a view into the most debilitating disease in psychiatry.

1. WHAT WE LEARNED
ABOUT THE
PHARMACOLOGICAL
TREATMENT OF
SCHIZOPHRENIA
DR.K.NAGI REDDY,MD PSYCHIATRY[AIIMS]
PRESIDENT IPS AP CHAPTER
ASHA KIRAN HOSPITAL,NR PETA
KURNOOL

2. TO KNOW
SCHIZOPHRENIA IS TO
KNOW PSYCHIATRY
• The most devastating
illness that psychiatrist
treat.
• One of the most
challenging diseases in
medicine
• 1% of population has
schizophrenia
• A major health concern for
society

3. WHAT IS SCHIZOPHRENIA?
Psychotic mental illness of unkown
aetiology characterized by disturbance
in
• Thinking[distortion of
reality,delusions,hallucinations]
• Mood[ambivalence and
inappropriate affect]
• Behaviour[apathetic,withdrawn,
bizarre activities]

4. WHAT ARE THE
MAJOR CHALLENGES
IN DIAGNOSIS?
• What is not perfect
• Subjective
• Heterogenesity
• No proven diagnostic
tests

5. NEW WAYS OF
LOOKING AT
SCHIZOPHRENIA
• stages
• Dimensions
• Neuroradiology
findings
• biomarkers

6. DSM-5 NO LONGER
RECOGNIZES THESE
SUBTYPES

7. STAGES OF SCHIZOPHRENIA
• stage 0-premorbid
• Stage 1-early prodrome
• Stage 1b-late prodrome
• Stage 2-psychosis with recovery
• Stage 3-psychosis with inter episodic deficits
• Stage 4-intractable psychosis and/or
deterioration

8. DIMENSIONS OF
SCHIZOPHRENIA
• Positive symptoms
• Negative symptoms
• Cognitive symptoms
• Mood symptoms
• Motor symptoms

9. EPIDEMIOLOGY
• Life time prevalence 1 to 1.5 percent
• Sex ratio: 60 percent of cases are male
• More prevalent in lower socio
economic groups.
• Common between 15 and 35 years
• Rare before 10 and after 40

10. AETIOLOGY
• Uncertain;however there is evidence for
several risk factors
• Biological
• Social
• psycological

11. BIOLOGICAL
• Genetic consideration: 1st degree and 2nd degree relatives
• Environmental:
1. Abnormalities of pregnancy and delivery
2. Maternal influenza
3. Fetal malnutrition
4. Low social class births

12. GENETICS
• Monozygotic twins-48%
• Dizygotic twins-17%
• First degree relatives-siblings with one
schizophrenia parent-10%
• Second degree relatives-grand children-
5%
• 3rd degree relatives-first cousins-2%
• General population-1%

13. SOCIAL
• Lower socioeconomic groups
• Urbanised areas
• Migrant population
• Cannabis users

15. PSYCOLOGICAL
• Abnormalities in processing sensory
information
• Problems in separating “signal from
background noise”
• Excessive life trauma

16. PATHOPHYSIOLOGY
• Abnormalities in neurotransmitters
• Disorders of dopamine function
• Elevated serotonin
• Elevated norepinephrine
• Elevated glutamate
• Decreased GABA

17. NEURO
RADIOLOGICAL
FINDINGS
• SPECT,PET,fMRI studies
• Reduction in gray matter
mainly in temporal lobe
• Reduced correlation between
frontal and temporal lobe
• Frontal temporal and parietal
connectivity may be the final
common pathway

18. SCHIZOPHRENIA-HUGE
TREATMENT GAP
• One of the top ten disabling health
conditions
• Poor awareness of the disorder
• Stigma
• Low count of psychiatrists
• Huge treatment gap-75 percent of
patients remain untreated
• Early detection and treatment gives
better prognosis
• Vast majority meet their family
physicians

19. HISTORICAL BACKGROUND
• Not a modern disorder
• ‘Unmada’-atharveda-1500 bc
• ‘Insane’-philosophers aretus,soranus -100 bc

20. COMORBIDITY
• Depression
• Substance abuse
• Increased mortality with
cardiovascular disorders

21. OUTCOME
• 45%recover after 1 or
more episodes
• 35% mixed
response(remission and
exacerbation)
• 10% unremitting course
• 10%suicide

22. PAST WITNESSED CRUDE AND
BIZARRE TREATMENTS
• Trephining of skull- “dispelling the poisoning
gases”
• Surgical removal of various body parts- “remove
the poison”
• Induction of coma

23. DARK AGES
FOR
PSYCHIATRY

24. EARLY INTERVENTION
AND PREVENTION
Can we prevent
devastation
• By diagnosing early
• By interfering early
• First psychotic episode

25. IDENTIFICATION OF HIGH RISK
Screening of high risk group
• Can we do it accurately
• Can we offer some treatment

26. OPTIMISING INDIVIDUAL TREATMENT OUTCOMES
• Medication-reduce symptoms,prevent relapse
• Rehabilitation-social skill training
• Support-employment
• Reduce the burden of disease-adding as little burden of
treatment as possible
• Goal is to live productive and meaningful life

27. COST OF
MODERN
MEDICINE IS A
MAJOR WORRY

28. THE TREATMENT
CHALLENGES
• Treatments are only partially effective
• Fairly effective for psychotic
symptoms
• Not very effective for negative and
cognitive symptoms
• Significant adverse effects-
neurological and metabolic
• Increasing mortality gap:15-20 years!!

29. PHARMACOLOGICAL
TREATMENT
• Antipsychotics are main stay
• Role of antidepressants
• Role of mood stabilizers
• Role of anxiolytics

30. IMPORTANCE OF
RELAPSE
PREVENTION
Each relapse is associated
with
• Increased distress and
dysfunction
• Vocational and social
disruption
• Increased risk of violence
and suicide
• Increased cost of care

31. WITH EACH
RELAPSE
• Subsequent recovery is
less complete
• Remission takes longer to
achieve
• Illness becomes more
resistant to treatment

32. HOW DO DIFFERENT
ANTIPSYCHOTICS
COMPARE

33. HOW MANY ANTIPSYCHOTIC
AGENTS ARE AVAILABLE IN
THE WORLD?
• 25??
• 35??
• 45???
• 55????
• 65????
• 75?????

34. CONVENTIONAL
ANTIPSYCHOTICS
• Typical
antipsychotics,first
generation antipsychotics
• 1952-chlorpromazine
• 1960-
haloperidol,trifluperizine,
fluphenazine

35. ATYPICAL
ANTIPSYCHOTICS
• Second generation
antipsychotics
• 1980-clozapine
• 1990-
respiridone,olanzapine,qu
itipin,ziprasidone
• 2000-
arpiprazole,palliperidone,
illoperidone,asenepine,lu
rasidone

36. BENEFITS WITH
SGAS
• Fewer EPS
• Better in negative
symptoms
• Better for cognition
• Better for depression

38. ARE ATYPICAL ANTIPSYCHOTICS
REALLY BETTER?
• CATIE-clinical antipsychotic trials of interaction
effectiveness
• EUEST-European first episode schizophrenia trial
• Efficacy differences???
• Side effect differences;EPS,metabolic

39. ARE ALL ATYPICALS THE
SAME?
• Considerations:
• Patient preference
• Prior treatment response
• Response in 1st degree relative
• Medical history and risk factors
• Adherence history

40. HOW TO SELECT
ANTIPSYCHOTICS
• All antipsychotics are effective against
psychotic symptoms
• Each medication has effective side
effects
• Each medication has unique
pharmacokinetics
• Individual patients may respond
preferentially to different medications
• First episode psychosis,the SGAs are
generally preferred

41. ANTIPSYCHOTICS IN TREATMENT
OF SCHIZOPHRENIA FACTS AND
FICTION
Clozapine likely more effective than
other agents in neuroleptic refractory
schizophrenia
None of the other 64 antipsychotic
agents shown to be clozapine like in this
regard
EPS avoidance is critical
Minimizing metabolic side effects

42. FGA AND SGA DICHOTOMY
IS NOT VERY MEANINGFUL
• Risk of EPS and metabolic side effects
are there in both classes
• No consistent difference in efficacy
across agents
• So better to chose an antipsychotic
with fewer EPS
• Effective for tackling negative
symptoms ,cognition ,depression and
TD

43. OTHER CLASSES OF
MEDICATION USEFUL IN
SCHIZOPHRENIA
• Antidepressants
• Benzodizapines
• anticonvulsants

44. LOOKING AT THE FUTURE TRENDS IN
PHARMACOTHERAPY OF SCHIZOPHRENIA
• New molecular targets
• Rational polypharmacy
• Phase-specific treatments
• Better individualising treatments

45. STEPS IN ANTIPSYCHOTIC THERAPY
SEQUENCY,DOSING,DURATION
• Start with a systematic 6 to 10 week trail with
optimal dosing
• Preferably monotherapy
• If needed follow with a trail of clozapine or
long acting agent
• Then only we can consider antipsychotic
polypharmacy.

46. WHERE DOSE LUROSIDONE
STAND IN MANAGEMENT OF
SCHIZOPHRENIA
• Atypical antipsychotic-
benzisothiazol
derivative
• Approved by FDA in
2011
• Efficient in acute
episode and
maintenance phase

47. LUROSIDONE-MECHANISM
OF ACTION
• High affinity for dopamine D2 and
serotonin 5HT 2A receptors
• Potential antagonist 5HT7,5HT1A and
alpha-2 adrenergic receptors
• Minimal binding at alpha-1
adrenergic ,histamine H1,muscarinic
M1 receptors.

48. PHARMACOKINETICS
OF LUROSIDONE
• Absorption of the drug
occurs over 1 to 3 hrs
• Serum halflife is 18 to 36 hr
Bioavailability increases 2-3
fold
• Not dependent on fat
content of foods

49. LUROSIDONE
• Major route of metabolism via CYP3A4
• Should not be use concomitant with CYP3A4
inhibitors-
ketoconazole,larithromycin,ritonavir
• Should be reduced to half dose while using
moderate CYP3A4
inhibitors[diltiazem,verapamil]
• Should not be used concomitantly with strong
CYP3A4
inducers[rifampin,phenytoin,carbamazepine]
• Grape fruit juice should be avoided

50. LUROSIDINE DOSAGE
• Available as 40 and 80 mg tablets
• OD dose
• The suggested initial dose is 40 mg
daily
• Dose reduction is needed in moderate
to severe renal or hepatic failure.

51. LUROSIDONE
Common side effects
• Somolence
• Akathesia
• Nausea
Less common side effects
• Acute dystonia
• Agitation
• Anxiety
• dizziness

52. ADVANTAGES OF
LUROSIDONE
• Weight gain was mild
• Fasting glucose is elevated
slightly
• Prolactin elevation is
minimal
• QT interval change is
insignificant
• Pregnancy risk category B

53. PROBLEMS WITH LUROSIDONE
• Not tested in children and adoloscents
• Injectable, sublingual and oral preparations are not available
• Cost of the treatment

54. BEAUTIFUL
MIND

56. THANK YOU