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.

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.

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.