Gary Remington, MD, PhD

This activity offers CE credits for:
	1. Physicians (CME)
	2. Other

All other clinicians either will receive a CME Attendance Certificate or may choose any of the types of CE credit being offered.

The goal of this activity is to provide a comprehensive understanding of the etiology, hypotheses, and treatment implications of negative symptoms in schizophrenia.

At the end of this CE activity, participants should be able to:

• Explain the historical bases for the understanding of negative symptoms

• Distinguish primary negative symptoms from secondary negative symptoms

• Identify the central feature of negative symptoms

• Understand the multi-faceted constructs of motivation deficits

• Discuss the current treatments for negative symptoms

This continuing medical education activity is intended for psychiatrists, psychologists, primary care physicians, physician assistants, nurse practitioners, and other health care professionals who seek to improve their care for patients with mental health disorders.

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Susana Da Silva, MSc, has no disclosures to report.

Sarah Saperia, has no disclosures to report.

Gary Remington, MD, PhD, reports that he has received research support from HLS Therapeutics Inc, the Canadian Institute of Health Research (CIHT); the Research Hospital Fund-Canada Foundation for Innovation.

George Foussias, MD, PhD, has no disclosures to report.

William P. Horan, PhD (peer/content reviewer), has no disclosures to report.

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Negative symptoms of schizophrenia are the most reliable predictors of poor outcomes. Negative symptoms are highly prevalent in individuals with schizophrenia. Typically emerging long before the onset of psychosis, these symptoms often persist throughout the course of the illness. Despite their importance in driving functional outcomes, however, effective treatment of negative symptoms remains elusive.

The historical evolution of negative symptoms

The recognition of negative symptoms in schizophrenia dates back to the early works of Kraepelin and Bleuler,

 with clinical descriptions of emotional disturbance and volitional deterioration as central features of the illness. Although for much of the 20th century emphasis was placed on the assessment and treatment of positive symptoms, the 1980s saw a renewed interest in understanding and conceptualizing negative symptoms.

 While definitions have varied over time, consensus from a National Institute of Mental Health (NIMH) Negative Symptom Initiative identified five core negative symptoms: affective flattening, alogia, avolition, asociality, and anhedonia.

 Recent efforts using factor and component analyses have allowed for an even more refined classification of negative symptoms as two separate, yet interrelated subdomains consisting of diminished emotional expression (ie, affective flattening, alogia) and amotivation (ie, anhedonia, asociality, avolition) reflected in the diagnostic criteria for schizophrenia in DSM-5.

Although many hypotheses have been proposed over the years, the etiology of negative symptoms in schizophrenia remains poorly understood. Neurobiological hypotheses of negative symptoms have focused on the role of dopamine, with evidence of hypodopaminergic dysfunction as well as structural and functional abnormalities in the frontal cortical regions of the brain.

 Specifically, studies have revealed relationships between negative symptom severity and volume reductions in the prefrontal cortex, temporal cortex, corpus callosum, and limbic structures as well as compromised white matter tract integrity.

 Negative symptoms have also been linked to ventral striatal reward system dysfunction, with more severe negative symptoms associated with reduced activation in the nucleus accumbens, orbital prefrontal cortex, anterior cingulate cortex, and the dorsolateral prefrontal cortex.

The cognitive model of negative symptoms presents an alternate biopsychosocial approach that emphasizes the role of maladaptive cognitions in the development and maintenance of negative symptoms in schizophrenia. This model relies on a diathesis-stress hypothesis, which posits that individuals predisposed to the illness are more vulnerable to negative life experiences, and to the subsequent development of dysfunctional attitudes and beliefs.

Specifically, psychological attributes such as defeatist beliefs about performance as well as low expectancies for pleasure and success may lead to reductions in goal-directed behavior, which in turn perpetuate the affective and motivational impairments that are often experienced by individuals with schizophrenia. While these hypotheses, along with many others, have contributed to our understanding of the multitude of factors associated with the expression of negative symptoms, there has not emerged a definitive cause for their development in schizophrenia.

Primary versus secondary negative symptoms: a clinical conundrum

One of the challenges in uncovering the underlying etiology of negative symptoms in schizophrenia stems from the difficulty in distinguishing between primary and secondary negative symptoms. This distinction has its origins in the early works of Carpenter and colleagues10 in the 1980s. They defined primary negative symptoms as idiopathic features of the disorder that in a subset of individuals with schizophrenia represent an enduring characteristic of their illness (ie, the “deficit” syndrome), and secondary negative symptoms as iatrogenic, environmental, or illness-related phenomena (eg, extrapyramidal symptoms, neuroleptic dysphoria, positive symptoms, depression).

From a clinical perspective such a distinction is imperative because the differentiation between primary and secondary negative symptoms has important implications for treatment. Specifically, primary negative symptoms are more resistant to pharmacological interventions, whereas secondary negative symptoms are typically responsive to treatment targeting the underlying cause. For example, negative symptoms resulting from antipsychotic-induced extrapyramidal symptoms or dysphoria may be improved with a change in medication type or dosage. Similarly, affective or depressive symptoms-commonly mistaken for negative symptoms-may be effectively treated with an antidepressant medication. The clinical presentation of primary and secondary negative symptoms is often indistinguishable, thus, ascertaining the root cause of these symptoms typically requires thorough knowledge of the longitudinal course of the patient’s illness and treatment history.

Motivation deficits: the central link to functioning

In addition to differentiating between primary and secondary negative symptoms, it is necessary to keep in mind that the construct of negative symptoms consists of two distinct subdomains: diminished expression and amotivation. While both are important from a phenomenological perspective, it is amotivation that has been shown to represent the most critical feature of negative symptoms, with research consistently pointing to motivation deficits as the driving force linking negative symptoms to poor treatment and functional outcomes in schizophrenia.

 Moreover, compared with diminished expression, symptoms within the amotivation subdomain have been shown to be more prevalent and persistent in persons with schizophrenia.

 The following is a typical case of an individual who endorses prominent negative symptoms, and in particular, motivation deficits.

Mr A is a 21-year-old patient with schizophrenia diagnosed 3 years ago. He initially presented to the emergency department at the local psychiatric hospital with a 1-year history of functional decline that began in the summer after graduating high school. At that time, his parents noted that he became more withdrawn and isolated with gradually deteriorating self-care. This was followed by the emergence of auditory hallucinations and persecutory delusions that prompted his family to bring him for psychiatric assessment.

Mr A subsequently received treatment in a local early psychosis intervention program, where he experienced a good response to low-dose treatment with a second-generation antipsychotic. He has remained treatment adherent and with no evidence of treatment-emergent adverse effects and has experienced full remission of psychotic symptoms. Despite this, however, Mr A has not been able to return to his premorbid level of functioning and continues to struggle with ongoing negative symptoms.

He currently lives at home with his parents and siblings. He has not pursued any formal education or employment since graduating from high school 4 years ago. During the interview, Mr A’s responses are notably delayed and often consist of one- or two-word answers. His affect is flat, with only rare instances of emotional expression. His current interests are limited to playing video games and watching movies. When asked about his typical day, he reports that he wakes up at noon, watches TV, and plays video games for most of the day, eats dinner, and then goes to bed.

He describes not feeling particularly engaged in his daily activities, with minimal interest in having new experiences or learning new things. His social life is also significantly impoverished, and he has no interest in maintaining relationships with others, resulting in infrequent and superficial interactions with family and friends.

Notably, Mr A reports an overarching feeling of “laziness”: activities outside of playing video games require too much energy and effort. He does not, however, describe sadness or depressed mood, or any feelings of guilt, low self-worth, or hopelessness. On physical examination there is no evidence of extrapyramidal symptoms or abnormal involuntary movements.

This case illustrates the clinical presentation of negative symptoms in schizophrenia, and the nature by which these expressive and motivational deficits pervade the lives of affected individuals. In particular, Mr A’s lack of interest and motivation to initiate and sustain goal-directed behaviors translate into poor functional outcomes across a number of domains including interpersonal relations and instrumental role functioning. In the absence of mood symptoms, co-occurring substance use, or extrapyramidal symptoms, it would appear that he is experiencing primary negative symptoms.

Motivation deficits: a multi-faceted construct

The identification of motivation as a fundamental construct by the NIMH Research Domain Criteria (RDoC) further underscores the importance of this symptom domain, and the critical need to advance our understanding of the behavioral and neurobiological underpinnings of motivation deficits.

 Current conceptualizations of motivation outline a multifaceted construct of inter-related reward processes, whereby reward responsiveness (ie, “liking”) and reward expectancy (ie, “wanting”) interact to inform both reward valuation and effort valuation. This is followed by decision-making and action selection to achieve a final motivated outcome.

 The following summarizes the behavioral and neurobiological findings that have emerged from examinations of isolated facets of motivation in schizophrenia.

Regarding reward responsiveness (ie, “liking”) in schizophrenia, there has existed a long-standing belief that the illness is characterized by anhedonia. However, this notion has been challenged by recent case-control studies revealing that patients with schizophrenia and healthy controls demonstrate statistically comparable levels of reward responsiveness or “in-the-moment” experience of pleasure, along with evidence from neuroimaging studies suggesting intact ventral striatal responses to reward.

Similarly, neurobiological investigations of reward expectancy (ie, “wanting”) in schizophrenia have demonstrated reduced ventral striatal activation in response to reward-predicting cues. Behavioral studies utilizing reinforcement-related speeding paradigms extend these findings, such that patients fail to modulate their behavior in response to reward cues.

Given the inherent learning component involved in the prediction and anticipation of rewards, there have also been numerous investigations into reward learning processes in schizophrenia. These studies have revealed that patients exhibit intact gradual or procedural learning but impaired rapid reward learning in the face of changing feedback. In terms of reward valuation, or the appraisal of reward value, studies have shown that in the context of delay discounting paradigms, individuals with schizophrenia discount the value of future rewards more rapidly than healthy controls, particularly for longer-term delays.

Closely related to reward valuation is effort valuation, which refers to one’s willingness to exert effort in the context of cost-benefit computations. Studies using effort-based decision-making paradigms have shown that patients with schizophrenia demonstrate impairments in the ability to efficiently allocate effortful choices across different probability and reward levels.

Lastly, action selection and/or preference-based decision making, as it relates to the planning and implementation of a desired goal, has also been examined with performance on gambling-based decision-making tasks suggesting impairments in schizophrenia. Neuroimaging studies have similarly demonstrated that individuals with schizophrenia exhibit reduced activation in the dorsolateral prefrontal cortex during these gambling tasks.

Taken together, these findings underscore the importance of recognizing the mechanistic heterogeneity of amotivation, with different underlying impairments in one or more facets leading to similar clinical presentations of motivation deficits across individuals with schizophrenia. Thus, delineating the differential profiles of amotivation is an important step towards identifying specific targets for the treatment of negative symptoms in schizophrenia.

Current treatments for negative symptoms in schizophrenia

Antipsychotic medications have represented the cornerstone of treatment for schizophrenia since the discovery of chlorpromazine in the 1950s. Acting as D2-receptor antagonists, these antipsychotic medications have proven effective at treating positive symptoms, but unfortunately, have offered little benefit for improving the negative symptoms of the disorder. While the introduction of newer second-generation antipsychotics initially generated considerable optimism, ensuing clinical trials have offered little evidence for their efficacy in treating primary negative symptoms, with clinical improvements typically attributed to the amelioration of positive symptoms and/or secondary negative symptoms.

Given the clinical parallels between depressive and negative symptoms in schizophrenia, the use of antidepressants has also been explored as a potential adjunctive therapy to antipsychotics; although evidence for their efficacy has generally been inconclusive, with findings suggestive of some small positive effects unlikely to translate into meaningful clinical improvements.

The use of stimulant, glutamatergic, and cholinergic augmentation has similarly failed to demonstrate consistent benefits for treating negative symptoms in schizophrenia.

 Beyond pharmacological interventions, psychosocial strategies have been examined as potential treatments for negative symptoms. In light of the promising findings of cognitive-behavioral therapy (CBT) for depression and anxiety, there has been increasing interest in the potential of CBT interventions that target negative symptoms in schizophrenia, with recent meta-analyses revealing potential benefits for negative symptoms, albeit with small effect sizes.

 Moreover, cognitive remediation, although primarily designed to target the cognitive deficits of the disorder, has also been shown to have some moderate associations with negative symptom reduction.

Lastly, non-invasive brain stimulation therapies including repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS) has gained momentum in the past decade as potential treatments for negative symptoms. rTMS has been extensively investigated in schizophrenia, with a number of studies and meta-analyses revealing small to large improvements, though not consistently. Research on the application of tDCS is still in its nascent stages, although early findings suggest that tDCS may offer some benefit for negative symptoms.

Negative symptoms-of which motivation deficits are a core feature-are prominent and pervasive in schizophrenia and currently represent an unmet therapeutic need. While several treatment modalities have been explored, their lack of broad efficacy to date may be attributed to a number of factors.

 Most studies evaluating treatments for negative symptoms have relied on overall symptom severity scores as their primary outcome; however, this may be too crude a method to capture meaningful differences in specific symptom domains. That is, negative symptoms are not a unitary construct, but rather, a broad cluster of multi-faceted symptoms, and must therefore be examined and treated as such.

 We continue to be faced with the challenge in distinguishing between primary and secondary negative symptoms. Moreover, our limited understanding of the pathophysiological underpinnings of negative symptoms inevitably restricts our ability to develop treatments targeting the specific underlying etiologies.

 It is important to acknowledge the possibility that negative symptoms may be caused by a complex interaction of biological and environmental factors, and as a result, no single treatment may act as a panacea for negative symptoms.

 Complementing symptom-targeted pharmacological therapy with psychosocial interventions may offer the most effective treatment strategy for ameliorating negative symptoms, and ultimately improving functional outcomes for individuals with schizophrenia.

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Ms Da Silva, Centre for Addiction and Mental Health and Institute of Medical Science, University of Toronto, Toronto, Canada; Ms Saperia, Centre for Addiction and Mental Health and Department of Psychology, University of Toronto, Scarborough, Canada; Dr Remington, and Dr Foussias, Centre for Addiction and Mental Health, Institute of Medical Science, University of Toronto, and Department of Psychiatry, University of Toronto.

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 Keshavan MS, Tandon R, Boutros NN, Nasrallah HA. Schizophrenia, “just the facts”: what we know in 2008 Part 3: neurobiology. 

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Articles

Negative symptoms are prominent in schizophrenia. Despite their importance in driving functional outcomes, however, effective treatment of negative symptoms remains elusive.

Gary Remington, MD, PhD

Articles

Negative Symptoms in Schizophrenia: Etiology, Hypotheses, and Treatment Implications