Affective Spectrum Disorders and Role of Serotonergic System of The

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168 © The Serbian Medical Society 2014 Review article Hospital Pharmacology. 2014;1(3):168-173 Srdjan Z.Marković A Ivana P. Timotijević A Brain Role ofSerotonergicSystemthe A depressants andalpha2deltaligandsforallkinds of painfulsymptomsina dromes andtheirtreatmentcanimprove. Therapeutic e in a Modern psychopharmacologycannolongerignorethe existenceofpainfulsymptoms are includedinthemechanism. ergic andnoradrenergicpathwaysvoltagesensitive channelsoftheirreceptors emotional stressorscancausepainfulsymptomsinbothgroupsofdisorders.Seroton- pathways, alsoatthelevelofthalamusandsensorycortex,trigeredbyan projections andtheirreceptors.Centralsuprasegmentalsenzitizationinnociceptive the descendinginhibitorypainmechanisms,includingserotonergicandnoradrenergic mechanism oforigin.Hypothesiscentralneuropathicpainexplainsthepossibility depressed mood,anxiety, andfunctionalsomaticsyndromescodeindicateasimilar depressive andanxietydisorders,suchasfatigue,sleepcognitive associated withserotoninandserotonergictransmissionintheCNS. The existenceof symptoms inbothgroups. The symptomsof a tion oftheseCNSstructuresandneurotransmittersystems,whichleadtosimilar along thesamespectrum,duetoasimilarneurobiochemicalmehanismanddysfunc- attitudes thata symptoms arecommoninpatientswithfunctionalsomaticsyndromes. This explains pression andanxiety, andsimilarly, depressedmood,anxietyandotherpsychiatric colon, tensionheadache.Pain asasymptomisoftenpresentinpatientswith de- A SUMMARY 4 3 2 1 A chronic pain,withnopathognomonictissuedamage,suchas functional somaticsyndromesdescribesdisordersinwhichthemainsymptomis Keywords: tion processingandreductionofsymptoms. neurotransmission inspeci disorders -serotonergicspectrumisexpected,dueto theimpactofdysfunctional tonergic system ClinicalCenter of Serbia Sebia, Belgrade, Medical faculty, University Serbia inBelgrade, Special psychiatric ordination Serbia Belgrade, «Ramah», «Euromedik» Policlinics, Medical faculty, University Serbia inBelgrade, ff ective spectrumdisordersincludemoodandanxietydisorders,whereastheterm ff ff ective disorderordepressiveandanxietysymptomsinfunctionalsomaticsyn- ective SpectrumDisordersand E-mail: “Euromedik” Polyclinic, Alekse Nenadovi Professor IvanaP. TIMOTIJEVI Corresponding author: Specialist inpsychiatry, subspecialistinclinicalpharmacology [email protected] a ff ective disorders,chronicpain,extendeda ff ective disordersandfunctionalsomaticsyndromesshouldbefound 3 1 , Dragana A.Kastratović , Mirjana M.Todorović fi cregionsoftheCNS,increasinge Ć , MD,PhD ć a 7,11000Belgrade, Serbia ff ective disorders,includingsomaticare 2 4 , Katarina B. Crnic ff ff ective spectrum,CNSsero- ects ofSSRIandSNRIanti- UDC: 616.89-008.441;616.89 doi:10.5937/hpimj1403168T fi ISSN 2334-9492(Online) bromyalgia, irritable bromyalgia, ffi ciency ofinforma- 2 , ff ective Timotijević IP et al: Aff ective Spectrum Disorders and Role of Serotonergic System of the Brain

INTRODUCTION toms may belong to diff erent organ systems and oft en include a variety of pain syndromes. Aff ective disorders include a wide range of Chronic pain as a symptom of aff ective disor- entities, symptoms and syndromes, which der is a reality which patients face and cope are based on the expression of emotion in the with, while psychopharmacology oft en over- broadest clinical sense. Th e psychological dy- lookes it and is engaged in the so-called ‘’core’’ namics is complex and specifi c to each disor- symptoms or primerily psychic functions dis- der, but a common denominator lies in biohe- orders [4, 5]. mcal - neuro mechanisms, joint structures of In another specifi c group of disorders, the CNS and their receptor - transmitter sys- which are called by generic name functional tems. Biological theories of aff ective disorders somatic syndromes, covering such disorders as in the center of events put limbic structures of fi bromyalgia, chronic fatigue, irritable colon, the brain, with all their connections with other tension and migraine headaches, chronic pain higher and lower structures of the CNS, while is the predominant symptom, in the absence serotonin, serotonergic transmission and sero- of pathognomonic tissue damage. In addition, tonergic system in general, or its dysfunction various psychological symptoms in a large are dominant factors in etiopathogenesis of percentage of cases are present - depression, all aff ective variabilities [1]. Also, the diff erent anxiety, sleep disorders, cognitive disorders. part of the symptomatology of the various en- Problems of proper diagnosis and timely and tities associated with dysfunction in seroton- eff ective treatment are important in this group ergic transmission of any routes that connect of disorders [6]. the parts of the limbic system, as the nuclei amygdala, hypothalamus and the hippocam- CENTRAL NEUROPHATIC PAIN pus, whether it is in pathways which connect TERM limbic system to the prefrontal cortex,basal ganglia, raphe nuclei and other nucleuses in Th ere are more and more experts who explore medulla oblongata,motoneurons in the fron- possible common grounds and reasons for the tal and lateral horns of the spinal cord. By the occurrence of chronic pain syndromes in these same logic, psychopharmacutics acting on se- groups, at fi rst glance the various disorders. It rotonergic transmission in specifi c regions of is assumed that similar neuro mechanism con- the CNS dysfunctional increase the effi ciency nects them, the involvement of the same brain of information processes in their pathways structures and their neurotransmitting system leading to the reduction of symptoms of af- [7]. fective disorders. Common ethiopathogenetic As the pain in both groups of disor- grounds justifyes attitudes about setting up the ders does not appear clearly and defi ned lesion many diff erent symptoms of aff ective disorders tissue or organs, the similarity is established in the same continuum of aff ective spectrum, with neurophatic pain genesis (“phantomic which aligns diagnostic and therapeutic atti- limb”, diabetic neurophaty) in which tissue le- tudes [2, 3]. sion existed and is cured but painful irritations and pain perceptions still exist usually along SOMATIC SYMPTOMS AND with intensive pain and chronifi cacion,as well SYNDROMES as ineffi ciency of usual pain therapy. Th erefore, the theory of central neuropathic pain has been It is generally known that the clinical symptoms accepted as an explanation of the occurrence of aff ective disorders, particularly depression of painful symptoms in aff ective disorders and and anxiety, oft en includes a variety of somatic functional somatic syndromes associated with symptoms, which are oft en not discriminatory psychical symptoms [3]. Mechanism of central according to current diagnostic classifi cations, neuropathic activity is in many ways a theo- although they sometimes dominate the clinical retical process. picture, they are not recognized and discredit the proper diagnosis and treatment. Th ey are CENTRAL SEGMENTAL oft en predictors of theraporesistant forms and SENTISIZATION THEORY the most common are residual symptoms - up to 76% which have the negative impact on One group of theory indicates that is respon- quality of life and social functionality. Symp- sible insuffi ciency of descending inhibitory www.hophonline.org 169 Hospital Pharmacology. 2014; 1(3):168-173

mechanism of pain due to lack of monoam- sumed disorder/damage to brain structures ines and their receptors at the level of the seg- of nociceptive pathways above the level of the ments of the spinal cord and the phenomenon spinal cord and medulla [3, 8]. of sensitization to painful stimuli. Nocicep- It is assumed that the presynaptic tive stimuli from visceral organs, muscles and membrane receptors lead to phosphorylation joints during movement and other irrelevant and permanent opening of sodium and calci- painful stimuli are veiled and imperceptive by um channels - the phenomenon of “gate open”, this mechanism, allowing normal functioning with increased activity of the postsynaptic [3, 7]. Th e descending inhibitory mechanism neurons, when the minimum irritation causes originates and is regulated mainly from the pe- an abundant synaptic transmission. Trigger for riaqueductal gray in medulla oblongata, where this mechanism may in these higher structures he acquired projections of nociceptive path- CNS-thalamus, sensory cortex, come from the ways and limbic structures and fi ring down CNS itself, inside, without the existence of towards the nuclei in the rostral ventromedial stimuli from the periphery. Stress or emotional medulla and from there to the segments of the trauma can be the discriminant irritation in- spinal cord.In some fi bers of the pathway are side, which will establish the sensitization and released endorphins and encephalin that aff ect lead to the experience of pain, which will be the presynaptic opioid receptors and inhibit associated with psychological symptoms. Rela- the transmission with nociceptive aff erent tion of stress and emotion, the limbic part of neurons.Another important mechanism is the the CNS and higher brain structures involved descending inhibitory spinal noradrenergic in pain perception, realized serotonergic pro- path, which begins in locus coeruleus and in- jections from the amygdala to the thalamus, nervates alpha-2 adrenergic receptors. and the amygdala to the raphe nuclei in the Th e next descending inhibitory medulla oblongata, so the possibility of af- mechanism is represented by spinal seroton- fecting various parts of the nociceptive times, ergic pathways, which origines from the raphe transmission and pain perception is important nuclei in the medulla to the postsynaptic 5-HT [2]. 1B and 5-HT1D receptor and blocks the trans- In some studies is confi rmed the im- mission of nociceptive impulses. Serotonergic portance of NMDA glutamate receptors in the mechanism may in certain situations facilitate mediation of transmission nociceptive impuls- and enhance the transmission of painful stim- es through non-myelinated C fi bers and their uli. association with HPA axis. Insuffi ciency of monoamine action and failed descendent inhibition in nocicep- EXTENDED AFFECTIVE tive pathways function leads to the tightening SPECTRUM AND THERAPEUTIC of perception of generally irrelevant nociceptive stimulus from the body, and with extra APPROACH additional mechanism of sensitization to pain, leads to the phenomenon of chronic pain, It is clear that the infl uence of ineffi cient se- where under threshhold irritations cause sig- rotonergic and noradrenergic transmission in nifi cant perception of repetitive or constant certain parts of the CNS in the development of pain.Sensitization of pain involves a complex depressive and anxiety disorders is established and closed-circuit events in the CNS, starting in biological theories of their etiopathogenesis, from certain segments of the spinal cord to while the impact on the development of pain- higher structures in nociceptive path, which ful symptoms within these disorders and func- involves a series of molecular, synaptic and the tional somatic syndromes are still investigat- structural changes and establish the process of ing. However, modern psychopharmacology “learning” painful experience [8]. can no longer ignore their existence and can improve their treatment with drugs, based on the knowledge gained so far. CENTRA SUPRASEGMENTAL Many experts argue that the aff ective SENTISIZATION THEORY spectrum should be extended to functional somatic syndromes, because it would signifi - In addition to the theory of central segmental cantly enhance the capabilities of faster and sensitization, there are theories of supraseg- more effi cient diagnosis and treatment of all mental central sentisization, where it is as- disorders in this continuum in order to achieve

170 Volume 1 • Number 3 • October 2014 • HOPH Timotijević IP et al: Aﬀ ective Spectrum Disorders and Role of Serotonergic System of the Brain complete remission and improved quality of Th e focus of the study include func- life of patients [3]. tional somatic syndromes, such as fi bromyal- From the earlier considered mecha- gia, chronic fatigue syndrome, irritable colon, nisms of the central neuropathic pain origin headaches, wherein the chronic pain is a lead- arise that effi cient medication should mean im- ing symptom, without defi ned lesion tissues or proving disordered transmission in the frame organs, oft en present with a variety of physi- of serotonergic and noradrenergic system, as ological symptoms. Th ey are, as a rule, the well as psychopharmaca with predominant problem of how to diagnose, and treat and sig- infl uence on the function of ionic channel of nifi cantly aff ect the social function of patients. receptor cells. Th e idea of extended aff ective aspect Th erefore, in the fi rst line of treat- of which, in addition to the typical aff ective ment are SNRIs and SSRIs antidepressants and disorders included a functional somatic syn- alpha 2 delta ligands (gabapentin and pregaba- dromes, represent many experts. Th eoretical lin) [9]. assumptions and fi ndings of modern psy- In the second line of treatment are chopharmacology of possible common neu- TCA antidepressants and mirtazapine, which rophysiological basis of pain syndromes and can be used in combination with SSRIs [3,10]. symptoms, with the presence of psychological As additional therapy in the treat- symptoms can signifi cantly improve their bet- ment of certain theraporesistant symptoms ter grasp and treatment. such as fatigue and tiredness, modafi nil may Th eories of central neuropathic pain, be used, bupropion, trazodone in sleep disor- crossing projections from the centers for emo- der, etc [11]. tion and nociceptive pathways at diff erent lev- Th e need for cooperation with other els of the CNS, with serotonergic dysfunction specialists, dose individualization [12] and transmission and noradrenergic neuronal net- comprehensive, multidisciplinary treatment works, which can be trigered by stress or emo- of painful symptoms and syndromes is em- tional trauma, leading to the onset of symp- phasized, any diagnostic category they belong toms are distinguished as key theories. to, just to achieve the previously highlighted In the fi rst line of treatment are pro- goals- complete remission of symptoms and posed SNRIs and SSRIs antidepressants and al- improved quality of life for patients. pha 2 delta ligands, which target just the places Although diagnostic criteria have not of disordered transmission of impulses, in- yet been standardized and treatment estab- crease the effi ciency of information processes lished, therapeutic utilitarian approach and fo- and lead to a reduction of symptoms that are cus of pharmacological actions towards hypo- otherwise refractory to conventional therapy thetically dysfunctional neural networks and approach. their systems, the transmitter can be a useful Openness to new knowledge and and effi cient approach [13]. treatment can improve the results of treatment and quality of life of patients from both groups CONCLUSIONS of disorders.

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172 Volume 1 • Number 3 • October 2014 • HOPH Timotijević IP et al: Aﬀ ective Spectrum Disorders and Role of Serotonergic System of the Brain

Prošireni afektivni spektar i serotonergički sistem CNS A Ivana P. Timotijević1, Mirjana M. Todorović2, Katarina B. Crnic2, Srdjan Z. Marković3, Dragana A. Kastratović4 A 1 «Euromedik» Poliklinika, Medicinski fakultet, Univerzitet u Beogradu, Srbija 2 Specijalistička psihijatrijska ordinacija «Ramah», Beograd, Srbija 3 Medicinski fakultet, Univerzitet u Beogradu, Srbija 4 Klinički centar Srbije, Beograd, Srbija.

KRATAK SADRŽAJ Afektivni spektar uključuje poremećaje raspoloženja i anksiozne poremećaje, dok termin funkcionalni somatski sindromi opisuje poremećaje u kojima je hronični bol vodeći simptom, bez patognomoničnog oštećenja tkiva, kao što su fi bromialgia, iri- tabilni kolon, tenziona glavobolja. Bol kao simptom je često prisutan kod pacijenata sa depresijom i anksioznosti, a slično tome, depresivno raspoloženje, anksioznost i drugi psihički simptomi su uobičajeni kod pacijenata sa funkcionalnim somatskim sindromima. To objašnjava stavove da bi afektivni poremećaji i funkcionalni somatski sindromi trebalo da se nađu duž istog spektra, zbog sličnog neurobiohemijskog mehanizma i disfunkcije istih struktura CNS i neurotransmiterskih sistema, koji dovode do sličnih simptoma u obe grupe. Simptomi afektivnih poremećaja, uključujući i somatske su povezani sa serotoni- nom i serotonergičkom transmisijom u CNS. Postojanje depresivnih i anksioznih poremećaja, kao što su umor, poremećaji spavanja, kognitivne smetnje, depresivno raspoloženje, anksioznost, kod funkcionalnih somatskih sindroma ukazuje na sličan mehanizam nastanka. Hipoteze o centralnom neuropatskom bolu objašnjavaju mogućnost poremećaja descendentnog inhibitornog mehanizma za bol, uključujući serotonergičke i noradrenergičke projekcije i njihove receptore. Centralne supraseg- mentne senzitizacije u nociceptivnim putevima, takođe, na nivou talamusa i senzo- rnog korteksa, pokrenute emotivnim stresorima, mogu uzrokovati bolne simptome u obe grupe poremećaja. Serotonergičke i noradrenergičke neuronske mreže, kao i senzitivni jonski kanali njihovih receptora su uključeni u taj mehanizam. Moderna psihofarmakologija ne može više ignorisati postojanje bolnih simptoma kod afektivnih poremećaja ili depresivne i anksiozne simptome kod funkcionalnih somatskih sindroma i može unaprediti njihov tretman. Terapijsko delovanje SNRI i SSRI antidepresiva i alfa 2 delta liganda za sve vrste bolnih simptoma kod poremećaja afektivnog - serotonergičkog spektra očekivano je, zbog uticaja na disfunkcionalnu neurotransmisiju u specifi čnim regionima CNS, podizanja efi kasnosti informacionih procesa i redukovanja simptoma. Ključne reči: afektivni poremećaji, hronični bol, prošireni afektivni spektar, serotonergički sistem CNS

Received: December 15, 2013 Accepted: February 18, 2014