International Clinical Psyehopharmacology 1997, 12 (suppl 2):S7-S10 Improvement of negative sympt assessment Naney C. Andreasen Department of Psychiatry, The University of lowa He 1A 52242, USA ‘The development of new medications for the treatment of schizop! teristic symptoms. In recent years, the symptoms have been di ing, bu less spectacular. Negative symptoms, which are sim and Bleuler, have not received mueh attention until recently beca documenting the response to carefully rated negative symptoms. tive symptoms that are primary rather than secondary to reduced: depression or deereases the demoralizing effets of pe primary negative symptoms i to study patients with high levels of the ear ut difficult to collet. Alternatively, when all confounders ca techniques to examine covariance. ive symptoms. O foms: concepts, definition and jospitals and Clinics, 200 Hawkins Drive, lowa City, nreniais closely tied tothe concept ofthe disorder and its charac- : positive and negative. Positive . ‘are more insidious and nila tothe core symptoms of schizophrenia defined by Krapaclin use of concern about reliability. However, rating sales with good bility are now available for use in elinieal and neurobiological studies. Clinical drug trials are also meeting the challenge of Tn addition, they are exploring the effects of medication on nega- extrapyramidal side effects, or of medication that lowers levels of, eal strategy for identifying the effects of medication on negative symptoms and low levels of positive symptoms, who are stages of the illness and have been given minimal treatment with classical neuroleptics, Such samples are highly informa- snnot be eliminated, the effects of medication ean be explored using Keywords: Schizophrenia, positive and negative symptoms, extrapyramidal side effects INTRODUCTION Schizophrenia is a multisystem disease that is probably caused by a variety of disturbances in brain structure, physi- ology and chemistry: The signs and symptoms of schizo phrenia affect a broad range of mental systems: percep- tion, inferential thinking, speech and language, social interactions and behaviour, motor behaviour, attention, vo- lition and drive, emotional expression and responsiveness, intellectual creativity, the eapacity to abstract and fluency of thought and speech. Unlike many other disorders in psychiatry or general medicine, schizophrenia does not have a single pathognomonic featur. ‘Because the symptoms of schizophrenia are diverse and complex, efforts have been made to divide them into sev- exal broad categories. One conceptualization that is widely used involves a subdivision into positive and negative symptoms. This distinction draws on ideas originally pre- sented by Hughlings-ackson (1931), who argued that the brain must be conceptualized as having multiple levels of integrated functions. ‘Disease is said to “cause” the symp- toms of insanity. I submit that disease only produces nega- tive mental symptoms answering to the dissolution, and that all elaborate positive mental symptoms (illusions, hal- lucinations, delusions, and extravagant conduct) are the (© 1997 Rapid Science Publishers ‘outcome of activity of nervous elements untouched by any pathological process; but they arise during activity on the Tower level of evolution remaining’ (Hughlings-Jackson, 1931), ‘More recently, a series of studies have explored the in- ter-relationship between these various symptoms, using factor analysis to determine whether they fall into natural categories by examining the extent to which they are cor: related with one another. A series of these factor analytic studies have consistently suggested that positive symptoms are further divided into two subcategories: psychosis and disorganization, The psychosis factor consists of delus- ions and hallucinations, while the disorganization factor is often composed of disorganized speech, bizarre behav jour and inappropriate affect (Bilder et a., 1985; Kulhara and Chadda, 1987; Lenzenweger et al., 1989; Arndt et al., 1991), Current reconceptualizations (Andreasen and Olsen, 1982; Andreasen et al., 1990) of Jacksonian ideas retain the distinction between positive symptoms as an exaggera- tion of normal functions (the presence of something that should be absent) and negative symptoms as a loss of nor- mal functions (the absence of something that should be International Clinical Pxychopharrnaology + Vol 12, Suppl2+ 1997 S7‘Table 1. Relationship between cognitive systems and schizo- phrenic symptoms. Cognitive system or subsystem symptoms Schizophrenic Positive Perception Hallucinations Inferential thinking Dolusions Language Disorganized speech {formal thought disorder Disorganized/ bizarra/ catatonic behaviour Behavioural monitoring Negative Conceptual fluency Alogia Emotional expression Alective blunting Experiencing pleasure Anhedonia Volition volition present), They also draw on observations derived from cog- nitive psychology and clinical practice. The array of signs, and symptoms classified as positive or negative is often summarized according to the range of cognitive and emo- tional domains involved, indicating that the two groups, include most of the human brain systems or subsystems. A summary of the symptoms and their corresponding cog- nitive systems or subsystems is given in Table 1 ‘THE IMPORTANCE OF NEGATIVE SYMPTOMS Negative symptoms are an important component of schizo phrenia, and the use of positive and negative terminology gives them recognition and equal weight. As the Bleulerian symptoms (Bleuler, 1950) received scant attention during. the 1980s because of concerns about reliability they left a void in the descriptive lexicon, Patients were designated as having ‘recovered’ when their delusions and hallucinations ‘were no longer present or prominent. Yet many patients remained unemployed, unable to return to school or work, 6 socially isolated. What might explain this outcome if theirsymptoms were genuinely absent? On reflection, itbe- came evident that only some symptoms were absent, and that an additional group of unrecognized or ignored symp- toms were the likely explanation, If these symptoms can be named negative, grouped together, measured objectively and reliably, and related to outcome and treatment, an im- portant mechanism for clinical description and communi- cation willbe restored. Ithas been useful so far to recognize that some symptoms tend to result in hospitalization and to call these positive, while other symptoms tend to lead to psychosocial morbidity and to call these negative. MEASUREMENT OF NEGATIVE SYMPTOMS. Standardized and reliable methods have been developed for assessing these symptoms and placing them in broad SB _ tovemationa Clinical Pyshopharmacoiogy* Vol 12, Suppl 2+ 1997 ANDREASEN general classes. The number of classes (or dimensions) and the relationship between them is receiving additional investigation, particularly in the case of positive symptoms. Rating scales such as the Scale forthe Assessment of Neg- ative Symptoms (SANS) and the Scale for the Assessment of Positive Symptoms (SAPS) have provided methods of rating and measuring positive and negative symptoms. Al- though scales have been available for most positive symp- toms, there were none for negative symptoms before the SANS was set up. The extensive and repeated documen- tation of its reliability has quieted concerns that negative symptoms are too soft to be assessed precisely, accurately and objectively (Andreasen, 1982; Andreasen and Olsen, 1982; Andreasen, 1983, 1989; Andreasen et al. 1992) ‘THE THREE DIMENSIONS OF SYMPTOMS. ‘The inter-relationship between positive and negative symp- toms has been studied using the techniques of factor anal- ysis to determine which specific symptoms tend to be cor- related with one another. This work has produced consistent results from a large number of research groups through- ‘ut the world, and led to the recognition that positive symp- toms should be further subdivided into a psychotic group (Comprising delusions and hallucinations) and a disorgan- ized group (usually comprising disorganized speech/for- mal thought disorder, disorganized behaviour, and incon- ‘gruous or inappropriate affect). Clinicians will probably continue to refer to both groups as positive symptoms, because they have similar clinical importance, in that both tend to command clinical attention and respond well to acute and aggressive treatment. Nonetheless, the symp toms of schizophrenia seem to be divided into three di- mensions: psychotic, disorganized and negative. ‘THE PRIMARY VERSUS SECONDARY DISTINCTION As efforts to study positive and negative symptoms have ‘evolved, the attempt to distinguish between secondary and primary or core negative symptoms has become increas- ingly important, The distinction between primary and sec- ‘ondary symptoms in schizophrenia dates back to Bleuler (1950), butithas acquired a new urgency and a qualitative difference because it has major significance for both the study of new treatments and the investigation of neural mechanisms One ofthe most difficult problems in the study of nega- tive symptoms in schizophrenia is that they may occur as a result ofa wide variety of factors. The most commonly implicated factors are neuroleptic side effects, depression and a response to positive symptoms (e.g. social avoid- ance secondary to paranoia). While there is a consensus that itis essential to try to disentangle primary from see- ondary negative symptoms, there is no agreement on the best way of doing this.IMPROVEMENTOF NHGATIVESYMPTOMS Carpenter etal, (1988) have proposed a useful approach for dealing with this problem. They have suggested that deficit (or primary) negative symptoms can be distin- guished from secondary negative symptoms on the basis of a careful and systematic assessment of clinical history and presentation, and have developed a structured assess- ‘ment instrument and operationalized criteria for making. this distinction, According to these criteria, subjects must display prominent negative symptoms for at least 12 months in the absence of likely secondary causes. Car- penter er al, (1988) have demonstrated adequate reliabil- ity using these instruments in their centre, and in catego- rizing patients as deficit or non-deficit. They have also sup ported the validity of the deficit versus non-deficit distinc tion by showing differences according to cognitive test- ing, magnetic resonance imaging measures and premor- bid functioning (Kirkpatrick and Buchanan, 1990). Nevertheless, there is still considerable concern about the practical ability of most clinical researchers to make this type of distinction with acceptable levels of reliabili- ty. This concem is supported by data from the Psychotic Disorders Field Trial for the fourth edition of the Diag- nostic and Statistical Manual of Mental Disorders (DSM- IV; American Psychiatric Association, 1994), which pro- vided a close approximation of routine clinical settings in which the distinction might be made. Without using an instrument specifically designed to determine whether symptoms were primary or secondary, clinicians were asked to make this decision based on a standard structured interview. In this instance, the reliability for distinguish- ing between primary and secondary negative symptoms was consistently poor, with x values of less than 5 for all symptoms (Flaum et al., 1993). An alternative approach, used in amisulpride trials, ap- plies strategies that rely on infotmative populations, lon- gitudinal observation and the collection of measures of the potential causes of secondary negative symptoms such as depression, akinesia or psychosis. Informative popula- tions include drug-naive patients or patients withdrawn from neuroleptic medication for substantial periods of time (to rule out neuroleptic treatment effects), or patients high oon negative symptoms and low on positive symptoms (10 rule out negative symptoms secondary to positive symp- toms; Andreasen ef al., 1990; Flaum et al, 1993). Obvi- ously, each of these groups may have some remaining con founders, such as the presence of depression, but these can usually be addressed by additional statistical analy- ses. Ratings of these features can be included as covari- ates in analyses ofthe relationship between negative symp- toms and confounding correlates. While this approach ob- Viates the need for potentially unreliable judgements on the source of a particular symptom, itcan lead to cumber- some multivariate statistical procedures Recent interest in studying the effects of treatment on negative symptoms, combined with efforts in the pharma- ceutical industry to develop better treatments for negative symptoms, makes the differentiation of primary and sec- ondary negative symptoms much more than an academic debate. Inferences about therapeutic efficacy depend on the ability to determine whether the effects of a drug oc- cur at a primary or secondary level, Observations on pa- tients over an extended period of time are also helpful INCLUSION OF NEGATIVE SYMPTOMS IN THE DIAGNOSTIC CRITERIA FOR SCHIZOPHRENIA ‘The concept of positive and negative symptoms has now been incorporated into the diagnostic criteria in new edi tions of both the American (DSM-IV) and te international (Unternational Classification of Disease or ICD-10; WHO, 1990) diagnostic systems. list ofthe characteristic symp- toms, as defined in DSM-IV, is given in Table 2. For the first time, the term ‘negative symptoms’ has been intro- uced into diagnostic criteria. More importantly, these negative symptoms are defined as being part of the ative phase ofthe illness and therefore as important targets for ‘uoatment. As long as negative symptoms are prominent, i is no longer possible to say thatthe patient has recovered from the active phasé and is now in a residual phase ‘Table 2. Characteristic symptoms of schizophrenia in the Diagnostic and Statistical ‘Manual of Mental Disorders (American Psychiatric Association, 1994) Characteristic symptoms: atleast to of the folowing, each present for a sigaificant portion f time during a t-montn period (or less i succosstuly treated). Delusions Hallucinations Disorganized speech (e.9. frequent derailment or incoherence) Grossly disorganized or catatonic behaviour Negative symptoms (affective fattening, alogia, or avolition) Only 1 symptom is required it delusions are bizarre or hallucinations consist of a voice keeping up a running commentary on the person’s behaviour or thoughts, or two or more voices conversing with each other. Intemational Clinical Psychopharnacology + Vol 12, Suppl2« 1997 SOCONCLUSIONS, Negative symptoms are now recognized as being among, the most important symptoms of schizophrenia. Although 4 similar group of symptoms was considered important within Bleulerian conceptualizations of schizophrenia ‘Bleuler, 1950), these core Bleulerian symptoms were ne- glected during the 1970s and 1980s because they were considered soft and unreliable. With the development of reliable rating scales and careful methods for distinguish ing between primary and secondary negative symptoms, however, their importance has been restored. These are ‘crucial symptoms, particularly from the perspective of patients and their families. They are now recognized as among the most important treatment challenges facing cli- nicians, and are an important target for new drug develop- ‘ment. ‘Acknowledgements ‘This research was supported in part by NIMH Grants ME31593, MH40856 and MHCRC43271, by a Research Scientist Award, ‘MH00625,andby an Established Investigator Avard from NARSAD. REFERENCES: American Psychiatric Association (1994) Diagnostic and Stats cal Manual of Mental Disorders (DSM-IV). Washington, DC: ‘American Psychiatrie Assocation ‘Andreasen NC (1982) Negative symptoms in schizophrenia: defini tion and reliability, Arch Gen Psychiatry 39:784~788. Andreasen NC (1983) The Scale or dhe Assessment of Negative Symp toms (SANS). lowa City: University of lowa s10 Iierational Ciical Psychopharmacology + Vel 12. Suppl 2+ 1997 ANDREASEN Andreasen NC (1989) Neural mechanisms of negative symptoms. Br J Psychiatry 158:93-98, “Andreasen NC, Olsen § (1982) Negative symptoms in schizophre- nia: definition and validation, Arch Gen Psychiatry 38:780-794 ‘Andreasen NC, Flaum M, Swayze Vr a. (1990) Positive and nega tive symptoms in schizophrenia a critical reappraisal. Arch Gen Psychiatry 47:615-621 ‘Andreasen NC, Flaum M, Arndt § (1992) The Comprehensive As- ‘sessment of Symptoms and History (CASH): an instrument for assessing diagnosis and psychopathology. Arch Gen Psychiatry 49:615-023 Amndt S,Allige RJ, Andreasen NC (1991) The distinction of posi- tiveand negative symploms: failure ofa two-dimensional model, BrJ Psychiatry 198:317-322. Bilder RM, Mukherjee S, Reider RO. et al. (1985) Symptomatic ‘and neuropsychological components of defect sates. Schizophr Bull 1409-419. Blevler E (1950) Dementia praecox or the group of schizophrenias (The 1911 German monograpk previously translated by J Zinkin), New York: Intemational University Press, (Carpenter WT, Heinrichs DW, Wagman AMI (1988) Deficit and non- deficit forms of schizophrenia: the concept. AmJ Psychiatry 148: 578-583. Flaum M, Arndt SV, Andreasen NC (1993) DSM-IV field trial for psychotic disorders. Schizophr Res 9:99 ‘Hughlings-Jackson J (1931) Selected Writings. Eiited by Taylor 3. London: Hodder and Stoughton. Kirkpatrick B, Buchanan RW (1990) Anhedonia andthe deficit sym- ‘drome of schizophrenia, Payehiatr Res 3125-30. Kara P, Chad R (1987) A stady of negative symptoms in schizo ‘phrenia and depression. Comprehensive Psychiatry 28:229-235, Lenzenweger MF, Dworkin RH, Wethington E (1989) Models of ‘sitive and negative symptoms in schizophrenia: an empirical ‘evaluation af latent structures. J Abnormal Psychol 98:62~70. ‘World Health Organization (1990) Mental and behavioural disor- ‘ders (including disorders of psychological development): diag nosis eriteria for research, I: International Classification of Dis- teases, Geneva: WHO,