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Deficit schizophrenia: An overview of clinical, biological and treatment aspects
European Psychiatry 24 (2009) 493–500
Review
Deficit schizophrenia: An overview of clinical, biological and treatment aspects S. Galderisi *, M. Maj Department of Psychiatry, Medical School, University of Naples SUN, Largo Madonna delle Grazie, 80134 Naples, Italy Received 21 July 2008; received in revised form 18 March 2009; accepted 19 March 2009 Available online 23 June 2009
Abstract The concept of deficit schizophrenia is regarded as one of the most promising attempts to reduce heterogeneity within schizophrenia. This paper summarizes the clinical, neurocognitive, brain imaging and electrophysiological correlates of this subtype of schizophrenia. Attempts to identify genetic and non-genetic risk factors are reviewed. Methodological limitations of studies supporting the efficacy of atypical antipsychotics in the treatment of the syndrome are highlighted. Two decades of research on deficit schizophrenia have failed to prove that it represents the extreme end of a severity continuum in schizophrenia, while some findings support the claim that it may be a separate disease entity. # 2009 Elsevier Masson SAS. All rights reserved. Keywords: Deficit Schizophrenia; Nondeficit schizophrenia; Heterogeneity; Schizophrenia subtypes; MRI; Genetic
1. Introduction Heterogeneity within schizophrenia has been acknowledged since the first descriptions of the disease. The original Kraepelinian description of dementia praecox already identified ‘‘two maladies’’ within the syndrome, a weakening of the will and the loss of unity of mental processes. The description of the former maladie provided by Kraepelin [57] is at the core of several attempts to identify a subtype of schizophrenia characterized by a ‘‘weakening of those emotional activities which permanently form the mainsprings of volition. . . emotional dullness, failure of mental activities, loss of mastery over volition, of endeavor and of ability for independent action’’. The notion of negative symptoms as a primary aspect of schizophrenia has been reproposed in the 1980s [2,18]. A large body of research, however, has highlighted several limitations of the positive/negative dichotomy, including its lack of diagnostic stability over time [37,66], its scarce prognostic implications [4,76], the inconsistency of the findings provided by correlational studies [30,38,60,79], and the failure of investigations based on factor analysis to support the twosyndrome model [62,75]. Heterogeneity within the positive and
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negative psychopathological domains might account for these limitations. As a matter of fact, different correlates have been reported for hallucination/delusion vs disorganization [30,62] as well as for enduring vs phasic negative symptoms [84,87]. In particular, heterogeneity within negative symptoms has been largely documented by studies showing that these symptoms may be secondary to identifiable sources, such as positive symptoms, treatment with antipsychotics or social isolation, and that the distinction between secondary and primary negative symptoms bears important therapeutic implications, since the former are susceptible of improvement following drug treatment, while the latter are likely to persist in spite of treatment with either conventional or second-generation antipsychotics. In 1988, Carpenter et al. [16] introduced the concept of deficit schizophrenia to identify a relatively homogeneous subgroup of patients with a diagnosis of schizophrenia, characterized by the presence of primary and enduring negative symptoms. They also suggested that deficit schizophrenia represent a different disease entity with respect to non-deficit schizophrenia. According to epidemiological data, deficit schizophrenia is a rare but persistent condition: among patients with schizophrenia, its prevalence is 15% in first-episode patients, 25–30% in clinical samples and 14–17% in population studies [49]. Its longitudinal stability is suggested by both retrospective [26,43]
0924-9338/$ – see front matter # 2009 Elsevier Masson SAS. All rights reserved. doi:10.1016/j.eurpsy.2009.03.001
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and prospective studies [1] (Galderisi et al., in preparation), reporting a degree of agreement higher than 80% between the first and the second diagnostic evaluation. 2. Diagnostic instruments for deficit schizophrenia The gold standard for the diagnosis of deficit schizophrenia is represented by the operational criteria of the Schedule for the Deficit Syndrome (SDS) [44], a semistructured interview that can be carried out by psychiatrists, psychologists or social workers with a large clinical experience in patients with schizophrenia. The deficit/non-deficit categorization is based on the interview with the patient, and the use of information provided by clinical records, relatives and health professionals well acquainted with patient’s past and present psychopathological state. All information should focus on times of clinical stability, as the categorization has no validity when made during acute psychotic states. The use of the SDS requires a training, involving accurate reading of information contained in the schedule, participating in a session led by an expert of the use of the instrument, viewing three audiovisual recorded interviews, evaluating at least three cases, discussing the evaluated cases with the expert and calculating the interrater coefficient of agreement. Although the diagnosis of deficit schizophrenia is a difficult one, especially for the need of ascertaining whether negative symptoms are primary or secondary, the interrater agreement is reported to be good, ranging from 0.73 to 1 for the overall classification into deficit or non-deficit subtype and from 0.60 to 0.81 for each of the six negative symptoms whose assessment is required for the categorization. Kirkpatrick et al. [42] provided data supporting the possibility of using the Proxy for the Deficit Syndrome (PDS) to diagnose deficit schizophrenia. The PDS is based on the subtraction of the Brief Psychiatric Rating Scale (BPRS) scores on affective items anxiety, guilt feelings, depressive mood and hostility from the item blunted affect, and, when compared with the gold standard evaluation, shows sensitivity and specificity rates of 79% and 89%, respectively. More recently, two proxy measures for the deficit syndrome based on the Positive and Negative Syndrome Scale (PANSS) have been evaluated [32]: the PDS1, based on an algorithm in which the score for the PANSS affective scale (anxiety, guilt, depression and hostility) is subtracted from the score for blunted affect, and the PDS2, in which only depression is subtracted from blunted affect. The two measures demonstrated good specificity (78.6% and 79.5%) and moderate to very good sensitivity (61.4% and 86.4%). 3. Clinical characteristics Patients with deficit schizophrenia differ from those with non-deficit schizophrenia on variables related to the syndrome construct (i.e., more negative symptoms) [26,29,46], but also for a lower prevalence of suspiciousness, dysphoria [26,43], hostility [29], suicidal ideation [25,26] and substance abuse [41]. A comparable severity of positive symptoms has been reported in the two groups [16,29,45,53].
Patients with deficit schizophrenia are also characterized by more severe neurological impairment. Using the Neurological Examination Scale (NES) [12], Buchanan et al. [13] observed worse ‘‘sensory integration’’ in patients with deficit than in those with non-deficit schizophrenia. Arango et al. [3] confirmed that deficit schizophrenia, but not negative symptoms as a whole, was associated with a lower score on the NES ‘‘sensory integration’’ subscale. Galderisi et al. [29] reported that patients with deficit schizophrenia were more impaired than those with non-deficit schizophrenia on the NES subscales ‘‘sensory integration’’, ‘‘motor coordination’’ and ‘‘sequences of complex motor acts’’. At odds with Arango et al.’s findings, a stepwise multiple regression analysis indicated that, after partialling out the influence of extrapyramidal symptoms, the deficit/non-deficit categorization was the only clinical variable entering the regression equation on the factor ‘‘sequencing of complex motor acts’’, while negative symptoms on the whole were associated with the factor ‘‘sensory integration’’. 4. Historical findings According to several investigators, psychosocial functioning is poorer in patients with deficit compared with non-deficit schizophrenia before the appearance of psychotic symptoms [13,26,29,40,53]. Studies using the Premorbid Adjustment Scale (PAS) [15] reported that, in deficit schizophrenia patients, premorbid adjustment is poor in all developmental stages, while in those with non-deficit schizophrenia the impairment appears in late adolescence or early adulthood [13,29]. Galderisi et al. [29] reported that the deficit/non-deficit categorization was significantly associated with childhood and early adolescence scores on the PAS, while negative symptoms as a whole were associated with the late adolescence score. The findings were considered in line with Buchanan et al.’s hypothesis that subjects with deficit schizophrenia represent an early onset subgroup, in which poor premorbid adjustment during childhood and early adolescence might represent the onset of deficit symptoms. 5. Stability of the diagnosis and long-term outcome Amador et al. [1] reported that deficit and non-deficit schizophrenia patients, when reassessed after an average of 3.8 years by independent raters, blind to their initial categorization, received the same diagnoses in 83% and 88% of cases, respectively. Data from an Italian follow-up study, in which patients were reassessed after at least 5 years, confirm that deficit and non-deficit schizophrenia subtypes are characterized by a high degree of longitudinal stability (Galderisi et al., in preparation). Long-term prognosis is worse in patients with deficit compared with non-deficit schizophrenia. The Strauss-Carpenter Outcome Scale (SCOS) [85] was used by Fenton and McGlashan [26] in a retrospective study in which the deficit/non-deficit categorization was made on the basis of chart records. They found that, at an average of 19 years’ follow-up, the outcome was significantly poorer in patients with deficit schizophrenia, despite a similar severity of delusions, hallucinations and thought
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disorder in the two groups. Kirkpatrick et al. [42,43] confirmed the stability of the clinical characteristics of patients with deficit and non-deficit schizophrenia after 1 to 2.5 years’ follow-up. Tek et al. [88] carried out a prospective study in which 46 patients with deficit schizophrenia and 174 patients with non-deficit schizophrenia were assessed after an average of 5 years: at follow-up, patients with deficit schizophrenia had a poorer quality of life, a poorer social and occupational functioning and more severe negative symptoms, but were less distressed and did not show more severe positive symptoms or thought disorder. The poorer outcome in deficit schizophrenia patients may also result from inefficacy of antipsychotic drugs on primary negative symptoms [7,10]. In fact, both first and second-generation antipsychotics may act on secondary negative symptoms by removing, in part or completely, some of their causes, such as positive symptoms, depression or extrapyramidal symptoms, but so far no conclusive evidence has been provided of their efficacy on primary and persistent negative symptoms. 6. Neurocognitive findings Neurocognitive studies have reported a significantly poorer performance on tests sensitive to frontal and parietal lobe dysfunction, but not on tests assessing temporal lobe functioning, in patients with deficit compared with non-deficit schizophrenia [8,14]. In an Italian study, the two patient subgroups did not show statistically significant differences in any neurocognitive domain, except global cognition (as measured by Intelligence Quotient [IQ]), which was more impaired in deficit schizophrenia patients [29]. A recent metaanalysis of neurocognitive findings [17] revealed that deficit patients were globally more neuropsychologically impaired than non-deficit patients (effect size [ES] = 0.41). Most ES were small, while those for tests of olfaction (ES = 1.11), social cognition (ES = 0.56), global cognition (ES = 0.52), and language (ES = 0.51) were moderate, suggesting that the neuropsychological impairment of deficit patients does not reflect either frontoparietal dysfunction or any other anatomically defined pattern of impairment. At the same time, the metaanalysis failed to support the hypothesis that deficit schizophrenia is the more severe end of a severity continuum in schizophrenia: if it were so, the greatest ES should be found for attention, working memory and cognitive flexibility, i.e. the domains involved in the neuropsychological profile generally observed in schizophrenia. More recently, Polgar et al. [77] used the ‘‘chaining habit learning task’’, in which participants were requested to navigate a cartoon character through a sequence of four rooms. The task includes a training phase, dominantly related to basal ganglia circuits, and a context-dependent probe phase, requiring intact medial-temporal lobe functioning. Both deficit and non-deficit patients were impaired on the context dependent probe phase of the task, but only deficit patients showed impairment during the learning phase, suggesting abnormal functioning of basal ganglia circuits. Correlational analysis revealed that errors during the latter phase were related to the severity of negative symptoms. As no analysis was provided aimed at disentangling
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the contribution of negative symptoms, deficit/non-deficit categorization, and treatment with first-generation antipsychotics, the relevance of the finding to deficit schizophrenia pathogenesis is to be demonstrated. 7. Brain imaging findings Magnetic resonance imaging (MRI) studies do not support the hypothesis that deficit schizophrenia represents the more severe end of a severity continuum in schizophrenia, but fail to identify clear morphological correlates of the deficit syndrome. Buchanan et al. [11] found that patients with non-deficit schizophrenia had smaller right and left prefrontal volumes in comparison with both healthy controls and deficit schizophrenia patients, while the latter did not differ on prefrontal measures from controls. Both patient subgroups had larger left caudate volumes and smaller right and left amygdala/ hippocampus complex than controls; a trend toward a larger right caudate volume was observed in deficit patients only. Three studies found no ventricular enlargement in deficit vs non-deficit schizophrenia patients [31,34,78]. Sigmundsson et al. [83], in a group of patients with primary and enduring negative symptoms compared with healthy subjects, found no difference for the lateral ventricles, in spite of significant deficits of gray and white matter volume in the patient group involving the left temporal and frontal lobe. The failure to find ventricular enlargement in patients with deficit features is surprising, as this is one of the most replicated findings in schizophrenia and has often, but not consistently, been reported in association with negative symptoms and poor outcome. Turetsky et al. [90] reported abnormal temporal lobe asymmetry only in patients with deficit schizophrenia, in whom a selective increase in left temporal lobe cerebrospinal fluid volume was observed in comparison with both non-deficit patients and healthy controls. According to Galderisi et al. [31], two distinct processes may occur in deficit and non-deficit schizophrenia. In fact, more abnormal scans in patients with non-deficit schizophrenia might reflect progressive ventricular enlargement, possibly related to the excitotoxic effect of repeated psychotic episodes, and be associated with normal early premorbid adjustment and general cognitive abilities, while in patients with deficit schizophrenia less abnormal scans might result from an early onset nonprogressive developmental process, interfering since childhood with the acquisition of basic cognitive and social skills. Several functional brain imaging studies suggest an involvement of frontoparietal brain circuits in deficit schizophrenia. A reduction of glucose metabolism and of cerebral blood flow in the frontal [33,35,57,86,92] and parietal regions [33,58,86] was reported in patients with deficit as compared with non-deficit schizophrenia. Neuronal loss in prefrontal cortex is suggested by a proton magnetic resonance spectroscopy study reporting a lower N-acetylaspartate/creatine ratio in this region in a small sample of patients with deficit schizophrenia compared to non-deficit patients and healthy controls [21]. In a postmortem study, patients with deficit schizophrenia, but not those with non-deficit schizophrenia,
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were found to have an increased density of the white matter interstitial cells in the inferior parietal cortex and in the dorsolateral prefrontal cortex as compared with healthy controls, suggesting an abnormal placement of neurons in the white matter in the deficit subgroup [48,52]. These findings should be considered as preliminary, due to differences in imaging techniques among studies, small sample sizes and heterogeneous treatment conditions (patients were drug-free in some studies, drug-treated in others). 8. Electrophysiological findings The hypothesis that deficit and non-deficit schizophrenia represent distinct disease entities has been also tested in a few electrophysiological investigations. All of them should be considered as preliminary, due to the lack of adequate replication and small sample sizes. Ross et al. [82] reported a significant association between abnormalities of eye-tracking and deficit schizophrenia. Nkam et al. [73] did not find eye-tracking differences between deficit and non-deficit patients, while Hong et al. [36] found that the two subgroups and their unaffected relatives shared some oculomotor abnormalities (i.e. predictive pursuit), but only deficit patients and their relatives showed poor initiation performance. Bucci et al. [9] investigated evoked and induced 40-Hz gamma power (thought to reflect cortical integration processes), as well as frontoparietal and frontotemporal event-related coherence, in patients with deficit or non-deficit schizophrenia and in matched healthy controls. A reduction of both induced gamma power and event-related coherence was observed in deficit, but not in non-deficit patients, suggesting poor integration of the neuronal activity within distributed neural network only in non-deficit schizophrenic patients. Turetsky et al. [91] investigated a putative endophenotype of schizophrenia, i.e. the left lateralized amplitude reduction of the P3 component of the event-related potentials. They found that the abnormality was present in the group with non-deficit schizophrenia, while in the deficit group the component was mainly reduced at the right parietal site. Mucci et al. [70] recorded event-related potentials during an auditory discrimination task and found evidence of a double dissociation: for N1, only deficit patients, as compared with healthy controls, showed an amplitude reduction over the scalp central leads and a reduced activity of the component generators in cingulated and parahippocampal gyrus. For P3, only non-deficit patients, as compared with healthy controls, showed a lateralized amplitude reduction over the left posterior regions and reduced generator activity in left temporal and bilateral frontal, cingulated and parietal areas. The deficit and non-deficit groups differed significantly from each other with regard to N1 amplitude and topography, as well as P3 amplitude and cortical sources. 9. Risk factors There is evidence that family history represents a risk factor for deficit schizophrenia. In fact, a greater risk of schizophrenia in relatives of probands with deficit than non-deficit schizo-
phrenia has been reported in some [24,54], but not all studies [65]. A lower risk for other psychiatric disorders has been found in relatives of probands with deficit vs non-deficit schizophrenia [54]. More severe social withdrawal was reported in nonpsychotic relatives of probands with deficit compared with nondeficit schizophrenia, in spite of reduced dysphoria and subclinical psychotic experiences [54]. The deficit/non-deficit categorization shows a high concordance rate in affected sibling pairs: i.e., deficit schizophrenia in one sibling predicts deficit schizophrenia in the other one, with an odds ratio of 3 [81]. The season of birth is a further double dissociation finding: in contrast with the repeatedly reported finding of a predominance of winter birth in schizophrenia [20], an association between summer birth and deficit schizophrenia has been found by several independent groups [23,42,47,50,55,68,88]. An analysis of pooled data from six different countries in the northern hemisphere reported an increased birth in June and July in deficit schizophrenia patients (odds ratio 1.9) [67]. Associations with viral infections as potential risk factors have also been investigated. An unreplicated association between Borna virus and deficit schizophrenia was reported [94]. More recently, deficit schizophrenia was found to be associated with the presence of serum antibodies to cytomegalovirus (odds ratio = 2.01), but not with other herpes virus antibodies [22]. 10. Genetic findings Genetic studies of deficit schizophrenia are in their infancy. Few investigations have been carried out so far, and their value is limited by small sample sizes and lack of replication. Minoretti et al. [69] investigated whether the functional singlenucleotide polymorphism (SNP) T393C in GNAS1 gene was involved in the risk of schizophrenia, and whether a specific association existed between the deficit and non-deficit forms of the disorder. They found that the frequency of the homozygous 393TT genotype was significantly higher in deficit schizophrenia patients compared to both non-deficit schizophrenia patients and healthy controls. The odds ratio after adjustment for potential confounders was 2.06. Wonodi et al. [95] investigated the association of the functional polymorphism Val 158 Met in the catechol-O-methyltransferase (COMT) gene with schizophrenia and its deficit/non-deficit subtypes and reported a significant difference in Val/Val genotype frequencies between schizophrenia cases (combined deficit/nondeficit) and healthy controls ( p = 0.004), but no difference in allele or genotype frequencies between deficit and non-deficit cases. Galderisi et al. [27,28] found no association between the same polymorphism and either schizophrenia or its deficit/nondeficit subtypes. In the whole sample of patients with schizophrenia, they found an association between the COMT Val 158 Met polymorphism and executive/attention dysfunction, while only in the subgroup with deficit schizophrenia they observed an association between the same polymorphism and motor impairment. In a recent association study, Bakker et al. [5] tested four schizophrenia candidate genes in patients with and without deficit schizophrenia, by genotyping SNP in the
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DTNBP1 (dysbindin), G72/G30, RGS4 and PIP5K2A genes. No specific association was found with the deficit subtype. In the absence of a strong candidate gene, large multicenter studies based on genome-wide scan seem to be the most appropriate strategy for future investigations. 11. Response to treatment While convincing evidence has been provided of the efficacy of second-generation antipsychotics on secondary negative symptoms, their impact on primary and persistent (deficit) ones remains controversial [10,51,55,59,63,89]. Methodological flaws account for this state of art: in the majority of trials suggesting efficacy of antipsychotics on deficit schizophrenia (or on primary negative symptoms), SANS or PANSS are used to assess negative symptoms, while these instruments do not capture the concept of deficit schizophrenia; some trials included acute patients, preventing conclusions concerning impact on primary vs secondary negative symptoms; most studies have an inadequate length, preventing conclusions relevant to primary and enduring negative symptoms. Amisulpride studies often claimed efficacy on deficit symptoms, especially at low doses. Leucht et al. [61], in a meta-analysis, came to the conclusion that, in patients suffering predominantly from persistent negative symptoms, amisulpride is significantly superior to placebo, but not to conventional antipsychotics. Four placebo-controlled studies were included in this meta-analysis [6,19,64,74]; none of them involved the use of the SDS for the diagnosis of deficit schizophrenia. In all of them, negative symptoms were considered primary based on the presence of high scores on the SANS (at least 60) and low scores on the Scale for the Assessment of Positive Symptoms (SAPS) (not higher than 50), and the primary efficacy measure was the change of SANS scores. The length of these studies ranged from 4 to 12 weeks, leaving open the possibility that, even when primary, the observed negative symptoms were not enduring. For all these reasons, the claim that amisulpride is efficacious on primary and persistent negative symptoms is not supported by adequate evidence so far. The study by Vaiva et al. [93] was not included in that meta-analysis. Nineteen patients with schizophrenia were treated with amisulpride 100 mg per day for 4 weeks and categorized as having deficit or non-deficit schizophrenia by using the SDS (though it is not clear whether an interview to patients and relatives was carried out). Changes of SANS scores, chosen as the efficacy measure, were higher in patients with non-deficit than in those with deficit schizophrenia. The study has several limitations, including a small sample size and the lack of a control arm. Several studies have compared the efficacy of clozapine vs haloperidol on primary and enduring negative symptoms. Breier et al. [7] treated two small groups of deficit schizophrenia patients with either clozapine or haloperidol and found no difference in the efficacy of the two drugs in
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treating negative symptoms. Buchanan et al. [10] compared the efficacy of the same drugs on negative symptoms in both deficit and non-deficit patients and reported that the two drugs yielded comparable effects on negative symptoms in both groups. Rosenheck et al. [80], in a large double blind 12-month study comparing clozapine and haloperidol, used a proxy measure to assign patients with refractory schizophrenia to either the deficit or non-deficit group, and reported no superiority of clozapine on clinical manifestations of the deficit syndrome. The other studies investigating the effects of clozapine on negative symptoms do not provide conclusive evidence of its efficacy on primary and enduring negative symptoms, due to the same limitations affecting amisulpride studies ([71] for a systematic review). Kopelowicz et al. [56] examined the effects of olanzapine on negative symptoms in 39 patients diagnosed as having deficit or non-deficit schizophrenia using the SDS, and found an improvement of positive, negative and extrapyramidal symptoms in the non-deficit group and an improvement of extrapyramidal symptoms only in the deficit group. They concluded that olanzapine is efficacious for secondary but not for primary negative symptoms of schizophrenia. At odds with these findings, Lindenmayer et al. [63] reported that olanzapine treatment was associated with significant improvement in primary negative symptoms, while haloperidol was not. Thirtyfive patients with schizophrenia, stable and with predominant negative symptoms, were enrolled. All of them satisfied the criteria for deficit schizophrenia as assessed by the SDS. Nineteen patients were assigned to the haloperidol (mean modal endpoint dose 17.11 mg per day), and 16 to the olanzapine group (mean modal endpoint dose 18.44 mg per day). The study design does not allow firm conclusions. In fact, patients fulfilling SDS criteria for deficit schizophrenia may have both primary and secondary negative symptoms; in the absence of a control group with non-deficit schizophrenia for each study arm, the possibility remains that the olanzapine group shows a reduction of the secondary negative symptoms, while the haloperidol group does not. In conclusion, findings for amisulpride and olanzapine might be considered promising, but certainly require validation from independent, placebo-controlled studies, including both deficit and non-deficit patients, matched at baseline on the severity of their negative symptoms. 12. Conclusions Two decades of research on deficit schizophrenia have failed to prove that it represents the extreme end of a severity continuum in schizophrenia. As a matter of fact, most of the studies have provided evidence that abnormalities observed in deficit schizophrenia are not more of the same observed in nondeficit schizophrenia, as we would expect in more severe forms of the same disease. Instead, some studies, especially those reporting double dissociation findings, suggest that deficit schizophrenia is a separate disease entity. However, for the time being, neither conclusion should be considered as the final one, because of the limited number of studies correctly addressing
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the topic, discrepancies in findings and small size of the enrolled patient samples. It is important to stress that not all patients considered as having ‘‘deficit schizophrenia’’ or ‘‘deficit state’’ actually correspond to the subtype described by Carpenter et al. The term deficit schizophrenia should be applied only to patients meeting the SDS diagnostic criteria, and even then, to ensure comparability with other studies, details on the training for the use of SDS should be reported. In fact, it is important to acknowledge that the diagnosis of deficit schizophrenia is a difficult one, requiring longitudinal evaluation, different sources of information and careful clinical inquiry to judge whether the observed negative symptoms should be considered as primary or secondary. The use of proxy measures is not sufficiently validated as an alternative to SDS, and must be very conservative. Further research involving independent groups and possibly multicenter studies recruiting large patient samples are clearly needed. Studies involving birth cohorts or individual at high risk for psychosis and focusing on primary and enduring negative symptoms during childhood and early adolescence might lead to the development of early intervention strategies preventing the full expression of the clinical picture. Furthermore, in the light of the recent investigations reporting that two factors can be identified in the SDS [39,72], future studies should clarify whether the two factors are actually associated with a different pattern of neurobiological correlates. Unfortunately, the low prevalence of the syndrome and the difficulties of the diagnostic process discourage many investigators and drug companies from investing more resources in this research area. References [1] Amador XF, Kirkpatrick B, Buchanan RW, Carpenter WT, Marcinko L, Yale SA. Stability of the diagnosis of deficit syndrome in schizophrenia. Am J Psychiatry 1999;156:637–9. [2] Andreasen NC, Olsen S. Negative versus positive schizophrenia. Arch Gen Psychiatry 1982;39:789–94. [3] Arango C, Kirkpatrick B, Buchanan RW. Neurological signs and the heterogeneity of schizophrenia. Am J Psychiatry 2000;157:560–5. [4] Arndt S, Andreasen NC, Flaum M, Miller D, Nopoulos P. A longitudinal study of symptoms dimensions in schizophrenia: prediction and patterns of changes. Arch Gen Psychiatry 1995;52:352–60. [5] Bakker SC, Hoogendoorn ML, Hendriks J, Verzijlbergen K, Caron S, Verduijn W, et al. The PIP5K2A and RGS4 genes are differentially associated with deficit and non-deficit schizophrenia. Genes Brain Behav 2007;6:113–9. [6] Boyer P, Lecrubier Y, Puech AJ, Dewailly J, Aubin F. Treatment of negative symptoms in schizophrenia with amisulpride. Br J Psychiatry 1995;166:68–72. [7] Breier A, Buchanan RW, Kirkpatrick B, Davis OR, Irish D, Summerfelt A, et al. Effects of clozapine on positive and negative symptoms in outpatients with schizophrenia. Am J Psychiatry 1994;151:20–6. [8] Bryson G, Whelahan HA, Bell M. Memory and executive function impairments in deficit syndrome schizophrenia. Psychiatry Res 2001;102:29–37. [9] Bucci P, Mucci A, Merlotti E, Volpe U, Galderisi S. Induced gamma activity and event-related coherence in schizophrenia. Clin EEG Neurosci 2007;38:97–104.
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Review
Deficit schizophrenia: An overview of clinical, biological and treatment aspects S. Galderisi *, M. Maj Department of Psychiatry, Medical School, University of Naples SUN, Largo Madonna delle Grazie, 80134 Naples, Italy Received 21 July 2008; received in revised form 18 March 2009; accepted 19 March 2009 Available online 23 June 2009
Abstract The concept of deficit schizophrenia is regarded as one of the most promising attempts to reduce heterogeneity within schizophrenia. This paper summarizes the clinical, neurocognitive, brain imaging and electrophysiological correlates of this subtype of schizophrenia. Attempts to identify genetic and non-genetic risk factors are reviewed. Methodological limitations of studies supporting the efficacy of atypical antipsychotics in the treatment of the syndrome are highlighted. Two decades of research on deficit schizophrenia have failed to prove that it represents the extreme end of a severity continuum in schizophrenia, while some findings support the claim that it may be a separate disease entity. # 2009 Elsevier Masson SAS. All rights reserved. Keywords: Deficit Schizophrenia; Nondeficit schizophrenia; Heterogeneity; Schizophrenia subtypes; MRI; Genetic
1. Introduction Heterogeneity within schizophrenia has been acknowledged since the first descriptions of the disease. The original Kraepelinian description of dementia praecox already identified ‘‘two maladies’’ within the syndrome, a weakening of the will and the loss of unity of mental processes. The description of the former maladie provided by Kraepelin [57] is at the core of several attempts to identify a subtype of schizophrenia characterized by a ‘‘weakening of those emotional activities which permanently form the mainsprings of volition. . . emotional dullness, failure of mental activities, loss of mastery over volition, of endeavor and of ability for independent action’’. The notion of negative symptoms as a primary aspect of schizophrenia has been reproposed in the 1980s [2,18]. A large body of research, however, has highlighted several limitations of the positive/negative dichotomy, including its lack of diagnostic stability over time [37,66], its scarce prognostic implications [4,76], the inconsistency of the findings provided by correlational studies [30,38,60,79], and the failure of investigations based on factor analysis to support the twosyndrome model [62,75]. Heterogeneity within the positive and
* Corresponding author. Tel.: +39 0815 666 504; fax +39 0815 666 523. E-mail address: [email protected] (S. Galderisi).
negative psychopathological domains might account for these limitations. As a matter of fact, different correlates have been reported for hallucination/delusion vs disorganization [30,62] as well as for enduring vs phasic negative symptoms [84,87]. In particular, heterogeneity within negative symptoms has been largely documented by studies showing that these symptoms may be secondary to identifiable sources, such as positive symptoms, treatment with antipsychotics or social isolation, and that the distinction between secondary and primary negative symptoms bears important therapeutic implications, since the former are susceptible of improvement following drug treatment, while the latter are likely to persist in spite of treatment with either conventional or second-generation antipsychotics. In 1988, Carpenter et al. [16] introduced the concept of deficit schizophrenia to identify a relatively homogeneous subgroup of patients with a diagnosis of schizophrenia, characterized by the presence of primary and enduring negative symptoms. They also suggested that deficit schizophrenia represent a different disease entity with respect to non-deficit schizophrenia. According to epidemiological data, deficit schizophrenia is a rare but persistent condition: among patients with schizophrenia, its prevalence is 15% in first-episode patients, 25–30% in clinical samples and 14–17% in population studies [49]. Its longitudinal stability is suggested by both retrospective [26,43]
0924-9338/$ – see front matter # 2009 Elsevier Masson SAS. All rights reserved. doi:10.1016/j.eurpsy.2009.03.001
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and prospective studies [1] (Galderisi et al., in preparation), reporting a degree of agreement higher than 80% between the first and the second diagnostic evaluation. 2. Diagnostic instruments for deficit schizophrenia The gold standard for the diagnosis of deficit schizophrenia is represented by the operational criteria of the Schedule for the Deficit Syndrome (SDS) [44], a semistructured interview that can be carried out by psychiatrists, psychologists or social workers with a large clinical experience in patients with schizophrenia. The deficit/non-deficit categorization is based on the interview with the patient, and the use of information provided by clinical records, relatives and health professionals well acquainted with patient’s past and present psychopathological state. All information should focus on times of clinical stability, as the categorization has no validity when made during acute psychotic states. The use of the SDS requires a training, involving accurate reading of information contained in the schedule, participating in a session led by an expert of the use of the instrument, viewing three audiovisual recorded interviews, evaluating at least three cases, discussing the evaluated cases with the expert and calculating the interrater coefficient of agreement. Although the diagnosis of deficit schizophrenia is a difficult one, especially for the need of ascertaining whether negative symptoms are primary or secondary, the interrater agreement is reported to be good, ranging from 0.73 to 1 for the overall classification into deficit or non-deficit subtype and from 0.60 to 0.81 for each of the six negative symptoms whose assessment is required for the categorization. Kirkpatrick et al. [42] provided data supporting the possibility of using the Proxy for the Deficit Syndrome (PDS) to diagnose deficit schizophrenia. The PDS is based on the subtraction of the Brief Psychiatric Rating Scale (BPRS) scores on affective items anxiety, guilt feelings, depressive mood and hostility from the item blunted affect, and, when compared with the gold standard evaluation, shows sensitivity and specificity rates of 79% and 89%, respectively. More recently, two proxy measures for the deficit syndrome based on the Positive and Negative Syndrome Scale (PANSS) have been evaluated [32]: the PDS1, based on an algorithm in which the score for the PANSS affective scale (anxiety, guilt, depression and hostility) is subtracted from the score for blunted affect, and the PDS2, in which only depression is subtracted from blunted affect. The two measures demonstrated good specificity (78.6% and 79.5%) and moderate to very good sensitivity (61.4% and 86.4%). 3. Clinical characteristics Patients with deficit schizophrenia differ from those with non-deficit schizophrenia on variables related to the syndrome construct (i.e., more negative symptoms) [26,29,46], but also for a lower prevalence of suspiciousness, dysphoria [26,43], hostility [29], suicidal ideation [25,26] and substance abuse [41]. A comparable severity of positive symptoms has been reported in the two groups [16,29,45,53].
Patients with deficit schizophrenia are also characterized by more severe neurological impairment. Using the Neurological Examination Scale (NES) [12], Buchanan et al. [13] observed worse ‘‘sensory integration’’ in patients with deficit than in those with non-deficit schizophrenia. Arango et al. [3] confirmed that deficit schizophrenia, but not negative symptoms as a whole, was associated with a lower score on the NES ‘‘sensory integration’’ subscale. Galderisi et al. [29] reported that patients with deficit schizophrenia were more impaired than those with non-deficit schizophrenia on the NES subscales ‘‘sensory integration’’, ‘‘motor coordination’’ and ‘‘sequences of complex motor acts’’. At odds with Arango et al.’s findings, a stepwise multiple regression analysis indicated that, after partialling out the influence of extrapyramidal symptoms, the deficit/non-deficit categorization was the only clinical variable entering the regression equation on the factor ‘‘sequencing of complex motor acts’’, while negative symptoms on the whole were associated with the factor ‘‘sensory integration’’. 4. Historical findings According to several investigators, psychosocial functioning is poorer in patients with deficit compared with non-deficit schizophrenia before the appearance of psychotic symptoms [13,26,29,40,53]. Studies using the Premorbid Adjustment Scale (PAS) [15] reported that, in deficit schizophrenia patients, premorbid adjustment is poor in all developmental stages, while in those with non-deficit schizophrenia the impairment appears in late adolescence or early adulthood [13,29]. Galderisi et al. [29] reported that the deficit/non-deficit categorization was significantly associated with childhood and early adolescence scores on the PAS, while negative symptoms as a whole were associated with the late adolescence score. The findings were considered in line with Buchanan et al.’s hypothesis that subjects with deficit schizophrenia represent an early onset subgroup, in which poor premorbid adjustment during childhood and early adolescence might represent the onset of deficit symptoms. 5. Stability of the diagnosis and long-term outcome Amador et al. [1] reported that deficit and non-deficit schizophrenia patients, when reassessed after an average of 3.8 years by independent raters, blind to their initial categorization, received the same diagnoses in 83% and 88% of cases, respectively. Data from an Italian follow-up study, in which patients were reassessed after at least 5 years, confirm that deficit and non-deficit schizophrenia subtypes are characterized by a high degree of longitudinal stability (Galderisi et al., in preparation). Long-term prognosis is worse in patients with deficit compared with non-deficit schizophrenia. The Strauss-Carpenter Outcome Scale (SCOS) [85] was used by Fenton and McGlashan [26] in a retrospective study in which the deficit/non-deficit categorization was made on the basis of chart records. They found that, at an average of 19 years’ follow-up, the outcome was significantly poorer in patients with deficit schizophrenia, despite a similar severity of delusions, hallucinations and thought
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disorder in the two groups. Kirkpatrick et al. [42,43] confirmed the stability of the clinical characteristics of patients with deficit and non-deficit schizophrenia after 1 to 2.5 years’ follow-up. Tek et al. [88] carried out a prospective study in which 46 patients with deficit schizophrenia and 174 patients with non-deficit schizophrenia were assessed after an average of 5 years: at follow-up, patients with deficit schizophrenia had a poorer quality of life, a poorer social and occupational functioning and more severe negative symptoms, but were less distressed and did not show more severe positive symptoms or thought disorder. The poorer outcome in deficit schizophrenia patients may also result from inefficacy of antipsychotic drugs on primary negative symptoms [7,10]. In fact, both first and second-generation antipsychotics may act on secondary negative symptoms by removing, in part or completely, some of their causes, such as positive symptoms, depression or extrapyramidal symptoms, but so far no conclusive evidence has been provided of their efficacy on primary and persistent negative symptoms. 6. Neurocognitive findings Neurocognitive studies have reported a significantly poorer performance on tests sensitive to frontal and parietal lobe dysfunction, but not on tests assessing temporal lobe functioning, in patients with deficit compared with non-deficit schizophrenia [8,14]. In an Italian study, the two patient subgroups did not show statistically significant differences in any neurocognitive domain, except global cognition (as measured by Intelligence Quotient [IQ]), which was more impaired in deficit schizophrenia patients [29]. A recent metaanalysis of neurocognitive findings [17] revealed that deficit patients were globally more neuropsychologically impaired than non-deficit patients (effect size [ES] = 0.41). Most ES were small, while those for tests of olfaction (ES = 1.11), social cognition (ES = 0.56), global cognition (ES = 0.52), and language (ES = 0.51) were moderate, suggesting that the neuropsychological impairment of deficit patients does not reflect either frontoparietal dysfunction or any other anatomically defined pattern of impairment. At the same time, the metaanalysis failed to support the hypothesis that deficit schizophrenia is the more severe end of a severity continuum in schizophrenia: if it were so, the greatest ES should be found for attention, working memory and cognitive flexibility, i.e. the domains involved in the neuropsychological profile generally observed in schizophrenia. More recently, Polgar et al. [77] used the ‘‘chaining habit learning task’’, in which participants were requested to navigate a cartoon character through a sequence of four rooms. The task includes a training phase, dominantly related to basal ganglia circuits, and a context-dependent probe phase, requiring intact medial-temporal lobe functioning. Both deficit and non-deficit patients were impaired on the context dependent probe phase of the task, but only deficit patients showed impairment during the learning phase, suggesting abnormal functioning of basal ganglia circuits. Correlational analysis revealed that errors during the latter phase were related to the severity of negative symptoms. As no analysis was provided aimed at disentangling
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the contribution of negative symptoms, deficit/non-deficit categorization, and treatment with first-generation antipsychotics, the relevance of the finding to deficit schizophrenia pathogenesis is to be demonstrated. 7. Brain imaging findings Magnetic resonance imaging (MRI) studies do not support the hypothesis that deficit schizophrenia represents the more severe end of a severity continuum in schizophrenia, but fail to identify clear morphological correlates of the deficit syndrome. Buchanan et al. [11] found that patients with non-deficit schizophrenia had smaller right and left prefrontal volumes in comparison with both healthy controls and deficit schizophrenia patients, while the latter did not differ on prefrontal measures from controls. Both patient subgroups had larger left caudate volumes and smaller right and left amygdala/ hippocampus complex than controls; a trend toward a larger right caudate volume was observed in deficit patients only. Three studies found no ventricular enlargement in deficit vs non-deficit schizophrenia patients [31,34,78]. Sigmundsson et al. [83], in a group of patients with primary and enduring negative symptoms compared with healthy subjects, found no difference for the lateral ventricles, in spite of significant deficits of gray and white matter volume in the patient group involving the left temporal and frontal lobe. The failure to find ventricular enlargement in patients with deficit features is surprising, as this is one of the most replicated findings in schizophrenia and has often, but not consistently, been reported in association with negative symptoms and poor outcome. Turetsky et al. [90] reported abnormal temporal lobe asymmetry only in patients with deficit schizophrenia, in whom a selective increase in left temporal lobe cerebrospinal fluid volume was observed in comparison with both non-deficit patients and healthy controls. According to Galderisi et al. [31], two distinct processes may occur in deficit and non-deficit schizophrenia. In fact, more abnormal scans in patients with non-deficit schizophrenia might reflect progressive ventricular enlargement, possibly related to the excitotoxic effect of repeated psychotic episodes, and be associated with normal early premorbid adjustment and general cognitive abilities, while in patients with deficit schizophrenia less abnormal scans might result from an early onset nonprogressive developmental process, interfering since childhood with the acquisition of basic cognitive and social skills. Several functional brain imaging studies suggest an involvement of frontoparietal brain circuits in deficit schizophrenia. A reduction of glucose metabolism and of cerebral blood flow in the frontal [33,35,57,86,92] and parietal regions [33,58,86] was reported in patients with deficit as compared with non-deficit schizophrenia. Neuronal loss in prefrontal cortex is suggested by a proton magnetic resonance spectroscopy study reporting a lower N-acetylaspartate/creatine ratio in this region in a small sample of patients with deficit schizophrenia compared to non-deficit patients and healthy controls [21]. In a postmortem study, patients with deficit schizophrenia, but not those with non-deficit schizophrenia,
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were found to have an increased density of the white matter interstitial cells in the inferior parietal cortex and in the dorsolateral prefrontal cortex as compared with healthy controls, suggesting an abnormal placement of neurons in the white matter in the deficit subgroup [48,52]. These findings should be considered as preliminary, due to differences in imaging techniques among studies, small sample sizes and heterogeneous treatment conditions (patients were drug-free in some studies, drug-treated in others). 8. Electrophysiological findings The hypothesis that deficit and non-deficit schizophrenia represent distinct disease entities has been also tested in a few electrophysiological investigations. All of them should be considered as preliminary, due to the lack of adequate replication and small sample sizes. Ross et al. [82] reported a significant association between abnormalities of eye-tracking and deficit schizophrenia. Nkam et al. [73] did not find eye-tracking differences between deficit and non-deficit patients, while Hong et al. [36] found that the two subgroups and their unaffected relatives shared some oculomotor abnormalities (i.e. predictive pursuit), but only deficit patients and their relatives showed poor initiation performance. Bucci et al. [9] investigated evoked and induced 40-Hz gamma power (thought to reflect cortical integration processes), as well as frontoparietal and frontotemporal event-related coherence, in patients with deficit or non-deficit schizophrenia and in matched healthy controls. A reduction of both induced gamma power and event-related coherence was observed in deficit, but not in non-deficit patients, suggesting poor integration of the neuronal activity within distributed neural network only in non-deficit schizophrenic patients. Turetsky et al. [91] investigated a putative endophenotype of schizophrenia, i.e. the left lateralized amplitude reduction of the P3 component of the event-related potentials. They found that the abnormality was present in the group with non-deficit schizophrenia, while in the deficit group the component was mainly reduced at the right parietal site. Mucci et al. [70] recorded event-related potentials during an auditory discrimination task and found evidence of a double dissociation: for N1, only deficit patients, as compared with healthy controls, showed an amplitude reduction over the scalp central leads and a reduced activity of the component generators in cingulated and parahippocampal gyrus. For P3, only non-deficit patients, as compared with healthy controls, showed a lateralized amplitude reduction over the left posterior regions and reduced generator activity in left temporal and bilateral frontal, cingulated and parietal areas. The deficit and non-deficit groups differed significantly from each other with regard to N1 amplitude and topography, as well as P3 amplitude and cortical sources. 9. Risk factors There is evidence that family history represents a risk factor for deficit schizophrenia. In fact, a greater risk of schizophrenia in relatives of probands with deficit than non-deficit schizo-
phrenia has been reported in some [24,54], but not all studies [65]. A lower risk for other psychiatric disorders has been found in relatives of probands with deficit vs non-deficit schizophrenia [54]. More severe social withdrawal was reported in nonpsychotic relatives of probands with deficit compared with nondeficit schizophrenia, in spite of reduced dysphoria and subclinical psychotic experiences [54]. The deficit/non-deficit categorization shows a high concordance rate in affected sibling pairs: i.e., deficit schizophrenia in one sibling predicts deficit schizophrenia in the other one, with an odds ratio of 3 [81]. The season of birth is a further double dissociation finding: in contrast with the repeatedly reported finding of a predominance of winter birth in schizophrenia [20], an association between summer birth and deficit schizophrenia has been found by several independent groups [23,42,47,50,55,68,88]. An analysis of pooled data from six different countries in the northern hemisphere reported an increased birth in June and July in deficit schizophrenia patients (odds ratio 1.9) [67]. Associations with viral infections as potential risk factors have also been investigated. An unreplicated association between Borna virus and deficit schizophrenia was reported [94]. More recently, deficit schizophrenia was found to be associated with the presence of serum antibodies to cytomegalovirus (odds ratio = 2.01), but not with other herpes virus antibodies [22]. 10. Genetic findings Genetic studies of deficit schizophrenia are in their infancy. Few investigations have been carried out so far, and their value is limited by small sample sizes and lack of replication. Minoretti et al. [69] investigated whether the functional singlenucleotide polymorphism (SNP) T393C in GNAS1 gene was involved in the risk of schizophrenia, and whether a specific association existed between the deficit and non-deficit forms of the disorder. They found that the frequency of the homozygous 393TT genotype was significantly higher in deficit schizophrenia patients compared to both non-deficit schizophrenia patients and healthy controls. The odds ratio after adjustment for potential confounders was 2.06. Wonodi et al. [95] investigated the association of the functional polymorphism Val 158 Met in the catechol-O-methyltransferase (COMT) gene with schizophrenia and its deficit/non-deficit subtypes and reported a significant difference in Val/Val genotype frequencies between schizophrenia cases (combined deficit/nondeficit) and healthy controls ( p = 0.004), but no difference in allele or genotype frequencies between deficit and non-deficit cases. Galderisi et al. [27,28] found no association between the same polymorphism and either schizophrenia or its deficit/nondeficit subtypes. In the whole sample of patients with schizophrenia, they found an association between the COMT Val 158 Met polymorphism and executive/attention dysfunction, while only in the subgroup with deficit schizophrenia they observed an association between the same polymorphism and motor impairment. In a recent association study, Bakker et al. [5] tested four schizophrenia candidate genes in patients with and without deficit schizophrenia, by genotyping SNP in the
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DTNBP1 (dysbindin), G72/G30, RGS4 and PIP5K2A genes. No specific association was found with the deficit subtype. In the absence of a strong candidate gene, large multicenter studies based on genome-wide scan seem to be the most appropriate strategy for future investigations. 11. Response to treatment While convincing evidence has been provided of the efficacy of second-generation antipsychotics on secondary negative symptoms, their impact on primary and persistent (deficit) ones remains controversial [10,51,55,59,63,89]. Methodological flaws account for this state of art: in the majority of trials suggesting efficacy of antipsychotics on deficit schizophrenia (or on primary negative symptoms), SANS or PANSS are used to assess negative symptoms, while these instruments do not capture the concept of deficit schizophrenia; some trials included acute patients, preventing conclusions concerning impact on primary vs secondary negative symptoms; most studies have an inadequate length, preventing conclusions relevant to primary and enduring negative symptoms. Amisulpride studies often claimed efficacy on deficit symptoms, especially at low doses. Leucht et al. [61], in a meta-analysis, came to the conclusion that, in patients suffering predominantly from persistent negative symptoms, amisulpride is significantly superior to placebo, but not to conventional antipsychotics. Four placebo-controlled studies were included in this meta-analysis [6,19,64,74]; none of them involved the use of the SDS for the diagnosis of deficit schizophrenia. In all of them, negative symptoms were considered primary based on the presence of high scores on the SANS (at least 60) and low scores on the Scale for the Assessment of Positive Symptoms (SAPS) (not higher than 50), and the primary efficacy measure was the change of SANS scores. The length of these studies ranged from 4 to 12 weeks, leaving open the possibility that, even when primary, the observed negative symptoms were not enduring. For all these reasons, the claim that amisulpride is efficacious on primary and persistent negative symptoms is not supported by adequate evidence so far. The study by Vaiva et al. [93] was not included in that meta-analysis. Nineteen patients with schizophrenia were treated with amisulpride 100 mg per day for 4 weeks and categorized as having deficit or non-deficit schizophrenia by using the SDS (though it is not clear whether an interview to patients and relatives was carried out). Changes of SANS scores, chosen as the efficacy measure, were higher in patients with non-deficit than in those with deficit schizophrenia. The study has several limitations, including a small sample size and the lack of a control arm. Several studies have compared the efficacy of clozapine vs haloperidol on primary and enduring negative symptoms. Breier et al. [7] treated two small groups of deficit schizophrenia patients with either clozapine or haloperidol and found no difference in the efficacy of the two drugs in
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treating negative symptoms. Buchanan et al. [10] compared the efficacy of the same drugs on negative symptoms in both deficit and non-deficit patients and reported that the two drugs yielded comparable effects on negative symptoms in both groups. Rosenheck et al. [80], in a large double blind 12-month study comparing clozapine and haloperidol, used a proxy measure to assign patients with refractory schizophrenia to either the deficit or non-deficit group, and reported no superiority of clozapine on clinical manifestations of the deficit syndrome. The other studies investigating the effects of clozapine on negative symptoms do not provide conclusive evidence of its efficacy on primary and enduring negative symptoms, due to the same limitations affecting amisulpride studies ([71] for a systematic review). Kopelowicz et al. [56] examined the effects of olanzapine on negative symptoms in 39 patients diagnosed as having deficit or non-deficit schizophrenia using the SDS, and found an improvement of positive, negative and extrapyramidal symptoms in the non-deficit group and an improvement of extrapyramidal symptoms only in the deficit group. They concluded that olanzapine is efficacious for secondary but not for primary negative symptoms of schizophrenia. At odds with these findings, Lindenmayer et al. [63] reported that olanzapine treatment was associated with significant improvement in primary negative symptoms, while haloperidol was not. Thirtyfive patients with schizophrenia, stable and with predominant negative symptoms, were enrolled. All of them satisfied the criteria for deficit schizophrenia as assessed by the SDS. Nineteen patients were assigned to the haloperidol (mean modal endpoint dose 17.11 mg per day), and 16 to the olanzapine group (mean modal endpoint dose 18.44 mg per day). The study design does not allow firm conclusions. In fact, patients fulfilling SDS criteria for deficit schizophrenia may have both primary and secondary negative symptoms; in the absence of a control group with non-deficit schizophrenia for each study arm, the possibility remains that the olanzapine group shows a reduction of the secondary negative symptoms, while the haloperidol group does not. In conclusion, findings for amisulpride and olanzapine might be considered promising, but certainly require validation from independent, placebo-controlled studies, including both deficit and non-deficit patients, matched at baseline on the severity of their negative symptoms. 12. Conclusions Two decades of research on deficit schizophrenia have failed to prove that it represents the extreme end of a severity continuum in schizophrenia. As a matter of fact, most of the studies have provided evidence that abnormalities observed in deficit schizophrenia are not more of the same observed in nondeficit schizophrenia, as we would expect in more severe forms of the same disease. Instead, some studies, especially those reporting double dissociation findings, suggest that deficit schizophrenia is a separate disease entity. However, for the time being, neither conclusion should be considered as the final one, because of the limited number of studies correctly addressing
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the topic, discrepancies in findings and small size of the enrolled patient samples. It is important to stress that not all patients considered as having ‘‘deficit schizophrenia’’ or ‘‘deficit state’’ actually correspond to the subtype described by Carpenter et al. The term deficit schizophrenia should be applied only to patients meeting the SDS diagnostic criteria, and even then, to ensure comparability with other studies, details on the training for the use of SDS should be reported. In fact, it is important to acknowledge that the diagnosis of deficit schizophrenia is a difficult one, requiring longitudinal evaluation, different sources of information and careful clinical inquiry to judge whether the observed negative symptoms should be considered as primary or secondary. The use of proxy measures is not sufficiently validated as an alternative to SDS, and must be very conservative. Further research involving independent groups and possibly multicenter studies recruiting large patient samples are clearly needed. Studies involving birth cohorts or individual at high risk for psychosis and focusing on primary and enduring negative symptoms during childhood and early adolescence might lead to the development of early intervention strategies preventing the full expression of the clinical picture. Furthermore, in the light of the recent investigations reporting that two factors can be identified in the SDS [39,72], future studies should clarify whether the two factors are actually associated with a different pattern of neurobiological correlates. Unfortunately, the low prevalence of the syndrome and the difficulties of the diagnostic process discourage many investigators and drug companies from investing more resources in this research area. References [1] Amador XF, Kirkpatrick B, Buchanan RW, Carpenter WT, Marcinko L, Yale SA. Stability of the diagnosis of deficit syndrome in schizophrenia. Am J Psychiatry 1999;156:637–9. [2] Andreasen NC, Olsen S. Negative versus positive schizophrenia. Arch Gen Psychiatry 1982;39:789–94. [3] Arango C, Kirkpatrick B, Buchanan RW. Neurological signs and the heterogeneity of schizophrenia. Am J Psychiatry 2000;157:560–5. [4] Arndt S, Andreasen NC, Flaum M, Miller D, Nopoulos P. A longitudinal study of symptoms dimensions in schizophrenia: prediction and patterns of changes. Arch Gen Psychiatry 1995;52:352–60. [5] Bakker SC, Hoogendoorn ML, Hendriks J, Verzijlbergen K, Caron S, Verduijn W, et al. The PIP5K2A and RGS4 genes are differentially associated with deficit and non-deficit schizophrenia. Genes Brain Behav 2007;6:113–9. [6] Boyer P, Lecrubier Y, Puech AJ, Dewailly J, Aubin F. Treatment of negative symptoms in schizophrenia with amisulpride. Br J Psychiatry 1995;166:68–72. [7] Breier A, Buchanan RW, Kirkpatrick B, Davis OR, Irish D, Summerfelt A, et al. Effects of clozapine on positive and negative symptoms in outpatients with schizophrenia. Am J Psychiatry 1994;151:20–6. [8] Bryson G, Whelahan HA, Bell M. Memory and executive function impairments in deficit syndrome schizophrenia. Psychiatry Res 2001;102:29–37. [9] Bucci P, Mucci A, Merlotti E, Volpe U, Galderisi S. Induced gamma activity and event-related coherence in schizophrenia. Clin EEG Neurosci 2007;38:97–104.
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