Schizophrenia Negative Symptoms.pdf.....

Schizophrenia including

1. Col VS Chauhan
Asst Prof Psychiatry

2. Introduction
Conceptualization of negative symptoms
Negative symptoms domains
Theories of causation
Assessment
Therapeutic options and their effectiveness
Achievements
Controversial aspects

3. 32yearold,Sep/HKCH(SC)staff,with13yrsofservice,acaseof
Schizophreniawithonsetofillness-2012andinLMCsince2014,with
erraticcompliancewithmedication,admittedatunitbeheston04Sep18
withhistoryofdemotivationtocontinueinservice.Onevaluation,hewas
notedtohavenegativesymptoms,intheformofavolition,asociality,
anhedoniaandapathy.HewasonInjPaliperidone75mgI/Mmonthly.
HeisbeingmanagedwithClozapine,Amisulpride,Escitalopram&
Psychosocialinterventionintheformofsocialskillstraining,behavioural
activationintheformofpleasantactivityscheduling,destressing/relaxation
techniques,problemsolving&Tokeneconomy.
With2monthsplustreatmenthehasonlyslightimprovementinhisabove
symptoms
3

4. Positive Symptoms
Delusions
Hallucinations
Negative Symptoms
Affective flattening
Alogia
Avolition
Anhedonia
Social withdrawal
Other Symptoms
Depression
Anxiety
Hopelessness
Demoralization
Stigmatization
Suicidality
Disorganization Symptoms
Formal thought disorder
Inappropriate Affect
Bizarre behaviour
Social/Occupational Dysfunction
Work
Interpersonal relationships
Self-care
Cognitive Deficits
Attention
Memory
Executive functions
(e.g., abstraction)

5. 50% -atleastone negative symptoms
Poor functional outcome
Burden-self, families & health care system
Key target-newer treatments
Remains a crucial unmet therapeutic need
-SircasMainarA, Maurino J,Ruiz-BeatoE,Navarro-ArteidaR. Impact of
negative symptoms on health care resource utilisation & associated
costs in adult outpatient with schizophrenia:apopulation based study.
BMC Psychiatry2014;14:225
5

6. Reynolds (1858)
◦Lack of “vital tonus”
Jackson (1889)
◦Loss of normal functions
Other “insufficiency” theories
◦Kraeplin(1893)-emotional dullness & avolition
◦Bleuler(1911)-expressionless & no initiative
◦Dideand Guiraud(1929)-athymhormia
◦Delay & Denikar(1961)-adynamia& indifference
-Kaplan & Sadock, Comprehensive text book of psychiatry, 10
th
edition

7. Crow (1980)
◦Type I and Type II syndromes
Andreasen & Olsen (1982)
◦Positive, Negative & Mixed
Carpenter et al (1988)
◦Deficit and non-deficit
Liddle (1987)
◦Dimensional model (psychomotor poverty,
disorganization, reality distortion)
-Kaplan & Sadock, Comprehensive text book of psychiatry,
10
th
edition

8. ICD-10-
-Marked apathy, paucity of speech & blunting
or incongruity of emotional responses
DSM-5-Criterion A5
-Includes-Affective flattening, Alogia, Avolition
-Anhedonia-associated symptom
8

9. Bluntedaffect
Inability to understand or recognize displays of emotion
from others and an inability to express emotion
Alogia
Reductioninquantityofwordsspokenandinspontaneous
elaboration
Asociality
Reducedsocialinteractionsandinitiativeduetodecreased
motivationforandinterestinformingandmaintaining
relationshipswithothers
-Kirkpatrick B, Fenton WS, Carpenter WT,Jr, Marder SR. NIMH-MATRICS consensus
statement on negative symptoms. SchizophrBull 2006;32:214-19 9

10. Anhedonia
Thelookingforwardtoareward,recreational
orotherpleasurableexperience(“wanting”)
(anticipatoryanhedonia)ismoreimpaired
thantheappreciation(“liking”)ofthe
experienceitself(consummatoryanhedonia)
Avolition
Reducedinitiationandpersistenceofgoal-
directedactivityduetoreducedmotivation
-Kirkpatrick B, Fenton WS, Carpenter WT,Jr, Marder SR. NIMH-MATRICS consensus
statement on negative symptoms. SchizophrBull 2006;32:214-19
10

11. Dimensional Vs Categorical
Categorical–
-Deficit (prim negative sym)
-Non –deficit(Sec Negative sym)
Dimensional
-Negative symptom-symptom domain (RDoC
framework)
-Schizophrenia, Schizoaffective, depression, at-risk
mental states
Kaplan & Sadock, Comprehensive text book of psychiatry, 10
th
edition

12. ➢Diminished Affect
➢Diminished Emotional Range
➢Poverty of speech
➢Curbing of interest
➢Decreased curiosity
➢Diminished sense of purpose
➢Diminished social drive
Understimulating Environment
Affective symptoms
EPS / Sedation
Deficit Symptoms
(Primary)
Secondary Negative
Symptoms
Enduring Negative Symptoms
Primary/Secondary

13. Avolition–apathy
• Curbed interests
• Diminished sense of purpose
• Diminished social drive
Expressive deficit
• Restricted affect
• Diminished emotional range
• Poverty of speech
Strauss GP, Horan WP, Kirkpatrick B, et al. Deconstructing negative symptoms of
schizophrenia: avolition-apathy and diminished expression clusters predict clinical
presentation and functional outcome. J PsychiatrRes 2013; 47: 783–90. 13

14. Motivation-related to goal directed behaviour
-Directional (approach or avoidance)
-Energetic aspects(vigour & persistence)
Stimulus-outcome & action-outcome assocto
be learned(incentive learning)
Motivation value system-DA –positive aspects
Motivation salience-DA activated for positive &
negative aspects
14

15. Motivational value system impairment
Impairment in anticipatory pleasure
Valuation of action & stimuli
Instrumental learning
Motivational salience impairment
Impairment in orienting to salient stimuli
Cognitive activation
General motivation
15

17. Related to neuro-cognitive or social cognition
deficits
Drug naïve patient with deficit schiz-expressive
deficit-assocsoft neurological signs-subtle,
diffuse neurodevelopmental abnormalities
ErgulC, UcokA. Negative symptom subgroups have different
effects on the clinical course of schizophrenia after the first
episode: a 24-month follow up study. Eur Psychiatry 2015; 30:
14–19.
17

18. Brainstem DA Neurons
Prefrontal cortex
Limbic Sites
Prefrontal cortex
Brainstem DA Neurons
Normal state Schizophrenia stateNormal state
Limbic SitesLimbic Sites

19. A lower plasma HVA-higher negative symptom
score
Reduced DA tx(mesocorticalpathway),
noradrenergic & serotonergic tx
Reduced serum BDNF
HypofunctioningNMDA system-Reduced NMDA
transmission(neuroinflammation)
Mitra etal. Negative symptoms in schizophrenia. Ind
Psychiatry J 2016;25:135-44 19

20. ➢Meta-analysis-Esterbergetal, small but significant incin
severity of negative symptoms-positive family history
➢Multifactorial etiology & small genetic changes in
multiple loci
➢rs4633-rs4680 haplotype of COMT gene
➢Sig corrb/w Wnt/B-catenin signaling pathway
genes(GSK3B & disheveled 2) & negative symptoms
➢Mitra etal. Negative symptoms in schizophrenia. Ind Psychiatry J 2016;25:135-44

21. Silvana Galderisi, Armida Mucci, Robert W Buchanan,
Celso Arango.Negative symptoms of schizophrenia:
new developments and unanswered research
questions. Lancet Psychiatry.Aug2018;(5):664-77
21

22. 30 items
30-40 minute semi-structured interview
Rating based on symptoms and functioning of the
previous week
Alogia, Blunted affect, emotional withdrawl,
passive social withdrawl, active social avoidance,
lack of spontaneity, disturbance of volition and
poor rapport
22

23. •Most frequently used scale in neg sx
•30 items—leading to scores in five symptom
complexes—alogia, affective flattening,
avolition-apathy, anhedonia-asocialityand
attentional impairment
•Suggested time frame for assessment—1 month
•No particular interview strategy outlined
23

24. 13 items scale
Emotional expression –four items
Motivation/Pleasure-nine items
Good test-retest stability & interratoragreement
Discriminant validity-independence from
depression, medication side effects & cognition
Ann M Kringetal. CAINS: Final development & Validation. American
Journal of Psychiatry. 2013;170(2):165-72
24

25. 13 item scale
6 subscales
Blunted Affect, Alogia, Asociality, Anhedonia,
Avolition & Distress
Good test-retest stability & inter-ratoragreement
Discriminant validity-independence from
depression, medication side effects & cognition
GP Strauss etal. Factor structure of BNSS. Schizophrenia research.
2012;142(1-3):96-98
25

26. 26

27. 27

28. 28

29. 29

30. 30

31. 31

32. 32

33. 33

34. Silvana Galderisi, Armida Mucci, Robert W Buchanan,
Celso Arango.Negative symptoms of schizophrenia:
new developments and unanswered research
questions. Lancet Psychiatry.Aug2018;(5):664-77
34

35. Apparent apathy, social withdrawal & alogia.
Persecutory delusions & hallucinations -precipitate
frantic attempts to protect safety -social withdrawal
Identification -internal experience of the patients
-“I would like to meet my friends, but I am afraid of
being mocked and the voices tell me not to do so”
-“I have no interest in going out or meeting
friends” 35

36. Can occur
-as a reaction to its burden
-when psychotic symptoms are reduced/ remitted
-in response to stressful life events
In clinical practice
-depressed mood, hopelessness, guilt, and
suicidal ideation-depression
-Blunted affect -negative symptoms.
36

37. The retrospective/prospective assessment of the
course of blunted affect & alogia -changes in
antipsychotic treatment -differential diagnosis
Drug-induced blunting of emotional response and
alogia follows dose increases
-Associated with other signs (EPS)
-Reducing the dose/changing the class of
antipsychotics
37

38. 38

39. Management of Negative Symptoms
Antipsychotics
•Rationalize antipsychotic treatment
•Anticholinergics
Antidepressants, anxiolytics
Psychotherapy
Understanding the reasons &
addressing the same
Environmental enhancement
Primary Negative symptoms
Demoralization
Psychosis
Neuroleptic adverse effects
Dysphoria
Understimulating environement
Causes of Secondary
Negative symptoms

40. *Amisulpride& Ziprasidone-large effect size
**26 week trial-showed a significant reduction in
negative symptoms for cariprazinecompared with
risperidone.
*DA agonist-methylphenidate, amphetamine,
modafinil, selegiline
Aleman A, Lincoln TM, Bruggeman R, et al. Treatment of negative symptoms: where do we stand, and
where do we go? Schizophr Res 2016; 186: 55–62.
Nemeth G, LaszlovszkyI, CzoborP, et al. Cariprazineversus risperidone monotherapy for treatment of
predominant negative symptoms in patients with schizophrenia: a randomised,double-blind, controlled
trial. Lancet 2017; 389: 1103–13.
40

41. A meta-analysis 96 of 23 trials from 22 publications
(n=819 participants) assessing the efficacy -
serotoninergic or noradrenergic drugs, or both(SSRIs,
mirtazapine, reboxetine, mianserin, trazodone &
ritanserin)
Concluded-adjunctive to DA antagonist better than
placebo
Problem-Depression was not exclusion criteria
-Singh SP, Singh V, Kar N, Chan K. Efficacy of antidepressants in
treating the negative symptoms of chronic schizophrenia:
meta-analysis. Br J Psychiatry 2010; 197: 174–79.
41

42. *In a meta-analysis (n=343) of 18 randomisedplacebo-
controlled studies with glutamatergic drugs-found a mean
reduction of four points on the PANSS–Negative symptoms
subscale.
**A more recent meta-analysis reported that D-serine, N-
acetyl-cysteine (NAC), and sarcosine (also known as N-
methylglycine), as add-on therapy to dopamine antagonists
other than clozapine,improve negative symptoms.
-*TuominenHJ,TiihonenJ,WahlbeckK.Glutamatergicdrugsforschizophrenia:a
systematicreviewandmeta-analysis.SchizophrRes2005;72:225–34.
-**SinghSP,SinghV.Meta-analysisoftheefficacyofadjunctiveNMDAreceptor
modulatorsinchronicschizophrenia.CNSDrugs2011;25:859–85.
42

43. Monoamine oxidase B inhibitors: selegiline and rasagiline
α7 nicotinic receptor (partial) agonists: bradaniclineor
encenicline, and α7 nicotinic receptor positive allosteric
modulators
Intranasal oxytocin
Minocycline-potential neuroprotective properties against
glutamate neurotoxicity
Oestrogensand selective oestrogenreceptor modulators
Serotonin 5-HT3 receptor antagonists: ondansetron,
granisetron, and tropisetron,alsoan α7 nicotinic receptor
agonist
43

44. Rehabilitation interventions are aimed at:
-Building social, vocational, cognitive and other skills
-Providing a supportive environment
to minimize the impact of deficit symptoms on the
patient’s adaptational capacity

45. Skills training
◦Assessment of the patient’s social adaptation prior to
onset of illness
◦Evaluation of current competence and skills
◦Expectations of social and family life and employment
◦Identify target deficits
◦Initiate attempts to train or retrain the patient to
correct the deficits

46. Frontal lobe training
◦Problem-solving strategies to encourage step-wise
solutions to complex tasks
◦Exercises to improve verbal fluency
◦Exercises to improve intellectual flexibility and ability
to change sets
◦Development of communication skills using a
behaviouralparadigm

47. Cognitive BehaviouralTherapy
Cognitive techniques
◦Psychoeducation
◦Learning coping statements
◦Emotive techniques such as role play, humor and
encouragement
◦Techniques fostering social cognition
◦Cognitive remediation
Behaviouraltechniques
◦Skills training
◦Behaviouralmodification using differential reinforcement

48. Group therapy
◦Specific life skills such as money management, IPR and
job skills—efficacious in the context of a multi-task group
therapy
◦SST in a group setting—modelling
◦Ensuring long-term social supports
◦Peer support groups and family networks
Family psychoeducation

49. *Social skills trgbetter than other interventions
**Cognitive therapy based on a goal-directed framework
and personalisedtreatment planning -significant
improvements compared with standard treatment in
avolition–apathy (d=0·66)
To undercut nihilistic beliefs-concomitantly increase
motivation for constructive activity.
Combine several different interventions (eg,environmental
support, CBT, and SST).
-*TurnerDT,vanderGaagM,KaryotakiE,CuijpersP.Psychologicalinterventionsforpsychosis:
ameta-analysisofcomparativeoutcomestudies.AmJPsychiatry2014;171:523–38.
-**GrantPM,HuhGA,PerivoliotisD,StolarNM,BeckAT.Randomizedtrialtoevaluatetheefficacyof
cognitivetherapyforlow-functioningpatientswithschizophrenia.ArchGenPsychiatry2012;69:121–27.
49

50. 50

51. Long-term trajectories of positive and negative symptoms in first
episode psychosis: A 10 year follow-up study in the OPUS cohort.
-Austin SF etal
-SchizophrRes.2015 Oct;168(1-2):84-91
-Response -28%, delayed response -19%, relapse -26% and
non-response -27%
-Disorganized symptoms (OR 2.01-2.38, p<0.05) and
schizophrenia diagnosis (OR 5.70-8.86, p<0.05) -associated
with poorer negative symptom trajectories(higher levels of
negative symptoms)
-
51

52. Silvana Galderisi, Armida Mucci, Robert W Buchanan, Celso
Arango.Negative symptoms of schizophrenia: new developments and
unanswered research questions. Lancet Psychiatry.Aug2018;(5):664-77
52

53. Factor analyses-confirms two domains
Established assessment instruments-addresses
distinction b/w primary & sec negative symptoms
A dimensional & a categorical approach are
reasonable approaches
Available antipsychotics are not effective for
primary & enduring negative symptoms
53

54. Advances in the conceptualisationand assessment of
negative symptoms have not yet been taken into account
by drug regulatory authorities
Current major classification systems that require the presence
of at least one psychotic symptom but not of a negative
symptom for the diagnosis of schizophrenia.
Schizophrenia with the presence of primary and enduring
negative symptoms and schizophrenia without primary and
enduring negative symptoms may differ in etiopathogenesis,
outcome, and response to treatment
54

55. Negativesymptomsarepresentindiseasesotherthan
schizophrenia;whethertheconstructs,theircorrelates,
andneurobiologicalunderpinningsarehomogeneous
acrossdiagnosesremainstobeclarified.
Systematicinvestigationrequiringtheinclusionoflarge
samplesofparticipantswithabroadrangeofnegative
symptomseverity,withandwithoutcomorbid
conditions(eg,depression),isstillnotadequately
pursued. 55

56. Kaplan & Sadock, Comprehensive text book of psychiatry, 10
th
edition
Silvana Galderisi, Armida Mucci, Robert W Buchanan, Celso
Arango.Negative symptoms of schizophrenia: new developments
and unanswered research questions. Lancet Psychiatry. Aug 2018
;(5) :664-77
Strauss GP, Horan WP, Kirkpatrick B, et al. Deconstructing negative
symptoms of schizophrenia: avolition-apathy and diminished
expression clusters predict clinical presentation and functional
outcome. J PsychiatrRes 2013; 47: 783–90.
Mitra etal. Negative symptoms in schizophrenia. Ind Psychiatry J
2016;25:135-44 56