Antidepresivos 2009 -II
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ANTIDEPRESIVOS Y
ESTABILIZANTES DEL HUMOR
(ESTADO DE ANIMO)
Unidad de Farmacologa
Miguel E MartnezSnchez,MD
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ANTIDEPRESIVOS
TRICCLICOS (HETEROCCLICOS) INHIBIDORES DE LA RECAPTACIN
DE SEROTONINA INHIBIDORES DE LA MONOAMINO -
OXIDASA (MAO)
ESTABILIZANTES DEL HUMOR TRIAZOLOBENZODIACEPINAS
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ANTIDEPRESIVOS
AGONISTAS PARCIALES DELRECEPTOR 5-HT1A INHIBIDOR DE LA RECAPTACIN
DE SEROTONINA Y ANTAGONISTADEL RECEPTOR 5-HT2 INHIBIDOR NO SELECTIVO DE LA
RECAPTACIN DENEUROTRASMISORESAMINERGICOS
TERAPIA ELECTROCONVULSIVATEC
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TEORIAS BIOQUMICAS DEL AFECTO
TEORIA DE LAS AMINASBIOGENAS (1950-1960)
INHIBIDORES DE LA M.A.O EFECTO DE LOS TRICCLICOS EFECTO DE LAS ANFETAMINAS REACCIONES PSICTICAS EFECTO DE LA RESERPINA
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orepinephrine
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Alpha Receptors
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Serotonin
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5-HT: Behavioral Actions
Food intake: increased 5-HT reducesFI (Fenfluramine)
Pain sensitivity (reduced 5-HT =
increased pain sensitivity) 5-HT is low during sleep 5-HT metabolite 5-HIAA is low in
suicides Loss of 5-HT transporters in MDMA
users
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Serotonin
Serotonin(5-HT) cells are mostlylocated in the gut (98%) with only 2%of serotonin cells in brain
Serotonin cell bodies are located in
brainstem raphe nuclei and project tocortex Serotonin systems:
D system originates in the dorsal raphenucleus but does not form synapses (5-HTas a neuromodulator)
M system originates from the median
raphe nucleus and these varicosities formsynapses4.11
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SINTOMAS DEPRESIVOS Y
SU RESPUESTA
NEUROVEGETATIVOS:Trastornos del sueo
Trastornos del apetitoTrastornos de la volicin
Trastornos sexuales
Ritmos diurnos anormales 10 dias a 2 semanas
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SINTOMAS DEPRESIVOS Y
SU RESPUESTA
PSICOMOTORES: AGITACIN O LENTIFICACIN 3-4 SEMANAS (MEJORIA 7-14 DIAS)
AFECTIVOS TRISTEZA (MELANCOLIA) INCAPACIDAD DE EXPRESIN LENTAMENTE Y POR ETAPAS
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SINTOMAS DEPRESIVOS Y
SU RESPUESTA
COGNOCITIVOS: CONCENTRACIN MEMORIA ATENCIN APRENDIZAJE
PSICTICOS INCAPACIDAD SOCIAL
LENTAMENTE Y POR ETAPAS
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DIMENSIN EXISTENCIAL
SOLEDAD CULPA
RUMIACININCAPACIDAD PARA LA
GRATITUD
CIRCULOS VICIOSOS
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ESTABLECER DIFERENCIAS
DUELO: CULPA/REPROCHE SINT SOMATICOS
MENOS DE SEISMESES FUNCIONAL NO SUICIDIO
DEPRESIN CULPA/REPROCHE SINT SOMATICOS
MAYOR A SEISMESES DEBILITAMIENTO
PROGRESIVO
POTENCIALMENTESUICIDA
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ESTABLECER DIFERENCIAS
DEMENCIAINSIDIOSA PROLONGADA
AFECTOVARIABLE DEF COGNITIVAS
CONSISTENTES
RESP ERRONEASEN EVAL NEUROLAFASIA,APRAXIA,
AGNOSIA
DEPRESINABRUPTA* CORTA*
AFECTODEPRESIVO DEF COGNITIVO
NO
PERSISTENTES NO DEFICIT
NEUROLOGICO
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ANTIDEPRESIVOS HETEROCCL ICOS
Am inas terciar ias
IMIPRAMINA AMITRIPTILINA TRIMIPRAMINA
DOXEPINA CLOMIPRAMINA
Tofranil
Tryptanol Surmontil
Anafranil
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ANTIDEPRESIVOS HETEROCCL ICOS
Am inas secundar ias
DESIPRAMINA NORTRIPTILINA PROTRIPTILINA AMOXAPINA MAPROTILINA Ludiomil
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FARMACODINAMIA
INHIBICIN DE LARECAPTACIN DENORADRENALINA
INHIBICIN DE LARECAPTACIN DE SEROTONINA
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EFECTOS SECUNDARIOS
LOS EFECTOS SECUNDARIOSSE CORRELACIONAN MEJORCON EL PERFIL
FARMACODINAMICO QUE STECON LOS EFECTOS CLNICOS
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EFECTOS SECUNDARIOS
ANTICOLINERGICOS SEQUEDAD DE LA BOCA VISIN BORROSA CONSTIPACIN RETENCIN URINARIA CONFUSIN
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EFECTOS SECUNDARIOS
ANTIHISTAMNICOS SEDACIN
SEROTONINRGICOS SEDACIN Y/O ACATISIA
ADRENRGICOS TEMBLOR, EXCITACIN PALPITACIONES GANANCIA DE PESO
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INHIB IDORES DE LA
RECAPTACIN DE SEROTONINA
FLUOXETINA
TRAZODONE SERTRALINA PAROXETINA FLUVOXAMINA CITALOPRAM
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INDICACIONES
Enfermedad cardiacaconcomitanteIntolerancia a los efectos
secundarios anticolinrgicosAlto riesgo de sobredosis
voluntaria
Aumento de peso excesivo La sedacin no es aconsejable Trastorno obsesivo-compulsivo
asociado
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EFECTOS SECUNDARIOS
Gastrointestinales: nausea,flatulencia, diarrea
S.N.C: insomnio, inquietud,irritabilidad, euforia, agitacin,temblores, distona*
Sexuales: eyaculacinretardada, anorgasmia
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SINDROME SEROTONINERGICO
HipertermiaInquietud, calambres
musculares, rigidez
Convulsiones y coma
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INHIBIDORES DE LA MAO
NO SELECTIVOSISOCARBOXAZI
DA TRANILCIPROMI
NA
SELECTIVOS MOCLOBEMIDA BROMFAROMINE
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EFECTOS SECUNDARIOS
Autonmicos: boca seca,mareo, estreimiento,
dificultad en la miccin,hipotensin postural
Centrales: cefalea, temblores,
parestesia Otros: edema en tobillos,
hepatotoxicidad
Trazodone (Desyrel)
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Trazodone (Desyrel)
SARI (serotonin antagonist/reuptakeinhibitor) Strong 5-HT2Aantagonist, relatively weak 5-HT
reuptake inhibitor Also an 1-adrenergic and H1 antagonist
Introduced in 82 as an atypical orsecond generation antidepressant
Chemically distinct from TCA, resemblesnefazadone
Highly protein bound, metabolized by 3A4,to mCPP (active metabolite), overall half-life < 24 hours.
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Trazodone (Desyrel) cont.
Bottom Line: Almost always used for insomnia. Watch for orthostatic hypotension Caution about priapism Remember, its an antidepressant!
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NEFAZODONE
INHIBIDOR DE LA RECAPTACIONDE SEROTONINA Y ANTAGONISTA
DEL RECEPTOR 5-HT2
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Nefazadone (Serzone)
SARI (serotonin antagonist/reuptakeinhibitor) Strong 5-HT2Aantagonist, relatively weak 5-HT
reuptake inhibitor
Weaker alpha 1 adrenergic and H1 antagonistcompared to trazadone. Approved in 1995, developed to improve
upon trazadone: no priapism and lesssedating.
Unfortunately, cases of liver failure1:200,000-300,000 has limited its use. Ageneric still available. Time to liver injury 2 weeks to 6 months.
Check LFTs
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Mirtazapine (Remeron)
NaSSA (noradrenergic specific
serotonergic antidepressant) Central alpha-2 adrenergic autoreceptorantagonist (leads to net NE and 5-HTneurotransmission
5-HT2A, 5-HT2C, 5-HT3 antagonist H1 antagonist (the most potent action)
Approved for MDD (may work faster thanSSRIs)
Also used for SSRI augmentation, anxiety,nausea Moderately protein bound, metabolized by
1A2, 2D6, 3A4. Half-life 20-40 hours.
Eliminated primarily via urine
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Mirtazapine (Remeron) cont.
Bottom Line: Can be good inpatient choice (helps
sleep, depression, appetite, no drug
interactions) Not popular first choice for outpatients
(oversedation, weight gain).
Avoids sexual dysfunction. Used for augmentation
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Bupropion (Wellbutrin IR, SR, XL)
NDRI (norepinephrine, dopamine receptorinhibitor) Inhibits reuptake of NE, lesser extent
DA but exact mechanism controversial. Initial release of IR delayed due to
seizures, re-released in 89(rarely used).In 96 SR released (now generic) and in03 XL form released.
FDA approved for MDD, smoking cessation(Zyban)
Also used for ADHD, SSRI induced sexualdysfunction, SSRI augmentation Highly protein bound, bupropion and its
active metabolites metabolized by 2B6.
Half life approx 21 hours. Mild 2D6inhibitor.
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Bupropion (Wellbutrin IR, SR, XL) cont.
Bottom Line: Activating so caution for depression with
comorbid panic/anxiety disorders.
Can be useful for anergic depression orwhen you wish to avoid sexualdysfunction.
Relatively ineffective for anxietydisorders. Commonly used to augment SSRIs. Screen for seizure history.
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VENLAFAXINE
INHIBIDOR NO SELECTIVO DELA RECAPTACIN DENEUROTRASMISORES
AMINRGICOS
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Venlafaxine (Effexor XR)
SNRI (serotonin, norepinephrine reuptakeinhibitor) At low doses (75 mg-150 mg), primarily SSRI At moderate/high doses, also NE reuptake
inhibitor FDA approved for MDD, social phobia and GAD
At higher doses, some evidence of higherremission rate for MDD compared to SSRIs.
Some evidence: chronic pain, panic disorder,
ADHD, OCD Poorly protein bound, XR formulation slowsabsorption but half-life still only about 15 hours.Metabolized by 2D6 to active O-desmethylvenlafaxine (ODV) Primarily eliminatedin urine.
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Venlafaxine (Effexor XR) cont.
Bottom Line: Potentiallymodestly more efficacious
antidepressant at high doses but
inconsistent. Watch for discontinuation syndrome. Consider checking BP at doses > 225
mg qd Commonly used after initial trial ofSSRI.
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cymbalta (Duloxetine)
SNRI (serotonin, norepinephrinereuptake inhibitor) Unlike venlafaxine, reuptake of NE, 5-
HT equally affected. Approved for MDD and diabeticperipheral neuropathy Some evidence for chronic pain,
anxiety disorders, urinary stressincontinence. Highly protein bound, metabolized by
2D6 and 1A2, Half life 12 hours
Moderate inhibitor of 2D6
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cymbalta (Duloxetine) cont.
Bottom Line: Newest antidepressant (04) Marketed for physical symptoms of
depression but not unique: tertiaryTCAs, venlafaxine
Some evidence for improved remission
vs SSRIs but jury still out.
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TERAPIA
ELECTROCONVULSIVA
INDICACIONES RIESGO SUICIDA
SINTOMAS CATATNICOSINFORMACIN DEL ELECTROCHOQUE AL TECAR
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THREE PHASES OF TREATMENT
Time
Normal
Acute
Phase (3 months+)
Continuation
Phase (6-12 months)
Maintenance
Phase (years)
Response
Remission
Relapse
Relapse Recurrence
> 50%
STOP
Rx
65 to 70%
STOP
Rx
Recovery
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Potential Adverse Effects of
Antidepressant Therapy
10/31/201345
Cardiac
Orthostasis
hypertension
heart block,
tachycardia
Urogenital
Erectile dysfunction,ejaculation disorder,
anorgasmia,
priapism
Central Nervous System
Dizziness, cognitive impairment,
sedation, light-headedness,
somnolence, nervousness,
insomnia, headache, tremor,
changes in satiety and appetite
Gastrointestinal
Nausea, constipation,
vomiting, dyspepsia,
diarrhea
Autonomic Nervous System
Dry mouth, urinary retention,
blurred vision, sweating
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ESTAB IL IZANTES DEL HUMOR
CARBAMAZEPINAACIDO VALPROICO
CARBONATO DE LITIO
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TRIAZOLOBENZODIACEPINAS
ALPRAZOLAMADINAZOLAM
AGONISTAS RECEPTOR
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AGONISTAS RECEPTOR
5HT1A
GEPIRONA IPSAPIRONA
Symptom Domains of
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Symptom Domains of
Bipolar Disorder
Racing thoughts Distractibility Disorganization
Inattentiveness
Delusions
Hallucinations
Cognitive Symptoms
Psychotic Symptoms
Euphoria Grandiosity Pressured speech Impulsivity Excessive libido Recklessness Social intrusiveness Diminished need
for sleep
Depression Anxiety
Irritability Hostility Violence or
suicide
Manic Mood and Behavior Dysphoric or NegativeMood and Behavior
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Bipolar I,Rapid Cycling and
Mixed State
Bipolar II DisorderCyclothymic Disorder
SchizoaffectiveDisorder,
Bipolar Type
BorderlinePersonality Disorder
Bipolar I,Depressed
Bipolar I,Classic Mania
The Bipolar Spectrum
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Bipolar Disorder: Subtypes of Illness(proposed for the DSM-V)
Bipolar I Mania + Major
Depression
Bipolar II Hypomania + Major
Depression
Bipolar III Cyclothymia
Bipolar IV Anti-depressant-
induced Hypomania
Bipolar V Recurrent MajorDepression with aFamily History ofBipolar Disorder
Bipolar VI Unipolar Mania
po ar sor er:
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po ar sor er:Prevalence and Course of
Illness Lifetime prevalence: 0.81.6% Gender influence: men = women Recurrent illness in >90% of patients Factors :episode frequency and severity
of residual symptoms between episodes Number of episodes may affect
subsequent treatment response 25-50% of patients attempt suicide > 1
time
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Genetic Risk: Bipolar Disorder
First-degree relativeafflicted
Bipolar disorder: 10-15% (10-12 times risk)
Monozygotic twin afflictedBipolar disorder: 60% (40times risk)
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What is the Ideal
Treatment ofBipolar Disorder?
An Ideal Primary Mood
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Any medication that stabilizes acute
manic symptoms, does not inducedepression, and prevents againstfuture relapses into (mania or
depression)
An Ideal Primary Mood
Stabilizer
Mood Stabilizing Agents
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*FDA approved for acute mania.
Mood-Stabilizing Agents Lithium* Antiepileptic medications
Valproate(Depakene,Depakote*,Depakote ER)
Carbamazepine(Tegretol)/Oxcarbazepine(Trileptal)
Gabapentin
(Neurontin
) Topiramate(Topamax)
Lamotrigine(Lamictal)
Typical antipsychotics
Novel antipsychotics Risperidone
(Risperdal) Ziprasidone
(Geodon
) Olanzapine
(Zyprexa)* Clozapine
(Clozaril
) Quetiapine
(Seroquel)
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ESTAB IL IZANTES DEL HUMOR
CARBONATO DE LITIO EVIDENCIA CLINICA USO CLINICO FARMACODINAMIA PROBABLE
SISTEMAS DE TRANSDUCCIN DEMEMBRANA (FOSFATIDIL INOSITOLES)
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EFECTOS SECUNDARIOS
TEMPRANOSsequedad de la bocased diuresis temblorpirosis, sabor metlico debilidad, fatiga
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EFECTOS SECUNDARIOS
TARDIOS temblor levepolidipsia, poliuria aumento de tamao del tiroides hipotiroidismo
alteraciones de memoria cambios en el EKG
TOXICIDAD
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TOXICIDAD
Vmito Diarrea Temblor intensoAtaxia, disartria Calambres musculares,
hiperreflexia Confusin, comaInsuficiencia renal Shock cardiovascular
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INTERACCIONES
Haloperidol Diurticos tiazdicos Relajantes muscularesAINES metronidazol, estreptomicina iECAS, metildopa antipsicticos, ISRS, TECAR
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Who Responds Best
to Lithium?
Factors Associated With
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Factors Associated With
Positive Response to Lithium
Bipolar I (euphoric/elatedmania)
First episode manic Prior response to lithium Limitations
No neurological impairment No substance abuse Relatively few illness episodes
(i.e., no rapid cycling, mixed,
other novel features)
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How are the
Antiepileptic
Medications Used inTreating Bipolar
Mania?
Treatment of Bipolar Mania:
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Treatment of Bipolar Mania:
Divalproex
Efficacy: comparable to lithiumin classic mania
Predictors of responseComparable efficacy in classicmania, mixed states, and rapidcycling