Schizophrenia Research 197 (2018) 269–273

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Schizophrenia Research

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The brief negative symptom scale (BNSS): Sensitivity to treatment effects

Brian Kirkpatrick a,⁎, Jay B. Saoud b, Gregory P. Strauss c, Anthony O. Ahmed d, Kazunori Tatsumi e, Mark Opler e,
Remy Luthringer f, Michael Davidson f
a
University of Nevada, Reno School of Medicine, Reno, NV, USA
b
PPRS Research, Inc., Groton, MA, USA
c
Department of Psychology, University of Georgia, Athens, GA, USA
d
Department of Psychiatry, Weill Cornell School of Medicine, USA
e
ProPhase LLC, New York City, New York, USA
f
Minerva Neurosciences, Inc., Waltham, MA, USA

a r t i c l e i n f o a b s t r a c t

Article history: The Brief Negative Symptom Scale (BNSS) grew out of a recommendation by the NIMH-sponsored Consensus De-
Received 5 June 2017 velopment Conference on Negative Symptoms that a scale based on contemporary concepts be developed. We
Received in revised form 25 October 2017 assessed sensitivity to change of the BNSS in a trial of MIN-101, which showed efficacy for negative symptoms
Accepted 24 November 2017
(PANSS pentagonal model) at daily doses of 32 and 64 mg/day. Using mixed-effects model for repeated mea-
Available online 21 December 2017
sures, we examined change in BNSS total score and in the BNSS factors of anhedonia/avolition/asociality
Keywords:
(AAA), and expressivity (EXP). Compared to placebo, the 64 mg group (N = 83) showed a significant decrease
Negative symptoms in BNSS total score (effect size d [ES] 0.56, p b 0.01) and both factor scores (AAA ES = 0.48, EXP ES = 0.46, p b
Psychometrics 0.02 for both). Patients in the trial had minimal depression and positive symptom scores; covarying for disorga-
Factor analysis nization, positive symptoms, or anxiety/depression did not cause a meaningful change in the significance of the
Schizophrenia BNSS total or factor scores in this group. The 32 mg group (N = 78) did not differ significantly from placebo (N =
Treatment 83) on BNSS total score (ES = 0.33, p b 0.09), AAA (ES = 0.25, p b 0.20) or EXP (ES = 0.30, p b 0.12) scores. These
results demonstrate the BNSS is sensitive to change.
© 2017 Published by Elsevier B.V.

1. Introduction The BNSS consists of 13 items organized into six subscales (Table 1).
Five of these subscales reflect the domains recognized as part of the con-
The NIMH Consensus Development Conference on Negative Symp- struct of negative symptoms: anhedonia, avolition, asociality, blunted
toms recommended that a negative symptom scale be developed that affect, and alogia. The Consensus Conference participants left open the
would embody recent changes in the concept of negative symptoms possibility that other domains belong in this construct, and the BNSS
(Kirkpatrick et al. 2006). In response to that recommendation, the contains an additional item, Lack of Normal Distress. A conceptually
Brief Negative Symptom Scale (BNSS), which was designed for ease of similar item, Diminished Emotional Range, is part of the Schedule for
us in clinical trials, was developed and tested. Psychometric studies of the Deficit Syndrome (SDS; Kirkpatrick et al. 1989). Psychometric stud-
the BNSS have shown excellent reliability, discriminant validity, and ies of the BNSS and the SDS (Bischof et al. 2016; Kimhy et al. 2006;
convergent validity in English and in translation (Kirkpatrick et al. Kirkpatrick et al. 2011; Mané et al. 2014; Mucci et al. 2015; Nakaya
2011; Strauss et al. 2012b; Mané et al. 2014; Mucci et al. 2015; Polat and Ohmori 2008; Polat Nazli et al., 2016; Strauss et al. 2012b) have sug-
Nazli et al., 2016; Bischof et al. 2016; Yao et al. 2014’ Strauss and Gold gested that this item's content also belongs in the construct of negative
2016; Strauss et al. 2016a). Translations and back translations exist in symptoms.
Spanish, Italian, Turkish, Chinese (simplified and traditional script), Ger- The BNSS has a two-factor structure in English and in translation
man, Russian, Dutch, Danish, Polish, Norwegian, Japanese, Korean, and (Kirkpatrick et al. 2011; Strauss et al. 2012a; Mucci et al. 2015; Yao et
Portuguese versions (Bischof et al. 2016; Choi et al. 2016; Mucci et al. al., 2014; Polat Nazli et al., 2016; Bischof et al. 2016) that is very similar
2015; Polat Nazli et al., 2016; Yao et al. 2014; and personal to the factor structure of the Scale for the Assessment of Negative Symp-
communications). toms (Blanchard and Cohen 2006) and the Clinical Assessment Inter-
view for Negative Symptoms (Blanchard et al. 2017). The two BNSS
⁎ Corresponding author at: Department of Psychiatry & Behavioral Sciences, 5190 Neil
factors consist of items from 1) the anhedonia, avolition, and asociality
Road, Suite 215, Reno, NV, USA. (AAA) subscales, and 2) the blunted affect and alogia subscales (expres-
E-mail address: [email protected] (B. Kirkpatrick). sivity; EXP). Although measures such as Cronbach's alpha suggest the

https://doi.org/10.1016/j.schres.2017.11.031
0920-9964/© 2017 Published by Elsevier B.V.
270 B. Kirkpatrick et al. / Schizophrenia Research 197 (2018) 269–273

Table 1 total score ≥ 20 on the PANSS negative syndrome subscale (items N1-
Items and subscales in the brief negative symptom scale. N7), and scores b4 on the PANSS excitement, hyperactivity, hostility,
Subscale Item AAA EXP suspiciousness, uncooperativeness, and poor impulse control items. Ex-
factor Factor clusions were a diagnosis of another mental disorder, a significant risk
Anhedonia Intensity of pleasure √ of suicide, a positive urine test for illicit drugs, a history of substance
Frequency of pleasurable activities √ abuse, or an unstable medical disorder. There were also exclusion
Intensity of expected pleasure √ criteria related to QT values, and for poor and intermediate metabolizers
Lack of normal distress Lack of normal distressa
for P450 CYP2D6 (Davidson et al., in press).
Asociality Asociality: behavior √
Asociality: Internal experience √
Avolition Avolition: behavior √ 2.2. Study design
Avolition: internal experience √
Blunted affect Facial expression √ Eligible patients were withdrawn from depot antipsychotics, if any,
Vocal expression √
Expressive gestures √
for ≥ 1 month. All patients were then hospitalized and withdrawn
Alogia Quantity of speech √ from all psychotropic drugs for ≥5 days prior to randomization to oral
Spontaneous elaboration √ MIN-101 32 mg/day, 64 mg/day, or placebo, in a 1:1:1 ratio. They
AAA: Anhedonia/avolition/asociality; EXP: Expressivity. remained hospitalized for at least 36 h after randomization, longer at
a
Lack of normal distress usually does not load strongly onto either factor. See text for the discretion of the investigator if clinically indicated.
references. Study treatment lasted for 12 weeks. No psychotropic medications
were allowed during the trial, other than 1) oral lorazepam, oral
BNSS Lack of Normal Distress item belongs in the construct of negative zolpidem, or injectable sodium amytal for insomnia or agitation, or 2)
symptoms (Strauss et al. 2012a), it does not load as strongly on either anticholinergic medications for any extrapyramidal symptoms that
factor as do the other BNSS items. emerged during the study. After the 12 weeks of double blind treat-
The BNSS has shown sensitivity to change in a psychosocial treat- ment, there was a 24-week open continuation phase. Data shown
ment trial (Choi et al. 2016), variation in multi-locus genetic profile here are from the double-blind phase only. The primary outcome mea-
scores reflecting elevated subcortical dopaminergic signaling capacity sure was the negative factor score of the PANSS from the pentagonal
(Eisenstein et al. 2017), and factor-specific correlations with regional structure model (N1-N4,G5-G8 G13,14; White et al. 1997).
brain activation (Kirschner et al. 2016) and real-world function
(Galderisi et al. 2014). The study of real world function demonstrated 2.3. BNSS factors
the practicality of use of the BNSS in large multicenter studies. The
BNSS has also shown sensitivity to groups differences in reward pro- As the BNSS item 4, Lack of Normal Distress, has not loaded as
cessing, which is currently the most influential theoretical model for strongly on either the AAA or EXP factor as do other items, it was not in-
negative symptoms, with the AAA factor having a specific relationship cluded in either of the factor scores in the current analyses. The AAA
to reward (Barch et al. 2014; Culbreth et al. 2016; Strauss et al. 2016b). score was therefore defined for the present analyses as the sum of the
MIN-101 (a proprietary drug of Minerva Neurosciences, Inc.) is an scores for items 1–3 and 5–8 (range: 0–42), and the EXP score was de-
antagonist of 5HT2A and sigma2 receptors (Mestre et al. 2013; Köster fined as the sum of the scores for items 9–13 (range 0–30).
et al. 2014; Davidson et al., in press). In a 12-week, double blind phase
2b trial, two doses of MIN-101 were found to be superior to placebo as 2.4. Analyses
monotherapy for negative symptoms (Davidson et al., 2017) as mea-
sured by the negative factor score of the pentagonal structure model We present data related to the BNSS or its performance; details on
of the PANSS (White et al. 1997). The results of the trial suggest the other measures can be found in Davidson et al. (2017).
change in negative symptoms were not “pseudospecific,” i.e. secondary Using Mixed-Effect Model Repeated Measure (MMRM) analysis, we
to changes in positive psychotic symptoms or depression, as there was examined changes in BNSS total score and the AAA and EXP factors in
no significant change in positive symptoms, and the negative symptom the three treatment arms. We also examined whether the effect of
effect remained significant after covarying for change in depression MIN-101 was specific to negative symptoms or could be attributed to
scores (and see below). changes in positive symptoms and/or depression anxiety, using
The BNSS was a secondary outcome measure in the MI-101 phase 2b MMRM covarying for the positive, disorganization, and depression
trial. As the BNSS has not previously been assessed in a pharmaceutical factors.
trial, we examined in detail its performance in that trial. Using data from the endpoint ratings, confirmatory factor analysis
was used to determine whether the raters separated the two factors
2. Materials and methods found in previous studies. We examined the relative fits of two-factor
and one-factor models of the BNSS, omitting the lack of normal distress
In brief, this was an international, multicenter, double-blind study item, using weighted least squares and maximum likelihood as
with three parallel arms: MIN-101 at a daily oral dose of either 32 mg methods of estimation. The comparative fit index (CFI), the Tucker
(N = 78) or 64 mg (N = 83), and placebo (N = 83; study registered Lewis Index (TLI), the root-mean-square-error-of-approximation
as EudraCT Number: 2014-004878-42). Both MIN-101 and placebo (RMSEA), and information criteria (Akaike [AIC], Bayesian [BIC], and
were given as monotherapy, and patients were withdrawn from any an- sample size adjusted BIC) were used to evaluate the relative fit of the
tipsychotic medication prior to receiving study treatment. For details of two models, and of a `m,v null model, in which items are assumed to
the protocol and detailed results, see Davidson et al. (in press). have zero covariance.

2.1. Inclusion/exclusion criteria 3. Results

Two hundred forty-four patients between the ages of 18 and 60 en- Consistent with the recommendation of the Consensus Develop-
tered the trial. Entry criteria included 1) a DSM-5 diagnosis of schizo- ment Conference on Negative Symptoms on appropriate selection
phrenia, 2) clinically stable and exhibiting negative symptoms for criteria for inclusion in negative symptom treatment trials
3 months prior to entering the study, as determined by their treating (Kirkpatrick et al. 2006), patients entering the study had substantial
psychiatrist, and 3) on the Positive and Negative Syndrome Scale, a negative symptoms but minimal positive and depressive symptoms.
 B. Kirkpatrick et al. / Schizophrenia Research 197 (2018) 269–273 271

100%
Table 2
Demographic and clinical characteristics of the sample.
98%
MIN-101

Placebo 32 mg/day 64 mg/day

% of baseline
96%
(N = 83) (N = 78) (N = 83)

Age (SD) 40.0 (10.2) 39.8 (10.2) 40.6 (10.6)

% male 57.8 52.6 57.8 94%
PANSS total score 80.2 (10.7) 81.2 (9.8) 79.7 (11.1)
PANSS pentagonal model 31.5 (4.7) 31.7 (4.2) 31.4 (4.3)
92% PANSS Negative PLC
negative symptom score (SD)
PANSS pentagonal model 10.4 (2.9) 10.5 (3.0) 10.2 (2.9) PANSS Negative 64mg
BNSS Total PLC
positive symptom score (SD) 90%
BNSS Total 64mg
Calgary depression scale for 2.2 (3.2) 2.2 (3.0) 2.0 (2.5)
schizophrenia score (SD)
88%
Baseline W2 W4 W8 W12

The three treatment groups were also similar on demographic factors Fig. 1. BNSS total score for drug (64 mg) vs. placebo: p b 0.01. W2, W4, etc. refer to weeks
(Table 2, and see Davidson et al., in press for further details). of the study. PLC: placebo arm.
At 12 weeks, the 64 mg treatment dose (N = 83) differed signifi-
cantly from placebo on BNSS total score (p b 0.01) and on the AAA
and EXP factors (p N 0.02 on both factors; Table 3, Figs. 1 & 2). The similar in effect size to that of the negative factor score of the pentagonal
32 mg group (N = 78) had greater change in these three measures structure model of the PANSS (Davidson et al., 2017). Covarying for dis-
than did the placebo group (Table 2, Figs. 3 & 4), but these differences organization, positive symptom, anxiety/depression measures did not
were not significant (total score, p b 0.09; AAA, p b 0.20; EXP, p b 0.12; cause a meaningful change in the significance in either of the BNSS fac-
Table 3, Figs. 3 & 4, Supplementary Table 1). tor scores. These finding suggest that the effect of MIN-101 may not
In the 64 mg group, the BNSS had effect sizes (Cohen's d) of 0.56, have been “pseudospecific,” that is, due to an effect on these causes of
0.48, and 0.46 for the total, AAA, and EXP scores. Among patients receiv- secondary negative symptoms (Kirkpatrick et al. 2006). Depression im-
ing the effective 64 mg group, the effect size for the two BNSS factors did proved in the MIN-101 trial, but the drug/placebo differences remained
not differ significantly, that is, the drug was not significantly more effec- significant after covarying for change in depression scores (Davidson et
tive for one factor than for the other (data not shown). Covarying for the al. 2017), and removing a small number of patients with the highest
disorganization, anxiety/depression, and positive symptom factors from scores on depression at baseline left a significant drug/placebo differ-
the PANSS produced no meaningful change in p-values for either the ence in negative symptoms, but no significant change in depression.
BNSS AAA or EXP factors (Table 4). In addition, removing a small num- Both BNSS factor scores (AAA and EXP) had a significant decrease
ber of patients with the highest scores on depression at baseline left a compared to placebo in the 64 mg treatment group. The confirmatory
significant drug/placebo difference in negative symptoms, but no signif- factor analysis suggests this was not due to a halo effect, that is, the
icant change in depression (data not shown). raters did not tend to give high ratings on the AAA items because of
Differences from placebo in the (smaller) 32 mg group were not sig- high EXP ratings, or vice versa, as the raters did preserve the factor
nificant, with respective effect sizes for BNSS total score, AAA, and EXP structure. This lack of a specific relationship to one of the factors con-
of 0.33, 0.25, and 0.30 (Table 3). trasts with the factor-specific correlations with regional brain activation
Confirmatory factor analysis showed that raters in this study sepa- (Kirschner et al. 2016) and real-world function (Galderisi et al. 2014) in
rated the AAA and EXP factors. The two-factor model, which was essen- studies that used the BNSS. However, in a psychosocial treatment trial
tially the structure found in previous studies (Supplementary Table 2), (Choi et al. 2016), both factors improved. The significance of this lack
provided a fit to the data (χ2 = 1199.80, p b 0.0001, CFI = 0.743, of specificity in the MIN-101 trial is not clear; future treatment studies
TLI = 0.854, RMSEA = 0.571) superior to the fit for a one-factor with MIN-101 may help clarify this issue.
model (χ2 = 1161.50, p b 0.0001, CFI = 0.732, TLI = 0.831, RMSEA = While results with the BNSS parallel those of the primary negative
0.603) or the null model (Supplementary Table 3). symptom measure in the MIN-101 phase 2b trial, there are limitations
to this study of the BNSS. The most important limitation of this
4. Discussion
102%
In this twelve week study of the efficacy of MIN-101 for negative
symptoms in schizophrenia, the BNSS showed sensitivity to change 100%

98%
Table 3
% of baseline

Effect size and p value of BNSS total and factor scores at 12 weeks. 96%
Group Adjusted score change Effect size p value
94%
Total score placebo −3.23 PANSS Negative PLC
32 mg −5.44 0.33 b0.09 92% PANSS Negative 64mg
64 mg −6.94 0.56 b0.01
AAA BNSS PLC
Factor scores 90%
AAA BNSS 64mg
AAA placebo −1.63 *
EXP BNSS PLC
32 mg −2.66 0.25 b0.20 88%
EXP BNSS 64mg *
64 mg −3.61 0.48 b0.02
EXP placebo −1.45 86%
32 mg −2.36 0.30 b0.12 Baseline W2 W4 W8 W12
64 mg −2.80 0.46 b0.02

Placebo: N = 83. Fig. 2. BNSS factor scores for drug (64 mg) vs. placebo: p b 0.02 for AAA, p b 0.02 for EXP.
32 mg: N = 78. W2, W4, etc. refer to weeks of the study. PLC: placebo arm. AAA: anhedonia/avolition/
64 mg: N = 83. asociality factor. EXP: expressivity factor.
272 B. Kirkpatrick et al. / Schizophrenia Research 197 (2018) 269–273

100%
Table 4
Change in p values in the BNSS AAA and EXP factors covarying for other factor scores: com-
98% bined 32 mg & 64 mg groups.

AAA EXP
96% Not covarying Covarying Not covarying Covarying
% of baseline

for the factor for the for the factor for the
factor factor
94%
Factor
Disorganization 0.0278 0.0240 0.0224 0.0210
92% PANSS Negative PLC Anxiety/depression 0.0278 0.0268 0.0224 0.0221
PANSS Negative 32mg Positive symptoms 0.0278 0.0283 0.0224 0.0222
BNSS Total PLC
90% BNSS Total 32mg AAA: Anhedonia/avolition/asociality factor; EXP: Expressed emotion factor.

and L.E.K. Consulting, and from an investment capital company through Guideposts. He
88%
consulted with Sterne Kessler, a law firm, about a pharmaceutical litigation issue. Dr.
Baseline W2 W4 W8 W12
Kirkpatrick receives fees from Walsh Medical Media for editorial services.
Drs. Kirkpatrick and Strauss receive licensing royalties from ProPhase LLC for use of
Fig. 3. BNSS total score for drug (32 mg) vs. placebo: p b 0.09. W2, W4, etc. refer to weeks the Brief Negative Symptom Scale (BNSS) by for-profit groups; these fees are donated to
of the study. PLC: placebo arm. the Brain and Behavior Research Foundation.
Dr. Saoud is an employee of PPRS Research, a consultant to Minerva Neurosciences,
Inc.
examination of the BNSS is that it is the first pharmacological study in Dr. Ahmed has no interests to disclose.
which the BNSS was used that had an effect on another negative symp- Mr. Tatsumi is an employee of ProPhase LLC, New York, NY, which provides training
tom measure that did not appear to be pseudospecific. The BNSS also on the BNSS.
showed sensitivity to change in one psychosocial treatment trial (Choi Dr. Mark Opler is an employee of ProPhase LLC, New York, NY, which provides training
on the BNSS. He has received grant funding from the National Institute of Mental Health
et al. 2016), but not in another study of a psychosocial intervention
(NIMH), the Stanley Medical Research Institute (SMRI), the Brain and Behavior Founda-
(Velligan et al. 2015), while two other scales did show a treatment ef- tion (BBF), and the Qatar National Research Fund (QNRF).
fect. This discrepancy may be due to the relatively small sample (N = Dr. Luthringer and Dr. Davidson are members of the management team of Minerva
51) in the study of Velligan and coworkers. Another limitation is that Neurosciences, Inc.
the MIN-101 phase 2b trial included patients with low depression and
positive symptom scores, rather than a sample with more variation in Role of funding
• No Grants
symptoms.
• Minerva Neurosciences had right of approval of publication.
Overall, the results of these studies suggest that the BNSS is success-
ful in its primary intended purpose, which is to serve as a sensitive out-
come measure in clinical trials. The BNSS has advantages over existing Contributors
scales for use in clinical trials, including its brief interview time, a com- **All authors had final approval.
prehensive manual, suitability for multicenter trials, crisp separation of Brian Kirkpatrick designed the analyses and wrote the first draft.
Jay Saoud did most of the analyses and helped in interpretation of the data.
the AAA and EXP factors, ease of training, successful translation and val- Gregory P. Strauss consulted on analyses and helped develop the concept of the
idation in multiple languages, standardized training materials, and im- paper.
plementation of recommendations of the Consensus Conference. Anthony O. Ahmed conducted some of the statistical analyses and helped with data
Supplementary data to this article can be found online at https://doi. interpretation.
Kaunori Tatsumi assisted in data analysis.
org/10.1016/j.schres.2017.11.031.
Mark Opler helped developed the concept of the paper.
Remy Luthringer helped design and oversee the clinical trial from which the data
Disclosures came.
Dr. Kirkpatrick received licensing royalties and travel support from ProPhase for use of Michael Davidson helped design and oversee the clinical trial from which the data
the Brief Negative Symptom Scale (BNSS) by for-profit groups; these fees are donated the came.
Brain and Behavior Research Foundation. He received consulting fees and/or travel sup-
port from Genentech/Roche, Allergan, Minerva Neurosciences, and ProPhase LLC, consult-
Acknowledgements
ing fees from anonymized pharmaceutical companies through Decision Resources, Inc.
None.
102%
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