ISCTM ~ ECNP Joint Conference ▪ 1 September 2017 ▪ Paris ▪ France
Negative symptoms:Prevalence, specificity, course and other
characteristics
Mark Weiser MDProfessor of Psychiatry, Tel Aviv University
Chief Psychiatrist, Sheba Medical CenterAssociate Director for Treatment Trials, the Stanley Medical Research
Institute Institute
NSANegative
symptoms
BNSSNegative
symptoms
SANSNegative
symptoms
PANSSNegative
symptoms
Communication
Emotion/affect
Social activity
Motivation
Psychomotor activity
Anhedonia
Lack of distress
Asociality
Avolition
Blunted affect
Alogia
Affective Flattening or Blunting
Alogia
Avolition – Apathy
Anhedonia –Asociality
Attention
Blunted affect
Emotional withdrawal
Poor rapport
Passive/apathetic social withdrawal
Difficulty in abstract thinking
Lack of spontaneity and flow of conversation
Stereotyped thinking
ISCTM ~ ECNP Joint Conference ▪ 1 September 2017 ▪ Paris ▪ France
Primary and Secondary Negative Symptoms
Fervaha et al, European Psychiatry 2014
ISCTM ~ ECNP Joint Conference ▪ 1 September 2017 ▪ Paris ▪ France
Prevalence of negative symptomsDependent on the threshold criteria
Bobes, Arango, et al (outpatients) :57.6%
NewMeds (Rabinowitz et al personal
communication 2017):
78% PANSS negative score >18
70% PANSS negative score >20
J Clin Psychiatry. 2011Schizophr. Res. 2017
Negative symptoms are not specific to schizophrenia
Idiopathic Parkinson
Major depression
Dementia(s) particularly frontal dementia
Mild to moderate mental retardation
Post brain trauma syndrome
Viral encephalitis (Mono)
Epilepsy
Post CVA
Autism spectrum
Schizotypal PD
Schizoid PD
Drug abuse
General population?
ISCTM ~ ECNP Joint Conference ▪ 1 September 2017 ▪ Paris ▪ France
PLOS ONE, 2015
ISCTM ~ ECNP Joint Conference ▪ 1 September 2017 ▪ Paris ▪ France
ISCTM ~ ECNP Joint Conference ▪ 1 September 2017 ▪ Paris ▪ France
The Lancet, 1994
When do negative symptoms appear?
ISCTM ~ ECNP Joint Conference ▪ 1 September 2017 ▪ Paris ▪ France
When do negative symptoms appear?
ISCTM ~ ECNP Joint Conference ▪ 1 September 2017 ▪ Paris ▪ France
ISCTM ~ ECNP Joint Conference ▪ 1 September 2017 ▪ Paris ▪ France
Am J Psychiatry. 1999
ISCTM ~ ECNP Joint Conference ▪ 1 September 2017 ▪ Paris ▪ France
Schizophr Bull. 1985
Am J Psychiatry. 1988
ISCTM ~ ECNP Joint Conference ▪ 1 September 2017 ▪ Paris ▪ France
J Psychiatr Res. 2013
ISCTM ~ ECNP Joint Conference ▪ 1 September 2017 ▪ Paris ▪ France
Arch Gen Psychiatry. 2001
Do negative symptoms change over time?
Longitudinal stability NS in 1st episode patients
Psychosis improves but not NS ISCTM ~ ECNP Joint Conference ▪ 1 September 2017 ▪ Paris ▪ France
ISCTM ~ ECNP Joint Conference ▪ 1 September 2017 ▪ Paris ▪ France
Improvement over time!
Parietal cortex
DLPFC
OFC*
ACC
Basal Ganglia
Amygdala** NucleusAccumbens
CaudatePutamen
VentralPallidum
SNrc
DA perikarya:Reward
Motivation
CP
VP
VTA
Pallidum
Thalamus (Glu)VTA (DA)
PFCX
Where in the brain are negative symptoms based? We don’t know
18ISCTM ~ ECNP Joint Conference ▪ 1 September 2017 ▪ Paris ▪ France
ISCTM ~ ECNP Joint Conference ▪ 1 September 2017 ▪ Paris ▪ France
Do antipsychotics induce negative symptoms?Can negative symptoms
improve in patients on them?Yes:• Dopamine is involved in pathways of pleasure in the brain• Antipsychotics block dopamine transmissionNo:• Negative symptoms were present before the usage of
antipsychotics (Kraeplin, Bleuler)• Some, but not other studies discontinuing antipsychotics on
stabilized pts showed no change or worsening of negative symptoms
ISCTM ~ ECNP Joint Conference ▪ 1 September 2017 ▪ Paris ▪ France
Am J Psychiatry. 1999
No change in negative symptoms with and without medication
ISCTM ~ ECNP Joint Conference ▪ 1 September 2017 ▪ Paris ▪ France
Neuropsychopharmacology. 1994
Worsening of negative symptoms with anti-psychotic withdrawal
ISCTM ~ ECNP Joint Conference ▪ 1 September 2017 ▪ Paris ▪ France
Anti-psychotics cause negative symptoms in healthy volunteers
23
Effect size32 mg: 0.4564 mg: 0.58AJP 2917
Improvement of negative symptoms on placebo
Negative
% C
hang
e -40
-30
-20
-10
0
10
D-serinePlacebo
Positive
General
Treatment Week0 4 8 12 16
-40
-30
-20
-10
0
10
*
Total
0 4 8 12 16
J. Clin. Psych 2012
Completed negative symptom studies: almost all add-on
Programs terminated
Atomoxetine (k=1)*
Positive replicated
Negative unreplicated
Positive and negative
Positive unreplicated
AZD-8529 (k=1)
Bitopertin (k=4)
Cariprazine(active control k=1)
Asenapine (k=2)Active control
Cilostazol (k=1)
Citalopram (k=2)*Desmopressin (k=1)*
Escitalopram (k=2)*
Encenicline (k=3)
Folate (k=2) Glycine
D-cycloserine
Chinese medicine (k=1)
Memantine (k=1)*
Minocycline (k=4)
Modafinil (k=1)*
Ondansetron (k=1)*
Olanzapine (active control k=1)
Oxytocin (k=1)*
Paroxetine (k=1)*
Pomaglumetadmethionil
Pregnenolone (k=4)
Quetiapine (active control k=1)
Raloxifene (for post-menopausalwomen) (k=2)
Rasagiline (k=1)*
Reboxetine (k=1)* Sarcosine (k=1)*
Selegiline (k=1)*
Simvastatin (k=1)*
TC-5619
MIN-101 (k=1)
Notes: Studies in bold large rigorous placebo controlled studies. *small studies n<=35 per arm
Negative replicated
Completed negative symptom studies: almost all add-on
J. Rabinowitz 2017, unpublished
Functioning
ISCTM ~ ECNP Joint Conference ▪ 1 September 2017 ▪ Paris ▪ France
Schizophr Res. 2012
ISCTM ~ ECNP Joint Conference ▪ 1 September 2017 ▪ Paris ▪ France
Schizophr Bull.2016
ISCTM ~ ECNP Joint Conference ▪ 1 September 2017 ▪ Paris ▪ France
ISCTM ~ ECNP Joint Conference ▪ 1 September 2017 ▪ Paris ▪ France
SummaryNegative symptoms are
• common
• non-specific
• often present before the onset of psychosis
• Severely effect functioning
• We better find a way to treat them!