ANTIDEPRESIVOS Y ESTABILIZANTES DEL HUMOR (ESTADO DE ANIMO)

Unidad de Farmacologa Miguel E Martnez Snchez,MD

ANTIDEPRESIVOS

TRICCLICOS (HETEROCCLICOS) INHIBIDORES DE LA RECAPTACIN DE SEROTONINA INHIBIDORES DE LA MONOAMINO OXIDASA (MAO) ESTABILIZANTES DEL HUMOR TRIAZOLOBENZODIACEPINAS

ANTIDEPRESIVOS

AGONISTAS PARCIALES DEL RECEPTOR 5-HT1A INHIBIDOR DE LA RECAPTACIN DE SEROTONINA Y ANTAGONISTA DEL RECEPTOR 5-HT2 INHIBIDOR NO SELECTIVO DE LA RECAPTACIN DE NEUROTRASMISORES AMINERGICOS TERAPIA ELECTROCONVULSIVA (TEC)

TEORIAS BIOQUMICAS DEL AFECTO

TEORIA DE LAS AMINAS BIOGENAS (1950-1960)

INHIBIDORES DE LA M.A.O EFECTO DE LOS TRICCLICOS EFECTO DE LAS ANFETAMINAS REACCIONES PSICTICAS EFECTO DE LA RESERPINA

Norepinephrine

Alpha Receptors

Serotonin

5-HT: Behavioral Actions

Food intake: increased 5-HT reduces FI (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

Serotonin

Serotonin (5-HT) cells are mostly located in the gut (98%) with only 2% of serotonin cells in brain Serotonin cell bodies are located in brainstem raphe nuclei and project to cortex Serotonin systems:
D system originates in the dorsal raphe nucleus but does not form synapses (5-HT as a neuromodulator) M system originates from the median 4.11 raphe nucleus and these varicosities form synapses

SINTOMAS DEPRESIVOS Y SU RESPUESTA

NEUROVEGETATIVOS: Trastornos del sueo Trastornos del apetito Trastornos de la volicin Trastornos sexuales Ritmos diurnos anormales 10 dias a 2 semanas

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

SINTOMAS DEPRESIVOS Y SU RESPUESTA

COGNOCITIVOS:
CONCENTRACIN MEMORIA ATENCIN APRENDIZAJE

PSICTICOS INCAPACIDAD SOCIAL

LENTAMENTE Y POR ETAPAS

DIMENSIN EXISTENCIAL

SOLEDAD CULPA RUMIACIN INCAPACIDAD PARA LA GRATITUD CIRCULOS VICIOSOS

ESTABLECER DIFERENCIAS

DUELO:
CULPA/REPROCHE SINT SOMATICOS MENOS DE SEIS MESES FUNCIONAL NO SUICIDIO

DEPRESIN
CULPA/REPROCHE SINT SOMATICOS MAYOR A SEIS MESES DEBILITAMIENTO PROGRESIVO POTENCIALMENTE SUICIDA

ESTABLECER DIFERENCIAS

DEMENCIA
INSIDIOSA PROLONGADA AFECTO VARIABLE DEF COGNITIVAS CONSISTENTES RESP ERRONEAS EN EVAL NEUROL AFASIA, APRAXIA, AGNOSIA

DEPRESIN
ABRUPTA* CORTA* AFECTO DEPRESIVO DEF COGNITIVO NO PERSISTENTES NO DEFICIT NEUROLOGICO

ANTIDEPRESIVOS HETEROCCLICOS Aminas terciarias

Tofranil Tryptanol Surmontil Anafranil

IMIPRAMINA AMITRIPTILINA TRIMIPRAMINA DOXEPINA CLOMIPRAMINA

ANTIDEPRESIVOS HETEROCCLICOS Aminas secundarias

DESIPRAMINA NORTRIPTILINA PROTRIPTILINA AMOXAPINA MAPROTILINA

Ludiomil

FARMACODINAMIA

INHIBICIN DE LA RECAPTACIN DE NORADRENALINA INHIBICIN DE LA RECAPTACIN DE SEROTONINA

EFECTOS SECUNDARIOS

LOS EFECTOS SECUNDARIOS SE CORRELACIONAN MEJOR CON EL PERFIL FARMACODINAMICO QUE STE CON LOS EFECTOS CLNICOS

EFECTOS SECUNDARIOS

ANTICOLINERGICOS
SEQUEDAD DE LA BOCA VISIN BORROSA CONSTIPACIN RETENCIN URINARIA CONFUSIN

EFECTOS SECUNDARIOS

ANTIHISTAMNICOS
SEDACIN

SEROTONINRGICOS
SEDACIN Y/O ACATISIA

ADRENRGICOS
TEMBLOR, EXCITACIN PALPITACIONES GANANCIA DE PESO

INHIBIDORES DE LA RECAPTACIN DE SEROTONINA

FLUOXETINA TRAZODONE SERTRALINA PAROXETINA FLUVOXAMINA CITALOPRAM

INDICACIONES

Enfermedad cardiaca concomitante Intolerancia a los efectos secundarios anticolinrgicos Alto riesgo de sobredosis voluntaria Aumento de peso excesivo La sedacin no es aconsejable Trastorno obsesivo-compulsivo asociado

EFECTOS SECUNDARIOS

Gastrointestinales: nausea, flatulencia, diarrea S.N.C: insomnio, inquietud, irritabilidad, euforia, agitacin, temblores, distona* Sexuales: eyaculacin retardada, anorgasmia

SINDROME SEROTONINERGICO

Hipertermia Inquietud, calambres musculares, rigidez Convulsiones y coma

INHIBIDORES DE LA MAO

NO SELECTIVOS
ISOCARBOXAZI DA TRANILCIPROMI NA

SELECTIVOS
MOCLOBEMIDA BROMFAROMINE

EFECTOS SECUNDARIOS

Autonmicos: boca seca, mareo, estreimiento, dificultad en la miccin, hipotensin postural Centrales: cefalea, temblores, parestesia Otros: edema en tobillos, hepatotoxicidad

Trazodone (Desyrel)

SARI (serotonin antagonist/reuptake inhibitor)

Introduced in 82 as an atypical or second generation antidepressant

Strong 5-HT2A antagonist, relatively weak 5-HT reuptake inhibitor Also an 1-adrenergic and H1 antagonist

Highly protein bound, metabolized by 3A4, to mCPP (active metabolite), overall halflife < 24 hours.

Chemically distinct from TCA, resembles nefazadone

Trazodone (Desyrel) cont.

Bottom Line:
Almost always used for insomnia. Watch for orthostatic hypotension Caution about priapism Remember, its an antidepressant!

NEFAZODONE

INHIBIDOR DE LA RECAPTACION DE SEROTONINA Y ANTAGONISTA DEL RECEPTOR 5-HT2

Nefazadone (Serzone)

SARI (serotonin antagonist/reuptake inhibitor)

Approved in 1995, developed to improve upon trazadone: no priapism and less sedating. Unfortunately, cases of liver failure 1:200,000-300,000 has limited its use. A generic still available.
Time to liver injury 2 weeks to 6 months. Check LFTs

Strong 5-HT2A antagonist, relatively weak 5-HT reuptake inhibitor Weaker alpha 1 adrenergic and H1 antagonist compared to trazadone.

Mirtazapine (Remeron)

NaSSA (noradrenergic specific serotonergic antidepressant)

Central alpha-2 adrenergic autoreceptor antagonist (leads to net NE and 5-HT neurotransmission 5-HT2A, 5-HT2C, 5-HT3 antagonist H1 antagonist (the most potent action)

Approved for MDD (may work faster than SSRIs) Also used for SSRI augmentation, anxiety, nausea Moderately protein bound, metabolized by 1A2, 2D6, 3A4. Half-life 20-40 hours. Eliminated primarily via urine

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

Bupropion (Wellbutrin IR, SR, XL)

NDRI (norepinephrine, dopamine receptor inhibitor) 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 in 03 XL form released. FDA approved for MDD, smoking cessation (Zyban) Also used for ADHD, SSRI induced sexual dysfunction, SSRI augmentation Highly protein bound, bupropion and its active metabolites metabolized by 2B6. Half life approx 21 hours. Mild 2D6 inhibitor.

Bupropion (Wellbutrin IR, SR, XL) cont.

Bottom Line:
Activating so caution for depression with comorbid panic/anxiety disorders. Can be useful for anergic depression or when you wish to avoid sexual dysfunction. Relatively ineffective for anxiety disorders. Commonly used to augment SSRIs. Screen for seizure history.

VENLAFAXINE

INHIBIDOR NO SELECTIVO DE LA RECAPTACIN DE NEUROTRASMISORES AMINRGICOS

Venlafaxine (Effexor XR)

SNRI (serotonin, norepinephrine reuptake inhibitor) 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 higher remission rate for MDD compared to SSRIs. Some evidence: chronic pain, panic disorder, ADHD, OCD Poorly protein bound, XR formulation slows absorption but half-life still only about 15 hours. Metabolized by 2D6 to active Odesmethylvenlafaxine (ODV) Primarily eliminated in urine.

Venlafaxine (Effexor XR) cont.

Bottom Line:
Potentially modestly 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 of SSRI.

cymbalta (Duloxetine)

SNRI (serotonin, norepinephrine reuptake inhibitor)

Unlike venlafaxine, reuptake of NE, 5HT equally affected.

Approved for MDD and diabetic peripheral neuropathy Some evidence for chronic pain, anxiety disorders, urinary stress incontinence. Highly protein bound, metabolized by 2D6 and 1A2, Half life 12 hours Moderate inhibitor of 2D6

cymbalta (Duloxetine) cont.

Bottom Line:
Newest antidepressant (04) Marketed for physical symptoms of depression but not unique: tertiary TCAs, venlafaxine Some evidence for improved remission vs SSRIs but jury still out.

TERAPIA ELECTROCONVULSIVA

INDICACIONES
RIESGO SUICIDA SINTOMAS CATATNICOS

INFORMACIN DEL ELECTROCHOQUE AL TECAR

THREE PHASES OF TREATMENT

Normal

Remission
Relapse

Recovery
Recurrence

Response Relapse

> 50% STOP Rx

65 to 70% STOP Rx

Acute Continuation Maintenance Phase (3 months+) Phase (6-12 months) Phase (years) Time

Potential Adverse Effects of Antidepressant Therapy

Cardiac
Orthostasis hypertension heart block, tachycardia

Central Nervous System

Dizziness, cognitive impairment, sedation, light-headedness, somnolence, nervousness, insomnia, headache, tremor, changes in satiety and appetite

Gastrointestinal Urogenital
Erectile dysfunction, ejaculation disorder, anorgasmia, priapism
45

Nausea, constipation, vomiting, dyspepsia, diarrhea

Autonomic Nervous System

Dry mouth, urinary retention, blurred vision, sweating
10/31/2013

ESTABILIZANTES DEL HUMOR

CARBAMAZEPINA ACIDO VALPROICO CARBONATO DE LITIO

TRIAZOLOBENZODIACEPINAS

ALPRAZOLAM ADINAZOLAM

AGONISTAS RECEPTOR 5HT1A

GEPIRONA IPSAPIRONA

Symptom Domains of Bipolar Disorder

Manic Mood and Behavior Euphoria Grandiosity Pressured speech Impulsivity Excessive libido Recklessness Social intrusiveness Diminished need for sleep
Psychotic Symptoms

Dysphoric or Negative Mood and Behavior Depression Anxiety Irritability Hostility Violence or suicide Cognitive Symptoms
Racing thoughts Distractibility Disorganization Inattentiveness

Delusions Hallucinations

Bipolar I, Classic Mania Borderline Personality Disorder The Bipolar Spectrum Bipolar I, Depressed

Schizoaffective Disorder, Bipolar Type

Bipolar I, Rapid Cycling and Mixed State

Cyclothymic Disorder

Bipolar II Disorder

Bipolar Disorder: Subtypes of Illness

(proposed for the DSM-V)

Bipolar I
Mania + Major Depression

Bipolar IV
Anti-depressantinduced Hypomania

Bipolar II
Hypomania + Major Depression

Bipolar V
Recurrent Major Depression with a Family History of Bipolar Disorder

Bipolar III
Cyclothymia

Bipolar VI
Unipolar Mania

Bipolar I Disorder: 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

Genetic Risk: Bipolar Disorder

First-degree relative afflicted

Bipolar disorder: 10-15% (1012 times risk)

Monozygotic twin afflicted

Bipolar disorder: 60% (40 times risk)

What is the Ideal Treatment of Bipolar Disorder?

An Ideal Primary Mood Stabilizer

Any medication that stabilizes acute manic symptoms, does not induce depression, and prevents against future relapses into (mania or depression)

Mood-Stabilizing Agents

Lithium* Antiepileptic medications

Valproate (Depakene, Depakote*, Depakote ER) Carbamazepine(Tegre tol)/ Oxcarbazepine(Trilept al) Gabapentin (Neurontin) Topiramate (Topamax) Lamotrigine (Lamictal)

Novel antipsychotics

Risperidone (Risperdal) Ziprasidone (Geodon) Olanzapine (Zyprexa)* Clozapine (Clozaril) Quetiapine (Seroquel)
*FDA approved for acute mania.

Typical antipsychotics

ESTABILIZANTES DEL HUMOR

CARBONATO DE LITIO
EVIDENCIA CLINICA USO CLINICO FARMACODINAMIA PROBABLE

SISTEMAS DE TRANSDUCCIN DE MEMBRANA (FOSFATIDIL INOSITOLES)

EFECTOS SECUNDARIOS

TEMPRANOS

sequedad de la boca sed diuresis temblor pirosis, sabor metlico debilidad, fatiga

EFECTOS SECUNDARIOS

TARDIOS temblor leve polidipsia, poliuria aumento de tamao del tiroides hipotiroidismo alteraciones de memoria cambios en el EKG

TOXICIDAD

Vmito Diarrea Temblor intenso Ataxia, disartria Calambres musculares, hiperreflexia Confusin, coma Insuficiencia renal Shock cardiovascular

INTERACCIONES

Haloperidol Diurticos tiazdicos Relajantes musculares AINES metronidazol, estreptomicina iECAS, metildopa antipsicticos, ISRS, TECAR

Who Responds Best to Lithium?

Factors Associated With Positive Response to Lithium

Bipolar I (euphoric/elated

mania) 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)

How are the Antiepileptic Medications Used in Treating Bipolar Mania?

Treatment of Bipolar Mania: Divalproex

Efficacy:

comparable to lithium in classic mania

Predictors

of response

Comparable efficacy in classic mania, mixed states, and rapid cycling