This presentation deals with atypical antipsychotics & new drugs in the pipeline (Clozapine, Risperidone, Olanzapine, Quetiapine, Ziprasidone, Aripiprazole, Second generation antipsychotics, atypical antipsychotics, Aspirin, Minocycline, Raloxifene, Estrogen, N-acetylcysteine). Introduction Major psychiatric disorders Psychoses & affective disorders Psychoses Disorders in which patients exhibit gross disturbances in their comprehension of reality as evidenced by false perception (hallucinations), false beliefs (delusions) and loss of contact with reality; schizophrenia most common form of psychosis (+ve n –ve symptoms) Mostly concerned Abt –ve because poor prognosis , more difficult to treat, persist after positive symptoms have resolved Mesolimbic Dopamine travels from the midbrain tegmental area to the nucleus accumbens. Increased activity in this pathway may cause delusions, hallucinations, and other so-called positive symptoms of schizophrenia. Mesocortical pathways Decreased activity in the pathway that goes from the midbrain to the prefrontal lobe cortex can cause apathy, withdrawal, lack of motivation and pleasure, and other so-called negative symptoms of schizophrenia. Mesocortical dysfunction also disinhibits the mesolimbic pathway. Nigrostriatal pathway from the substantia nigra to the striatum is involved in the coordination of body movements. Inhibition of this pathway causes the extrapyramidal side effects of antipsychotic drugs. Tuberoinfundibular pathway from the hypothalamus to the pituitary inhibits the release of prolactin. Inhibition of this pathway leads to elevated serum prolactin levels. 2nd generation antipsychotics Clozapine, Risperidone, Olanazapine, Quetiapine, Ziprasidone, Aripiprazole (MOA, Dose, Brand name & A/E and receptor affinities) Why do 1st gen. antipsychotics cause EPS & 2nd gen. do not? “Hit and run” hypothesis Inflammation & schizophrenia New drugs in pipeline Aspirin, Minocycline, Raloxifene, Estrogen, N-acetylcysteine (MOA and rationale of use) Potential future targets of schizophrenia

1. Recent advances in the
treatment of psychoses
Moderator – Dr. Ali Ahmad
Resident – Dr. Karun Kumar

4. Dopamine receptors in brain

7. 5 HT2 receptor in brain

9. Second generation
anti-psychotics
1.Clozapine
2.Risperidone
3.Olanzapine
4. Quetiapine
5. Ziprasidone
6. Aripiprazole

10. New drugs in the
pipeline
1.Aspirin (Antiplatelet)
2.Minocycline (A.b.)
3.Raloxifene (SERM)
4.Estrogen (HRT)
5.N-acetylcysteine (PCM)

12. Clozapine (Clozaril, Fazclo)
• Both positive & negative symptoms are improved
• Most effective drug  Refractory schizophrenia
• Lower incidence of EPS
• S/E  Weight gain, diabetes, agranulocytosis
(fatal), hyperlipidemia, ↓ threshold for seizures
• Weekly monitoring of leukocyte counts required
• Dose  200-600 mg/day

14. Risperidone (Risperidal)
• Both positive & negative symptoms are improved
• S/E  Hyperprolactinemia & QT interval
prolongation
• Other agents with similar pharm. profile 
Ziprasidone, Lurasidone, Iloperidone, Paliperidone
• Dose  2-4 mg/day

16. Olanzapine (Zyprexa)
• Chemical analogue of Clozapine
• Effective against negative & positive symptoms
• Fewer autonomic s/e compared to Clozapine
• Strongly associated with weight gain and insulin
resistance
• Broader spectrum  Mania, schizoaffective
disorder
• Dose  7.5-20 mg/day

18. Quetiapine (Seroquel)
• Used for maintenance therapy
• S/E  Sedation, QT prolongation, cataracts
• No benefit in negative symptoms
• Evidence of efficacy
1. Mania
2. Bipolar depression
• Dose  200-600 mg/day

20. Ziprasidone (Geodon, Zeldox)
• Indications
1. Mania
2. Schizophrenia
• Side effects
1. Nausea & vomiting
2. QT interval prolongation
• Dose  120-160 mg/day

22. Aripiprazole (Abilify)
• Indications
1. Schizophrenia
2. Mania
3. Bipolar illness
• Side effects
1. Weight gain
2. ↑ blood sugar level
3. QT interval prolongation
• Dose  10-20 mg/day

23. Mechanism of action

26. Mechan
ism
Therapeutic effects Adverse effects
α1 block -- Dizziness, orthostatic
hypotension, reflex tachyc.
D2 block +ve sympt ↓ EPS & ↑ Prolactin
D4 block -ve sympt. & EPS ↓ --
H1 block Sedation Drowsiness & ↑ appetite &
wt.
M block -- Dry mouth, etc.
5-HT2 bl -ve sympt. & EPS ↓ Anxiety & insomnia

27. Inflammation & schizophrenia
• Oxidative stress & ↓ antioxidants [glutathione]
(Looney and Childs, 1934)
• Lipid peroxidation  ↑ Malondialdehyde (Berk et al.,
2013)
• Polymorphisms in glutamate-cysteine ligase gene
(Dean et al., 2009)
• ↑ maternal levels of IL-8 during pregnancy  ↑ risk
for schizophrenia in the offspring (Brown, 2006)

28. • Glutamatergic & dopaminergic sys.  Modulating effect
1.Immune system 2.Trp-kynurenine metabolism, both
involved in the pathophysiology of schizophrenia (Muller
and Schwarz, 2007)
• IL-12, TNF-α, IFN-γ & soluble CD25  Trait markers of
schizophrenia (Miller et al., 2011)
• IL-1β, IL-6 and TGF-β  State markers of acute
schizophrenia (Miller et al., 2011)
• IL-6 levels  Correlate with a poorer prognosis (Lin et al.,
1998)

30. Aspirin
• ATL (Aspirin triggered lipoxins) (Berk et al., 2013)
1. ‘Braking signals’ in inflammation, dampening the
inflammatory response
2. Inhibit neutrophil & eosinophil recruitment and
activation
3. Stimulate NAB1 gene expression  Endogenous
anti-inflammation and resolution

31. • COX-1  Key component in neurodegeneration
and neuroinflammation (Aid et al., 2008)
• Aspirin better choice than COX-2 inhibitor
1. Well estd. Cardioprot. effects (Hayden et al.,2002)
2. Preferentially targets COX-1 rather than COX-2
• Admin. of aspirin prior to acute stress exposure 
Prevented ↑ in iNOS expression, TNF-α, MDA and
oxidative stress (De Cristobal et al., 2002)
• Aspirin enhances NMDA receptor activity (Goff and
Coyle, 2001)

32. • 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

34. Minocycline
• Excellent penetration of the blood–brain barrier
1. Glutamate effects
Damaged glutamate NMDA receptors  Impaired
glutamate transmission  hypoglutamatergic states
Minocycline  enhances NMDA receptor activation
2. Microglia activation
↑ microglia activation  ↑ proinflammatory factors
Minocycline  Inhibits microglia activation

35. 3. Apoptotic effects
Vulnerability of apoptosis increased in schizophrenia
Minocycline  reduces apoptosis in neuronal cells
4. Antioxidant properties and free radical scavenger
Oxidative stress  ↑ reactive species 
cellular dysfunction  ↓ antioxidant levels
Minocycline  Prevent ↑ in production of reactive
species

36. • 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)

39. 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)

40. • 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)

41. 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)

42. 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

43. • 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)

46. Potential future targets
• Targeted gene therapy  Dysbindin, Neurogelin 1,
COMT, DISC1
• Enhancement of BDNF
• Targets  GSK 3 & PKC (enz.); GABAA receptor
• PDE inhibitors (particularly at PDE10A)
• Functional selectivity (at receptor level)
• Cannabinoid receptor antagonist
• Agmatine
• Antibiotics & antivirals
• Ampakines

47. References
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glutathione content of the blood of schizophrenic
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schizophrenia? Animal models and relevance to
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properties and therapeutic potential for mental
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• Brown AS: Prenatal infection as a risk factor for
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48. • Muller N, Schwarz MJ: The immune-mediated
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49. • Laan W, Grobbee DE, Selten JP, Heijnen CJ, Kahn RS,
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55. Made by a patient suffering from schizophrenia