negative symptoms - isctm · 2017. 10. 26. · isctm~ecnpjoint conference 1 september 2017 paris...

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!