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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
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)
antidepressant classes2
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)
antidepressant therapy treatment decisions
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
antidepressant therapy treatment decisions4
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
antidepressant therapy
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
antidepressant therapy6
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
antidepressant therapy7
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
antidepressant therapy8
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
antidepressants in pregnancy
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)
antidepressants in pregnancy10
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
ssri snri discontinuation syndrome in adults
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)
ssri snri toxicity in adults
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
antidepressant use during breastfeeding
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 )
antidepressant treatment principles
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)
antidepressant treatment principles15
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
antidepressant treatment principles follow up
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
star d trial
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)
star d trial18
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)
star d trial19
STAR-D trial

Level I

4,041 enrolled

3671

1425

remission

Follow-up

Citalopram (Celexa)

Exit (766)

1430

To Level II

(no remission)

star d trial20
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
star d trial21
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)

star d trial22
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)

star d trial23
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

star d trial24
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

star d trial25
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