More than 50% of individuals with schizophrenia experience negative symptoms, which are associated with substantial challenges for patients and their families.1 Those affected have been found to have poor treatment response and worse functional outcomes compared with patients without negative symptoms.2

Despite the high prevalence and associated burden, however, there is a dearth of effective treatment strategies for these symptoms. This may be at least partly attributed to the lack of clarity regarding the conceptualization and assessment of negative symptoms. In recent years, researchers have increased efforts to elucidate these topics, with some success.

A paper published in the Lancet Psychiatry examined the main achievements (points that have been clarified) and remaining controversies in this area, as highlighted below.1

Achievements

  • The negative symptom dimension is heterogeneous, and “failure to distinguish between primary enduring and secondary negative symptoms might hinder the research progress on pathophysiological mechanisms and new treatment discoveries, and might prevent attempts to adequately address sources of secondary negative symptoms,” the authors wrote.
  • Established assessment tools for negative symptoms contain items that are no longer relevant to the current conceptualization. In addition, these instruments overemphasize behavioral aspects vs internal experience, which may result in overlap with other dimensions. More recently developed validated instruments, including the Brief Negative Symptom Scale and the Clinical Assessment Interview for Negative Symptoms, have shown promise and may prove useful in future studies.
  • Factor analyses show that negative symptoms often group in 2 factors: avolition–apathy and expressive deficit. In light of such findings, future research should include data on each of these factors, rather than a total score for negative symptoms.
  • Although there is no consensus on whether a dimensional or categorical approach is superior in studying negative symptoms, there is evidence to support both approaches.
  • Currently available antipsychotic agents are not effective in reducing primary and enduring negative symptoms.
  • “Transnosographic studies of negative symptoms appear of interest in the search for biomarkers and innovative treatments, provided that recent advances in concepts and assessment are taken into account,” the authors stated.
  • There has been significant progress in research investigating pathophysiological mechanisms and biomarkers pertaining to negative symptoms, and these endeavors may inform the development of novel therapies.

Controversial aspects

  • Drug regulatory authorities and randomized trials have not yet begun incorporating the updated findings regarding conceptualization and assessment of negative symptoms.
  • Although negative symptoms are considered a core aspect of schizophrenia, current classification systems do not require a negative symptom for diagnosis.
  • Pathogenesis, outcome, and treatment response may vary between schizophrenia with vs without primary and enduring negative symptoms.
  • It is possible that some or all “negative symptoms could be better conceptualised as cognitive dysfunctions (eg, alogia as an impairment of verbal fluency, or avolition–apathy as impaired salience or reward processing),” as noted in the paper.
  • While the presence of negative symptoms is not exclusive to schizophrenia, it is unclear whether the “constructs, their correlates, and neurobiological underpinnings are homogeneous across diagnoses. …”
  • There is a need for studies with large sample sizes of patients with a wide range of negative symptom severity, including those who have comorbid conditions, such as depression, as well as patients without comorbidities.

For additional discussion about negative symptoms in schizophrenia, Psychiatry Advisor spoke with Jacob Ballon, MD, a psychiatrist at Stanford Health Care and director of the INSPIRE Clinic at Stanford, which provides interdisciplinary care for people experiencing psychosis, and Ellen Lee, MD, a physician-scientist in the Department of Psychiatry at the University of California, San Diego, School of Medicine.

Psychiatry Advisor: What are some of the outcomes associated with negative symptoms in schizophrenia; for example, how do they influence the course of the illness?

Dr Ballon: Negative symptoms have a profound impact on the course of schizophrenia. If a person has difficulty engaging in or feeling motivated toward activities, difficulty interacting with peers and other people, and challenges with hygiene, this all can get in the way of successfully working toward other goals. Ultimately, negative symptoms often interfere with even being able to come up with treatment goals, and that can get in the way of knowing exactly what important outcomes should be pursued.

Dr Lee: Negative symptoms in schizophrenia greatly impact functioning and quality of life for patients. For example, they are associated with impaired social functioning, worse interpersonal relationships, and impaired work performance. Of course, negative symptoms may overlap with the manifestations of depressed mood and poor cognition. However, studies have shown that the effect of negative symptoms is independent of cognition and depression. In older people with schizophrenia, negative symptoms may be more common, as aging is associated with psychomotor retardation and cognitive impairment.

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There is a phenomenon called “burnout” in older persons with schizophrenia, in which positive symptoms improve, or the psychosis “burns out,” but the negative symptoms do not appear to worsen. Furthermore, insight into their illness improves, and medication adherence can also improve. In some extraordinary cases like the mathematician John Nash and the law professor and author Elyn Saks, the psychotic symptoms can remit to the point where medications are no longer necessary, and as they age, the patients can be incredibly productive.

Psychiatry Advisor: What are some of the current gaps in treatment for these symptoms?

Dr Ballon: Negative symptoms are in and of themselves a treatment gap. Currently, there is no medication that reliably attenuates negative symptoms. Cognitive behavioral therapy for psychosis (CBTp) can be helpful, but it would be ideal if there were also medication treatments that could be used in concert with CBTp. Ultimately, negative symptoms cover a broad range of symptoms; thus, pharmacological targets are difficult, and there is great room for making progress in this area.

Dr Lee: There is no US Food and Drug Administration-approved or clear treatment, either pharmacological or psychosocial, for negative symptoms in schizophrenia. However, there has been some evidence that a variety of medications and psychosocial interventions, and even other environmental or lifestyle factors, could improve negative symptoms in certain patients. For example, smoking may reduce negative symptoms as well as extrapyramidal symptoms. Unfortunately, the current body of evidence is not robust and definitive enough to pinpoint a clear treatment.

We need large-scale studies of interventions that examine a broader group of patients over a longer period of time, to assess the generalizability of the intervention. Understanding which types of patients are most likely to benefit from a specific intervention can help clinicians assess the risk/benefit ratio for each patient. Clarifying and assessing which patients have primary vs secondary negative symptoms can also help gauge the likelihood of treatment response and when to consider other contributing environmental factors.

We also need rigorous trials of novel agents, including new pharmaceutical interventions and herbal supplements. We also lack biomarkers and endophenotypes of negative symptoms that could guide participant selection and assess treatment response.

Psychiatry Advisor: What should be the focus of additional research in this area?

Dr Ballon: Research should continue to focus on the 2 major fronts that we have for working on negative symptoms: psychotherapy and pharmacotherapy. As newer medications come on board that may target these symptoms better, understanding how to best blend those new medications with current antipsychotics, as well as how to maximize their effectiveness with CBTp techniques geared toward specific symptoms, would be helpful.

Dr Lee: Clearly, there are a number of important next steps in this area of study. Broadly speaking, there may be a key role for technology in better understanding negative symptoms. Passive sensors and ecological momentary assessment may be more sensitive and objective ways to assess the presence and characteristics of negative symptoms. Similarly, bioinformatics approaches may help to identify patient characteristics of those most likely to develop negative symptoms, or to predict poor outcomes related to negative symptoms. Again, this knowledge would aid in targeting treatment trials to the patient populations who are most impaired and most likely to benefit.

Future studies that focus on the underlying neurobiological mechanisms of the different pharmacological and psychosocial interventions may help elucidate why certain interventions can help certain patients. This may further inform interventions of direct brain manipulation, such as repetitive transcranial magnetic stimulation and transcranial direct current stimulation, potentially paving the way for even deep brain stimulation or biofeedback.

The importance of psychosocial interventions cannot be underestimated. Using rigorous study methodology to test combinations of biological and psychosocial interventions may help account for both physiological and environmental influences on negative symptoms and outcomes.

Last, the phenomenon of negative symptoms is not limited only to schizophrenia, but also has been observed in some patients with bipolar disorder. Understanding the neurobiological differences between persons with and without negative symptoms, across a broad spectrum of psychiatric disorders, may help us learn more about what causes and influences negative symptoms.

Psychiatry Advisor: What are some key treatment recommendations for clinicians regarding negative symptoms in this population?

Dr Ballon: First is to ask about negative symptoms: assess for social activity level and interest. It is easy to miss these symptoms because they are not as out in the open and do not often cause the same level of distress in family members as positive symptoms do. Remember that these symptoms are largely responsible for the ultimate prognosis and are necessary for figuring it out, as these symptoms may present as barriers in working toward other treatment goals.

Second is to focus on finding support for helping to increase goal directed behavior: Is there a clubhouse in your area that the patient can go to? Can they be engaged in supported employment or education? Negative symptoms can interfere in the goal-making process, but it is still important to identify positive goals with your patients and use progress toward those goals as measures of overall success in treatment.

Dr Lee: Though negative symptoms are often resistant to treatment, they greatly impact functional and quality-of-life outcomes for patients with schizophrenia. Researchers have tested a wide variety of medications and psychosocial interventions, and the current literature does not support any 1 intervention, unequivocally, for negative symptoms. However, a number of clinically accessible interventions (antidepressants, antipsychotics, psychosocial treatments, repetitive transcranial magnetic stimulation) have been shown to have some efficacy in certain patients and should be considered when clinically appropriate. Of course, side effects of pharmacologic and brain stimulation modalities must be considered carefully as well.

References

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

2. Bucci P, Galderisi S. Categorizing and assessing negative symptoms. Curr Opin Psychiatry. 2017;30(3):201-208.