Negative symptoms: Prevalence, specificity, course and other - - PowerPoint PPT Presentation

ISCTM ~ ECNP Joint Conference ▪ 1 September 2017 ▪ Paris ▪ France

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

NSA Negative symptoms BNSS Negative symptoms SANS Negative symptoms PANSS Negative symptoms

 Communication  Emotion/affect  Social activity  Motivation  Psychomotor activity  Anhedonia  Lack of distress  Asociality  Avolition  Blunted affect  Alogia  Affective Flattening

• r 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 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

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

• ver time!

Parietal cortex

DLPFC OFC*

ACC Basal Ganglia

Amygdala**

Nucleus Accumbens Caudate Putamen Ventral Pallidum

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

18

ISCTM ~ 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 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

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

• f 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 size 32 mg: 0.45 64 mg: 0.58

AJP 2917

Improvement

• f negative

symptoms on placebo

Negative

% Change

• 40
• 30
• 20
• 10

Positive General Treatment Week

• 40
• 30
• 20
• 10

*

Total

• 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)

Ondansetron (k=1)* Olanzapine (active control k=1) Oxytocin (k=1)* Paroxetine (k=1)* Pomaglumetad methionil Pregnenolone (k=4) Quetiapine (active control k=1) Raloxifene (for post-menopausal women) (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

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!