1. Schizophrenia is a chronic neuropsychiatric disorder affecting about 1% of the world's population that imposes a large economic burden. 2. While the exact causes remain unclear, current research suggests schizophrenia involves alterations in brain development and circuits during early development. Genetics also play a role as risk factors. 3. Recent advances in treatment include new atypical antipsychotic medications that target both dopamine and serotonin receptors, as well as research into alternative treatments targeting negative symptoms, cognitive impairments, and underlying neuropathology and metabolic abnormalities.

1. RECENT ADVANCES IN
MANAGEMENT OF SCHIZOPHRENIA
Presenter : Dr. Shravan Kumar
Moderator : Prof. R. K. Gaur

2. INTRODUCTION
• Schizophrenia is common, chronic and frequently devastating
neuropsychiatric disorder, affecting about 1% of the world’s
general population.
• It imposes a disproportionately large economic burden in
terms of hospitalization, chronic treatment and rehabilitation,
and lost productivity.
• It is among the ten leading causes of disability worldwide.

3. • The onset of schizophrenia ranges from mid to late
adolescence through; it occurs more often in males and affects
them more severely than it does females.
• Although minor physical anomalies and subtle motor, social or
cognitive impairments are often observed during the
premorbid stage of the illness, these differences generally fail
to place individuals outside the normal range of functioning.

4. • After the onset of the full syndrome substantial functional
deterioration ( e.g. work, interpersonal relationships, or self
care) typically occurs, especially during the first five to ten
years, and then clinical deterioration reaches a plateau.
• Schizophrenia is further defined by characteristic but
nonspecific disturbances in the form and content of thought,
perception, cognition, and emotion, sense of self, volition,
social relationship, and psychomotor behavior

5. Francisco Goya – The Madhouse 1812

6. • Current treatment modalities have certain limitations: about
30% of patients with schizophrenia are refractory.
• Negative symptoms like alogia, avolition, anhedonia,
attentional impairment and executive dysfunction can be
worsened by medication and coexisting depression.
• There are no effective remedies for primary negative
symptoms.

7. • Cognitive impairments, primarily in the areas of attention,
information processing, problem solving, processing speed,
verbal/visual learning and working memory show poor
response to the treatment with either first generation or second
generation antipsychotic.
• A majority of the patients have relapsing and remitting course
even while on medication.

8. • The development of effective treatments for these
psychopathological domains is of critical clinical importance
since they account for much of the long term morbidity and
poor functional outcome in schizophrenia.
• The relative lack of efficacy for these domains has led to the
search for alternative pathophysiological hypothesis and
treatment of negative symptoms and cognitive impairments.

9. • A century ago we had large public institutions for severe
mental illness, tuberculosis and leprosy.
• Of these three, today only mental illness, especially
schizophrenia, remains unchanged in prevalence and
disability .
• Sustained recovery is less than 14% within the first 5 years
following a psychotic episode.
Thomas Insel; Rethinking Schizophrenia; Nature vol 468, November 201;
doi:10.1038/nature09552

10. OTHER CONDITIONS RESEMBLING
ACUTE SCHIZOPHRENIA
• Tumors: temporal lobe (auditory), occipital lobe (visual),
limbic and hypothalamus (delusions)
• Seizures: temporal lobe, grand-mal (post-ictal psychosis)
• Parkinson’s disease
• Huntington’s disease
• Multiple Sclerosis
• Amyotrophic lateral sclerosis
• Neurosyphilis
• Meningitis/encephalitis
• HIV
• Hypo/hyperthyroidism

11. • Hypo/hyper parathyroidism
• Adrenal disorders (Addison’s or Cushing’s disease)
• Systemic Lupus erythematosus
• Sodium/potassium inbalance
• Hepathic encephalopathy
• Uremic encephalopaty
• Acute intermittent porphyria
• Vitamin B12 or folate deficiency
• Heavy metal poisoniong
• Wilson’s disease
• Dialysis

12. SUBSTANCES LEADING TO
SCHIZOPHRENIA LIKE CONDITION
• Amphetamines, hallucinogens or cannabis
• Corticosteroid treatment
• Alcohol intake
• Dopaminergic drugs (L-dopa, Amantadine)
• Interferon
• Anticholinergics
• Cardiovascular drugs

13. • Anesthetics
• Antimalarial drugs
• Antituberculous drugs: d-cycloserine, ethambutol, isoniasid
• Antibiotics: cprofloxacin
• Antivirals: HIV medications (efavirenz, acyclovir)
• Antineoplasic drugs
• Sympatomimetics
• Pain medications (meperidine, pentazocine, indomethacin)

14. BASIC APPROACHES IN
CURRENT TREATMENT OF
SCHIZOPHRENIA

15. • Neurochemical transmission in the dopaminergic system,
especially via D2 receptors, and related changes in
postsynaptic signal transduction are very important in both the
development of schizophrenia and its current
pharmacotherapeutic treatment with antipsychotic drugs.
• Along with D3 and D4 receptors, dopamine D2 receptors and
their synaptic localization remain importance in schizophrenia
pharmacotherapy.

17. • Serotonergic 5-HT2A and 5-HT2C receptor blockage is the
mechanism of action of new-generation antipsychotics
mechanism of action.
• There is a functional interaction between the serotonergic and
dopaminergic systems and blockage of 5-HT2A receptors can
reinforce dopaminergic activity.
• In contrast to classic antipsychotic drugs, many recently
developed atypical antipsychotics bind to 5-HT2A receptors
more than to dopamine D2 receptors and bind with higher
affinity than classical antipsychotics.

18. D2 ANTAGONIST ACTIONS:
CONVENTIONAL/ATYPICALANTIPSYCHOTIC
D2

19. -D2 antagonist action
-5HT2A antagonist action
atypical antipsychotic
5HT2A
D2

21. • Neurodevelopmental dysfunctions in the GABAergic and
glutamatergic systems are also related to the development of
schizophrenia.
• Contemporary research into the etiopathogenesis of
schizophrenia focuses on the expanding role of neurogenesis
and neurotrophic factors, primarily in the dopaminergic
system, but also in the serotonergic, GABAergic, and
glutamatergic systems.

22. ADVANCEMENTS IN
NEUROPATHOGENESIS
AND GENETICS OF
SCHIZOPHRENIA

23. • Schizophrenia is a collection of neurodevelopmental disorders
that involve alterations in brain circuits during early
development.
• Psychosis is a late occurrence in schizophrenia.
• Preventive approaches seen as the main intervention.
Thomas Insel; Rethinking Schizophrenia; Nature vol 468, November 201; doi:10.1038/nature09552

24. • Birth cohort studies demonstrate that individuals who develop
schizophrenia differ from the general population on a range of
developmental indices some of which occur as early as the
first year of life.
Joy Welham,2 Matti Isohanni,3 Peter Jones,4 and John McGrath; The Antecedents of
Schizophrenia: A Review of Birth Cohort Studies; Schizophr Bull. 2009 May; 35(3):
603–623, . doi: 10.1093/schbul/sbn084

25. Stages of Schizophrenia as a
Neurodevelopmental Disorder

26. SCHIZOPHRENIAAND BRAIN TISSUE LOSS
MRI IMAGE OF AN AVERAGED PROFILE OF BRAIN TISSUE LOSS
FROM A GROUP OF PATIENTS WITH EARLY- ONSET
SCHIZOPHRENIA (5 YEARS INTERVAL)

27. MECHANISM OF BRAIN TISSUE LOSS
• Schizophrenia is a disease of progressive reductions in grey
matter, and the more lost, the worse the outcome.
• Schizophrenia is not a disease that kills massive amounts of
cells, the way Alzheimer’s disease does.
• In schizophrenia primarily there is a loss of cell processes,
because of low levels of neurotrophins e.g. NT-3, NGF,
GDNF, BDNF

28. CORTICAL PYRAMIDAL NEURONS

30. REALISTIC PERSPECTIVE ON GENES IN
SCHIZOPHRENIA
• There is no gene for schizophrenia, bipolar disorder,
depression or anxiety and there will never be one.
• Genes do not code for psychiatric illnesses or for behaviors or
for symptoms of psychiatric illnesses.
• Genes operate at a very basic cellular level. They code for
proteins that may lead to subtle molecular abnormalities in
cells.

32. • Genes are Risk Factors for Mental Illness
• Genes do not respect the boundaries of psychiatric disorders or
even the boundaries of medical disciplines.
• For instance most risk genes for schizophrenia are present also
in bipolar disorder, schizoaffective disorder, ASD,
Alzheimer’s disease and anxiety.
• There are vulnerability genes as well as resilience genes.
• The chance that two patients with schizophrenia will have
exactly the same combination of mutations is small.

33. • Deletion of 22q11.2 is one of the highest risk factors for
schizophrenia and it also leads to Velo-Cardio-Facial
Syndrome (VCFS).
• VCFS leads to schizophrenia in 33% cases.

34. • Spontaneous genetic mutations or “de novo” mutations play a
significant role in schizophrenia.
• The function of the mutated gene and when the gene is
expressed are critically important in determining the risk for
schizophrenia.

35. RESEARCH DOMAIN CRITERIA (RDOC)
• RDoC is an experimental approach to the classification of
mental disorders that incorporates multiple dimensions:
behavior, thought patterns, neurobiological measures, and
genetics.
• The aim of the project is to develop a more accurate diagnostic
system.

36. SCHIZOPHRENIAAND METABOLISM
• Normally the brain uses glucose as its main energy source,
with ketone bodies as an alternative.
• In schizophrenia brain energy supply is scarce due to
mitochondrial dysfunction.
• The brain shifts its energy supply towards ketone bodies, and
fatty acid metabolism.
• Liver metabolism is shifted towards producing the necessary
ketone bodies.

38. METABOLIC BIOMARKERS IN
SCHIZOPHRENIA
• The following set of metabolic biomarkers have identical
sensitivity and specificity as the MSE:
 Glycerate
 Eicosenoic acid
 Beta-hydroxybutirate
 Pyruvate
 Cysteine
 Urine beta hydroxybutirate
Potential Metabolite Markers of Schizophrenia; J. Yang et al.; Molecular Psychiatry(213) 18, 67-78;
doi:10.1038/mp.131

39. RECENT
IMPROVEMENTS IN
THE TREATMENT OF
SCHIZOPHRENIA

40. FDA APPROVED ANTIPSYCHOTICS THIS
DECADE
• Aripiprazol (2002)
• Fazaclo (Sept, 14, 2005)
• Paliperidone (December 19, 2006)
• Illoperidone (May 7, 2009)
• Asenapine (August 15, 2009)
• Lurasidone (October 29, 2010)

41. NEW DRUGS IN THE PIPELINE
• Aspirin
• Minocycline
• Raloxifene
• Estrogen
• N-acetylcysteine

42. ILOPERIDONE
• Indicated for acute schizophrenia in adults.
• Dosing:
• Day 1--1mg bd
• Day2 –2mg bd
• Day3—4mg bd
• Day4—6mg bd
• Day5—8mg bd
• Day6—10mg bd
• Day7—12mg bd

43. Tolerability
• Moderate effects on body weight
-Iloperidone-induced changes in weight are independent from significant
changes in glucose or lipid levels
• Low rate of akathisia
• Slow titration and careful monitoring of orthostatic hypotension
are required
-Especially in the elderly or when used in combination with other
medications that may induce orthostasis (e.g., diuretics, TCA)
• Significant risk of QTc prolongation
Tarazi F, Stahl SM Expert Opinion Pharmacotherap 2012 Epub ahead of print

44. ASENAPINE
• Indicated for acute schizophrenia.
Sublingual Formulation
-bioavailability when swallowed is very low
-avoid eating or drinking for 10 min after administration
Typical dose
-Schizophrenia 5 mg BID
-Bipolar mania 10 mg BID
May be useful as a rapid-acting PRN antipsychotic
No dose adjustment necessary in patients with moderate
hepatic or renal impairment
Tarazi F, Stahl SM Expert Opinion Pharmacotherap 2012 Epub ahead of print

45. Tolerability:
Limited effects on weight
-small, non-significant effects on fasting glucose levels have been
observed
-no clinically significant effects on total cholesterol or fasting
triglycerides have been observed
Slightly elevated risk of akathisia and EPS
Oral hypoesthesia and somnolence are not uncommon
May induce orthostatic hypotension and syncope
Marginal effects on QTc interval
Benign effects on prolactin.
Tarazi F, Stahl SM Expert Opinion Pharmacotherap 2012 Epub ahead of print

46. LURASIDONE
• Recommended starting dose 40 mg/day
• Maximum recommendined dose was originally 80 mg/day,
now 160.
-In May 2012 FDA approved an extended dose range of 40-160 mg/day for
schizophrenia
-120 mg tablet currently in development
• No titration required
• Should be taken with food (at least 350 calories)
• Should not exceed 40 mg/day in patients with moderate to
severe renal or hepatic impairment.

47. Tolerability:
• Benign metabolic profile
-minimal changes in body weight
-no significant changes in total cholesterol, triglycerides, LDLs, HDLs or
fasting glucose
• Risk of akathisia at higher doses
• No QTc prolongation
• Small increase in prolactine
• Administering Lurasidone at night may reduce side-effects

48. CARIPRAZINE
• D2 partial agonist
o more of an antagonist than Aripiprazole
o In late stage clinical testing for schizophrenia, acute bipolar mania, bipolar
depression and treatment resistant depression
o higher doses for schizophrenia and mania (antagonist actions)
o lower doses for depression (agonist action)
• Stronger affinity for D3 than D2 receptors
• Few metabolic side effects and low risk for EPS
• Long lasting metabolite.
Stahl SM Stahl’s Essential Psychopharmacology; The Prescriber’s Guide 4th ed 2011

49. BREXPIPRAZOLE
• D2 partial agonist
-more of an antagonist than Aripiprazole
• Very low risk for EPS and rare akathisia so far despite strong
affinity for D2 receptors
-possibly due to potent 5HT2A antagonism, 5HT1A antagonism
and alpha 1 antagonism
• Potential treatment for agitation and psychosis in dementia
Stahl SM Stahl’s Essential Psychopharmacology; The Prescriber’s Guide 4th ed 2011

50. ASPIRIN
• Aspirin is irreversible inhibitor of both COX-1 and COX-2.
• It is more potent in its inhibition of COX-1 than COX-2, and
targeting COX-2 alone may be a less viable therapeutic
approach in neuropsychiatric disorders such as depression.
• COX-2 inhibition decreases the production of PGE-2, which
drives the negative immunoregulatory effects on ongoing
inflammatory responses.
• Lipoxins  A new genus of lipid mediators that actively limit
inflammation and promote resolution.

51. • Aspirin as adjuvant therapy  ↓ symptoms of schizophrenia
spectrum disorders (Laan et al., 2010)
• Largest effect of adjuvant aspirin (Laan et al., 2010)
1. Most altered immune balance
2. Shorter disease durations
• Future studies  Patients with recent onset of disease & more
disturbed immune functions

53. MINOCYCLINE

55. • Addition of minocycline to atypical antipsychotic drugs in
early schizophrenia (Oya et al., 2014)
1. Significant efficacy on negative symptoms (Ghanizadeh et al.,
2014)
2. Slight effect on the attention domains of patients with
schizophrenia (Liu et al., 2014)
• Treatment with minocycline (3mg/kg/day)  Normalized
microglial cytokine production in the hippocampus and
rescued neurogenesis and behaviour (Mattei et al., 2014)

56. RALOXIFENE
• The role of SERM in the treatment of positive psychotic
symptoms has been documented (Kulkarni et al., 2008)
• Raloxifene  Exhibit agonistic and protective action on the
brain by modulating the monoaminergic neurotransmission of
dopamine, serotonin and GABA (Garcia-Segura et al., 2001)

57. • Addition of Raloxifene (60 mg/day) to regular antipsychotic
treatment ↓ negative, positive & general psychopathological
symptoms in comparison with women receiving antipsychotic
medication alone (Usall et al., 2011)
• Advantage over estrogens  Patients in Raloxifene group did
not have more adverse effects than patients in the placebo
group (Chua et al., 2005)

58. ESTROGEN
• Short term  rapid membrane effects by altering functional
activity in the dopaminergic synapse (di paolo, 1994)
• Long term  modifies synthesis in dopamine receptors (di
paolo, 1994)
• Estrogen alters serotonergic system (moses et al., 2000)
• Estrogen promotes neuronal regeneration & blocks
mechanisms of neuronal death (doncarlos et al., 2009)

59. N -ACETYL CYSTEINE
• Glutathione is a major antioxidant that protects cells against
oxidative stress (Meister and Anderson, 1983)
• Glutathione potentiates NMDA receptors (Choi and Lipton,
2000; Kohr et al, 1994)
• In schizophrenia, glutathione dysregulation  NMDA
receptor hypofunction

60. • NAC (GSH precursor)  Improved auditory cortical
functioning as indexed by the mismatch negativity
(Lavoie et al., 2008)
• Mismatch negativity (MMN)  An auditory evoked
potential (AEP) component related to NMDA receptor
function
• Participants treated with NAC  Improvements in
insight, self-care, social interaction, motivation, volition,
psychomotor stability and stabilization of mood (Berk et
al., 2010)

61. CHOLINERGIC AGENTS
• Ach. modulates dopamine transmission in striatum, where
dopamine dysregulation may contribute to both positive and
negative symptoms and in the cortex, where dopamine
transmission deficits have been postulated to contribute to
cognitive deficits, particularly in attention, learning and
memory.
• In a recent SPECT study, muscarinic receptors were
significantly reduced in the cortex, thalamus, and basal ganglia
in patients with schizophrenia.

62. Nicotine receptors
• Nicotine administration improves various measures of
cognition that may ease some of the side effects of anti-
psychotics.
• Freedman et al tested a cholinergic nicotinic partial agonist
selective for the alfa7-selective agonist DMXB-A, in 31
clinically stable outpatients with chronic schizophrenia
receiving maintenance antipsychotic medications, using a
placebo controlled crossover design.

63. • The investigators did not find significant improvement on their
primary outcome measure of cognition, the MATRICS
consensus battery but they did see a therapeutic effect on
negative symptoms measured by scale for the assessment of
negative symptoms.
• The partial agonist activity of DMXB-A may help to minimize
the problem of tachyphylaxis observed with full agonist
nicotine.
• Though, there is one recent study which shows positive effect
on neurocognition.

64. Muscarinic receptors
• Among 5 types of these receptors (M1-M5), M1 is linked to
cognition in schizophrenia and is most abundant of muscarinic
receptors in forebrain and hippocampus.
• Action at M1 receptors has been proposed to be a major
contributor in cognition enhancement effects of clozapine
which is a weak partial agonist at M1 receptor.
• Its metabolites including clozapine-N-oxide and N-
desmethylclozapine (NDMC) are in focus.

65. Acetylcholinesterase inhibiting agents
• The most frequently tested AChEIs is donepezil which has
been found to be beneficial in cognitive impairment in small
sampled controlled studies.
• Galantamine is another agent whose treatment is associated
with selective benefit for attention and delayed memory and
visual recognition.
• In addition to its selective action, galantamine is also a positive
allosteric modulator of the alfa4beta4 and alfa7-nicotine
receptors.

66. DOPAMINERGIC AGENTS
• Low doses of selective D1 agonists have cognition enhancing
actions in nonhuman primates and short term administration of
the D1 selective agonist, ABT-431 reversed working memory
deficits with chronic antipsychotic therapy.
• D4 receptors may play an important role in impulsivity and
working memory.
• High affinity of clozapine for these receptors led to speculation
that these receptors may be clozapine’s ‘magic receptor’.
• However, clinical trials have not shown any appreciable
efficacy in treatment of schizophrenia.

67. • COMT is a postsynaptic enzyme that methylates and
deactivates synaptically released catecholamines, particularly
dopamine.
• A selective reversible inhibitor of COMT, tolcapone, has been
reported to improve working memory in rodents and has been
shown to improve cognitive dysfunction in patients with
advanced Parkinsonism, though use is limited due to a risk of
liver failure.
• Other COMT inhibitors are currently being investigated for
cognitive dysfunctions in schizophrenia.

68. GLUTAMATERGIC TARGETS
• Glutamate is the primary excitatory neurotransmitter in brain
contained as a neurotransmitter in about 60% of the brain
neurons.
• Schizophrenia is associated with reduced glutamatergic neuro-
transmission.
• Treatment requires to potentiate glutamatergic
neurotransmission at either NMDA or non-NMDA receptors

69. • 7 small-scale studies using full agonists (Glycine at doses of
0.4-0.8 g/kg(30-60 g/d), D-serine 100mg/kg (2.1 g/d) and D-
alanine 100mg/kg (7g/d)) with anti-psychotic medication have
shown 20% improvement in negative symptoms.
• 2 small-scale studies with naturally occurring compound
sarcosine at the dose of 2 g/d have shown 17% reduction in
negative symptoms in patients stabilized on FGAs or SGAs.

70. • Another agent LY2140023, a selective agonist for
metabotropic glutamate 2/3 (mGluR2/3) when compared with
placebo or olanzapine in a 4-week randomized controlled trial
involving 196 patients with the dose of 80 mg/day showed
better safety, tolerability and rapid onset of efficacy.
• Improvement in both positive and negative symptoms of
schizophrenia was observed only after one week of treatment.
• EPS and weight gain were comparable with placebo.

71. SEROTONERGIC AGENTS
• Activating 5-HT1A receptors with a single dos of
tandospirone, a 5-HT1A partial agonist, diminished explicit
memory function in demented patients, though chronic
administration of tandospirone enhanced verbal memory in
patients with schizophrenia.
• 5-HT2A receptors are particularly abundant in the pyramidal
neurons from cortical layer V, where they have been described
to co localize with NMDA glutamate receptors, suggesting a
role in modulating cognitive functions.

72. ALPHA -2 ADRENERGIC RECEPTORS
• Combined treatment of a typical antipsychotic with the highly
selective alpha-2 adrenergic receptor antagonist, idazoxan, has
been reported to produce a profile of antipsychotic activity
similar to clozapine.
• Thus, as alpha-2-adrenergic receptor activity may be important
in developing new drugs for schizophrenia that can improve
cognition, balancingalpha-2-adrenergic receptor activity to
achieve both antipsychotic and procognitive efficacy may be
challenging.

73. GABA-A RECEPTORS
• Appropriately synchronized GABA neurotransmission in the
dorsolateral prefrontal cortex is required for adequate working
memory, suggesting that impairments in GABA-mediated
inhibition could contribute to the cognitive impairments in
schizophrenia.
• Studies have shown that antagonists or inverse agonists at
alpha-5-containing GABA-A receptors may hold promise in
the treatment of the cognitive dysfunction in schizophrenia.

74. NEUROSTEROID AND SIGMA
RECEPTORS
• Neurosteroids, such as dehydroepiandrosterone (DHEA) and
allopregnanolone, have been implicated in neuroprotection and
enhancement of NMDA receptor neurotransmission, possibly
through interaction with sigma-1 receptors, suggesting
therapeutic potential for enhancing cognition in schizophrenia.

75. NK3 RECEPTOR ANTAGONIST
• Activation of NK3 receptors lead to activation and release of
dopamine, 5HT and NA.
• Recent evidence suggests the clinical efficacy of two distinct
NK3 receptor antagonists: osanetant and talnetant.
• These have been evaluated in double-blind, placebo controlled
clinical trials in schizophrenia.
• Osanetant and talnetant represent distinct chemical classes and
their properties are also markedly different, albeit with the
common traits of NK3 receptor antagonism and a potentially
similar efficacy in schizophrenia.

76. CANNABINOID RECEPTOR ANTAGONIST
• Some preclinical and clinical evidence suggests that
cannabidiol may have anti schizophrenic potential mostly
against negative symptoms.

77. AGMATINE
• Agmatine is a cationic amine synthesized from arginine via the
enzyme arginine decarboxylase.
• Agmatine reduces morphine or alcohol withdrawal symptoms
in rodents.NMDA receptor blockade may be responsible for
this.
• These properties of agmatine (NMDA receptor blockade) can
be useful in treating excitatory neuropsychiatric disorders.
• Agmatine could be a new target in the treatment of
schizophrenia.

78. ADVANCES IN
SOMATIC THERAPIES

79. REPETITIVE TRANSCRANIAL
MAGNETIC STIMULATION
• It is thought to work by modifying cortical excitability, with
high frequency or fast rTMS(>1Hz) having an activating effect
on neuronal circuits and slow rTMS(<1Hz) an inhibitory effect
.
• Data from different studies suggest that improvement in
auditory hallucinations occur when rTMS of the left temporal
parietal cortex is used to augment antipsychotic treatment.
• A recent mata-analysis concluded that rTMS efficiently
reduces resistant auditory hallucinations in patients with
schizophrenia.

80. • For patients with prominent negative symptoms, small open
studies of high frequency rTMS (10-20 Hz, given for 1-4 wks)
of the left dorsolateral prefrontal cortex have reported
beneficial effects on measures of negative symptoms with
improvement being maintained after one month in one study.
• Although these findings are interesting and worthy for future
research rTMS has not been approved for use in patients with
schizophrenia and there is insufficient to recommend its use in
clinical practice.

81. RECENT ADVANCES
IN PSYCHOSOCIAL
INTERVENTIONS

82. • As a part of comprehensive treatment approach, psychosocial
interventions can improve the course of schizophrenia when
integrated with psychopharmacological treatments.
• Psychosocial interventions can provide additional benefits for
patients in such areas as relapse prevention, improved coping
skills, better social and vocational functioning, and ability to
function more independently.

83. COGNITIVE BEHAVIOR THERAPY
• Several randomized controlled trials examining significant
correlations between improvements in positive symptoms and
some evidence of improved functioning but this did not quite
reach significant.

84. SOCIAL SKILLS TRAINING
• Social skill and social competence can be viewed as protective
factors in the vulnerability stress- protective factor model of
schizophrenia.
• While social skills training may have a positive effect on social
role functioning. It is not effective for reducing for reducing
symptoms or preventing relapse.
• There are several reports of controlled studies in which social
skills training significantly reduced relapse rates and symptom
levels, but more research is needed to document the extent to
which social skills training actually protects patients from
relapse.

85. COGNITIVE REHABILITATION
• Several recent studies have shown decrease in positive and
total symptoms score significantly on cognitive remediation
therapy and negative symptoms did not change regardless of
cognitive remediation therapy used.
• Some cognitive remediation therapies may be able to induce
subjective improvement of cognitive functioning in patients
with schizophrenia.

86. YOGA THERAPY
• A recent study by Duraiswamy et al, that yoga as add on
treatment along with antipsychotic is beneficial in
psychopathology, social and occupational functions, and
quality of life.
• Though, it remains to establish whether benefits extend to
cognitive deficits and are enduring.

87. GROUP MUSIC THEARPY
• It has been found that there are significant effects of music
therapy on schizophrenia patient’s self-evaluation of their
psychosocial orientation and for negative symptoms.
• No differences were found on quality of life.

88. FUTURE BIOLOGICAL TREATMENT
ALGORITHM
Dx by MSE
verified by
Schizophrenia
metabolomic
panel
Determine the
affected domain
of schizophrenia
Choosing best
therapy
(cultured patient
specific neurons)
Assessment of
Tx efficacy
(dendritic spine
density
measurement)
Staging of the
illness (fMRI
+connectomics)

89. A VISION FOR SCHIZOPHRENIA OVER THE
NEXT DECADE

90. REFERENCES
• Looney JM, Childs HM: The lactic acid and glutathione content of the
blood of schizophrenic patients. J Clin Invest 1934, 13:963-968.
• Dean et al: A role for glutathione in the pathophysiology of bipolar
disorder and schizophrenia? Animal models and relevance to clinical
practice. Current Medicinal Chemistry 2009, 16:2965-2976
• Berk et al.: Aspirin: a review of its neurobiological properties and
therapeutic potential for mental illness. BMC Medicine 2013 11 :74.
• Brown AS: Prenatal infection as a risk factor for schizophrenia. Schizophr
Bull 2006, 32:200-202.
• Muller N, Schwarz MJ: The immune-mediated alteration of serotonin and
glutamate: towards an integrated view of depression. Mol Psychiatry
2007, 12:988-1000
• Miller BJ, Buckley P, Seabolt W, Mellor A, Kirkpatrick B: Meta-analysis of
cytokine alterations in schizophrenia: clinical status and antipsychotic
effects. Biol Psychiatry 2011, 70:663-671.
• Lin A et al The inflammatory response system in treatment-resistant
schizophrenia: increased serum interleukin-6. Schizophr Res 1998, 32:9-15
• Aid S et al: Neuroinflammatory response to LPS is exacerbated in mice
genetically deficient in COX-2. J Neuroinflammation 2008, 5:17.

91. • Liu F et al.Minocycline supplementation for treatment of negative
symptoms in early-phase schizophrenia: a double blind, randomized,
controlled trial. Schizophr Res. 2014 Mar;153(1-3):169-76.
• Mattei D et al.Minocycline rescues decrease in neurogenesis, increase in
microglia cytokines and deficits in sensorimotor gating in an animal model
of schizophrenia. Brain Behav Immun. 2014 May;38:175-84.
• Oya K, Iwata N. Efficacy and tolerability of minocycline augmentation
therapy in schizophrenia: a systematic review and meta-analysis of
randomized controlled trials. Hum Psychopharmacol. 2014 Sep;29(5):483-
91.
• Kulkarni J, de Castella A, Fitzgerald PB, Gurvich CT, Bailey M,
Bartholomeusz C, Burger H. Estrogen in severe mental illness: a potential
new treatment approach. Arch Gen Psychiatry. 2008 Aug; 65(8):955-60.
• Kulkarni J, Riedel A, de Castella AR, et al. Estrogen –a potential treatment
for schizophrenia. Schizophr Res. 2001; 48(1):137-144.
• Akhondzadeh S, Nejatisafa AA, Amini H, et al. Adjunctive estrogen
treatment in women with chronic schizophrenia: a double-blind,
randomized, and placebo-controlled trial. Prog Neuropsychopharmacol
Biol Psychiatry. 2003; 27(6):1007-1012.

92. • Lindamer LA, Buse DC, Lohr JB, et al. Hormone replacement therapy in
postmenopausal women with schizophrenia: positive effect on negative
symptoms? Biol Psychiatry. 2001; 49(1):47-51.
• Usall J, Huerta-Ramos, Iniesta R, et al. Raloxifene as Adjunctive Treatment
for Postmenopausal Women with Schizophrenia: A Double-Blind,
Randomized, Placebo-Controlled trial. J Clin Psychiatry 2011;
72(11):15552-1557.
• Kulkarni J, Gurvich C, Lee SJ, et al. Piloting the effective therapeutic dose
of adjunctive selective estrogen receptor modulator treatment in
postmenopausal women with schizophrenia. Psychoneuroendocrinology.
2010;35(8):1142-1147
• Berk M, Munib A, Dean O et al. Qualitative methods in earlyphase drug
trials: data and methods from a trial of N-acetyl cysteine in schizophrenia.
J Clin Psychiatry 2010 Sep. 1 [Epub ahead of print].
• Suzie Lavoie, Micah M Murray , Patricia Deppen, Maria G Knyazeva,
Michael Berk Olivier Boulat, Pierre Bovet, Ashley I Bush, Philippe Conus,
David Copolov, Eleonora Fornari,Reto Meuli, Alessandra Solida, Pascal
Vianin, Michel Cue´nod, Thierry Buclin and Kim Q Glutathione Precursor,
N-Acetyl-Cysteine, Improves Mismatch Negativity in Schizophrenia
Patients. Neuropsychopharmacology (2008) 33, 2187–2199.

93. THANK YOU