Clinical Staging in Schizophrenia Spectrum Disorders

*Zsófia Borbála Dombi, Ágota Barabássy, Barbara Sebe, István Laszlovszky and György Németh*

#### **Abstract**

The aim of this chapter is to summarize the state-of-the-art knowledge of clinical staging in schizophrenia spectrum disorders. Clinical staging has been introduced to psychiatry in the past two decades. Its primary goal is to divide the course of the disorder into recognizable stages based on seriousness, development and symptom characteristics in order to better predict prognosis and to adopt the most appropriate treatment strategies. The first staging model was developed in 1982. Since then several distinct concepts of clinical staging in psychiatry have emerged. To date, there is no clinical consensus regarding which staging model is the gold standard, nonetheless when merging them together an integrated staging concept arises. The integrated staging model of schizophrenia spectrum disorders is composed of four stages. The chapter will introduce the different staging models in a historical order as well as present the integrated staging model detailing the characteristics, timeline and dominating symptoms of each stage. Appropriate treatment strategies for the distinct stages will also be outlined.

**Keywords:** schizophrenia spectrum disorders, clinical staging

#### **1. Introduction**

Schizophrenia spectrum disorders (SSD) are a collection of psychotic disorders defined by abnormalities in one or more of the following symptom domains: hallucinations, delusions, disorganized thinking, catatonic behavior and negative symptoms [1]. The word 'spectrum' has been first added in the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-V) [1, 2], reflecting the notion that psychiatric disorders lie on a spectrum with no sharp boundaries between them [3, 4]. According to the DSM-V, SSD include schizophrenia, schizophreniform disorder, schizoaffective disorder, delusional disorder, brief psychotic disorder, psychotic disorders due to another medical condition or substance/medication, and unspecified or specified schizophrenia spectrum and other psychotic disorders [1]. The prevalence rate for SSD is estimated to be 7 per 1000 [5], with higher rates in men than in women [6]. Currently, there are over 21 million people who are affected by this condition [7]. Diagnosis is made along a spectrum of symptoms and severity via clinical interviews as no confirmatory and diagnostic laboratory nor radiological tests are available [2]. Although schizophrenia represents only about one third of the SSD cases [8], it is the most researched disorder out of all [9].

Besides the internationally used diagnostic systems such as DSM or the International Classification of Diseases (ICD), there is another, complementary form of classifying psychiatric disorders called clinical staging [10]. First introduced in cardiology and oncology [11], clinical staging is different from the conventional diagnostic practices in a sense that it does not only define the extent of illness progression but also where a patient lies within the course of the disorder [10]. The basic assumptions of clinical staging are that (a) treatment in the early stages of the disorder is more efficient, (b) patients experience greater symptom severity in the later stages of the illness, and (c) the process of transferring to a later stage is connected with a typical clinical profile [12]. Although clinical staging as a model for classifying the development of disorders had been ignored in psychiatry in the past, several concepts have emerged in the past few decades [11]. The primary aim of clinical staging is promoting recovery in the early stages of psychiatric disorders as well as preventing progression to later stages [10]. Importantly, clinical stages of psychiatric disorders can be defined by many different aspects from symptom severity and persistence, through neurobiological changes, to the emotional processes that happen within the patient [10]. In this chapter, we aim to present, summarize and synthetize the clinical staging concepts of SSD through a systematic review.

#### **2. Clinical staging concepts of schizophrenia spectrum disorders**

The systematic review was conducted in November 2020 using the MEDLINE, EMBASE and Cochrane databases from 1999 with the following search terms: 'stage/staging', combined using the Boolean 'AND' operator with 'psychiatric disorder/schizophrenia/ psychosis/psychotic disorder'. Additionally, a manual search was also performed. Titles and abstracts were screened by one of the authors (Zs.D.) and relevant articles were independently assessed by two authors (A.B. and Zs.D.). English-language articles published in peer-reviewed journals describing complete staging models on SSD or psychiatric disorders, in general, were eligible to be included in the chapter (inclusion critera).

As a result of the systematic search, a total of 2045 articles were identified. After reviewing the abstracts to exclude those which clearly did not meet the abovementioned criteria, 27 articles remained. Of these, 9 articles were included in the final review.

#### **2.1 The Hoffman staging concept**

Although most reviews do not count the staging model of schizophrenia proposed by Brian Hoffman in 1982, it can be considered to be the first attempt to divide the course of the disorder into recognizable stages [11, 13]. In his concept, Hoffman described the stages of schizophrenia based on the patient's reaction to his or her symptoms, beginning with anxiety (stage 1) and ending with acceptance (stage 5) (**Figure 1**) [13]. In the early phase of schizophrenia, before the first episode, the patient goes through considerable changes in their behavior and experience disturbance in thinking which can result in fear and anxiety or even anger [13]. Then, during the first episode of schizophrenia, the patient experiences a stage of denial (stage 2) where they no longer acknowledge that they have problem mainly due to excessive positive symptoms [13]. The third stage is about ambivalence, where the patients begin to have some insight into their disorder but might reject medication and go through multiple hospitalizations [13]. Before the final stage, acceptance (stage 5), there is a stage of depression (stage 4) where the

*Clinical Staging in Schizophrenia Spectrum Disorders DOI: http://dx.doi.org/10.5772/intechopen.98276*

**Figure 1.**

*The Hoffman staging concept.*

patient realizes the seriousness of the disorder [13]. During this stage it is important to monitor the patient to prevent suicide and alter the medication doses accordingly [13]. Although this staging concept is different from the others, it recognizes the importance of taking into account the patient's emotional response to his or her symptoms and the progression of the disorder which is now considered vital in a modern, person-centered care [14].

#### **2.2 The Fava and Kellner staging concept**

The first staging model of schizophrenia is attributed to Fava and Kellner who proposed their concept in 1993 [11, 15]. According to their model, schizophrenia starts with a prodromal stage (stage 1), where mainly negative and affective symptoms are present with considerable deterioration in functioning (**Figure 2**) [15]. The second stage is the acute episode of schizophrenia, dominated by positive symptoms [15]. The residual or third stage is described by the absence of positive symptoms and increased presentation of negative symptoms (resembling to stage 1) [15]. Finally, the authors differentiate between subchronic (stage 4) and chronic (stage 5) phases based on the duration of the illness; if it persists more than 6 months but less than 2 years then it is stage 4, if it is present for more than 2 years then it is stage 5 [15]. Additionally, it is also emphasized that a "rollback phenomenon" can also occur where patients in stage 2 progress to stage 1 instead of stage 3 and achieve remission eventually [15].


**Figure 2.**

*The Fava & Kellner staging concept.*

#### **2.3 The staging concepts of Lieberman and Insel**

According to Lieberman, schizophrenia is composed of three pathophysiologic phases described in four stages [11, 16]. The first is the neurodevelopmental or premorbid phase which begins in early adolescence or even sooner and is characterized by mild cognitive and social impairments (stage 1) (**Figure 3**) [16]. Then the second phase is the neuroplastic phase which can be further divided into prodromal, and onset and deterioration sub-phases and is referred to as stage 2 and 3 in the model,

#### **Figure 3.**

*The staging concepts of Lieberman and Insel.*

accordingly [16]. Throughout the prodromal stage besides the above mentioned deficits, mild psychotic symptoms might be already present which lead to a fullblown psychosis during the onset (stage 3) [16]. The final pathophysiological phase is the neuroprogressive one, which is described as the chronic or residual stage characterized by considerable negative and cognitive symptoms as well as further psychotic episodes [16]. Lieberman recommends the use of antipsychotic medication only after the onset of the first psychotic episode [16]. Similarly, to Lieberman, 9 years later Insel also identified the same stages of schizophrenia albeit with slightly different names; pre-symptomatic risk (stage 1), pre-psychotic prodrome (stage 2), acute psychosis (stage 3) and chronic illness (stage 4) [17, 18]. In his staging concept, he also details the features, diagnosis, disability and intervention at each distinct stage [17].

#### **2.4 The Singh staging concept**

The staging concept by Singh and colleagues focuses predominantly on the chronology of psychosis onset [19]. Their model beings with the prodrome (stage 1), which is further divided into two parts; a period of unease (P1) and a period of non-diagnostic symptoms (P2) [19]. Then, the second stage is when the first psychotic symptoms appear, which refers to positive symptoms such as delusions and hallucinations [19]. Before receiving a definite diagnosis (stage 4), there is an intermediate stage where the symptoms build up, and there is already a diagnostic impression of schizophrenia (stage 3) [19]. Although this staging concept does not describe a complete model of SSD, its detailed description of the beginning of the disorder made it worthy of being included in this review (**Figure 4**).

**Figure 4.** *The Singh staging concept.*

#### **2.5 The Agius staging concept**

The simplest and probably most known concept of schizophrenia staging was described by Agius after about a decade of the Lieberman model [12]. Based on his research, the development of schizophrenia was divided into three distinct stages; the prodrome (stage 1), then the first episode (stage 2) and finally, the chronic phase (stage 3) (**Figure 5**) [12]. Although it was not included in the model as a separate stage, Agius also agrees on the fact that there is a premorbid phase before the prodrome [12]. It is also emphasized that the treatment of schizophrenia needs to be in accordance with the different stages of the disorder in order to achieve the desired outcomes [12].


**Figure 5.** *The Agius staging concept.*

#### **2.6 The McGorry staging concept**

One of the most developed and referenced [20–24] staging model of schizophrenia was proposed by McGorry and colleagues [10, 11]. This concept starts with stage 0, where the patient has no current symptoms yet, but an increased risk of psychotic disorder is present (**Figure 6**) [10]. Then, stage 1 (mild and moderate symptoms) is divided into two substages; 1a with mild and non-specific symptoms and 1b with subthreshold or moderate symptoms [10]. The first episode of psychosis defined to be at stage 2, followed by the three substages of stage 3 (incomplete remission and relapse(s)); incomplete remission (3a), relapse of psychotic disorder (3b) and multiple relapses (3c) [10]. Finally, stage 4 represents a persistent and severe illness [10]. Importantly, this staging concept can be applied not only to patients with SSD but also to patients with other severe mood disorders such as depression or bipolar disorder [10]. Besides the description of different stages, McGorry and colleagues also provided information regarding the potential interventions as well as indicative biological and endophenotypic markers to each stage in their framework [10].

**Figure 6.** *The McGorry staging concept.*

#### **2.7 The Cosci staging concept**

In 2013, Cosci and colleagues – similarly to this book chapter – aimed to summarize and integrate the staging models of schizophrenia, and other major psychiatric disorders through a systematic review and came up with a general staging concept that is composed of four stages (**Figure 7**) [11]. The model starts with a prodromal phase (stage 1) and follows the basic stages of psychiatric disorders in a longitudinal fashion with stage 2 being the acute manifestation, stage 3 the residual phase and stage 4 the chronic phase [11]. In contrast to McGorry [10] and Lieberman [16], the premorbid or increased risk phase was not included in this concept as they found no adequate support from the literature and argued that it has less clinical relevance as it can be only appraised retrospectively [11].

**Figure 7.** *The Cosci staging concept.*

#### **2.8 The Fountoulakis staging concept**

A novel concept of clinical staging in schizophrenia was proposed by Fountoulakis and colleagues in 2019 using the Positive and Negative Syndrome Scale (PANSS) and the 5-factor model (a model based on the notion that schizophrenia is characterized by positive, negative, cognitive, affective and hostility symptoms) [25]. They aimed to develop a staging concept empirically through analyzing a very large sample (n = 2358) of stabilized schizophrenia patients with varying ages [25]. Based on the results, they identified 4 major stages of schizophrenia (**Figure 8**), starting with stage 1, dominated by positive symptoms. Besides describing the most influential symptom domain of each stage, they also provided a timeline of the disorder. According to this timeline, stage 1 lasts about 3 years on average [25]. In this first stage, excitement and hostility symptoms were found to increase over time and becoming the leading symptom group of stage 2, that lasts

#### **Figure 8.** *The Fountoulakis staging concept.*

#### *Clinical Staging in Schizophrenia Spectrum Disorders DOI: http://dx.doi.org/10.5772/intechopen.98276*

about 9 years on average [25]. Throughout the first two stages, negative and depression/ anxiety symptoms were stable and started to increase steadily around the end of stage 2 [25]. Importantly, the second stage was further divided into 2 substages: stage 2a and 2b [25]. The latter lasts about 6 years and is described by the rise of negative, depressive and cognitive symptoms. During stage 3, which lasted 13 years on average, the most dominant symptoms were the depressive ones [25]. In the first phase of stage 3 (3a), hostility symptoms were found to decline, while negative and cognitive symptoms were increasing [25]. Then, in the second part of stage 3 (3b), positive and hostility symptoms almost disappeared [25]. Finally, the fourth stage was found to be characterized by cognitive symptoms, and according to their timeline, it begins 25 years after the first episode on average [25]. Similarly to the previous stages, stage 4 is also divided into 4a and 4b substages; 4a lasts about 15 years on average and is described by the robust increase of negative and cognitive symptoms, while 4b starts about 40 years after the first onset and is found to be dominated by mainly the neurocognitive deficits that the patients experience [25].

#### **2.9 Similarities and differences between the historical staging concepts**

A summary of the reviewed historical staging models of SSD is presented in **Table 1**. Interestingly, only about half of the staging concepts begin with a premorbid phase (Singh starts with prodrome which has a sub-stage, P1, that can be regarded as a premorbid phase), and except Fountoulakis and colleagues, all models have a prodromal phase. Importantly, the acute and chronic phase is present in all models (the Singh staging concept is not counted here, as it focused on the beginning of the disorder), while only again about half of the models included a residual or subchronic phase. In terms of the underlying pathophysiological changes of SSD in relation to the different stages, evidence from brain imaging studies provide support for the general notion that abnormalities are more prevalent in later stages than in earlier ones, these abnormalities are progressively worsening while patients advance from an earlier to a later stage and finally, supportive treatments such as essential fatty acid supplementation are more effective in the beginning of the disorder [26, 27]. Nonetheless, it is challenging to validate one particular model via pathophysiological changes described by brain abnormalities or other biomarkers as there is considerable heterogeneity in the clinical and pathophysiological picture of SSDs [27]. For instance, the size of the ventricles does not necessarily correlate with the severity or progression of symptoms nor signposts the patient's response to treatment [27].



#### **Table 1.**

*Summary of the reviewed staging concepts.*

#### **3. The integrated staging model of schizophrenia spectrum disorders**

excitement & hostility symptoms

& anxiety symptoms cognitive symptoms

Although the reviewed historical staging concepts of SSD are slightly different from one another, they can easily be integrated into one coherent model. To start with, there is one clinical stage that is present in all concepts: the first episode of psychosis. This acute phase can be interpreted as a milestone that divides the course of the disorder into a *before* and an *after* phase and so can be set as the first stage of the disorder. It is also the stage where the patient is most likely to be recognized and treated for the first time.

Most, but not all clinical staging concepts deal with the *before* phase, officially called the prodrome, since it is often determined retrospectively and is highly debated from the perspective of treatment [11]. Nonetheless, evidence is emerging regarding early interventions and it might become more and more relevant in the future [28]. Hence, in the integrated staging model, the prodromal phase is regarded as stage 0, representing its importance but debated nature. In many of the reviewed staging models, prodrome was further divided into substages, i.e. increased risk or pre-morbid phase, and mild symptoms or prodromal phase [10, 16, 17]. Although these substages might be important in the development of SSD, recognizing them may be even more challenging and unnaturalistic in reallife settings [11, 28, 29]. Thus, in the integrated model, this stage is not subdivided further.

Similarly, to the *before* phase, there are slight differences between the historical staging concepts in terms of what happens *after* the first onset of psychotic symptoms. Some argue that there is only one stage after the acute manifestation

**Figure 9.**

*The intergraded staging model of schizophrenia spectrum disorders.*

of symptoms [12, 16, 17] while others define three or even more distinct stages [13, 15, 25]. The most influential models opt however for two subsequent stages [10, 11, 19]; a residual or pre-chronic stage characterized by incomplete remission, relapses as well as depressive symptoms, and a chronic stage with persistent symptoms dominated by neurocognitive deficits. In the integrated staging model these phases represent stage 2 (remission and relapse) and 3 (chronic psychosis), respectively (**Figure 9**).

#### **3.1 The prodrome (stage 0)**

In the integrated staging model of SSD, stage 0 is called the prodrome. This is a period of the disorder when some mild or even moderate symptoms are present, however there is no sign of full-blown psychosis yet [10]. Given the fact that this phase is just preceding the first onset of psychotic symptoms, the prodrome is a retrospective concept that can be mainly recognized and defined afterwards [28, 29]. In terms of timeline, the prodrome can last from weeks to even years, but most typically, its duration is about a year [28].

During the prodrome, the patient goes through considerable changes in their behavior and might start to experience disturbance in thinking which in turn results in anxiety or even anger [13]. The symptoms present during this time are heterogenous; mostly negative symptoms such as anhedonia, asociality or amotivation along with changes in perception, mood, beliefs and cognition [29, 30]. In terms of neurobiological changes, there are signs of abnormal dopamine synthesis, prefrontal cortex (PFC) dysfunctions and gray matter volume reductions in several brain regions including the PFC, hippocampal gyrus and lateral temporal lobe [31–34].

Given the notion that the earlier the treatment is received, the better the prognosis of SSD, there is considerable interest in starting pharmacological interventions during the prodrome [28, 29]. However, the main problem with this concept is the potential number of false positives, those individuals who, despite having symptoms and distress, will not develop psychosis after the prodromal period [29]. Thus, many argue that prescribing antipsychotic medication to these individuals is highly questionable from an ethical perspective, claiming that even the newest antipsychotic medications are not without side effects, might induce cognitive harm and can stigmatize the patient for life [28, 29, 35].

To overcome the barrier of treating individuals in the prodrome while also excluding the false positives, there are tendencies of developing new criteria that can accurately detect patients who are in an 'ultra-high risk' (UHR) mental state and hence are most likely to develop psychosis and benefit from pharmacological treatment too [29, 36]. An example of such criteria is the Personal Assessment and Crisis Evaluation (PACE), which defines someone at UHR of psychosis if they have one or more of the following diagnosis; "(a) attenuated psychotic symptoms, (b) brief limited intermittent psychotic symptoms, (c) a significant decrease in functioning (maintained for at least a month) with either schizotypal personality disorder or a first-degree relative with psychotic disorder" [28, 36, 37].

The aims of early intervention in the UHR group are threefold: first, to alleviate the symptoms that the patient experiences; second, to decrease the risk of transitioning to a first episode of psychosis; and third, to reduce the time before starting an antipsychotic treatment after the onset of psychosis [36]. To date, there are only a few pharmacological trials with antipsychotic medication in this patient group, both indicating a tendency for a decreased rate of conversion to psychosis after one year [38, 39]. Nonetheless, more research is required to understand the risks and benefits of pharmacological treatment during the UHR period. Meanwhile, according to current guidelines the use of antipsychotic medication during the prodrome is only recommended in case of the more complex cases [40, 41], while the recommended interventions are family psychoeducation, individual or group cognitive behavior therapy, active substance use reduction and neuroprotective agents such as omega-3 [10].

#### **3.2 The onset (stage 1)**

The first stage of the integrated staging model of SSD starts with the acute manifestation of psychotic symptoms or in other words the onset of the first episode of psychosis. Throughout this stage of the disorder patients experience predominantly positive symptoms such as hallucinations, paranoia or delusions and are likely to be in denial of accepting that there is something wrong and that they need medical help [10, 13]. This denial often manifests in aggression or agitation and might as well result in the hospitalization of the patient [42]. Besides the dominating positive symptoms, negative symptoms such as alogia or asociality and hostility may also be present [16, 25].

Currently, there is no strong scientific evidence on the cut-off point for the end of the first episode, nonetheless, it is estimated to be within the first 2–5 years following the onset of the psychotic symptoms [43–45]. Indeed, Fountoulakis and colleagues found that the first stage of SSD lasts 3 years on average [25].

The main treatment goal during the first stage of SSD is to resolve psychotic symptoms and to increase the chances of the patients to returning to their normal life as effectively and expeditiously as possible [41]. To do so, antipsychotic medications are utilized [46], in most cases in the form of oral antipsychotics due to being less invasive and more accepted in the long run [47]. Many patients, however, might need long-acting, injectable antipsychotics in order to increase compliance [48], as several studies indicated that more than 40% of patients are nonadherent during the first 9 months of treatment, hence increasing their chance to relapse [49].

In addition to pharmacological treatment it is also important to provide further support to the patients and their caregivers via clinical psychologists, occupational therapists and social workers [10, 41]. The family or caregivers might need to attend psychoeducation or other therapy as well in order to ensure better coping [41].

After the first episode, there are multiple trajectories possible how the disorder can continue. According to the thumb rule described by Shepherd and colleagues, one third of the patients will go on remission and will not experience any more subsequent episode, the second third of the patients will experience one or more psychotic episodes (stage 2), while the third group of patients will experience multiple relapses and unremitting illness which will be later described as chronic disorder (stage 3) [50].

#### **3.3 Remission and relapse (stage 2)**

Between stage 1 and 3 is the most heterogenous phase of the disorder, the remission and relapse stage. During this period of SSD, patients first experience a temporary or incomplete remission from the first episode, but then there is a relapse or even multiple relapses of psychotic symptoms in the form of episodes [10]. If looking at the chain of events in a chronological order, before being in remission, the patient first responses to the treatment, which is usually determined by a certain amount of reduction in symptoms (between 20–50%) on a validated rating scale such as the Positive and Negative Syndrome Scale (PANSS) or the Clinical Global Impression (CGI) [51, 52]. Then the patient moves to remission, which, according to the Remission in Schizophrenia Working Group (RSWG), is an "increasingly achievable stage in the treatment of schizophrenia, serving to expand the current ceiling of patient progress beyond "stability" [53]. Although there are various criteria on how remission is defined, it essentially means a period of the disorder when symptoms are mild and/or there is no "active" psychosis [53]. When symptoms start to reappear after this mild or symptom-free period, and the patient is experiencing a worsening in functioning, we are talking about relapse [54, 55]. Nonetheless, as mentioned previously, a third of patients might not relapse rather achieve recovery [50], a state where the patient is able to function both socially and occupationally and has considerable symptomatic improvement [55, 56].

The second stage of SSD is hence quite various in terms of the type and severity of symptoms. Nonetheless, in most cases, the negative and depressive / anxiety-like symptoms [25] are highly dominant in-between relapses, affecting the patient's quality of life enormously [57]. Throughout a relapse the positive and hostilityrelated symptoms might particularly increase [25, 55].

According to Fountoulakis and colleagues, the duration of this second phase is around 9 years on average, followed by a 13 years-long period dominated by depressive symptoms [25], so an up to 10-year long period for the second stage is adapted.

The primary treatment goal during this stage is first to achieve complete remission and then to prevent relapse as well as to stabilize the patient mediated by specialist care services [10]. Given the high level of negative and depressive/ anxiety-like symptoms, the secondary aim should be to alleviate these, either by using a novel second-generation antipsychotic medication such as cariprazine and amisulpride or a combination of antipsychotic and antidepressant medication [58].

#### **3.4 Chronic psychosis (stage 3)**

The third and final stage of the integrated staging model is the chronic psychosis stage. Throughout this period of the SSD the symptoms are still severe, persistent or unremitting [12]. The patients might continue to experience numerous relapses while usually suffering mostly from negative, affective (depressive/ anxiety-like) and neurocognitive symptoms, with the latter increasingly becoming the most prominent symptom group of the disorder over time [12, 25]. Suicidal ideation might also be more common at this stage of the illness [59]. Nonetheless, patients usually develop some kind of acceptance and integrate the fact of the disorder into their life [13].

The chronic psychosis stage of SSD begins about 15–20 years after the first episode [25, 45]. Patients in this late stage are usually disabled at a certain degree and are likely to be unemployed or retired [45].

Treatment in the chronic disorder stage is similar to stage 2 treatment with a high emphasis on the prevention of further exacerbation of the illness and longterm stabilization alongside with augmentation strategies and other psychosocial therapies such as active social participation and/or vocational rehabilitation [10]. Preferred pharmacological treatments include clozapine and long-acting antipsychotic medications [12], although drugs addressing negative and cognitive symptoms (such as cariprazine and amisulpride) may also be of benefit [58].

#### **3.5 Summary of the integrated staging model**

The integrated staging model starts with the prodrome (stage 0), which is a period of the SSD where patients are already experiencing some changes in their behavior alongside mild negative and affective symptoms (**Figure 10**). Diagnosis is usually not yet received as the symptoms are too mild and unspecific to be certain about what causes them. This period can last from a few weeks to years. Pharmacological interventions throughout the prodrome are still researched, nonetheless psychosocial therapies are thought to be beneficial.

The first stage of the SSD according to the integrated staging model is the onset of the first episode of psychosis characterized by positive and hostility-like symptoms. This period can last between 2 and 5 years in average. Regarding treatment, the emphasis is on alleviating mostly positive symptoms and stabilizing the patient.

The second stage is the remission and relapse stage which is the most heterogenous phase of the disorder. Throughout this period some patients might experience one or multiple relapses, however about a third of the patients will stay in remission and may go to recovery. The dominating symptoms in-between episodes are the negative and affective ones. The remission and relapse stage last about ten years, between the 5th and 15-20th year of the illness. The primary goal of treatment during this stage is the prevention of relapses and achieving complete remission and recovery.

The final stage of SSD is the chronic psychosis stage dominated by increasing neurocognitive symptoms. Patients arriving to this late stage are likely to be suffering from disability and unemployment. Alongside the pharmacological treatments that aim to prevent the further exacerbation of illness there is an emphasis on psychosocial therapies to increase the everyday functioning of patients.

#### **Figure 10.**

*The integrated staging model of schizophrenia spectrum disorders with timeline and symptom domains.*

### **4. Conclusion**

Clinical staging is a more refined form of diagnosis that provides information on how an illness progresses and where the patient lies within this progression [10]. It is based on the assumption that each stage can be described by a typical clinical profile with later stages being associated with greater symptom severity and that treating patients in the early stages of the disorder is more efficient [12]. The primary aim of introducing clinical staging into the field of psychiatry was to promote remission and recovery in the early stages of psychiatric disorders and hence to prevent patients to progress to later stages [10].

Since 1982, several staging concepts describing the course of psychiatric disorders have emerged. In this systematic review, we have identified and summarized 9 concepts that outline the clinical staging of schizophrenia spectrum disorders. Although there were some variations between the models, all identified the first episode of psychosis as a distinct stage that divides the course of the disorder into a *before* and *after* phase. Most of the variations in the concepts were due to the fact that there were disagreements in the number of stages before and after the first onset.

In order to unify the described concepts an integrated staging model of schizophrenia spectrum disorder has emerged that describes the course of SSD in four stages; the prodrome (stage 0), the onset (stage 1), remission and relapse (stage 2) and chronic psychosis (stage 3). The integrated model also provides timeline around when patients are likely to enter the next stage as well as what symptoms dominate and how to best treat them. Nonetheless, it is also important to note that not all patients will go through all stages and the primary goal of any treatment is to prevent patients to enter a later stage.

### **Conflict of interest**

All authors are co-workers of Gedeon Richter Plc.

### **Author details**

Zsófia Borbála Dombi\*, Ágota Barabássy, Barbara Sebe, István Laszlovszky and György Németh Gedeon Richter Plc., Budapest, Hungary

\*Address all correspondence to: dombizsb@richter.hu

© 2021 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

## **References**

[1] American Psychiatric Association. American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders Fifth Edition. Arlington. 2013.

[2] Bhati MT. Defining psychosis: The evolution of DSM-5 schizophrenia spectrum disorders. Curr Psychiatry Rep. 2013;15(409).

[3] Guloksuz S, Van Os J. The slow death of the concept of schizophrenia and the painful birth of the psychosis spectrum. Psychol Med. 2018;48(2):229-244.

[4] Adam D. On the spectrum. Nature. 2013;496.

[5] John M, Sukanta S, David C, Joy W. Schizophrenia: A concise overview of incidence, prevalence, and mortality. Epidemiol Rev. 2008;30(1):67-76.

[6] Orrico-Sánchez A, López-Lacort M, Munõz-Quiles C, Sanfélix-Gimeno G, Diéz-Domingo J. Epidemiology of schizophrenia and its management over 8-years period using real-world data in Spain. BMC Psychiatry. 2020;20(149).

[7] WHO. WHO | Schizophrenia. Schizophrenia. 2018.

[8] Perälä J, Suvisaari J, Saarni SI, Kuoppasalmi K, Isometsä E, Pirkola S, et al. Lifetime prevalence of psychotic and bipolar I disorders in a general population. Arch Gen Psychiatry. 2007;64:19-28.

[9] Os J van. "Schizophrenia" does not exist. BMJ. 2016;352:i375.

[10] McGorry PD, Nelson B, Goldstone S, Yung AR. Clinical staging: A heuristic and practical strategy for new research and better health and social outcomes for psychotic and related mood disorders. Canadian Journal of Psychiatry. 2010.

[11] Cosci F, Fava GA. Staging of mental disorders: Systematic review. Psychother Psychosom. 2013;82:20-34.

[12] Agius M, Goh C, Ulhaq S, McGorry P. The staging model in schizophrenia, and its clinical implications. Psychiatr Danub. 2010;22:211-2020.

[13] Hoffman BF. The stages of schizophrenia and their management. Can Fam physician. 1982;28:2046-2050.

[14] Dave S, Boardman J. Personcentered care in psychiatric practice. Indian J Soc Psychiatry. 2018;34(4):333-336.

[15] Fava GA, Kellner R. Staging: A neglected dimension in psychiatric classification. Acta Psychiatr Scand. 1993;87:225-230.

[16] Lieberman JA, Perkins D, Belger A, Chakos M, Jarskog F, Boteva K, et al. The early stages of schizophrenia: Speculations on pathogenesis, pathophysiology, and therapeutic approaches. Biol Psychiatry. 2001;50:884-897.

[17] Insel TR. Rethinking schizophrenia. Nature. 2010;468(188):187-193.

[18] Khamker N. First episode schizophrenia. South African Fam Pract. 2015;57(5):29-33.

[19] Singh SP, Cooper JE, Fisher HL, Tarrant CJ, Lloyd T, Banjo J, et al. Determining the chronology and components of psychosis onset: The Nottingham onset schedule (NOS). Schizophr Res. 2005;80:117-130.

[20] Godin O, Fond G, Bulzacka E, Schürhoff F, Boyer L, Myrtille A, et al. Validation and refinement of the clinical staging model in a French cohort of outpatient with schizophrenia

*Clinical Staging in Schizophrenia Spectrum Disorders DOI: http://dx.doi.org/10.5772/intechopen.98276*

(FACE-SZ). Prog Neuro-Psychopharmacology Biol Psychiatry. 2019;92:226-234.

[21] Berendsen S, van der Paardt JW, Van HL, van Bruggen M, Nusselder H, Jalink M, et al. Staging and profiling for schizophrenia spectrum disorders: Inter-rater reliability after a short training course. Prog Neuro-Psychopharmacology Biol Psychiatry. 2020;99:109856.

[22] Addington J, Liu L, Goldstein BI, Wang J, Kennedy SH, Bray S, et al. Clinical staging for youth at-risk for serious mental illness. Early Interv Psychiatry. 2020;1-9.

[23] Griffa A, Baumann PS, Klauser P, Mullier E, Cleusix M, Jenni R, et al. Brain connectivity alterations in early psychosis: from clinical to neuroimaging staging. Transl Psychiatry. 2019;9(62).

[24] Lee TY, Kim M, Kim SN, Kwon JS. Reconsidering clinical staging model: A case of genetic high risk for schizophrenia. Psychiatry Investig. 2017;14(1):107-109.

[25] Fountoulakis KN, Dragioti E, Theofilidis AT, Wikilund T, Atmatzidis X, Nimatoudis I, et al. Staging of schizophrenia with the use of PANSS: An international multi-center study. Int J Neuropsychopharmacol. 2019;22(11):681-697.

[26] Wood SJ, Yung AR, McGorry PD, Pantelis C. Neuroimaging and treatment evidence for clinical staging in psychotic disorders: From the at-risk mental state to chronic schizophrenia. Biological Psychiatry. 2011.

[27] Mathalon DH. Challenges associated with application of clinical staging models to psychotic disorders. Biol Psychiatry. 2011;70(7):600-601.

[28] Cornblatt B, Lencz T, Obuchowski M. The schizophrenia prodrome: Treatment and high-risk perspectives. Schizophr Res. 2002;54:177-186.

[29] Addington J. The prodromal stage of psychotic illness: Observation, detection or intervention? J Psychiatry Neurosci. 2003;28(2):93-97.

[30] Conroy SK, Francis MM, Hulvershorn LA. Identifying and treating the prodromal phases of bipolar disorder and schizophrenia. Curr Treat Options Psychiatry. 2018;5(1):113-128.

[31] Buehlmann E, Berger GE, Aston J, Gschwandtner U, Pflueger MO, Borgwardt SJ, et al. Hippocampus abnormalities in at risk mental states for psychosis? A cross-sectional high resolution region of interest magnetic resonance imaging study. J Psychiatr Res. 2010;44(7):447-453.

[32] Jung WH, Kim JS, Jang JH, Choi JS, Jung MH, Park JY, et al. Cortical thickness reduction in individuals at ultra-high-risk for psychosis. Schizophr Bull. 2011;37(4):839-849.

[33] Fusar-Poli P, Broome MR, Woolley JB, Johns LC, Tabraham P, Bramon E, et al. Altered brain function directly related to structural abnormalities in people at ultra high risk of psychosis: Longitudinal VBM-fMRI study. J Psychiatr Res. 2011;45(2):190-198.

[34] D. Howes O, Fusar-Poli P, Bloomfield M, Selvaraj S, McGuire P. From the Prodrome to chronic schizophrenia: The neurobiology underlying psychotic symptoms and cognitive impairments. Curr Pharm Des. 2012;18(4):459-465.

[35] Cornblatt BA, Lencz T, Kane JM. Treatment of the schizophrenia prodrome: Is it presently ethical? Schizophr Res. 2001;51:31-38.

[36] McGuire P, Selvaraj S, Howes O. Is clinical intervention in the ultra high

risk phase effective? Rev Bras Psiquiatr. 2011;33(Supl II).

[37] Yung AR, Phillips LJ, McGorry PD, McFarlane CA, Francey S, Harrigan S, et al. Prediction of psychosis. A step towards indicated prevention of schizophrenia. Br J Psychiatry Suppl. 1998;172(33):14-20.

[38] McGorry PD, Yung AR, Phillips LJ, Yuen HP, Francey S, Cosgrave EM, et al. Randomized controlled trial of interventions designed to reduce the risk of progression to first-episode psychosis in a clinical sample with subthreshold symptoms. Arch Gen Psychiatry. 2002;59(10):921-928.

[39] McGlashan TH, Zipursky RB, Perkins D, Addington J, Miller T, Woods SW, et al. Randomized, doubleblind trial of olanzapine versus placebo in patients prodromally symptomatic for psychosis. Am J Psychiatry. 2006;163:790-799.

[40] Schmidt SJ, Schultze-Lutter F, Schimmelmann BG, Maric NP, Salokangas RKR, Riecher-Rössler A, et al. EPA guidance on the early intervention in clinical high risk states of psychoses. Eur Psychiatry. 2015;30(3):388-404.

[41] Agius M, Butler S, Holt C. Does early diagnosis and treatment of schizophrenia lead to improved longterm outcomes? Neuropsychiatry (London). 2011;1(6):553-565.

[42] Roberts J, Gracia Canales A, Blanthorn-Hazell S, Craciun Boldeanu A, Judge D. Characterizing the experience of agitation in patients with bipolar disorder and schizophrenia. BMC Psychiatry. 2018;18(104).

[43] Breitborde NJK, Srihari VH, Woods SW. Review of the operational definition for first-episode psychosis. Early Interv Psychiatry. 2009;3(4): 259-265.

[44] McGlashan TH. A selective review of recent north American long-term followup studies of schizophrenia. Schizophr Bull. 1988;14:515-542.

[45] Costa LG, Massuda R, Pedrini M, Passos IC, Czepielewski LS, Brietzke E, et al. Functioning in early and late stages of schizophrenia. Trends Psychiatry Psychother. 2014;36(4):209-213.

[46] Wyatt RJ. Neuroleptics and the natural course of schizophrenia. Schizophr Bull. 1991;17(2):325-351.

[47] Patel MX, De Zoysa N, Bernadt M, David A. Depot and oral antipsychotics: Patient preferences and attitudes are not the same thing. J Psychopharmacol. 2009;23(7):789-796.

[48] Johnson DAW, Freeman H. Drug defaulting by patients on long-acting phenothiazines. Psychol Med. 1973;3(1):115-119.

[49] Miller BJ. A review of secondgeneration antipsychotic discontinuation in first-episode psychosis. J Psychiatr Pract. 2008;14(5):289-300.

[50] Shepherd M, Watt D, Falloon I, Smeeton N. The natural history of schizophrenia: A five-year follow-up study of outcome and prediction in a representative sample of schizophrenics. Psychol Med Monogr Suppl. 1989;15:1-46.

[51] Leucht S, Kane JM, Kissling W, Hamann J, Etschel E, Engel R. Clinical implications of brief psychiatric rating scale scores. Br J Psychiatry. 2005;187:366-371.

[52] Correll CU, Kishimoto T, Nielsen J, Kane JM. Quantifying clinical relevance in the treatment of schizophrenia. Clin Ther. 2011;33:B16–B39.

[53] Andreasen NC, Carpenter WT, Kane JM, Lasser RA, Marder SR,

*Clinical Staging in Schizophrenia Spectrum Disorders DOI: http://dx.doi.org/10.5772/intechopen.98276*

Weinberger DR. Remission in schizophrenia: Proposed criteria and rationale for consensus Nancy. Am J Psychiatry. 2005;162:441-449.

[54] San L, Serrano M, Cañas F, Romero SL, Sánchez-Cabezudo Á, Villar M. Towards a pragmatic and operational definition of relapse in schizophrenia: A Delphi consensus approach. Int J Psychiatry Clin Pract. 2015;19:90-98.

[55] Lee BJ, Kim SW, Kim JJ, Yu JC, Lee KY, Won SH, et al. Defining treatment response, remission, relapse, and recovery in first-episode psychosis: A survey among Korean experts. Psychiatry Investig. 2020;17(2):163-174.

[56] Menezes NM, Arenovich T, Zipursky RB. A systematic review of longitudinal outcome studies of firstepisode psychosis. Psychol Med. 2006;36:1349-1362.

[57] Novick D, Montgomery W, Cheng Y, Moneta V, Haro JM. Impact of negative symptoms on quality of life in patients with schizophrenia. Value Heal. 2015;18(7):A836–A837.

[58] Cerveri G, Gesi C, Mencacci C. Pharmacological treatment of negative symptoms in schizophrenia: Update and proposal of a clinical algorithm. Neuropsychiatr Dis Treat. 2019;15:1525-1535.

[59] Roy A. Suicide in chronic schizophrenia. Br J Psychiatry. 1982;141(2):171-177.

#### **Chapter 4**

## The Many Faces of Negative Symptoms in Schizophrenia

*Mihaela Fadgyas Stanculete and Octavia Capatina*

#### **Abstract**

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.

**Keywords:** anhedonia, avolition, alogia, blunted affect, negative symptoms, schizophrenia

#### **1. 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 [3–5].

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 [11–13]. 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].

Negative symptoms have been commonly described as first symptoms of schizophrenia, and very frequently, they appear during the prodromal phase of the disorder [18, 19]. The prevalence of negative symptoms is hard to establish, with reports from literature ranging between 40% and 90%, these differences result from the heterogeneity of the used definitions, constitutive factors, and assessment methods [20]. The European First Episode Schizophrenia Trial reported that at least one negative symptom was noted in up to 54.2% of the patients at baseline [21]. The Clinical Antipsychotic Trials of Interventions Effectiveness, which is one of the most extensive controlled studies for schizophrenia, reported negative symptoms in 40% of the patients [22], and the CLAMORS study reported one or more negative symptoms were present in 57.6% of patients [23]. What is known is that they can occur at any point during the illness, but the long-term course is less clear. Some studies report stability of negative domain [24], while others describe an unstable course [25]. Many factors could be accountable for this difference, but it is widely accepted that improvement in negative symptoms is more common during the first years of the disorder, and an exacerbation is frequently seen in chronic patients [26].

Across studies, it is generally evidenced that negative symptoms are frequently reported in any disease phase. They are associated with poor functional outcomes, which is why it is imperative to assess and address these symptoms to improve the quality of life for patients with schizophrenia.

#### **2. 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 [27–30].

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].

#### **2.2 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 [37–41]. 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


#### **Table 1.**

*Diagnostic criteria for deficit schizophrenia [34–36].*

primary and secondary symptoms, making the diagnosis very difficult. Moreover, first psychotic episode patients represent another diagnostical challenge [42–44].

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


**Table 2.**

*Definition of negative symptoms of schizophrenia [45].*

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 [46–48]. 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) [51–53]. 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].

#### **3. 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].

#### **3.1 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 [37–41]. 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 [37, 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 [65–68]. 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, 40, 69, 70].

#### **3.2 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, 71–73].

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 [74–77].

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].

#### **3.3 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, 82–85].

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 [89–92].

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 [98–100]. 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].

#### **4. 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.

*The Many Faces of Negative Symptoms in Schizophrenia DOI: http://dx.doi.org/10.5772/intechopen.98412*


*Transporting ATPase Interacting 2), 22q11DS (22q11 deletion syndrome).*

#### **Table 3.**

*Genes potentially involved in negative symptoms' pathogenesis.*

#### **5. 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.

### **Conflict of interest**

The authors declare no conflict of interest.

#### **Author details**

Mihaela Fadgyas Stanculete\* and Octavia Capatina Department of Neurosciences, University of Medicine and Pharmacy Iuliu Hatieganu, Cluj Napoca, Romania

\*Address all correspondence to: mihaelastanculete@yahoo.com

© 2021 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

*The Many Faces of Negative Symptoms in Schizophrenia DOI: http://dx.doi.org/10.5772/intechopen.98412*

#### **References**

[1] Kahn R, Sommer I, Murray R, Meyer-Lindenberg A, Weinberger D, Cannon T et al. Schizophrenia. Nature Reviews Disease Primers. 2015;1(1).

[2] Charlson F, Ferrari A, Santomauro D, Diminic S, Stockings E, Scott J et al. Global Epidemiology and Burden of Schizophrenia: Findings From the Global Burden of Disease Study 2016. Schizophrenia Bulletin. 2018;44(6):1195-1203.

[3] Lindenmayer, J. P., Grochowski, S., & Hyman, R. B. (1995). Five factor model of schizophrenia: replication across samples. *Schizophrenia research*, *14*(3), 229-234.

[4] Wallwork, R. S., Fortgang, R., Hashimoto, R., Weinberger, D. R., & Dickinson, D. (2012). Searching for a consensus five-factor model of the Positive and Negative Syndrome Scale for schizophrenia. *Schizophrenia research*, *137*(1-3), 246-250.

[5] van der Gaag, M., Cuijpers, A., Hoffman, T., Remijsen, M., Hijman, R., de Haan, L., ... & Wiersma, D. (2006). The five-factor model of the Positive and Negative Syndrome Scale I: confirmatory factor analysis fails to confirm 25 published five-factor solutions. *Schizophrenia research*, *85*(1-3), 273-279.

[6] Fervaha, G., Foussias, G., Agid, O., & Remington, G. (2014). Impact of primary negative symptoms on functional outcomes in schizophrenia. *European Psychiatry*, *29*(7), 449-455.

[7] Jonathan Rabinowitz, Stephen Z. Levine, George Garibaldi, Dragana Bugarski-Kirola, Carmen Galani Berardo, Shitij Kapur,Negative symptoms have greater impact on functioning than positive symptoms in schizophrenia: Analysis of CATIE data,Schizophrenia Research, Volume 137, Issues 1-3,

[8] Foussias, G., Agid, O., Fervaha, G., & Remington, G. (2014). Negative symptoms of schizophrenia: clinical features, relevance to real world functioning and specificity versus other CNS disorders. *European Neuropsychopharmacology*, *24*(5), 693-709.

[9] Correll CU, Schooler NR. Negative Symptoms in Schizophrenia: A Review and Clinical Guide for Recognition, Assessment, and Treatment. Neuropsychiatr Dis Treat. 2020 Feb 21;16:519-534. doi: 10.2147/NDT. S225643. PMID: 32110026; PMCID: PMC7041437.

[10] Harvey PD, Strassnig M. Predicting the severity of everyday functional disability in people with schizophrenia: cognitive deficits, functional capacity, symptoms, and health status. World Psychiatry. 2012;11(2):73-79. doi:10.1016/j.wpsyc.2012.05.004

[11] Foussias, G., Mann, S., Zakzanis, K. K., Van Reekum, R., Agid, O., & Remington, G. (2011). Prediction of longitudinal functional outcomes in schizophrenia: the impact of baseline motivational deficits. *Schizophrenia research*, *132*(1), 24-27.

[12] CĂPĂȚÎNĂ, O., & MICLUȚIA, I. (2018). Internalized stigma as a predictor of quality of life in schizophrenia. *Journal of Evidence-Based Psychotherapies*, *18*(2), 35-53.

[13] Sicras-Mainar, A., Maurino, J., Ruiz-Beato, E., & Navarro-Artieda, R. (2014). Impact of negative symptoms on healthcare resource utilization and associated costs in adult outpatients with schizophrenia: a population-based study. *BMC psychiatry*, *14*(1), 1-8.

[14] Möller HJ. The Relevance of Negative Symptoms in Schizophrenia and How to Treat Them with

Psychopharmaceuticals? Psychiatr Danub. 2016 Dec;28(4):435-440. PMID: 27855437.

[15] Fusar-Poli, P., Papanastasiou, E., Stahl, D., Rocchetti, M., Carpenter, W., Shergill, S., & McGuire, P. (2015). Treatments of negative symptoms in schizophrenia: meta-analysis of 168 randomized placebo-controlled trials. *Schizophrenia bulletin*, *41*(4), 892-899.

[16] Aleman A, Lincoln TM, Bruggeman R, Melle I, Arends J, Arango C, Knegtering H. Treatment of negative symptoms: Where do we stand, and where do we go? Schizophr Res. 2017 Aug;186:55-62. doi: 10.1016/j. schres.2016.05.015. Epub 2016 Jun 9. PMID: 27293137.

[17] Căpățînă, O.O., Micluția, I.V., & Fadgyas-Stănculete, M. (2021). Current perspectives in treating negative symptoms of schizophrenia: A narrative review (Review). Experimental and Therapeutic Medicine, 21, 276. https:// doi.org/10.3892/etm.2021.9707

[18] Piskulic D, Addington J, Cadenhead KS, et al. Negative symptoms in individuals at clinical high risk of psychosis. Psychiatry Res. 2012;196(2-3):220-224. doi:10.1016/j. psychres.2012.02.018

[19] Velthorst E, Nieman DH, Becker HE, et al. Baseline differences in clinical symptomatology between ultra high risk subjects with and without a transition to psychosis. Schizophr Res. 2009;109(1– 3):60-65. doi:10.1016/j. schres.2009.02.002

[20] Makinen J, Miettunen J, Isohanni M, Koponen H. Negative symptoms in schizophrenia: a review. Nord J Psychiatry. 2008;62 (5):334-341. doi:10.1080/08039480801959307

[21] Galderisi, S., Mucci, A., Bitter, I., Libiger, J., Bucci, P., Fleischhacker, W. W., ... & Eufest Study Group. (2013).

Persistent negative symptoms in first episode patients with schizophrenia: results from the European First Episode Schizophrenia Trial. *European Neuropsychopharmacology*, *23*(3), 196-204.

[22] Rabinowitz, J., Berardo, C. G., Bugarski-Kirola, D., & Marder, S. (2013). Association of prominent positive and prominent negative symptoms and functional health, well-being, healthcare-related quality of life and family burden: a CATIE analysis. *Schizophrenia research*, *150*(2- 3), 339-342.

[23] Bobes, J., Arango, C., Garcia-Garcia, M., & Rejas, J. (2009). Prevalence of negative symptoms in outpatients with schizophrenia spectrum disorders treated with antipsychotics in routine clinical practice: findings from the CLAMORS study. *The Journal of clinical psychiatry*, *71*(3), 280-286.

[24] Austin SF, Mors O, Budtz-Jorgensen E, et al. Long-term trajectories of positive and negative symptoms in first episode psychosis: a 10year follow-up study in the OPUS cohort. Schizophr Res. 2015;168(1- 2):84-91. doi:10.1016/j. schres.2015.07.021

[25] Heilbronner U, Samara M, Leucht S, Falkai P, Schulze TG. The Longitudinal Course of Schizophrenia Across the Lifespan: Clinical, Cognitive, and Neurobiological Aspects. Harv Rev Psychiatry. 2016 Mar-Apr;24(2):118-28. doi: 10.1097/HRP.0000000000000092. PMID: 26954596; PMCID: PMC5079232.

[26] Pogue-Geile MF, Harrow M. Negative symptoms in schizophrenia: their longitudinal course and prognostic importance. Schizophr Bull. 1985;11(3):427-439. doi:10.1093/ schbul/11.3.427

[27] Marneros A, Andreasen N, Tsuang M. Negative versus positive *The Many Faces of Negative Symptoms in Schizophrenia DOI: http://dx.doi.org/10.5772/intechopen.98412*

schizophrenia. Berlin: Springer-Verlag; 1991.

[28] Malaspina D, Walsh-Messinger J, Gaebel W, Smith L, Gorun A, Prudent V et al. Negative symptoms, past and present: A historical perspective and moving to DSM-5. European Neuropsychopharmacology. 2014;24(5):710-724.

[29] Kraepelin E. Dementia praecox and paraphrenia. Miami, FL: HardPress Pub.; 2013.

[30] Andreasen N. The evolving concept of schizophrenia: From Kraepelin to the present and future. Schizophrenia Research. 1997;28(2-3):105-109.

[31] Ban TA. Fifty years chlorpromazine: a historical perspective. Neuropsychiatric Disease and Treatment. 2007;3(4):495-500.

[32] Andreasen N. Negative v Positive Schizophrenia. Archives of General Psychiatry. 1982;39(7):789

[33] Crow - Crow T. The Two-syndrome Concept: Origins and Current Status. Schizophrenia Bulletin. 1985;11(3): 471-488.

[34] Carpenter W , Heinrichs D, Wagman A. Deficit and nondeficit forms of schizophrenia: the concept. American Journal of Psychiatry. 1988;145(5):578-583.

[35] Diagnostic and statistical manual of mental disorders. DSM-III-R. Prep. Washington: American Psychiatric Ass; 1987.

[36] Diagnostic and statistical manual of mental disorders. DSM-IV. Washington, DC: American Psychiatric Association; 1995.

[37] Kirkpatrick B, Buchanan R, Ross D, Carpenter W. A Separate Disease Within the Syndrome of Schizophrenia.

Archives of General Psychiatry. 2001;58(2):165.

[38] Blanchard J, Horan W, Collins L. Examining the latent structure of negative symptoms: Is there a distinct subtype of negative symptom schizophrenia?. Schizophrenia Research. 2005;77(2-3):151-165.

[39] Messias E, Kirkpatrick B, Bromet E, Ross D, Buchanan B, Carpenter W et al. Summer birth and deficit schizophrenia: A pooled analysis from five countries. Schizophrenia Research. 2003; 60(1):45-46.

[40] Galderisi S, Maj M. Deficit schizophrenia: An overview of clinical, biological and treatment aspects. European Psychiatry. 2009;24(8): 493-500.

[41] Galderisi S, Quarantelli M, Volpe U, Mucci A, Cassano G, Invernizzi G et al. Patterns of Structural MRI Abnormalities in Deficit and Nondeficit Schizophrenia. Schizophrenia Bulletin. 2007;34(2):393-401.

[42] Buchanan R. Persistent Negative Symptoms in Schizophrenia: An Overview. Schizophrenia Bulletin. 2007;33(4):1013-1022.

[43] Mäkinen J, Miettunen J, Isohanni M, Koponen H. Negative symptoms in schizophrenia—A review. Nordic Journal of Psychiatry. 2008;62(5): 334-341.

[44] Kelley M, Haas G, van Kammen D. Longitudinal progression of negative symptoms in schizophrenia: A new look at an old problem. Schizophrenia Research. 2008;105(1- 3):188-196.

[45] Kirkpatrick B, Fenton W, Carpenter W, Marder S. The NIMH-MATRICS Consensus Statement on Negative Symptoms. Schizophrenia Bulletin. 2006;32(2):214-219.

[46] Blanchard J, Cohen A. The Structure of Negative Symptoms Within Schizophrenia: Implications for Assessment. Schizophrenia Bulletin. 2005;32(2):238-245.

[47] Messinger J, Trémeau F, Antonius D, Mendelsohn E, Prudent V, Stanford A et al. Avolition and expressive deficits capture negative symptom phenomenology: Implications for DSM-5 and schizophrenia research. Clinical Psychology Review. 2011;31(1):161-168.

[48] Park S, Llerena K, McCarthy J, Couture S, Bennett M, Blanchard J. Screening for negative symptoms: Preliminary results from the self-report version of the Clinical Assessment Interview for Negative Symptoms. Schizophrenia Research. 2012;135(1-3):139-143.

[49] Kirkpatrick B, Strauss G, Nguyen L, Fischer B, Daniel D, Cienfuegos A et al. The Brief Negative Symptom Scale: Psychometric Properties. Schizophrenia Bulletin. 2010;37(2):300-305. 48. Mucci A, Galderisi S. The secondgeneration assessment scales: Brief negative symptom scale and clinical assessment interview for negative symptoms. European Psychiatry. 2016;33:S70.

[50] Horan W, Kring A, Gur R, Reise S, Blanchard J. Development and psychometric validation of the Clinical Assessment Interview for Negative Symptoms (CAINS). Schizophrenia Research. 2011;132(2-3):140-145.

[51] Galderisi S, Bucci P, Mucci A, Kirkpatrick B, Pini S, Rossi A, Vita A, Maj M. Categorical and dimensional approaches to negative symptoms of schizophrenia: focus on long-term stability and functional outcome. Schizophr Res. 2013 Jun;147(1):157-62.

[52] Strauss GP, Horan WP, Kirkpatrick B, Fischer BA, Keller WR, Miski P, Buchanan RW, Green MF, Carpenter WT Jr. Deconstructing negative symptoms of schizophrenia: avolition-apathy and diminished expression clusters predict clinical presentation and functional outcome. J Psychiatr Res. 2013 Jun;47(6):783-90.

[53] Liemburg E, Castelein S, Stewart R, van der Gaag M, Aleman A, Knegtering H; Genetic Risk and Outcome of Psychosis (GROUP) Investigators, 2013. Two subdomains of negative symptoms in psychotic disorders: established and confirmed in two large cohorts. J. Psychiatrs. Res.47, 178-725. http:// dx.doi.org/10.1016/j.jpsychires. 2013.01.024

[54] Rocca P, Montemagni C, Zappia S, Piterà R, Sigaudo M, Bogetto F. Negative symptoms and everyday functioning in schizophrenia: A cross-sectional study in a real world-setting. Psychiatry Research. 2014;218(3):284-289.

[55] Galderisi S, Mucci A, Buchanan R, Arango C. Negative symptoms of schizophrenia: new developments and unanswered research questions. The Lancet Psychiatry. 2018;5(8):664-677.

[56] Marder S, Galderisi S. The current conceptualization of negative symptoms in schizophrenia. World Psychiatry. 2017;16(1):14-24.

[57] Kirkpatrick B, Castle D, Murray, R.M., Carpenter Jr WT. Risk factors for the deficit syndrome of schizophrenia. Schizophr. Bull. 2000: 26 (1), 233-242.

[58] Kirkpatrick B. The deficit syndrome: Marker of a separate disease within schizophrenia. Biological Psychiatry. 1997;42(1):203S.

[59] Turetsky BI, Colbath EA, Gur RE. P300 subcomponent abnormalities in schizophrenia: I. Physiological evidence for gender and subtype specific differences in regional pathology. Biol. Psychiatry. 1998; 43 (2), 84-96.

*The Many Faces of Negative Symptoms in Schizophrenia DOI: http://dx.doi.org/10.5772/intechopen.98412*

[60] Galderisi S, Quarantelli M, Volpe U, Mucci A, Cassano GB, Invernizzi G, Rossi A, Vita A, Pini S, Cassano P, Daneluzzo E, De Peri L, Stratta P, Brunetti A, Maj M. Patterns of structural MRI abnormalities in deficit and nondeficit schizophrenia. Schizophr. Bull.2008;34 (2), 393-401.

[61] Gonul A, Kula M, Eşel E, Tutuş A, Sofuoglu S. A Tc-99m HMPAO SPECT study of regional cerebral blood flow in drug-free schizophrenic patients with deficit and non-deficit syndrome. Psychiatry Research: Neuroimaging. 2003;123(3):199-205.

[62] Tamminga C. Limbic System Abnormalities Identified in Schizophrenia Using Positron Emission Tomography With Fluorodeoxyglucose and Neocortical Alterations With Deficit Syndrome. Archives of General Psychiatry. 1992;49(7):522-530.

[63] Mucci A, Dima D, Soricelli A, Volpe U, Bucci P, Frangou S et al. Is avolition in schizophrenia associated with a deficit of dorsal caudate activity? A functional magnetic resonance imaging study during reward anticipation and feedback. Psychological Medicine. 2015;45(08):1765-1778.

[64] Morris R, Quail S, Griffiths K, Green M, Balleine B. Corticostriatal Control of Goal-Directed Action Is Impaired in Schizophrenia. Biological Psychiatry. 2015;77(2):187-195.

[65] Lindenmayer J, Khan A, Iskander A, Abad M, Parker B. A Randomized Controlled Trial of Olanzapine Versus Haloperidol in the Treatment of Primary Negative Symptoms and Neurocognitive Deficits in Schizophrenia. The Journal of Clinical Psychiatry. 2007;68(03):368-379.

[66] Murphy B, Chung Y, Park T, McGorry P. Pharmacological treatment of primary negative symptoms in

schizophrenia: A systematic review. Schizophrenia Research. 2006;88(1- 3):5-25.

[67] Leucht S. Amisulpride, an Unusual "Atypical" Antipsychotic: A Meta-Analysis of Randomized Controlled Trials. American Journal of Psychiatry. 2002;159(2):180-190.

[68] Möller H, Riedel M, Müller N, Fischer W, Kohnen R. Zotepine Versus Placebo in the Treatment of Schizophrenic Patients with Stable Primary Negative Symptoms: A Randomized Double-Blind Multicenter Trial. Pharmacopsychiatry. 2004;37(6):270-278.

[69] Maj M, Galderisi S. Deficit schizophrenia: a valid categorical subtype of schizophrenia?. Schizophrenia Research. 2008;102(1-3):45.

[70] Arango C, Garibaldi G, Marder S. Pharmacological approaches to treating negative symptoms: A review of clinical trials. Schizophrenia Research. 2013;150(2-3):346-352.

[71] Üçok A, Ergül C. Persistent negative symptoms after first episode schizophrenia: A 2-year follow-up study. Schizophrenia Research. 2014;158(1-3):241-246.

[72] López-Díaz Á, Lara I, Lahera G. Is the Prevalence of the Deficit Syndrome in Schizophrenia Higher than Estimated? Results of a Meta-Analysis. Psychiatry Investigation. 2018;15(1):94-98.

[73] Bobes J, Arango C, Garcia-Garcia M, Rejas J. Prevalence of Negative Symptoms in Outpatients With Schizophrenia Spectrum Disorders Treated With Antipsychotics in Routine Clinical Practice. The Journal of Clinical Psychiatry. 2009;71(03):280-286.

[74] Meisenzahl E, Koutsouleris N, Bottlender R, Scheuerecker J, Jäger M, Teipel S et al. Structural brain alterations at different stages of schizophrenia: A voxel-based morphometric study. Schizophrenia Research. 2008;104(1-3):44-60.

[75] Sigmundsson T, Suckling J, Maier M, Williams S, Bullmore E, Greenwood K et al. Structural Abnormalities in Frontal, Temporal, and Limbic Regions and Interconnecting White Matter Tracts in Schizophrenic Patients With Prominent Negative Symptoms. American Journal of Psychiatry. 2001;158(2):234-243.

[76] Bodnar M, Hovington C, Buchy L, Malla A, Joober R, Lepage M. Cortical Thinning in Temporo-Parietal Junction (TPJ) in Non-Affective First-Episode of Psychosis Patients with Persistent Negative Symptoms. PLoS ONE. 2014;9(6):e101372.

[77] Hovington C, Lepage M. Neurocognition and neuroimaging of persistent negative symptoms of schizophrenia. Expert Review of Neurotherapeutics. 2012;12(1):53-69.

[78] Orsolini L, Valchera A, De Berardis D, Vecchiotti R, Iasevoli F. The novel antipsychotic cariprazine (RGH-188): State-of-the-art in the treatment of psychiatric disorders. European Psychiatry. 2016;33:S228.

[79] Nemeth G, Laszlovszky I, Czobor P, et al. Cariprazine versus risperidone monotherapy for treatment of predominant negative symptoms in patients with schizophrenia: a randomised, double-blind, controlled trial. Lancet 2017; 389: 1103-13.

[80] Davidson M, Saoud J, Staner C, Noel N, Luthringer E, Werner S et al. Efficacy and Safety of MIN-101: A 12-Week Randomized, Double-Blind, Placebo-Controlled Trial of a New Drug in Development for the Treatment of Negative Symptoms in Schizophrenia. American Journal of Psychiatry. 2017;174(12):1195-1202.

[81] Morris RW, Quail S, Griffiths KR, Green MJ, Balleine BW. Corticostriatal control of goaldirected action is impaired in schizophrenia. Biol Psychiatry 2015; 77: 187-95.

[82] Galderisi S, Färden A, Kaiser S. Dissecting negative symptoms of schizophrenia: History, assessment, pathophysiological mechanisms and treatment. Schizophrenia Research. 2017;186:1-2.

[83] Trémeau F, Nolan K, Malaspina D, Javitt D. Behavioral validation of avolition in schizophrenia. Schizophrenia Research. 2012; 138(2-3):255-261.

[84] Barch DM, Pagliaccio D, Luking K. Mechanisms underlying motivational deficits in psychopathology: similarities and differences in depression and schizophrenia. Curr Topics Behav Neurosci 2016; 27: 411-49.

[85] Radua J, Schmidt A, Borgwardt S, et al. Ventral striatal activation during reward processing in psychosis: a neurofunctional meta-analysis. JAMA Psychiatry 2015; 72: 1243-51.

[86] Beck A, Grant P, Huh G, Perivoliotis D, Chang N. Dysfunctional Attitudes and Expectancies in Deficit Syndrome Schizophrenia. Schizophrenia Bulletin. 2011; 39(1):43-51.

[87] Grant P. Randomized Trial to Evaluate the Efficacy of Cognitive Therapy for LowFunctioning Patients With Schizophrenia. Archives of General Psychiatry. 2012;69(2):121-127.

[88] Lindenmayer J, Nasrallah H, Pucci M, James S, Citrome L. A systematic review of psychostimulant treatment of negative symptoms of schizophrenia: Challenges and therapeutic opportunities. Schizophrenia Research. 2013;147(2-3):241-252.

*The Many Faces of Negative Symptoms in Schizophrenia DOI: http://dx.doi.org/10.5772/intechopen.98412*

[89] Sethom M, Fares S, Bouaziz N, Melki W, Jemaa R, Feki M et al. Polyunsaturated fatty acids deficits are associated with psychotic state and negative symptoms in patients with schizophrenia. Prostaglandins, Leukotrienes and Essential Fatty Acids. 2010;83(3):131- 136.

[90] Tsapakis E, Dimopoulou T, Tarazi F. Clinical management of negative symptoms of schizophrenia: An update. Pharmacology & Therapeutics. 2015;153:135-147.

[91] Ellman L, Cook A, Schaefer C, Bresnahan M, Susser E, Brown A. 113. Maternal inflammation during pregnancy and symptom profiles of offspring diagnosed with schizophrenia. Brain, Behavior, and Immunity. 2014;40:e33.

[92] Oya K, Kishi T, Iwata N. Efficacy and tolerability of minocycline augmentation therapy in schizophrenia: a systematic review and meta-analysis of randomized controlled trials. Human Psychopharmacology: Clinical and Experimental. 2014;29(5):483-491.

[93] Freitas C, Fregni F, Pascual-Leone A. Meta-analysis of the effects of repetitive transcranial magnetic stimulation (rTMS) on negative and positive symptoms in schizophrenia. Schizophrenia Research.

2009;108(1-3):11-24.

[94] Dlabač-de Lange J, Knegtering R, Aleman A. Repetitive Transcranial Magnetic Stimulation for Negative Symptoms of Schizophrenia. The Journal of Clinical Psychiatry. 2010;71(04):411-418.

[95] Smith R, Boules S, Mattiuz S, Youssef M, Tobe R, Sershen H et al. Effects of transcranial direct current stimulation (tDCS) on cognition, symptoms, and smoking in schizophrenia: A randomized controlled study. Schizophrenia Research. 2015;168(1-2):260-266.

[96] Fitzgerald P, McQueen S, Daskalakis Z, Hoy K. A Negative Pilot Study of Daily Bimodal Transcranial Direct Current Stimulation in Schizophrenia. Brain Stimulation. 2014;7(6):813-816.

[97] Cohen A, Morrison S, Brown L, Minor K. Towards a cognitive resource limitations model of diminished expression in schizotypy. Journal of Abnormal Psychology. 2012;121(1):109-118.

[98] Lepage M, Sergerie K, Benoit A, Czechowska Y, Dickie E, Armony J. Emotional face processing and flat affect in schizophrenia: functional and structural neural correlates. Psychological Medicine. 2011;41(09): 1833-1844.

[99] Stip E, Fahim C, Liddle P, Mancini-Marïe A, Mensour B, Bentaleb L et al. Neural Correlates of Sad Feelings in Schizophrenia with and without Blunted Affect. The Canadian Journal of Psychiatry. 2005;50(14):909-917.

[100] Aleman A, Kahn R. Strange feelings: do amygdala abnormalities dysregulate the emotional brain in schizophrenia? Prog. Neurobiol. 2005;77 (5), 283-298.

[101] Hager O, Kirschner, M, Bischof M, Hartmann-Riemer M, Kluge A, Seifritz E, Tobler P, Kaiser S. Rewarddependent modulation of working memory is associated with negative symptoms in schizophrenia. Schizophr. Res. 2015;168 (1-2), 238-244.

[102] Bor J, Brunelin J, d'Amato T, Costes N, Suaud-Chagny M, Saoud M et al. How can cognitive remediation therapy modulate brain activations in schizophrenia?. Psychiatry Research: Neuroimaging. 2011;192(3):160-166.

[103] Elis O, Caponigro J, Kring A. Psychosocial treatments for negative symptoms in schizophrenia: Current practices and future directions. Clinical Psychology Review. 2013;33(8):914-928.

[104] De Berardis D, Marini S, Iasevoli F, Tomasetti C, deBartolomeis A, Mazza M, Valchera A. The role of intranasaloxytocinin the treatment of patients with schizophrenia: a systematic review. CNSNeurol. Disord. DrugTargets. 2013:12:252-264.

[105] Sullivan PF, Kendler KS, Neale MC. Schizophrenia as a complex trait: evidence from a meta-analysis of twin studies. Archives of general psychiatry. 2003 Dec 1;60(12):1187-92.

[106] Fanous AH, Van Den Oord EJ, Riley BP, Aggen SH, Neale MC, O'neill FA, Walsh D, Kendler KS. Relationship between a high-risk haplotype in the DTNBP1 (dysbindin) gene and clinical features of schizophrenia. American Journal of Psychiatry. 2005 Oct 1;162(10):1824-32.

[107] DeRosse P, Funke B, Burdick KE, Lencz T, Ekholm JM, Kane JM, Kucherlapati R, Malhotra AK. Dysbindin genotype and negative symptoms in schizophrenia. American Journal of Psychiatry. 2006 Mar 1;163(3):532-4.

[108] Pelayo-Terán JM, Crespo-Facorro B, Carrasco-Marín E, Pérez-Iglesias R, Mata I, Arranz MJ, Leyva-Cobián F, Vázquez-Barquero JL. Catechol-Omethyltransferase Val158Met polymorphism and clinical characteristics in first episode nonaffective psychosis. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics. 2008 Jul 5;147(5):550-6.

[109] Wessman J, Paunio T, Tuulio-Henriksson A, Koivisto M, Partonen T, Suvisaari J, Turunen JA, Wedenoja J, Hennah W, Pietiläinen OP, Lönnqvist J. Mixture model clustering of phenotype features reveals evidence for association of DTNBP1 to a specific subtype of schizophrenia. Biological psychiatry. 2009 Dec 1;66(11):990-6.

[110] Bertolino A, Fazio L, Caforio G, Blasi G, Rampino A, Romano R, Di Giorgio A, Taurisano P, Papp A, Pinsonneault J, Wang D. Functional variants of the dopamine receptor D2 gene modulate prefronto-striatal phenotypes in schizophrenia. Brain. 2009 Feb 1;132(2):417-25.

[111] Petrovsky N, Quednow BB, Ettinger U, Schmechtig A, Mössner R, Collier DA, Kühn KU, Maier W, Wagner M, Kumari V. Sensorimotor gating is associated with CHRNA3 polymorphisms in schizophrenia and healthy volunteers. Neuropsychopharmacology. 2010 Jun;35(7):1429-39.

[112] Xu C, Aragam N, Li X, Villla EC, Wang L, Briones D, Petty L, Posada Y, Arana TB, Cruz G, Mao C. BCL9 and C9orf5 are associated with negative symptoms in schizophrenia: metaanalysis of two genome-wide association studies. PloS one. 2013 Jan 29;8(1):e51674.

[113] Mezquida G, Penades R, Cabrera B, Savulich G, Lobo A, González-Pinto A, Penzol MJ, Corripio I, Fernandez-Egea E, Gassó P, Cuesta MJ. Association of the brain-derived neurotrophic factor Val66Met polymorphism with negative symptoms severity, but not cognitive function, in first-episode schizophrenia spectrum disorders. European Psychiatry. 2016 Oct;38:61-9.

[114] Edwards AC, Bigdeli TB, Docherty AR, Bacanu S, Lee D, De Candia TR, Moscati A, Thiselton DL, Maher BS, Wormley BK, Molecular Genetics of Schizophrenia Collaboration (MGS). Meta-analysis of positive and negative symptoms reveals

*The Many Faces of Negative Symptoms in Schizophrenia DOI: http://dx.doi.org/10.5772/intechopen.98412*

schizophrenia modifier genes. Schizophrenia bulletin. 2016 Mar 1;42(2):279-87.

[115] Gao J, Yi H, Tang X, Feng X, Yu M, Sha W, Wang X, Zhang X, Zhang X. DNA methylation and gene expression of matrix metalloproteinase 9 gene in deficit and non-deficit schizophrenia. Frontiers in genetics. 2018 Dec 11;9:646.

[116] Schneider M, Armando M, Schultze-Lutter F, Pontillo M, Vicari S, Debbané M, Eliez S. Prevalence, course and psychosis-predictive value of negative symptoms in 22q11. 2 deletion syndrome. Schizophrenia research. 2019 Apr 1;206:386-93.
