The Many Faces of Negative Symptoms in Schizophrenia

Negative symptoms are relatively frequent across schizophrenia spectrum disorders diagnostic categories and they represent deficits in different domains such as emotional, volitional and experiential. Even though negative symptoms have long been recognized as a core feature of schizophrenia, their definition has been changing over time. Different conceptualization classified this category of symptoms as primary or secondary, persistent or transient. At the current moment there are five agreed upon domains of the concept of negative symptoms, which are separated into two dimensions—experience (anhedonia, avolition, asociality) and expression (blunted affect, alogia). Multiple mechanistic pathways have been proposed and investigated for each dimension and for each domain. The current chapter attempts to address recent advances in the literature regarding the concepts, definitions and classifications of negative symptoms and their etiological model.


Introduction
Schizophrenia is a chronic, debilitating disorder that affects approximately 1% of the world's population [1]. The disorder is a significant socioeconomic burden because of the early onset of the disease, the low remission rates, and their debilitating consequences: as the disease's progression leads to the inability, for a significant share of schizophrenic patients, to fulfill their professional, social and household roles [2]. Phenomenologically schizophrenia is considered to be a heterogeneous syndrome including several dimensions: positive, disorganization, cognitive, affective, and negative dimension. These are the most commonly reported by factor analytic studies dimensions of schizophrenia [3][4][5].
Negative symptoms have long been recognized as a core feature of schizophrenia, and the current studies report that their severity has a more significant impact on real-world functioning and quality of life than other categories of symptoms [6-10]. Negative symptoms, by their definition, interfere with the patient's ability to maintain social activities or personal relationships, to work or study, and even to live independently and are minimally influenced by antipsychotic medication [11][12][13]. Even though the attention has shifted from the positive to the negative symptoms in the last decades, the latter still represent an unmet therapeutical target, and very few pharmaceutical agents are labeling indications for negative symptoms [14-17].

The concept of negative symptoms in schizophrenia 2.1 Early descriptions
The classification of the symptoms of schizophrenia as being positive or negative regards the fact that positive symptoms are a surplus to normal experiences, for example, hallucinations or delusions, whereas the negative symptoms are represented by diminished experiences or expression [27]. The term of negative symptoms was borrowed from neurology, and it was coined by John Reynolds in 1858 and was introduced in psychiatry by the French psychiatrists Gaetan Gatian de Clerambault and Henry Ey [28].
The negative symptoms were considered a fundamental feature of the disease since its first descriptions by Emil Kraepelin and Eugen Bleuler [27]. Emil Kraepelin, influenced by the work of Alois Alzheimer, was the one who named the disease dementia praecox. He considered that the process underpinning the manifestation of the disease was an affective degeneration. In his treatise "Dementia praecox and paraphrenia", he described the flat affect and the motivational deficits, which are now called negative symptoms, and he proposed the theory that the affective deficit represents the basis for the psychopathological process [27][28][29][30].
Eugen Bleuler renamed the disease schizophrenia and emphasized that there is a group of disorders under this name. At a descriptive level, he introduces a dichotomy between the symptoms of schizophrenia, and he labels the fundamental and accessory symptoms. The fundamental symptoms are described as the essence of the illness necessary to diagnose loose associations, ambivalence, affective flattening, and avolition. The accessory symptoms are hallucinations and delusions that were not necessary to diagnose schizophrenia but were highly visible and often the reason for clinical presentation. Unlike his predecessor, he considers that the affect as a process is intact in schizophrenia and that the fundamental psychopathological process is the splitting between affect and cognition, from which the symptoms of the disease arise [27, 28,30]. The interest for negative symptoms decreased and shifted towards the positive symptoms once Chlorpromazine was developed and introduced in psychiatric wards in 1952. The awareness regarding the importance of these symptoms reemerged in the last decades because of their negative influence on the patients' real-life function [10, 11, 31].

Current perspective
The interest for the negative symptoms is constantly growing, although it has been about 40 years since Nancy Andreasen and co-workers (1982) resumed this research area and highlighted the importance of this category of symptoms. Andreasen defined twenty negative symptoms, which were grouped into five factors: flat affect, alogia, avolition/apathy, anhedonia/social withdrawal, and attention deficit. She proposed that negative and positive symptoms are part of a continuum representing the extreme and opposite poles of this continuum. Patients presenting mixed symptoms, positive and negative symptoms, were considered intermediate patients [28,32].
Later, Timothy Crow [33] postulated the hypothesis of two types of disease, schizophrenia type I and type II. Type I is characterized by positive symptoms (hallucinations, delusions), showing a good response to neuroleptic medication, without intellectual deficit, and with an increase in D2 receptors. Type II is characterized by negative symptoms (alogia, affective flattening, decreased interest, and pleasure), an inadequate response to neuroleptic medication, intellectual deficits, and changes in the temporal lobes' neural structures. According to this author, type I could develop negative symptoms and progress to type II, but type II could not transform into type I, even though positive symptoms could appear [33].
In 1988 William Carpenter and collaborators brought to attention a new perspective on the concept of negative symptoms and made an essential distinction between idiopathic, primary negative symptoms and secondary negative symptoms. Secondary negative symptoms occur as side effects of neuroleptic medication (extrapyramidal symptoms, sedation) or secondary to depression, social deprivation or substimulation or secondary to positive symptoms (active social withdrawal secondary to paranoid ideation, or diminished expression, which could be a coping strategy for patients in an acute psychotic episode who are unable to process tumultuous hallucinations). At a phenomenological level, primary and secondary negative are very similar and yet very hard to distinguish. The diagnosis of primary negative symptoms, according to Carpenter, should be only a diagnosis of exclusion. The importance of distinguishing these categories of symptoms is that secondary negative symptoms may be responsive to specific treatments [34].
As a result of this classification, deficit schizophrenia was introduced to define patients with primary and persistent negative symptoms. The dichotomy, deficit/ non-deficit schizophrenia, is based exclusively on the presence or absence of primary and stable negative symptoms [34]. The diagnostic criteria for deficit schizophrenia are presented in Table 1. Several subsequent studies have compared patients with deficit schizophrenia versus non-deficit schizophrenia and found overwhelming evidence that the two types are different in that concerns risk factors, premorbid functioning, disease evolution, neurobiological basis, and response to treatment. The clinical picture of deficit schizophrenia shows more significant social withdrawal, anergia, more severe cognitive impairments, poorer premorbid adjustment than non-deficit schizophrenia, and often summer birth instead of non-deficit schizophrenia, which predominates winter birth [35][36][37][38][39]. Although the two diagnostic categories have been validated in several studies, the evolution over time of negative symptoms does not always allow a clear distinction between primary and secondary symptoms, making the diagnosis very difficult. Moreover, first psychotic episode patients represent another diagnostical challenge [40][41][42].
A different approach, which tried to reduce the heterogeneity of negative symptoms, was proposed by the National Institute for Mental Health (USA) in The Consensus Statement on Negative Symptoms (2006), which defined the constitutive factors of the negative domain: flat affect, alogia, social withdrawal, avolition, and anhedonia, essentially the same areas that have been defined by Nancy Andreasen (1982) except for the attention deficit. A short definition of each symptom, according to this consensus, is presented in Table 2 [45].
As a result of the same consensus, the National Institute for mental Health defined the concept of persistent negative symptoms, which is more applicable in the clinical setting than the concept of deficit schizophrenia because of its more permissive criteria. The criteria for the persistent negative symptoms imply only a period of six months, with at least moderate intensity negative symptoms and low levels of positive, depressive, and extrapyramidal symptoms. Secondary negative symptoms can be included in this category if they are not responsive to a specific treatment [45].
In the attempt to describe the nature, the etiology, and find operational criteria for research in the field, other specific terms were defined: predominant, prominent, enduring/non-enduring negative symptoms. Unfortunately, there is Flat affect A decrease in the expression of emotions and emotional reactivity to events, observed spontaneously during speech or after targeted questions (facial expression, intonation, and gestures)

Alogia
Quantitative reduction of speech and spontaneity (the amount of information spontaneously developed by the patient in addition to the necessary answers to the questions).

Social withdrawal
Interactions and initiatives to have social contacts are diminished due to decreased motivation and decreased desire to form or maintain relationships with other people.

Anhedonia
Diminished experience of pleasure for a variety of activities or events, over time of the activities or events (consumer anhedonia) or for subsequent activities and events (anticipatory anhedonia)

Avolition
Reducing the initiative and persistence of goal-oriented activities due to diminished motivation Table 2.
Definition of negative symptoms of schizophrenia [45].
a. The presence of at least two of the following six negative symptoms: i. Decreased emotional expression (observed behavior); ii. Affective flattening (e.g. a narrow range of the patient's subjective emotional experience); iii. Alogia; iv. Diminished interests; v. Diminished goals; vi. Diminished social interest; b. The presence of symptoms described in point (a) for at least 12 months including periods of clinical stability; c. The symptoms described at point (a) are primary symptoms, not secondary to other factors such as anxiety, medication side effects, psychotic symptoms, intellectual disability or depression; d. The patient meets the DSM criteria (3rd edition, or later editions) for schizophrenia. no consensus regarding the exact definition of any of these terms as they were only used for research purposes [9]. Up to the present point, negative symptoms are considered to represent a heterogeneous domain of psychopathology. Recent factor analytic studies have provided evidence that the domain of negative symptoms can be grouped into two factors: avolition/apathy and diminished expression. The apathy/avolition subdomain includes avolition, social withdrawal, and anhedonia, and the diminished expression includes affective flattening and alogia [46][47][48]. This factorial structure has been confirmed by several studies using different scales for the evaluation of negative symptoms: Scale for the Assessment of Negative Symptoms (SANS), Positive and Negative Syndrome Scale (PANSS), Negative Symptoms Assessment Scale (NSA-16) and more recently developed scales Clinical Assessment Interview for Negative Symptoms (CAINS) and Brief Negative Symptom Scale (BNSS), which were specially developed to evaluate this factorial structure [49,50]. Several studies have compared the importance of these domains regarding clinical features, disease progression, and impact on functioning. The domain of diminished expression (DE) turned out to be more persistent over time, have a higher prevalence in the early stages of the disease, and be associated with a longer duration of the prodromal phase of the disease than the apathy/avolition (AA) [51][52][53]. The AA domain is associated with poorer functioning, with a longer duration of untreated psychosis and non-adherence to treatment. These associations were not reported for the DE domain [47,52,54]. Research up to this point provided evidence that the AA and DE domains represent different clinical aspects of schizophrenia. Moreover, if these areas have different etiologies and should be approached differently from a therapeutic point of view are elements in an ongoing investigation, neuroimaging studies currently support this hypothesis [8,55].
To date, no consensus has been reached on how to approach negative symptoms: categorical versus dimensional. Numerous studies demonstrated the validity of deficit schizophrenia construct or the subtype characterized by primary and persistent negative symptoms [51,52,54]. However, the dimensional approach is supported by several studies that have shown the presence of negative symptoms in other disorders than schizophrenia, such as schizoaffective disorder, depression, Parkinson's disease, Huntington's disease, Alzheimer's disease, temporal lobe epilepsy, and even in the general population [8, 55,56].

The neurobiology of negative symptoms in schizophrenia
The heterogeneity in etiology and clinical manifestation of the negative symptoms in schizophrenia led to the exploration of several structural abnormalities, pathways, and mechanisms which may underlie this complex of symptoms. The attempt to reduce these symptoms' heterogeneity leads to concepts of deficit and non-deficit schizophrenia and diminished expression and avolition/apathy domains. Different hypotheses have been constructed for these models' pathophysiological mechanisms, but unfortunately without fully satisfying results [8,9,55,56].

Deficit schizophrenia versus non-deficit schizophrenia
After deficit schizophrenia was described, several studies brought out data supporting the hypothesis that deficit schizophrenia differs from non-deficit schizophrenia in terms of risk factors, premorbid functioning, the evolution of the disease, neurobiological basis, and response to treatment [35][36][37][38][39]. Epidemiological studies support a prevalence of deficit schizophrenia: 15% of patients with a first episode of the disease, 25-30% in clinical trials, and 14-17% in population studies [35,57,58]. Structural and functional brain imaging studies have highlighted several differences between patients with deficit and non-deficit schizophrenia. Abnormalities and asymmetries in the temporal lobe level, cerebrospinal fluid accumulations in the left temporal lobe, volume reduction of the right temporal lobe have been reported in patients with deficit schizophrenia compared with patients with non-deficit schizophrenia and healthy subjects. Both groups of patients had a reduced volume of the dorsolateral prefrontal cortex and temporal lobes than healthy subjects [59,60]. Several studies have reported white matter abnormalities, especially in the frontoparietal and frontotemporal circuits in patients with deficit schizophrenia. These patients present discontinuities in the inferior longitudinal fasciculus, arcuate fasciculus, and uncinate fasciculus, and it has been suggested that there may be a connection between these structural changes and the social and emotional dysfunctions characteristic for deficit schizophrenia [59,60]. Functional imaging investigations report a decrease in glucose metabolism and a decrease in the frontal and parietal lobes' blood flow in cases of deficit schizophrenia versus non-deficit schizophrenia or healthy volunteers [61,62]. Studies that used functional MRI to assess the response to the reward reported a reduction of dorsal caudate nucleus activity in patients with deficit schizophrenia [63,64].
Regarding the treatment of deficit schizophrenia, respectively of primary negative symptoms, the efficacy of several antipsychotics was evaluated: clozapine, olanzapine, zotepine, and amisulpride. These therapeutic options are superior to placebo therapy and first-generation antipsychotics, but not other classes of atypical antipsychotics, data suggesting that they would be effective for secondary negative symptoms [65][66][67][68]. Recent studies have evaluated the efficacy of addon therapies with agents that stimulate NMDA receptors: glycine, D-serine, and D-cycloserine, but no significant improvement in symptoms was reported on the primary negative ones [15,38,69,70].

Persistent negative symptoms
Persistent negative symptoms are a looser category than deficit schizophrenia as potential causes of secondary negative symptoms are not completely ruled out, but it is assumed that the secondary negative symptoms' clinical expression is mild [45]. Also, this category includes all negative symptoms, primary or secondary, that do not respond to commonly used treatments, which are apparent during periods of clinical stability of the disease and interfere with the patient's functionality [45]. There is great variability in the prevalence of persistent negative symptoms due to different definitions used for this category. Prevalence of persistent negative symptoms are higher than deficit schizophrenia and were estimated between 35% and 60% [21,[71][72][73].
Structural and functional imaging studies have reported volume reduction of the gray matter in the temporal lobes, cortical atrophy of the right superior temporal gyrus, right parahippocampal gyrus, and left orbitofrontal gyrus, and that structural abnormality of the white matter in the frontal lobes could be associated with persistent negative symptoms [74][75][76][77].
Dopaminergic antagonism is the only common mechanism of drugs used to treat psychosis. However, subcortical dopamine excess is accompanied by a prefrontal dopaminergic function, which encompasses a reduced D1 receptor activation in the prefrontal cortex, dopamine hypoactivity in the caudate nucleus, and modifications in D3 receptor activity. These alterations appear to contribute to the pathogenesis of negative symptoms. Cariprazine is an atypical antipsychotic that is a partial agonist of dopamine receptors D3 and D2, with high selectivity for D3 receptors, which have been shown to be effective for predominant negative symptoms [78,79]. Another compound, MIN-101, that has no affinity for dopaminergic receptors and acts on sigma-2 and serotonergic receptors 5-HT2A effectively reduces persistent negative symptoms [80].

Negative symptoms domains: avolition/apathy and diminished expression
Factor analysis studies have suggested that negative symptoms include two domains: apathy/avolition and diminished expression, which led to building separate hypotheses for these domains [45,47,52]. In current conceptualizations, the avolition/apathy domain is defined as deficits in different motivation areas. Two possible mechanisms and circuits are considered to be involved: the reward circuit and the salience circuit [81]. Functional MRI studies tried to elucidate the substrate of the motivational deficit using tasks involving reward anticipation, and it was found that there is an association between the activation of the ventral striatum and the apathy/ avolition domain. This relationship has not been confirmed for the diminished expression domain. Only a limited number of studies have investigated the correlations between neural structures and the apathy/avolition domain, and the following results were reported: a low volume of the frontal lobes, thinning of the anterior cingulate cortex and orbitofrontal cortex, and structural abnormalities of connectivity between the medial orbitofrontal cortex and the anterior rostral cingulate cortex [55,[82][83][84][85].
Cognitive-behavioral therapy was the first form of alternative therapy targeting poor motivation, anhedonia, and irrational cognitions. It promotes the patient's involvement in defining goals and aims and targets, improving functionality and recovery of the patients. A positive effect of cognitive-behavioral therapy on negative symptoms in combination with antipsychotic medication has been proved, and the beneficial effects persist even after stopping therapy. Functional changes, highlighted by functional brain imaging studies, at striatal levels underlie this type of therapy's effectiveness [86,87].
Some studies suggest that dopaminergic agonists: methylphenidate, amphetamine, lisdexamfetamine, modafinil, selegiline are involved in relieving negative symptoms without worsening the positive symptoms. The exact mechanisms by which this class acts are not completely elucidated. Increasing dopamine and noradrenaline at the frontocortical level or the dopamine action at the striatal limbic level are possible mechanisms involved in the assumed action of dopaminergic agonists on a motivational deficit [17,55,88].
The inflammatory hypothesis of schizophrenia suggests that alterations in the prenatal immune system are involved in the disease's etiology. Anti-inflammatory agents studied so far are pregnenolone, acetylsalicylic acid, cyclooxygenase-2, minocycline, N-acetylcysteine, and omega-3 fatty acids. To date, clinical trials have seemed promising, but these studies need to be replicated on a larger scale [89][90][91][92].
High frequency transcranial magnetic stimulation (≤10 Hz) intensifies metabolism and excitability in the prefrontal cortex. It has been proved to be effective in treating negative symptoms when applied in the early stages of schizophrenia. The mechanisms of action of this method involve modulation of NDMA receptors and striatal dopamine release. This technique has not been proven effective for alogia, but only for the other negative symptoms [93,94].
Transcranial direct current stimulation has been mainly studied for positive symptoms, auditory hallucinations, but an improvement of negative symptoms as a subsidiary result, especially motivational deficits, has been reported. The modulation of cortical-subcortical networks can explain the benefits for negative symptoms [95,96].
The diminished expression domain's pathophysiological mechanisms have received less attention than those involved in the apathy/avolition domain. It has been hypothesized that this domain is correlated with neurocognitive deficits and social cognition deficits [97]. In treatment naïve patients, there is an association between expressive deficits and neurological soft signs, which suggests the existence of diffuse neurodevelopmental abnormalities. Functional neuroimaging studies that investigated impaired emotional processing have shown a hypoactivity of different neural networks: the prefrontal, ventrolateral cortex, the amygdala, cingulate cortex, and the cuneus [98][99][100]. Activation of the anterior rostral cingulate cortex was negatively correlated with the diminished expression domain in the tasks which involve an interaction between reward and cognition [101].
Cognitive training, which aims to improve neurocognitive skills and social cognition, has been shown to restore the disrupted neural networks in the prefrontal cortex and anterior rostral cingulate cortex [102].
Social skills training for emotion perception, recognition, and expression, aims to educate patients about the necessity of social skills, verbal and nonverbal communication improvement, and it has been shown that it facilitates the release of oxytocin [103]. Considering the hypothesis that the strengthening social cognition could have beneficial effects on the diminished expression, the administration of intranasal oxytocin was studied, given its action on serotonin and dopamine in the nucleus accumbens and amygdala. Oxytocin is effective in emotion recognition and the theory of mind as add-on therapy and being used in the long term [104].

Genetic basis of negative symptoms
The progress in the genetics of schizophrenia in the last years has been noticeable. Heritability represents a statistical estimate to quantitate the relative genetic contribution to a trait relative to its environmental contributors. Heritability is the amount or proportion of phenotypic variance of the disease of interest in the population that is inherited through genetic factors. The heritability of schizophrenia has been established at 81% [105], making the genetic factor the most significant for the disease.
According to evidence from previous family and association studies, it has been suggested that genetic factors are involved in the development of schizophrenia and also in its clinical presentation. Studies that investigated genes potentially involved in negative symptoms pathogenesis highlighted that classifying patients with schizophrenia into specific subtypes based on predominant symptoms is useful for selecting the specific treatment. The findings, and references for these studies are summarized on Table 3.
Genetics is rapidly growing, with technological discoveries making it increasingly possible to identify common and rare variants on genomic DNA. Much new and confirmatory work remains to be performed to elucidate the role of specific genetic variants in negative symptoms development and the distinct ways the genes and environment interact to result in schizophrenia susceptibility.

Conclusions
Conceptual work has highlighted that negative symptoms can be defined as primary or secondary, persistent, or transient, and they encompass two distinct domains: avolition/apathy and diminished expression. Deficit schizophrenia is defined as primary enduring negative symptoms, but more operative for research and clinical setting is the concept of persistent negative symptoms. Considering the heterogeneity of negative symptoms has brought some progress in research on their genetic and neurobiological basis and treatment approaches. Unfortunately, their underlying pathophysiology is still unknown, and the treatment remains a critical unmet need.
Several hypotheses have been proposed for the pathophysiology of schizophrenia, from which the dopaminergic hypothesis remains the leading one. The  dopaminergic hypofunction of the frontal lobe and the mesolimbic structures seems to be underlying the negative symptoms. Despite the advances in the field, many clinical trials still consider the negative symptoms as a monolithic construct which might be the reason for the unsatisfactory results. Further research directions should concentrate on the two distinct negative symptoms dimensions apathy/avolition and diminished expression, and even further on each symptom and its pathophysiology. Another interesting approach is the transdiagnostic one, which could be helpful in the attempt to disentangle the mechanisms underlying this category of symptoms by using information gathered from depression or Parkinson's disease.