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Antidepressant Classes

Antidepressant Classes. Selective Serotonin Reuptake Inhibitor (SSRI) Sertraline (Zoloft) Fluoxetine (Prozac) Paroxetine (Paxil) Citalopram (Celexa) Escitalopram (Lexapro) Tricyclic Antidepressant (TCA) Amitriptyline (Elavil) Nortriptyline (Pamelor) Imipramine (Tofranil)

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Antidepressant Classes

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  1. Antidepressant Classes • Selective Serotonin Reuptake Inhibitor (SSRI) • Sertraline (Zoloft) • Fluoxetine (Prozac) • Paroxetine (Paxil) • Citalopram (Celexa) • Escitalopram (Lexapro) • Tricyclic Antidepressant (TCA) • Amitriptyline (Elavil) • Nortriptyline (Pamelor) • Imipramine (Tofranil) • Desipramine (Norpramin) • Doxepine (Sinequan) • Trimipramine (Surmontil) • Protriptyline (Vivactil) • Maprotiline (Ludiomil) • Amoxapine (Ascendin) • Clomipramine (Anafranil)

  2. Antidepressant Classes • Serotonin-Norepinephrine Reuptake Inhibitors (SNRI) • Venlafexine (Effexor) • Desvenlafaxin (Pristiq) • Duloxetine (Cymbalta) • MAO Inhibitors • Phenelzine (Nardil) • Tranylcypromine (Parnate) • Atypical Antidepressants • Bupropion (Wellbutrin) • Trazodone (Desyrel) • Mirtazepine (Remeron)

  3. Antidepressant Therapy: Treatment Decisions Risk of treatment vs. no treatment of depression • No treatment • Self-medication (alcohol, tobacco, other drugs) • Impaired judgment  poor or noncompliance with prenatal care • Poor appetite  poor nutrition • Anxiety • Insomnia • Disruption in family relationships: • Impaired maternal-infant (or other children) bond  psychosocial problems • Impaired relationship with partner  paternal depression

  4. Antidepressant Therapy: Treatment Decisions Risk of treatment vs. no treatmentof depression • No treatment • Postpartum depression • Suicide • Not fully characterized/not conclusive: preterm birth, low birth weight, miscarriage, hyperemesis gravidarum • Treatment • Side effects of medication • Teratogenicity • Neurobehavioral syndrome

  5. Antidepressant Therapy • Teratogenicity • Background risk to fetus (general population) of minor or major malformation ≈ 2 to 4 % • Overall, antidepressants appear safe in pregnancy Caveats: • many drugs are relatively new – insufficient data exists • we cannot ethically subject pregnant women to randomized controlled trials to determine drug safety – we are limited to observation studies • distinguishing problems due to medication from the small but significant background rate of congenital anomalies is difficult

  6. Antidepressant Therapy Teratogenicity • TCAs Since they have been in use for a relatively long time, are considered to have the lowest known risk in pregnancy (and breastfeeding) • TCAs are much more dangerous if overdosed • SSRIs • Paroxetine (Paxil) – 1st trimester  atrial and ventricular septal defects + right ventricular outflow defects • Sertraline (Zoloft) – atrial and ventricular septal defects + oomphalocele • Citalopram (Celexa) + Esitalopram (Lexapro) – anencephaly, omphalocele, craniosynostosis

  7. Antidepressant Therapy • SSRIs and TCAs – late pregnancy  persistent pulmonary hypertension • Fluoxetine (Prozac) – best studied SSRI (safety/efficacy in pregnancy and lactation) but has a long half life + high rate of transfer to neonate through breastfeeding • Miscarriage/stillbirth/low birth weight – data is conflicting and inconclusive

  8. Antidepressant Therapy Summary • Defects are rare – absolute risk is very small – probably not enough to warrant a switch or discontinuation • May be enough data to not pick as first line drug in pregnancy (or planning pregnancy): • Paroxetine (Paxil) • Fluoxetine (Prozac) – if will be breastfeeding • Larger prospective studies with better controls for confounding variables are required

  9. Antidepressants in Pregnancy • Neonatal Behavioral Syndrome • SSRI “class effect – late use (after 24 weeks) in pregnancy • Withdrawal vs. serotonin toxicity syndrome? • Absolute risk – up to 30 % of exposed neonates • Symptoms may arise immediately after birth and resolve within 2 weeks • Most reports have involved Fluoxetine (Prozac) and Paroxetine (Paxil)

  10. Antidepressants in Pregnancy • Neonatal Behavioral Syndrome • Jitteriness/tremor • Irritability/constant crying • Mild respiratory distress/tachypnea • Hypoglycemia • Poor tone • Weak cry • Desaturation on feeding • Temperature instability

  11. SSRI/SNRI Discontinuation Syndrome in Adults F.I.N.I.S.H. • Flu-like symptoms:fatigue, muscle aches, headache, diarrhea • Insomnia:vivid or disturbing dreams • Nausea • Imbalance:gait instability, dizziness, lightheadedness, vertigo • Sensory disturbance: paresthesia, “electric shock” sensation, visual disturbance • Hyperarousal: anxiety, agitation • Onset:24-72 hours+Resolution:1-14 days • Incidence:~ 20 - 40 %(who have been treated at least 6 weeks)

  12. SSRI/SNRI Toxicity in Adults • CNS & Neuromuscular:tremor, restlessness, agitation, insomnia, dystonia, hypertonia, dyskinesia, paresthesia, convulsion, congnitive impairment • GI:nausea, vomiting, diarrhea • Autonomic instability:respiratory distress, tachypnea, hyperthermia, temperature instability, chills, rigors, diaphoresis, tachycardia • Onset: variable • Resolution: hours to several days

  13. Antidepressant use during breastfeeding • Less data re: long-term neurodevelopmental consequences of neonatal exposure (vs. in utero exposure) • Few isolated cases of adverse effects reported • In general: a) risk of not breastfeeding > risk of antidepressants; b) placental passage of antidepressant > breast milk – makes sense to continue medication started during pregnancy • General recommendations: • Take antidepressant immediately after breastfeeding to minimize exposure to peak drug concentrations • Monitor for effects on infant: sedation, irritability, change in feeding • Sertraline (Zoloft) and Paroxetine (Paxil) appear safest • Fluoxetine (Prozac) – avoid due to long T ½ (safer after 4 months )

  14. Antidepressant Treatment Principles • Begin with a modest dose • For partial response or nonresponse: • Optimize dose or duration of therapy • Minimum of six (6) weeks. If a patient exhibits a significant partial response during this initial period, another 4-6 weeks of treatment should be added (Total: 10-12 weeks) • Some may benefit from antidepressant dosages that are higher than recommendations • Drug Substitution • If no (or inadequate) response – switch to another antidepressant class • Exception: SSRI • Combination Therapy – add another antidepressant (another class)

  15. Antidepressant Treatment Principles Partial response and Nonresponse • Augmentation – add a second agent (not an antidepressant) • Lithium • Thyroid hormone (Cytomel) • Pindolol (Viskin) • Buspirone (BuSpar) • Electoconvulsive Therapy • For psychotic depression and severe refractory depression

  16. Antidepressant Treatment Principles: Follow-up • Every 1-2 weeks for six to eight weeks during the initiation phase of medication treatment – office visits for supportive care, access to provider by phone, and/or proactive phone calls to check on therapeutic response, side effects, and adherence to treatment • First episode of depression – medication for at least 6-9 months after remission • Two or more episodes of depression – two years (or more) of medication • Taper medication over 2-4 weeks to avoid withdrawal

  17. STAR-D trial • Sequenced Treatment Alternatives to Relieve Depression • Funded by National Institute of Mental Health and published 11/2006 • The largest and longest study to evaluate depression treatment • Overall objective: define preferred treatments for depression – in a way that mirror methods that clinicians use in practice: • Determine best “next-step” treatments for depressions not responding satisfactorily to one or more prior treatment attempts • Compare relative efficacy of different treatment approaches • Participants: • 18-75 years old (64 % female) • Met DSM-IV criteria for Major Depressive Disorder • Not pregnant or breastfeeding • 4,041 enrolled at 41 clinical sites (18 primary care + 23 psychiatric care)

  18. STAR-D trial • All patients were treated for 12 weeks at each level • All patients who achieved remission of depression could enter a 12-month follow-up phase (continue with effective medication + any psychotherapy, medication, or medication dosage change could be made) • All patients who did not achieve remission (or were unable to tolerate their medication) were strongly encouraged to proceed to the next treatment phase (level)

  19. STAR-D trial Level I 4,041 enrolled 3671 1425 remission Follow-up Citalopram (Celexa) Exit (766) 1430 To Level II (no remission)

  20. STAR-D trial Level II • Participants were asked: • Would it be equally acceptable to receive “switch” or “augmentation”? (21/1430) • Would you accept only one or the other approaches? (1409/1430) From Level I Switch option randomized Augment option 1430 238 239 250 62 279 286 85 Cognitive Behavioral Therapy Cognitive Behavioral Therapy Sertraline Bupropion-SR Venlafaxine-XR Bupropion-SR Buspirone (Wellbutrin) (BuSpar) (Zoloft) (Wellbutrin) (Effexor) + citalopram + citalopram + citalopram • Switch Option: • more severely ill + more side effects (citalopram) • side effects, efficacy, time to remission, drop out rates were the same

  21. STAR-D trial Level II From Level I randomized 1430 238 239 250 62 279 286 85 Cognitive Behavioral Therapy Cognitive Behavioral Therapy Sertraline Bupropion-SR Venlafaxine-XR Bupropion-SR Buspirone (Wellbutrin) (BuSpar) (Zoloft) (Wellbutrin) (Effexor) + citalopram + citalopram + citalopram Exit (389) Follow-up (544) Exit (38) Follow-up (78) To Level III (359) To Level II A (31)

  22. STAR-D trial For participants (31) who received cognitive therapy alone or cognitive therapy plus citalopram at Level II and either did not receive remission or were unable to tolerate Level II A * This step was included to ensure that all participants who entered Level III had received at least two medication trials 15 16 Bupropion-SR Venlafaxine-XR (Wellbutrin) (Effexor) Exit (5) Follow-up (8) To level III (18)

  23. STAR-D trial • Augmentation: • Lithium and T3 equally effective • 23 % stopped Lithium due to side effects (vs. 10 % with T3) From Level 2 A (18) Level III From Level 2 (359) randomized • Switch: • No difference between Remeron and Pamelor 377 121 114 69 73 Mirtazapine (Remeron) Nortriptyline (Pamelor) Lithium + Level 2 treatment T3 + Level 2 treatment Switch Exit (169) Follow-up (99) To level IV (109) Augment

  24. STAR-D trial From Level 3 Level IV randomized (109) Switch Tranylcypromine (Parnate) Venlafaxine XR (Effexor XR) + Mirtazapine (Remeron) * Effexor/Remeron was significantly better tolerated ~ 10 % achieved remission

  25. STAR-D trial Cumulative Remission Rates Level I 100 37 % 37 (Celexa) Theoretical cumulative remission rate: Level II 63 37 + 19 + 6 + 5 = 67/100 31 % (Zoloft, Wellbutrin SR, Effexor XR, BuSar, Cognitive Behavioral Therapy) 19 Level III 44 14 % (Remeron, Pamelor, Lithium, T3) 6 Level IV 38 13 % (Parnate, Effexor XR, Remeron) 5

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