Read the Signs: Using Indicators from the First Psychotic Episode as Foreshadowing

September 30, 2020

Do neurological signs at illness onset predict long-term outcome schizophrenia?

Minor neurological signs are subtle deficits in sensory integration, motor coordination, and sequencing of complex motor acts that are present in excess at the onset of illness in psychosis.1 They are also present in non-psychotic first-degree relatives of patients with psychosis.2 However, it is unclear whether these signs vary with the clinical course of psychosis and have clinical utility as markers of long-term disease outcome. The longest such study found that over 5 years, total neurological signs did not change, and baseline primitive reflexes predicted poorer functional outcome in 17 patients with first-episode psychosis.3 Nevertheless, neurological signs, particularly sensorimotor deficits, appear to be one of the core dimensions of psychosis and are easily quantified.4

Ferrucio and colleagues5 examined the relationship between multiple domains of neurological function at psychosis onset and 10-year outcomes, as well as change in signs over this time period. They hypothesized that higher and more persistent motor neurological signs at onset would be associated with a non-remitting illness course over a 10-year period. The study was conducted as part of the Aetiology and Ethnicity in Schizophrenia and Other Psychoses (AESOP-10) study of patients presenting to secondary mental health services in the United Kingdom for the first episode of a functional psychotic illness. Neurological function was assessed at baseline and follow-up with the Neurological Evaluation Scale (NES).6 Information on course of illness and symptom history were obtained retrospectively at follow-up using an extended version of the World Health Organization Life Chart based on case notes and clinical interview with patients and treating clinicians. Changes in neurological signs over time were analyzed with repeated measures ANOVA. Hierarchical linear regression was used to explore whether baseline neurological signs predicted functioning at follow-up.

A total of 233 patients had baseline neurological assessment and data on illness course. Of these patients, n = 147 (63%) had a non-remitting and n=86 (37%) a remitting course of illness. A total of 56 patients had a second neurological assessment approximately 10 years later. The study also included n = 172 controls aged 16 to 64 years without psychosis as a control group.

At baseline, non-remitting individuals had significantly more neurological signs than both remitting individuals and controls, including total signs, primary, motor coordination, and motor sequencing signs. Remitting individuals had more total signs and motor coordination signs than controls. These findings remained after controlling for age, gender, ethnicity, and IQ. Neurological signs also predicted functional outcome over and above baseline employment status.

Over the first 10 years of illness, both non-remitting and remitting persons showed an increase in score over time for total signs, primary, and sensory integration, but not motor coordination. There was a non-significant increase in motor sequencing signs only in the non-remitting group. There were no differences in the proportion of non-remitting and remitting participants based on first- versus second-generation agents, drug-free versus naïve status at baseline, and antipsychotic dose. Furthermore, baseline neurological signs were not correlated with baseline antipsychotic dose, and neurological signs at follow-up were not correlated with the number of weeks on medications, suggesting findings are unlikely to be related to antipsychotic exposure.

The authors conducted the first large, longitudinal study of neurological function in first-episode psychosis across multiple functional domains and over a long duration of illness. They found that patients who subsequently develop a more severe (non-remitting) illness course already show more neurological signs than those with a more favorable (remitting) illness course or controls. They also found that impairments in motor coordination remain stable over time and represent a trait-like feature of psychosis, whereas other deficits may reflect illness duration. These findings appear to be independent of the effects of antipsychotic medications.

The bottom line

Some neurological abnormalities, specifically motor coordination problems, may be a useful indicator of subsequent clinical outcome in psychosis.

Dr Miller is professor, Department of Psychiatry and Health Behavior, Augusta University, Augusta, GA. He is the Schizophrenia Section Chief for Psychiatric Times. The author reports that he receives research support from Augusta University, the National Institute of Mental Health, the Brain and Behavior Research Foundation, and the Stanley Medical Research Institute.


1. Dazzan P, Murray RM. Neurological soft signs in first-episode psychosis: a systematic review. Br J Psychiatry Suppl. 2002;43:s50–s57.

2. Chan RC, Xu T, Heinrichs RW, et al. Neurological soft signs in non-psychotic first-degree relatives of patients with schizophrenia: a systematic review and meta-analysis. Neurosci Biobehav Rev. 2010;34:889–896.

3. Behere RV. Dorsolateral prefrontal lobe volume and neurological soft signs as predictors of clinical social and functional outcome in schizophrenia: a longitudinal study. Indian J Psychiatry. 2013;55:111–116.

4. Bernard JA, Mittal VA. Updating the research domain criteria: the utility of a motor dimension. Psychol Med. 2015;45:2685–2689.

5. Ferruccio NP, Tosato S, Lappin JM, et al. Neurological signs at the first psychotic episode as correlates of long-term outcome: results from the AESOP-10 study. Schizophrenia Bulletin. 2020; doi:10.1093/schbul/sbaa089

6. Buchanan RW, Heinrichs DW. The Neurological Evaluation Scale (NES): a structured instrument for the assessment of neurological signs in schizophrenia. Psychiatry Res. 1989;27:335–350.