Events that Shaped the Development ofAntipsychotics this Decade: 2003 Human Genome Project results were published. 2009 Human Epigenome Project published results. 2009 Human Connectome Project began. Novel neuroimaging Techniques Discovery of the Ultramicrotome
From Freud to Prozac
The Brain as a Black BoxUpbringing determines the output 19th and early 20th century paradigm
Biochemical ParadigmFrom blaming the mother to blaming neurotransmitters Second half of the 20th century 1954 discovery of Chlorpromazine Psychopharmacology The biochemical trinity: -dopamine -serotonin - norepinephrine
Computational Paradigm Putting Brains Back in Psychiatry
Computation: Information Processing - Brain is the hardware, mind is the softwareAdvances in microscopy and imaging: 150 billion neurons Each neuron up to 900 synapses Number of connections - trillions Connections organized in hubs and networks
Large Brain NetworksThe salience network initiates dynamic switching between the central-executive and default-mode networks, and mediates between attentionto endogenous and exogenous events.Large Scale Brain Networks in Cognition, emerging methods and principles;Steven Bresler, Vinod Menon;Trends in cognitive science, Vol 14,June 2010, pages277-290;http://dx.doi.org/10.1016/j.tics2010 .04.004
Advances in Functional MRI fMRIrevealed: the brain to be a highly connected organ
Advantages & Disadvantages offMRI In vivo(can see the brain at work) The resolution of fMRI is 1 mm 1000 neurons per mm of gray matter Regional connectomics
Automated Tape-CollectingUltramicrotome (ATUM)
Connectomics in Schizophrenia Bullmore&Sporns, Nat Rev Neuroscii 2009
Schizophrenia : fronto-temporal dysconnectivity Graph Analysiss schizophrenia patients healthy subjects Nodes= small , large or average clustering
Causes of Psychosis Tumors: temporal lobe (auditory), occipital lobe (visual), limbic and hypothalamus (delusions) Seizures: temporal lobe, grand-mal (post-ictal psychosis) Parkinson’s disease: secondary to mood disorders, dementia or antiparkinsonian drugs Huntington’s disease Multiple Sclerosis Amyotrophic lateral sclerosis Neurosyphilis Meningitis/encephalitis HIV Hypo/hyperthyroidism 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
Psychosis – A Brain Arrhythmia? Default mode of information processing to which the brain resorts under stress. The amount of stress necessary to activate psychotic information processing mode depends on the cerebral reserve.
Brains Default Mode Network The brains default mode network -- a series of connected areas that work hardest when most of the brain is at rest Two major hubs: -posterior cingulate cortex with the precuneus -medial prefrontal cortex
Brain’s “Default Mode” Awry in SchizophreniaAmerican Journal of Psychiatry 164: 450-457 (March 2007)
Newest Antipsychotics AdvantagesIloperidone (Fanapt) Asenapine LurasidoneEfficacy comparable to other Mild metabolic risk; no prolactin Lack of affinity at H1 andatypicals elevation M1receptors allows treatment to begin at therapeutically effective dose; rapid onset of actionNot approved for mania, but No dose titration needed 40-80 mg/day effective for acutepotentially effective. exacerbation of schizophreniaHas very low (placebo-level) EPS Long half-life; once-daily dose is Appears to have a benignand little or no akathisia theoretically possible metabolic profile without affecting QTc prolongation; low EPSPotent alpha 1 blocking Sublingual tablet good for Once-daily administration isproperties suggest potential utility reliable, compliant patient possiblein PTSDBinding properties suggest Not approved for depression, buttheoretical efficacy in depression binding profile suggests potential use in treatment resistant cases
Newest Antipsychotics DisadvantagesIloperidone Asenapine LurasidoneDose-dependent QTc Not absorbed once swallowed; EPS and akathisia, but seems toprolongation must be administered be reduced if taken at night sublinguallySlow titration Common side effect: oral Will require confirmation from hypoesthesia real world clinical experienceUse caution with patients Patients may not eat or drinksensitive to orthostasis (young, for 10 minutes afterelderly, CV problems) administration to increase bioavailabilityIn presence of 2D6 inhibitors Somnolence/sedation/EPS(paroxetine, fluvoxamine, duloxetine) reduce dose by halfWeight gain/metabolic profile Inhibits 2D6 and is a substratecomparable to Risperidone for 1A2
Iloperidone DosingDay 1 Day 2 Day 3 Day 4 Day 5 Day 6 Day 71 mg 2 mg 4 mg 6 mg 8 mg 10 mg 12 mgBID BID BID BID BID BID BID
Iloperidone -Tolerability Moderate effects on body weight-Iloperidone-induced changes in weight are independent from significant changes in glucose or lipid levels Low rate 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
Asenapine DosingSublingual Formulation-bioavailability when swallowed is very low-avoid eating or drinking for 10 min after administrationTypical dose-Schizophrenia 5 mg BID-Bipolar mania 10 mg BIDMay be useful as a rapid-acting PRN antipsychoticNo dose adjustment necessary in patients with moderate hepatic or renal impairmentTarazi F, Stahl SM Expert Opinion Pharmacotherap 2012 Epub ahead of print
Asenapine TolerabilityLimited 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 observedSlightly elevated risk of akathisia and EPSOral hypoesthesia and somnolence are not uncommonMay induce orthostatic hypotension and syncopeMarginal effects on QTc intervalBenign effects on prolactin.Tarazi F, Stahl SM Expert Opinion Pharmacotherap 2012 Epub ahead of print
Lurasidone DosingRecommended starting dose 40 mg/dayMaximum recommendined dose was originally80 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 developmentNo titration requiredShould be taken with food (at least 350 calories)Should not exceed 40 mg/day in patients withmoderate to severe renal or hepatic impairment.
Lurasidone TolerabilityBenign metabolic profile-minimal changes in body weight-no significant changes in total cholesterol, triglycerides, LDLs, HDLs or fasting glucoseRisk of akathisia at higher dosesNo QTc prolongationSmall increase in in prolactineAdministering Lurasidone at night may reduce side-effects
CariprazineD2 partial agonist-more of an antagonist than AripiprazoleIn late stage clinical testing for schizophrenia, acute bipolar mania, bipolar depression and treatment resistant depression-higher doses for schizophrenia and mania (antagonist actions)-lower doses for depression (agonist action)Stronger affinity for D3 than D2 receptorsFew metabolic side effects and low risk for EPSLong lasting metabolite.Stahl SM Stahl’s Essential Psychopharmacology; The Prescriber’s Guide 4th ed 2011
BrexpiprazoleD2 partial agonist-more of an antagonist than AripiprazoleVery 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 antagonismPotential treatment for agitation and psychosis in dementiaStahl SM Stahl’s Essential Psychopharmacology; The Prescriber’s Guide 4th ed 2011
Glutamate in Schizophrenia NMDA hypofunction hypothesis of schizophrenia Neurodevelopmentally abnormal glutamate synapses Hypofunctional NMDA receptors Modulation of glutamatergic transmission as a potential treatment strategy-direct acting glycine agonists-mGluR 2/3 presinaptic agonist-GlyT1 inhibitors (SGRIs)Stahl SM Stahl’s Essential Psychopharmacology; The Prescriber’s Guide 4th ed 2011
The trouble with the world isnot that people know toolittle, is that they know somany things that just aren’tso Mark Twain
Both Psychosis and SomeAntipsychotics Cause Brain Tissue Loss
Brain Changes Associated withAntipsychoticsTypical antipsychotics: enlargement of the putamen reduction of lobulus paracentralis, anterior cingulate gyrus, superior and medial frontal gyri, superior and middle temporal gyri, insula and precuneus).Atypical antipsychotics:enlargement of the thalami.
Atypical AntipsychoticsPromote Neurogenesis NGF, BDNF,GDNF, fibroblast growth factors (FGF)are decreased by 60% in first episode psychosis (FEP). Over two dosed studies showed that atypical antipsychotics increase growth factors, stimulate neurite extension, neurogenesis and cell survival Typical antipsychotics lower BDNF levels, reducing neuroprotection in the brain.Psychiatr Danub. 2012 Sep;24 Suppl 1:S95-9.The differences between typical and atypical antipsychotics: the effects onneurogenesis.Nandra KS, Agius M.Clare College Cambridge, Cambridge, UK.
Growth Factor and Antipsychotics
Long Term Antipsychotic Treatment and BrainVolumes: A longitudinal Study of First-EpisodeSchizophreniaAn average of 7.2 years of continuous typicalantipsychotic therapy was associated withgeneralized and specific reductions in brain tissue.Archives of General Psychiatry. 2011;68(2):128-137.doi: 10.1001/archgenpsychiatry.2010.199
TD as an Indicator of Tissue Loss 1 Year Incidence of TD with Atypical vs. Typical AntipsychoticsKane JM in Bloom FE, Kupfer DJ, Psychopharmacology: The fourth generation of progress. Philadelphia Raven 1996National Alliance on Mental illness. Tardive dyskinesia Available atwww.nami.org/ContentGroups/Helpline1/Tardive_Dyskinesia.html
Schizophrenia and 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)Thompson, P.M. et al: Mapping Adolescent brain change reveals dynamic wave of accelerated gray matter lossin very early-onset schizophrenia. Proc Natl Acad Sci USA 98, 11650-11655
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, BDNFPsychiatr Danub. 2012 Sep;24 Suppl 1:S95-9.The differences between typical and atypicalantipsychotics: the effects on neurogenesis. Nandra KS, Agius M. Clare College Cambridge,Cambridge, UK.
Alzheimer’s - massive cell apoptosisSchizophrenia - apoptosis of cellprocesses (dendrites)
Cortical Pyramidal NeuronsApoptotic mechanisms and the synaptic pathology of schizophrenia; Leisa A. Glantza, John H. Gilmorea, Jeffrey A. Liebermanb, L.Fredrik Jarskoga, , Department of Psychiatry, University of North Carolina—Chapel Hill, CB# 7160, Chapel Hill, NC 27599-7160, U.S.A.b Department of Psychiatry, Columbia University, New York, NY 10032, U.S.A.http://dx.doi.org/10.1016/j.schres.2005.08.014,
Metabolomic Biomarkers inSchizophreniaThe following set of metabolic biomarkers have identical sensitivity and specificity as the MSE Glycerate Eicosenoic acid Beta-hydroxybutirate Pyruvate Cysteine Urine beta hydroxybutiratePotential Metabolite Markers of Schizophrenia; J. Yang et al.; Molecular Psychiatry(213) 18, 67-78; doi:10.1038/mp.131
Cultured Patient Specific Neurons Exposed toAntipsychotics or Neuroprotective Agents Personalized Medicine Ability to identify medications that work best for a specific individual prior to the initiation of therapy.Modeling Schizophrenia Using Human Induced Pluripotent Stem Cells;Kristen J. Bernnand et al.; Nature473, 221-225 (12 May 2011) doi:10.1038/nature09915
Patient Specific Cultured Neurons Exposed to LoxapineCultured neurons from patients with schizophrenia present with decreasedneuronal connectivity.Adding Loxapine resulted in improvement in neuronal connectivityModeling Schizophrenia Using Human Induced Pluripotent Stem Cells;Kristen J. Bernnand et al.; Nature473, 221-225 (12 May 2011) doi:10.1038/nature09915
Analysis of Dendritic Spine Density andMorphology in Cultured Neurons Software for high-resolution imaging of dendritic spines in cultured live neurons.
Future Treatment Algorithm Dx by MSE Determine the verified by affected Schizophrenia domain of metabolomic schizophrenia panel Staging of the illness (fMRI +connectomics) Choosing best Assessment of therapy Tx efficacy (cultured (dendritic spine patient specific density neurons) measurement)
The best way to become boring is to say everything. Voltaire