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Depressive Disorders

Abbreviations. APA: American Psychiatric Association DA: dopamineDSM-IV-TR: Diagnostic and Statistical Manual of Mental Disorders, 4th ed., text revisionECT: electroconvulsive therapy5-HT: serotoninHAMD: Hamilton depression scaleMAOI: monoamine oxidase inhibitorMDD: major depressive disorder

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Depressive Disorders

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    1. Depressive Disorders Chapter 71

    2. Abbreviations APA: American Psychiatric Association DA: dopamine DSM-IV-TR: Diagnostic and Statistical Manual of Mental Disorders, 4th ed., text revision ECT: electroconvulsive therapy 5-HT: serotonin HAMD: Hamilton depression scale MAOI: monoamine oxidase inhibitor MDD: major depressive disorder NE: norepinephrine NIH: National Institutes of Health REM: rapid eye movement SNRI: serotonin-norepinephrine reuptake inhibitor SSRI: serotonin-selective reuptake inhibitor STAR* D: Sequenced treatment alternatives to relieve depression TCA: tricyclic antidepressant TRD: treatment-resistant depression

    3. Introduction Major depressive episode defined by Diagnostic and Statistical Manual of Mental Disorders, 4th ed., text revision (DSM-IV-TR) criteria Published by American Psychiatric Association Depression associated with functional disability, morbidity and mortality Newer antidepressants as effective and better tolerated than older agents

    4. Epidemiology True prevalence unknown The National Comorbidity Survey Replication 16.2% of population studied had history of major depressive disorder >6.6% had episode in past 12 months Women at increased risk of depression from early adolescence until their mid-50s Lifetime rate 1.7 to 2.7 times greater than for men

    5. Epidemiology Adults 18 to 29 years: highest rates of major depression Estimated lifetime prevalence of MDD in individuals 65 to 80 years 20.4% in women 9.6% in men Depressive disorders common during adolescence Comorbid substance abuse Suicide attempts

    6. Epidemiology Depressive disorders and suicide tend to occur within families ~8% to 18% of MDD patients have > one 1st-degree relative with history of depression, compared with 5.6% of 1st-degree relatives of those without depression 1st-degree relatives of patients with depression 1.5 to 3 times more likely to develop depression than controls

    7. Epidemiology Prevalence influenced by genetic and environmental factors Heritability of liability for major depression 37% 63% of variance in liability caused by individual-specific environment

    8. Etiology Depressive disorder etiology too complex to be explained by single social, developmental, biologic theory Several factors work together to cause/precipitate depressive disorders Major depressionsymptoms consistently reflect changes in brainmonoamine neurotransmitters Norepinephrine(NE) Serotonin(5-hydroxytryptamine[5-HT]) Dopamine(DA)

    10. Biogenic Amine Hypothesis Depression linked to decreased NE,5-HT,DA in the brain Actual cause unknown Based on observations from early 1950s Antihypertensive drugreserpinedepletes neuronal storage granules of NE, 5-HT, DA produces clinically significant depression >15% patients

    11. Biogenic Amine Hypothesis Monoamine (e.g., NE, 5-HT) reuptake blockade occurs immediately on antidepressant administration Antidepressant clinical effects generally not seen until after ~4 weeks May be result of cascade of events from receptor occupancy togenetranscription caused researchers to focus on adaptive changes induced by antidepressants

    12. Theories of Postsynaptic Changes in Receptor Sensitivity Discrepancy between timing of monoamine reuptake blockade (immediate) and measurable improvement in symptoms Some theories focus on adaptive/chronic changes in amine receptor systems compared with acute changes Mid-1970s: chronic (not acute) antidepressant administration to animals causeddesensitizationof NE-stimulated cyclicadenosinemonophosphate synthesis

    13. Theories of Postsynaptic Changes in Receptor Sensitivity Downregulation of-adrenergic receptors accompanies desensitization for most antidepressants Desensitization or downregulation of NE receptors corresponds to clinically relevant time course for antidepressant effects Other studies reveal desensitization of presynaptic5-HT1Aautoreceptors following chronic antidepressant administration

    14. Dysregulation Hypothesis Incorporates diversity of antidepressant activity with adaptive changes in receptor sensitization over several weeks Emphasizes failure of neurotransmitter system homeostatic regulation rather than absolute increases or decreases in activities Hypothesis: antidepressants restore efficient regulation to dysregulated neurotransmitter systems

    15. 5-HT/NE Link Hypothesis No single neurotransmitter theory adequate Maintains serotonergic and noradrenergic systems both involved in antidepressant response Consistent with rationale of postsynaptic alteration theory Emphasizes importance of-adrenergic receptor down regulation for antidepressant effect Both serotonergic and noradrenergic medications downregulate-adrenergic receptors Link between 5-HT and NE

    16. Role of DA in Depression Traditional explanations focused on NE and5-HT biogenic amine hypothesis does not distinguish between NE and DA Evidence suggests decreased DA transmission in depression agents that increase dopaminergic transmission are effective antidepressants Studies suggest increased DA transmission in mesolimbic pathway accounts for part of antidepressant mechanism

    17. Role of DA in Depression Mechanisms by which antidepressants alter DA transmission unclear Can be mediated indirectly by actions at NE or 5-HT terminals Complexity of interaction between 5-HT, NE, and possibly DA gaining greater appreciation Precise mechanism not known

    18. Biologic Markers Search for biologic orpharmacodynamicmarkers to assist in MDD diagnosis and treatment Although no biologic marker has been discovered, several biologic abnormalities are present in many depressed patients Sleep studies in MDD patients identified several abnormalities More pronounced with advancing age Occur in other psychiatric disorders Not diagnostic formajor depression

    19. Biologic Markers ~45% to 60% of MDD patients have a neuroendocrine abnormality Cortisol hypersecretion: lack of cortisol suppression afterdexamethasoneadministration Indicates hypothalamic-pituitary-adrenal axis overactivity or dysregulation High rate offalse-positiveandfalse-negativeresults limits usefulness of testing Relative lack of use in clinical practice Abnormal/diminished response to thyroid-stimulatinghormone

    20. Clinical Presentation Withdrawal from substances of abuse (e.g., cocaine) can cause depressive symptoms Rule out medical conditions or concomitant medication Complete physical exam and medication review Mental status examination Laboratory workup Complete blood count with differential Thyroid function tests Electrolytes

    21. Medical Conditions Associated with Depressive Symptoms

    22. Substance Use Disorders Associated with Depressive Symptoms

    23. Medications Associated with Depressive Symptoms

    24. Clinical Presentation Stressors/life events trigger depression in some individuals Patients may have >1 recurrent episodesduring lifetime

    25. DSM-IV-TRCriteria for MDD

    26. Emotional Symptoms Persistent diminished ability to experience pleasure Loss of interest/pleasure in usual activities, hobbies, work Appear sad or depressed Often pessimistic Believe nothing will help them feel better Feelings of worthlessness/inappropriate guilt Identify patients at risk for suicide ~90% of MDD patients have anxiety symptoms

    27. Emotional Symptoms Unrealistic guilt feelings Can reach delusionalproportions Patients can feel they deserve punishment View illness as punishment MDD patients with psychotic features May hear voices (auditory hallucinations) saying he/she is a bad person and should commit suicide Can require hospitalization if patient becomes danger to self or others

    28. Physical Symptoms Often motivate patients to seek medical attention Chronic fatigue Often worse in morning; does not improve with rest Pain (especially headache) often accompanies fatigue Sleep disturbances Frequent early morning awakening with difficulty returning to sleep Difficulty falling asleep Frequent nighttime awakening Increased sleep (hypersomnia)

    29. Physical Symptoms Appetite disturbances Decreased appetite Can result in substantial weight loss, especially elderly patients Other patients overeat/gain weight Gastrointestinal complaints Cardiovascular complaints Palpitations Loss of sexual interest/libido

    30. Intellectual/Cognitive Symptoms Decreased ability to concentrate Slowed thinking Poor memory of recent events Confusion and indecisiveness Consider depression when elderly patients have cognitive symptoms

    31. Psychomotor Disturbances Psychomotor retardation: noticeably slowed Physical movements Thought processes Speech Psychomotor agitation: purposeless, restless motion Pacing Wringing of hands Shouting outbursts

    32. Suicide Risk Evaluation/Management Center for Disease Control lists suicide as 3rd leading cause of death in those aged 15 to 24 years 2nd leading cause of death in those aged 25 to 34 years Widely held myths regarding suicide People more likely to commit suicide if asked about it People talking about suicide are looking for attention and are not serious Suicidal people are crazy Most suicides caused by sudden traumatic event

    33. Suicide Risk Evaluation/Management Assess all MDD patients for suicidal potential Factors increasing suicide risk Suicidal plans/attempts Male gender Being single or living alone Inpatient status Feelings of hopelessness, relationship difficulties General medical condition, alcohol/substance abuse More work hours missed in past week

    34. Suicide Risk Evaluation/Management High suicide risk: detailed plan with intention and ability to carry it out Hints of suicidal ideation used to assess severity of suicidal thoughts Personality change Sudden decision to make a will/give away possessions Recent gun purchase; obtaining large supply of medications or other potentially toxic substances Suicide risk can increase as MDD patients develop energy and capacity to act on a plan made earlier

    36. Treatment Goals Reduce acute symptoms Facilitate return to level of functioning before illness Prevent further episodes Decision to hospitalize based on Suicide risk Physical health Social support system Psychotic and/or catatonic symptoms

    37. General Approach to Treatment Phases of treatment Acutephase: 6 to 10 weeks; goal isremission(i.e., absence of symptoms) Continuationphase: 4 to 9 months after remission achieved; goal to eliminate residual symptoms or preventrelapse(i.e., return of symptoms <6 months of remission) Maintenancephase: >12 to 36 months; goal to prevent recurrence (i.e., separate episode of depression)

    38. General Approach to Treatment Risk of recurrence increases as number of past episodes increases Duration of therapy depends on risk of recurrence Some investigators recommend lifelong maintenance therapy for persons at greatest risk for recurrence <40 years of age with >2 prior episodes Any age with >3 prior episodes Educate patient and his/her support system Delay in antidepressant effects Importance of adherence

    39. Nonpharmacologic Therapy Psychotherapy and antidepressant effects considered additive Mild to moderate depressive episode: psychotherapy can be 1st line therapy Severe and/or psychotic MDD: psychotherapy alone not recommended for acute treatment Maintenance psychotherapy generally not recommended as sole treatment to prevent recurrence

    40. Nonpharmacologic Therapy Electroconvulsive therapy(ECT): safe, effective treatment for certain severe mental illnesses including MDD Candidates for ECT Rapid response needed Risks of other treatments outweigh potential benefits History of poor antidepressant response History of good ECT response Patient prefers ECT

    41. Nonpharmacologic Therapy General ECT course Unilateralor bilateral 2 to 3 times/week 6 to 12 treatments Rapid therapeutic response (10 to 14 days) Conditions associated with increased risk Increasedintracranial pressure, cerebral lesions Recentmyocardial infarction Recent intracerebral hemorrhage Bleeding Unstable vascular condition

    42. Nonpharmacologic Therapy Anesthetics and nondepolarizing neuromuscular blocking agents decrease ECT morbidity ECT adverse effects Cognitive dysfunction Cardiovascular dysfunction Prolonged apnea Treatment-emergentmania Headache Nausea Muscle aches

    43. Nonpharmacologic Therapy Cognitive changes associated with ECT Confusion Memory disturbance Most cognitive disturbances transient Some patients report permanent memory loss for events months before, after, during treatment Relapserates high during year following ECT unless maintenance antidepressant prescribed

    44. Nonpharmacologic Therapy Bright light therapy: patients gaze into 10,000-lux intensity light box ~30 minutes/day Can use with antidepressants Effective for seasonal affective disorder (SAD) and adjunctive use in MDD with seasonal exacerbations Well tolerated Most frequently reported adverse event: minor visual complaints Baseline and periodic eye examinations recommended

    46. Adult Dosagesa

    47. Adult Dosagesa

    48. Adult Dosagesa

    49. Adult Dosagesa

    50. Pharmacologic Therapy Antidepressants are of equivalentefficacywhen administered in comparable doses Initial choice made empirically Cannot predict which antidepressant will be most effective in a patient Failure to respond to 1 class or 1 drug in a class does not predict failed response to another drug class or another drug within the class

    51. Pharmacologic Therapy Factors that influence antidepressant choice History of response Pharmacogenetics Familial antidepressant response history Medical history Symptoms Potential drug-drug interactions Adverse events profile Patient preference Drug cost

    52. Relative Potencies and Side-Effect Profile

    53. Relative Potencies and Side-Effect Profile

    54. Relative Potencies and Side-Effect Profile

    55. Relative Potencies and Side-Effect Profile

    56. Mixed Serotonin and Norepinephrine Reuptake Inhibitors: TCAs Other antidepressants are as effective as TCAs but are safer in overdose and better tolerated than TCAs Potentiate NE and5-HTactivity by blocking reuptake Potency and selectivity vary greatly Adverse effects common; affect other receptor systems Cholinergic Neurologic Cardiovascular

    57. Triazolopyridines Trazodoneand nefazodone Dual actions on serotonergic neurons 5-HT2receptor antagonists and 5-HT reuptake inhibitors Also enhance 5-HT1A-mediated neurotransmission

    58. Triazolopyridines Trazodone blocksa1-adrenergic and histaminergic receptors Increased side effects limit use (e.g., dizziness, sedation) Nefazodone use declined after reports of hepatic toxicity Black box warning: rare cases of liver failure

    59. Aminoketone Bupropion No appreciable effect on 5-HT reuptake Reuptake properties at NE andDAreuptake pumps Unique among currently available antidepressants

    60. Mixed Serotonin-Norepinephrine Effects Mirtazapine Enhances central noradrenergic and serotonergic activity Antagonism of central presynaptica2-adrenergic autoreceptors and heteroreceptors Also antagonizes5-HT2, 5-HT3, and histamine receptors Lower anxiety and gastrointestinal side effects Histamine receptor blockade associated with sedativeproperties

    61. Monoamine Oxidase Inhibitors Increase NE,5-HT, DA in neuronal synapse by inhibiting MAOenzyme Chronic therapy changes receptor sensitivity Downregulation of-adrenergic,a-adrenergic, serotonergic receptors Phenelzineandtranylcypromine:nonselective MAO-A and MAO-B inhibitors Selegilinetransdermal patch allows inhibition of brain MAO-A and MAO-B with reduced effects on MAO-A in the gut

    62. St. John's Wort Mixed results regarding efficacy Herbal medication available over-the-counter Not FDA regulated Manufacturers not required to provide proof of safety and/or efficacy Recommend single-source product from reputable manufacturer Significantdrug interactionswith commonly used medications

    64. TCAs Common side effects dose related; associated with cholinergic receptor blockade Dry mouth Constipation Weight gain Sexual dysfunction Blurred vision

    65. TCAs Orthostatic hypotension common Dose-related Potentially problematic Attributed to affinity for adrenergic receptors Cardiac conduction delays Heart block in patients with preexisting conduction disorders Overdose can produce severe arrhythmias Exercise caution if patients have clinically significant cardiac disease

    66. TCAs Abrupt TCA withdrawal Cholinergic rebound symptoms Dizziness Nausea Diarrhea Insomnia Restlessness Especially if dose >300 mg/day Taper dose over several days

    67. SNRIs Venlafaxine adverse effects similar to those of SSRIs Nausea Sexual dysfunction Activation Dose-related increase indiastolic blood pressure Baseline blood pressure not useful predictor of occurrence Monitor blood pressure regularly Reduce dose/discontinue if hypertension sustained

    68. SNRIs Duloxetine relatively well tolerated in short-termclinical trials long-term studies in larger patient population will more clearly define risks and benefits most common adverse events nausea dry mouth constipation

    69. SSRIs Low affinity for histaminergic,a1-adrenergic, muscarinic receptors Fewer anticholinergic and cardiovascular adverse effects than TCAs Not usually associated with significant weight gain Common adverse effects generally mild, short lived Nausea,vomiting, diarrhea Sexual dysfunction Headache Insomnia

    70. SSRIs Discontinuation/withdrawal syndrome can occur if abruptly discontinued Longer drugand active metabolite half-life: less likely withdrawal syndromewill occur SSRIs improve anxiety symptoms associated with depression Some patients experience increased anxiety symptoms or agitation early in treatment

    71. Triazolopyridines Trazodoneandnefazodonehave minimal anticholinergic effects and5-HTagonist side effects Trazodone adverse effects Orthostatic hypotension Sedation Cognitive slowing Dizziness Priapism rare, potentially serious

    72. Triazolopyridines Nefazadone adverse effects Light-headedness, dizziness Orthostatic hypotension Somnolence Dry mouth Nausea Asthenia (weakness) Hepatic injury (black box warning) Do not initiate in patients with active liver disease or elevated baseline serum transaminases

    73. Aminoketone Bupropionadverse effects Nausea,vomiting Tremor Insomnia, activation, agitation Dry mouth Skin reactions Seizures Appears to be dose-related Increased by predisposing factors: history of head trauma, CNS tumor

    74. Mixed Serotonin-Norepinephrine Effects Mirtazapine adverse effects Somnolence Weight gain Dry mouth Constipation Side effects such as weight gain can be less with larger doses Increased noradrenergic transmission as dose increased

    75. Monoamine Oxidase Inhibitors Adverse effects Postural hypotension (minimize with divided doses) Weight gain Sexual side effects Phenelzine: mild to moderate sedation Tranylcypromine: can be stimulating Insomnia Fever Myoclonic jerking Brisk deep tendon reflexes

    76. Monoamine Oxidase Inhibitors Hypertensive crisis Rare Potentially serious and life-threatening Can occur when MAOIs taken with certain foods High in tyramine or certain medications 10 mg of tyramine can cause marked pressor effect 25 mg can result in serious hypertensive crisis Can culminate incerebrovascular accidentand death

    77. Monoamine Oxidase Inhibitors Hypertensive crisis symptoms Occipital headache Stiff neck Nausea Vomiting Sweating Sharply elevated blood pressure

    78. Dietary Restrictions for Patients Taking MAOIsa

    79. Medication Restrictions for Patients Taking MAOIs

    80. Clinical Controversy Numerous FDA reports warn of adverse effects associated with antidepressant use in various populations Many warnings accompanied by product labeling changes includingblack box warnings Some warnings not unequivocally supported in scientific literature Examine and understand reports Consider in context of scientific literature

    81. TCA Pharmacokinetics Low bioavailability (30% to 70% for most TCAs) 1st-pass hepatic effect Interindividual variation Largevolume of distribution Concentrate in brain and cardiac tissue Extensive and strong binding Plasma albumin Erythrocytes a1-acid glycoprotein Lipoprotein

    82. TCA Pharmacokinetics Major metabolic pathways Demethylation Aromatic and aliphatic hydroxylation Glucuronide conjugation Enterohepatic cycling Linear metabolism within usual dosage range Elimination half-lives vary greatly among individuals

    83. Pharmacokinetics

    84. Pharmacokinetics

    85. Pharmacokinetics

    86. Pharmacokinetics

    87. SNRI Pharmacokinetics Venlafaxine metabolized to active metaboliteO-desmethylvenlafaxine Lowest plasma protein binding of any antidepressant (27%30%) Different formulations have different pharmacokinetics and adverse-effect profiles Venlafaxine extended-release: sustained plasma concentrations associated with higher rates of sexual dysfunction (37%) compared to immediate release (6%)

    88. SSRI Pharmacokinetics SSRIs have diverse pharmacokinetics Pharmacokinetic attributes can guide treatment Extensively distributed to tissues Nonlinear drug accumulation with long-term administration Possible exceptions: citalopram,sertraline Relationship between dose and observed effect (e.g., side effects) can change over time for nonlinear SSRIs

    89. Bupropion Pharmacokinetics Metabolized to multiple active metabolites 3 formulations considered bioequivalent Immediate release, sustained release, extended release Peak plasma concentrations lower for sustained-release formulation Believed to contribute to lower seizure risk

    90. Mirtazapine Pharmacokinetics Extensive biotransformation to several metabolites Primarily renal elimination Metabolites present at low plasma concentrations Minimally contribute to overall pharmacologic profile

    91. TCA Altered Pharmacokinetics Factors that influence plasma concentration Disease states, e.g., hepatic disease Genetics Age Cigarette smoking Concurrent drug administration Renal failure does not alternortriptylinemetabolism 10-hydroxy metabolite can accumulate Protein binding can be diminished: enhanced drug sensitivity

    92. SSRI Altered Pharmacokinetics Hepatic impairment Twofold increase in paroxetine plasma concentrations Cirrhosis Fluoxetineand norfluoxetine t1/2 increased to 7.6 and 12 days, respectively Sertraline t1/2 2.5 times greater than in patients without liver disease

    93. Altered Pharmacokinetics Renal impairment Two- to fourfold increase in paroxetine plasma concentrations compared with normal volunteers Clearance ofvenlafaxine,mirtazapine and their metabolites Reduced by hepatic or renal disease Adjust dose accordingly

    94. Plasma Concentration and Clinical Response Clinical response dictates dosage adjustments Correlation not established between plasma concentration and clinical response or adverse effects for newer antidepressants Nortriptyline,desipramine, imipramine, andamitriptyline have evidence to support association between plasma concentrations and clinical response Plasma concentration monitoring not routinely performed

    95. TCA Plasma Concentration Monitoring Indications Inadequate response, relapse Serious or persistent adverse effects Higher than standard doses Suspected toxicity Elderly patients Pregnancy Cardiac disease Suspected nonadherence or drug interactions

    97. TCA Drug Interactions Metabolized in liver through cytochrome P450 system interact with drugs that modify hepaticenzyme activity or hepatic blood flow Extensively protein bound Certain SSRIs and TCAs (e.g. paroxetine, fluoxetine) inhibit cytochrome P450 (e.g., CYP2D6) increase TCA plasma concentrations MAOIs and TCAs can be coadministered severe reactions/fatalities reported monitor carefully

    98. Pharmacokinetic Drug Interactions Involving TCAs

    99. Pharmacodynamic Drug Interactions Involving TCAs

    100. Pharmacodynamic Drug Interactions Involving TCAs

    101. SSRI Drug Interactions CYP2D6 and CYP3A4 responsible for metabolism >80% of currently marketed drugs Patients receiving stable dose of medication known to interact with SSRIs Low SSRI starting dose Titrate carefully to evaluate importance of interaction

    102. SNRI Drug Interactions

    103. SSRI Drug Interactions

    104. SSRI Drug Interactions

    105. SSRI Drug Interactions

    106. SSRI Drug Interactions

    107. Drug Interactions

    108. CYP450 Enzyme Inhibitory Potential

    109. SSRI Pharmacodynamics SSRI pharmacodynamicdrug interactionscan occur Require close monitoring Combining anSSRIwith another drug that augments serotonergic function (e.g.,linezolid) can lead to serotoninsyndrome Symptoms: clonus, hyperthermia, mental status changes 2 to 5 week wash out period (depends on SSRIt1/2) can be necessary before initiating another serotonergic medication

    110. Pharmacodynamics Drug interactions of newer-generation antidepressants (venlafaxine,duloxetine, mirtazapine, bupropion)primarily pharmacodynamic Relative lack of cytochrome P450 inhibition compared to SSRIs

    112. Elderly Patients Depression often inadequately treated or missed/mistaken for another disorder Depressed mood can be less prominent than other symptoms; frequently somatic complaints Loss of appetite Cognitive impairment Sleeplessness Anergia Loss of interest in/enjoyment of normal pursuits

    113. Elderly Patients Important to recognize/treat depression Individuals >65 years have highest suicide rate compared to other age groups Increased suicidal attempts Firearm access Diminished cognitive functions Sleep disruptions Poor social interactions, inattention from caregivers SSRIs usually first-choice in elderly patients

    114. Pediatric Patients Symptoms vary from accepted diagnostic criteria; nonspecific Boredom Anxiety Failing adjustment Sleep disturbance Sparse data supportingefficacyof antidepressants in children and adolescents FluoxetineFDA-approved for depression in patients <18 years; other antidepressants have been studied

    115. Pediatric Patients March 2004:FDAissued black box warning for increased risk of suicidal ideation and behavior with antidepressants in pediatric and adolescent patients Retrospective longitudinal reviews found no significant increase in risk of suicide attempts or death Untreated adolescents may successfully commit suicide Further study needed to resolve controversy

    116. Pediatric Patients Cases ofsudden death reported in children and adolescents taking antidepressants such asdesipramine Baseline electrocardiogram (ECG) recommended before TCA initiation Many clinicians recommend additional ECG when steady-state plasma concentrations achieved

    117. Pregnant and Lactating Patients ~14% of pregnant women develop serious depression Women who discontinued antidepressant therapy 5 times more likely to relapse during pregnancy than those who continued treatment in one study Prenatal SSRI exposure Risk of low birth weight and respiratory distress Relationship remained after accounting for maternal illness severity

    118. Pregnant and Lactating Patients Weigh risks and benefits ofdrug therapyduring pregnancy Risks of untreated depression Low birth weight due to poor maternal weight gain Suicidality Potential hospitalization Potential marital discord Inability to engage in appropriate obstetric care Difficulty caring for other children Do not underestimate or minimize risks of not treating

    119. Pregnant and Lactating Patients Possible approaches Discontinue antidepressant before conception if patient stable and appears likely to remain well while not taking antidepressant Continue antidepressant until conception Continue antidepressant throughout pregnancy in patients with history of relapseafter medication discontinuation Further evaluations of newer antidepressant agents needed to understand risks at various stages of gestation

    120. Refractory Patients Most "treatment-resistant" depressed patients likely result of inadequate therapy (relative resistance) Sequenced treatment alternatives to relieve depression (STAR* D) National Institutes of Health (NIH)-sponsored study 1 in 3 patients who did not achieveremissionusing an antidepressant became symptom-free with an additional medication 1 in 4 patients achieved remission after switching to a different antidepressant

    121. Refractory Patients Assessing treatment refractory patients Correct diagnosis? Psychotic depression? Adequate treatment dose/duration? Do adverse effects preclude adequate dosing? Patient adherence? Stepwise treatment approach used? Treatment outcome adequately measured? Coexisting or preexisting medical/psychiatric disorder? Do other factors interfere with treatment?

    122. Refractory Patients Non-drug modalities often beneficial Environmental manipulation Family counseling Cognitive therapy Interpersonal psychotherapy >40% of MDD patients do not achieveremissioneven after 2 optimal antidepressant trials

    123. Clinical Controversy No universally agreed uponalgorithms/guidelines for treatment-resistant depression (TRD) Patients do not achieve remission even after 2 optimal antidepressant trials Approaches Stop current antidepressant, initiate trial with unrelated agent augment current antidepressant with another agent Lithium, T3, atypical antipsychotic Combination antidepressant therapy

    124. 124

    125. Clinical Application: Dosing Elderly patients: start with usual starting dose, increase slowly Use caution when switching from one antidepressant to another 3 to 4 weeks usually required before mood-elevating response is seen Adequate trial: 6-weeks at maximum dosage Counsel patients about expectedlag timebefore onset of clinical response to improve adherence

    126. Therapeutic Outcome Evaluation Monitoringparameters Adverse effects Target symptom remission Changes in social/occupational functioning Blood pressure for patients receivingvenlafaxine ECG for patients >40 years before starting TCA therapy with periodic follow-up Suicidal ideation after initiation

    127. Therapeutic Outcome Evaluation Psychometricrating instruments Patient- and clinician-rated scales Rapid, reliable measurement of symptom nature and severity Administerprior to treatment, 6 to 8 weeks after initiation of therapy, then periodically Interview family member/friend (with patient's permission) regarding symptoms and daily functioning

    128. Therapeutic Outcome Evaluation Psychometricscale definitions Nonresponse: <25% decrease in baseline symptoms Partial response: 26% to 49% decrease in baseline symptoms Partialremission/response: >50% decrease in baseline symptoms Remission: return to baseline functioning; no symptoms

    129. Collaborative Practice Pharmacists can play a crucial role in screening, recognition, treatment High index of suspicion for MDD in certain patients Adolescents, young adults Family or personal history of depression Chronic illness/pain Perception or experience of recent loss Sleep disorders Multiple unexplained somatic complaints

    130. Collaborative Practice Pharmacists play a crucial role in ensuring medication adherence Assess willingness and ability to take medications Assess financial viability Patient education regarding dosing, side effects, drug interactions Guidance regarding follow-up appointments with prescribers

    131. Conclusions MDD remains one of the most commonly occurring mental illnesses in adults Often undiagnosed and untreated Pharmacologic intervention is cornerstone of treatment Antidepressants have broad spectrum of neurochemical effects and influence variety of receptors peripherally and centrally Safe/effective antidepressant use requires thorough understanding of pharmacology and principles of monitoringefficacy/adverse effects

    132. Acknowledgements Prepared By/Series Editor: April Casselman, Pharm.D., CGP, BCPS Editor-in-Chief: Robert L. Talbert, PharmD, FCCP, BCPS, FAHA Chapter Authors: Christian J. Teter, PharmD, BCPP Judith C. Kando, PharmD, BCPP Barbara G. Wells, PharmD, FASHP, FCCP, BCPP Peggy E. Hayes. PharmD Section Editor: Barbara G. Wells, PharmD, FASHP, FCCP, BCPP

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