Understanding what Schizophrenia is along with the Hypothesis of Dopamine, glutamate, and Serotonin. Conventional antipsychotics along with novel drugs and targets in the treatment of Schizophrenia.

1. Presented by: Hemen Ved (Dept. of Pharmacology)
Guided by: Dr. Gaurav Doshi

2.  What is Schizophrenia ?
 Psychotic condition characterized by
 Disturbances in thinking,
 Emotion and perception of clear
consciousness
 Leading to Social withdrawal (1)
lot of symptoms
different patients ~ different symptoms
of Control
of reference
absence of sensation
word salad
DISORGANISED SPEECH
DISORGANISED BEHAVIOUR
bizarre, no purpose
CATATONIC BEHAVIOUR
Movements & responses
POSITIVE
*psychotic symptoms*
DELUSIONS
HALLUCINATIONS
* S Y M P T O M S *
NEGATIVE
*removal of normal process
* emotions
*Loss of interests
FLAT EFFECT
Inappropriate response
ALOGIA
poverty of speech
AVOLITION
motivation
COGNITIVE
*affects
memory
learning
understanding
*Subtle; difficult to notice
Category of Risk factors Specific Risk Factor
Genetic Factors
 Child/Sibling of Schizophrenic patient (46%)
 Twin of Schizophrenic patient (14-46%)
Environmental Factors
 High levels of stress production of hormone cortisol.
 Prenatal exposure to Viral Infection & low O2 levels during birth.
 Physical or Sexual abuse in childhood.
Physiological Factors
 Enlarged Brain ventricles – Deficit in the volume of brain tissue.
 Abnormally low activity in the frontal lobe
 Abnormalities in the Temporal lobes, hippocampus & Amygdala.
(2)

3. Affects 1% of the Global population (3)
*Pathophysiology*
• Enlargement of lateral ventricles
• Smaller than normal brain volume
• Cortical atrophy
• Widening of third ventricle
• Smaller hippocampus
• Abnormal neurotransmission
*Hypotheses of Schizophrenia*
 Dopamine Hypotheses
 Dopamine hyperactivity in mesolimbic pathway
 Hypofunction in mesocortical pathway
 Glutamate Hypotheses
 NMDA Hypofunction
 Serotonin Hypotheses
 5-HT2A receptor hyperfunction in the cortex
*Diagnosis* (DSM-V)
a) Two of the following:
Hallucinations
Delusions
Disorganized speech
Negative symptoms
Disorganized/
Catatonic behavior
(At least one
of these)
b) Ongoing for
6 months
Prodromal
[ Active ] ~ 1 month
Residual
c) Not another
condition
eg. Drug abuse
(4)

4. *Current approaches in the treatment of Schizophrenia*
Pharmacological
treatment
Non-
Pharmacological
treatment
Antipsychotic
agents
First generation
Antipsychotics
(Typical)
Chlorpromazine
Fluphenazine
Haloperidol
Perphenazine
Thioridazine
Trifluoperazine
Second generation
Antipsychotics
(Atypical)
Clozapine
Risperidone
Olanzapine
Quetiapine
Aripiprazole
Ziprasidone
Antipsychotic
polypharmacy
Psychotherapy
Cognitive Behavior
Therapy (CBT)
Family intervention
Art therapy
Social skill therapy
Electroconvulsive therapy
& other treatments
(5)

5.  First-Generation Antipsychotics
Effective against positive symptoms
Working of FGA’s :
a) inhibits D2 Dopamine receptors
b) blocking activity on noradrenergic, cholinergic, and
histaminergic receptors.
Mesocortical pathway
Nigrostriatal pathway
Mesolimbic pathway
Tuber infundibular
pathway
Cognitive impairments & Negative symptoms
High dose ~ block pathway ~ cause Side effects
D2 receptor antagonism ~ Increase in EPS
Inhibit D2 receptors throughout the pathway
D2 blockade raises prolactin levels ~ weight
gain & neuropsychological disturbances
Effective in positive and negative symptoms
Advantage ~ (clozapine, risperidone, olanzapine) but not
all atypicals when compared with typicals.
Working of SGA’s:
a) D2 dopamine receptor activity (weak) &
b) 5-HT2A subtype of serotonin receptor activity
 Second-Generation Antipsychotics
SGA
Presynaptic
neuron
SGA
Presynaptic
neuron
Presynaptic
neuron
(6)

6. Electroconvulsive therapy
(ECT)
• Effective ~ symptoms of
Catatonia present or drug
resistance
• Seizures ~ electrically
induced grand mal seizure
• In conjunction ~ clozapine
Psychotherapy
• Scheduled talks b/w ~
Patient & mental health
professional
• Supportive, reality
oriented, individual
therapy ~ beneficial for
outpatients with
schizophrenia
Family intervention
• Reduced feelings ~
isolation, burden & stress
of family members
• Various coping strategies
& problem solving skills ~
improved outcome of the
patient
Social skill therapy
• Along with
pharmacological therapy
• Focuses on improving
communications & social
interactions.
• Not effective for reducing
symptoms/preventing
relapse
Cognitive behavior therapy
• Learning & strengthening
skills ~ coping & reducing
symptoms & stress
• Problem solving strategies
~ reduce relapse
• Critical analysis ~ beliefs
about auditory
hallucinations
Art therapy
• complementary treatment
~ antipsychotics
• Aim ~ enhance creativity,
emotional expression,
communication, insight &
ability to relate
• Improvement in the
positive symptoms.
(7) (8)

7. *Need for Novel approach in the treatment of Schizophrenia*
• Improving negative & cognitive symptoms
• Better side effect profiles
• Safety/tolerability of current treatments
 Cost of nonadherence
• Identifying novel treatments based on better understanding of pathophysiology
 Refining approach to current targets
Novel Treatment Targets
Hypothesis Target Strategy
Dopamine Dopaminergic stabilizers Improve medication adherence
Glutamate NMDAR, AMPA receptor, or
metabotropic receptors
Improve negative symptoms and
cognitive impairments
Serotonin 5-HT1A agonists, 5-HT reuptake
inhibitors, 5-HT2C antagonists and
agonists, 5-HT3 antagonists, 5-HT6
antagonists, and 5HT7 antagonists
Reduce the extrapyramidal effects
Improve negative symptoms and
cognitive impairments
Potential treatment for different
phases of the illness
Acetylcholine α-7 nicotinic and M1
muscarinic agonists and
positive allosteric modulators
Nicotinic agonists for cognitive symptoms
Muscarinic agonists for positive symptoms
Gamma-aminobutyric acid Selective GABA-A agonists, GABA-B
antagonists, and allosteric modulators
at GABA-A receptor subtypes
Augmentation of psychosis treatment
(9)

8. Dopaminergic Antagonists and Stabilizers
• Antipsychotic therapies developed ~ antagonism of dopaminergic receptors/stabilizers including D2/D3 partial agonists
aripiprazole
• Armodafinil ~ improve cognitive functioning, attenuate fatigue, inactiveness and other negative functions such as weight gain.
• Cariprazine ~ dopamine D3/D2 receptor partial agonist ~ higher affinity for the D3 receptor ~ alleviated symptoms of schizophrenia
~ minimal effect on metabolic parameters, prolactin level, & cardiac conduction.
• Molindone ~ blocking the effects of dopamine ~ diminished symptoms of psychosis.
• Aplindore fumarate, nemonapride, thiothixene (causes EPS)
(9) (10)

9. Glutamatergic Agents
• NMDAR agonists are neurotoxic ~ NMDARs indirectly
stimulated by using glycinergic agents (serine and
cycloserine) and glycine transport (GlyT1) inhibitors
(bitopertin)
• Moderate benefits ~ negative a during clinical trials
• D-serine ~ effective in reducing cognitive dysfunction
 Animal studies ~ memory deficits in S-D rats treated
with the NMDA receptor antagonist PCP at different
developmental stages ~ reversed with D-serine
administration
 Rare side effects even at high doses
MODULATORY
SITES
RECEPTOR
SITE
glycine
polyamines
Glycine
antagonists
Polyamine
antagonists
glutamate
-Mg 2+
NMDA
antagonists
Channel blocking
drugs
-
(9) (10)

10. Serotonin Agents
• Alternative 5-HT approaches ~ 5-HT1A agonists, 5-HT
reuptake inhibitors, 5-HT2C antagonists & agonists, 5-HT3
antagonists, 5-HT6 antagonists, & 5HT7 antagonists
individually/combination with D2 antagonism / 5-HT2A
antagonism or both
• 5-HT3 antagonists ~ ondansetron, tropisetron and
granisetron ~ adjunctive agents for negative and cognitive
symptom
• tropisetron ~ improve cognitive and perceptual disturbances
with risperidone.
• Lurasidone ~ potent 5-HT7 antagonism ~ reduce the risk of
relapse ~ minimal side effects
GABAAllosteric Modulators
• Allosteric modulators at GABA-A receptor ~ evaluated in
schizophrenia treatment
• Quercetin ~ blocking GABA-A receptors push synaptic
activity levels above the threshold ~ trigger homeostatic
mechanisms ~ restore inhibition and functional E/I balance
• several GABA-A receptor inverse agonists ~ potential for
treating cognitive symptoms
Cholinergic Agonists
• α-7 nicotinic and M1 muscarinic agonists and positive
allosteric modulators are of greatest interest
• Encenicline ~ potent and selective partial agonist at α7
nAChR ~ improve overall cognition & reduce negative
symptoms (phase II trial)
(5) (10)
(15)
(16)

11. Neuropeptides
NK3 receptor antagonists ~
• Activation of NK3 receptors lead to activation & release of DA, 5HT & NA
• Osanetant, Talnetant ~ NK3 receptor antagonists suggest clinical efficacy
• Evaluated in double blind, placebo controlled Clinical trials in Schizophrenia
• Osanetant & Talnetant show distinct chemical class & properties
• common traits of NK3 receptor antagonism & similar efficacy
(9,11)
Ligand Affinity at receptor
Osanetant 1.2
Talnetant 1.0
Cannabinoid receptor antagonist
• THC may be psychotogenic through involvement in dopaminergic, GABA,
and glutamatergic neurotransmission
• Cannabidiol ~ prevent psychotic-like symptoms induced by high doses of
THC by acting as an indirect antagonist of cannabinoid (CB) receptors
• CBD decreases Mesolimbic DA activity
(12, 13)

12. Treatment Company Receptor/mechanism of action Adverse effects
F17464 (Phase-II) Pierre Fabre Medicament D3 antagonist, 5-HT1A partial agonist Insomnia, agitation, and increased
triglycerides
Lumateperone (Phase-III,
under FDA review)
Intracellular therapies (ITI) 5-HT2A antagonist, 5-HT transport
inhibitor, presynaptic D2 partial agonist and
postsynaptic D2 antagonist, D1-regulated
NMDA and AMPA agonist
Somnolence, dry mouth, headache
RO5263397 & SEP-363856
(Phase-III)
N/A TAAR1 agonist Somnolence, nausea, diarrhoea,
dyspepsia
BI-425809 (Phase-II) Boehringer Ingelheim Glycine-transporter-1 (GLYT-1) inhibitor N/A
Paliperidone Palmitate (Phase-II) Janssen 5-HT2A antagonist D2 antagonist N/A
Samidorphan + Olanzapine
(ALKS3831)
(Phase-III, under FDA review)
Alkermes μ-opioid antagonist + olanzapine Weight gain, somnolence, dry mouth,
anxiety, headache, and schizophrenia
Aripiprazole Lauroxil
NanoCrystal ® Dispersion (FDA
approved)
Alkermes Partial D2 agonist Injection pain, headache, weight gain,
insomnia, dyspepsia, and anxiety1
Novel and emerging pharmacological treatments for schizophrenia
(13)

13. Sodium nitroprusside (nitric oxide donor)
• Nitric oxide ~ pathophysiology of Schizophrenia ~ gas that mediates the release of neurotransmitters, and seems to be involved in
learning, memory, and neurodevelopment
• Administration of sodium nitroprusside ~ improvement of positive, negative, anxiety, and depressive symptoms taking
antipsychotics.
• Efficacy of sodium nitroprusside ~ consideration future trials
Novel FDA approved antipsychotics
Fazaclo (Sept, 14, 2005)
Paliperidone (December 19, 2006)
Illoperidone (May 7, 2009)
Asenapine (August 15, 2009)
Lurasidone (October 29, 2010)
New drugs in the pipeline
Aspirin
Minocycline
Raloxifene
Estrogen
N-acetylcysteine
(13)

14. Lurasidone
• Maximum recommended dose was originally 80 mg/day
• In May 2012 FDA approved an extended dose range of 40-
160 mg/day for schizophrenia
• 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 prolactin
Cariprazine
• D2 partial agonist
• higher doses for schizophrenia and mania (antagonist actions)
• lower doses for depression (agonist action)
• Stronger affinity for D3 than D2 receptors
• Few metabolic side effects and low risk for EPS
Brexpiprazole
• • D2 partial agonist
• 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
(14)
(17)
(18)

15. Aspirin
• Aspirin as adjuvant therapy ~ ↓ symptoms of schizophrenia
spectrum disorders
• Future studies ~ Patients with recent onset of disease & more
disturbed immune functions
Minocycline
• Addition of minocycline to atypical antipsychotic drugs in
early schizophrenia ~ Significant efficacy on negative
symptoms
• Normalized microglial cytokine production in the
hippocampus
(19)
(20)

16. Raloxifene
• Exhibit agonistic and protective action ~ modulating the
monoaminergic neurotransmission of dopamine, serotonin and
GABA
• In women addition to regular antipsychotic treatment ↓
negative, positive & general psychopathological symptoms
Estrogen
• Alters serotonergic system & modifies synthesis in dopamine
receptors
• Promotes neuronal regeneration & blocks mechanisms of
neuronal death
* Agmatine (NMDA receptor blockade) could be a new target in the treatment of schizophrenia.
N -acetyl cysteine
• Glutathione is a major antioxidant that protects cells against oxidative stress
• Improvements in insight, self-care, social interaction, motivation, volition, psychomotor stability and stabilization of mood
(21) (21)
(22)
(23)

17. Advances in somatic therapies
 Repetitive transcranial magnetic stimulation
• Modifying cortical excitability, with high frequency or fast rTMS(>1Hz) ~ activating effect on neuronal circuits and slow rTMS(<1Hz)
an inhibitory effect
• rTMS efficiently reduces resistant auditory hallucinations in patients
• beneficial effects on measures of negative symptoms with improvement
• Not been approved for use in patients with schizophrenia and there is insufficient data to recommend its use in clinical practice.
Advances in psychosocial interventions
 Yoga therapy
• As add on treatment along with antipsychotic ~ beneficial in psychopathology, social and occupational functions, and quality of life
 Group music therapy
• Significant effects of music therapy ~ on self-evaluation of the psychosocial orientation and negative symptoms.
(24)
(25)

18. Current treatment modalities have certain
limitations: about
30% of patients with schizophrenia are refractory
There are no effective remedies for primary negative
symptoms.
patients have relapsing and remitting course
even while on medication.
Development of effective treatment ~ clinical
importance ~ poor functional outcome
lack of efficacy for these domains ~ search for
alternate pathophysiological hypothesis
Conclusion
Dated 9th October 2019
(www.nytimes.com/2019/10/08/health/johnson-
and-johnson-risperdal-verdict)

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26. https://www.youtube.com/watch?v=Pr8IyNGAqlw&t=4s

22. THANK YOU
“If you talk to God, you’re praying,
If God talks to you, you may have Schizophrenia”