Galore International Journal of Health Sciences and Research Vol.4; Issue: 1; Jan.-March 2019 Website: www.gijhsr.com Review Article P-ISSN: 2456-9321

Negative Symptoms- an Update

Dr Pavithra P. Rao1, Dr Preethi Rebello2, Dr P. John Mathai3

1Assistant Professor, Department of Psychiatry. Father Muller Medical College, Mangalore, Karnataka, India. 2Senior Resident, Department of Psychiatry, Father Muller Medical College, Mangalore, Karnataka, India. 3Professor. Department of Psychiatry, Jubilee Mission Medical College, East Fort Thrissur. Kerala. India.

Corresponding Author: Dr P. John Mathai

ABSTRACT INTRODUCTION Negative symptoms (NS) are Negative Symptoms in psychiatry are deficits in abnormal absence of normal behaviour and experience and behavior that are attributed to experience, attributed to the loss of normal loss of functions of brain. Negative symptoms functions of the brain. The NS are defined have been conceptualized as the core aspect of as absence of experience/behaviour that and have been recognized as [1] important ever since the days of Griesinger, should have been present. They are Kraepelin and Bleuler. But over the years the general descriptive terms used for the significance of the negative symptoms was various clinical manifestations of the deleted and emphasis was placed almost diminished capacity for ordinary exclusively on positive symptoms. The return of behavioural functioning (behavioural negative symptoms in schizophrenia was deficits). [2] Though there are differences in inevitable. The five general categories of the language used to refer to NS such as, negative symptoms include avolition, deficits symptoms, defect state symptoms, , affective blunting, alogia and type II symptoms, core symptoms, asociality. The subdomains of negative fundamental symptoms, primary symptoms symptoms are experience domain (avolition and and basic symptoms, there are definite anhedonia) and expressivity domain (affective [3-7] blunting and alogia). consensus about its clinical significance. In this review article the authors discuss the The NS are important in the diagnosis, evolution of the concept, the current prognosis as well as in understanding the [4,7] conceptualization, consensus general categories neurobiology of schizophrenia. The NS and subdomains of negative symptoms, the and the cognitive deficits are considered as relationships to symptoms of other domains, the core aspects of schizophrenia. [3-7] In negative symptoms in the different phases of ICD-10 and DSM5 the NS are neither schizophrenia, Primary Enduring Negative necessary nor sufficient for diagnosis of Symptoms (PENS) and Persistent Negative schizophrenia. The primary enduring NS Symptom (PNS), the nonspecific, specific and (PENS) and the persistent NS(PNS) predict new generation scales for assessment. The poor outcome in patients with clinical importance of negative symptoms in terms of diagnosis, prognosis and treatment schizophrenia. The concept of NS options, the impact on comprehension of challenged the then existent frontiers and neurobiology of schizophrenia and the resultant concepts of schizophrenia. This paved way modifications in clinical and etiological models for researchers to develop new models of of schizophrenia are discussed. Further the schizophrenia and new biological and authors briefly discuss negative symptoms in neurological explanations for schizophrenia. other psychiatric disorders. The concept of NS was reintroduced to

psychiatry in 1974. [2] Since early 1980’s Keywords: Negative Symptoms, Deficits, Core there has been a rekindled interest in NS of Schizophrenia, Category, Sub-domain. among schizophrenia researchers. [3-7] This renewed interest resulted in the

Galore International Journal of Health Sciences and Research (www.gijhsr.com) 162 Vol.4; Issue: 1; January-March 2019 Pavithra P. Rao et.al. Negative Symptoms- an Update development of competing concepts, acceptance of Schneider’s FRS as soon as it assessment methods, biological and was published. First Rank Symptoms neurological models and new treatment consist of exclusively positive symptoms options for schizophrenia. [3,7] and they became so popular that most of the diagnostic criteria for schizophrenia were EVOLUTION OF THE CONCEPT based exclusively on the presence of the Recognizable descriptions of the NS FRS until recently. The reasons for the of schizophrenia can be found as early as neglect of the NS described as core features the mid-1800s, with Griesinger’s by Kraepelin and Bleulermay include the descriptions of an “absence of following; the florid expression and will,” followed by Kraepelin’s description manifestations of the positive symptoms, the of a “weakening of volition” among some dramatic response of positive symptoms to people with schizophrenia. Since Emil dopamine receptor antagonists, the fact that Kraepelin and EugenBleuler consolidated it is easier to define, assess and document the concepts of praecox and positive symptoms compared to the NS and schizophrenia, it has been recognized that the universal popularity of the FRS. In the disorders are heterogeneous. Clinicians addition to the views of Kraepelin and and investigators had struggled to find out Bleuler, the concept of the core symptoms of schizophrenia. NS ‘Institutionalization’(Wing 1970) and were given a more prominent place in the Barton’s Neurosis(Institutional Neurosis) earlier concepts of schizophrenia. Emil were major influences in support of NS. [5-7] Kraepelin in his writings on dementia The return of NS in schizophrenia was praecox described the ‘avolition syndrome’ inevitable because of their universal as characteristic of the disorder. Emotional presence and endurance and the fact that the dullness, loss of inner sympathy, loss of positive symptoms failed to explain chronic interest, loss of motivation, loss of goal state, deterioration, residual phase, disability directed movements and deterioration were and treatment refractoriness. [3] described as core aspects of dementia It is generally held that John praecox. EugenBleuler described emotional Hughlings Jackson introduced the negative deterioration as characteristic of and positive symptom concept to neurology schizophrenia. He recognized that the (1875, 1889). This was done based on his fundamental symptoms (primary symptoms) complex hierarchical organization theory of were more important for diagnosis of the brain. Berrios (1985) in his historical schizophrenia than delusions and review remarks that it was in fact John hallucinations. The primary symptoms Russell Reynolds (1857) who introduced the (4As) have very strong resemblance to the NS to neurology. [8] Reynolds’s concept of current NS. [3,7] Kurt Schneider described NS was not based on any theory as such. It emotional withdrawal and lack of empathy is generally believed that the NS were as characteristic features of schizophrenia. reintroduced to psychiatry by Strauss and But he did not include such symptoms in his Carpenter (1974). HoweverBerrios mentions First Rank Symptoms. that it was De Clerambault (1942) who Both Kraepelin and Bleuler introduced the concept to psychiatry and considered NS as fundamental or core Crow remarks that it was introduced to psychopathology of schizophrenia. But over psychiatry by Snezhenesky(1968). [8] It is the years the significance of the NS was generally accepted that the reintroduction of brought down and emphasis was placed NS and the initial semantic work was done almost exclusively on positive symptoms by Strauss et al (1974), the empirical like delusions, hallucinations, formal research was kicked off by Crow(1980) and thought disorders and catatonic symptoms. the initial codification was completed by This fact is evidenced by the universal Andreasen (1981, 1982). [1-4,9] Mathai and

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Gopinath introduced NS to psychiatric depression or neuroleptic medication are the research in India during 1982-84. [3,6,7,10] ICD-10 NS of schizophrenia. The DSM 5 CURRENT CONCEPTULIZATION includes diminished emotional response and Most of the current investigators have used avolition as characteristic NS of the concept of NS to refer to the reduction schizophrenia.To reduce the differences in or loss of normal functions. The current this area the consensus conference of concept is descriptive, not based on theories experts on NS held in the NIMH in 2005 and does not imply neurobiology or described five general categories of NS. relationship to other symptoms. Hence it They are Avolition, Anhedonia, Affective could be argued that the current concept is Blunting, Asociality and Alogia. [15] more Reynoldian than Jacksonian. The NS Avolition and Anhedonia are the most include pertaining to common NS. During the conference the two affective, cognitive, volitional and social possible subdomains within the NS were behaviour domains of the higher functions discussed and agreed upon by the experts. of the brain. They indicate the loss of [16] emotional experience, conceptual fluency, Five General Categories of NS the experience of pleasure, volition and Avolition means loss of will or [3] ability for interpersonal relationship. drive. The term may be considered as There is no unanimity on the number, having almost similar meaning to abulia in category and components of NS. The list of neurology. Avolition and are closely NS given in Scale for Assessment of related concepts. Avolition is deficit in NS(SANS), Positive And Negative ability to act whereas apathy is the lack of Syndrome Scale(PANS), Schedule for the concern for an idea or task. Avolition is the Deficit Syndrome(SDS),ICD-10 and DSM 5 inability to initiate and persist in goal are more or less similar, but not exactly the directed activities. When severe enough to same. As a matter of fact some of the be considered pathological, avolition is components in SANS and PANS are pervasive and prevents the person from positive symptoms. The NS in SANS completing many different types of include affective blunting/ flattening, alogia, activities (examples: work, intellectual avolition, apathy, anhedonia, asociality and pursuits and self-care). [17] attention impairment (seven As). [9,10] Anhedonia specifically refers to a Apathy and attention impairment are not loss of ability to experience joy and accepted by other researchers as NS. pleasure, a deficiency which is pervasive. Blunted affect, emotional withdrawal, poor [18] Anhedonia is the loss of ability to find or rapport, passive/ apathetic social derive pleasure out of activities or withdrawal, difficulty in abstract thinking, relationships. It is manifested as pervasive lack of spontaneous flow of conversation loss of interest and pleasure. It is reported as and stereotyped thinking are the NS in the most persistent of NS in schizophrenia. PANS. But difficulty in abstract thinking According to DSM 5 anhedonia is lack of and stereotyped thinking are considered as enjoyment from, engagement in or energy positive symptoms by other investigators. for life’s experiences; deficits in the [11] Restricted affect, diminished emotional capacity to feel pleasure and take interest in range, poverty of , curbing of things. Anhedonia is a facet of the broad interest, diminished sense of purpose and personality trait domain detachment. [17] diminished social drive are the NS in SDS. Anhedonia is one of the most characteristic [12-14] Marked apathy, paucity of speech and diagnostic criteria for depressive disorder in blunting/ incongruity of emotional both ICD-10 and DSM5. Anhedonia is also responses usually resulting in social described in schizophrenia. Deconstructed withdrawal and lowering of social into its component parts, the anhedonia in performance and not attributable to schizophrenia is reported to be

Galore International Journal of Health Sciences and Research (www.gijhsr.com) 164 Vol.4; Issue: 1; January-March 2019 Pavithra P. Rao et.al. Negative Symptoms- an Update disproportionately more conspicuous in alogia) and the experience domain anticipatory hedonic experience deficit and (avolition and anhedonia). The expressivity social specific hedonic deficits. [18] subdomain has strong correlation with Affective Blunting is Inability to asociality. It is postulated that these two understand and recognize displays of subdomains are possibly connected to two emotion from others and an inability to different areas in the brain and have express emotion. It is manifested with different circuits. [16] But the significance of significant reduction in intensity of affect the two domains has no clear cut reported and consequent reduction in range and research evidences to date. reactivity of affect. There may be deficits in Classification of NS tone of voice, facial expressions, gestures, The NS are classified into different prosody and understanding the social groups: Primary and Secondary, Enduring signals. Affective Flattening is a more and Non enduring, Persistent and Non severe degree of blunting manifested with persistent, Deficit and Transitory and Type unresponsive and immobile face, poor eye A and Type B. A working classification for to eye contact and reduced body language. clinical use is offered by Greden and Blunted affect is significant reduction in the Tandon. [3] According to this classification intensity of emotional expression in DSM5. the NS are classified mainly into the Asociality is the passive or apathetic Enduring and the Non enduring symptoms. social withdrawal manifested with Both are further classified as Primary and indifference to social relationships, decrease Secondary. Primary Enduring Negative in drive to socialize, decrease in sexual Symptoms (PENS) have been reported to be desire and interest and inability to feel the core of schizophrenia that would predict intimacy and closeness. According to DSM poor outcome and treatment failure. They 5 asociality is reduction in initiative for are persistent, stable, non-responsive to interacting with other people. drugs and psychosocial methods of Alogia includes loss of production of treatment, and are responsible for the deficit thinking (negative ) and state. [14,19-21] deficits in content with normal volume of The NS were initially classified into words. It is manifested as decrease in verbal Primary and Secondary Negative Symptoms communication, increased latency to by Carpenter. [12,14] Primary NS are integral response, short verbal responses, paucity or aspect of schizophrenia and not caused by complete lack of spontaneous speech and other psychopathology or medicines or brief, laconic, empty replies. According to environmental factors. Primary NS manifest DSM 5 alogia is an impoverishment in more commonly in the prodromal and thinking that is inferred from observing residual phases of schizophrenia. They have speech and language behavior. There may no significant correlation to positive be brief and concrete replies to questions symptoms, cognitive deficits or the and restriction in the amount of spontaneous depressive symptoms. They have significant speech (termed poverty of speech). positive correlation with severity, poor Sometimes the speech is adequate in amount outcome and poor response to antipsychotic but conveys little information because it is medication. The secondary NS are on the over concrete, over abstract, repetitive or other hand believed to be caused by stereotyped (termed poverty of content). [17] antipsychotic adverse effects, depression, Subdomains of NS demoralization, psychotic process, Subsequent to the description of the general environmental deprivation and chronic categories of NS the two subdomains effects of the disorder. The primary/ werereported by Blanchard and Cohen and secondary distinction has been disputed of Kirkpatrick and Fischer in 2006. They are late because we have no research evidences the expressivity domain (blunted affect and to support the same. The akinetic extra

Galore International Journal of Health Sciences and Research (www.gijhsr.com) 165 Vol.4; Issue: 1; January-March 2019 Pavithra P. Rao et.al. Negative Symptoms- an Update pyramidal symptoms and the depressive evaluation of the NS. However, the NS have symptoms both of which are common in no significant correlation to depressive schizophrenia could very well be integral symptoms or cognitive impairments. The aspects of the disorder like the positive and NS have no definite relationship with NS rather than the causes for NS. The positive symptoms. Among the positive phenomenological characteristics of primary symptoms formal thought disorders are and secondary NS are one and the same and reported to have the best relation to NS. they are indistinguishable. The distinction is However the negative and positive currently made entirely by clinical judgment symptoms are reported to co-vary or statistical computation based on the particularly in the active phase of association with sources of causative schizophrenia. In general the NS have no factors. [19,20] Persistent Negative Symptoms significant correlation to the cognitive (PNS)a concept introduced by Buchanan is impairment. Cross-sectional correlation perhaps better for clinical trials than PENS. between NS and cognitive impairment is not [14, 21] The PNS is larger than PENS. It is a statistically insignificant [3,5-7,15,22-27] But broader concept and includes both primary there are reports regarding significant and secondary NS that persist despite correlation of NS to cognitive impairment in treatment. PNS at the same time is less some of the longitudinal investigations heterogeneous than the general concept of [23,25,26] Being the core dimensions of NS. PNS is operationally defined for schizophrenia the relationship between NS research in terms of moderate severity, and cognitive deficits is of immense defined threshold of positive symptoms, importance. Four theoretical models are absence of or low depressive symptoms, proposed to understand the relationship absence or low extrapyramidal symptoms between them. [26] First model indicates that and demonstrated clinical stability for an NS and cognitive deficits are overlapping extended period of time prior to trial ( for at single dimension of symptoms produced by least 6 months). [21] same etiology (one etiology produces Relationships to other Symptoms of negative cognitive dimension). According to Schizophrenia second model same etiology produces the Schizophrenia is more than two distinct dimensions of symptoms (one . The positive symptoms etiology produces negative dimension and (delusions, hallucinations, formal thought cognitive dimension of symptoms). disorders and catatonia), the NS, the mood According to the third model there are two symptoms (depressive symptoms and manic separable but related etiologies each one of symptoms) and cognitive impairments are them causing two related but distinct all described as symptoms of schizophrenia. dimensions of symptoms(etiology one The symptoms of schizophrenia are not produces both dimensions and another necessarily unique to schizophrenia. The related second etiology also produces both brain circuits and the neurotransmitter tracts dimensions of symptoms). Fourth model are different for the different dimensions of indicates that NS and positive symptoms are the clinical manifestations in schizophrenia. independent dimensions but are related [22] The negative, positive, depressive and either due to overlapping measurements or cognitive symptoms are probably different definition or due to shared correlation with aspects of schizophrenia. There are overlaps distal measures(etiology one and etiology between NS and cognitive and depressive two produces overlapping but distinct symptoms. Such overlaps could be negative and cognitive dimensions of attributed to the problems related to symptoms). German investigators do not conceptual clarity and the degree of tend to agree that the so called ‘basic interference of coexistent other dimensions symptoms’ are synonymous to’ NS’. It has of symptoms in the accurate assessment and been reported that the ‘basic symptoms’ are

Galore International Journal of Health Sciences and Research (www.gijhsr.com) 166 Vol.4; Issue: 1; January-March 2019 Pavithra P. Rao et.al. Negative Symptoms- an Update in fact the core of schizophrenia and they ASSESSMENTOF NS manifest subsequently as NS and cognitive Although the NS are the core features or the symptoms. fundamental symptoms of schizophrenia The validity of the concept of NS is they are not well defined and unambiguous. not well established. Blanchard and Cohen They are difficult to be measured properly. examined the structural validity of NS in But due to the increasing interest in the NS terms of whether NS represent a domain and related dichotomy of schizophrenia, a separate from other symptoms of good number of scales are proposed to rate schizophrenia and whether there are and identify the NS. Today we have a structural multiple dimensions within the reasonably large list of assessment tools for NS. In their review of exploratory and NS with different definitions, methods and confirmatory factor analytic studies the concepts (Table-I). [1-3,5-7,15,29] There are two authors report that the NS appear to broad categories of rating scales, the scales consistently emerge as separate from which are not specific for NS assessment positive symptoms, affective symptoms and and the scales which are specific. There are symptoms of disorganization. Factor various basic problems in the assessment of analytic studies suggest that the NS the NS. First of all the NS represent the construct is multidimensional; involving at absence of behaviour or function and we least two dimensions (diminished have to rate the ‘absence’. We do not have expression and anhedonia-asociality). The the exact agreement on the components of later suggestion is not conclusive in view of the NS. The relative importance assigned to the serious limitations of the studies each component of the NS remains ill reviewed. [28] defined. We require multiple sources of NS and Phases of Schizophrenia information for rating NS. All these Although considered the hallmarks problems are compounded by the ambiguity of chronic state, the NS as a matter of fact and the uncertain validity of the concept. are manifest in all phases of schizophrenia. The complexity of the concept calls for [3,6,7,12,15,27,29] In the prodromal phase the NS operational definitions. Before the characteristically occur along with pre- introduction of the specific scales for NS, psychotic behaviour and social role deficits. the non-specific scales such as Wing’s They are present in the early phase of Rating Scale, Manchester Scale, BPRS and schizophrenia along with or without positive CPRS were used in research. The non- symptoms. During the active phase of specific scales are sensitive to change. schizophrenia they apparently tend to co- Currently SANS, PANS and SDS are the vary especially with treatment related most widely used scales for NS. [3,6,7,9,11-13] remission and relapse. The NS are more The specific scales have relative similarities, likely to become more prominent in the later differences and distinctions. The NS are phase of the disorder after remission of the better defined in the specific scales. By and positive symptoms. NS are likely to persist large their reliability and internal and to provide the substrate upon which consistency are established. But their socio occupational deterioration develop validity remains uncertain. The specific and progress. [3,12,15, 23, 24, 27] The prevalence scales for NS are not sensitive to change of NS reported in the prodromal stage is as although they are extensively used for high as 73%. NS is reported to occur in 15% RCTs. To overcome some of the during the first episode of schizophrenia and shortcomings of the commonly used scales 25 – 30% in patients with chronic three new generation scales for assessment schizophrenia. During residual phase 75 % of NS are introduced recently (NSA-4, BNS of patients with schizophrenia have manifest and CAINS). [30-34] avolition and apathy and 71% have anhedonia-asociality. [3,5-7,15, 23,24]

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TABLE-I. SCALES FOR ASSESSMENT OF NEGATIVE SYMPTOMS Name of Scales Authors Year Non Specific Rating Scales Wing Rating Scale (WRS) Wing et al 1961 Brief Psychiatric Rating Scale (BPRS) Overall and Gorham 1962 Krawiecka Manchester Scale (KMS) Krawieka et al 1977 Comprehensive Psychopathology Rating Scale (CPRS) Asberg et al 1978 Schedule for Affective Disorders and Schizophrenia. SADS. Endicott and Spitzer 1978 Specific Subjective Rating Scal Subjective Deficit Syndrome Scale (SDSS) Petho and Bitter 1985 Subjective Experience of Deficit Scale (SEDS) Liddle and Barnes 1988 Specific Objective Rating Scales Scale for Emotional Blunting (SEB) Abrams and Taylor 1978 Scale for Assessment for Negative Symptoms (SANS) Andreasen. NC. 1981 Negative Symptom Scale- LFM. (NSS-LFM) Lewine, Fogg& Meltzer 1983 Negative Symptom Scale- PGH. (NSS-PGH) Pogue-Geile& Harrow 1984 Negative Symptom Rating Scale (NSRS) Iager et al 1985 Bonn Scale for Assessment of Basic symptoms (BSABS) Gross et al 1987 Positive And Negative Symptom Scale (PANSS) Kay et al 1987 Schedule for Deficit Syndrome (SDS) Carpenter et al 1988 Negative Symptom Assessment Scale (NSA-26) Alphs et al 1989 Negative Symptom Assessment Scale (NSA-16). Axelrod etal 1993 Motor Affective Social Scale (MASS) Tremeau et al 2008 Brief Negative Symptom Scale (BNSS) Kirkpatrick et al 2010 Negative Symptom Assessment Scale (NSA-4) Alphs et al 2011 Clinical Assessment Interview for NS (CAINS) Blanchard J J et al 2011

The authors hold the view that the NIMH 6. Structure of the Scale for the Assessment MATRICS Consensus Statement on NS of NS (SANS) is preferred to that of the highlights the current concepts about NS. Positive and Negative Syndrome [25] Briefly the following are the areas of Scale(PANS). However, the PANS, agreement among the experts. SANS, and perhaps other assessment 1. NS constitute a distinct therapeutic approaches are appropriate for indication area in schizophrenia. application in current clinical trials. 2. NS and cognitive impairment represent 7. Persistent and clinically significant NS different domain. The areas of are an unmet therapeutic need for a large interaction and overlap could be defined proportion of patients with in future. Current documented available schizophrenia. data indicate substantial distinction 8. Within NS definition of a clinically between NS and cognitive impairment meaningful effect size needs further in schizophrenia. review. 3. NS have face validity as disorder 9. Length of clinical trial will vary with the manifestations and they represent loss or purpose of the trial. Proof of concept diminution of normal functions. study may be brief. The preliminary 4. The domains of NS include blunted efficacy studies may be 4-6 weeks. affect, alogia, asociality, anhedonia, and Registration studies are likely to be avolition. There are substantial substantially longer (in the range of 6 correlations across these domains, but months) in order to document persistent they may have separate neurobiological efficacy. substrates and may represent separate 10. Paradigmatic design for clinical trials of therapeutic targets. The structure of persistent NS would include clinically relationships among these domains and stable patients whose NS persist with their predictive validity require further adequate antipsychotic drug treatment. study. This would be a double-blind, placebo- 5. Distinction between primary and controlled comparison of parallel secondary NS is not essential for groups, in which the putative NS research on treatment for NS in treatment is administered as a co- schizophrenia. medication with a second-generation

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antipsychotic. blunting and alogia are significantly more 11. Paradigmatic design for a co- common in schizophrenia and they are most administered drug is less satisfactory characteristic of the disorder. We have when testing a broad spectrum reported from India that the NS are integral antipsychotic agent, that is, one that may part of schizophrenia and that they are have superior efficacy for both positive independent of the environment and medical and NS. and psychosocial treatment received by the The experts also agreed on the following patient. [6,7] We have also reported that the recommendations. The development of a NS in SANS could not distinguish new instrument that includes the five schizophrenia from depressive disorder. It is agreed-upon domains would advance work recently reported that the finer aspects of the in this area. Such an instrument needs to be phenomena of anhedonia, avolition and applicable in both in-patient and outpatient asociality and subjective awareness of NS clinical trials and needs to be sensitive to are possibly different in schizophrenia and change. There is need to establish a major depressive episodes. [18,36-39] framework to promote the identification and The diagnostic potential of NS is testing of drugs for a NS indication. It is recognized and the major current diagnostic likely that this process would be similar to systems include them in their criteria for the MATRICS process for drug discovery diagnosis of schizophrenia. [3,40] In both for the treatment of cognitive impairment in ICD-10 and DSM 5 the NS are given schizophrenia. [25] importance. They are included under CLINICAL IMPORTANCE characteristic symptoms for diagnosis. The The NS have clinical importance in NS when manifest alone is insufficient to the diagnosis, prognosis and treatment of make a diagnosis of schizophrenia. They are schizophrenia as well as in understanding not necessary to make a diagnosis. In ICD- the biology of schizophrenia. The presence 10 the NS belong to one of the nine groups of NS and their importance in other of characteristic symptoms of psychiatric disorders like depressive schizophrenia. They do not belong to the disorder, and schizotypal first four groups that are given most disorder are recognized. significance for diagnosis of schizophrenia. Diagnosis of Schizophrenia In DSM 5 the NS are one among the five The NS are not pathognomonic of groups of characteristic symptoms of schizophrenia and are not exclusive to schizophrenia. They are not among the most schizophrenia. They are reported to be significant symptoms for diagnosis. DSM present in other disorders and states. They IV TR included alternative dimensional are manifest in other psychiatric disorders, models of schizophrenia (negative medical disorders and other conditions. dimension) under criteria sets and axes [15,24,27,35,36] NS are reported to occur in provided for further study. Such Schizophrenia, Depressive Disorder, dimensional models are discarded in DSM 5 Organic Mental Disorders(Dementia), due to lack of research evidences. [17] Anxiety disorders(Obsessive Compulsive Whether NS are given the due importance Disorder), Schizotypal Disorder, Personality that they deserve in the diagnosis of Disorder (Schizoid and Anankastic PD), schizophrenia in ICD 10 and DSM 5 is an Bipolar Mood Disorder, Schizoaffective arguable issue. [40] On the contrary Disorder, Neuroleptic Induced Deficit anhedonia is given due importance in the Syndrome, Parkinson’s , Basal diagnosis of depressive disorders in ICD-10 Ganglia , Frontal Lobe Syndromes, and DSM 5. Diabetes Mellitus, Prisoners, Prognosis of Schizophrenia Institutionalization and in Healthy Clinical experience and research Individuals. Pervasive avolition, affective evidences suggest that the NS are by and

Galore International Journal of Health Sciences and Research (www.gijhsr.com) 169 Vol.4; Issue: 1; January-March 2019 Pavithra P. Rao et.al. Negative Symptoms- an Update large associated with socio occupational associated with NS. [41,46] With over 25 deterioration and interpersonal deficits. The years of clinical experience involving SGA, NS are accepted as one of the predictors of there have been further setbacks in our poor prognosis in schizophrenia. Although thinking. Initial enthusiasm regarding the research data is insufficient to draw definite clinical benefits of SGAs over FGAs for conclusions due to methodological symptoms beyond psychosis has been limitations, it is universally accepted in eroded considerably based on accumulated clinical practice that persistent/ primary research data. Concurrently, the relevance enduring NS carry poor outcome. It is of both negative and cognitive symptoms in reported that the PENS and PNS do not terms of functional recovery has become respond to treatment and indicate poor central to the concept of measurements of outcome whereas the other NS have at least outcome and hence in establishing effective modest response to Clozapine/ SGA, treatments in schizophrenia. [22,41,46] Existing therefore need not necessarily indicate poor pharmacological options may be effective in prognosis. [2-7,12,14,15,21,29] The NS have treating secondary causes of NS, such as significant correlation with treatment antipsychotic side effects and depression. resistance, poor quality of life, poor Pharmacotherapy and psychosocial subjective well-being and interpersonal treatments are being developed and tested in deficits. There are reports that they have TRS patients with PNS as their primary strong association with persistent cognitive targets. [22,23, 41, 43, 45,46] deficits and that the NS provoke more The treatment approach in expressed emotions. schizophrenia with prominent NS, with and Treatment of Schizophrenia without positive and other domain Parallel to the introduction of second symptoms are different. Other than the FDA generation antipsychotics in 1990s, there approved indications of clozapine in have been several important changes in schizophrenia, prominent PENS/PNS is a conceptualization of schizophrenia. First of clinical indication for clozapine treatment. all, the concept of schizophrenia However, there are no currently FDA transitioned from a disorder defined by approved treatments for severe and psychosis to one with multiple symptom persistent NS (PNS) that are not responsive domains. The NS, the mood symptoms and to treatments for secondary causes. The the cognitive symptoms are recognized as treatment methods are based on the different integral manifestations of the disorder. assumptions about the probable causes of Secondly, discussions and debates on NS. But despite such conspicuous functional versus clinical recovery paved limitations we have several therapeutic way to the inclusion of functional recovery techniques that could be put together in an in the definition of outcome in effective treatment program. The secondary schizophrenia. Thirdly, early evidences NS by and large respond to treatment. indicated that SGAs, with their different Primary non enduring NS respond to SGAs mechanisms of actions, could effectively where as the primary enduring NS/ treat all the domains of manifestations. [22,23, persistent NS has poor response. [22,23,41,45,46] 41-46] NS are more difficult to treat than the The SGAs, other drugs acting through the positive symptoms of schizophrenia and cholinergic, adrenergic, serotonin and other represent an unmet therapeutic need for neurotransmitter systems along with large number of patients with schizophrenia. cognitive, occupational and social [22,23,25,41-46] While antipsychotic medications rehabilitation procedures offer promising to treat the symptoms of schizophrenia have rational approach towards treatment of the been around for six decades, they have done NS in schizophrenia. Clinical experience is little to address the significant functional in favour of reduction/ replacement/ impairments in the disorder that are avoidance of FGAs. The first line medicines

Galore International Journal of Health Sciences and Research (www.gijhsr.com) 170 Vol.4; Issue: 1; January-March 2019 Pavithra P. Rao et.al. Negative Symptoms- an Update advocated to treat NS are SDA/DPA. mine (LDX) used as augmenters are in Clozapine, Amisulpride and Levosulpiride literature. A recent meta-analysis reports are second line drugs. Other drugs used to efficacy of Modafinil and Armodafinil in augment efficacy include a different class of the treatment of NS, but the effect size is SDA, SSRI, NRI, Modafinil and NMDA small. Early reports suggest that LDX may Antagonists. Research evidences indicate improve NS. [41,46,51] There are no specific that the treatment at best has only modest research reports in favor of efficacy of effectiveness on the PNS and clozapine is anticonvulsants in NS in schizophrenia perhaps the most effective available although they are frequently used to medicine. Other medicines used to treat NS augment the antipsychotics. [41, 46] have uncertain efficacy. [15, 22, 23, 27,41,44-46] Despite equivocal clinical evidence A large variety of drugs have been there has been lot of clinical trials on the investigated for their efficacy and efficacy of glutamate targeted drugs in the effectiveness in schizophrenia with NS that treatment of NS. Numerous compounds, include antipsychotics, antidepressants, involving both ionotropic and metabotropic CNS stimulants, anticonvulsants, drugs receptors, have been evaluated over the last related to NMDA, Serotonin and two decades. Two meta-analyses, not Cholinergic receptors, Neurosteroids, Sex specific to NS, suggest favorable, but small Hormones, Oxytocin, anti-inflammatory size efficacy of drugs enhancing NMDA drugs and others(Table-II). The notion that receptor activity such as d-Serine, pharmacological treatment could favorably Sarcosine, N-Acetyl-cysteine, and D- influences NS originated from reports about Cycloserine. Other compounds targeted at the unique effectiveness of clozapine NMDA receptors through other mechanisms amongst antipsychotics in treatment- have been investigated. Notable among resistant schizophrenia. Clozapine and other them are GlyT1 Inhibitor (Glycine SGAs including Olanzapine, Risperidone, Transporter 1 Inhibitor -Bitopertin), Quetiapine, Amisulpride, Ziprasidone and mGluR2/3-positive allosteric modulator Lurasidone are used to treat NS in (LY2140023) and NMDA receptor schizophrenia. Several recent meta-analyses antagonists (Amantadine and Memantine). report that the newer antipsychotics are not Despite the initial enthusiasm, disappointing superior to their conventional counterparts recent results with Bitopertin and in the treatment of NS and that the effect in LY2140023 have led to their either case is modest. [41,46-48] discontinuation for this indication. A meta- There are several reports on the analysis examining Amantadine and efficacy of antidepressants in the treatment Memantine does not support the utility of of NS in schizophrenia. Most recent meta- these medications in the treatment of NS, analysis reports that antidepressants have although the focus is not on NS specifically. some beneficial effects on NS that differ An RCT published subsequently and between agents and that the evidence is not looking at NS as the primary outcome strong enough to support their clinical use. reports that Memantine is effective in Two earlier meta-analyses provide improvement of NS with a large effect size. equivocal evidence and a lack of support for [41,46,52,53] antidepressant use. Bupropion fails to A meta-analysis evaluating demonstrate efficacy but Reboxetine and cholinesterase inhibitors in schizophrenia Mirtazapine are found to have efficacy on (Rivastigmine, Donepezil, Galantamine) NS. But in such clinical trials the NS is not reports improvement in selected measures the primary target. [41,46,49,50] of cognition, but not NS. Another meta- Reports on clinical trials on efficacy analysis evaluating drugs targeted of methylphenidate, d-Amphetamine, glutamatergic, serotonergic and cholinergic Modafinil, Armodafinil and Lisdexamfeta- receptors does not report effect on NS with

Galore International Journal of Health Sciences and Research (www.gijhsr.com) 171 Vol.4; Issue: 1; January-March 2019 Pavithra P. Rao et.al. Negative Symptoms- an Update

Donepezil, and Galantamine. But a are investigated for their efficacy on NS in Cochrane review around the same time, and schizophrenia. The neurosteroids and specific to cholinesterase inhibitors in oxytocin have evidences in favor of their schizophrenia, indicates a signal for efficacy in some of the clinical trials. [45,46] improvement of NS. The authors could not Minocycline, a broad-spectrum tetracycline come across any RCTs involving a antibiotic with neuroprotective properties cholinesterase inhibitor where NS are the mediated through anti-inflammatory, anti- primary outcome. [41,45,46,54] apoptotic, and antioxidant effects has A number of newer α7 nicotinic received the greatest attention. A recent acetylcholine receptor (α7 nAChR) meta-analysis supports its value in the agonists/partial agonists as well as positive treatment of NS, although this domain is not allosteric modulators are investigated for the primary outcome. ASA, Cox-2 their efficacy on NS in schizophrenia. CDP- inhibitors, Dextromethorphan, Methotre- Choline, α7 nAChR agonist TC-5619 and xate, Interferon-y, Atorvastatin, Pravastatin EVP-6124 are examples of such drugs. and Pioglitazone are under investigation for [41,45,46] Selective 5-HT2 antagonists their efficacy on NS in schizophrenia. Based (Ritanserin) and selective 5-HT3 antagonists on current available research data the most (Ondansetron, Tropisetron, Granisetron) are promising drugs for NS are the investigated for efficacy specifically on NS Neurosteroids (Pregnenolone), NMDA in schizophrenia. Neurosteroids (DHEA, receptor targeted drugs (d-serine and Pregnenolone, l-Theanine), adrenal Memantine) Glycine transporter-1 hormones involved in the production of inhibitors, α7-Nicotinic receptor targeted androgens and estrogens, Raloxifene drugs, Oxytocin and Anti-inflammatory (estrogen receptor modulator) and oxytocin drugs (Minocycline). [41,45,46]

TABLE-II. LIST OF DRUGS AND OTHER TREATMENTS EVALUATED 1. FGA: Loxapine, Molindone, Sulpiride, Pimozide, Fluspireline, Penfluridol, Flupenthixol 2. Clozapine. 3. SDA: Risperidone, Olanzapine, Amisulpride, , Quetiapine, Ziprasidone, Lurazidone, Bonanserine, Zoptepine. 4. Antidepressants: SSRI. MAOI. Bupropion. Reboxetine. Mirtazapine. 5. CNS Stimulants: Methylphenidate. d-Amphetamine. Modafinil. Armodafinil. LDX 6. Anticonvulsants: Divalproate. Carbamazepine. Oxcarbazepine. 7. NMDA /Glutamate Targeted Drugs: D-Serine. Sarcosine. N-Acetyl-Cysteine. D-cycloserine. Bitupertin. LY21 40023. Memantine. Amantadine. Lamotrigine. Rituzole, AMPA Kines. 8. Cholinesterase Inhibitors. [Donepezil. Galantamine. Rivastigmine. 9. Nicotine Receptor (Alpha 7 nAChR) Targeted Drugs: CDP- Choline. TC 5619. EVP 6124 Anabaseine. 10. Serotonin Receptor Targeted Drugs: Ritanserin (S2). Ondansetron. Tropisetron. Granisetron (S3) Lecozatan. Buspirone. Tandospirone. Gepirone. Vilazodone. Epivanserin. Agomelatin. Vibicaserin. 11. Neurosteroids: DHEA. Pregnenolone. l-theanine. 12. Hormones: Raloxifene. Oxytocin. 13. Anti-inflammatory Drugs: Minocyline. ASA. Cox-2 Inhibitors. 14. Drugs Targeted on Cannabinoid Receptors: Rimonabant, AVE 1625. 15. Newer Drugs Targeted at Dopamine Receptors:Bifeprunox. Sarzotzn. Nemonapride. Fananserin. 16. COMT Inhibitors:Tolcapone. Nitecapone. 17. Drugs targeted at Peptide Receptors:Neurokinin (NK3 --Talnetant, Osnetant.). Neurotensin. CCK. Cytokines. 18. Free Radical Scavengers: Vitamin E, Lazaroids. 19. Drugs Targeted at Sigma-1 Receptors: BMY 14802. OPC-1. 20. Other Drugs: Dextromethorphan. Methotrexate. Interferon Y. Atorvastatin. Parvastatin. Pioglitazone. 21. Prodromal Schizophrenia Treatment with multiple drugs. 22. Multiple Drug Treatment: (APP + Augmenters). 23. Brain Stimulation: TMS. TCS. VNS. ECT. DBS. 24. Psychosocial Methods: Environmental Enhancement. Skill Training. Cognitive Remediation Therapy. Nidotherapy. CBT.

Brain stimulation is another line of and Deep Brain Stimulation are investigated investigation that currently generates to evaluate their efficacy on NS in considerable interest on NS in schizophrenia. There are no reports schizophrenia. Transcranial Magnetic indicating their probable benefits on NS but Stimulation, Transdirect Current there are no conclusive evidences for their Stimulation, ECT, Vagal Nerve Stimulation efficacy. [41] There are research reports

Galore International Journal of Health Sciences and Research (www.gijhsr.com) 172 Vol.4; Issue: 1; January-March 2019 Pavithra P. Rao et.al. Negative Symptoms- an Update about the feasibility and effectiveness of validity. Such evidences include structural psychosocial methods of treatment as and functional brain imaging, adjuncts to medical treatment for NS in neurophysiological, neurochemical, schizophrenia. The effectiveness of long neuroendocrine and neurocognitive data. term psychosocial treatment may Although not substantial, there are correspond to the favorable neuroplastic significant differences in research data in changes in brain. [22,23,41,55,56] substantial number of schizophrenia patients with NS and positive symptoms. For Biology of Schizophrenia example the structural brain abnormalities The progress in the understanding of (developmental/ degenerative) are more in NS and their importance in schizophrenia Type 2, Negative, Deficit and Residual challenged the then existent frontiers and Schizophrenia in comparison to their concepts of schizophrenia. [3,22,23,57] Parallel counterparts. Several other data including to this advance in the knowledge of NS, the neurophysiological, cognitive, endocrine unique effectiveness of Clozapine in TRS and neurological biomarkers are and the introduction of the SGA contributed significantly different in the new clinical to the modifications in the conceptualization models of schizophrenia. [1,4,12-14,23,57-61] of schizophrenia. We arrived at the New Neurotransmitter Pathways realization that schizophrenia is more than Results of investigations on the NS psychosis. Essentially there has been a implicate new neurotransmitters and transition in the concept from a pathways as explanations for the symptoms. disorderdefined by psychosis to a [3,22,23,52,57,58,61,62] The dopamine hypothesis heterogeneous one with multiple symptom is modified to includeprefrontal cortex domains and delicately defined frontiers dopamine deficiency (DLPFC D1) in with uncertain limits and boundaries.The addition to subcortical dopamine excess research on NS has contributed much (LS, BG, D2).Cholinergic hyperactivity in towards better understanding of the biology limbic system is reported to be related to NS of schizophrenia. It is clear now that single and cholinergic hypoactivity to PS. The receptor dysfunction, single pathology, fluctuation in the limbic and prefrontal single marker or single etiology will not cholinergic and dopaminergic balance is explain the complex process and reported to be one of the reasons for the pathophysiology of schizophrenia. Research wide variations in the symptoms of evidences on NS generated different clinical schizophrenia. State dependent and etiological models of schizophrenia norepinephrine dysregulation is associated with different biological and neurological with NS and PS. Norepinephrine excess is explanations. [3,23,57-60] associated with NS in and both New Clinical Models of negative and positive symptoms in active Schizophrenia New clinical models of phase. Norepinephrine deficiency is schizophrenia defined essentially in terms associated with NS in the residual phase. NS came in to existence in clinical practice The secondary NS due to D2 receptor and research. They are Type 2 antagonists are associated with Schizophrenia (Crow, 1980), Negative norepinephrine deficiency. Norepinephrine Schizophrenia (Andreasen, 1982), Deficit system is essential for D1 and D2 receptor Schizophrenia (Carpenter, 1988), Residual sensitivity. The state dependent Schizophrenia (ICD-10, DSM III to DSM norepinephrine dysregulation is perhaps IV TR), Negative (Deficit) Dimension another reason for clinical heterogeneity in (DSM IV TR). [1,4,12-14,57-60] Unlike the schizophrenia. Serotonin (5HT1 & 5HT2) classical subtypes of schizophrenia the new receptor activity deficiency is reported to clinical models are supported by more have significant association to NS and research evidences in favor of substantial cortical atrophy in patients with

Galore International Journal of Health Sciences and Research (www.gijhsr.com) 173 Vol.4; Issue: 1; January-March 2019 Pavithra P. Rao et.al. Negative Symptoms- an Update schizophrenia. Excess GABA and deficient Brain Structure, Function and dopamine receptor activity have significant Neuropathology association to prominent NS and low GABA Structural and functional brain and high dopamine activity is associated images in schizophrenia indicate ventricular with prominent positive symptoms. Both dilatation (fourth and third ventricles),global hyperglutamateric state leading to and regional cortical atrophy(FL TL LS excitotoxicity and neuronal loss, and BG), global and regional grey matter hypoglutamatergic state are associated with density loss (PFL), reduction and NS. enlargement of specific brain regions and Brain Areas and Circuits structures (hippocampus, temporal lobe, Ventromedial PFC and the Ventral frontal cortex, corpus callosum, amygdala, Anterior Cingulate Cortex are the brain para hippocampal region, hypothalamus, areas associated with NS in schizophrenia. medial temporal areas, anterior cingulate The cortico- striato- thalamo- cortical cortex and caudate nucleus) white matter circuits (CSTC) from the ventromedial structural and functional changes, global prefrontal cortex(VMPFC) is reported to be and regional metabolic and molecular involved in the manifestation of NS. The alterations in functions in schizophrenia [61- mesocortical dopamine pathway to VMPFC 64] The neuropathological studies reveal (MC DA Pathway), the mesolimbic primary or secondary brain cell damage dopamine pathway(ML DA Pathway) such as definite brain atrophy, dysmorphism through the reward system, the cortico and gliosis, which are diffuse but with focal brainstem glutamate pathway(CBS GLU predominance in the above regions in the Pathway), corticostriatothalamo cortical brain. The structural and neuropathological glutamate pathway (CSTC GLU Pathway) abnormalities are more severe and more and the serotonin pathways(5HT1, 5HT2) common in negative schizophrenia/ deficit modulating the dopamine and glutamate schizophrenia. [3,57,61,62] pathways are implicated in pathophysiology Etiological Models of Schizophrenia of negative schizophrenia /deficit All the accepted models of etiology schizophrenia. [3, 61,62] of schizophrenia are supported by and Neuroendocrine changes explained by the NS. The genetic model, the Neuroendocrine changes differ in neuro developmental model, the schizophrenia depending on predominance degenerative model and immunological of negative or positive symptoms. GH model are supported by the NS. The response to TRH is increased in NS negative schizophrenia/ deficit implicating the cholinergic activity. GH schizophrenia is more genetic, more response to apomorphine, clonidine, developmental and more degenerative than hypoglycemia and sleep is reduced the positive schizophrenia. [3,57,61,62] implicating dopamine and norepinephrine NEGATIVE SYMPTOMS IN OTHER systems. DST non- suppression is seen in PSYCHIATRIC DISORDERS NS with venticulomegaly. Increase in NS are reported and investigated in vasopressin is implicated in NS in deficit Depressive Disorder, Bipolar Mood state. Reduced CCK in hippocampus and Disorder and Schizotypal Disorder. increased substance P also has been found [6,18,35,36,65-70] Recent reports suggest that in NS. Others like VIP, Somatostatin, primary NS (anhedonia, affective blunting Opioids, Neurotensin and Bombesin, and avolition) could be core features of Prolactin, FSH and LH have also been MDD and they have significant correlation implicated in NS. These neuroendocrine to cognitive deficits and structural and alterations in NS indicate complex functional changes in the brain. [69] involvement of multiple neurotransmitters Qualitative finer distinction of the NS in in schizophrenia. [3,22,23,57,61,62] depressive disorder and schizophrenia is an

Galore International Journal of Health Sciences and Research (www.gijhsr.com) 174 Vol.4; Issue: 1; January-March 2019 Pavithra P. Rao et.al. Negative Symptoms- an Update area of current research. [18,69] Based on NS matter of fact are manifest in all phases of schizotypal disorder can be classified into schizophrenia. The available nonspecific positive and negative subtypes. [70] and specific scales for assessment of NS have certain unique merits and significant CONCLUSIONS demerits (Wing, Crow, Andreasen, Kay). NS in psychiatry are deficits in The new generation assessment instruments experience and behavior that are attributed BNS and CAINS are likely to give more to loss of functions of brain. NS have been reliable and valid data that are more conceptualized as the core aspect of sensitive to change (Kirkpatrick, schizophrenia. The other probable core Blanchard). The ‘NIMH MATRICS domain is cognitive deficits. Strauss, Consensus Statement on NS’ highlights Carpenter and colleagues reintroduced NS most of the current concepts about NS. to psychiatry in 1974. The current concept is Clinical significance of NS in terms descriptive, not based on any theory and of diagnosis, prognosis and treatment does not imply neurobiology or relationship options in schizophrenia has been to other symptoms. The NS concept in recognized. The NS are not diagnostic of psychiatry is more Reynoldian than schizophrenia and are not exclusive to Jacksonian. schizophrenia. They are manifest in other The five general categories of NS psychiatric disorders, medical disorders and include avolition, anhedonia, affective other conditions. Finer qualitative aspects of blunting, alogia and asociality. The NS and subjective awareness and concern subdomains of NS are experience domain for NS are possibly different in (avolition and anhedonia) and expressivity schizophrenia and major depressive domain (affective blunting and alogia). The episodes. Substantial research evidences NS are initially classified into primary and support the clinical realization that secondary NS (Carpenter). Primary prominent NS particularly PNS/PENS Enduring NS (PENS) have been reported to indicate poor outcome and quality of life in be the core of schizophrenia that would schizophrenia. The available predict poor outcome and treatment failure. . pharmacological options fail to be effective The importance of primary versus in schizophrenia patients with prominent secondary NS distinction has been currently PNS/PENS. Several recent meta-analyses disputed in the light of absence of research report that the newer antipsychotics evidences to support the same. The including clozapine are not superior to their Persistent NS (PNS-Buchanan) is perhaps conventional counterparts in the treatment better for clinical trials than the PENS. The of NS and that the effect with clozapine is at NS have no definite relationship with best only modest. Researchers are positive symptoms.There are overlaps investigating drugs that act on new sets of between NS and cognitive and depressive receptors. Based on current available symptoms. Such overlaps could be research data the most promising drugs for attributed to the problems related to NS are the neurosteroids (pregnenolone), conceptual clarity and the degree of NMDA receptor targeted drugs(d-serine and interference of coexistent other dimensions memantine) glycine transporter-1 inhibitors, of symptoms in the accurate assessment and α7-nicotinic receptor targeted drugs, evaluation of the NS. However, the NS have oxytocin and anti-inflammatory drugs no significant correlation to depressive (minocycline). The concept of NS brought symptoms or cognitive deficits. Though the about substantial modifications in our NS have adequate reliability the validity of understanding of neurobiology of the concept of NS is not well established. schizophrenia and etiological and clinical Although considered as the hallmarks of models of schizophrenia. NS are related to chronic state in clinical practice, the NS as a brain damage in schizophrenia due to

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