Psychiatry

Schizophrenia

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Treatment Perspectives: The Negative Symptoms of Schizophrenia

expert roundtables by John M. Kane, MD; Jonathan M. Meyer, MD; Leslie Citrome, MD, MPH

Overview

The development of newer treatments that would be effective against the primary negative symptoms of schizophrenia continues to be of great interest. Given the current landscape, the recognition of potentially treatable negative symptoms is emphasized, including those from comorbid depression and secondary negative symptoms from antipsychotics that exhibit excessive D2 antagonism.

Q:

How do you assess and treat patients with schizophrenia who manifest negative symptoms?

John M. Kane, MD

Senior Vice President, Behavioral Health Services
Northwell Health
Zucker Hillside Hospital
Professor and Chairman, Department of Psychiatry
Donald and Barbara Zucker School of Medicine at Hofstra/Northwell
New Hyde Park, NY

“Generally, antipsychotic drugs do not work as well on the core negative symptoms of schizophrenia as they do on the positive symptoms, so there is great interest in this domain as it relates to the development of newer treatments.”

John M. Kane, MD

Negative symptoms of schizophrenia, along with cognitive deficits, substantially contribute to a patient’s diminished ability to function, whether socially, vocationally, or in other ways. Most patients with schizophrenia, even first-episode patients, have some negative symptoms. In fact, the earliest signs of the disorder are often depressive and negative symptoms. Rates of negative symptoms vary with the definitions used, but more than half of patients with schizophrenia, at some point, will experience clinically relevant negative symptoms that require treatment.

Managing negative symptoms has been a challenge for clinicians, for a variety of reasons. These symptoms, which can overlap with depressive symptoms at times, may be a core manifestation of schizophrenia or they might be secondary to positive symptoms or the antipsychotic medication itself. Generally, antipsychotic drugs do not work as well on the core negative symptoms of schizophrenia as they do on the positive symptoms, so there is great interest in this domain as it relates to the development of newer treatments. Dopamine partial agonists may have some advantages over pure antagonists in this respect. In particular, cariprazine was shown to be superior to risperidone. As antipsychotic augmentation therapy, aripiprazole has demonstrated efficacy against negative symptoms as well, and lumateperone monotherapy was effective against negative symptoms in a single placebo-controlled study. However, the pharmacologic treatment of negative symptoms remains largely an unmet need, and there are also challenges in the assessment of negative symptoms. There is no standard practice for assessing or treating negative symptoms, and distinguishing them from depression can be difficult. Antidepressants may be somewhat effective for both, which may, at times, introduce confusion, but the bottom line is that we are still searching for better treatments for negative symptoms.

Leslie Citrome, MD, MPH

Clinical Professor
Department of Psychiatry and Behavioral Sciences
New York Medical College
Valhalla, NY

“Second-generation antipsychotics have been somewhat more successful than first-generation agents for negative symptoms, possibly because they do not induce the secondary negative symptoms that are often seen with first-generation agents.”

Leslie Citrome, MD, MPH

Second-generation antipsychotics have been somewhat more successful than first-generation agents for negative symptoms, possibly because they do not induce the secondary negative symptoms that are often seen with first-generation agents. So that is encouraging, but a definitive effect of the second-generation antipsychotics on negative symptoms has not yet been established, and we do not currently have agents that are US Food and Drug Administration approved specifically to treat negative symptoms in schizophrenia.

The negative symptoms really do have a substantial impact on functioning. If a patient has positive symptoms that are adequately controlled, that individual may be able to work. However, if the patient has negative symptoms, the volition to work may be absent, and they may not be able to get to work, particularly if they also have cognitive impairment. For such individuals, it is important to develop new interventions in order to improve functional status. We have a range of available options for the positive symptoms, but we simply do not have the same tools for the negative symptoms.

Jonathan M. Meyer, MD

Clinical Professor of Psychiatry
University of California, San Diego
Psychopharmacology Consultant
California Department of State Hospitals
Sacramento, CA

“It is important to determine if the negative symptoms may be treatable, perhaps with antidepressant therapy in the case of depression or by switching antipsychotic therapy in the case of negative symptoms due to excessive D2 blockade.”

Jonathan M. Meyer, MD

As suggested by my colleagues, a large part of the treatment decision involves trying to determine whether a patient is experiencing primary negative symptoms that are a core feature of the disease vs secondary symptoms. Negative symptoms may arise secondarily due to a psychiatric comorbidity such as major depressive disorder. Alternatively, they may arise due to excessive D2 blockade from antipsychotic therapy; some of these patients may seem slowed, unmotivated, and even anhedonic, all of which are adverse effects stemming from excessive D2 occupancy in the limbic areas of the striatum. Switching their antipsychotic medication, perhaps to a less potent D2 antagonist or to a partial dopamine agonist, may be helpful in this scenario.

To reiterate, the first step is to determine whether the negative symptoms may be treatable. Depressive symptoms are chronic and persistent in up to 40% of patients with schizophrenia, and these individuals should receive an antidepressant trial. For patients with schizoaffective disorder, bipolar type who may be destabilized by traditional antidepressant therapy, alternatives to be considered include switching the antipsychotic to lurasidone or cariprazine, 2 medications with indications for bipolar I depression. If negative symptoms appear as a core feature of the schizophrenia spectrum disorder, we have relatively few effective treatment options, although favorable results were reported with cariprazine (compared with risperidone), as mentioned by Dr Kane. 

References

Correll CU, Davis RE, Weingart M, et al. Efficacy and safety of lumateperone for treatment of schizophrenia: a randomized clinical trial [published correction appears in JAMA Psychiatry. 2020;77(4):438]. JAMA Psychiatry. 2020;77(4):349-358. doi:10.1001/jamapsychiatry.2019.4379

Correll CU, Schooler NR. Negative symptoms in schizophrenia: a review and clinical guide for recognition, assessment, and treatment. Neuropsychiatr Dis Treat. 2020;16:519-534. doi:10.2147/NDT.S225643

Galling B, Roldán A, Hagi K, et al. Antipsychotic augmentation vs. monotherapy in schizophrenia: systematic review, meta-analysis and meta-regression analysis. World Psychiatry. 2017;16(1):77-89. doi:10.1002/wps.20387

Németh G, Laszlovszky I, Czobor P, et al. Cariprazine versus risperidone monotherapy for treatment of predominant negative symptoms in patients with schizophrenia: a randomised, double-blind, controlled trial [published correction appears in Lancet. 2017;389(10074):1102]. Lancet. 2017;389(10074):1103-1113. doi:10.1016/S0140-6736(17)30060-0

Strauss GP, Nuñez A, Ahmed AO, et al. The latent structure of negative symptoms in schizophrenia. JAMA Psychiatry. 2018;75(12):1271-1279. doi:10.1001/jamapsychiatry.2018.2475

John M. Kane, MD

Senior Vice President, Behavioral Health Services
Northwell Health
Zucker Hillside Hospital
Professor and Chairman, Department of Psychiatry
Donald and Barbara Zucker School of Medicine at Hofstra/Northwell
New Hyde Park, NY

Jonathan M. Meyer, MD

Clinical Professor of Psychiatry
University of California, San Diego
Psychopharmacology Consultant
California Department of State Hospitals
Sacramento, CA

Leslie Citrome, MD, MPH

Clinical Professor
Department of Psychiatry and Behavioral Sciences
New York Medical College
Valhalla, NY

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