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Negative symptoms comprise, among others, ﬂattening of aﬀect, reduction of speech, and social withdrawal. They occur in diﬀerent psychiatric diseases, but especially in schizophrenia, where they are traditionally seen as an important part of the symptomatology. In the last decade, they have evoked a special research interest due to the fact that novel atypical antipsychotics have been developed with an improved therapeutic eﬃcacy in negative symptoms of schizophrenia.
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1. Deﬁnition Of Negative Symptoms
Negative symptoms in schizophrenia comprise broadly of blunted aﬀect, apathy, attentional impairment, poverty of thought or speech, incoherence, loosening of association, thought blocking, and social withdrawal. However, there is no unanimous agreement on the concept of negative symptoms in schizophrenia: some authors adhere to a broad interpretation (Meltzer and Zureick 1989, Rosler and Hengesch 1990), while others prefer a narrow approach (Crow 1985, Strauss et al. 1974, Wing 1989). The controversy centers on incoherence, loosening of association, and thought-blocking, since these are also attributes of positive symptoms. This disparity in the selection of items also manifests itself in the outcome of patient testing with diﬀerent rating scales. Diﬀerent authors use diﬀerent concepts and deﬁnitions for the type and number of symptoms implicated (Rosler and Hengesch 1990).
These problems of deﬁnition can also be identiﬁed in the rating scales used for measuring negative symptoms.
2. History Of The Term ‘Negative Symptoms’
The origins of the positive negative distinction are usually attributed to Jackson (1887), the British neurologist who drew the distinction in order to delineate primary from secondary neurological phenomena. Accordingly, positive symptoms are deﬁned as the presence of a Behavioral function that is otherwise not normally present in an individual. Negative symptoms are deﬁned as the absence of a Behavioral function that is usually present in the normal individual. Negative symptoms all appear to be characterized by the loss of an important cognitive or Behavioral function, while positive symptoms represent an exaggeration or distortion of a normal function.
3. Standardized Assessment And Dimensional Diﬀerentiation Of Negative Symptoms
To improve the reliability of diagnostic assessment of negative symptoms, several scales have been developed, mostly in the last two decades (SANS: 1981, PANSS: 1987, SAPS: 1991).
Standardization of the assessment of negative symptoms through rating scales had a positive eﬀect on reliability. For example, the interclass correlations for the Scale for the Assessment of Negative Symptoms (SANS) and the Scale for the Assessment of Positive Symptoms (SAPS) complex global ratings range between 0.70 and 0.88. Principally, the negative symptoms can be rated with as much reliability as positive symptoms.
Rating scales applied in the past decade include, among others, the anergia score of the Brief Psychiatric Rating Scale (BPRS), the Manchester Scale and Crow’s modiﬁcation of this scale, the negative score of the Positive and Negative Scale (PANSS), the SANS, and Abrams and Taylor’s Rating Scale for Emotional Blunting. Nowadays, the SANS and the PANSS are the most frequently used rating scales.
In nearly all studies in which a broad spectrum of negative symptoms was investigated by a factor analytical approach, two or three dimensions of negative symptoms were found. This emphasizes the inadequacy of a unidimensional concept of negative symptoms in the complex phenomenology of this domain (Meltzer and Zureick 1989).
4. Symptomatic Overlap With Parkinsonism And Depression
The diﬀerentiation between depression and negative symptoms is diﬃcult on the basis of both clinical phenomenology and rating scales, and therapeutic eﬀects on depressive symptoms might be misinterpreted as successful treatment of negative symptoms and vice versa. Gaebel (1989) reported a correlation of r = 0.34–0.57 at diﬀerent measurement points for the BPRS scores depression and anergia. In a follow-up study on schizophrenic patients, the correlation between the scores for depression and retardation apathy in the Inpatient Multidimensional Psychiatric Scale (IMPS) amounted to r = 0.35 (Moller and von Zerssen 1986).
Another problem in the interpretation of rating scale data from studies in this ﬁeld is that the negative symptoms score correlates positively with the drug- induced Parkinson syndrome. Furthermore, there is a correlation between negative symptoms and hyperkinetic neurological symptoms such as akathisia and dyskinesia. One could therefore conclude that drugs without extrapyramidal side eﬀects in general may appear to be more advantageous in treating negative symptoms.
5. Negative Symptoms In Schizophrenia
Both Kraepelin and Bleuler described a core of schizophrenic symptoms corresponding to the modern concept of negative symptoms (Table 1). Later, this position was gradually displaced by an emphasis on productive features as being pathognomonic of schizophrenia, in fact, as being a prerequisite for its diagnosis. This is exempliﬁed in the diagnostic criteria for schizophrenia put forward by Schneider 1959, Feighner et al. (1972), in the research diagnostic criteria (Spitzer et al. 1978), and in the Diagnostic and Statistical Manual DSM-III, DSM-III-R, and DSMIV criteria.
The need to incorporate both negative and positive features into a model of schizophrenia was brought out by the factor analytic studies of the 1960s and in particular by the research of Strauss et al. (1974), who adapted Jackson’s (1887) terminology for classifying diﬀerent proﬁles in schizophrenia.
Whereas Crow’s (1980b) model viewed the positive and negative symptoms as annulated facets of schizophrenia that may reﬂect separate pathological processes, Andreasen (1982) proposed instead a typological model. They described positive and negative symptoms as opposing features that characterize diﬀerent subtypes.
Which symptoms of schizophrenia are considered positive or negative varies across diﬀerent authors. Nearly all authors include ﬂat aﬀect and poverty of speech among the negative symptoms, and hallucinations and delusions among the positive symptoms. Most regard anhedonia, apathy, avolition, or abolia as negative symptoms. Thought disorder, bizarre Behavior, and inappropriate aﬀect, however, are variably classiﬁed as positive or negative.
6. Negative Symptoms In Other Psychiatric/Mental Disorders
Anergia, anhedonia, poverty of speech, and aﬀective ﬂattening, which occur as part of the negative symptoms in schizophrenia, were also observed in patients severely ill with depressive disorder. Although negative symptoms of schizophrenia may be diﬀerent from depressive symptoms in depression, they do overlap, thus making negative symptom complexes and psychomotoric retardation, lack of energy, anhedonia, and other symptoms of depression signiﬁcantly associated. On the other hand, it was observed that a distinct hypokinetic syndrome involving anhedonia, depressed mood, and cognitive impairment existed not only in negative schizophrenia and retarded depression, but also in Parkinson’s disease, suggesting that reduced dopamine turnover might play a role in the pathophysiology of each.
7. Primary And Secondary Negative Symptoms
The diﬀerentiation between primary and secondary negative symptoms, as proposed by Carpenter et al. (1985), seems of great theoretical and clinical relevance. While primary negative symptoms are the consequence of a morbogenic deﬁcit state, secondary negative symptoms are the consequence of:
(a) positive symptoms (e.g., social withdrawal because of paranoid ideas);
(b) extrapyramidal eﬀects (e.g., motor retardation as an indicator of neuroleptogenic akinesia);
(c) depressive symptoms (e.g., postpsychotic or pharmacogenic depression); or
(d) social understimulation (e.g., hospitalization).
According to this distinction, the treatment of negative symptoms has to be diﬀerentiated concerning the diﬀerent causes.
Angst et al. (1989) underlined the necessity of discriminating negative symptoms according to different stages in the course of schizophrenia, i.e., the prepsychotic period, the productive psychotic period (characterized by a mixture of positive and negative symptoms, whereby negative symptoms may be hidden at this stage), and the postpsychotic period (characterized by residuum or defect with or without positive symptoms, postpsychotic endogenous, or reactive depression, postremissive exhaustion).
Crow (1980a) postulated the stability of a speciﬁc subtype of schizophrenia with positive symptoms (type I) and a subtype with negative symptoms (type II), explaining this by diﬀerent biological causes. Most other authors stressed the point that negative and positive symptoms can be combined cross-sectionally or longitudinally and cannot be taken as indicators for a speciﬁc biological or phenomenological subtype of schizophrenia.
8. Relationship Between Positive And Negative Symptoms In Schizophrenia
The positive negative distinction may represent different manifestations of the common underlying process. It may also suggest the existence of diﬀerent pathophysiologies in schizophrenia. Hints about the inter-relationships of these processes may be gleaned from the intercorrelations among their ﬁnal common expressions as symptomatic phenomenology. An initial eﬀort by Andreasen (1982) showed that the positive and negative symptoms clusters were signiﬁcantly correlated within clusters and inversely correlated between clusters, suggesting a bipolar construct with positive and negative symptoms at the opposite ends of a continuum. This was replicated by another group. However, later investigations showed little or no relationship between positive and negative symptoms, strongly suggesting that they are independent processes within schizophrenia.
Since both positive and negative symptoms are frequent in schizophrenia, they are likely not to be completely independent (Moller et al. 1995). However, some ﬁndings have been controversial. For example, Rosen et al. (1984) failed to ﬁnd a positive negative symptom correlation.
9. Course Of Negative Symptoms In Schizophrenia
Findings on the course of positive and negative symptoms over time have aroused considerable controversy. In acute and/or ﬁrst episode cases, negative symptoms are sparse and linked tightly to the presence of other manifestations of psychoses, especially to positive symptoms (Moller and von Zerssen 1986). In the North American Risperidone Study (Marder and Meibach 1994), in which risperidone was compared to haloperidol, both drugs improved positive and negative symptoms signiﬁcantly. Similar results were obtained in clinical trials on other novel atypical neuroleptics such as olanzapine, sertindole, amisulpride, etc. Clearer results may be obtained if more sophisticated designs are used for psychopharmacological trials on negative symptoms. A European collaboration group therefore made some suggestions (Moller et al. 1994), focusing on patients with predominantly negative symptoms (Table 2).
During the acute phase, negative symptoms can often be unstable. For example, McCreadie (1989) studied schizophrenic patients suﬀering a ﬁrst episode at three points in time (admission, one and twoyear follow-up). The percentages of patients with positive and negative symptoms were 96 and 23 percent at admission, 22 and 40 percent at the one-year follow-up, and 21 and 25 percent at the two-year follow-up, respectively. Other studies with acute patients have shown that negative symptoms are more stable over time. Ragin et al. (1989) found an increase in the level of poverty of speech between index admission and seven months after discharge. Wagman et al. (1987) found that the anergia score of the BPRS was signiﬁcantly correlated across four months of repeated measures in patients with deﬁcit symptoms, but not in patients without deﬁcit symptoms.
Overall, negative symptoms appear to be more stable in subacute/subchronic patient samples. Pogue-Geile and Harrow (1985) recorded high and stable levels of anhedonia one and three years after episodes of schizophrenia. Biehl et al. (1986) found that negative symptoms had signiﬁcant retest stability between years two and ﬁve in a sample from the International Pilot Study of Schizophrenia.
In a follow-up study of schizophrenia carried out in Munich (Moller and von Zerssen 1986), patients were rated using the IMPS at admission, discharge, and at a ﬁve-year follow-up. A decrease was observed in the mean score of positive symptoms and also in syndrome retardation as an indicator of negative symptoms. The correlation for the retardation score between discharge and follow-up was 0.36. In a similar 15 years follow-up study on ﬁrst hospitalized patients with schizophrenia, a decrease of negative symptoms was found between admission and discharge, and an increase between discharge and follow-up (Moller et al. in press).
Many authors came to the conclusion that, in contrast to the views of Crow (1980b), the negative subtype and the positive subtype of schizophrenia are not stable conditions during the short or long-term course of the disease. Most authors stressed the point that negative and positive symptoms can be combined cross-sectionally or longitudinally, and cannot be taken as indicators of a speciﬁc biological or phenomenological subtype.
10. Biological Correlates Of Negative Symptoms In Schizophrenia
The most prominent biochemical ﬁnding in schizophrenic patients with negative symptoms appears to be the reduction in central dopaminergic, serotonergic, and noradrenergic activity, and, if at all, a general common pattern can be described. This decrease in amine activity tends to be associated with structural brain abnormalities, i.e., cortical atrophy or enlarged ventricles. There are indications that typical neuroleptics reduce at least those negative symptoms of schizophrenia that are secondary to positive symptoms when the positive symptoms are eﬀectively treated. However, negative symptoms of schizophrenia that occur independently of positive symptoms may also be reduced, especially through treatment with atypical antipsychotics or with antidepressants. The eﬃcacy of drug treatment of negative symptoms seems to be related to their pharmacological proﬁle, i.e., their interference with dopaminergic, noradrenergic, and serotonergic receptor systems. As to atypical antipsychotics, among others the 5-HT A blockade was hypothesized as being a relevant mechanism for the eﬃcacy of atypical antipsychotics in treating negative symptoms.
As mentioned above, there is a considerable overlap in the symptomatology of psychiatric disorders with respect to negative symptoms. Also, diﬀerent types of negative symptoms in schizophrenia have to be considered. In addition, the lack of homogeneity in the deﬁnition and assessment of negative symptoms in schizophrenia can be a problem. All these diﬃculties have consequences for research and explain some of the inconsistencies in biochemical and pharmacologic schizophrenia research (Meltzer and Zureick 1989). The results of biochemical investigations as well as of positron emission tomography and magnetic resonance imaging studies on negative symptoms, warrant further research eﬀorts in this ﬁeld to ﬁnd, among others, a rationale of neuroleptic drug treatment in negative symptoms of schizophrenia.
11. Treatment Of Negative Symptoms In Schizophrenia
There has been a strong debate in the literature on whether neuroleptics can really reduce negative symptoms, and especially whether they can reduce primary negative symptoms and not just secondary negative symptoms. An earlier review found evidence that some neuroleptics, especially some atypical neuroleptics, can reduce negative symptoms. However, since most of the trials were carried out in patients with negative and positive symptoms during acute exacerbations of schizophrenic psychoses, the question arises whether only those negative symptoms were reduced that were secondary to positive symptoms. In addition, the overlap between negative symptoms of schizophrenia and extrapyramidal side eﬀects and depression has to be taken into account. As an alternative hypothesis to the direct eﬀect of a drug on negative symptoms, the possibility that a drug reduces depression, akinesia, sedation, etc., and in this way also reduces negative symptoms, must be considered seriously.
One possibility of diﬀerentiating between direct and indirect drug eﬀects on negative symptoms is to use statistical procedures. Formerly, only two studies had used an elementary statistical approach to account for the possibility of indirect eﬀects on negative symptoms. Meltzer (1985) used a covariance analysis and found that the neuroleptic eﬀect on negative symptoms could not be explained via a neuroleptic eﬀect on positive symptoms alone. Van Kammen et al. (1987) used a regression analysis which showed that the neuroleptic eﬀect on negative symptoms could be explained by the eﬀect on positive symptoms.
More complex statistical approaches were not used until the mid-1990s. Moller et al. (1995) applied a complex statistical model, a path analysis, to the data of the North American Risperidone Study (Marder and Meibach 1994), including eﬀects on positive, negative, and extrapyramidal symptoms to determine whether risperidone had a more potent direct eﬀect on negative symptoms than haloperidol. The aim was to determine whether a (direct) eﬀect on negative symptoms remains after the eﬀects which are possibly caused through the reduction of positive and extrapyramidal symptoms have been excluded. The estimate from the path model showed that even after statistical control for indirect eﬀects on secondary negative symptoms, risperidone improved negative symptoms to a greater extent than haloperidol.
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