) 85 (33.1%) 46 (27.5%)Severe of regulation in stressfulsituations 52 (34.0%) 59 (22.9%) 36 (21.6%)Table 2: Health indicators in differentage groups according to the health questionnaire PHQ.Parameters/groups 21-34 years, N = 153 35-50 years, N = 257 51-65 years, N = 167Mild somatic symptoms 52 (34.0%) 89 (34.6%) 36 (21.6%)Moderate somatic symptoms 53 (34.6%) 108 (42.1%) 46 (27.5%)Severe somatic symptoms 48 (31.4%) 60 (23.3%) 85 (50.9%)Mild alcohol use 52 (34.0%) 57 (22.2%) 36 (21.6%)Moderate alcohol use 48 (31.4%) 88 (34.2%) 46 (27.5%)Severe alcohol use 53 (34.6%) 112 (43.6%) 85 (50.9%)Mild eating disorders 53 (34.6%) 57 (22.2%) 46 (27.5%)Moderate eating disorders (overeating) 52 (34.0%) 112 (43.6%) 85 (50.9%)Severe eating disorders (overeating) 48 (31.4%) 88 (34.2%) 36 (21.6%)Table 3: The effectiveness of therapy with the synthesized analogue of the endogenous peptide taftcin in the study groups;assessment was performed with the PHQ scale.Symptoms Score Baseline 14 days (end of treatment) 28 days (follow-up)MG CG MG CG MG CGSomatic symptoms Mean score 5.1 ± 1.0 3.6 ± 0.8 1.9 ± 0.6* - 1.2 ± 0.5*/** 3.6 ± 0.8Symptoms prevalence 100% 100% 80% - 73% 100%Nutritional disorders Mean score 2.3 ± 0,8 2.7 ± 0.7 0.1 ± 0.1 - 0.1 ± 0.1*/** 3.4 ± 0.6*Symptoms prevalence 73% 93% 13% - 13% 100%Alcohol consumption Mean score 1.3 ± 0.4 1.3 ± 0.4 0.3 ± 0.1 - 0.3 ± 0.1*/** 1.5 ± 0.4Symptoms prevalence 80% 73% 13% - 13% 80%Notes: *-statisticallysigniicant(p<0.05)comparedtotheinitialstate,**-statisticallysigniicant(p<0.05)comparedtoCG.5
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