Avolition schizophrenia

Avolition also known as apathy or amotivation, is a severe problem with initiation or reduced motivation to initiate or persist in goal-directed activity ¹. Avolition may reflect a general lack of motivation and drive. Avolition is commonly seen as one of the negative symptoms in patients with schizophrenia, and is also common in frontal lobe disorders affecting medial frontal systems. Anhedonia is a reduced experience of pleasure ². Anhedonia and avolition are common features of schizophrenia that have substantial effects on functional outcome, but are poorly understood and treated ³.

The neurobiological underpinnings of avolition in schizophrenia remain unclear ⁴. Most brain imaging research has focused on reward prediction deficit and on ventral striatum dysfunction, but findings are not consistent.

Negative symptoms have long been considered a core feature of schizophrenia ⁵. They represent a separate domain of schizophrenia ⁶ and have been associated with poor functional outcome, worse quality of life and poor response to pharmacological treatment ⁷.

According to the literature, negative symptoms include blunted affect (reduced intensity and range of emotional expression), alogia (reduced spontaneous speech and loss of conversational fluency), avolition (reduced interest and motivation for productive activities, or sense of purpose), asociality (diminished interest in social drive or interest and desire for affiliation) and anhedonia (reduced ability to experience or anticipate pleasure) ⁸.

Several analytic studies have reported that negative symptoms can be divided into two domains referred to as Avolition-apathy (which includes avolition, anhedonia and asociality) and Expressive deficit (which includes alogia and blunted affect) ⁹. These two domains have been shown to have different behavioral and neurobiological correlates and they may also be targeted by different therapeutic options ⁷.

Avolition-apathy has been associated with a dysfunction of brain circuits involved in motivation ¹⁰, in particular to those subtending the ability to anticipate pleasure and learn from rewards ¹¹ or to integrate reward value with performed actions ¹². These functions are subtended by the circuit corresponding to the NIMH Research Domain Criteria (https://www.nimh.nih.gov/research/research-funded-by-nimh/rdoc/index.shtml) “positive valence system” ¹³. This system involves dopamine neurons located in the ventro-tegmental area and in the ventro-medial substantia nigra pars compacta with projections to orbito-frontal cortex, ventro-medial prefrontal cortex, nucleus accumbens, dorsal striatum, amygdala and insular cortex ⁸.

Open issues in the field include whether Avolition-apathy and all component symptoms share the same neurobiological underpinnings, in particular for what concerns the anticipatory (failure to anticipate reward or pleasurable experiences) and consummatory aspects of anhedonia (in the moment experience of pleasure during pleasurable situations).

It is highly controversial whether consummatory anhedonia can be found in non-depressed individuals with schizophrenia ¹⁴, as several studies documented an intact ability to experience pleasure in the moment in these subjects ¹⁵. In contrast, an impairment in pleasure anticipation, due to a dysfunction of the motivation circuits, was consistently reported in individuals with schizophrenia, both at first-episode and during the chronic phase of the disease ¹⁶. Thus, only anticipatory anhedonia might share the same neurobiological correlates of the Avolition-apathy domain ¹⁷. This issue could not be tested adequately in the past. In fact, most of the old assessment instruments either did not evaluate anhedonia or did not distinguish between consummatory and anticipatory anhedonia ¹⁸. Indeed, both the Positive and Negative Syndrome Scale (PANSS) ¹⁹ and the Scale for the Assessment of Negative Symptoms (SANS) ²⁰ had several limitations. The PANSS did not evaluate avolition and anhedonia, while the SANS rated together anhedonia and asociality, and did not distinguish between the two aspects of anhedonia. These limitations have been overcome by the introduction of second generation clinician-rated scales, such as the Brief Negative Symptoms Scale (BNSS) ²¹, in which the anhedonia subscale has separate items for the assessment of the intensity and frequency of pleasure during activities (consummatory pleasure) in the last week and the intensity of expected pleasure from future activities (anticipatory pleasure).

Some electrophysiological studies, investigating abnormalities of reward anticipation and evaluation in individuals with schizophrenia, found that anhedonia was associated with abnormal reward processing, evaluated using the Stimulus Preceding Negativity (SPN) and the P300 event-related potential (ERP) ²². In the study conducted by Wynn et al. ²³, the Stimulus Preceding Negativity (SPN), a negative event-related potential (ERP) component involved in the anticipation of feedback, correlated with trait anhedonia and with the total negative symptoms score, assessed using the Scale for the Assessment of Negative Symptoms (SANS). Vignapiano et al. ²² investigated cue P300 ERP components during the anticipation of reward and loss (using the Monetary Incentive Delay task). They found that in healthy controls and in individuals with schizophrenia, early P300 amplitude for large reward and large loss was inversely related to social anhedonia, assessed using the Chapman Social Anhedonia Scale ²⁴. The same study did not find any correlation of the P300 amplitude with the Avolition-apathy or Expressive deficit domain.

The results of task-related ERP investigations could be confounded by neurocognitive deficits that are prominent in individuals with schizophrenia ²⁵ and suffer from an a priori selection of the component of interest.

For these reasons, ERP results might be integrated by complementary analyses, using, for instance, indices of resting state activity within distributed neural networks. One such method is the so-called microstates analysis ²⁶. This kind of EEG analysis defines the global functional state of the brain by its momentary scalp electric field configuration ²⁷. Cluster analytical approaches showed that there is a small set of prototypical microstate configurations, which constitutes a basic repertoire of brain functional states. The sequence of microstates and the rules governing these sequences may represent the subsecond switching between various types of such integrative states ²⁸. The microstates can be considered “atoms of thought”, since they are associated with different classes of mentation and reflect the coordinated activity of distributed neural networks ²⁹. As a matter of fact, the different microstate (MS) classes were associated with distinct resting state neural networks (RSNs) in different studies, using different methodologies ³⁰, with only few exceptions in which only one microstate demonstrated a significant association with two resting state neural networks (RSNs) ³¹.

Two of the studies reporting a significant association between microstates and RSNs, used simultaneous EEG-fMRI recording ³². In the study conducted by Britz et al. ³³, the authors extracted 4 microstates (MS-A/-B/-C/−D) and they reported that these microstates were associated with BOLD signal within brain areas subtending phonological, visual, salience and attention networks. Yuan et al. (2012), using a temporal independent component analysis, extracted 13 MS and found that six of them were associated with one or two RSNs, while the others to more than two networks.

The other studies investigated the relationships between microstates and RSNs, applying source localization methods to multichannel data ³⁴. The four MS classes were found to be associated with sources in the anterior and posterior cingulate cortices and bilateral parietal-occipital regions, areas which belong to the default mode network ³⁵. A recent study ³⁰, using a source localization method closer to the approach used by Britz et al. ³³, extracted seven maps and demonstrated that maps labelled as A, B, F and D (corresponding to maps A-B-C-D in Britz et al., 2010) were linked to similar RSNs described in Britz et al. ³³.

In addition, other studies attempted to alter the temporal characteristics of the four microstates through behavioral manipulation ³⁶ and reported that temporal parameters of MS-B were increased during visualization ³⁶ or verbalization ³⁷, and those of MS-A were increased during visualization ³⁷.

Taking into account that microstates A and B have been linked to fronto-temporal and occipital regions, areas belonging to the phonological and visual networks and that microstates C and D have been linked to cingulate cortex, right superior and middle frontal gyri, the right superior and inferior parietal lobules, regions involved in the default mode, salience and attention networks ³⁰, it is possible to extrapolate that microstates A and B reflect the extrinsic system of distributed resting state connectivity (as demonstrated also by the task-specific alteration of the temporal parameters of these two microstates), while the other two classes are the expression of the intrinsic system (for definition and characteristics of the two systems ³⁸. Indeed, the extrinsic system is constituted by two modules, which are located in the primary somatosensory areas (M2a) and visual areas (M2b), while the intrinsic system includes three modules that are involved in generation of spontaneous thoughts (M1a), inner maintenance and manipulation of information (M1b), cognitive control and switching activity (M1c).

Although the comparison of aforementioned studies is made difficult due to the methodological differences, taken together they suggested a relationship between microstates and RSNs. Therefore, EEG microstate analysis can be an advantageous, inexpensive, and non-invasive method to assess global functional states of the brain and to correlate these states with clinically relevant measures.

In individuals with schizophrenia, several studies have suggested changes in MS topography and/or temporal parameters ³⁹.

All the aforementioned studies have suggested a reduced presence of microstates B and D and increased presence of C and A (although the latter alteration is far less consistent within studies) in individuals with schizophrenia versus healthy controls.

A recent meta-analysis demonstrated that the reduced contribution and duration of MS-D, the increased contribution and occurrence of MS-C and the reduced duration of MS-B are consistent across studies ⁴⁰; on the contrary, the meta-analysis did not demonstrate any consistent effect for MS-A.

Some studies have reported that individual MS classes may be associated with specific clinical features of schizophrenia, such as hallucinations, positive symptoms, duration of illness and negative symptom total score ³⁹. In particular, MS-D was found to be significantly associated to paranoid-hallucinatory symptomatology ⁴¹ or to the experience of hallucinations ⁴². An early study also has reported that, in chronic individuals with schizophrenia, the overall average duration of microstates was negatively correlated with the duration of disease and the frequency of psychotic exacerbations and was positively correlated with Brief Psychiatric Rating Scale (BPRS) total score and negative symptoms total score, assessed using the SANS ⁴³.

Schizophrenia

Schizophrenia is a chronic and severe mental disorder that affects how a person thinks, feels, and behaves. People with schizophrenia may seem like they have lost touch with reality. Although schizophrenia is not as common as other mental disorders, the symptoms can be very disabling.

Schizophrenia signs and symptoms

Symptoms of schizophrenia usually start between ages 16 and 30. In rare cases, children have schizophrenia too.

The symptoms of schizophrenia fall into three categories: positive, negative, and cognitive.

Positive symptoms

“Positive” symptoms are psychotic behaviors not generally seen in healthy people. People with positive symptoms may “lose touch” with some aspects of reality. Symptoms include:

• Hallucinations
• Delusions
• Thought disorders (unusual or dysfunctional ways of thinking)
• Movement disorders (agitated body movements)

Negative symptoms

“Negative” symptoms are associated with disruptions to normal emotions and behaviors. Symptoms include:

• “Flat affect” (reduced expression of emotions via facial expression or voice tone)
• Reduced feelings of pleasure in everyday life
• Difficulty beginning and sustaining activities
• Reduced speaking

Cognitive symptoms

For some patients, the cognitive symptoms of schizophrenia are subtle, but for others, they are more severe and patients may notice changes in their memory or other aspects of thinking. Symptoms include:

• Poor “executive functioning” (the ability to understand information and use it to make decisions)
• Trouble focusing or paying attention
• Problems with “working memory” (the ability to use information immediately after learning it)

Risk factors for developing schizophrenia

There are several factors that contribute to the risk of developing schizophrenia.

Genes and environment

Scientists have long known that schizophrenia sometimes runs in families. However, there are many people who have schizophrenia who don’t have a family member with the disorder and conversely, many people with one or more family members with the disorder who do not develop it themselves.

Scientists believe that many different genes may increase the risk of schizophrenia, but that no single gene causes the disorder by itself. It is not yet possible to use genetic information to predict who will develop schizophrenia.

Scientists also think that interactions between genes and aspects of the individual’s environment are necessary for schizophrenia to develop. Environmental factors may involve:

• Exposure to viruses
• Malnutrition before birth
• Problems during birth
• Psychosocial factors

Different brain chemistry and structure

Scientists think that an imbalance in the complex, interrelated chemical reactions of the brain involving the neurotransmitters (substances that brain cells use to communicate with each other) dopamine and glutamate, and possibly others, plays a role in schizophrenia.

Some experts also think problems during brain development before birth may lead to faulty connections. The brain also undergoes major changes during puberty, and these changes could trigger psychotic symptoms in people who are vulnerable due to genetics or brain differences.

Schizophrenia treatments and therapies

Because the causes of schizophrenia are still unknown, treatments focus on eliminating the symptoms of schizophrenia. Treatments include:

Antipsychotics

Antipsychotic medications are usually taken daily in pill or liquid form. Some antipsychotics are injections that are given once or twice a month. Some people have side effects when they start taking medications, but most side effects go away after a few days. Doctors and patients can work together to find the best medication or medication combination, and the right dose.

Psychosocial treatments

Psychotherapy sometimes called “talk therapy” is a term for a variety of treatment techniques that aim to help a person identify and change troubling emotions, thoughts, and behavior. Most psychotherapy takes place with a licensed and trained mental health care professional and a patient meeting one on one or with other patients in a group setting. These treatments are helpful after patients and their doctor find a medication that works. Learning and using coping skills to address the everyday challenges of schizophrenia helps people to pursue their life goals, such as attending school or work. Individuals who participate in regular psychosocial treatment are less likely to have relapses or be hospitalized.

Coordinated specialty care

This treatment model integrates medication, psychosocial therapies, case management, family involvement, and supported education and employment services, all aimed at reducing symptoms and improving quality of life. The National Institute of Mental Health (NIMH) Recovery After an Initial Schizophrenia Episode (RAISE) research project seeks to fundamentally change the trajectory and prognosis of schizophrenia through coordinated specialty care treatment in the earliest stages of the disorder. RAISE is designed to reduce the likelihood of long-term disability that people with schizophrenia often experience and help them lead productive, independent lives (https://www.nimh.nih.gov/health/topics/schizophrenia/raise/index.shtml).

Avolition treatment

As concluded in the recently published meta-analysis ⁴⁴, there is insufficient evidence at present to support a specific treatment for negative symptoms, such as apathy, lack of emotion, and poor social functioning. This is despite a tremendous increase in interest in the topic, as well as studies where negative symptoms are the identified primary outcome ⁴⁵. Table ​1 summarizes the literature discussed.

A number of factors may contribute to the lack of success to date. Diagnostically, it is difficult distinguishing primary from secondary negative symptoms, just as it is a challenge differentiating negative symptoms from other psychiatric diagnoses such as depression ⁴⁵. Current understanding regarding underlying pathophysiological processes is not well established, resulting in strategies for treatment that are, at best, speculative. This is perhaps best captured by the numerous trials that choose to assess multiple symptom domains rather than focusing specifically on negative symptoms. From a conceptual standpoint, the very definition of negative symptoms represents a work in progress, and it has been demonstrated that outcomes can be influenced by the measures employed ⁴⁶. More recently, guidelines have been forwarded regarding study trial design ⁴⁷, but, in fact, much of the work to this point falls short of these standards. It is now common to isolate different components under the framework of negative symptoms ⁴⁸, but this strategy is in its earliest stages and it is unclear how these may differentially respond to treatment. Scientists continue to seek biomarkers and/or endophenotypes that may not only improve diagnosis but, in addition, advance the field in clinical subtyping; already, different trajectories have been reported ⁴⁹ but this work too is in its earliest stages. It has been established that negative symptoms predate the onset of positive symptoms, and there is speculation that aberrations occurring during neurodevelopment are responsible. This underscores the importance of timing of interventions, and expectations regarding the success of treatments that are implemented later in the illness course. Indeed, it is possible that effective treatments await that time when we can reliably identify those who will go on to develop schizophrenia, which would also permit interventions well in advance of when diagnosis occurs, that is when psychotic features are evident for the first time. Where benefits have been recorded to this point, the reported effect size is often not of a magnitude to be clinically significant ⁴⁴. Finally, there is evidence that non-biological factors may play a role ⁵⁰, which raises questions as to the limitations of somatic interventions and the need to investigate their benefits in combination with non-biological strategies.

Future drug development in the field of schizophrenia clearly identifies negative symptoms as an important unmet need ⁵¹. This is undoubtedly driven, at least in part, by evidence that negative symptoms play a critical role in the functional decline observed in many individuals with schizophrenia, a decline that is not necessarily addressed with adequate control of positive symptoms. What is less clear, however, is what lines of investigation hold promise of success or, in fact, whether effective strategies can be developed until they are able to reliably diagnose schizophrenia and implement treatments earlier in the illness’ evolution.

Table 1. Treatment of negative symptoms in Schizophrenia

Topic	Literature	Comments
Comprehensive meta-analysis	A meta-analysis of randomized controlled trial interventions to December 2013 involving 168 trials (N = 6503 in treatment arm, N = 5815 in placebo arm).	Treatments evaluated included antipsychotics (first and second generation), antidepressants, pharmacological combinations (e.g., antipsychotic + antipsychotic; antipsychotic + antidepressant), glutamatergic agents, brain stimulation, and psychological interventions. Some differences were statistically significant but none reached threshold for clinical significance 44
Specific somatic interventions
Antipsychotics	The introduction of “atypical” antipsychotics came with claims of superior efficacy in the treatment of negative symptoms. This had been identified with clozapine in trials evaluating its efficacy in treatment-resistant schizophrenia	Modest improvement, not clinically significant, may be observed with antipsychotic treatment, possibly related to efficacy on other symptom domains and/or dopamine “sparing”. Two recent meta-analyses, one specific to negative symptoms, do not support superiority of the newer antipsychotics 52. Going forward, the notion of developing an agent that can significantly and simultaneously impact the different symptom domains of schizophrenia seems unlikely
Antidepressants	This work has been built around augmentation with SSRIs and, more recently, the newer classes of antidepressants that have followed	Only one of three earlier meta-analyses focused on negative symptoms offered support for such an approach 53. The fourth and most recent meta-analysis also did not identify changes that were clinically significant 44. This said, ADs are used routinely with APs in schizophrenia and as they evolve it is likely that new ADs will be evaluated in negative symptoms
CNS stimulants	This literature has included trials involving ADHD drugs and, more recently, drugs indicated in the treatment of excessive sedation (e.g., modafanil). Lisdexamfetamine, indicated for ADHD, was recently evaluated for a possible indication in negative symptoms but this line of investigation has been terminated	Collectively, this line of investigation has established that such agents can be used safely in individuals with psychosis. A review in 2013 specific to negative symptoms concluded evidence supports larger trials be done 54, although a more recent meta-analysis confined to modafanil/armodafanil reported only a small effect size 55
Anticonvulsants	Anticonvulsants are frequently used in schizophrenia and it is in this context that a potential effect on negative symptoms has been reported	This area has not generated a lot of interest. To date, there are no published randomized controlled trials specifically evaluating this class of medications in trials focused on negative symptoms
Glutamate	This line of investigation has garnered a great deal of research although drawing conclusions is complicated by different mechanisms of action. Much of this work is not confined to negative symptoms per se	Two earlier meta-analyses, not specific to negative symptoms, suggested these drugs could be effective 56, and a recent small randomized controlled trial (N = 35) involving d-serine supported this position 57. However, trials with agents working through other mechanisms (e.g., bitopertin, LY2140023) have been terminated for this indication. A meta-analysis examining N-methyl-d-aspartate antagonists (8 studies, N = 406) did not support their use in negative symptoms 58, but a small randomized controlled trial (N = 40) since reported a large effect size 59. The recently published meta-analysis looking at numerous treatments did not report clinically significant results for glutamatergic agents as a class 44. Despite these mixed results, work along these lines is likely to continue
Acetylcholine	This focus has also garnered considerable interest in recent years, but once again the focus is not specific to negative symptoms. The research can be divided into work involving cholinesterase inhibitors (e.g., donepezil) and a newer group of α7 nicotinic acetylcholine receptor agonists/partial agonists as well as positive allosteric modulators	Three meta-analyses examining the cholinesterase inhibitors, but not specific to negative symptoms, have suggested potential benefits 60 but no such randomized controlled trials have been published as of yet. Taken together, results with the newer α7 nicotinic acetylcholine receptor agents have not been favorable, and it is presently unclear if efforts specific to negative symptoms will be continued
Serotonin	Earlier work involving selective 5-HT2 antagonists (e.g., ritanserin) has given way to research focused on 5-HT3 agents (e.g., ondansetron)	A recent meta-analysis looking at different domains in schizophrenia has offered support for this approach 61, as have several randomized controlled trials specific to negative symptoms 62
Sex Hormones	Support for this line of investigation arises from work identifying a relationship between neurosteroids/sex hormones and negative symptom severity, in addition to treatment trials	A small number of trials specific to negative symptoms, and utilizing different agents (DHEA, pregnenolone, raloxifene) have been carried out, with favorable results 63. Oxytocin is receiving considerable attention at present, particularly in terms of measures of social cognition. A recent meta-analysis indicated it may have a role to play in schizophrenia and alluded to some evidence regarding its value in negative symptoms 64. As of yet, though, specific trials of this sort have not been published
Inflammation/Immunology	This particular research aligns closely with the shift in focus to neurodevelopmental models of schizophrenia and, like other areas discussed, is not specific to negative symptoms or, in fact, schizophrenia	Much of the work to date has involved minocycline, with randomized controlled trials specific to negative symptoms providing mixed results 65. Compounds reviewed under other categories here (e.g., d-serine [Glutamate); pregnenolone [Sex Hormones]) may, at least in part, establish their response through these mechanisms as well. Larger trials with minocycline are underway 66, and it can be expected that other agents will be evaluated in trials where negative symptoms are the primary outcome
Brain Stimulation	Brain stimulation, including both ECT and repetitive transcranial magnetic stimulation, has a history in refractory forms of schizophrenia (e.g., TRS, refractory hallucinations) although considerable work with repetitive transcranial magnetic stimulation is now focused on negative symptoms	While earlier meta-analyses supported the efficacy of repetitive transcranial magnetic stimulation in negative symptoms 67, the largest trial to date, just published, failed to find benefits 68. A number of identified moderators of response complicate comparison across studies, and newer techniques (e.g., direct transcranial stimulation, deep brain stimulation) have little or no data. Given the evidence to date, conflicting as it is, further studies of this sort are likely to continue

Abbreviations: AD = antidepressant; ADHD = attention deficit hyperactivity disorder; AP = antipsychotic; DBS = deep brain stimulation; dTCS = direct transcranial stimulation; 5HT = serotonin; nAChR = nicotinic acetylcholine receptor; NMDA = N-methyl-d-aspartate; rTMS = repetitive transcranial magnetic stimulation; SSRI = selective serotonin reuptake inhibitor.

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