Chapter 2 - Depression.pdf

Chapter 2 - Depression Definition ○ Mental state characterized by depressed mood with feelings of furstration and hopelessness ○ Characterized - misery, guilt, low self-esteem without cause, lack of motivation, missing drive to act Unipo...

Chapter 2 - Depression Definition ○ Mental state characterized by depressed mood with feelings of furstration and hopelessness ○ Characterized - misery, guilt, low self-esteem without cause, lack of motivation, missing drive to act Unipolar depression - depressive phase only Bipolar disoder - depression alternates with mania Mania ○ Expressive, impulsive and hyper-excitability nature of an individual having a range of symptoms lasting for several months ○ Opposite symptoms of depression (over production of neurotransmitter) ○ Hallucination, mood swing Depression associated with functional disability, morbidity and mortality Newer antidepressants as effective and better tolerated than older agents Women at increased risk of depression from early adolescence until mid-50s ○ Lifetime rate 1.7 to 2.7 times greater than man Adults 18 to 29 years - highest rates of major depression Depressive disorders common during adolescence ○ Comorbid substance abuse ○ Suicide attempts Major depression symptoms consistently reflect changes in brain monoamine neurotransmitters ○ Norepinephrine ○ Serotonin (5-hydroxytryptamine / 5-HT) ○ Dopamine Clinical presentation Withdraw from substances of abuse such 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 Stress / life events trigger depression in some individuals Patients may have more than 1 recurrent episodes during lifetimes Medical conditions associated with depressive symptoms 1  ○ Substance use disorders associated with depressive symptoms ○ Medications associated with depressive symptoms ○ The DSM V Criteria Individuals must be experiencing five or more symptoms during the same 2-week period and at least one of the symptoms should be either (1) depressed mood or (2) loss of interest or pleasure These symptoms must cause individual clinically significant distress or impairment in social, occupational, or other important areas of function Symptoms must not be a result of substance abuse or another medical condition Higher score, higher risk of getting depression 2  1 Depressed mood most of the day, nearly every day. 2 Markedly diminished interest or pleasure in all, or almost all, activities most of the day, nearly every day. 3 Significant weight loss when not dieting or weight gain, or decrease or increase in appetite nearly every day. 4 A slowing down of thought and a reducting of physical movement (observable by others, not merely subjective feelings of restlessness or being slowed down). 5 Fatigue or loss of energy nearly every day. 6 Feelings of worthlessness o excessive or inappropriate guilt nearly every day. 7 Diminished ability to think or concentrate, or indecisiveness, nearly every day. 8 Recurrent thought of death, recurrent suicidal ideatiion without a specific plan, or a suicide attempt or a specific plan for committing suicide. Emotional symptoms Persistent diminished ability to experience pleasure Loss of interest / pleasure in usual activities, hobbies, work Appear sad or depressed ○ Often pessimistic ○ Beleive nothing will help them feel better Feelings of worthlessness / inappropriate guilt ○ Identify patients at risk for suicide ○ ~ 90% major depressive disorder patients have anxiety symptoms Unrealstic guilt feelings ○ Can reach delusional proportions Patients can feel they deserve punishment ○ View illness as punishment Major depressive disorder with psychotic features ○ May hear voices (auditory hallucinations) saying he / she is a bad person and should commit suicide ○ Can require hospitalization if aptient becomes danger to self or others Physical symptoms Often motivate patients to seek medical attention Chronic fatigue ○ Often worse in morning; not improve with rest ○ Pain (especially headache) often accompanies fatigue Sleep disturbances ○ Frequent early morning awakening with difficulty returning to sleep ○ Difficult to fall asleep ○ Frequent nighttime awakening ○ Increase sleep (hypersomnia) 3  Appetite disturbances ○ Decrease appetite - cause substantial weight loss, especially elderly patients ○ Other patients overeat / gain weight GI complaints Cardiovascular complaints - palpitations Loss of sexual interest / libido Intellectual / cognitive symptoms Decrease ability to concentrate Slowed thinking Poor memory of recent events Confusion and indecisiveness Consider depression when elderly patients have cognitive symptoms Psychomotor disturbance Psychomotor retardation - noticeably slowed ○ Physical movements ○ Thought processes ○ Speech Psychomotor agitation - purposeless, restless motion ○ Pacing ○ Wringing of hands ○ Shouting outbursts Suicide risk evaluation / management Center for Disease Control lists suicide as ○ 3rd leading cause of death - age 15 - 24 years ○ 2nd leading cause of death - age 25 - 34 years Widely held myths regarding suicide ○ People more likely to commit suicide if asked about it ○ People talking abour suicide are looking for attention ○ Suicidal people are crazy ○ Most suicides caused by sudden traumatic event Factors increasing suicicde 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 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 4  Suicide risk increase as major depressive disorder patients develop energy and capacity to act on a plan made earlier Clinician rating scales a. The Hamilton Rating Scale for Depression (HAM-D) ○ Efficacy in clinical trials for FDA approval of antidepressant ○ Score greater than 18 = moderate-severe depression ○ Response usually defend as at least a 50% reduction in HAM-D score ○ “Remission” return to normal state or HAM-D of 7 or less b. The Clinical Global Impression (CGI) Scale ○ Evaluate severity and improvement of patients overall c. The Montgomery-Asberg Depression Rating Scale (MADRS) ○ Evaluates symptoms of depression Patient rating scales a. Patient health questionnaire-9 (PHQ-9) ○ Based on DSM-5 diagnostic criteria for major depression ○ Often used in primary care setting ○ Patients can be screened with abbreviated version (the PHQ-2) Positive - administered PHQ-9 ○ Monitor treatment response b. Beck Depression Inventory c. Quick Inventory of Depressive Sympotms Self-Rated Therapeutic options Goal ○ Reduce acute symptoms ○ Facilitate return to level of functioning before illness ○ Prevent further episodes ○ Decision to hospitalized based on Suicide risk Physical health Social support ystem Psychotic and / or catatonic symptoms 5  Phase of treatment ○ Acute phase Continuation phase Maintenance phase 6 to 10 weeks 4 to 9 months after > 12 to 36 months remission acheived Goal is remission Goal to eliminate residual Goal to prevent symptoms or prevent recurrence relapse Absence of symptoms Return of symptoms Separate episode of < 6 months of remission depression ○ Risk of recurrence increase as number of past episodes icnrease Duration of therapy depends on risk of recurrence Lifelong maintenance therapy for persons at greatest risk for recurrence ○ < 40 years of age with ≥ 2 prior episodes ○ Any age with ≥ 3 prior episodes 6  Educate patient and his / her support system ○ Delay in antidepressant effects ○ Importance of adherence Non-pharmacological a. Psychotherapy and exercise ○ Example: interpersonal psychotherapy, cognitive behavioral therapy ○ With psychotherapy, it takes longer to observe effectiveness, pharmacotherapy makes it more effective ○ Mild to moderate depressive episode: psychotherapy can be 1st line therapy ○ Severe and / or psychotic major depressive disorder: psychotherapy alone not recommended for acute treatment ○ Maintenance psychotherapy not recommended as sole treatment to prevent recurrence b. St. John’s Wort ○ Not FDA regulated ○ Manufacturers not required to provide proof of safety and / or efficacy ○ Recommend single=source product from reputable manufacturer ○ Significant drug interactions with commonly used medications c. Electroconvulsive therapy (ECT) ○ Safe, effective treatment for several menatl illnessess including major depressive disorder ○ Condidate Rapid response needed Risks of other treatments outweigh potential benefits History of poor antidepressant response History of good ECT response Patient prefers ECT Depression in pregnancy ○ Suggested as initial treatment if symptoms are severe or life-threatening ○ General ECT course Unilateral or bilateral 2 - 3 times / week 6 to 12 treatments ○ Rapid therapeutic response (10 to 14 days) ○ Conditions associated with increased risk Increase intracranial pressure Recent myocardial infarction Recent intracerebral hemorrhage Bleeding unstable vascular condition ○ Anesthetic and non-depolarizing neuromuscular blocking agents decrease ECT morbidity ○ Adverse effects Cognitive dysfunction Confusion Memory disturbance )memory loss for events months before, after, during treatment) Cardiovascular dysfunction Prolonged apnea 7  Treatment-emergent mania Headache Nausea Muscle aches ○ Relapse rate high during year following ECT unless maintenance antidepressant prescribed d. Bright light therapy ○ Patients gaze into 10,000-lux intensity light box ~30 minutes / day Use with antidepressants Effective for seasonal affective disorder (SAD) and adjunctive use major depression disorder with seasonal exacerbations Well tolerated Frequently reported adverse event - minor visual complaints Baseline and periodic eye examinations recommended Pharmacotherapeutic Consideration and key to use ○ Selection - factors that influence antidepressant choice History of response (response - 50% reduction in symptoms) Pharmacogenetics - familial antidepressant response history Medical history Symptoms Potential drug-drug interactions Drug disease interaction Adverse events profile Patient preference Drug cost ○ Onset In general, it takes 4-6 weeks to see full antidepressant effects, given correct drug, dose and adherence, but sometime it takes 6 to 8 weeks to see response Remission (return to normal) take up to 12 weeks Symptoms such sleep disturbance show improvement in 1 to 2 weeks ○ Adequate trial Include correct drug and dose, ranges from 4 to 8 weeks Failure to respond to 1 class or 1 drug in calss does not preedict failed response to another drug class or another drug in class 8  Selective Serotonin Reuptake Inhibitors Serotonin Norepinephrine Reuptake Tricyclic Antidepressant (TCA) (SSRIs) Inhibitors (SNRIs) First line treatment for major depressive disorder First antidepressant, seldom used for depression but have sevceral off-label indications, pain syndrome, migraine prophylaxis and anxiety disorder Potent serotonergic activity Dual action Block reuptake of 5-HT and norepinephrine, Block reuptake of norepinephrine and 5-HT tertiary amines more potent for norepinephrine Low affinity for histaminergic, alpha-1 adrenergic, uptake and metabolized to active secondary muscarinic receptors amines Block alpha adrenergic, antihistamine effects and anticholinergic effects which lead to orthostatic, sedation and anticholinergic symptoms respectively Combine with others drugs affecting serotonin More effective than SSRIs Effective but limited due to ADR profile lead to serotonin syndrome Related with extrapyramidal symptoms including ADR profile similar to SSRIs Adverse effects common; affects other receptor akathiasia, dystonia, bradykinesia but not systems common Venlafaxine adverse effects similar to SSRIs Cholinergic Nausea ○ Dry mouth Common adverse effects (mild, short lived) Sexual dysfunction ○ Constipation Nausea Activation ○ Weight gain Vomiting Dose-related increase in diastolic blood ○ Sexual dysfunction Diarrhea pressure ○ Blurred vision Sexual dysfunction ○ Baseline blood pressure not useful ○ Urinary retention Headache predictor of occurrence ○ Dizziness Insomnia ○ Monitor blood pressure regularly ○ Tachycardia ○ Reduce dose / discontinue if ○ Memory impairment hypertension sustained ○ Delirium at high dose Neurologic Cardiovascular 9  Duloxetine well tolerated in short-term clinical ○ Orthostatic hypotension trials ○ Cardiac conduction delays Nausea Heart block in patients with Dry mouth pre-existing conduction Constipation disorders Decreased appetite Overdose produce severe Insomnia arrhythmias Increased sweating Exercise caution if patients have clinically significant cardiac disease Citalopram cause risk of QT prolongation at dose Produce neuroleptic malignant syndrome Abrupt TCA withdrawal > 40 mg/day (life-threatening idiosyncratic reaction Cholinergic rebound symptoms characterized by fever, altered mental status, ○ Dizziness muscle rigidity, and autonomic dysfunction) or ○ Nausea serotonin syndrome ○ Diarrhea ○ Insomnia ○ Restlessness Especially dose > 300 mg / day Taper dose over several days Low cost, better tolerability Sertaline better than fluoxetine Precaution Fluoxetine better than paroxetine Metabolism affected by smoking, bard, Escitalopram better then citalopram estrogens, neuroleptics, anticonvulsants Lower seizure threshold All TCA cause vagal block, postural hypotension, arrhythmias, sinus tachycardia All potentiate CNS depressants (BZDs, Barbs, ETOH) → coma and death In bipolar disorder may rpecipitate acute mania or rapid cycling 10  Caution in patient with cardiac disease or seizure disorders Patients at risk of orthostatic hypotension increased risk of falls if they take these agents, and appropriate caution should be taken Therapeutic serum concentration can be measured Adult dose Adult dose Adult dose Generic name Trade Initial dose Usual Generic name Trade name Initial dose Usual Generic name Trade name Suggest Initial Usual ed dose dosage name (mg / day) dosage (mg / day) dosage therapeu (mg / day) range range range tic (mg / day) (mg / day) (mg / day) plasma conc. (ng / mL) Citalopram Celexa 20 20-60 Venlafaxine Effexor 37.5 - 75 75 - 225 Tertiary amines Escitalopram Lexapro 10 10-20 Duloxetine Cymbalta 30 30 - 90 Amitriptyline Elavil 120 - 25 100 - 300 Fluoxetine Prozac 20 20-60 Desvenlafaxine Pristiq 50 50 - 100 250 Clomipramine Anafranil 25 100 - 250 Fluvoxamine Luvox 50 50-300 Milnacipran Savella 12.5 100 Doxepin Sinequan 25 100 - 300 Paroxetine Paxil 20 20-60 Elderly patients usuallty treated with Imipramine Tofranil 200 - 25 100 - 300 Sertraline Zoloft 50 50-200 approximately ½ of dose listed. 350 Secondary amines Patient with QT prolongation (congenital long QT syndrome, bradycardia, hypokalemia, Desipramine Norpramin 100 - 25 100 - 300 hypomagnesemia, recent acute myocardial 300 infarction, uncompensated heart failure) or Nortripytline Pamelor 50 - 25 50 - 200 concomitant medication that increase QT interval 150 not treated with citalopram Combined imipramine + desipramine concentrations should fall between 150 - 240 ng / mL 11 Relative potencies and side-effect profile 12  Triazolopyridines Aminoketone Mirtazapine Drugs: Trazodone, Nefazodone Drugs: Bupropion Mixed serotonin-norepinephrine effects Dual actions on serotonergic neurons No appreciable effect on 5-HT reuptake Enhance central noradrenergic and serotonergic 5-HT-2 receptor antagonists and 5-HT activity reuptake inhibitors Antagonism of central presynaptic Enhance 5-HT-1A-mediated ɑ2-adrenergic autoreceptors and neurotransmission heteroreceptors Antagnoizes 5-HT2, 5-HT3, and histamine receptors Lower anxiety and GI side effects Histamine receptor blockade associated with sedative properties Trazodone block ɑ1-adrenergic and histaminergic Inhibit dopamine and norepepinephrine reuptake receptors at high dose Increase side effects limit use such dizziness, sedation Adverse effects Adverse effect Orthostatic hypotension Aomnolence Sedation Weight gain Cognitive slowing Dry mouth Dizziness Constipation Priapism rare, potentially serious Weight gain can be less with larger doses - increased noradrenergic transmission as dose increase 13 Nefazodone declined after report of hepatotoxicity Unique Black box warning: rare cases of liver Increase risk of seizure failure Common adverse effects Consider as second or third line agent Insomnia Require liver function test monitoring Anxiety Adverse effect Irritability ○ Light-headedness Headache ○ Dizziness Decrease appetite ○ Orthostatic hypotension Increase energy ○ Somnolence Psychosis ○ Dry mouth Nausea ○ Nausea Vomiting ○ Asthenia (weakness) Tremor ○ Hepatic injury (black box warning) Activation Do not initiate in patients with Agitation active liver disease or elevated Dry mouth baseline serum transaminiases Skin reaction Seizures Adult dose Adult dose Adult dose Generic Trade Initial dose Usual Generic Trade Initial dose Usual Generic Trade Initial dose Usual name name (mg / day) dosage name name (mg / day) dosage name name (mg / day) dosage range range range (mg / day) (mg / day) (mg / day) Nefazodone Serzone 100 200 - 600 Bupropion Wellbutrin 150 150 - 300 Mirtazapine Remeron 15 15 - 45 hydrochloride Trazodone Desyrel 50 150 - 300 Bupropion Aplenzin 174 174 - 348 Elderly patient susually treated with hydrobromide approximately ½ of dose listed Elderly patient usually treated with approximately ½ opf dose listed Elderly patient usually treated with approximately ½ of dose listed 14  Monoamine Oxidase Inhibitors (MOIs) Phenelzine - non-selective MAO-A Tranylcypromine - non-selective MAO-B Selegiline - inhibit brain MAO-A and MAO-B with reduced effects on MAO-A in gut Block enzyme responsible for the breakdown of certain neurotransmitter such norepinephrine Patients with MOIs must educated and moitoried avoid food high in tyramine food (cheesem preserved metas) because of potential for precipitating hypertensive crises Hypertensive crisis Rare, serious, life-threatening Occur when MAOIs taken with certain food ○ High in tyramine or certain medications ○ 10mg tyramine cause marked pressor effects ○ 25mg cause serious hypertensive crisis Can culminate in cerebrovascular accident and death Symptoms ○ Occipital headache ○ Stiff neck ○ Nausea ○ Vomiting ○ Sweating ○ Sharply elevated blood pressure Precaution Wine-and-cheese reactioin ○ Fatal interaction with tyramine-containing foods (fermented foods such wine and cheese) ○ Normally tyramine and other amine rapidly inactivated by MAO in gut ○ MAO-inhibition allow uptake of tyramine, which displaces norepinephrine in storaye vesicles → norepinephrine released → induced hypertensive crisis → lead to intracranial bleeding and other organ damage 15 Increase norepinephrine, 5-HT, dopamine in neuronal synapse by inhibit MAO enzyme Chronic therapy changes receptor sensitivity Downregulation of beta-adrenergic, alpha-adrenergic, serotonergic receptors Adverse effect Postural hypotension (minimized with divided doses) Weight gain Sexual side effects Phenelzine - mild to moderate sedatives Tranylcypromine Insomnia Fever Myoclonic jerking Brisk deep tendon reflexes 16 Restriction when taking MAOIs 17 When switching patient from another antidepressant to MAOI need to wait 2 weeks after antidepressant discontinued before initiating MAOIs (except fluoxetine, which waiting period should be 5 to 6 weeks) MAOIs → another antidepressant require 2 weeks washout period Generic name Trade name Initial dose Usual dosage range (mg / day) (mg / day) Phenelzine Nardil 15 30 - 90 Selegiline (transdermal) Emsam 6 6 - 12 Tranylcypromine Parnate 10 20 - 60 18  Signs and symptoms of serotonin syndrome Cognitive-bahvioral dysfunction Autonomic nervous system dysfunction Neuromuscular dysfunction Confusion Diarrhea Myoclonus Hypomania Shivering Hyperreflexia Agitation Fever Tremor Diaphoresis Seizure Change in blood pressure Death Nausea and vomiting 19 20 21