A ff ective Spectrum Disorders and Role of Serotonergic System of the Brain A

Aff ective Spectrum Disorders and Role of Serotonergic System of the Brain A Ivana P. Timotijević1, Mirjana M. Todorović2, Katarina B. Crnic2, Srdjan Z. Marković3, Dragana A. Kastratović4 A 1 «Euromedik» Policlinics, Medical faculty, University in Belgrade, Serbia 2 Special psychiatric ordination «Ramah», Belgrade, Serbia 3 Medical faculty, University in Belgrade, Serbia 4 Clinical Center of Sebia, Belgrade, Serbia


INTRODUCTION
Aff ective disorders include a wide range of entities, symptoms and syndromes, which are based on the expression of emotion in the broadest clinical sense.Th e psychological dynamics is complex and specifi c to each disorder, but a common denominator lies in biohemcal -neuro mechanisms, joint structures of the CNS and their receptor -transmitter systems.Biological theories of aff ective disorders in the center of events put limbic structures of the brain, with all their connections with other higher and lower structures of the CNS, while serotonin, serotonergic transmission and serotonergic system in general, or its dysfunction are dominant factors in etiopathogenesis of all aff ective variabilities [1].Also, the diff erent part of the symptomatology of the various entities associated with dysfunction in serotonergic transmission of any routes that connect the parts of the limbic system, as the nuclei amygdala, hypothalamus and the hippocampus, whether it is in pathways which connect limbic system to the prefrontal cortex,basal ganglia, raphe nuclei and other nucleuses in medulla oblongata,motoneurons in the frontal and lateral horns of the spinal cord.By the same logic, psychopharmacutics acting on serotonergic transmission in specifi c regions of the CNS dysfunctional increase the effi ciency of information processes in their pathways leading to the reduction of symptoms of affective disorders.Common ethiopathogenetic grounds justifyes attitudes about setting up the many diff erent symptoms of aff ective disorders in the same continuum of aff ective spectrum, which aligns diagnostic and therapeutic attitudes [2,3].

SOMATIC SYMPTOMS AND SYNDROMES
It is generally known that the clinical symptoms of aff ective disorders, particularly depression and anxiety, oft en includes a variety of somatic symptoms, which are oft en not discriminatory according to current diagnostic classifi cations, although they sometimes dominate the clinical picture, they are not recognized and discredit the proper diagnosis and treatment.Th ey are oft en predictors of theraporesistant forms and the most common are residual symptoms -up to 76% which have the negative impact on quality of life and social functionality.Symp-toms may belong to diff erent organ systems and oft en include a variety of pain syndromes.Chronic pain as a symptom of aff ective disorder is a reality which patients face and cope with, while psychopharmacology oft en overlookes it and is engaged in the so-called '' core'' symptoms or primerily psychic functions disorders [4,5].
In another specifi c group of disorders, which are called by generic name functional somatic syndromes, covering such disorders as fi bromyalgia, chronic fatigue, irritable colon, tension and migraine headaches, chronic pain is the predominant symptom, in the absence of pathognomonic tissue damage.In addition, various psychological symptoms in a large percentage of cases are present -depression, anxiety, sleep disorders, cognitive disorders.Problems of proper diagnosis and timely and eff ective treatment are important in this group of disorders [6].

CENTRAL NEUROPHATIC PAIN TERM
Th ere are more and more experts who explore possible common grounds and reasons for the occurrence of chronic pain syndromes in these groups, at fi rst glance the various disorders.It is assumed that similar neuro mechanism connects them, the involvement of the same brain structures and their neurotransmitting system [7].
As the pain in both groups of disorders does not appear clearly and defi ned lesion tissue or organs, the similarity is established with neurophatic pain genesis ("phantomic limb", diabetic neurophaty) in which tissue lesion existed and is cured but painful irritations and pain perceptions still exist usually along with intensive pain and chronifi cacion,as well as ineffi ciency of usual pain therapy.Th erefore, the theory of central neuropathic pain has been accepted as an explanation of the occurrence of painful symptoms in aff ective disorders and functional somatic syndromes associated with psychical symptoms [3].Mechanism of central neuropathic activity is in many ways a theoretical process.mechanism of pain due to lack of monoamines and their receptors at the level of the segments of the spinal cord and the phenomenon of sensitization to painful stimuli.Nociceptive stimuli from visceral organs, muscles and joints during movement and other irrelevant painful stimuli are veiled and imperceptive by this mechanism, allowing normal functioning [3,7].Th e descending inhibitory mechanism originates and is regulated mainly from the periaqueductal gray in medulla oblongata, where he acquired projections of nociceptive pathways and limbic structures and fi ring down towards the nuclei in the rostral ventromedial medulla and from there to the segments of the spinal cord.In some fi bers of the pathway are released endorphins and encephalin that aff ect the presynaptic opioid receptors and inhibit the transmission with nociceptive aff erent neurons.Another important mechanism is the descending inhibitory spinal noradrenergic path, which begins in locus coeruleus and innervates alpha-2 adrenergic receptors.
Th e next descending inhibitory mechanism is represented by spinal serotonergic pathways, which origines from the raphe nuclei in the medulla to the postsynaptic 5-HT 1B and 5-HT1D receptor and blocks the transmission of nociceptive impulses.Serotonergic mechanism may in certain situations facilitate and enhance the transmission of painful stimuli.
Insuffi ciency of monoamine action and failed descendent inhibition in nociceptive pathways function leads to the tightening of perception of generally irrelevant nociceptive stimulus from the body, and with extra additional mechanism of sensitization to pain, leads to the phenomenon of chronic pain, where under threshhold irritations cause signifi cant perception of repetitive or constant pain.Sensitization of pain involves a complex and closed-circuit events in the CNS, starting from certain segments of the spinal cord to higher structures in nociceptive path, which involves a series of molecular, synaptic and the structural changes and establish the process of "learning" painful experience [8].

CENTRA SUPRASEGMENTAL SENTISIZATION THEORY
In addition to the theory of central segmental sensitization, there are theories of suprasegmental central sentisization, where it is as-sumed disorder/damage to brain structures of nociceptive pathways above the level of the spinal cord and medulla [3,8].
It is assumed that the presynaptic membrane receptors lead to phosphorylation and permanent opening of sodium and calcium channels -the phenomenon of "gate open", with increased activity of the postsynaptic neurons, when the minimum irritation causes an abundant synaptic transmission.Trigger for this mechanism may in these higher structures CNS-thalamus, sensory cortex, come from the CNS itself, inside, without the existence of stimuli from the periphery.Stress or emotional trauma can be the discriminant irritation inside, which will establish the sensitization and lead to the experience of pain, which will be associated with psychological symptoms.Relation of stress and emotion, the limbic part of the CNS and higher brain structures involved in pain perception, realized serotonergic projections from the amygdala to the thalamus, and the amygdala to the raphe nuclei in the medulla oblongata, so the possibility of affecting various parts of the nociceptive times, transmission and pain perception is important [2].
In some studies is confi rmed the importance of NMDA glutamate receptors in the mediation of transmission nociceptive impulses through non-myelinated C fi bers and their association with HPA axis.

EXTENDED AFFECTIVE SPECTRUM AND THERAPEUTIC APPROACH
It is clear that the infl uence of ineffi cient serotonergic and noradrenergic transmission in certain parts of the CNS in the development of depressive and anxiety disorders is established in biological theories of their etiopathogenesis, while the impact on the development of painful symptoms within these disorders and functional somatic syndromes are still investigating.However, modern psychopharmacology can no longer ignore their existence and can improve their treatment with drugs, based on the knowledge gained so far.
Many experts argue that the aff ective spectrum should be extended to functional somatic syndromes, because it would significantly enhance the capabilities of faster and more effi cient diagnosis and treatment of all disorders in this continuum in order to achieve complete remission and improved quality of life of patients [3].
From the earlier considered mechanisms of the central neuropathic pain origin arise that effi cient medication should mean improving disordered transmission in the frame of serotonergic and noradrenergic system, as well as psychopharmaca with predominant infl uence on the function of ionic channel of receptor cells.
Th erefore, in the fi rst line of treatment are SNRIs and SSRIs antidepressants and alpha 2 delta ligands (gabapentin and pregabalin) [9].
In the second line of treatment are TCA antidepressants and mirtazapine, which can be used in combination with SSRIs [3,10].
As additional therapy in the treatment of certain theraporesistant symptoms such as fatigue and tiredness, modafi nil may be used, bupropion, trazodone in sleep disorder, etc [11].
Th e need for cooperation with other specialists, dose individualization [12] and comprehensive, multidisciplinary treatment of painful symptoms and syndromes is emphasized, any diagnostic category they belong to, just to achieve the previously highlighted goals-complete remission of symptoms and improved quality of life for patients.
Although diagnostic criteria have not yet been standardized and treatment established, therapeutic utilitarian approach and focus of pharmacological actions towards hypothetically dysfunctional neural networks and their systems, the transmitter can be a useful and effi cient approach [13].

CONCLUSIONS
Disorders of aff ective spectrum are well known and thoroughly studied in the light of the biological theory of their etiopathogenesis.Dysfunction of specifi c brain regions and disrupted transmission in complex neuronal circuits that connect them, are the cause of many symptoms along the continuum of the spectrum.Although they are not discriminatory for diagnosis, diff erent somatic symptoms, and among them painful symptoms of various organs are common in clinical aff ective disorders.Th ey complicate the process of disease, compromising the achievement of complete remission and in many cases they cause thraporesistance.
Th e focus of the study include functional somatic syndromes, such as fi bromyalgia, chronic fatigue syndrome, irritable colon, headaches, wherein the chronic pain is a leading symptom, without defi ned lesion tissues or organs, oft en present with a variety of physiological symptoms.Th ey are, as a rule, the problem of how to diagnose, and treat and signifi cantly aff ect the social function of patients.
Th e idea of extended aff ective aspect of which, in addition to the typical aff ective disorders included a functional somatic syndromes, represent many experts.Th eoretical assumptions and fi ndings of modern psychopharmacology of possible common neurophysiological basis of pain syndromes and symptoms, with the presence of psychological symptoms can signifi cantly improve their better grasp and treatment.
Th eories of central neuropathic pain, crossing projections from the centers for emotion and nociceptive pathways at diff erent levels of the CNS, with serotonergic dysfunction transmission and noradrenergic neuronal networks, which can be trigered by stress or emotional trauma, leading to the onset of symptoms are distinguished as key theories.
In the fi rst line of treatment are proposed SNRIs and SSRIs antidepressants and alpha 2 delta ligands, which target just the places of disordered transmission of impulses, increase the effi ciency of information processes and lead to a reduction of symptoms that are otherwise refractory to conventional therapy approach.
Openness to new knowledge and treatment can improve the results of treatment and quality of life of patients from both groups of disorders.