Major Depressive Disorder (MDD)

Major Depressive Disorder (MDD) PARNA HAGHPARAST, PHARMD, BCPS ASSOCIATE PROFESSOR, PHARMACY PRACTICE PHAGHPARAST@WESTCOASTUNIVERSITY.EDU 1 Objectives To understand the diagnostic criteria of major depressive disorder Compare and contrast efficacy and safety profile of different antidepressants Be able to recommend the most appropriate antidepressant based on patient factors and side effect profile Monitor for adverse events or severe toxicity that may be associated with a particular medication regimen Describe general approach to management of serotonin syndrome and discontinuation syndrome 3 Risk Factors and Protective Factors for Mental Health Disorders Risk Factors for Mental Health Disorders Protective Factors for Mental Health Disorders 5 Types of Depressive Disorders Major Depressive Disorder (MDD) Persistent Depressive D/O (used to be called “Dysthymia”)depressive sx that lasts at least every day/nearly every for at least 2 years ( and never without symptoms for more than 2 months) Substance/medication Induced Depressive D/O Premenstrual Dysphoric Syndrome Depressive Disorder due to Medical Condition 6 DSM-5 MDD Risk Factors thoughts Temperamental Environmental Genetics Course Modifiers negative • Neuroticism • Adverse childhood experiences, • Stress life events • 1st degree family member= risk for MDD 2-4 folds • Chronic/disabling conditions, increases risk for MDD 7 DSM-5 MPD or chargeinmonoamine neurotransmitters GAPS in Treatment Cost • Underinsured, or lack of insurance can prevent people from getting help Stigma • Hide their mental health issues Logistics • Transportation, clinic time conflicting with work/school schedule, money Awareness • Lack of awareness and misunderstandings about treatment options, side effects, cost 8 Patient Assessment Physical Exam Mental Status Exam history Lab work up CBC w/ diff, thyroid, electrolytes Medical hx Medication/ substance use hx Depression rating scales Smost important part 14 Patient Assessment Cont’d Emotional symptoms Physical symptoms Intellectual/psychomotor disturbances symptoms Sad, depressed mood Sleep disturbances? Slowed thinking? Loss of pleasure/interest in work/hobbies Fatigue? Memory problems? Pain: muscle pain, HA? Restless/agitated? Appetite disturbances? Low libido? 16 Drugs Associated with Depression Medication Classes Examples Acne Treatment Isotretinoin Anticonvulsants Levetiracetam (Keppra ®) Topiramate (Topomax ®) Vigabatrin (Sabril ®) Antimigraine Triptans Cardiovascular B-blockers Clonidine Methyldopa Hormone Therapy Gonadotropin-releasing hormone Oral contraceptives Steroids (eg. Prednisone) Tamoxifen (Soltamox ®, Nolvadex ®) Immunologic Agents Interferons Smoking cessations Varenicline (Chantix ®) Others (including illicit drugs) Alcohol Hallucinogens including phencyclidine Inhalants Opioids Sedative, hypnotic, or anxiolytics Amphetamines (and other stimulants) Cocaine DSM-5, 2013 17 Dipiro JT. et al, 2016 Rating Scales Clinician rated scales Self-rated instruments • Hamilton Depression Rating Scale (HDRS or HAM-D) • Montgomery and Asberg Depression Rating Scale (MADRS) • Children Depression Rating Scale – Revised (CDRS-R) • Patient Health Questionnaire (PHQ) • PHQ-2 • PHQ-9 MDD Diagnostic Criteria A. ≥ 5 symptoms have to be present during the same 2-week period (daily or nearly daily) and represent a change in functioning B. Symptoms cause significant distress/impairment in social/occupational functioning of patient C. Episode is NOT attributed to other medical conditions/effects of other substances D. Should rule out schizophrenia/schizoaffective/psychotics/bipolar disorders 25 DSM-5, 2013 Depression Symptoms 1. 2. 3. 4. 5. 6. S=Sleep I=Interest G=Guilt E=Energy C=Concentration A=Appetite P=Psychomotor sx S=Suicidality Depressed Mood Interest or pleasure in nearly all activities Weight gain/loss or changes in appetite nearly every day Insomnia/hypersomnia Fatigue/loss of energy Psychomotor agitation or retardation nearly every day (observable by others, not merely subjective feelings of restlessness or being slowed down) 7. Feeling of worthlessness or excessive/inappropriate guilt 8. Concentration or indecisiveness nearly every day 9. Recurrent thoughts of death, suicidality, specific plan to commit suicide 26 DSM-5, 2013 Suicide Evaluation, Risk and Management Evaluate all patients with MDD should be evaluated Risk factors for suicide behavior/attempt Past history of suicide attempts/threats, family history of suicide behavior Presence of borderline personality Poor impulse control Males: 20-30 yo or > 50 yo; Females: 40-60 yo Substance abuse Marital status: single, divorced or widowed Sudden change in socioeconomic status (e.g losing job) 27 DSM-5, 2013 WFSBP guideline, 2013 Suicide Evaluation, Risk and Management Cont’d ALL antidepressants have boxed warning for increase risk of suicidal thinking and behavior in children and adolescent 18-24 yo during initial stages of treatment o Fluoxetine and venlafaxine did not show increased suicidality in youth Closely monitor patients for SI at the beginning of treatment and among younger patients Encourage patients to seek help if behavioral agitation or anger occur Admission to psychiatric ward Limited supply of AD (e.g weekly) for those at risk of over dose (e.g TCA, or MAOI) 28 et al, 2016 Dipiro JT. Treatment Goal Prevention of further episodes of depression (i.e relapse or recurrence) Resolution of current symptoms (i.e remission) 29 5 R’s to antidepressant treatment Response: ≥ 50% improvement of symptoms from baseline ◦ Partial response: 25%-49% reduction in symptom scores ◦ No response: < 25% reduction in symptom scores Remission: asymptomatic (not meeting MDD criteria) w/ minimal residual sx + improvement psychosocial/occupational functioning with or without treatment Relapse: Return of symptoms to meet criteria for MDD during remission but before recovery Recovery: Involves both relief of symptoms and improvement of functioning after cessation of AD (recovery of episode not necessarily the illness) lasting at least about 4-6 months Recurrence: A separate episode of depression during recovered period WFSBP, 2013 CANMAT, 2016 30 31 BP Offs Treatment Phases (WFSBP guideline) Campa Acute Phase: at least 8-10 weeks may be required for remission ◦ The time between therapy initiation to remission ◦ Evaluate pt in 2 week and optimize tx if needed ◦ Goal= remission (asymptomatic and improvement in psychosocial and occupational functioning) Continuation Phase: continue AD 6-9 months after remission is achieved ◦ Goal= Preserve remission (ie. Prevent relapse), eliminate residual symptoms ◦ Residual symptoms (partial remission) are strong predictors of subsequent early relapse continue treatment until residual sx have subsided  Psychotherapy may be added for residual sx ◦ Same antidepressant successfully used to achieve response/remission in the acute-phase therapy should be continued at the same dose during the continuation phase ◦ If no relapse occurs during continuation therapy, a gradually discontinue the AD in case of first episodes  If tapering off results in a return of symptoms, AD should be re-instated in the original dose for at least another 6 months before attempting discontinuation again Maintenance Phase (prophylactic): 3 years to lifelong ◦ Exact duration has not been determinized (depend on risk of recurrence) ◦ Goal= Prevent recurrence (ie. New episode) ◦ Longer treatments recommended if worse prognosis WFSBP, 2013 WFSBP, 2015 32 Treatment Phases (CANMAT guideline) The CANMAT guideline identify 2 phases of depression treatment: o Acute phase (getting to symptomatic remission)  Evaluate for early improvement in 2-4 weeks ◦ >20%-30% reduction from baseline in a depression rating scale after 2-4 weeks ◦ If no improvement, consider dose optimization if AD can be tolerated  Continue treatment for 6-8 weeks o Maintenance phase (preventing relapse and recurrence)  6 to 9 months after achieving symptomatic remission,  If risk factors for recurrence are present, extend treatment to ≥2 years CANMAT, 2016 33 Risk of Recurrence Duration of AD depends on risk of recurrence Risk factors to consider long term AD • Frequent, recurrent episodes • Severe episodes (psychosis, severe impairment, suicidality) • Co-morbid psychiatric or other medical condition • Residual symptoms or difficult-to-treat episodes 35 Dipiro JT. et al, 2016 CANMAT, 2016 Question 1 Which of the following increases risk of depression recurrence/relapse? (Select all that applies) ◦ ◦ ◦ ◦ A. Long remission periods B. Mild depressive symptoms C. Depression with psychotic symptoms D. Frequent, recurrent episodes of depression 37 Non-pharmacological Psychotherapy (e.g. CBT) ◦ 1st line in mild-moderate depression ◦ Alternative to antidepressants in moderate depression Electroconvulsive therapy (ECT) ◦ ◦ ◦ ◦ ◦ ◦ Severe depression w/ psychomotor retardation “True” treatment resistant cases/suicidality Severe psychotic depression Persistent refusal of food Previous positive response to ECT Pregnant women especially during the 1st trimester Light therapy ◦ Seasonal affective disorder ◦ Using fluorescent light box or 1 hr outdoor morning walk CBT: cognitive Behavioral Therapy IPT: Interpersonal Therapy WFSBP, 2013 39 Herbal Remedies St. John’s Wort o Mild-moderate depression o 600-900 mg/d o CYP3A4 inducer o Lots of drug-drug interactions  Serotonin syndrome o Photosensitivity 40 WFSBP, 2013 Pharmacological Treatment SSRIs Citalopram SNRI TCAs Mixed 5-HT Duloxetine Nortriptyline Nefazodone Escitalopram Fluoxetine Desvenlafaxine Phenelzine Ketamine Selegiline Esketamine Tranylcypromine Dextromethor phan/bupropi on Vilazodone Imipramine Paroxetine Sertraline NMDA Antagonist Trazodone Amitriptyline Fluvoxamine MAOIs Mirtazepine Desipramine Venlafaxine Miscellaneous Levomilnicipran SSRI: Selective serotonin reuptake inhibitor SNRI: Serotonin Norepinephrine Reuptake inhibitor TCA: Tricyclic antidepressants 5-HT- serotonin MAOI: Monoamine oxidase inhibitors Doxepin Bupropion Vortioxetine 41 medadherence Considerations when choosing antidepressants Safety/side effect profile Pharmacokinetics parameter e.g. half life Drug interactions Past medication history/prior treatment experience Patient preference Cost 42 Selective serotonin reuptake inhibitors (SSRI) Efficacy Superior to placebo and comparable to other classes of AD Side Effect • N/V, diarrhea, sexual side effects, sleep disturbances, headache, anxiety/restlessness, SIADH, bleeding, Qtc prolongation (dose related with citalopram & escitalopram) interaction especially with paroxetine, fluoxetine, Drug Interactions CYP450 fluvoxamine • E.g TCAs + fluoxetine/paroxetine high plasma level of TCA ( strong CYP2D6 inh) • TCA+ SSRIs Risk of SS • Caution: concomitant QTc prolonging drugs and medications increasing risk of bleeding SIADH: Syndrome of inappropriate antidiuretic hormone 43 SSRI Usual dose (mg/d) Comments Citalopram (Celexa) 20 mg 20-40 mg Doses >40 mg/day not recommended due to QT prolongation risk; maximum 20 mg/day for CYP2C19 poor metabolizers or coadministration with CYP2C19 inhibitors (e.g. omeprazole, clopidogrel); 20 mg/day recommended for patients >60 years of age Escitalopram (Lexapro) 10 mg 10-20 mg Max 20 mg/day; dose may be increased to maximum daily dose after at least 1 week if needed Fluoxetine (Prozac, Sarafem*) 20 mg 20-60 mg Max 80 mg/day; dose may be increased in 20 mg increments; doses of 5 or 10 mg/day have been used as initial therapy; doses >20 mg/day may be given in a single daily dose or divided twice daily. Delayed release capsules: weekly dose (fluoxetine 20 mg/day = delayed-release fluoxetine 90 mg/week) Paroxetine (Paxil, Brisdelle) 20 mg 20-50 mg Maximum 50 mg/day (IR); titrate 10 mg/day increments weekly Maximum 62.5 mg/day (CR); titrate 12.5 mg/day increments weekly Sertraline (Zoloft) 50 mg 50-200 mg Maximum 200 mg/day; titrate 25 mg/day increments weekly Fluvaxamine (Luvox) *Premenstrual Dysphoric Syndrome Initial dose (mg/d) Daily doses >100 mg total dose should be divided twice daily, with the larger dose given at night. Off-label dosing for 44 et al, 2016 Dipiro JT. depression: 5-300 mg/d General SSRI tolerability • Highest rate of discontinuation o Paroxetine, Fluvaxamine • Insomnia (stimulating) o Sertraline, fluoxetine • Most activating initial anxiety o Fluoxetine • Most anticholinergic side effect o Paroxetine weight gain • Highest rate of fatigue o Sertraline • Highest rate of sexual dysfunction o Sertraline, paroxetine • Highest rate of hyponatremia o Paroxetine, citalopram, escitalopram • Highest rate of diarrhea o Sertraline Ferguson JM, 2001 Best Tolerated Citalopram/escitalopram Fluoxetine Sertraline Paroxetine Fluvoxamine Least Tolerated 49 Serotonin Norepinephrine Reuptake Inhibitor (SNRI) Efficacy Side Effect Comparable to other drug classes Similar to SSRIs • N/V, sexual side effects, activation/insomnia, increase in blood pressure and heart rate (mild), constipation Drug Interactions • Fewer CYP 450 interactions compared to SSRIs; • Duloxetine also CYP2D6 inhibitor (moderate) & substrate of CYP1A2; levomilnicipran is substrate of CYP3A4 • Caution with drugs increasing risk of bleeding 50 et al, 2016 Dipiro JT. SNRI Initial dose Usual dose (mg/d) Comments Venlafaxine (Effexor IR, XR) 37.5-75 mg 75-225 mg Maximum 375 mg/day (IR); maximum 225 mg/day (ER); may increase in increments up to 75 mg/day at a minimum of every 4 days. Desvenlafaxine (Pristiq) 50 mg 50 mg Doses up to 400 mg/day have been studied; however, AEs are increased and no additional benefit has been shown at doses exceeding 50 mg/day. Active metabolite of venlafaxine Duloxetine (Cymbalta) 60 mg daily (or 20 mg BID or 30 mg BID) 30-90 mg Maximum 120 mg/day (given once or twice daily); doses exceeding 60 mg/day not shown to provide increased efficacy for the treatment of MDD. Also indicated for diabetic neuropathy, anxiety, fibromyalgia. CYP1A2 substrate, moderate inhibitor of 2D6 Levomilnacipran (Fetzima, Khedzela) 20 mg 40-120 mg Initial dose (20 mg) for 2 days before dose increases are recommended at intervals of two or more days. Dose adjustment or discontinuation may be required if sustained elevated heart rate. Substrate of CYP3A4 Taku fool(mg/d) Milnacipran (Savella) Approved for fibromyalgia (not MDD). Off label dose for depression is 50 mg BID *Dose reductions or discontinuation may be required if sustained hypertension occurs Dipiro JT. et al, 2016 Sansone RA. Et al, 2014 51 SNRI Clinical Pearls prozac longerhalf life Duloxetine has the most FDA indications Venlafaxine has the shortest half life discontinuation syndrome Relatively shorter half lives (8-14 hrs) compared to SSRI/TCAs Avoid duloxetine in chronic liver disease/cirrhosis Duloxetine (CYP1A2 substrate) interacts with smoking (CYP1A2 inducer) Sansone RA. Et al, 2014 52 Initial vs Later Side Effects of SSRI/SNRI Initial Serotonergic effects Later side effects • GI: diarrhea, nausea • Headache • “Activating effects” – nervousness, anxiety • Weight gain • Sexual dysfunction • Sleep disturbances 53 Noradrenergic Side Effects Hypertension Sweating/night sweats Dry mouth Tremor Constipation Urinary retention 54 Question 2 Which SSRI has to be taken in the morning because of its stimulating effect? A. B. C. D. Paroxetine Citalopram Duloxetine Prozac 56 Tricyclic antidepressants MOA Efficacy Older generation SNRI + blocks acetylcholine, histamine & alpha-adrenergic system Equal efficacy among members but different side effect profiles Side Effects • Anticholinergic • Antihistaminergic • Alpha-adrenergic blockade • Neurologic 57 et al, 2016 Dipiro JT. TCA Side Effects Anticholinergic Dry mouth, constipation, blurred vision, urinary retention, tachycardia, confusion Antihistaminergic Sedation, memory impairment, weight gain Alphaadrenergic blockade Orthostatic hypotension (dose-related), bradyarrythmias, tachycardia Neurologic Seizure in OD, delirium in elderly, tremor Other hepatic failure, sexual side effect 58 I Tricyclic antidepressants Secondary amine vs tertiary amine o Secondary less side effects  Nortriptyline and desipramine Caution o In elderly and patients with moderate-severe of cardiac disease (nortriptyline is safest) o Do not use in patients with BPH, cognitive impairment, seizures, delirium o Pregnancy o Diabetes (glucose dysregulation) o Hepatic and renal impairment o History of suicide (narrow therapeutic index) CYP interactions o Substrate of Cyp2D6 o Do not give with potent cyp2D6 inh (fluoxetine and paroxetine) 59 et al, 2016 Dipiro JT. TCAs Initial dose (mg/day) Usual dose (mg/day) Comments Nortriptyline (Pamleor) 25 mg 50-150 mg Maximum 150 mg/day; total daily may be given as a single daily dose (if tolerated) or 25 mg doses given three to four times daily; Has safest cardiac profile and lowest risk of orthostatic hypotension Desipramine (Norpramin) 25 mg 100-200 mg Maximum 300 mg/day Amitriptyline (Elavil) 25 mg 100-200 mg Maximum 300 mg/day for MDD; depending on the total dose, it may be given as a single daily dose at bedtime or in divided doses throughout the day; Imipramine (Trofanil) 25 mg 100-200 mg Maximum 300 mg/day; may be given in a single daily dose at bedtime (if tolerated) or in divided doses throughout the day. Highest risk of orthostatic hypotension Doxepin (Sinequan, Silenor) 25 mg 100-200 mg Maximum 300 mg/day; may be given in a single daily dose at bedtime (if tolerated) or in divided doses throughout the day; a single dose should not exceed 150 mg. Also approved for sleep maintenance 60 et al, 2016 Dipiro JT. Mixed serotonergic/multimodal medications predation Trazodone and nefazodone have dual actions on serotonergic neurons ◦ 5-HT2 antagonists + 5-HT reuptake inhibitors ◦ Enhance 5-HT1A-mediated neurotransmission Trazodone (Desyrel ®, Oleptro ®) ◦ ◦ ◦ ◦ Also blocks alpha 1-adrenergic and histaminergic receptors dizziness and sedation Antidepressant starting dose: 150 mg daily in divided doses after light snack (food increases absorption) Off-label for sleep- 50-100 mg at night Side effects: orthostatic hypotension, sedation, dizziness, priapism (rare) Nefazodone (Serzone ®) ◦ Initial Dose: 100 mg BID ◦ Side effect: orthostatic hypotension, dizziness, sedation, liver failure (BBW) ◦ DDI: CYP 3A4 Inhibitor Dipiro JT. et al, 2016 Micromedex 61 Mixed serotonergic/multimodal medications Continued Vilazodone (Viibryd ®) ◦ ◦ ◦ ◦ ◦ ◦ point see it as SSRI + 5-HT1A receptor partial agonist Dose: initially 10 mg QD x 7 days, then 20 mg QD (Max: 40 mg/d) Administration: with food Side effect: GI, diarrhea, dizziness, insomnia, decreased libido (esp in men) Metabolized by CYP3A4 Niche: co-morbid anxiety often Vortioxetine (Trintellix ®) ◦ SSRI + 5HT3, 5HT1D, 5HT7 receptor antagonist + 5HT1A agonist + 5HT1B receptor partial agonist ◦ Dose: Initially 10 mg QD, then 20 mg once daily as tolerated ◦ Side effect: GI, sexual dysfunction in men (esp at 20 mg dose), cautious in patients w/ seizures (post marketing data but not contraindication) ◦ Niche: those w/ accompanying cognitive difficulties Dipiro JT. et al, 2016 62 Micromedex Ng callbaton and Zuber Miscellaneous Mirtazapine (Remeron ®): ◦ ◦ ◦ ◦ good if sexoner distinct Noradrenergic and specific serotonergic antidepressant (NaSSA) increase in NE and serotonin + alpha 2 adrenergic receptor antagonist Dose: Dose: 15 -45 mg/day Side effect: weight gain, sedation (inverse-relationship?), hyperlipidemia, anticholinergic effects, akathisia, hyponatremia (low risk compared to others), orthostatic hypotension, less sexual side effects that other antidepressants ◦ Niche: insomnia, low appetite/anorexic, sexual side effect Bupropion Hydrochloride (Wellbutrin ®, Zyban ®) smoking sustained ◦ Norepinephrine + DA reuptake inhibitor ◦ Contraindications: with eating disorders such as bulimia and anorexia, Seizure disorders, abrupt d/c of alcohol, BZDs and antileptics, concomitant bupropion products, HTN ◦ Dosing: ◦ ◦ ◦ (IR) Initial, 100 mg orally BID x 3 days, may increase to 100 mg TID; MAX dose is 450 mg/day given as 150 mg TID OR 100 mg QID; separate all doses by at least 6 hours; MAX single dose is 150 mg (SR) Initial, 150 mg orally QD in AM x 3 days, may increase to 150 mg BID; MAX dose is 400 mg/day given as 200 mg BID; separate all doses by at least 8 hours; MAX single dose is 200 mg (XR) Initial, 150 mg orally QD in AM x3 days, may increase to 300 mg QD; MAX dose is 450 mg/day given as a single dose ◦ Side effects: N/V, tremor, insomnia, dry mouth, skin reactions, lowers seizure threshold (dose related), anxiety? ◦ Drug interactions ◦ Caution with CYPD6 inhibitors e.g fluoxetine and paroxetine seizures 63 Dipiro JT. et al, 2016 Micromedex Monoamine Oxidase Inhibitors (MAOI) MOA increase NE, 5-HT and DA through inhibition monoamine enzyme Types Selective vs non-selective • Non-selective (MAOI-A + MAOI-B): phenelzine, isocarboxazid, Tranylcypromine • Selective MAOI • MAOI-B: Selegiline below dose Efficacy Comparable to other AD classes Side Effects • Orthostatic hypotension (more w/ phenelzine), hypertensive crisis and serotonin syndrome with tyramine containing food 64 et al, 2016 Dipiro JT. MOAI Initial dose Usual dose (mg/day) (mg/day) Comments Phenelzine (Nardil) 15 mg 30-90 mg Early phase recommended dosing: 15 mg three times daily; dosing may be increased to 90 mg/day based on tolerance and response; Maintenance phase: dose should be reduced over several weeks to a daily dose as low as 15 mg/day or 15 mg every other day. Sedating effect Isocarboxazid (Marplan) 40 mg 20-40 mg Max dose: 60 mg/d- dose given in 2-4 divided doses Tranylcypromine (Parnate) 10 mg 20-40 mg Maximum 60 mg/day; divided dosing; if no response after 2 weeks, increase by 10 mg increments at 1- to 3-week intervals; Medication cross-taper: allow at least 1 medication-free week, an then initiate tranylcypromine at 50% of usual starting dose for at least 1 week. Stimulating effect Selegeline (Emsam) 6-12 mg Patch- Not to exceed 12 mg/24 hours; dose may be increased by 3 mg/day increments every 2 weeks; transdermal delivery system designed to deliver dose continuously over a 24-hour period. Oral formulation approved for Parkinson. 6 mg 65 et al, 2016 Dipiro JT. MOAI Drug interactions Serotonergic drugs esp SSRI serotonin syndrome Avoid use within 14 days other serotonergic agents (including linezolid, methylene blue, tramadol, meperidine) Fluoxetine: At least 5 weeks should elapse before initiating MAOIs Sympathomimetic drugs hypertension crisis (HTN, hyperthermia, mental status change) Pseudoephedrine, phenylephrine, dextromethorphan (also serotonergic) Stimulants e.g amphetamines Epi/NE/DA 66 et al, 2016 Dipiro JT. Auvelity (Dextromethorphan + Bupropion) Approved Aug 2022 Dose: 1 tablet x 3 days, followed by BID dosing thereafter (doses must be separated by at least 8 hrs) XR tablet (45 mg/105 mg) Warning/Precaution Dextromethorphan  NMDA antagonist + Sigma 1 agonist Bupropion  Acts as CYP2D6 inhibitor to increase dextromethorphan levels BBW  SI in pediatric and young adults  Not approved in pediatric        Seizure Abrupt d/c of alcohol, BZD, barbiturates Bulimia, anorexia nervosa Dizziness Pregnancy (avoid use) Psychosis HTN Most common ADR: dizziness, headache, diarrhea, somnolence, dry mouth, sexual dysfunction, and hyperhidrosis DDI: this medication interacts with     CYP2D6 inhibitors CYP2B6 inducers Digoxin May cause false positive for urine lab results for amphetamine 67 bepregyt on't pt Brexanolone (Zulresso ®) Schedule IV • Approved in 2019 for post partum depression • Used alone or in combination w/ oral AD • MOA: (GABA) A receptor positive modulator • A healthcare provider must be available on site to continuously monitor the patient, and intervene as necessary, for the duration of the infusion • Continuous IV infusion over 60 hours (2.5 days) as follows: • • • • • 0 to 4 hours: Initiate with a dosage of 30 mcg/kg/hour 4 to 24 hours: Increase dosage to 60 mcg/kg/hour 24 to 52 hours: Increase dosage to 90 mcg/kg/hour (alternatively consider a dosage of 60 mcg/kg/hour for those who do not tolerate 90 mcg/kg/hour) 52 to 56 hours: Decrease dosage to 60 mcg/kg/hour 56 to 60 hours: Decrease dosage to 30 mcg/kg/hour • Warning: Suicidal Thoughts and Behaviors: Consider changing the therapeutic regimen, including discontinuing ZULRESSO, in patients whose PPD becomes worse or who experience emergent suicidal thoughts and behaviors. • BBW: excessive sedation/loss of consciousness. Need continuous monitoring of pulse oximetry. • ADR (common): sedation/somnolence, dry mouth, loss of consciousness, and flushing/hot flush. • Pregnancy: May cause fetal harm 68 ptcan'tbeperiod Zuranolone (Zurzavae ®) •Approved in 2023 for post partum depression •Used alone or in combination w/ oral AD •MOA: (GABA) A receptor positive modulator •Administer w/ fat containing food •Dose: 50 mg orally (capsule) once daily in the evening for 14 days • Dosage may be reduced to 40 mg once daily if CNS depressant effects occur. • Reduce dose in severe hepatic/mod-severe renal impairment •Contraindications: None •Warning • CNS depression (somnolence, confusion): do not drive for at least 12 hrs post dose for 14 days---BBW • SI • Embryo-fetal toxicity (do not use in pregnant patients—use effective contraception during tx and for one week after last dose) •ADR (common): somnolence, dizziness, diarrhea, fatigue, nasopharyngitis, and UTI •DDI: • avoid use w/ CYP3A4 inducers, reduce dose w/ strong CYP3A4 inhibitors • CNS depressants: can exacerbate CNS depressive effects…may need dose reduction 69 Sexual side effect Implications of sexual dysfunction ◦ Impacts adherence to antidepressants ◦ Poor quality of life ◦ Possibility of relapse Questions to consider ◦ Timing of sexual dysfunction? ◦ Contributing factors? ◦ Did sexual dysfunction get worse? Sexual side effect risk (dose-related) ◦ Highest risk with SSRI, TCA, and venlafaxine ◦ SSRI > mirtazapine, bupropion, nefazodone 72 Zajecka J, 2001 Sexual side effect Management Choose antidepressant with favorable side effect at initiation Reduce antidepressa nt dose if sexual dysfunction occurs Wait for adaptation Consider weekend “drug” holiday Use of antidotes as adjunct Antidepressant with lower risk of sexual side effects: • Bupropion Buspirone (Buspar) Bupropion, mirtazapine • Mirtazapine • Vilazodone Antidote • Vortioxetine Ginkgo Biloba Extract (60Sildenafil (Viagra) prn 240 mg/d in divided doses) 73 Zajecka J, 2001 Question 3 What is the mechanism of action for venlafaxine? A. B. C. D. Selective serotonin reuptake inhibitor (SSRI) Serotonin and dopamine reuptake inhibitor Norepinephrine and dopamine reuptake inhibitor (NDRI) Serotonin and norepinephrine reuptake inhibitor (SNRI) 76 Approach to Depression Treatment 84 Timing of Antidepressant Effects Side Effects Antidepressant Effect 85 Monitoring Parameters Efficacy/response to antidepressant (change from baseline) Adherence Tolerability (GI, sexual dysfunction) Sleep pattern Appetite/weight Drug levels for some TCAs/genotyping New medications added or removed (interactions, doses) 86 Special population and depression Pregnancy Gastrointestinal bleeding ◦ SSRIs have increased hemorrhage risk ◦ Other antidepressants are not well studied and are not necessarily safer ◦ Adding a PPI can decrease risk of bleeding ◦ For SSRIs, best available data is for citalopram and sertraline ◦ Avoid paroxetine and fluoxetine in pregnancy heart malformations ◦ TCA’s appear to have no teratogenicity ◦ MAOI are CI hypertensive crisis ◦ Psychotherapy and ECT are alternatives ◦ Post-partum depression: Brexanolone, zuranolone Elderly (age > 65) ◦ Higher risk of orthostatic hypotension and falls ◦ Start patients at lower dose ◦ TCAs not recommended WFSBP, 2013 88 Choosing the right antidepressant based on comorbidities Cognitive impairment ◦ Vortioxetine (level 1) ◦ Bupropion, duloxetine, SSRIs (Level 2) Sleep disturbances ◦ Mirtazapine ◦ Trazodone Somatic symptoms ◦ Duloxetine (pain, energy) ◦ Bupropion (fatigue) Post-partum depression ◦ Brexanolone (IV) ◦ Zuranolone (PO) CANMAT, 2016 Yekehtaz H. et al, 2013 Dipiro JT. et al, 2016 89 pod General Approach to Treatment nonofirst Optimize dose Allow time for the medication to work chrosstitrate tonedose Avoid duplication • SSRI + SSRI/SNRI • MAOI + serotonergic AD (e.g SSRI/SNRI/TCA) •Combining antidepressants NOT recommended as initial MDD tx •Combining SSRIs with mirtazapine, bupropion, TCA is ok! •If medication was partially ineffective, consider increasing the dose •If switching antidepressants, best approach is to cross-titrate WFSBP guideline, 2013 90 ptgetssidefed a Discontinuation syndrome Approximately in 20% of patients after abrupt discontinuation (after at least 6 weeks) of antidepressants Symptoms: F: flu-like sx o Flu-like symptoms, HA, lethargy, muscle cramps I: imbalance o Insomnia N: nausea o N/V I: insomnia o Imbalance S: sensory disturbances o Hyperarousal e.g agitation, anxiety H: hyperarousal o Irritability o Electric shock sensations o Cholinergic rebound (e.g sweating, nausea, vomiting, diarrhea, urinary urgency) esp w/ TCAs Onset & Duration: within 3 days of stopping or starting a taper and may last for 1-2 weeks Short half life vs long half life medications 93 Waner CH. et al, 2006 WET-DOG-SHAKE: shaking, trembling, sweating Serotonergic Syndrome •Potentially life threatening Mental Status Change Neuromuscular hyperactivity Autonomic hyperactivity •Caused by use of serotonergic agents o Caution with use of multiple serotonergic medications o Within 24 hours of an increased serotonin •Discontinue causative agent, maintain hydration •Stabilize vital signs, treat hyperthermia (cooling measures, reduction of muscle activity) Anxiety Tremor Mydriasis Lethargy Hyperreflexia Hypertension Clonus (muscle o BZD helps w/ sedation, agitation, mild HTN and tachycardia Confusion Watch video for clonus and hyperreflexia: https://www.youtube.com/watch?v=1X-br14gCVo Coma spasm when stretching the muscle)-lower extremity Cogwheel rigidity (lower extremity) Tachycardia Diaphoresis 96 Volpi-Abadie J, et al, 2013 Important Serotonergic Medications • • • • • • • • • • • • Antidepressants with serotonergic activity eg SSRI, mirtazapine, MOAI etc. Buspirone Triptans e.g sumatriptan St. John Wort Lithium Metoclopramide All opioids eg. Methadone, tramadol, tapentadol, meperidine, fentanyl Dextromethorphan Cocaine, LSD, ecstasy (ask about illicit drug use) Phentermine Linezolid Antiemetics: 5HT3 antagonists (e.g ondansetron) Volpi-Abadie J, et al, 2013 97 Serotonergic syndrome management 1. Discontinue the offending agent 2. Stabilize vital signs, treat hyperthermia (cooling measures, reduction of muscle activity) • • BZD helps w/ sedation, agitation, mild HTN and tachycardia HTN nitroprusside or other short acting agents 3. Cardiac monitoring 4. If hyperthermia/agitation persists or temp > 41 C • 5. Avoid antipyretics, use cooling blankets instead Consider intubation with muscle paralysis • Non-depolarizing paralytics/intubation o 1. Avoid succinylcholine due to risk of hyperkalemia exacerbate rhabdomyolysis May use 5-HT antagonist (cyproheptadine, chlorpromazine) if BZD and supportive care is not enough Volpi-Abadie J, et al, 2013 98 Summary 99 Foong AL. et al, 2018 Treatment-Resistant Depression 101 Introduction •1/3-2/3 of patients will NOT respond to the first antidepressant prescribed •15 to 33% will not respond to multiple interventions •Different definitions for treatment-resistant depression o Most commonly employed definition: inadequate response to ≥ 2 antidepressants (different class) •Treatment-resistant depression may require long-term treatment Little A. Treatment-resistant depression. Am Fam Physician. 2009;80(2):167-172. 102 Treatment Strategy Check adherence, adequate dose, and duration (≥ 6 weeks) Add adjunct medication or switch to another non-MOAI antidepressant 1.Switch AD: within class or to a different class 2.Combination: Antidepressants + another non-MOAI antidepressant 3.Augmentation: Antidepressants + non-antidepressant agent Non-pharmacological Interventions/neurostimulation approaches • ECT remains one of the most effective therapy for treatment-resistant symptoms • Repetitive transcranial magnetic stimulation (rTMS) • Depression-focused psychotherapy (adjunct) for residual sx CANMAT 2016 Clinical Guidelines for the Management of Adults with Major Depressive Disorder: Section 3. Can J Psychiatry. 2016;61(9):540–560 Clinical guidelines for the management of treatment-resistant depression: French recommendations from experts, the French Association for Biological Psychiatry and 104 Neuropsychopharmacology and the fondation FondaMental. BMC Psychiatry. 2019;19(1):262. Published 2019 Aug 28. Strategy 1: Switching Antidepressants •May consider switching to one of the antidepressants with superior efficacy: sertraline, escitalopram, venlafaxine, mirtazapine Within same class Different class Strategy 2: Combining two antidepressants Bupropion + SSRI/SNRI • May be helpful in patients with low energy or have sexual side effects Mirtazapine + SSRI/SNRI • May be helpful for sleep disturbances • Low incidence of sexual side effects TCA + SSRI/SNRI Caution with SSRI + SNRI or SSRI + SSRI due to increased risk of serotonin syndrome Strategy 3: Augmenting with nonAntidepressants Antipsychotic as adjunct Lithium Atypical antipsychotics •More evidence with Lithium augmenting TCAs •Check plasma levels (0.5-0.8 mmol/L) •Risks: thyroid, CV and renal •1st line in French guideline, 2nd line in CANMAT Tri-iodothyronine (T3) Lamotrigine •Well tolerated, not widely used •In combination w/ SNRIs or TCAs •Baseline TSH and EKG •Dose: 25-50 µg/d •Target TSH levels: 0.1-1 µg/L •Second line agent (French guidelines) •Dose: 200-400 mg/day Stimulants Esketamine Buspirone (Buspar) •Lisdexamphetamine (Vyvanse) •Mixed results •Modafinil (Provigil) •Marginal efficacy (compared to placebo) •AE similar to placebo •Other stimulants (eg. Methylphenidate) •Negative results •Not in guidelines yet •Indication: TRD and SI •30-60 mg/day •Off-label •Not mentioned in guidelines lakapinetetabolicsy on weightt CANMAT 2016 Clinical Guidelines for the Management of Adults with Major Depressive Disorder: Section 3. Can J Psychiatry. 2016;61(9):540–560 Clinical guidelines for the management of treatment-resistant depression: French recommendations from experts, the French Association for Biological Psychiatry and Neuropsychopharmacology and the fondation FondaMental. BMC Psychiatry. 2019;19(1):262. Published 2019 Aug 28. BO firm Antipsychotics Used as Adjunct for MDD 1. Aripiprazole (Abilify) 2. Brexpiprazole (Rexulti) 3. Cariprazine (Vraylar ®) 4. Quetiapine XR (Seroquel) 5. Olanzapine/fluoxetine (Symbyax) 6. Ziprasidone (Geodon)-off-label 7. Risperidone (Risperdal)-off-label 108 Ketamine •N-methyl-D-aspartate receptors (NMDA) antagonist •Off-label (FDA approved for procedural sedation and adjunct anesthesia) o 0.5 mg/kg •Formulations o IV/IM •Administered in healthcare setting •Metabolism: CYP2B6 and 3A4 substrates •Antidepressant response within hours •Concerns o The benefits and safety of longer-term ketamine treatment are not known o Tolerance or tachyphylaxis can occur—May require repeated use w/ higher doses ketamine dependence and new epidemic 112 Esketamine (Spravato ®) FDA Indication: adjunct for TRD or acute suicidality REMS program (Esketamine only) ◦ Dispensed and administered in healthcare setting ◦ Patients and healthcare setting must be registered Treatment Resistant Depression (TRD) ◦ 56 or 84 mg intranasally ◦ Frequency  Weeks 1 - 4 – Two times/week (induction)—evaluate benefit after 4 weeks  Weeks 5 - 8 – Once/week (maintenance)  Thereafter – Once every one to two weeks (maintenance) Depressive symptoms in patients with acute suicidal ideation or behavior ◦ 84 mg intranasally (may give 56 mg if can’t tolerate higher dose) ◦ Frequency  Weeks 1 - 4 – Two times/week (induction)  Thereafter: evaluate benefit of ongoing therapy 113 notsafetodrive A Bad taste Esketamine (Spravato ®) •BBW: Sedation; Dissociation; Abuse and Misuse; and Suicidal Thoughts and Behaviors o Monitor patients for at least 2 hours after administration. •Warnings/ Adverse Effects: N/V, dysgeusia (altered taste/bad/metallic/bitter taste), dissociative disorder, increased BP, drug dependence •Monitoring: check BP before and after administration (40 min post dose) o Elevated BP lasts 4 hours o Consider delaying therapy if BP > 140/90 mmHg prior to administration •Counselling: advise patients to avoid food for at least 2 hours before administration and to avoid drinking liquids at least 30 minutes prior to administration due to N/V •DDI o CNS depressants: additive effect o Stimulants and MOAI: increase BP Esketamine. Prescribing Information. Janssen Pharmaceuticals Inc. Accessed October 26, 2020. 114 115 Switch or add an adjunct? Switch • 1st antidepressant trial • Poorly tolerated/ side effects • No response (<25% improvement) • More time to wait for response (eg. Less severe depression) • Patient prefers to switch CANMAT, 2016 Slide adopted from 2019 MDD Lecture by Michael Pondrom, PharmD, BCPP Adjunct • 2 or more previous antidepressant trials • Well tolerated 1st antidepressant • Partial response (>25% improvement) • Specific residual symptoms or side effects targeted • Less time to wait for response (eg. More severe or functional impairment) • Patient prefers augmentation Summary of Options for partial response/treatment Resistant Dose Optimization Switch AD • Within same class • Different class Combining two AD • Bupropion • Mirtazapine • TCAs Augmenting AD with other agents • Eg. Atypical AP, lithium Combining AD with non-pharmacological tx • ECT, VNS WFSBP, 2013 118 Question 4 All of the following psychotropic medications have relatively lower/no sexual dysfunction side effect, except: A. B. C. D. Paroxetine Bupropion Mirtazapine Buspar 120 Summary Use of antidepressants in moderate-severe depression • SSRI/SNRI • Mirtazapine • Bupropion • Vortioxetine 1st 2nd • TCA • Vilazodone • Trazodone • Levomilnicipran • Selegiline transdermal • MAOI 3rd 121 CANMAT, 2016 Summary Algorithm • Early improvement: 20-30% reduction in sx from baseline in a depression rating scale after 2-4 weeks o lack of early improvement is a predictor of later antidepressant nonresponse/non-remission • CANMAT recommends increasing the AD dose for non-improvers at 2 to 4 weeks if the medication is tolerated o Then consider switching or using an adjunct • Acute Phase: 6-8 weeks • Maintain patient on AD for at least 6-9 months after remission o If risk factors for recurrence > 2 years CANMAT, 2016 122 Summary Antidepressant classes are generally considered equally efficacious Factors such as age, side effects, past history response can aid in selection of AD Must determine if patient has had an adequate trial (dose, duration, adherence) before considering modifications to treatment Can take up to 6-8 weeks to see full benefits from AD Consider QOL and tolerability of agents when assessing response to treatment 124 125 Resources Substance Abuse and Mental Health Services Administration (SAMHSA) help line: 1-800-662-HELP National Suicide Prevention Lifeline: 1-800273-TALK 127