Abstract
Negative symptoms generally refer to a reduction in normal functioning. In schizophrenia they encompass apathy, anhedonia, flat affect, avolition, social withdrawal and, on some accounts, psychomotor retardation.
Negative symptoms have been identified in other psychiatric disorders, including melancholic depression, and also in neurological disorders, such Parkinson’s disease. Achieving a better understanding of negative symptoms constitutes a priority in mental health. Primarily, negative symptoms represent an unrelenting, intractable and disabling feature for patients, often amounting to a severe burden on families, carers and the patients themselves. Identifying and understanding subgroups within disorders may also contribute to the clinical care and scientific understanding of the pathophysiology of these disorders. The purpose of this paper is to review the current literature on negative symptoms in schizophrenia and explore the idea that negative symptoms may play an important role not only in other psychiatric disorders such as melancholic depression, but also in neurological disorders, such as Parkinson’s disease. In each disorder negative symptoms manifest with similar motor and cognitive impairments and are associated with comparable neuropathological and biochemical findings, possibly reflecting analogous impairments in the functioning of frontostriatal-limbic circuits.
Negative symptoms are a cluster of symptoms generally characterised by the absence of normal levels of activation, initiative, and affect. They are a well established aspect of the symptomatology in schizophrenia. Unlike the episodic, treatment–responsive nature of positive symptoms, negative symptoms in schizophrenia tend to be enduring and less reactive to medication. They are perhaps the most unrelenting and disabling features , constituting a severe burden on relatives as well as on the patient themselves. Over the past decade there has been a resurgence of interest in negative symptoms, related partially to their significant prognostic value and additionally to the development and partial success of atypical antipsychotic medication in treating negative symptoms.
Although negative symptoms are considered an important feature of schizophrenia, they are not pathognomic of it.
Over recent years, the concept of negative symptoms has also been described as a prominent feature, distinct from depression, in other neurological and psychiatric disorders including melancholic depression ; Parkinson’s disease; Alzheimer’s disease; fronto-temporal dementia.
Recognising that negative symptoms are not limited to patients with schizophrenia is important, not only for clinical implications regarding potential treatment, but also to enhance the current understanding of the neurobiological substrate of an apparently homogeneous group of symptoms. To avoid variability within studies and consequent inconsistency between findings, it is essential for both research and clinical purposes to have an understanding of the existence of subgroups. The purpose of this paper is to review the current literature on negative symptoms in schizophrenia and explore the idea that negative symptoms play an important role in other neurological and psychiatric disorders, in particular melancholic depression and Parkinson’s disease. Clinical presentations and aetiological models will be considered.
1. The concept of negative symptoms in schizophrenia:
from 1900s to modern times
The term negative symptoms originated over 100 years ago in the domain of neurology within the writings of Jackson . Broadly, he proposed that negative symptoms represented an essential loss, or diminished level of normal function across the domains of movement, cognition and emotional states. Around the same period, Kraepelin’s early descriptions of ‘dementia praecox’ introduced the concept of negative symptoms to schizophrenia, whereby he described a group of patients with an ‘emotional dullness’ and loss of ‘mastery over volition’.
Following decades of a clinical focus on positive symptoms, which contrast with negative symptoms and represent additional, unwanted sensations and functions and generally include delusions, hallucinations, thought disorder or bizarre behavior, Strauss et al. reintroduced the concept of negative symptoms to schizophrenia. They divided schizophrenia symptoms into three clusters: positive symptoms, negative symptoms and disorders of interpersonal relationships. Interest in negative symptoms subsequently escalated and a number of models on the subtyping of schizophrenia emerged. The most recent factor analytic studies have identified at least five syndromes or dimensions within schizophrenia: negative, positive, excitement, cognitive and depression/anxiety.
Although recent multi-model approaches to schizophrenia agree on the existence of negative symptoms, there is dispute regarding what constitutes negative symptoms. Factor analytical studies have most strongly supported the inclusion of apathy (lack of feeling, emotion, interest, or concern), flat affect (almost no emotional expression) and isolation. Avolition (an inability to initiate and persist in goal-directed activities), psychomotor retardation (generalized slowing of movements and speech), anhedonia (inability to feel enjoyment) and attentional impairment are specifically less associated with negative symptoms, but included in some rating scales. Negative symptoms are closely correlated with one another; however, they do not correlate with positive symptoms, suggesting that they may involve independent processes.
2. Beyond schizophrenia: negative symptoms in major depressive disorder
A number of researchers have noted that many individuals with major depression display impairments that are very similar to negative symptoms in schizophrenia. Prevalence ratings indicate that 32–77% of patients with major depression exhibit some form of negative symptoms. Furthermore, the frequency and severity of negative symptoms have been reported as similar between groups of patients with schizophrenia and those with major depression. In particular, investigators have suggested that it is the ‘melancholic’ subtype of major depression, marked by the presence of psychomotor retardation, as well as loss of facial expression, a reduction in reactivity, difficulty of initiation, anhedonia and attentional disturbances, that bears a strong resemblance to the negative symptoms of schizophrenia. Indeed, like schizophrenia, major depressive disorder has been conceptualized as a heterogeneous disorder and melancholic depression is the most consistently described subtype, considered qualitatively different to non-melancholic depression in terms of cognitive and motor impairments, as well as underlying neuropathology .
The relationship between negative and depressive symptoms in major depression remains unclear. Although one study suggested that negative symptoms in most patients with depression are an epiphenomenon of depressive symptoms , other studies have suggested that that while depressive and negative symptoms frequently coexist in major depression, they constitute discrete syndromes.
3. Negative symptoms in Parkinson’s disease
Although tremor, rigidity and bradykinesia are the hallmarks of idiopathic Parkinson’s disease (PD), subgroups of patients also show notable impairments in areas of motivation, drive, initiation and emotional reactivity. The most commonly described negative symptom in PD is apathy, defined by Marin as a lack of motivation that is not attributable to diminished level of consciousness, cognitive impairment, or emotional distress. Reported prevalence estimates of apathy in PDcurrently range from approximately 16.5% to 45% . Apathy in PD is considered unrelated to depressive symptoms and not simply a reaction to the physical disability. Pluck and Brown demonstrated that a group of individuals with PD had significantly higher levels of apathy than a group of people with a non-neurological physical disease (osteoarthritis) and suggested the behaviour changes seen in PD (including impairments in motivation, drive, initiation and emotional reactivity) are not a primary consequence of physical disability, but a true feature of the PD process. Similarly, Isella et al. demonstrated that apathy scores are not related to duration or severity of illness. Levels of apathy are also unrelated to levels of depression or anxiety, suggesting they are an independent clinical phenomena. Hence, apathy and the concept of negative symptoms, as they have been applied within psychiatric disorders, are also a frequent and functionally relevant feature of PD .
4. Clinical findings
4.1. Motor impairment in PD, melancholic depression and negative symptoms of schizophrenia
Bermazohn and Siris postulated that akinesia, consisting of slowed motor activity with difficulty initiating and sustaining behaviours, is a transdiagnostic symptom, common to retarded or melancholic depression, the negative symptoms seen in schizophrenia and PD. The similarities of the motor impair ments across subgroups of these disorders is striking and appears to extend beyond a general motor slowing to encompass a more general impairment of willed action. A slowness in the initiation (akinesia) and execution (bradykinesia) of movement has been demonstrated in PD, in patients with schizophrenia demonstrating prominent negative symptoms, as well as in melancholic depression. Difficulties self-initiating movements (in the absence of external cues) are a prominent feature of PD, but are also reported in melancholic – but not non-melancholic – depression and in the negative symptoms of schizophrenia. Increases in task complexity exacerbate movement difficulties in each of these disorders. For instance in PD programming sequences of movements, or carrying out two actions simultaneously, are impaired relative to controls. Similarly, patients with melancholia exhibit difficulties executing complex and sequential movements, as do patients with schizophrenia who present with marked negative symptoms.
The Bereitschaftspotential is an electrophysiological measure recorded over the scalp approximately 1–1.5 s prior to the execution of a self-paced or self-initiated voluntary movement. The Bereitschaftspotential is considered to consist of an early component reflecting volitional motor preparatory processes, and a later component associated with the endogenous intention to act. One of the markers of motor impairment in PD is an abnormality (reduced amplitude) of the Bereitschaftspotential, particularly in the context of selfinitiated movements and skilled motor learning.
A reduction in the amplitude of both the early and late components of the Bereitschaftspotential has also been reported before self-initiated movements in patients with schizophrenia who have high ratings of negative symptoms. Measures of Bereitschaftspotentials in depression are limited, but findings suggest that while there are no differences in the amplitudes of Bereitschaftspotentials between those with ‘primary depression’ and healthy controls, maximal Bereitschaftspotential amplitudes are smaller in patients with melancholic depression.
Taken together, these findings suggest similar motor impairments in each of these disorders encompassing an impairment in the internal generation of movements, particularly when movement complexity increases. Furthermore, reductions in Bereitschaftspotentials, thought to be related to faulty output from the basal ganglia to the supplementary motor area, are present in each of these conditions prior to the generation of willed movements. Hence, these studies provide evidence for similar impairments in these three patient populations that may reflect dysfunction within frontostriatal circuits.
4.2. Cognitive impairment in PD, melancholic depression and negative symptoms of schizophrenia
Neuropsychological assessment has revealed differences between patients with schizophrenia who have primary and enduring negative symptoms, and patients with other forms of schizophrenia. Similarly, melancholic depression is associated with a distinct pattern of neuropsychological impairments that can be distinguished from non-melancholic depression. Although motor abnormalities are the predominant feature in PD, cognitive deficits are reported, and there is a significant association between apathy and cognitive impairment in PD. Similar impairments in tests of executive function are observed in each of these patient populations. Verbal fluency deficits are reported in PD and significantly correlated with apathy scores. Verbal fluency deficits are also associated significantly with melancholic symptoms in depression and negative symptoms in schizophrenia. Deficits in tasks involving higher level control over attention have also been reported in all three disorders. For example, set changing difficulties are described in schizophrenia patients with negative symptoms, melancholic depression and PD. Inhibitory deficiencies are described in negative symptoms of schizophrenia andPD, but are not well reported in melancholic depression (but see). Similarly, working memory impairments are described in the negative symptoms of schizophrenia and PD, but not well reported in melancholic depression. Thus, deficits in the higher level control over attention may underpin the set-changing, working memory and inhibitory control impairments reported in each of these disorders.
5. Models of negative symptoms
5.1. Neurocognitive models
A number of neurocognitive theories have been put forward to explain the phenomenology of negative symptoms in terms of a reduction in goal-directed behaviours. Frith proposed that various behavioural signs associated with negative symptoms could be understood in terms of a core deficit in the generation of willed action. He noted that while many patients with negative symptoms are compliant and will perform complex psychological tests when requested, the lack of behaviour in patients with negative features seems to occur specifically for those actions which are self-generated. Hence, he described that while “stimulus-driven” actions remain largely intact, there is a problem with the generation of spontaneous, self-initiated behaviours. Frith proposed that problems generating spontaneous, willed actions may extend to a more basic poverty of action, or gestures, and communication that underlies behavioural signs such as flattening of affect and social withdrawal.
Frith described these impairments of willed actions in terms of Shallice’s Supervisory Attentional System (SAS). When functioning normally, the SAS modulates activity via inhibiting inappropriate routine actions and instigating novel actions in situations in which no routine action is triggered and no environmental signals are available. In contrast, those individuals who have abnormalities associated with their SAS, are unable to self-initiate behaviours, and in the absence of environmental signals they will do nothing or perseverate.
5.2. Neuropathological models
A high prevalence of negative symptoms appear in patients with pathology involving frontal and subcortical structures. Bhatia and Marsden reported that of a total of 240 patients with basal ganglia lesions, the most common behavioural disturbance was abulia (apathy with loss of initiative and of spontaneous thought and emotional responses), which was most commonly present following lesions involving the caudate. Similarly, in their study of 70 patients with acquired brain injury (traumatic brain injury, cerebrovascular accident, or hypoxic brain injury), Finset, Andersson and colleagues concluded that apathy was related to subcortical and right hemisphere lesions. Negative symptoms, including a reduction in emotion and motivation are also reported in patients with lesions of the lateral frontal cortex. Some studies have, however, found that correlations between lesion site and affective symptoms, such as apathy, are not significant; hence it is unlikely that one structure is uniquely responsible for the production of negative symptoms. Rather, as suggested by Brown and Pluck , dysfunction within a network of cortical and subcortical areas is likely to be involved, with an increased susceptibility to negative symptoms likely to be associated with dysfunction to any of these systems.
5.2.1. Structural imaging
5.2.1.1. Structural imaging in schizophrenia and negative symptoms. Structural changes associated with negative symptoms and schizophrenia have been described in prefrontal and striatal regions. Significantly smaller prefrontal white matter volumes (particularly in the orbitofrontal subregion) have been reported in schizophrenia patients with high negative symptom scores (when compared to those patients with low negative symptom scores). Both white and grey matter reductions have been reported in the anterior cingulate, left temporal lobe, and insular cortex in a symptomatically homogeneous group of patients with primary and enduring negative symptoms. In line with these findings, a reduction in the grey matter of the superior temporal gyrus was reported in patients with predominantly negative symptoms. Ventricular enlargement is also associated with negative symptoms and in particular, associated with enduring negative symptoms.
5.2.1.2. Structural imaging in melancholic depression.
Although melancholic depression has been hypothesized to involve frontostriatal dysfunction , evidence for structural changes is limited. When investigating morphological features of the subgenual prefrontal cortex (anterior cingulated areas located ventral to the genu of the corpus callosum), Pizzagalli et al. did not find structural differences between melancholic and nonmelancholic groups. In contrast, in a group of patients with severe melancholic depression, Pujol et al. reported an enlargement of the cerebrospinal fluid space in the Sylvian fissure region (gathering lateral frontotemporal cortices and subcortical structures), particularly in the left hemisphere.
5.2.1.3. Structural imaging in Parkinson’s disease.
Pathology during the early stages of PD is often confined to striatal regions, characterised by the progressive deterioration of the dopaminergic nigrostriatal tracts. Magnetic resonance imaging (MRI) studies have reported structural changes in the substantia nigra (even in patients in early stages of the disease) and changes in the limbic/paralimbic areas and prefrontal cortex in more advanced stages of the disease. Magnetization transfer
ratio has revealed changes in patients with moderate PD in paraventricular white matter and brainstem regions, including the substantia nigra, red nucleus and pons. In terms of structural changes associated specifically with negative symptoms in PD, data are limited and Isella et al. found only a slight (nonsignificant) correlation between apathy scores and two measures of temporal atrophy.
5.2.2. Functional imaging
5.2.2.1. Functional imaging in schizophrenia and negative symptoms.
Studies investigating cerebral perfusion correlates of negative symptomatology are consistent with the structural evidence implicating reduced activity in frontal, prefrontal and striatal regions and also indicate some parietal involvement. An increase in negative symptom scores has been associated with decreased perfusion in a number of areas, including the frontal cortex; medial and right prefrontal regions; right inferior frontal gyrus; parietal association cortex; posterior cingulate cortices ; basal ganglia ; thalamic regions. Individual negative symptoms have been associated with reductions in the activity of different regions. For instance, affective flattening and emotional withdrawal inversely correlated with left hemispheric rCBF ratios (including the basal ganglia and thalami); difficulties in abstract thinking inversely correlated with right hemispheric rCBF (including basal ganglia and thalami); reduced spontaneity and stereotyped ideas showed an inverse correlation with bitemporal rCBF ratios.
5.2.2.2. Functional imaging in melancholic depression.
Despite limited evidence for structural changes in melancholic depression, functional imaging studies implicate frontostriatal dysfunction, particularly within the prefrontal cortex. Melancholic features, including psychomotor retardation, anhedonia and flat affect, have been associated with decreased perfusion in the dorsolateral prefrontal cortex and the angular gyrus, on the left. In a recent electroencephalographic (EEG) and positron emission tomography (PET) study, unmedicated melancholic patients exhibited decreased activity in the subgenual prefrontal cortex, when compared to unmedicated, nonmelancholic patients, even though both groups had similar levels of depression severity. Increased blood flow in the left ventrolateral prefrontal cortex has also been observed in melancholic patients, and right prefrontal hyperactivity has been observed in both nonmelancholic and melancholic patients, but it is only associated with increased levels of anxiety and depression severity in the melancholic group.
5.2.2.3. Functional imaging in Parkinson’s disease.
Neuroradiological data measuring patterns of activity specific to negative symptoms in PD are very limited. Generally, different parkinsonian symptoms are associated with differential involvement of motor circuits spanning the cortex (see for a review): for example, akinesia (difficulty initiating internally generated movements) is associated with dysfunction of premotor regions and with hypoactivation of the supplementary motor area, and bradykinesia (slowing of movement execution, secondary to reduced amplitude scaling and limb velocity) is linked to abnormal functioning within intrinsic basal ganglia circuitry, and is associated with underactivation in basal ganglia regions (e.g. putamen and globus pallidus). In sum, these findings support a reputed model of negative symptoms based on dysfunction predominantly within the frontosubcortical-limbic circuits that play a key role in transforming motivation to action.
5.3. Biochemical models
The biochemical basis for negative symptoms has been discussed in the context of reduced availability of the neurotransmitters dopamine, serotonin and noradrenaline. Evidence supporting this theory has been reported in schizophrenia, melancholic depression and PD.
5.3.1. Biochemical findings in negative symptoms of schizophrenia
One recent version of the dopamine hypothesis of schizophrenia postulates that an excess of dopamine subcortically is associated with positive symptoms, while negative symptoms are thought to arise from a deficit of dopamine in the cortex. Although the observed structural impairment in the prefrontal cortex of individuals evidencing the negative symptomatology of schizophrenia has been hypothesized to arise from a central hypodopaminergic substrate, direct evidence is lacking. Homovanillic acid (HVA) is the major metabolic product of dopamine that is released from the brain into the circulation and it has been proposed that plasma HVA concentrations are particularly sensitive to central dopamine metabolism. A number of studies have reported low levels of plasma HVA that correlate inversely with negative symptoms scores. Longitudinal studies have associated worsening of negative symptoms with increased availability of striatal dopamine D2 receptors, further suggesting negative symptoms in schizophrenia may be related to decreased dopaminergic neurotransmission. Analogous to the dopamine hypothesis, a noradrenaline hypothesis has been proposed that suggests overactivity of the central noradrenergic (NA) system corresponds to positive symptoms, while underactivity corresponds to negative symptoms. Support for this notion comes from observations that selective NA agonists have favourable effects on negative symptoms (such as idazoxan; imipramine), while chronic abuse of not only the mixed dopamine/NA effective methamphetamine and cocaine but also NAselective ephedrine can induce negative-like symptoms. NAconcentration in cerebrospinal fluid andMHPG(3-methoxy- 4-hydrophenylglycol: a major metabolite of NA excreted in urine) concentrations in urine were observed to be decreased in patients with negative symptoms.
Serotonergic networks may also be involved in negative symptoms. Although direct evidence is lacking, features of negative symptoms (ventricular enlargement and chronicity) are associated with decreased serotonin turnover. Furthermore, peripheral serotonin concentrations are reported to be lower in patients with negative symptoms, when compared to healthy controls. A link between serotonergic activity and negative symptoms is also loosely supported by the seemingly superior efficacy of antipsychotics that combine serotonergic actions with dopaminergic blockade (see review by Moller). However, little is known about the interaction of serotonin and dopamine in the brain, and whether 5-HT2 (serotonin receptor) blockade is reversing a primary abnormality in
serotonergic neurotransmission, or acting in a secondary fashion via modulation of dopamine release.
In addition to imbalances within the dopamine, serotonin and NA systems, hypofunctionality of N-methyl-d-aspartate (NMDA)-type glutamate receptors may contribute to the pathophysiology of negative symptoms of schizophrenia. The NMDA hypofunction hypothesis is supported by (i) administration of NMDA glutamate receptor antagonists, such as phencyclidine or ketamine, which induces neurobehavioural changes that mimic symptoms of schizophrenia (particularly negative symptoms) in healthy volunteers; (ii) NMDAagonists, such as glycine and d-cycloserine, are effective in treatment of persistent negative symptoms; (iii) postmortem studies reveal alterations in glutamate receptors and their modulators in patients with schizophrenic.
5.3.2. Biochemical findings in melancholic depression
Monoaminergic underactivity is thought to play a key role in the biochemistry of depression, with antidepressants enhancing the concentrations of one or more of the monoamines. Malhi et al. proposed that while perturbations in all three monoamine systems (serotonin, noradrenaline and dopamine) may underlie all sub-types of depression, the relative emphasis of each neurotransmitter system is likely to vary according to the depression subtype, with melancholic depression having a core serotonergic dysfunction with contributions from the noradrenergic system. In line with this theory, several studies have reported that dual action antidepressants (those acting on the noradrenergic and serotonergic systems) are more effective than selective serotonin reuptake inhibitors in melancholic depression. In terms of serotonergic dysfunction, patients with melancholic depression exhibit impaired sensitivity of post-synaptic 5-HT receptors. While dysfunction of the serotonergic and noradrenergic systems may contribute to melancholic features such as disturbances in drive, energy and volition, psychomotor retardation may be largely attributable to dopamine dysfunction. Indeed, in depressed patients with psychomotor retardation, cerebrospinal fluid levels of the dopamine metabolite HVA are significantly reduced. Recent functional neuroanatomical studies provide further indirect evidence for dopamine dysregulation in melancholic depression. Results of functional MRI (fMRI) in combination with a dopaminergic probe (oral dextroamphetamine sulfate) indicated a hypersensitive response to the rewarding effects of dextroamphetamine in patients with major depressive disorder that correlated with the severity of anhedonic symptoms. Furthermore, the fMRI data suggested that the regions that mediate the reward response, and contain mesocortical dopaminergic neurons, are the caudate, putamen and prefrontal cortex.
5.3.3. Biochemical findings in Parkinson’s disease
Like negative symptoms of schizophrenia and melancholic depression, dopaminergic depletion in PD, resulting from degeneration of nigrostriatal neurons, is widely reported. Hence, the prominent biochemical findings in each of these disorders appear to involve a reduction in central dopaminergic activity, with implications for reductions in serotonergic and noradrenergic activity.
6. Negative symptoms: a common fronto-striatal-limbic pathology
There are striking similarities between the clinical profiles of negative symptoms in schizophrenia, melancholic depression and PD: movement initiation takes longer and movements are slowed, particularly when tasks are internally driven, complex or sequential. Performance on cognitive tasks becomes impaired when higher level control of attention is required. Negative symptoms in each of these disorders are associated with a reduction in brain activation in prefrontal, frontal, striatal and limbic regions. Structural changes are also reported in prefrontal, striatal and temporal regions, although melancholic depression is yet to be associated with clear structural changes (suggesting that perhaps negative symptoms in melancholia may represent a functional form of the structural deficits present in PD and schizophrenia, as suggested by Rogers et al. ). The bases of these functional changes are unknown, but may stem from a central hypodopaminergic state. Views of the organisation of striatal–thalamocortical-limbic connections suggest a number of circuits connect anatomically and/or functionally distinct striatal, frontocortical, thalamic and limbic regions. Whether these circuits are structurally and functionally segregated (a view pioneered by Alexander et al. ), or interconnected , remains unclear. Nevertheless, these models provide a basis to describe the changes
in motor, cognitive and affective functioning associated with negative symptoms. It is possible that disruptions to the frontosubcortical- limbic circuitry in each of these disorders may stem from a reduction in dopamine and result in: difficulties in the initiation and execution of movement, particularly when external guidance is not available; ‘executive dysfunction’ including planning, selecting and initiating goal-directed behaviours; emotional symptoms such as reduced spontaneity and initiative.
7. Conclusions
This review has attempted to provide a fronto-striatal-limbic framework to explain the similarities in the motor and cognitive deficits of PD, melancholic depression and the negative symptoms of schizophrenia. It is important to note that although these conditions display considerable overlap, they nevertheless diverge in terms of their symptom profile and the relative contributions of cognitive, affective and motor components, as well as their associated discipline (i.e. psychiatry or neurology). Hence, while schizophrenia is mostly affective and cognitive (though motor impairments are increasingly recognised); depression is predominantly affective (with motor and cognitive involvement reported, particularly in melancholic depression); PDis largely motor (but with cognitive and affective components increasingly reported). The clinical parallels in the motor and cognitive presentations of negative symptoms in schizophrenia, melancholic depression and PD do, however, suggest that these subgroups are not mutually exclusive and it is possible that a unified hypothesismayemerge. Current research supports a putative model of negative symptoms based on dysfunction within the fronto-striatal-limbic circuits that play a key role in goal-directed behaviours. Selection of more homogeneous subgroups within these disorders will provide a better basis for future research designed to clarify the biological and social factors that underpin negative symptoms as well as contributing to advances in clinical care. Achieving a better understanding of negative symptoms constitutes a priority in mental health. Primarily, negative symptoms constitute an unrelenting, intractable and disabling feature for patients, often amounting to a severe burden on relatives as well as on the patient themselves. Systematic clinical investigations are warranted to: (i) further elucidate the underlying neuropathology of negative symptoms, either as a syndrome or in terms of distinct symptoms of apathy, amotivation, anhedonia, etc.; (ii) develop treatments that target negative symptoms; (iii) explore rehabilitative techniques that focus on cognitive, motor and emotional aspects of negative symptoms; (iv) to determine the indications, benefits, limitations and risks of treating negative symptoms in different disorders.