Updated perspectives on the clinical significance of negative symptoms in patients with schizophrenia

ABSTRACT

Introduction

Negative symptoms in schizophrenia are associated with poor response to available treatments, poor quality of life, and functional outcome. Therefore, they represent a substantial burden for people with schizophrenia, their families, and health-care systems.

Areas covered

In this manuscript, we will provide an update on the conceptualization, assessment, and treatment of this complex psychopathological dimension of schizophrenia.

Expert opinion

Despite the progress in the conceptualization of negative symptoms and in the development of state-of-the-art assessment instruments made in the last decades, these symptoms are still poorly recognized, and not always assessed in line with current conceptualization. Every effort should be made to disseminate the current knowledge on negative symptoms, on their assessment instruments and available treatments whose efficacy is supported by research evidence. Longitudinal studies should be promoted to evaluate the natural course of negative symptoms, improve our ability to identify the different sources of secondary negative symptoms, provide effective interventions, and target primary and persistent negative symptoms with innovative treatment strategies. Further research is needed to identify pathophysiological mechanisms of primary negative symptoms and foster the development of new treatments.

KEYWORDS:

• Primary negative symptoms
• secondary negative symptoms
• avolition
• assessment
• treatment

1. Introduction

Negative symptoms represent a fundamental clinical aspect of schizophrenia [1–4]. They are associated with scarce response to available treatments, and poor quality of life and functional outcome [5–14]. Therefore, they represent a substantial burden for patients, relatives, and health-care systems, and remain an unmet need in the care of people with schizophrenia [1,2,15,16].

The last decades have testified important advances in the clinical characterization of negative symptoms which, however, remain poorly recognized and not always evaluated according to current definitions and conceptualizations both in research and clinical settings [1].

In this manuscript, we will provide clinicians with an update on the conceptualization, assessment, and treatment of this complex and often neglected psychopathological dimension of schizophrenia. For this narrative review, we searched the pertinent literature on PubMed until January 2022, focusing on systematic reviews and original studies published in the last 5 years. Other older reviews and landmark studies were selected from the reference list of these more recent papers.

2. Burden of negative symptoms

Negative symptoms represent a reduction in normal behaviours and functions. For some of them, i.e. avolition, anhedonia, and asociality, the reduction involves motivation and interest; for others, i.e. blunted affect and alogia, it is relevant to expressive aspects of mental life [1,3,17]. Fifty percent of subjects with schizophrenia have at least one negative symptom of moderate severity and approximately 10–30% of them experience two or more negative symptoms [1]. A greater severity of negative symptoms has been reported in males, as compared to female subjects with schizophrenia [18–21].

The huge burden of these symptoms depends mostly on their ‘direct’ or ‘indirect’ (e.g. through resilience, internalized stigma, service engagement) impact on different domains of real-life functioning. Indeed, they limit patient’s abilities to live independently, work, study, perform daily activities, be socially active, and maintain personal relationships [5–14]. Unfortunately, limited treatment options are available for the care of negative symptoms, especially when they are primary and enduring.

Negative symptoms might be present since the early phases of the illness, in first-episode psychosis (FEP), and in at-risk states for psychosis (HR) and show an elevated stability along the course of the illness [22–25]. In the early phases of the disorder [18,19,26,27], as well as in high-risk states [28] a gender difference has been reported, with males experiencing more severe negative symptoms, as compared to females. In FEP subjects, negative symptoms are associated with poor premorbid functioning, increased risk of deliberated self-harm [26,27,29,30], scarce treatment adherence [31], poor quality of life, and functional outcome [32,33], the latter one reported as poor up to 7 years after the first presentation to psychiatric services [34,35]. In subjects at risk of psychosis, negative symptoms emerge before the attenuated psychotic symptoms [36–39] and have a higher prevalence than the positive ones [38,40,41]. Severity of negative symptoms in these subjects is associated with the risk of conversion to psychosis [40,42–45], as well as with poor functioning [1,41–43,46–52].

In the light of these observations, negative symptoms have become an important focus for the development of new treatments.

3. Conceptualization and classification of negative symptoms

3.1. Negative symptoms domains

According to current views, negative symptoms include (1) blunted affect, i.e. a reduction in the expression of emotions, characterized by diminished facial and vocal expression, as well as body gestures; (2) alogia, i.e. a reduction in quantity of words spoken and amount of spontaneous elaboration; (3) avolition, i.e. a reduction in the ability to initiate and persist in goal-directed activities, due to a lack of motivation; (4) asociality, i.e. a reduction in the drive to engage in relationships with a consequent reduction of social interactions; and (5) anhedonia, i.e. a reduction in the ability to experience pleasure for current events (consummatory anhedonia) or for future anticipated activities (anticipatory anhedonia) [53] (Table 1). While several studies reported deficits in the anticipation of pleasure both in the early stages and chronic phase of the disease, it is controversial whether non-depressed subjects with schizophrenia experience consummatory anhedonia [54–63]. However, the use of first-generation rating scales, which are unable to discriminate between anticipatory and consummatory anhedonia, has hampered the clarification of this issue [1,64–68].

Table 1. Definitions of negative symptoms [53].

Negative symptom	Definition
Avolition	Reduction in the ability to initiate and persist in goal-directed activities due to a lack of motivation.
Anhedonia	Reduction in the ability to experience pleasure for current events (consummatory anhedonia) or for future anticipated activities (anticipatory anhedonia).
Asociality	Reduction of social interactions due to a reduced drive to engage relationships with others.
Blunted affect	Reduction in the expression of emotions, characterized by diminished facial expression, body gestures and vocal expressions.
Alogia	Reduction in quantity of words spoken and amount of spontaneous elaboration.

Several factor analytic studies, using different assessment scales, demonstrated that negative symptoms in subjects with schizophrenia cluster in two domains: the Experiential domain, consisting of avolition, anhedonia, and asociality, and the Expressive domain, consisting of blunted affect and alogia [1,69–73]. More recently, it has been shown that a five-factor model reflecting the five individual negative symptoms and a hierarchical model (five individual negative symptoms as first-order factors and the two factors, Experiential and Expressive, as second-order factors) provide a better fit as compared with the two-factor solution [74–79]. However, these findings need replications. The two-factor solution is supported by the evidence that the two factors (Experiential and Expressive) show different behavioral and neurobiological correlates, as well as different clinical and social outcomes [17]. Some studies have shown that the Experiential domain has a greater impact on real-world functioning than the Expressive one [7,9–11,22,59,80–83].

The factor structure of negative symptoms in FEP and HR subjects is much more controversial, since most studies used scales adapted from the adult population and/or scales not in line with the current conceptualization of negative symptoms [39,43,84–96].

Some studies using either the Positive and Negative Syndrome Scale (PANSS) [97] or the Scale for the Assessment of Positive/Negative Symptoms (SAPS/SANS) [98,99] analyzed the scale as a whole and reported a unidimensional structure of negative symptoms in FEP subjects [84–86]. However, the inclusion of aspects that are not conceptualized as negative symptoms limits the interpretation of these results. Very few studies used the same scales to investigate the factor structure of negative symptoms in FEP and focused on the negative scale or subscales only [87–90]. In particular, one study [87] conducted a factor analysis on the SANS and found a three-factor model of negative symptoms in first episode schizophrenia subjects (FES): the Expressive factor (including the SANS item ‘Poverty of Speech’ and the SANS ‘Affective Flattening’ subscale without the item ‘inappropriate affect’ which was not included in the analysis), the Experiential factor (including the SANS ‘Anhedonia-Asociality’ and ‘Avolition/Apathy’ subscales), and the Alogia/Inattention factor (including the SANS ‘Attention’ subscale and the items ‘Poverty of Content of Speech’, ‘Blocking’ and ‘Increased latency of Response’) [87]. However, the authors included in their analysis the attention subscale and the item poverty of content of speech, which evaluate aspects related to cognitive impairment and disorganization but not to negative symptoms as currently conceptualized [1].

A recent study [88] conducted in FES supported a two-factor solution of negative symptoms evaluated with the PANSS: an Experiential factor, including the PANSS items ‘Poor Rapport’, ‘Passive/Apathetic Social Withdrawal’, ‘Active Social Avoidance’ and ‘Lack of Spontaneity’, and an Expressive factor, including PANSS items ‘Blunted Affect’, ‘Emotional Withdrawal’ and ‘Motor Retardation’. Only the Expressive factor correlated with the functioning as measured with the Global Assessment Scale. However, the results are inconsistent with a large literature body that reported an association of the Experiential factor with the impairment of functioning [17,100–102]. The same research group conducted two other factor analytic studies and found that a three-factor solution was more appropriate in FES whereas a two-factor solution was more appropriate in FEP without schizophrenia-spectrum disorders [89,90]. However, the interpretation of these results is limited by the inclusion of some aspects, such as motor retardation and active social avoidance, which currently are not conceptualized as negative symptoms. Indeed, these symptoms are related to other clinical features: motor retardation may be due to extrapyramidal symptoms or depression and active social avoidance to social anxiety or suspiciousness/persecutory delusions [1].

As to the negative symptom structure in HR populations, some studies using either the Comprehensive Assessment of the At-Risk Mental State (CAARMS) [103] or the Structured Interview for Psychosis-Risk Syndromes (SIPS) [104] analyzed the scale as a whole and reported a unidimensional structure of negative symptoms [39,43,95,96]. However, the inclusion of aspects other than negative symptoms might have influenced the results. Very few studies, on the other hand, examined the factor structure of negative symptoms in HR populations focusing on the negative symptom scale or subscale only [52,91–94].

A confirmatory factor analysis, conducted on the PANSS negative items, showed a two-factor structure for both schizophrenia and HR subjects: an Expressive and an Experiential factor [91]. The latter predicted functioning in both groups at one-year follow-up. However, the authors used the PANSS, a scale developed for adult psychosis populations, and included motor retardation and active social avoidance, which currently are not conceptualized as negative symptoms [1]. Another study [92] using the SIPS supported the two-factor solution of negative symptoms: an Expressive factor (expression of emotions, experience of emotions, and social anhedonia) and an Experiential factor (occupational functioning and avolition). The latter was strongly correlated with role functioning while the Expressive factor showed only a weak correlation. However, the authors included in their analysis the occupational functioning, an aspect that is not conceptualized as a negative symptom and is in overlap with the role functioning. A more recent study conducted in children and adolescents at ultra-high risk to develop psychosis, using the SIPS without considering the occupational functioning, found a two-factor solution of negative symptoms: an Expressive factor (expression of emotions, experience of emotions and ideational richness) and an Experiential factor (avolition and social anhedonia), and also found a strong correlation of the latter with role functioning [52].

Finally, two studies [93,94] used the Brief Negative Symptom Scale (BNSS) [105] for the evaluation of negative symptoms in HR subjects. The exploratory factor analysis [93] supported the two-factor solution of negative symptoms, with the Experiential factor correlating with functioning. The confirmatory factor analysis [94] showed that the 5-factor model provided a better fit, as compared to the two-factor model.

Given the high heterogeneity of negative symptoms, factor analytic studies using scales in line with the current conceptualization of negative symptoms are hence crucial for an optimal management of negative symptoms especially in FEP and HR populations.

3.2. Primary and secondary negative symptoms

An important aspect of the conceptualization of negative symptoms, too often neglected by current research and clinical practice, is the differentiation between primary and secondary negative symptoms. While primary negative symptoms are a core feature of the disorder, whose pathophysiology remains to be clearly identified, secondary negative symptoms are due to factors other than the disorder itself, such as positive symptoms, depression, iatrogenic parkinsonism or environmental hypostimulation [1,17,106–108]. This distinction has important clinical implications, both from a therapeutic and a prognostic perspective. In fact, primary negative symptoms tend to be persistent and treatment resistant [1,17,107,109], while factors underlying secondary negative symptoms can be often identified and effectively treated, leading to an improvement of the symptomatology and, consequently, of functional outcome. The identification of sources of secondary negative symptoms is sometimes difficult and may require a longitudinal observation that, especially in first-episode subjects is not always feasible. The secondary nature of observed negative symptoms might be suggested by the presence of negative symptoms during periods of psychotic exacerbation or co-occurring with depressive symptoms or following changes in pharmacotherapy. For instance, clinicians should evaluate whether negative symptoms, e.g. the social withdrawal, might be induced by persecutory delusions, mind reading, thought insertion, other psychotic symptoms, or depression. The presence of sadness, hopelessness and guilt should be evaluated since it might suggest that the negative symptomatology could be secondary to depression. Similarly, changes in antipsychotic treatment and concomitant occurrence of extrapyramidal side effects and negative symptoms strongly suggest that both are due to the antipsychotic drug treatment: an augmentation of the drug dose might induce the occurrence or increase in the severity of some extrapyramidal signs, such as hypomimia, which might be regarded as blunted affect. A standard clinical examination aimed to evaluate the presence of other extrapyramidal signs, such as tremor or rigidity to rule out or diagnose drug-induced parkinsonism may clarify the picture.

3.3. Transient and persistent negative symptoms

Negative symptoms may be transient or persistent over time. The presence of at least two primary and persistent negative symptoms (for at least 12 months including periods of clinical stability) is the basis for the diagnosis of Deficit Schizophrenia (DS), regarded by some researchers as a separate disease entity with respect to non-deficit schizophrenia (NDS). This distinction has clinical implications since subjects with DS, in comparison with subjects with NDS, show a greater impairment of neurocognitive and social cognition abilities, a poorer response to treatment and a worse outcome [107,108,110–118]. To date, the Schedule for the Deficit Syndrome (SDS) [119] is the gold standard instrument for the diagnosis of DS. However, to correctly address the differentiation between DS and NDS, clinicians need to conduct a careful longitudinal evaluation, which is particularly difficult especially in subjects with a first-episode psychosis, thus limiting the use of this construct in clinical settings and stimulating the formulation of alternative constructs, such as the ‘persistent negative symptoms’ construct, that refers to the presence of negative symptoms of at least moderate severity for at least 6 months [53,112] (Table 2). Persistent negative symptoms are associated with a prolonged duration of untreated psychosis, poor patient functioning and worse quality of life [1,109]. Compared to the DS construct, this concept shows several advantages, since it identifies a larger patient population and requires a shorter longitudinal observation. In clinical trials, also the ‘predominant negative symptoms’ and ‘prominent negative symptoms’ constructs (Table 2) have been used to describe the severity of negative symptoms, without looking at their persistence. However, the use of these constructs should be improved, as their definitions are inconsistent across studies and standardized methods for ruling out possible confounding factors (i.e. positive symptoms, depression and extrapyramidal symptoms) are rarely used [1].

Table 2. Criteria for ‘persistent negative symptoms’, ‘predominant negative symptoms’, and ‘prominent negative symptoms’ [1].

Persistent Negative Symptoms	1. Presence of at least moderate* for at least three negative symptoms, or at least moderately severe** for at least two negative symptoms 2. Defined threshold levels of positive symptoms, depression, and extrapyramidal symptoms on accepted and validated rating scales 3. Persistence of negative symptoms for at least 6 months	*e.g. a score of 4 on the PANSS or a score of 3 on the BNSS **e.g. a score of 5 on the PANSS or a score of 4 on the BNSS
Predominant Negative Symptoms	(A) 1. Presence of at least moderate* for at least three negative symptoms or at least moderately severe** for at least two negative symptoms or 2. Any score on PANSS negative subscale but at least 6 points greater than the PANSS positive subscale score or 3. PANSS Negative subscale score of at least 21 and at least 1 point greater than the PANSS positive subscale score or 4. PANSS negative subscale score greater than the PANSS positive subscale score. (B) 1. Positive PANSS subscale score less than 19, depressive and extrapyramidal symptoms lower than a defined threshold on a validated rating scale or 2. Severity of positive, depressive, and extrapyramidal symptoms not specified	*e.g. a score of 4 on the PANSS **e.g. a score of 5 on the PANSS
Prominent Negative Symptoms	Presence of at least moderate* for at least three symptoms or at least moderately severe** for at least two symptoms on the PANSS negative subscale	*e.g. a score of 4 on the PANSS **e.g. a score of 5 on the PANSS

PANSS: Positive and Negative Syndrome Scale; BNSS: Brief Negative Symptom Scale.

4. Assessment instruments for the evaluation of negative symptoms

An accurate evaluation of negative symptoms, including both quantitative (frequency, duration, and intensity) and qualitative aspects (such as differentiation between anticipatory and consummatory aspects of anhedonia, or differentiation between behavioral and experiential aspects) requires the use of validated instruments.

First-generation assessment tools, developed before the National Institute of Mental Health (NIMH) consensus initiative on negative symptoms [53], such as the PANSS [97] and the SANS [98], include features which at that time were erroneously regarded as negative symptoms, such as disorganization and cognitive impairment or aspects largely overlapping subject’s psychosocial functioning. In fact, PANSS negative subscale includes stereotyped thinking, a psychopathological feature part of the disorganization dimension, and difficulty in abstract thinking, relevant to the cognitive dimension. In some studies, the PANSS items ‘motor retardation’ and ‘active social avoidance’ were included within the negative symptoms factor [1]; of course, these symptoms are not conceptualized as negative symptoms any longer, as they more often reflect other aspects: motor retardation may be due to extrapyramidal symptoms or depression, and active social avoidance to social anxiety or suspiciousness/persecutory delusions. The SANS includes the attention subscale in the evaluation of negative symptoms, and current conceptualizations require the exclusion of cognition-related items from instruments aimed to assess negative symptoms; it includes also other items, such as ‘poverty of content of speech’, and ‘inappropriate affect’, which are relevant to the disorganization dimension [1]. Furthermore, the PANSS does not evaluate avolition and anhedonia, while the SANS rates together anhedonia and asociality, and does not distinguish between anticipatory and consummatory anhedonia [120]. Finally, both PANSS and SANS focus on behavioral observation as opposed to internal experiences in the assessment of negative symptoms. For instance, the SANS evaluates asociality through the observed behavior without considering the environment in which the subject lives and the desire to have social relationships [1].

The introduction of second-generation clinician-rated scales, such as the BNSS [105,121] and the Clinical Assessment Interview for Negative Symptoms (CAINS) [122] has been instrumental to overcome these limitations. Both BNSS and CAINS are in line with the current conceptualization of negative symptoms, as they do not include symptoms relevant to other psychopathological dimensions or functioning [1,3,17,105,121,122]; both scales take into account subject’s internal experiences together with observed behaviors and provide a separate assessment of consummatory and anticipatory anhedonia. In particular, the BNSS provides separate ratings for internal experiences and observed behaviors. Both BNSS and CAINS have been translated and validated into several languages and showed high validity across different countries/languages [1,15,121,123–133]. A recently validated self-assessment instrument, the Self-evaluation of Negative Symptoms (SNS) [134,135], has been developed according to the current conceptualization of negative symptoms. This scale includes an evaluation of the two aspects of pleasure (consummatory and anticipatory) and is regarded as a useful instrument to integrate the clinician-based assessment of negative symptoms [135,136]. SNS demonstrated good psychometric properties [134], has been validated in several European countries [135,137] and was also used in a general adolescent population [137].

A brief description of the above-mentioned rating scales is provided in Table 3.

Table 3. Available instruments to assess negative symptoms in schizophrenia.

Instrument		Assessment instrument features
First-generation scales
PANSS (Administration time: ~45 minutes)	Positive subscale Negative subscale Blunted affect Emotional withdrawal Poor rapport Passive/apathetic social withdrawal Difficulty in abstract thinking Lack of spontaneity and flow of conversation Stereotyped thinking General Psychopathology subscale	- PANSS does not evaluate avolition and anhedonia, does not distinguish between anticipatory and consummatory anhedonia, and focuses on behavioral observation as opposed to internal experiences in the assessment of negative symptoms - Studies using PANSS for the evaluation of negative symptoms should include only blunted affect, emotional withdrawal, poor rapport, passive/apathetic social withdrawal, and lack of spontaneity and flow of conversation
SANS (Administration time: ~30 minutes)	Affective Flattening or Blunting subscale Unchanging Facial Expression Decreased Spontaneous Movements Paucity of Expressive Gestures Poor Eye Contact Affective Nonresponsivity Lack of Vocal Inflections Inappropriate Affect Alogia subscale Poverty of Speech Poverty of Content of Speech Blocking Increased Latency of Response Avolition-Apathy subscale Grooming and Hygiene Impersistence at Work or School Physical Anergia Anhedonia-Asociality subscale Recreational Interests and Activities Sexual Interest and Activity Ability to Feel Intimacy and Closeness Relationships with Friends and Peers Attention subscale Social Inattentiveness Inattentiveness During Mental Status Testing	- SANS rates together anhedonia and asociality, does not distinguish between anticipatory and consummatory anhedonia, and focuses on behavioral observation as opposed to internal experiences in the assessment of negative symptoms. -Studies using SANS for the evaluation of negative symptoms should include the following subscales: Affective Flattening without the item ‘inappropriate affect’, Alogia without the item ‘poverty of content of speech’, Avolition-Apathy, and Anhedonia-Asociality
Second-generation scales
BNSS (Administration time: ~20-25 minutes)	Anhedonia subscale Intensity and frequency of pleasure during activities Intensity of expected pleasure from future activities Distress subscale Asociality subscale Asociality: behavior and inner experience Avolition subscale Avolition: behavior and inner experience Blunted Affect subscale Facial and vocal expression and expressive gestures Alogia subscale Quantity of speech and spontaneous elaboration	- BNSS is in line with the current conceptualization of negative symptoms, as it does not include aspects related to other psychopathological dimensions or functioning - It takes into account subject’s internal experiences together with observed behaviors (separate ratings for these two aspects) for asociality and avolition and provide a separate assessment of consummatory and anticipatory anhedonia.
CAINS (Administration time: ~15-30 minutes)	Motivation and Pleasure (MAP) scale Motivation for close relationships; frequency of pleasurable social activities (past week) and of expected pleasure from social activities (next week) Motivation for work and school activities and frequency of expected pleasure from work and school activities (next week) Motivation for recreational activities; frequency of pleasurable recreational activities (past week) and of expected pleasure from recreational activities (next week) Expression (EXP) scale Facial and vocal expression, expressive gestures and quantity of speech	- CAINS is in line with the current conceptualization of negative symptoms, as it does not include symptoms identified as aspects of other psychopathological dimensions or functioning. - It takes into account subject’s internal experiences together with observed behaviors and provide a separate assessment of consummatory and anticipatory anhedonia
Self-evaluation scales
SNS (Administration time: ~5 minutes)	Social withdrawal domain Social, family, and friend relationships, desire to establish new relationships Reduced emotional range domain Happiness or sadness as perceived by the patient in situations in which happiness or sadness is usually felt Alogia domain Difficulty in speaking as perceived by the patient and efforts required by the patient to interact with others Avolition domain Difficulty in achieving the goals a person has set with respect to activities of daily life, due to a lack of motivation, and energy Anhedonia domain Consummatory and anticipatory pleasure perceived by the patient	- SNS is in line with the current conceptualization of negative symptoms - This scale includes an evaluation of the two aspects of pleasure (consummatory and anticipatory) and is regarded as a useful instrument to integrate the clinician-based assessment of negative symptoms

Included instruments: PANSS: Positive and Negative Syndrome Scale [97]; SANS: The Scale for Assessment of Negative Symptoms [98]; BNSS: Brief Negative Symptom Scale [105]; CAINS: Clinical Assessment Interview for Negative Symptoms [122]; SNS: Self-Evaluation of Negative Symptom [134].

The recognition and correct evaluation of negative symptoms is also important in first-episode subjects and in subjects at risk to develop psychosis. In both cases, first-generation scales are more frequently used than the second-generation ones, despite having the same limitations described above for chronic patients. Unfortunately, also second-generation rating scales designed for adult subjects might not be sensitive enough to capture subtle negative symptoms of children, adolescents and young adults and have not been validated in first episode studies [15].

Similar limitations apply to studies including the assessment of negative symptoms in HR subjects. Actually, adapted versions of the BNSS and CAINS have been developed and tested in small samples [93,94,138,139] and the Prodromal Inventory of Negative symptoms (PINS) [140] has been recently developed specifically for use in the HR population. Although they currently represent the best available measures of negative symptoms in this population, as they are adapted, such as BNSS and CAINS or are developed specifically for HR subjects, such as PINS, further studies are needed to confirm their sensitivity to detect negative symptoms in HR subjects [1,48].

5. Main pathophysiological hypotheses of negative symptom domains

Understanding the pathophysiological mechanisms of negative symptoms could foster the development of new care strategies [141–144].

One of the most up-to-date pathophysiological hypotheses underlying negative symptoms indicates a relationship between the Experiential domain and an impairment in several aspects of motivation [17,59,70,145–152], which might be underpinned by abnormalities in two brain circuits, the ‘Motivational value circuit’ and the ‘Motivational salience circuit’ [17,71,153,154]. The former one, which is activated only in positive situations, is related to the evaluation of stimuli and action, anticipated pleasure and instrumental learning [17,155]; the latter one, which is activated in both negative and positive situations, refers to the more general aspects of motivation, cognitive activation, and the ability to orient to salient stimuli [17,156–159]. Different treatment approaches should target the impairment of these two circuits. For instance, if there is a dysfunction of the motivational value circuit, pharmacological and/or psychosocial interventions should aim to increase the salience of stimuli and stimulate cognition; in case of a dysfunction of the motivational salience circuit an enhancement of instrumental learning and of reward processes might be necessary.

The Expressive deficit domain has been less investigated than the Experiential domain. Several studies suggest that it is linked to cognitive impairment and might be subtended by a diffuse neurodevelopmental alteration in brain connectivity leading to deficits in neurocognition, social cognition, and neurological soft signs, often observed in subjects with schizophrenia, especially in those with a high genetic risk for schizophrenia [3,71,109,114,116,145–148,160–163]. Despite the interest of the hypothesis, relevant findings are inconsistent and need further investigation.

In a near future, new research methods, like multiomics (genomics, transcriptomics, epigenomics, proteomics, metabolomics, connectomics, and gut microbiomics), and inducible pluripotent stem cells (IPSCs), might lead to progress in the identification of pathophysiological mechanisms of persistent negative symptoms [164–169]. To date, these techniques are at the beginning, and much effort is needed for their implementation in research and clinical practice.

For instance, a recent study by Kauppi et al. [169,170], using protein interactome to map polygenic link between antipsychotic drug targets and schizophrenia risk genes, found that some risk genes (e.g. CHRN, PCDH, and HCN families) involved in the pathophysiology of schizophrenia might represent reliable targets to treat some aspects of schizophrenia that do not respond to current available treatments, like negative symptoms and cognitive dysfunctions [170].

Furthermore, iPSCs from human donors, by retaining the genetic background of risk genetic variants, represent novel basic research tools developed with the aim to model psychiatric disorders and to discover novel pharmacologic treatments [164]. One iPSC study [171], for instance, found in iPSC-derived cortical interneurons of subjects with schizophrenia a metabolic abnormality, i.e. a mitochondrial bioenergetic deficit, which could be reverted with Alpha Lipoic Acid/Acetyl-L-Carnitine [164]. Considering the role that dopamine dysfunctions play in the pathophysiology of motivational deficits in subjects with schizophrenia [17], it would be interesting to investigate metabolic dysfunctions also in iPSC-derived dopamine neurons [164]. This approach might offer the perspective of the development of new therapeutic drugs targeting, for instance, the metabolism of iPSCs-derived neurons. It is hoped that in the next few years this method will be able to provide a meaningful characterization of schizophrenia subtypes, e.g. subjects with primary and persistent negative symptoms and favor the development of specific treatments.

6. Psychopharmacological and psychosocial interventions for negative symptoms

Limited treatment options are available for the care of negative symptoms, especially when they are primary and enduring over the time. The lack of effective treatments for negative symptoms might derive from a great amount of literature that did not distinguish between primary and secondary negative symptoms and/or used a global/total score for these symptoms and/or used outdated tools for assessing negative symptoms [1].

Antipsychotic drugs generally ameliorate negative symptoms secondary to positive symptoms during acute phases of schizophrenia. In subjects treated with an antipsychotic medication and presenting negative symptoms considered secondary to positive symptoms, a change of antipsychotic or an increase in the drug dose should be considered. In the presence of negative symptoms regarded as secondary to treatment-resistant positive symptoms, a pharmacological switch to clozapine should be taken into account [122,172]. When the negative symptomatology is considered as an adverse effect of the pharmacotherapy, a dose range optimization or a switch to another antipsychotic with lower risk of extrapyramidal and/or sedative side effects could be helpful. Moreover, in subjects with negative symptoms secondary to depression a clinical improvement could be reached with a switch to an antipsychotic with antidepressant properties (e.g. quetiapine, amisulpride, cariprazine, aripiprazole, clozapine, and olanzapine) [173,174] or with an add-on antidepressant treatment or with the integration of cognitive behavior therapy [173,174] (Figure 1).

Figure 1. Treatment of secondary negative symptoms-decision tree.

While secondary negative symptoms generally improve with the above-mentioned strategies, primary and persistent negative symptoms do not respond satisfactorily to available antipsychotics. A careful comparison of the efficacy of various treatments for the care of negative symptoms in schizophrenia is challenging since most studies did not distinguish between primary and secondary negative symptoms and/or used a global/total score for these symptoms and/or used outdated tools for assessing negative symptoms [15].

A meta-analysis conducted by Fusar-Poli et al. [175], to investigate the effects of antipsychotics (first-generation antipsychotics-FGAs, and second-generation antipsychotics-SGAs) as compared to placebo in improving negative symptoms, found a small improvement in these symptoms with SGAs, but not with FGAs. Within SGAs, Leucht and colleagues [173] reported that amisulpride, clozapine, olanzapine, and risperidone were more efficacious than FGA in improving negative symptoms. However, in these metanalyses, included clinical data were very heterogeneous, and no specific information on the characteristics of negative symptoms was provided.

Another meta-analysis has specifically analyzed the results of available trials in the population of patients with prominent or predominant negative symptoms [176]. However, most studies included in this metanalysis, especially those focused on prominent negative symptoms, did not take into account the effects of possible confounding factors, such as depression, positive symptoms or extrapyramidal side effects. In addition, most included studies were sponsored by pharmaceutical companies. According to this metanalysis, olanzapine and quetiapine significantly outperformed risperidone in ameliorating prominent negative symptoms; these data, however, are based on single studies [177,178] and need replications.

As regards to predominant negative symptoms, the metanalysis of Krause and colleagues [176] found some promising results for amisulpride and cariprazine. According to this meta-analysis, only amisulpride was more efficacious than placebo in ameliorating predominant negative symptoms, but also depressive symptoms [176]. Amisulpride is both a selective dopamine D2/D3 receptor antagonist (which could explain its efficacy vs predominant negative symptoms) and a 5-HT7 antagonist, a profile that accounts for antidepressant effects [179]. As depressive and negative symptoms overlap, without a proper evaluation and differentiation of negative symptomatology, it is difficult to say whether amisulpride reduces primary or only negative symptoms secondary to depression [15].

Cariprazine, approved by the FDA in September 2015 for the treatment of schizophrenia and bipolar disorder, is a dopamine D3-D2 receptor partial agonist and serotonin 5-HT1A receptor partial agonist [180]. This drug has showed a beneficial effect in the treatment of patients with predominant and enduring negative symptoms in schizophrenia [176,181–186]. In particular, in a 26-week, multinational, multicenter, randomized, double-blind manufacturer-sponsored study, the efficacy of cariprazine versus risperidone was investigated in adult patients with schizophrenia and with predominant and enduring negative symptoms [184]. Sources of secondary negative symptoms, such as positive symptoms, depression, and extrapyramidal side effects were also controlled. This manufacturer-sponsored study found that cariprazine outperformed risperidone in the treatment of predominant and enduring negative symptoms as measured by a negative factor of the PANSS [184]. Deconstructing the PANSS factor into individual items, the effect of cariprazine was observed on the PANSS items N1-N5 (blunted affect, emotional withdrawal, poor rapport, passive/apathetic social withdrawal, difficulty in abstract thinking) but not on N6 (lack of spontaneity/flow of conversation) or N7 (stereotyped thinking) [187].

Furthermore, some studies investigated the potential role of different molecules, such as pro-dopaminergic agents, anti-inflammatory drugs, or antibiotics as add-on treatments to antipsychotics for negative symptoms [15]. However, findings are not consistent, and no conclusion can be drawn yet about their efficacy [15].

Available evidence on pharmacological treatments for negative symptoms is scarce and in need for further research. Given that negative symptoms represent an unmet therapeutic need, there is hope that new solutions will be provided by the search for new drugs and the development of innovative treatments, such as trace amine receptor 1 (TAAR1) agonist (SEP-856) [188] and roluperidone (MIN-01) [189]. SEP-856 is an agonist of the trace amine-associated receptor 1 (TAAR1) and 5-HT_1a receptor, which has shown potential activity in targeting positive and negative symptoms in preclinical studies [188,190]. MIN-101 is a new sigma-2 receptor antagonist [191]. In a 12-week randomized, double-blind, placebo-controlled phase 2b trial conducted in subjects with schizophrenia, roluperidone has shown superiority over placebo in improving negative symptoms [189,192]. Results from the roluperidone phase 3 trial do not lead to solid conclusions. Indeed, in 513 patients with moderate-to-severe negative symptoms, using the intent-to-treat (ITT) analysis data set, there was no statistically significant difference between two doses of roluperidone (32 and 64 mg), as compared to placebo, in ameliorating negative symptoms. However, using the modified ITT data set (excluding from the dataset implausible behavioral and physiological data), the 64 mg dose of roluperidone showed superiority over placebo (p ≤ .044) in improving negative symptoms [191]. Despite the potential of this new pharmacological treatment in targeting negative symptoms, these data need replication and further investigation.

Other biological interventions, such as transcranial magnetic stimulation and transcranial direct current stimulation, have gained attention as a promising approach for the treatment of negative symptoms in association with SGA, although there is no sufficient evidence of their positive effects on negative symptoms [193–196].

Also, some psychosocial interventions have shown efficacy in improving negative symptoms [15]. In particular, different systematic reviews and meta-analyses demonstrated the efficacy of social skills training, as compared to active controls and treatment as usual, in ameliorating negative symptoms of subjects with schizophrenia [15,197–199]. Furthermore, also cognitive remediation might improve negative symptoms in subjects with schizophrenia, in particular, in those who also show impairment in neurocognition and social cognition [15,199–203]. Other interventions include body-oriented and mind–body psychotherapies [204,205], art therapy and music therapy [206,207], physical exercise [208–210], as well as cognitive-behavioral therapy (CBT); however, to date, available data are not sufficient to demonstrate their efficacy in targeting negative symptoms.

Given the key role of negative symptoms in determining a poor functioning in subjects with schizophrenia, every effort should be made to foster the advancement in the knowledge of negative symptoms, and in the development of innovative treatments.

7. Expert opinion

There are still many gaps in the management of negative symptoms in subjects with schizophrenia. These symptoms are still poorly recognized by physicians, family members/caregivers and by patients themselves, probably because they cause much less concern than other clinical features, such as positive symptoms, aggressiveness or psychomotor agitation.

Despite the effort made in the last decades to advance the conceptualization of negative symptoms and develop state-of-the-art assessment instruments, their evaluation needs to be improved both in research and clinical settings. Indeed, after more than 15 years from the NIMH consensus initiative on negative symptoms, different investigations and clinical trials use first-generation rating scales for the evaluation of negative symptoms, thus including also aspects that are not currently conceptualized as negative symptoms (e.g. for the PANSS, active social avoidance and motor retardation; for the SANS, the attention subscale and poverty of content of speech). As a matter of fact, the improvement in the conceptualization and evaluation of negative symptoms has not yet been taken into account by drug regulatory authorities and consequently by designers of randomized controlled trials, hindering research progress related to the use of second-generation rating scales [17].

The inclusion of aspects not conceptualized as negative symptoms should be avoided, and researchers and clinicians should be encouraged to enhance the dissemination of second-generation rating scales which have been developed according to the consensus conference and provide a better assessment of negative symptoms. To this aim, the training of psychiatrists should focus more on the careful and up-to-date recognition and evaluation of negative symptoms, implementing the use of more appropriate assessment tools in daily clinical practice and including the evaluation of internal experience and the promotion of self-reporting of negative symptoms. For this purpose, state-of-the-art assessment instruments are available and have been translated and validated in several languages showing a good agreement between clinicians across many countries [1,15,121,123–133]. In addition, the use of these instruments would be important also to clarify whether the greater severity of negative symptoms, widely reported in male patients as compared to females, involves all negative symptoms or only one of the two negative symptom domains (the Experiential or the Expressive Deficit domain). This would have prognostic and therapeutic implications, since it has been found that the two negative symptom domains are subtended by different pathophysiological mechanisms and show different associations with patient’s functioning [17,19]. In particular, as male subjects have a greater severity of negative symptoms than females both in the UHR and in the first-episode groups, it can be hypothesized that they present a higher frequency of neurodevelopmental alterations and primary negative symptoms of the Expressive deficit type, which might be related to more severe neurodevelopmental disturbances, as indicated by their association with low general cognitive abilities and soft neurological signs [17]. The validation of this hypothesis would have diagnostic and therapeutic implications for the early recognition of male subjects with poor outcome.

Large multicenter longitudinal studies are highly needed to evaluate the natural course of negative symptoms and detect the impact of possible confounding factors, such as positive symptoms, depression, extrapyramidal side effects and hypostimulation, at different stages of the disorder, to improve our ability to identify the different sources of secondary negative symptoms, provide effective interventions, and target primary and persistent negative symptoms with innovative integrated treatment strategies.

Moreover, the differentiation between primary and secondary negative symptoms should be carefully considered when conducting research on these symptoms in transdiagnostic samples [211]. Indeed, although negative symptoms are typically described in subjects with schizophrenia, they might be observed in other mental disorders (e.g. schizoaffective disorder, bipolar disorder, major depressive disorder), in neurological disorders (e.g. multiple sclerosis, Parkinson’s disease) and also in the general population. However, it is not clear whether negative symptoms that occur in disorders other than schizophrenia might be primary to the disease process or whether they are always secondary to other factors (e.g. cognitive impairment) [211]. It still remains to be clarified whether the negative symptom constructs, their correlates, and neurobiological underpinnings are homogeneous across diagnoses [17]. A detailed characterization of the occurrence of the different negative symptoms, their course and association with other clinical features and neurodevelopmental indices, might represent a step towards a transdiagnostic approach to mental illnesses or might contribute to model the boundaries between categories that present important overlap in terms of biological underpinnings, etiopathological mechanisms, clinical presentations and outcomes [4,13].

It is hoped that innovative methods, like multiomics, IPSCs, and computational neuroscience, in the near future might contribute to clarify pathophysiological mechanisms of negative symptoms and develop new treatments [164,168,212].

In conclusion, every effort should be made to (i) provide a clinical assessment of negative symptoms using state-of-the-art assessment tools; (ii) promote large-scale longitudinal studies; (iii) take into account all available treatment whose efficacy is supported by research evidence; (iv) support translational research in order to improve knowledge on the pathophysiology of negative symptoms and foster the development of innovative treatments.

Article highlights

• Negative symptoms are associated with poor functional outcome and represent a substantial burden for people affected from schizophrenia, their families, and health-care systems.

• Negative symptoms are currently conceptualized as five individual domains: blunted affect, alogia, avolition, asociality, and anhedonia.

• Second-generation rating scales are available for the assessment of negative symptoms, in line with current conceptualizations.

• Despite the progress made in the last decades in the conceptualization of negative symptoms and development of second-generation rating scales, these symptoms are still poorly recognized, and not always assessed in line with their current conceptualization.

• The development of specific assessment instruments for negative symptoms in subjects at risk to develop psychosis and in those with a first episode of psychosis should represent a priority within early intervention settings.

• Clear procedures for the differentiation between primary and secondary negative symptoms should be developed, in order to plan appropriate interventions.

• Limited treatment options are available for negative symptoms and, therefore, they remain an unmet therapeutic need for the care of people with schizophrenia.

• Further research studies are needed in order to improve the knowledge on the negative symptom pathophysiology to foster the development of innovative treatment strategies.

Declaration of interests

S Galderisi has been consultant and/or advisor to and/or received honoraria or grants from Millennium Pharmaceutical, Innova Pharma-Recordati Group, Janssen Pharmaceutica NV, Sunovion Pharmaceuticals, Gedeon Richter-Recordati, Lundbeck and Angelini. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

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Funding

This paper was not funded.