1 Jaime Grodzicki, MD Montevideo, 1 de julio, 2017Sicofarmacos con los que no contamos en el Uruguay Farmacologia y Experiencia Clinica Jaime Grodzicki, MD Montevideo, 1 de julio, 2017

2 Objetivos Descripcion de la farmacologia y uso clinico de sicofarmacos todavia no introducidos en el Uruguay Breve presentacion sobre Genetic Testing en siquiatria. Presentation de casos clinicos, su desarrollo y tratamiento Discusion e intercambio de ideas.

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4 ANTIDEPRESIVOS Levomilnacipran (Fetzima) Vortioxetine (Trintelix)Vilazodone (Viibryd) Levomilnacipran (Fetzima)

5 VORTIOXETINE (TRINTELLIX)CLASS: Multimodal antidepressant INDICATION: Major Depressive Disorder Generalized Anxiety Disorder Cognitive Symptoms Associated with Depression Depression in the Older Adult MECHANISM OF ACTION: Increases the level of several neurotransmitters: Serotonin, Norepinephrine, Dopamine, Glutamate, Acetyl choline and Histamine

6 VORTIOXETINE (TRINTELLIX): Mechanism of ActionBlock serotonin reuptake pump (Transporter) Binds to G-protein-linked receptors Full agonist at serotonin 1A receptors Partial agonist at Serotonin 1B receptors Antagonist at Serotonin 1D receptors and serotonin 7 receptors. Binds to Ion-Channels- linked receptors Full agonist at pre-synaptic serotonin 1A receptors – antidepressant action Full agonist at post-synaptic serotonin 1A receptors – improves sexual dysfunction Antagonist actions at serotonin 3 receptors – increased NE, Ach, and glutaminergic activity – antidepressant and improves cognition Antagonistic action at serotonin 7 receptors – reduces insomnia and improves cognition Antagonist action at serotonin 1B receptors – increased serotonin, Ach, and histamine release

7 VORTIOXETINE (TRINTELLIX) Side EffectsGastrointestinal: Nausea, vomiting constipation Sexual dysfunction: Less than with other antidepressants Weight Gain: low rate of weight gain Sedation CAREFUL WITH PATIENTS WITH: History of seizures History of bipolar disorder

8 VORTIOXETINE (TRINTELLIX)DOSING: Tablets 5, 10, 15 and 20 mg. Start with 10 mg daily (may start at 5 mg) Max. dosing: 20 mg daily WARNINGS: Use with caution with antidepressants that are CYP450 2D6 inhibitors (e.g. bupropion, duloxetine, fluoxetine, paroxetine) May cause hyponatremia May interact with Tramadol – Increased risk of seizures MAOI – serotonin syndrome Sumatriptan and other triptans – serotonin syndrome Anticoagulants – increased risk of bleeding

9 VILAZODONE (VIIBRYD) CLASS : SPARI = Serotonin Partial Agonist Reuptake Inhibitor Dual action: Serotonin Reuptake Inhibitor + 5HT 1A Partial Agonist INDICATION: Major Depressive Disorder Anxiety OCD MECHANISM OF ACTION: Boosts Serotonin Blocks serotonin reuptake pump Desensitizes serotonin receptors

10 VILAZODONE (VIIBRYD) Side EffectsMost common side effects: Diarrhea, Nausea, Vomiting, Headache Insomnia, Dizziness, rare sedation Bruising, rare bleeding Hyponatremia (seldom) Rare sexual dysfunction Akathisia, anxiety, agitation Weight gain, unusual Seizures (seldom)

11 RISK OF SEROTONIN SYNDROMEVILAZODONE (VIIBRYD) Pharmacokinetics Half Life 12 hours Metabolized by CYP450 3A4 DOSING: Tablets 10, 20 and 40 mg. Start with 10 mg daily, increase to 20 mg after 1 week, to 40 mg after another week Take with food WARNINGS: May interact with Tramadol – Increased risk of seizures MAOI – serotonin syndrome Sumatriptan and other triptans – serotonin syndrome Anticoagulants and NSAIDs – increased risk of bleeding Inhibitors of CYP450 3A4: Decrease clearance and increase plasma levels e.g: nefazodone, fluoxetine, grape juice Inducers of CYP450 3A4: Increase clearance and decrease therapeutic effects e.g: carbamazepine. CONTRAINDICATED IN PATIENTS TAKING OR WITHIN 14 DAYS OR STOPPING MAOIs DUE TO RISK OF SEROTONIN SYNDROME

12 LEVOMILNACIPRAN (FETZIMA)CLASS : SNRI = Dual Serotonin and Norepinephrine Reuptake Inhibitor INDICATION: Major Depressive Disorder Fibromyalgia Neuropathic/Chronic pain MECHANISM OF ACTION: Increase release of Serotonin, Norepinephine and Dopamine Blocks norepineprhine reuptake pump (transporter) Blocks serotonin reuptake pump (transporter) Dopamine is inactivated by the NE reuptake in the frontal cortex – it appears to be an increase of Dopamine determined by the blocking of the NE reuptake

13 LEVOMILNACIPRAN (FETZIMA) Side EffectsMost common side effects: Constipation, Nausea, Dizziness Sweating Palpitations, tachycardia Erectile Dysfunction Urinary hesitancy Weight gain, unusual Sedation rare Anxiety, akathisia

14 LEVOMILNACIPRAN (FETZIMA)Pharmacokinetics Half Life 12 hours Metabolized by CYP450 3A4 DOSING: Tablets 20, 40, 80 and 120 mg. Start with 20 mg daily, increase to 40 mg after 2 days, to 80 mg after another 2 days Max dose : 120 mg/day WARNINGS: History of Seizure disorder History of Bipolar Disorder History of Urological Disorders Hypertension Angle Closure Glaucoma May interact with Tramadol – Increased risk of seizures MAOI – serotonin syndrome Anticoagulants and NSAIDs – increased risk of bleeding Alcohol: May cause pronounced accelerated drug release = DRUG DUMPING

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16 ANTISICOTICOS ATIPICOSLurasidone (Latuda) Asenaprine (Saphris) Palperidone (Invega) Cariprazine (Vraylar) Brexpiprazole (Rexulti)

17 LURASIDONE (LATUDA) CLASS : Atypical Second Generation Antipsychotic : Serotonin and Dopamine Antagonist INDICATION: Schizophrenia Bipolar Disorder Off label: Acute mania/Mixed mania Other psychotic disorders Bipolar maintenance Treatment resistant depression Behavioral disturbances in dementia Impulsive control MECHANISM OF ACTION: Blocks D2 receptors Blocks serotonin 2A receptors Blocks serotonin 7 receptors Partial agonist at serotonin 1A , alpha2A and alpha 2C receptors (beneficial for mood, anxiety and cognition) Lacks potent action on D1 receptors and muscarinic M1 receptors = less propensity to cause cognitive impairment, weight gain and sedation.

18 LURASIDONE (LATUDA) Side EffectsSedation Akathisia Nausea Weight gain, unusual Sedation rare Hyperglycemia Metabolic syndrome is less frequent = “metabolic friendly”

19 LURASIDONE (LATUDA) DOSING: DRUG INTERACTIONS:Pharmacokinetics Half Life hours Metabolized by CYP450 3A4 DOSING: Tablets 20, 40, 80 and 120 mg. Start with mg daily for schizophrenia Start with mg daily for bipolar depression Take with food Once a day dosing DRUG INTERACTIONS: Inhibitors of CYP450 3A4 – increase plasma levels of lurasidone e.g. nefazodone, fluvoxamine, fluoxetine Moderate inducers of CYP450 3A4 – decrease plasma levels of lurasidone CONTRAINDICATED WITH: Strong Inhibitors of CYP450 : Ketoconazole Strong Inducers of CYP450: Rifampin

20 ASENAPINE (SAPHRIS) CLASS: Atypical Antipsychotic – serotonin-dopamine antagonist SGA INDICATION: Schizophrenia (acute and maintenance) Acute mania/mixed mania Psychotic disorders Bipolar disorder Treatment of resistant depression Behavioral disturbances in dementia, and impulse control behaviors in children and adolescents MECHANISM OF ACTION Blocks Dopamine D2 and Serotonin 2A Receptors Serotonin 2C, Serotonin 7 and Alpha 2 antagonist properties may contribute to antidepressant action.

21 ASENAPINE (SAPHRIS) Side EffectsDizziness, sedation, hypotension (Alpha1 adrenergic receptor blockage) Extrapyramidal symptoms (D2 receptor blockage in the striatum) Hyperprolactinemia (D2 receptor blockage in the pituitary) Oral hypoesthesia Hyperglycemia, dyslipidemia Weight gain

22 ASENAPINE (SAPHRIS) PHARMACOKINETICS: DOSING: DRUG INTERACTIONS:Half Life: Hours. Inhibits CYP450 2D6; Substrate for CYP450 1A2 DOSING: Tablets 5 and 10 mg sublingual (patient may not eat or drink for 10 min. following administration. 10 – 20 mg/day in 2 divided doses for schizophrenia mg in 2 divided doses for bipolar depression DRUG INTERACTIONS: May increase effects of antihypertensives May antagonize levodopa CYP450 1A2 inhibitors increase plasma levels of asenapine PRECAUTIONS: In patients with hypotension In patients with dysphagia: Increases risk of aspiration pneumonia

23 PALIPERIDONE (INVEGA)CLASS: Atypical Antipsychotic – serotonin-dopamine antagonist SGA INDICATION: Schizophrenia (maintenance) Psychotic disorders Bipolar disorder Behavioral disturbances in dementia, and impulse control behaviors in children and adolescents MECHANISM OF ACTION Blocks Dopamine D2 and Serotonin 2A Receptors Serotonin 7 antagonist properties may contribute to antidepressant action.

24 PALIPERIDONE (INVEGA) Side EffectsDizziness, sedation, orthostatic hypotension (Alpha1 adrenergic receptor blockage) Extrapyramidal symptoms (D2 receptor blockage in the striatum) Hyperprolactinemia (D2 receptor blockage in the pituitary) Hypersalivation Hyperglycemia Weight gain (dose dependent)

25 PALIPERIDONE (INVEGA)PHARMACOKINETICS: Half Life: 23 hours Hours. Active metabolite of risperidone DOSING: Tablets 1.5mg, 3 mg, 6 mg, 9mg oral administration. Start 3-6 mg in am; increase by 3 mg every 5 days Long acting form IM (Sustenna): 39 mg, 78mg, 117 mg, 156mg, 234mg Day 1: 234 mg IM gluteal and Day mg IM in deltoid. Maintenance dose: 117 mg every days DRUG INTERACTIONS: Other Antipsychotics (e.g. asenapine, thorazine) Oncological medications

26 CARIPRAZINE (VRAYLAR)CLASS: Atypical Antipsychotic INDICATION: Schizophrenia Acute treatment of manic and mixed episodes associated with Bipolar I Disorder in adults Persistent negative symptoms in schizophrenia MECHANISM OF ACTION Dopamine D3 and D2 Receptors partial agonist with preferential binding to D3 Serotonin 7 antagonist properties may contribute to antidepressant action.

27 CARIPRAZINE (VRAYLAR) Side EffectsEPS and akathisia Nausea and vomiting Metabolic changes: hyperglycemia, Dyslipidemia, Weight gain, DM Leukopenia, Agranulocytosis Orthostatic hypotension – syncope Seizures Lethargy and restlesness Dysphagia

28 CARIPRAZINE (VRAYLAR)PHARMACOKINETICS: Strong CYP3A4 inhibitors increase Vraylar concentration DOSING: Tablets 1.5mg, 3 mg, 4.5 mg, 6mg oral administration. DRUG INTERACTIONS:

29 BREXPIPRAZOLE (REXULTI)CLASS: Atypical Antipsychotic INDICATION: Adjuvant therapy to antidepressants in MDD adults MECHANISM OF ACTION Partial agonist of Serotonin 5HT1A Receptors Partial agonist D2 receptors Serotonin 5-HT 2A partial antagonist

30 BREXPIPRAZOLE (REXULTI) Side EffectsDizziness, sedation, fatigue Akathisia Anxiety Tremor Constipation Weight gain/ increase appetite

31 BREXPIPRAZOLE (REXULTI)PHARMACOKINETICS: DOSING: Tablets 0.5mg, 1 mg, 2 mg, 3mg oral administration. Start 0.5 mg daily for 7 days and 1 mg daily for the next 7 days DRUG INTERACTIONS:

32 Genomind and The Genecept Assay™

33 Treatment Resistance in PsychiatryDiagnosis Initial Remission Rate Treatment Resistant/Relapse Depression (MDD)1 30-37% (STAR-D) 30% treatment resistant following 4 treatments Bipolar Disorder (BD)2 24-77% (STEP-BD) 50-70% relapse rates Schizophrenia3,4 16-44% (CATIE) Up to 74% discontinue medications due to lack of efficacy or poor side effects after 18 months Anxiety (GAD)5,6 12-60% Recurrence in up to 50% Obsessive Compulsive Disorder (OCD)7 25-71% Up to 80% in 10 year follow-up This slide is meant to highlight the fact that with “treatment as usual”, many patients are left with resistant psychiatric symptoms. Star-D, STEP-BD and CATIE are all NIMH (National Institute of Mental Health) studies and are considered the gold standard trials in their respective disease states. This is meant to set the stage for alternatives to “treatment as usual” Bipolar: Randomised controlled trial of efficacy of teaching patients with bipolar disorder to identify early symptoms of relapse and obtain treatment BMJ 1999; 318 doi: 16 January 1999)Cite this as: BMJ 1999;318:149 High relapse rates in bipolar disorder confirmed By Sarah Pritchard, medwireNews Reporter 09 April 2014 J Clin Psychiatry 2014; 75: 254–263 GAD: Eur Arch Psychiatry Clin Neurosci. 2009 Feb;259(1): doi: /s Epub 2008 Jun 24. The generalized anxiety spectrum: prevalence, onset, course and outcome. Angst J1, Gamma A, Baldwin DS, Ajdacic-Gross V, Rössler W. Phenomenology and course of generalised anxiety disorder. K A Yonkers, M G Warshaw, A O Massion, M B Keller DOI:  /bjp  Published 1 March 199 OCD: J Clin Psychiatry. 2006 Feb;67(2): Response versus remission in obsessive-compulsive disorder. Simpson HB1, Huppert JD, Petkova E, Foa EB, Liebowitz MR. Long-Term Outcomes Are Poor in Obsessive-Compulsive Disorder Deborah Cowley, MD reviewing Bloch MH et al. Depress Anxiety 2013 Mar 26. 30-80% of psychiatric patients have unresolved symptoms. Many have abandoned drug therapies due to inefficacy or side effects STAR-D Shaw et al. A systematic review and analysis of long-term outcomes in attention deficit hyperactivity disorder: effects of treatment and non-treatment. 2012 K A Yonkers, M G Warshaw, A O Massion, M B Keller STEP-BD Schizophrenia and Related Disorders Alliance of America (SARDAA) Eur Arch Psychiatry Clin Neurosci Feb;259(1): doi: /s Epub 2008 Jun 24. National Institute of Mental Health (NIH) 3333

34 The Genecept Assay The Genecept Assay was introduced commercially in 2010: Patented gene-based assay informs treatment decisions for patients with mental health conditions, such as; depression, anxiety, obsessive-compulsive disorder (OCD), attention deficit hyperactivity disorder (ADHD), bipolar disorder, post traumatic stress disorder (PTSD), autism, schizophrenia, chronic pain and substance abuse Analyzes neurotransmitter based genes, including serotonin, dopamine, and glutamate Analyzes pharmacokinetic genes, related to drug and nutritional metabolism Over 60,000 patients have been tested in the U.S. to date Over 3,000 clinicians have ordered the test for their patients to date Clinicians are using the Assay as a standard of care in their practices Clinicians initially used the Assay for more treatment-resistant patients; however, the number of patients tested with no previous treatment trials has doubled since launch Pharmacodynamic Pharmacokinetic Data on file. Genomind 2016.

35 Personalized TreatmentNature vs. Nurture = GENES Environment Phenotype In psychiatry we do a good job of determining what environmental factors have contributed to a particular disorder Until now, we have not had access to a large component of our phenotype…..genetic factors This slide is meant to highlight the fact that our genes are NOT deterministic. Environmental factors impact the expression of these genes and clinicians should be careful to always include clinical/ environmental patient history when making clinical decisions. The genes in the Genecept Assay present risk factors for some drug therapies and should be used as supplemental data to all other clinical information. = GENECEPT ASSAY Patient History Personalized Treatment Bay et al 2011 3535

36 CYP450 Variations Mediate Drug ResponseGene variants associated with altered liver enzyme metabolism activity may lead to side effects and toxicity PM Poor metabolizers or inhibitors of P450 may have increased drug serum levels and adverse events. IM Intermediate metabolizers or inhibitors of P450 may have increased drug serum levels and adverse events. EM Extensive metabolizers metabolize substrates normally. UM Ultra-rapid metabolizers or inducers of P450 may have reduced drug serum levels and poor efficacy. IM 4 possible phenotypes for CYP450. PM and UM are your highest risk populations Dosing document is available upon request Highlight the FDA guidance concerning P450 gene variants. Approximately 2-7% of the population are poor metabolizers for the CYP2C19 enzyme. Citalopram is associated with QTc prolongation The FDA has provided guidance on several other psychiatric drugs which is noted with a Rx symbol on our report. These drugs can be found on the report interpretation guide FDA warning (Aug 2011): Citalopram maximum dose of 20mg in CYP2C19 poor metabolizers and those receiving CYP2C19 inhibitors Swen et al 2011; 3636

37 Case Study 3737

38 Case Study 42 y/o male, fully employed with 2 childrenChronic diagnosis of MDD for more than 20 years Presents with refractory depression, thoughts of sadness and suicidal ideation and mood swings Fluoxetine and escitalopram led to minimal improvement of symptoms, d/c due to inefficacy and/or side effects 3838

39 Case Study What would your treatment choice be? Sertraline DuloxetineCurrently taking no meds, but admits to periodic ETOH binge use What would your treatment choice be? Sertraline Duloxetine Bupropion Mood stabilizer Methylfolate 3939

40 Patient Results 4040 Data on file. Genomind 2016.

41 Patient Results Data on file. Genomind 2016.

42 Patient Results 4242 Data on file. Genomind 2016.

43 Interpretation Lack of efficacy for SSRI’s could be related to the SLC6A4 or 2C19 variants SNRIs and atypical antidepressants are relevant for this patient; clinician decided to prescribe duloxetine Caution with any drugs metabolized by 2C19 or 2B6 4343 Data on file. Genomind 2016.

44 Interpretation CACNA1C variation in combination with clinical presentation, led clinician to try lurasidone. Careful monitoring of weight gain was warranted due to the MC4R variation. An exercise regimen was recommended due the presence of this variant as well as the BDNF variation. 4444 Data on file. Genomind 2016.

45 Interpretation L-methylfolate and Omega-3 fatty acids were also added to the patients regimen due to the presence of variations in MTHFR and CACNA1C Data on file. Genomind 2016.

46 Follow-up Patient reportedStable mood, with no new depressive episodes No sexual side effects Reduction of HAM-D from 20 to 5 Reduction of depressive thoughts, suicidal ideation, and mood swings has allowed him to become more productive in work and in his social life Compliant with regimen and exercise plan Fully Employed, recently separated with 2 children, presents with depression, irritability, fatigue and amotivation and passive suicidal ideation 4646

47 Casos Clinicos

48 Caso 1: Ramon Historia ClinicaRamon es un hombre de 30 años, vive solo en un residencial Historia de depresion desde los 13 aos desencadenado por un abuso sexual y cambio de escuela. Historia de accidente transito a la edad de 7 anos y sensacion premanente de que “el mundo no es seguro” 2 intentos de suicidios severos Alcoholismo Historia de delirio persecutorio y alucinaciones auditivas Niega sintomas de enfermedad bipolar

49 Caso 1: Ramon Historia ClinicaTratamiento recibido antes de llegar a mi clinica Rehabilitacion por alcoholismo y tratamiento en residencial (por alcoholismo y depresion) Historia familiar: Alcoholismo Historia medica: negativa Abuso de sustancias: Dependencia al Alcohol Dpendencia a las Benzodiazepinas Dependencia a la Nicotina

50 Caso 1: Ramon Historia ClinicaExamen Mental: Hombre de complexion normal, alerta, distante, vestido de negro con tatuajes, aspecto inusual, tono de voz y afecto monotono. El curso de pensamiento en normal. No presenta sintomas sicoticos. Niega ideas suicidas. Inteligencia es normal. Introspeccion es limitada.

51 Caso 1: Ramon Historia Farmacologica Dextroamfetamina (10 años)Olanzepina Fluoxetina Bupropion Clonazepam (5 años) Alomoxetina Lamotrigina

52 Caso 1: Ramon Discusion del caso:

53 Caso 2: Lucero Historia ClinicaLucero es una adolescente de 17 años que reside con sus padres y su hermano Historia de depresion cronica desde los 9 años desencadenada por la mudanza de sus padres a otro pais y la perdida de amistades y entorno. Sintomas: tristeza melancolica profunda, ideas de suicidio, aislamiento social, disminucion the capacidad de concentracion, alucinaciones tactiles, llanto facil, perdida de apetito y de peso, pobre rendimiento escolar con multiples ausencias, muy baja autoestima y falta de motivacion.

54 Caso 2: Lucero Historia ClinicaTratamiento recibido antes de llegar a mi clinica Sicoterapia individual Farmacoterapia Hospitalizacion 21 dias Historia familiar: depresion Historia medica: negativa Abuso de sustancias: negativa

55 Caso 2: Lucero Examen MentalJoven adolescente, delgada, aseo descuidado, fragil, aprehensiva, que pide juguetes o muñecas en la sesion, no habla espontaneamente. Sus movimientos son lentos y se resiste a la entrevista siquiatrica. Afecto depresivo y distante. Niega alucinaciones auditivas pero admite alucinaciones tactiles. Curso del pensamiento es normal con contenido nihilista.

56 Caso 2: Lucero Historia Farmacologica Sertralina FluoxetinaApipiprazole Quatiepina

57 Caso2: Lucero Discusion del caso:

58 Caso 3: Miguel Historia ClinicaHombre de 27 años que vive solo en un apartamento compartido con otras dos personas Historia de enfermedad maniaca depresiva con delirio mesianico y conviccion que el fin del mundo se acerca rapidamente. Problemas de comportamiento desde su niñez , agresion verbal, antagonismo, masturbacion compulsiva precoz (desde los 10 años) y profund culpa y verguenza Admite alucinaciones auditivas (la voz le dice que el es el Mesias) provocando miedo y reclusion social, agitacion severa y sensacion de desintegracion mental

59 Caso 3: Miguel Historia ClinicaTratamiento recibido antes de llegar a mi clinica 3 hospitalizaciones Tratamientos en policlinicas y residenciales Farmacoterapia Sicoterapia individual Historia familiar: --- Historia medica: negativa Abuso de sustancias: alcohol, marijuana, cocaina, experimentacion con alucinogenos

60 Caso 3: Miguel Examen MentalPaciente de complexion normal, pelo largo y decuidado, barba, vestido con ropa holgada. Actitud desafiante, demandante. Presenta enojo, sospecha, agitacion y su tono de voz era alto. Curso de pensamiento tangencial, circumstancial y con contenido mesianico, ideas de referencia y delirio paranoidal. Su afecto era mixto, predominantemente depresivo y su experiencia subjetiva era de “profundo sufrimiento” Inteligencia normal; muy poco nivel de instrospeccion

61 Caso 3: Miguel Historia Farmacologica Aripripazole OlanzepinaQuetiapina Risperidona Clozapina Fluoxetina Litio Acido Valproico

62 Caso 3: Miguel Discusion del caso:

63 Caso 4: Ana Maria Historia ClinicaAna Maria es una mujer casada, 39 años, que reside con su marido y dos hijas Historia de sintomas depresivos desde su adolescencia temprana Sintomas actuales: tristeza, angustia, disminucion de capacidad de concentracion, aumento de peso (50 Kg en 1 año), cansancio, perdida de motivacion, ideas suicidas, llanto facil, soledad, irritabilidad

64 Caso 4: Ana Maria Historia ClinicaTratamientos recibidos antes de llegar a mi clinica Multiples antidepresivos Antisicoticos Benzodiazepinas Sicoterapia cognitiva Sicoterapia de corte sicoanalitico TMS (18 tratamientos sin respuesta) Historia familiar Depresion y enfermedad bipolar Problemas medicos Obesidad (130 Kg) Hipotiroidismo

65 Caso 4: Ana Maria Examen MentalPaciente triste, obesa, alerta, cooperativa, vestida con ropa oscura que cubre todo su cuerpo. Aseo adecuado. Aspecto depresivo. Niega ideas suicidas. No presenta sintomas sicoticos. Inteligencia es normal. Nivel de instropeccion es aceptable. Curso de pensamiento es normal.

66 Caso 4: Ana Maria Historia Farmacologica Acido Valproico LitioEscitalopram Citalopram Sertralina Bupropion Aripiprazole Dextroamphetamine Modafinil Quetapine Alprazolam Trazodona Ketamina Lamotrigina

67 Caso 4: Ana Maria Discusion del caso:

68 PREGUNTAS ?

69 Jaime Grodzicki, MD [email protected]Sicofarmacos con los que no contamos en el Uruguay Farmacologia y Experiencia Clinica GRACIAS POR SU PRESENCIA Y ATENCION! Jaime Grodzicki, MD