1. Antidepressant Classes 1.Selective Serotonin Reuptake Inhibitor (SSRI) Sertraline (Zoloft) Fluoxetine (Prozac) Paroxetine (Paxil) Citalopram (Celexa) Escitalopram (Lexapro) 2.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 3.Serotonin-Norepinephrine Reuptake Inhibitors (SNRI) Venlafexine (Effexor) Desvenlafaxin (Pristiq) Duloxetine (Cymbalta) 4.MAO Inhibitors Phenelzine (Nardil) Tranylcypromine (Parnate) 5.Atypical Antidepressants Bupropion (Wellbutrin) Trazodone (Desyrel) Mirtazepine (Remeron)

3. Antidepressant Therapy: Treatment Decisions Risk of treatment vs. no treatment of depression 1.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 treatment of depression 1.No treatment Postpartum depression Suicide Not fully characterized/not conclusive: preterm birth, low birth weight, miscarriage, hyperemesis gravidarum 2.Treatment Side effects of medication Teratogenicity Neurobehavioral syndrome

5. Antidepressant Therapy 1.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 1.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 2.SSRIs Paroxetine (Paxil) – 1 st 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 3.SSRIs and TCAs – late pregnancy  persistent pulmonary hypertension 4.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 5.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 2.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 2.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: 1.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 2.Drug Substitution →If no (or inadequate) response – switch to another antidepressant class  Exception: SSRI 3.Combination Therapy – add another antidepressant (another class)

15. Antidepressant Treatment Principles Partial response and Nonresponse 4.Augmentation – add a second agent (not an antidepressant) Lithium Thyroid hormone (Cytomel) Pindolol (Viskin) Buspirone (BuSpar) 5.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 Citalopram (Celexa) Follow-up remission To Level II 3671 Exit (766) 1425 1430 (no remission)

20. STAR-D trial Level II randomized Bupropion-SRVenlafaxine-XRSertraline Cognitive Behavioral Therapy Bupropion-SRBuspirone Cognitive Behavioral Therapy (Zoloft)(Wellbutrin)(Effexor) (Wellbutrin)(BuSpar) 2382392502792868562 + citalopram 1430 Switch option Augment option From Level I Switch Option: more severely ill + more side effects (citalopram) side effects, efficacy, time to remission, drop out rates were the same 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)

21. STAR-D trial Level II randomized Bupropion-SRVenlafaxine-XRSertraline Cognitive Behavioral Therapy Bupropion-SRBuspirone Cognitive Behavioral Therapy (Zoloft)(Wellbutrin)(Effexor) (Wellbutrin)(BuSpar) 2382392502792868562 + citalopram 1430 To Level III (359) Exit (389)Follow-up (544) To Level II A (31) Exit (38)Follow-up (78) From Level I

22. STAR-D trial Level II A Bupropion-SR (Wellbutrin) Venlafaxine-XR (Effexor) 1516 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 Exit (5)Follow-up (8) To level III (18) * This step was included to ensure that all participants who entered Level III had received at least two medication trials

23. STAR-D trial Level III randomized Mirtazapine (Remeron) Nortriptyline (Pamelor) Lithium + Level 2 treatment T3 + Level 2 treatment From Level 2 A (18) From Level 2 (359) Switch Augment 1211146973 To level IV (109) Follow-up (99) Exit (169 ) 377 Augmentation: Lithium and T3 equally effective 23 % stopped Lithium due to side effects (vs. 10 % with T3) Switch: No difference between Remeron and Pamelor

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

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