Recent advances in the treatment of psychoses

Moderator – Dr. Ali Ahmad Resident – Dr. Karun Kumar

Dopamine receptors in brain

5 HT2 receptor in brain

Second generation anti-psychotics

1.Clozapine

2.Risperidone

3.Olanzapine

4. Quetiapine

5. Ziprasidone

6. Aripiprazole

New drugs in the pipeline

1.Aspirin (Antiplatelet)

2.Minocycline (A.b.)

3.Raloxifene (SERM)

4.Estrogen (HRT)

5.N-acetylcysteine (PCM)

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

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

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

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

Ziprasidone (Geodon, Zeldox)

• Indications

1. Mania

2. Schizophrenia

• Side effects

1. Nausea & vomiting

2. QT interval prolongation

• Dose 120-160 mg/day

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

Mechanism of action

Mechanism

Therapeutic effects Adverse effects

α1 block -- Dizziness, orthostatichypotension, 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

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)

• 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)

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

• 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)

• 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

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

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

• 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)

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)

• 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)

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)

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

• 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)

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

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.

• Laan W, Grobbee DE, Selten JP, Heijnen CJ, Kahn RS, Burger H: Adjuvant aspirin therapy reduces symptoms of schizophrenia spectrum disorders: results from a randomized, double-blind, placebo-controlled trial. J Clin Psychiatry 2010, 71 :520-527

• Ghanizadeh A, Dehbozorgi S, Sigaroodi MO, RezaeiZ. Minocycline as Add-On Treatment Decreases the Negative Symptoms of Schizophrenia; A Randomized Placebo-Controlled Clinical Trial. Recent Pat Inflamm Allergy Drug Discov. 2014 Oct 29.

• Milanovic S. Estrogen for the Treatment of Women with Schizophrenia. Published: September 22, 2008.

• 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. SchizophrRes. 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. ProgNeuropsychopharmacol Biol Psychiatry. 2003; 27(6):1007-1012.

• 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 [Epubahead 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.

• Goff DC, Coyle RJ. The emerging role of glutamate in the pathophysiology and treatment of schizophrenia. Am J Psychiatry. 2001;158:1367-1368

• De Cristobal et al.Aspirin inhibits stress-induced increase in plasma glut,brain oxidative damage and ATP fall in rats. Neuroreport 2002,13:217-21

• Hayden M et al.Aspirin for the primary prevention of cardiovascular events: Ann Intern Med. 2002; 136:161

Made by a patient suffering from schizophrenia