Antidepressant Pharmacotherapy

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Antidepressant Pharmacotherapy. Charles DeBattista, MD Stanford University. Outline. Phenomenology of MDD Risk Factors Co morbid conditions Economics Pathophysiology Monoamines Stress/Neurotrophic factors Classes of Agents SSRIs TCAs SNRIs MAOIs Other Agents - PowerPoint PPT Presentation

Text of Antidepressant Pharmacotherapy

  • Antidepressant PharmacotherapyCharles DeBattista, MDStanford University

  • OutlinePhenomenology of MDDRisk FactorsCo morbid conditionsEconomicsPathophysiologyMonoaminesStress/Neurotrophic factorsClasses of AgentsSSRIsTCAsSNRIsMAOIsOther AgentsFuture Classes of Drugs

  • Teaching PointsOur knowledge of the pathophysiology of depression is incompleteLimitation of current treatment include slow onset, tolerability, and lack of adequate efficacy for many patientsEach class of antidepressants has unique risks and benefits

  • Pre-Lecture ExamQuestion 1The most common side effects early in the course of SSRI treatment leading to discontinuation is GI upsetLoss of libidoHeadache Weight gain

  • Question 2The most common cause of death in TCA overdose is ArrhythmiaSeizureCongestive heart failureStroke

  • Question 3Noradrenergic side effects of antidepressants may includeSedationWeight gainTachycardiaAll of the above

  • Question 4The neurotrophic hypothesis of depression suggestsDepression is related to loss of neurotrophic supportAntidepressants increase neurotrophic factors such as BDNFDepression is associated with a progressive loss of volume in areas such as the hippocampusAll of the above

  • Question 5Foods that are likely be problematic for patients on MAOIs includeSoy sauceAmerican CheesePasteurized BeerAll of the above

  • MAJOR DEPRESSION: DSM-IV DIAGNOSTIC CRITERIADepressed mood most of the day, nearly every dayDiminished interest or pleasure in activitiesMajor change in appetite or weightInsomnia or hypersomniaPsychomotor agitation or retardationFatigue or loss of energyFeelings of worthlessness or excessive or inappropriate guiltDiminished ability to think or concentrate, or indecisivenessRecurrent thoughts of death, dying, or suicide

    APA Diagnostic and Statistical Manual. 1994

  • Developments in Medical Treatment of DepressionLithiumBlack bile1900ECTTCAsSSRIsPharmacologicRefinements1st century30s80s90s



    60sMAOIsKaplan HI, Sadock BJ. In: Pocket Handbook of Psychiatric Drug Treatment. 1996.


  • Epidemiology of Depression17% lifetime prevalence of a major depressive episodeUp to 15% of patients with major depressive disorder requiring hospitalization commit suicideTotal annual cost to society $44 billion, 55% of which is due to lost productivityKessler RC et al. Arch Gen Psychiatry. 1994;51:8-19.Depression Guideline Panel. AHCPR publication 93-0550. 1993.Greenberg PE et al. J Clin Psychiatry. 1993;54:405-418.

  • RISK FACTORS FOR MAJOR DEPRESSIONRisk factorAssociationGenderTwice as likely in womenAgePeak age of onset is 2040 yearsFamily history1.5 to 3.0 times higher riskMarital statusHigher rates in separated, widowed, and divorced persons Married males lower than never married Married females higher than never marriedBlazer. Am J Psychiatry. 1994Stahl. Essential Psychopharmacology. 1996

  • Phases of Treatment for DepressionEuthymiaSymptomsSyndromeTreatment phasesProgressionto disorderAcute(612 wk)Continuation(49 mo)Maintenance( 1 yr)TimeIncreased severityRelapseResponseRemissionRecurrenceRelapseKupfer DJ. J Clin Psychiatry. 1991;52(suppl 5):28.++

  • Patients with Major DepressionKeller MB, Boland RJ. Biol Psychiatry. 1998;44:348-360.010203040501245671012Weeks since recovery3 or more previous episodes0 - 3 previous episodesCumulative Probability of Relapse% relapsed

  • DepressionImpact vs. Other Chronic Medical Conditions+ = Worse Functioning in DepressionWells, JAMA, 1989Hypertension++++++Diabetes++++++Advanced CAD+++Arthritis++++++MedicalPhysicalSocialRoleBedCurrent HealthBodily PainConditionFunctionFunctionFunctionDaysPerception

  • Economics of DepressionTotal Annual Cost ~$44 BillionLost productivity55%Outpatient care6%Suicide17%Inpatient care19%Pharmaceuticals3%Greenberg PE et al. J Clin Psychiatry. 1993;54:405-418.

  • Monoamines, and Receptors:Proposed Mechanisms of Action of AntidepressantsBlockade of neuronal re-uptake of monoaminesAdaptive down-regulation of receptorsBlockade of serotonin-2 receptorsInhibition of MAOPost-synaptic cascades giving rise to neuroadaptive changesHormonal effects of antidepressants

  • MONOAMINE HYPOTHESISDepression is caused by a deficiency ofSEROTONIN,NOREPINEPHRINE,or BOTHEvery approved antidepressant can increase serotonin neurotransmission, norepinephrine neurotransmission,or both

  • Neurotransmitter Regulation of Mood, Cognition, and BehaviorStahl SM. Essential PsychopharmacologyFoote Sl, Pharmacology and physiology of central noradrenergic systems, Psychopharmacology, 1995NorepinephrineSerotoninMoodAnxietyAlertnessDriveAttention Pleasure/RewardMotivationDopamineObsessive Compulsive Disorder

  • Affinities (Ki) of Antidepressants for Monoamine Transporters and ReceptorsKi = inhibition constant, nmol/LOwens MJ et al. J Pharmacol Exp Ther. 1997;283:1305-1322.SerotoninNorepinephrineDesipramine1633.5Fluoxetine202186Imipramine20142Nefazodone549713Paroxetine.83328Sertraline3.31716Venlafaxine1021644

  • Neurotrophic Hypothesis of DepressionDepression is associated with loss of neurotrophic support in key brain regions such as the hippocampusAll effective antidepressant therapies increase neurotrophic support in specific brain regions through secondary cascade systems

  • Limitations of Current AntidepressantsSlow OnsetIncompletely effectiveMultiple Side effectsNon-generics are costlyPotential for drug interactions

  • Antidepressant Adverse Effects

  • Current Depression Treatment OptionsPharmacologicAntidepressant medications NonpharmacologicPsychotherapyCognitive behavioral therapyInterpersonal therapyPsychodynamic therapyElectroconvulsive therapyPhototherapyRapid transcranial magnetic stimulation (RTMS) Vagus nerve stimulation Depression Guideline Panel. Depression in Primary Care: Vol 1. Detection and Diagnosis. Clinical Practice Guideline No. 5, 1993

  • New Generation AntidepressantsFluoxetine (Prozac) 1988Bupropion (Wellbutrin IR) 1989Sertraline (Zoloft) 1992Paroxetine (Paxil) 1993Venlafaxine (Effexor) 1994Fluvoxamine (Luvox) 1994Nefazodone (Serzone) 1995Mirtazapine (Remeron) 1996Citalopram (Celexa) 1998Escitalopram (Lexapro) 2003Duloxetine (Cymbalta)2004Selegiline transdermal (Emsam)2006Desvenlafaxine (Pristiq)2008

  • The Utility of Antidepressant Therapy50-60% of depressed patients respond to any given antidepressant, and 80% to 95% respond to one or a combination of therapeutic interventions if multiple therapies are tried (Thase and Rush, Psychopharmacology: Fourth Generation of Progress, 1995). Half of depressed patients will experience a remission within 6 months of an index case of depression, and perhaps more than 75% will remit by 2 years (Keller et al, Arch Gen Psychiatry, 1992).Antidepressants appear effective in reducing relapse rates

  • Limitations of Antidepressant TherapyThe percentage of patients who remain well during the18-month period following successful treatment for depression is disappointingly low: 19% to 30% in one study (Shea, et al. Arch Gen Psychiatry, 1992).At least 20% of treatment nave patients fail to achieve remission even 4 sequential treatment trials with monotherapy and combinations (Rush et al, NEJM, 2006)More than half of patients fail to ever attain remission in acute trials, and those that do commonly may not sustain remission

  • Clinical Correlates of Enhanced NeurotransmissionSerotonergic side effectsGI upset Sexual dysfunctionSleep disturbance With long-term useWeight gainSuppression of dopamine neurotransmission may lead to:Decrease in ability to experience pleasureApathy and decreased motivationDecreased attention and cognitive slowing

    Noradrenergic side effectsTremorTachycardia

    Dopaminergic side effectsPsychomotor activationAggravation of psychosisStahl SM. Essential PsychopharmacologyRichelson E., Pharmacology of antidepressants, Mayo Clin Proc, 1994Kapur, Serotonin-dopamine interaction and its relevance to schizophrenia, Am J Psychiatry, 1996

  • Deficiencies in Current Antidepressant TherapySlow onset of actionInadequate response for many patientsExpenseToxicityStigma

  • Common Features of AntidepressantsAll work on MonoaminesAll take 3-8 weeks to be maximally effectiveAll have equivalent response rates (50-70% and remission rates (35-50 %)All have serotonin or NE side effectsPlacebo drug differences are greatest in more severe depression

  • The Selective Serotonin Reuptake InhibitorsRepresent over 60-70 % of new prescriptions in MDDEasy to use and doseHigh Therapeutic IndexBroad spectrum of activity

  • Current SSRIsFluoxetine (Prozac)Sertraline (Zoloft)Paroxetine (Paxil)Fluvoxamine (Luvox)Citalopram (Celexa)Escitalopram (Lexapro)

  • Indications (FDA)MDDOCDPanicSocial AnxietyPTSDPMDD

  • Fluoxetine

  • Actions of SSRIs

  • Selective Serotonin Reuptake Inhibitors: ProzacProsSafeEasy dosingFew side effectsBroad Spectrum of activityConsGI/Sexual AEsSlowModerate efficacyCost

  • In Vitro P450 Inhibition by SSRIs

  • Cytochrome P450 (CYP450):Enzymes and Selected Substrates

  • Common SSRI Side Effects

  • Gastrointestinal Side Effects with SSRIsSimilarities > differencesAdaptation: 1-2 weeksMay be managed by dose reduction

  • Antidepressant-Induced Sexual DysfunctionMost patients will not complain of antidepressant-induced sexual dysfunction e