Summary

Guidelines state three aims of treatment planning: to promote and maintain recovery, to maximize quality of life and adaptive functioning, and to reduce or eliminate symptoms. In trials, symptom outcomes are measured on the PANSS (range 30 to 210). A CGI rating of minimally improved corresponds to a PANSS reduction of 19% to 28% and a rating of much improved to 40% to 53%, which is the basis for the 20% and 50% response thresholds; the authors recommend at least a 50% reduction as the response criterion in acute trials and note that a 25% cut-off might be appropriate in treatment-resistant populations. An absolute reduction of about 15 PANSS points corresponds to minimal improvement on the CGI, and an anchor-based analysis of CATIE data estimated the minimum clinically important difference at 15.3 points (34.0%) with the clinician-rated CGI and 11.2 points (24.6%) with the patient-rated CGI.

Against these thresholds, 51% of participants receiving antipsychotics and 30% receiving placebo had at least a minimal response in placebo-controlled trials of mainly chronic participants, and 23% and 14% had a good response. In first-episode trials, 81.3% reached a 20% reduction and 51.9% a 50% reduction. Absence of a 20% reduction at week 2 predicted nonresponse at endpoint with a positive predictive value of 90%. The mean drug-placebo difference in PANSS change rises with baseline severity, from 9.5 points at a baseline score of 58 to 24.0 points at a baseline score of 116. In NOVA-1, the week 4 change in PANSS total score was −14.3 points with LB-102 50 mg, −14.0 with 75 mg, and −9.3 with placebo.

Remission is defined by consensus criteria as no more than mild positive and negative symptoms sustained for at least 6 months. With maintenance treatment, relapse at 1 year occurred in 24% to 27% of participants receiving antipsychotics and 61% to 64% receiving placebo, and hospitalization in 7% and 18%. The median proportion meeting recovery criteria that combine clinical and social outcomes was 13.5%.

Aims of treatment planning: APA practice guideline

“The overarching aims of treatment planning are 1) to promote and maintain recovery, 2) to maximize quality of life and adaptive functioning, and 3) to reduce or eliminate symptoms.” (opens the source at this quote in a new tab)

Response thresholds on the PANSS linked to clinical global impressions

“To be "minimally improved" according to the CGI score was associated with a mean percentage PANSS reduction of 19%, 23%, 26% and 28% at weeks 1, 2, 4 and 6, respectively.” (opens the source at this quote in a new tab)
“The corresponding figures for a CGI rating "much improved" were 40%, 45%, 51% and 53%.” (opens the source at this quote in a new tab)
“Such studies may ideally use at least a 50% reduction from baseline cut-off to define response rather than lower thresholds.” (opens the source at this quote in a new tab)
“In treatment resistant populations, however, even a small improvement can be important, so that a 25% cut-off might be appropriate.” (opens the source at this quote in a new tab)

Absolute PANSS change linked to clinical global impressions

“An absolute reduction of the BPRS/PANSS by approximately 10/15 points corresponded to a CGI change of ‘minimally improved’ and to a change of the CGI severity score by one severity step.” (opens the source at this quote in a new tab)
“Less severely ill patients required less BPRS/PANSS total score reduction to achieve the same CGI-improvement score than more severely ill patients.” (opens the source at this quote in a new tab)

Minimum clinically important difference on the PANSS

“The MCID for PANSS scores using this scale equaled a 15.3 point (34.0%) change from baseline.” (opens the source at this quote in a new tab)
“With the patient-rated CGI as the anchor, PANSS scores were higher for CGI scores of 1 through 4 and the MCID was lower, 11.2 points (24.6%).” (opens the source at this quote in a new tab)

Early response as the expected course

“Available evidence suggests that patients who have not exhibited at least a 20% reduction in symptoms (or minimal improvement) by about 2 weeks on a therapeutic dose are unlikely to be much improved at 4–6 weeks as reflected by at least a 50% reduction in symptoms” (opens the source at this quote in a new tab)

Remission criteria

“The first consensus-based operational criteria for symptomatic remission in schizophrenia are based on distinct thresholds for reaching and maintaining improvement, as opposed to change criteria, allowing for alignment with traditional concepts of remission in both psychiatric and nonpsychiatric illness.” (opens the source at this quote in a new tab)

“remission, consisting of no more than mild positive and negative symptoms for ≥6 months” (opens the source at this quote in a new tab)

Relapse prevention and hospitalization on maintenance treatment

“Fewer patients given antipsychotic drugs than placebo were readmitted (10%vs 26%; RR 0·38, 95% CI 0·27-0·55; NNTB 5, 4-9), but less than a third of relapsed patients had to be admitted.” (opens the source at this quote in a new tab)

“Hospitalisation was also reduced, however, the baseline risk was lower (drug 7% versus placebo 18%, 21 RCTs, n = 3558, RR 0.43, 95% CI 0.32 to 0.57, NNTB 8, 95% CI 6 to 14; high‐certainty evidence).” (opens the source at this quote in a new tab)
“For people with schizophrenia, the evidence suggests that maintenance on antipsychotic drugs prevents relapse to a much greater extent than placebo for approximately up to two years of follow‐up.” (opens the source at this quote in a new tab)

Quality of life and functioning

“Quality of life (SMD 0.35) and functioning (SMD 0.34) improved even in the short term.” (opens the source at this quote in a new tab)

“Quality of life might be better in drug‐treated participants (7 RCTs, n = 1573 SMD ‐0.32, 95% CI to ‐0.57 to ‐0.07; low‐certainty evidence)” (opens the source at this quote in a new tab)

Functional recovery

“Based on the best available data, the median proportion of individuals with schizophrenia who met our recovery criteria was 13.5%.” (opens the source at this quote in a new tab)

LB-102 primary outcome in NOVA-1

“The primary end point of the change from baseline to week 4 in PANSS total score showed statistical superiority with LB-102 50 mg and 75 mg compared with placebo using the Hochberg correction” (opens the source at this quote in a new tab)
“Additionally, although LB-102 demonstrated broad symptomatic efficacy, it is possible that, in an acute 4-week trial, improvements in negative symptoms may be secondary to the resolution of positive symptoms (pseudospecificity); further studies are required to disentangle these effects.” (opens the source at this quote in a new tab)