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Negative symptoms are a key feature of schizophrenia. Novel (atypical) antipsychotic drugs, unlike conventional antipsychotics, cause substantial reductions in Positive and Negative Symptom Scale (PANSS) scores. Negative symptoms, however, can arise from both the pathology of the disease (primary negative symptoms) and as side effects of antipsychotic drugs (secondary negative symptoms). Before the efficacy of a drug against negative symptoms can be determined, the physician must establish whether the positive results stem from reductions in primary negative symptoms or are merely due to improved extrapyramidal tolerability. Until recently, shortcomings in the design of clinical trials and the lack of distinction between primary and secondary symptoms made it impossible to answer this question. However, advances in clinical trial methodologies now make it possible to assess negative symptoms accurately, and a complex statistical approach, the path analysis, has been developed to differentiate between the direct and indirect effects of antipsychotic drugs on negative symptoms. With this approach, it has been shown that the efficacy of novel antipsychotics, such as sertindole, against negative symptoms is achieved largely through direct effects on primary negative symptoms. The requirements for an accurate assessment and differentiation of negative symptoms are outlined, and the importance of this for improving the treatment of schizophrenia is emphasized.
Negative symptoms are important features in schizophrenia, so in milder form they might also serve as indicators of "unexpressed" liability to schizophrenia among patients' adult relatives without schizophrenia. To address this question, we assessed negative symptoms in 39 stable schizophrenia or schizoaffective outpatients, 39 of their siblings, 38 well control probands, and 38 of their siblings. Negative symptom measures included standard behavior ratings of the core negative symptoms of affective flattening and alogia, as well as a self-report measure of social anhedonia. As expected, even stable outpatients with schizophrenia exhibited significantly more negative symptoms than control probands and control siblings. However, negative behavioral symptoms of affective flattening, alogia, and anhedonia did not significantly differentiate the siblings of the schizophrenia patients from the control probands or their siblings, although there were some trends for anhedonia. The findings suggest that core negative symptoms of observed affective flattening and poverty of speech are not likely to be useful as strong indicators of "unexpressed" liability to schizophrenia.
Negative symptoms have been assessed in 34 cases of major endogenous depression (RDC) using the Scale for Assessment of Negative Symptoms. Correlation coefficients between negative symptoms and improvement rated on a 5-point scale were determined. Poverty of speech, affective flattening and avolition-apathy were found to be related with poor outcome. There was also a negative relationship between improvement and certain frequently occurring negative symptoms: inability to feel emotions, feelings of emptiness in thinking and feeling of avolition. High total negative symptom scores predicted poor outcome.
Negative symptoms have been associated with structural impairment in the PFC, and hypothesized to arise from a central hypodopaminergic substrate. Corticofugal PFC neurons, which are inhibited by VTA DA innervation, exert a tonic excitatory modulation on DA activity in the NAS. Lesions of ascending DA forebrain projections "uncouple" the functional link between D1 and D2 receptors, permitting independent activation of D1 sites in generating behavioral output. A previously identified absence of this D1/D2 link in schizophrenic brain suggests that functional activation of PFC D1 receptors may induce hyperinhibition of descending corticofugal efferents to the NAS. Consequent hypoactivity of DA in the NAS is proposed to give rise to negative symptoms of schizophrenia, and low dose DA agonist treatments may mimic behavioral features of this symptom profile via direct PFC D1 stimulation. It follows that clozapine's efficacy for negative symptoms may be attributable, in part, to blockade of PFC D1 receptors, with subsequent enhancement of glutamate-facilitated NAS DA activity.
Negative symptoms of schizophrenia remain an area of substantial unmet clinical need. By convening a consensus conference in January 2005, the NIMH has taken a leading role in stimulating a resurgence of interest in methodological considerations related to development of new medications for treating negative symptoms. One audience for this work is clinical researchers in industry. They must take ideas, like those emerging from this consensus meeting, and determine whether they can be applied to their global trials in order to meet the needs of a broad group of customers, which include patients, clinicians, regulators, and payers. This article takes the ideas that surfaced from the NIMH consensus work and interprets them in terms of issues that industry faces for its clinical trials. Particular emphasis is given to addressing hurdles to study design and analysis that come when developing broad-spectrum or adjunctive agents that may be effective for negative symptoms.
Interest in the distinction between positive and negative symptoms has reached a peak in the last decade and has led to research in different fields like phenomenology, ethiopathogenesis, treatment, course and outcome. Which symptoms are considered positive or negative varies across different authors, although there seems to be agreement on a core syndrome. The definition problems can be also found in the rating scales used for measuring positive and negative symptoms. The positive/negative distinction may represent different manifestations of a common underlying process. It also may suggest the existence of different pathophysiologies in schizophrenia. Since both positive and negative symptoms are frequent in schizophrenia, they are most likely not completely independent. The negative/positive syndrome is not sufficient to describe the dimensions of the complex phenomenology of schizophrenia. Among others, a depressive syndrome needs to be integrated. There is much controversy concerning the course of positive and negative symptoms over time. In subacute and chronic patients the negative syndrome seems to be more stable than the positive syndrome. The differentiation between primary and secondary negative symptoms seems to have great relevance to clinical and research aspects. This differentiation is an important factor in the interpretation of neuroleptic trials on negative symptoms. One way of differentiating between direct and indirect drug effects on negative symptoms is to use sophisticated statistical procedures, for example path analysis.
To determine whether depression and neuroleptic-induced parkinsonism confound the clinical assessment of negative symptoms in schizophrenics, we evaluated 45 outpatient schizophrenics for depression, parkinsonian symptoms, and negative symptoms using standard clinical rating scales. Neuroleptic and anticholinergic dose and plasma activity were also determined. Associations between negative symptoms and these clinical and drug variables were examined using a multivariate statistical model. Negative symptoms were significantly correlated with several parkinsonian symptoms, some vegetative features of depression, and with anticholinergic dose. No significant correlations were found between negative symptoms and cognitive features of depression, or neuroleptic and anticholinergic plasma activity. These findings suggest that assessment criteria for negative symptoms, depression, and drug-induced parkinsonism overlap in treated schizophrenics. Strategies for differentiating these clinical syndromes are discussed.
The present study examined a prominent symptom subtype conception of the psychopathology of schizophrenia. It analysed the presumed dichotomy between hallucinations, delusions and formal thought disorder as positive symptoms and flattening of affect and poverty of speech as negative symptoms, and tested predictions concerning the nature of the mediating processes of positive and negative symptoms. Four different analyses were applied to the transcripts of speech produced by 9 normals, 10 chronic schizophrenics with only positive symptoms of whom 7 had incoherence of speech, and 9 chronic schizophrenics with only negative symptoms of whom 4 had poverty of speech. The conception of the nature of the mediating processes of positive and negative symptoms was not supported by the results. Further, a clear dichotomy between positive and negative symptom groups was not shown to exist, because positive speech disorder and negative speech disorder did not follow the presupposed dichotomy. Thus, contrary to existing conceptions of speech disorder in schizophrenia, both positive and negative speech disorder are marked by poverty of thought, as measured by the production of fewer and shorter ideas and lower speech variability.
Taking into account the wellknown frequency of depressive and extrapyramidal symptoms in schizophrenia and the rare studies about their evolution, several questions can be raised: How do these different symptoms move? Are there specific characters of each of them? First, stability of negative symptoms evaluated by the Scale for the Assessment of Negative Symptoms (SANS) was studied among 57 schizophrenic patients at admission and at discharge. The course of negative symptoms was compared to that of depressive MADRS (Montgomery et Asberg Depression Rating Scale) and akinetic symptoms (Extrapyramidal Symptom Rating Scale). All the subscores of the SANS decreased significantly but 4 items belonging to the affective flattening subscale and one item belonging to the alogia subscale did not vary significantly, showing the necessity of taking into account the individual items of the SANS rather than the subscale scores to evaluate the course of negative symptoms. Changes in all the SANS subscores except the alogia and anhedonia subscores were associated with variations in scores of other scales. Correlations between the changes of negative symptoms and the changes of depressive symptoms showed the necessity to do more specific scales, for example, scales for depression in schizophrenia. Langlois-Théry et al. (1994) evaluated among 53 schizophrenic patients stabilized with neuroleptic treatment, depressive symptomatology with Echelle de Ralentissement Dépressif (ERD, Widlöcher, 1983) and MADRS, negative symptomatology (Positive and Negative Syndrome Scale) and akinesia (ESRS), to determinate whether ERD composed of 3 subscores (motor, ideic and subjective) could be able to evaluate the depressive symptomatology, independently of the measures of negative and akinetic symptomatology.(ABSTRACT TRUNCATED AT 250 WORDS)
The Frankfurter Beschwerde-Fragebogen (FBF), assessing basic symptoms (B-S), and the Scale for the Assessment of Negative Symptoms (SANS) were administered to 30 patients satisfying DSM-III-R criteria for the diagnosis of schizophrenia. Considering the relationship between BS and negative symptoms (N-S), we identified the key role of the impairment of receptive and expressive language for the correlation of these two orders of phenomena.
Negative symptoms have emerged as a replicable factor of symptomatology within schizophrenia. Although rating scales provide assessments along dimensions of severity, categorization into a negative symptom subtype is typically conducted. A categorical view of negative symptoms is best reflected in the proposal that enduring, primary negative symptoms, or deficit symptoms, reflect a distinct subtype of schizophrenia . Despite an accumulation of findings that support a categorical conceptualization, the data are also consistent with a dimensional-only model where negative symptom subtypologies simply reflect an extreme on a continuum of severity. Using taxometric statistical methods , the present study examined whether a taxonic, or latent class, model best describes negative symptoms in a sample of 238 schizophrenia patients. In order to obtain more stable estimates of symptoms, ratings on the Scale for the Assessment of Negative Symptoms [Andreasen, N.C., 1982. Negative symptoms in schizophrenia: Definition and reliability. Arch. Gen. Psychiatry 39, 784-788.] were averaged across two assessments over a 6-month period. Two taxometric methods, maximum covariance analysis (MAXCOV) and mean above minus below a cut (MAMBAC) identified a latent class or taxon with a base rate of approximately 28-36%. Members of the negative symptom taxon differed from the nontaxon class in that taxon members were more likely to be male and demonstrated poorer social functioning. Taxon and nontaxon schizophrenia patients did not differ in psychotic or affective symptoms. The findings converge to provide support for a categorical view of negative symptoms. Further research is required to replicate the present taxonic findings and to examine characteristics (including possible etiological factors) associated with this negative symptom taxon.
Coined by Sifneos in 1972, alexithymia refers to a relative narrowing in emotional functioning, an inability to find appropriate words to describe their emotions and, a poverty of fantasy life. Although initially described in the context of psychosomatic illness, alexithymic characteristics may be observed in patients with a wide range of medical and psychiatric disorders: Parkinson disease, depression, anxiety, substance abuse and eating disorders. Flattening of affect and poverty of speech, major negative symptoms, referred to chronic schizophrenia: there is a lack of outward display of emotion. Accordingly, some disturbances of alexithymia's scores would be expected in schizophrenic patients. The purpose of this study was to estimate and compare the prevalence of alexithymia in deficit and non-deficit schizophrenia. The term "deficit symptoms" may be used as Carpenter, to refer specifically to those negative symptoms that are not considered secondary. The influence of patients' symptoms has also been studied on alexithymia scores: negative and positive symptoms of schizophrenia, depression, anxiety, anhedonia and effects of neuroleptics. Twenty-five patients, meeting DSM III-R criteria for schizophrenia have been studied. All of them treated by neuroleptics, were in a stable clinical status for at least one month. The patients have been categorized into deficit (n = 12) and non-deficit (n = 13) subgroups by one trained psychiatrist (SD), using the Schedule for the Deficit Syndrome. The subjects have been assessed by the same rater (IN), blind to deficit status, using six rating scales: Beth Israel Questionnaire (BIQ) and Toronto Alexithymia Scale (TAS) for alexithymia, Positive and Negative Syndrome Scale (PANSS), Montgomery and Asberg Depression Rating Scale (MADRS), revised Physical Anhedonia Scale (PAS), and finally, Extrapyramidal Symptom Rating Scale (ESRS). Using TAS, alexithymic characteristics were more prevalent in the deficit subgroup as compared to non-deficit subgroup (83% versus 30.76%; p < 0.01). Significant correlations were observed in the non-deficit subgroup between: TAS and anxiety (r = 0.743; p < 0.01), TAS and depression (r = 0.568; p < 0.05), BIQ and blunted affect (r = 0.636; p < 0.02), BIQ and poverty of speech (r = 0.629; p < 0.02). These correlations were not significant in the deficit group of patients. Alexithymia in schizophrenic patients seems to be a trait characteristic in deficit patients, and a state related to many symptoms, such as flattening of affect, poverty of speech, depression and anxiety in nondeficit patients.
In a double-blind, placebo-controlled trial of treatment with the neuroleptic pimozide, negative symptoms improved in schizophrenic patients who showed an antipsychotic response. Furthermore, there was a significant positive correlation between changes in positive and negative symptoms for the group as a whole, including both pimozide responders and nonresponders. In our patient sample, neuroleptic treatment did not exert a differential effect on the positive and negative symptoms of schizophrenia. It is conceivable that negative symptoms are state dependent and may become neuroleptic nonresponsive over time just as positive symptoms do in some chronic patients.
It is recognized that persons with schizophrenia tend to cope with stress in a relatively avoidant and ineffectual manner and that this coping style is linked to poorer outcome. Less is understood, however, about the interrelationship between symptoms, deficits in neurocognition and coping style in schizophrenia. To determine the extent to which various neurocognitive deficits and symptoms are related to coping style in schizophrenia, measures of positive symptoms, negative symptoms, state and trait anxiety levels, verbal memory and executive function were correlated with self-report of preference for a range of active and avoidant coping strategies. Participants were 42 persons with schizophrenia spectrum disorders enrolled in outpatient psychiatric care. Stepwise multiple regressions indicated that greater preferences for taking action when faced with a stressor were significantly (p<.05) linked to lesser positive symptoms and lesser state anxiety while greater preferences for thinking or talking about possible solutions were linked to lesser impairments in neurocognition. A greater preference for resigning in the face of stress was significantly linked to greater levels of negative symptoms and trait anxiety, while a preference to ignore stressors was linked to both greater levels of positive symptoms and graver impairments in neurocognition. Implications for understanding the genesis of psychosocial dysfunction and for the development of rehabilitative interventions are discussed.
Definitions of negative symptoms and deficit syndromes are reviewed in this article; rating scale criteria (the Scale for Assessment of Negative Symptoms and the Positive and Negative Syndrome Scale); Crow's type II syndrome; Carpenter's deficit syndrome; and the draft of DSM-IV. The core negative symptoms identified by these investigators also describe the neuroleptic-induced deficit syndrome (NIDS). Study designs and assessment methods to distinguish NIDS from the symptoms of schizophrenia are presented. Assessment methods include rating scales and a novel method that uses descriptive symptom vignettes. Designs include neuroleptic discontinuation studies, dose comparisons and comparison of atypical antipsychotic medicines to typical neuroleptic drugs.
The high-frequency repetitive transcranial magnetic stimulation (HF-rTMS) over the prefrontal cortex is a promising method for the treatment of negative symptoms of schizophrenia. Using double-blind sham-controlled parallel design, we evaluated the effect of HF-rTMS over the left dorsolateral prefrontal cortex (DLPFC) on negative symptoms in patients with schizophrenia. Sixteen schizophrenia patients with predominantly negative symptoms on stable antipsychotic medication were treated with 20 Hz rTMS (90% of motor threshold, 2000 stimuli per session) over ten days within 2 weeks with six weeks follow-up. The effect was assessed using PANSS, CGI, MADRS and neuropsychological tests. We failed to find any significant effect of active rTMS. Sham rTMS showed a trend for improvement over time on positive and negative subscales of PANSS and MADRS. Between-group comparisons failed to reveal any significant differences on any rating scales except a positive subscale of PANSS after 8 weeks. Results from our study did not confirm that HF-rTMS over the left DLPCF affects the negative symptoms of schizophrenia and alternative rTMS approaches are discussed.
Seventy schizophrenia patients and 97 depressives were studied prospectively while in the hospital and at periodic follow-ups. Positive symptoms, negative symptoms, and post-hospital functioning were assessed at the 2-year follow-up; and suicidal activity, at the 7.5-year follow-up. The results support an interactive model of suicide risk. Psychotic symptoms (i.e., hallucinations, delusions) predict later suicidal activity only for the schizophrenia patients. Deficit symptoms (psychomotor retardation, concreteness) predict later suicidal activity only for the depressive group. Adequacy of overall functioning predicts later suicidal activity for both diagnostic groups and appears to mediate the effects of psychosis in the schizophrenia group.