recent advances in the treatment of psychoses
TRANSCRIPT
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