Primary Negative Symptoms: Refining the Research Target

Negative symptoms contribute to poor function and quality of life in many people with schizophrenia. These symptoms often improve when there is improvement in positive psychotic symptoms—hallucinations, delusions, and disorganized thought and behavior—demonstrating that negative symptoms can be secondary to other clinical problems. To give an example, a person with schizophrenia might have the negative symptom of asocial behavior because of depression, anxiety, or overwhelming suspiciousness. However, a lack of interest in relationships is also found in people with schizophrenia who do not have these other symptoms, suggesting some negative symptoms are idiopathic or primary. People with primary negative symptoms (PNS) have poorer function than do others with schizophrenia, and this difference cannot be accounted for by differences in demographics, treatment, drug abuse, depression, or a greater severity of positive psychotic symptoms.^1–3 Psychosocial treatments as well as antipsychotic, antidepressant, and anti-anxiety medications all may treat secondary negative symptoms. However, there are no established treatments for PNS.

Redefining the target of research may help advance the study of this aspect of schizophrenia, as there are problems in the assessment of clinical features. First, research on PNS depends on rating scales. Rating scales are vulnerable to imprecise and invalid ratings because they rely on accurate memory of symptoms and activities over the previous week or month, an ability to self-observe accurately, and imperfect human raters. Some of these drawbacks may be particularly problematic in assessing people with PNS, since as a group they have greater cognitive impairment and less awareness of their impairment than do other people with schizophrenia.^4,5 Rating scales also do not distinguish primary vs secondary negative symptoms. Digital phenotyping may offer a method of assessment that is more precise and accurate than the use of rating scales. This method for “moment-by-moment quantification of the individual-level human phenotype in situ using data from personal digital devices” ⁶ is well accepted by research participants with schizophrenia.⁷ In this approach, smart phones and wearable devices generate questions about patients’ symptoms and activities at the time, and gather objective measures such as accelerometry, physiological variables, detection of ambient speech, and automated ratings of blunted affect, many of these without the research subject having to respond. This method has been used extensively in schizophrenia, with good validity not only for positive symptoms but also for negative symptoms.^8–11

There have been 2 approaches to distinguishing people with schizophrenia who have PNS from those who do not. The first is use of the Schedule for the Deficit Syndrome (SDS),¹² a semistructured clinical interview tool that categorizes subjects with schizophrenia or nonaffective psychosis into deficit (PNS are present) or nondeficit groups (PNS are absent). The existence of separate groups is supported by taxometric studies.^13–15 The SDS is designed to yield categorizations that are not confounded by the presence in the deficit group of a greater length of illness, more severe positive psychotic symptoms (hallucinations + delusions, and disorganized thought or behavior), more severe mood symptoms (depression or anxiety), or more severe extrapyramidal symptoms associated with antipsychotic medications. When the SDS is used to define groups with and without negative symptoms in a published study, providing information on these characteristics in the 2 groups is crucial for determining whether different authors are talking about the same population.

Another approach to defining PNS groups is the Proxy for the Deficit Syndrome, which can be implemented using ratings of negative symptoms, dysphoria (depression/guilt/anxiety), and positive psychotic symptoms. Academics have often used the Proxy to calculate a score that is then used to categorize people in a sample into putative deficit and nondeficit groups.¹⁶ The pharmaceutical industry has taken a conceptually similar approach by including in negative symptom treatment trials only those patients with minimal or absent depression, positive symptoms, and extrapyramidal symptoms.¹⁷ Both of these approaches identify groups whose negative symptoms are more often primary than secondary. Industry researchers usually conceptualize their research participants as having predominant negative symptoms (a concept different from prominent negative symptoms) rather than deficit/nondeficit groups. The Proxy and predominant negative symptom approaches both probably yield groups that are more heterogeneous than groups diagnosed with the SDS, so the certainty that any individual patient has deficit schizophrenia is less. On the other hand, the SDS requires considerable training and entails an evaluation in addition to administration of other, more commonly used instruments such as the Positive and Negative Syndrome Scale, making it impractical for use in large multicenter trials.

The use of the Proxy has led to replication of some SDS findings, and the groups generated by the Proxy have symptom profiles very similar to those of groups diagnosed by the SDS. However, unlike the SDS, the Proxy does not assess symptom persistence, as it is usually based on a cross-sectional evaluation and only one negative symptom (typically blunted affect) is used to calculate the individual scores. This agreement is largely due to the dysphoria component of the formula for the Proxy score.¹⁶

There is now a considerable amount of evidence supporting the validity of the distinction between primary and secondary negative symptoms.^1–3 One interpretation of this evidence is that people who have schizophrenia and PNS have a disease that is separate from the disease found in other people with schizophrenia, as (1) the 2 groups differ on dimensions that typically distinguish diseases, ie, signs and symptoms, course of illness, biological correlates, risk factors, and treatment response; (2) these findings are not confounded by differences in treatment, the severity of psychosis, or demographics; and (3) a person in the deficit group does not simply have a more severe case of the same disorder as those in the nondeficit group, as by some measures the deficit group is less impaired and for some variables there is a double dissociation.

However, is the concept of a separate psychotic illness characterized by PNS the most useful way to advance the study of these symptoms? There is reason to question this approach. Some negative symptoms are found in other neuropsychiatric disorders, including depression and some forms of dementia, although the same terms may not be used in the literature on these other disorders. The concept of a cohesive set of symptoms within psychosis may also be misleading. The influential Research Domain Criteria (RDoC) concept promulgated by the U.S. National Institute of Mental Health is an implicit challenge to the utility of the concept of separate neuropsychiatric diseases.¹⁸

Several studies have shown that there are 5 negative symptom factors that cross rating scales and cultures: anhedonia, asociality, avolition, alogia, and blunted affect.¹⁹ While there is some covariation across these domains, it is limited and people rarely have moderate or severe impairment in all 5 PNS. It is unclear whether the correlates of deficit schizophrenia, such as summer birth or greater cognitive impairment than in other people with schizophrenia, might relate to 1, 2, or all of the negative symptom domains found in the factor analysis studies. If the 5 negative symptom domains have separate etiopathophysiologies, clinical trials that use total negative scale scores as the outcome variable may be falsely negative if a treatment is effective for one domain but not others. Similarly, studies of mechanism may also lead to false negatives. While examining the relationship of each domain to an intervention or correlate raises the problem of multiple comparisons and the need for large samples, if the 5 domains were routinely examined in secondary analyses, positive results could then lead to hypothesis-testing follow-up studies.

Despite these issues of diagnosis and definition, the current evidence suggests that the etiopathophysiology of PNS differs in some ways from that of secondary negative symptoms. Rather than exploring the psychological, biological, and environmental mechanisms underlying deficit schizophrenia, which entails a cohesive set of negative symptoms, a better strategy may be to focus on the 5 symptom domains, their relationships to each other and to other variables, and the treatment of each. That approach suggests future research questions.

1. Does each PNS domain have risk factors, mechanisms, and treatment response that differ from those of other domains?

2. Does each PNS domain have risk factors and mechanisms that differ from those of secondary negative symptoms?

3. What is the degree of overlap between predominant negative symptoms and PNS?

4. For any treatment shown to have efficacy for predominant negative symptoms, which domains improve? Is there also efficacy for PNS?

5. One network analysis of a successful treatment study of predominant negative symptoms found avolition was highly central in patients receiving placebo and that successful treatment reduced this centrality, suggesting that decreasing the influence of motivation on other negative symptom domains is needed for an overall improvement in negative symptoms.²⁰ Can this finding be replicated with the drug tested in that trial, or with other drugs?

6. Can digital phenotyping lead to a more useful definition of the clinical profile of PNS than rating scales provide, that is, more closely related to mechanisms, risk factors, level of function, and treatment response?

7. Do PNS have early life psychosocial risk factors, such as sexual abuse or migration? If so, which domains are affected?

8. Do PNS have early life biological risk factors other than summer birth, such as low birth weight, cannabis use, head injury, or advanced paternal age? If so, which domains are affected?

9. Are there risk factors and mechanisms for PNS that are associated with risk beyond schizophrenia? Are these the same risk factors and mechanisms for PNS that are found in schizophrenia?

10. Factors that are likely to worsen secondary negative symptoms include depression, anxiety, suspiciousness, overwhelming hallucinations, disorganized thought and behavior, medical illness, extrapyramidal side effects of antipsychotic medications, and self-defeating beliefs. What are the relationships of each of these to the 5 negative symptom domains? What other factors are associated with more severe secondary negative symptoms?

11. What are the network characteristics of secondary negative symptoms in treatment and observational studies?

The concept of separate diseases has been a powerful tool in psychiatry and the rest of medicine. However, medical research has frequently benefited from the definition of more homogeneous groups within diagnostic categories. Approaching PNS as if they were a cohesive set of symptoms that are markers of a disease separate from the rest of schizophrenia has been a fruitful strategy, but recent developments suggest it may not be the optimal approach to the study of these impairments. Further reduction of heterogeneity based on the 5 negative symptom domains may lead to greater understanding of these problems, improved treatment, and an improved quality of life for people with these disabilities.