Negative symptoms: Prevalence, specificity, course and other characteristics Mark Weiser MD Professor of Psychiatry, Tel Aviv University Chief Psychiatrist, Sheba Medical Center Associate Director for Treatment Trials, the Stanley Medical Research Institute Institute ISCTM ~ ECNP Joint Conference ▪ 1 September 2017 ▪ Paris ▪ France
PANSS SANS BNSS NSA Negative Negative Negative Negative symptoms symptoms symptoms symptoms Anhedonia Communication Affective Flattening Blunted affect or Blunting Lack of distress Emotion/affect Emotional withdrawal Alogia Poor rapport Asociality Social activity Avolition – Apathy Avolition Motivation Passive/apathetic Anhedonia – social withdrawal Psychomotor activity Asociality Blunted affect Difficulty in abstract Attention Alogia 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
Prevalence of negative symptoms Dependent 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. 2011 Schizophr. Res. 2017 ISCTM ~ ECNP Joint Conference ▪ 1 September 2017 ▪ Paris ▪ France
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?
PLOS ONE, 2015 ISCTM ~ ECNP Joint Conference ▪ 1 September 2017 ▪ Paris ▪ France
ISCTM ~ ECNP Joint Conference ▪ 1 September 2017 ▪ Paris ▪ France
When do negative symptoms appear? The Lancet, 1994 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 ISCTM ~ ECNP Joint Conference ▪ 1 September 2017 ▪ Paris ▪ France
Am J Psychiatry. 1988
J Psychiatr Res. 2013 ISCTM ~ ECNP Joint Conference ▪ 1 September 2017 ▪ Paris ▪ France
Do negative symptoms change over time? Arch Gen Psychiatry. 2001 ISCTM ~ ECNP Joint Conference ▪ 1 September 2017 ▪ Paris ▪ France
Longitudinal stability NS in 1 st episode patients Psychosis improves but not NS ISCTM ~ ECNP Joint Conference ▪ 1 September 2017 ▪ Paris ▪ France
Improvement over time! ISCTM ~ ECNP Joint Conference ▪ 1 September 2017 ▪ Paris ▪ France
Where in the brain are negative symptoms based? We don’t know Parietal cortex Basal Ganglia ACC Caudate DLPFC Pallidum Putamen CP Ventral VP Pallidum VTA (DA) Thalamus (Glu) OFC* PFCX SNrc VTA Amygdala** DA perikarya: Nucleus Accumbens Reward Motivation ISCTM ~ ECNP Joint Conference ▪ 1 September 2017 ▪ Paris ▪ France 18
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 transmission No: • 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
No change in negative symptoms with and without medication Am J Psychiatry. 1999 ISCTM ~ ECNP Joint Conference ▪ 1 September 2017 ▪ Paris ▪ France
Worsening of negative symptoms with anti- psychotic withdrawal Neuropsychopharmacology. 1994 ISCTM ~ ECNP Joint Conference ▪ 1 September 2017 ▪ Paris ▪ France
Anti- psychotics cause negative symptoms in healthy volunteers ISCTM ~ ECNP Joint Conference ▪ 1 September 2017 ▪ Paris ▪ France
Improvement of negative symptoms on placebo Effect size 32 mg: 0.45 64 mg: 0.58 AJP 2917 23
Completed negative symptom studies: almost all add-on Negative Positive 10 0 -10 * -20 D-serine -30 Placebo % Change -40 Total General 10 0 -10 J. Clin. Psych 2012 -20 -30 -40 0 4 8 12 16 0 4 8 12 16 Treatment Week
Completed negative symptom studies: almost all add-on Negative replicated Positive replicated Positive and negative Programs terminated Pregnenolone (k=4) Encenicline (k=3) D-cycloserine Bitopertin (k=4) Pomaglumetad methionil TC-5619 MIN-101 (k=1) Atomoxetine (k=1)* Asenapine (k=2) Active control AZD-8529 (k=1) Cariprazine Quetiapine (active control k=1) (active control k=1) Escitalopram (k=2)* Cilostazol (k=1) Rasagiline (k=1)* Olanzapine Raloxifene (active control k=1) (for post-menopausal Citalopram (k=2)* Desmopressin (k=1)* women) (k=2) Chinese medicine (k=1) Selegiline (k=1)* Paroxetine (k=1)* Ondansetron (k=1)* Folate (k=2) Glycine Modafinil (k=1)* Simvastatin (k=1)* Memantine (k=1)* Oxytocin (k=1)* Minocycline (k=4) Reboxetine (k=1)* Sarcosine (k=1)* Positive unreplicated Negative unreplicated Notes: Studies in bold large rigorous placebo controlled studies. *small studies n<=35 per arm J. Rabinowitz 2017, unpublished
Functioning 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
Summary Negative symptoms are • common • non-specific • often present before the onset of psychosis • Severely effect functioning • We better find a way to treat them! ISCTM ~ ECNP Joint Conference ▪ 1 September 2017 ▪ Paris ▪ France
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