ISSUES IN DEPRESSION
| DEPRESSION DURING CHILDBEARING —Sheila M. Marcus, MD, Clinical Assistant Professor, Department of Psychiatry,
University of Michigan Medical School, and Director, Depression Center, Veterans Affairs Ann Arbor Healthcare
System
|
| General considerations: pregnancy not honeymoon from depression; ≈10% to 12% of women present with depression
in pregnancy; often underdiagnosed because of stigma, rapid obstetric visits, and confusion with usual physical symptoms
of pregnancy; predictors of risk—poor nutrition, substance abuse, inadequate weight gain, and inadequate prenatal
care; biologic etiology—evidence of elevated plasma and salivary cortisol and corticotropin-releasing hormone-
binding protein (CRH-BP) in women with depression; may effect uterine environment and cord blood
|
| Spectrum of postpartum mood disorders: postpartum blues—common and transient; begins within ≈3 days postpartum;
resolves by 2 wk postpartum; characterized by mood lability, tearfulness, and sleep disturbances; symptoms
should not affect functioning; postpartum depression—onset generally 2 days to 6 mo postpartum; affects 12% to 15%
of all pregnancies; etiology—rapid hormone changes, ie, progesterone, prolactin, oxytocin, and variations in thyroid hormone;
risk factors—≈30% chance with previous episode of major depressive disorder (MDD); ≈50% chance with one
previous episode of bipolar illness; ≈70% chance with one previous episode of postpartum psychosis; clinical features—
time of onset major difference between postpartum depression and nonpuerperal depression; postpartum depression simply
episode of depression occurring within interval after birth; commonly, recurrence of previously existing depressive illness;
clinically identical to nonpuerperal major depression, but anxiety more prominent; postpartum psychosis—occurs
in ≈0.1% to 0.2% of pregnancies; characterized by rapid decline over 2 wk; woman presents often in highly agitated state;
preoccupied about harm to infant at own hands or through demonic presence; psychotic delusions common, eg, infant
switched at birth; mother may feel infant better off without her; psychiatric emergency; electroconvulsive therapy (ECT)
safe and effective; considered affective psychosis; treated with mood stabilizers, antipsychotics, and benzodiazepines
|
| Medication issues: selective serotonin reuptake inhibitors (SSRIs), tricyclic antidepressants (TCAs), and antipsychotic
agents used for postpartum unipolar depression; data show ≈50% of women discontinue psychotropic medication at time
of conception because of concerns about fetal compromise; 75% relapse rate by third trimester in women who discontinue
medication; considerations in whether to discontinue or maintain medication—maternal illness history, frequency
of recurrences, patient’s wishes, fertility status, and reproductive safety data; evaluating fetal safety of antidepressant
therapy—consider congenital anomalies, neonatal withdrawal syndrome, and developmental sequelae;
SSRIs—data show no significant evidence of teratogenic toxicity; studies show SSRIs and citalopram safe; single study
suggests possibility of third trimester small for gestational age (SGA) infants of mothers who used fluoxetine (Prozac);
infants have greater chances of being observed in neonatal intensive care unit (NICU; may be due to vigilance of staff);
neonatal syndromes—may be worse in shorter-acting agents, specifically venlafaxine (Effexor) and paroxetine (Paxil);
some suggestion of lower scores on motor and orientation packets on neonatal testing; no clinically significant neonatal
complications reported; majority of infants discharged from hospital with mother; if difficulty occurs, generally involves
temperature regulation and jitteriness; small study shows developmental disorders identical among sibling pairs exposed
and unexposed to psychotropic medication
|
| Medications: TCAs—multiple prospective and retrospective studies; no apparent teratogenic or behavioral toxicities; associated
with neonatal syndromes and neonatal withdrawal similar to SSRIs; benzodiazepines—data show ≈1% risk for
cleft anomalies when used in first 8 wk; speaker uses intermittently in second trimester and sometimes in third trimester;
if possible, discontinue before delivery to avoid sequelae in infant; bupropion (Wellbutrin)—limited data; no anecdotal
evidence of increased anomalies; mood stabilizers—all associated with congenital anomalies when used in first trimester;
lithium-associated Epstein’s anomaly (1-2/1000 risk); valproic acid and carbamazepine (Tegretol) associated with
neural tube defects (≈2% risk); absolute risk of lithium considerably less than initially thought; with severe recurrent illness,
may be riskier to stop medication than to continue; fetal surveillance at 16 to 18 wk recommended
|
| Management strategies: bipolar illness—discontinuation of medication during first trimester dependent on frequency
and severity of symptoms; data suggest ≈60% rate of relapse in recurrently ill bipolar women who discontinue mood stabilizers
during second and third trimesters; encourage planned pregnancy so medication can be tapered gradually; consider
resuming medication at 24 to 26 wk to prevent relapse in second and third trimesters and postpartum period;
speaker considers medication for patient with moderate symptoms of MDD, eg, insomnia, diminished appetite, significant
anxiety; fluoxetine and citalopram (Celexa) have highest numbers in studies; speaker also uses sertraline (Zoloft);
TCAs fine; no SSRIs absolutely contraindicated; titrate dose to manage symptoms; as pregnancy progresses, medication
may become inadequate as plasma volume increases
|
| Impact of postpartum depression: mothers smile less and interact less with infant; by 2 mo, infants of depressed
women less socially responsive to mothers and nondepressed strangers; infants more predisposed to insecure attachment;
by 5 yr of age, children show increased risk for developmental problems and psychiatric illness
|
| Estrogen: effective in treatment of postpartum depression; generally not used because of hypercoagulable state after delivery;
interpersonal therapy (IPT)—beneficial for people undergoing any life transition, eg, pregnancy, postpartum, recent
episode of loss, professional reversal
|
| Self-management recommendations: maintain sleep hygiene and circadian rhythm; plan social support respite; exercise
(7 cal/kg workout 3 times weekly approximately equal to SSRI effect); lactation—SSRIs and TCAs preferred agents; risks
associated with lithium (toxicity if infant becomes dehydrated); divalproex (Depakote) being used with increased frequency
after first 3 days of life; relative increased risk in premature infants; impact of low serum levels and higher brain levels of antidepressant
agents on infant development uncertain
|
| A RATIONAL SOLUTION TO TREATMENT OF DEPRESSION —Owen Wolkowitz, MD, Professor of Psychiatry,
University of California, San Francisco, School of Medicine
|
| General considerations: data indicate similar rates of patient response to all antidepressant agents; choice of agent must
be predicated on agent’s tendency to invoke particular constellation of side effects, as well as specific factors related to
patient’s psychiatric and medical history, family history of psychiatric disorders, and response to specific treatments; all
antidepressant agents effective, and all about equally effective in producing response; no strong empirical evidence prescribing
particular antidepressant medication based on clinical phenotype of depression better than selecting one based
on avoidance of side effects; currently, no biologic test available to assist in selecting right medication
|
| Initial prescribing considerations: 3 different aspects to personality theorized, ie, harm avoidance, reward dependence,
and novelty seeking; low-serotonin depression associated with harm-avoidance symptoms, eg, phobias, agoraphobia, obsessive-compulsive
disorder (OCD); may respond well to serotonin antidepressant, but not to catecholamine antidepressant; patient
with low-catecholamine depression may have difficulty experiencing reward, ie, anhedonia; novelty-seeking patient may
have attention–deficit/hyperactivity disorder (ADHD) and prone to self-medicating with stimulating substances, eg, nicotine,
cocaine (clue patient may have low-catecholamine depression); patient with low-catecholamine depression tends to respond
well to catecholamine reuptake inhibitors, eg, bupropion, but not as well to SSRIs; prescribing dual-action drugs—
speaker does not endorse idea; stimulate serotonin and norepinephrine, ie, venlafaxine (Effexor), nefazodone (Serzone), mirtazapine
(Remeron), duloxetine (Cymbalta); doing so may overstimulate nondeficient area in brain; consider starting with
drug that targets primary symptoms and fine tune if further improvement necessary or with development of side effects; use of
SSRI secondarily may produce side effects, and benefits of dopamine may be lost; patient may report apathetic state; noradrenergic
drugs can cause tremor, tachycardia, dry mouth, and insomnia; potential for psychomotor activation and insomnia
with dopamine drugs; may cause aggravation of psychosis in susceptible patients
|
| Mechanism of action of antidepressant agents: low levels of intrasynaptic dopamine, norepinephrine, or serotonin in
patient with depression; presynaptic specificity—antidepressants work by blocking presynaptic reuptake of neurotransmitters;
bupropion acts primarily as dopamine reuptake blocker; hydroxybupropion (metabolite) acts as norepinephrine reuptake
blocker; bupropion increases dopamine and norepinephrine, but has no effect on serotonin; TCAs and heterocyclic
antidepressants, eg, venlafaxine, mirtazapine, nefazodone, and duloxetine act on norepinephrine and serotonin; SSRIs, ie,
fluoxetine, sertraline, paroxetine, citalopram, and escitalopram relatively selective for serotonin; bupropion has dopamine
and norepinephrine reuptake inhibition; venlafaxine and duloxetine have norepinephrine and serotonin reuptake inhibition;
increasing venlafaxine dosage—increases drug quantitatively and qualitatively; has calming effect at low dose (75 mg
daily), but becomes more activating at increased dosage; postsynaptic selectivity—14 types of serotonin receptors; 5-
HT1A receptor most important for antidepressant response; binding of serotonin to 5-HT2 receptor not beneficial for treating
depression; can cause sexual side effects, insomnia, and agitation; gastrointestinal (GI) side effects when serotonin stimulates
5-HT3 receptor
|
| Dual-action medications: nefazodone—mild serotonin and norepinephrine reuptake blocker; high doses (400 to 600 mg
per day) necessary for effectiveness; postsynaptic 5-HT2 blockade; associated with fewer sexual side effects, less agitation,
and less insomnia; good choice for patient with anxiety, agitation, and insomnia; black-box warning because of liver toxicity
(rare); speaker considers nefazodone third-line choice and obtains informed consent; mirtazapine—increases norepinephrine
and serotonin; leaves 5-HT1A open, but blocks 5-HT2 and 5-HT3 ; low incidence of sexual side effects, anxiety, agitation,
or insomnia (tends to be sedating); fewer gastrointestinal (GI) effects; blockage of 5-HT3 makes it effective antiemetic;
antihistamine effects result in sedation and weight gain; sedation inversely related to dose (higher doses less sedating than
lower ones)
|
| Selective serotonin reuptake inhibitors: fluoxetine—has serotonin reuptake inhibition and some degree of norepinephrine
reuptake inhibition; most activating of SSRIs; directly stimulates 5-HT2 receptor; not appropriate for patient with
anxiety, panic, insomnia, and agitation in short term; whether particular medication activating or sedating often relevant issue
in first few weeks of use; generally, tolerance to activation and sedating effects develop, but patient may become noncompliant
with medication until then; may be good first-line medication for patient needing more activating qualities;
potentially more advantageous for patient with bulimia and binge eating, hypersomnia, or psychomotor retardation;
sertraline—serotonin effects; slight dopamine effects; mildly activating; effective for anxiety; can be overstimulating
(monitor patient closely in first 2 wk); paroxetine—serotonin effects; no norepinephrine effects until dose higher than clinically
used; slight muscarinic anticholinergic effects; very mild; can be sedating; contraindicated in patients with narrow-angle
glaucoma, benign prostatic hypertrophy, Alzheimer’s disease, cognitive disorders, Sjogren’s syndrome, and chronic
constipation; withdrawal symptoms most likely with paroxetine, sertraline, and venlafaxine (mimic flu); more sedating initially;
may be good choice for patient with anxiety and insomnia; associated with higher rates of sexual dysfunction than
other SSRIs; citalopram—few secondary binding effects; neither activating nor sedating; slight antihistaminic effects;
escitalopram (Lexapro)—≈2 to 4 times as potent as citalopram; fewer antihistaminic effects; probably most neutral of all
antidepressants; fewer pharmacokinetic interactions
|
| Activation vs sedation: issue only for first 3 wk of treatment; adjunctive medication can be used until desired qualities of
medicine kick in; consider medication best for patient long term; bupropion most activating of all antidepressants; fluoxetine
most activating of SSRIs, followed by sertraline; venlafaxine has mixed effects; escitalopram most neutral; citalopram slightly
sedating; paroxetine more sedating; nefazodone very sedating; trazodone (Desyrel) strongly sedating; mirtazapine potentially
most sedating (can become less sedating with higher dose)
|
| Side effects: most common reason for stopping medication; weight gain—does not occur acutely, happens after 6 mo on
medication; mirtazapine can cause weight gain in first 2 mo, then plateaus; bupropion least likely to cause weight gain of
all antidepressants; data show it can promote weight loss; nefazodone relatively neutral for weight gain; all SSRIs and
dual-action antidepressants cause weight gain; more weight gain with paroxetine than other SSRIs; mirtazapine associated
with greatest potential for weight gain; sexual side effects—≈37% of patients experience significant sexual dysfunction
on antidepressant medication; paroxetine, venlafaxine, sertraline, citalopram, and fluoxetine associated with
higher incidence; nefazodone, mirtazapine, and bupropion associated with lower incidence; bupropion least likely to
cause sexual side effects; nefazodone and mirtazapine neutral; ≈35% incidence with SSRIs and dual-action drugs;
antidotes—reducing dosage not recommended; switching antidepressant is option; adding antidote preserves antidepressant
effect, but targets sexual side effects; speaker recommends adding 300 mg daily of bupropion to SSRI (provides
dopamine); other options nefazodone or mirtazapine; pharmacokinetic interactions—venlafaxine least likely to have
pharmacokinetic interaction; escitalopram, citalopram, mirtazapine, and sertraline fairly clean; fluoxetine pharmacokinetically
“dirtiest” drug
|
Educational Objectives
| The goal of this program is to educate the listener about current approaches to the treatment of depression. After hearing
and assimilating this program, the clinician will be better able to:
|
 | 1. Discuss the characteristics of the 3 types of postpartum mood disorders, risk factors for postpartum depression, and
the importance of treating postpartum depression.
|
| 2. Describe the possible biologic etiology and clinical features of postpartum depression.
|
| 3. Monitor the safety of psychotropic medications during pregnancy.
|
| 4. Explain how depression phenotype and knowledge of which neurotransmitter receptor the medication works on can
help in the selection of an antidepressant.
|
| 5. Manage side effects associated with antidepressant medications.
|
Discussed on This Program
Bupropion HCl [Wellbutrin, Wellbutrin SR, Wellbutrin XL, Zyban]
Carbamazepine [Carbatrol, Epitol, Tegretol, Tegretol-XR] Citalopram HBr [Celexa]
Duloxetine [Cymbalta]
Escitalopram oxalate [Lexapro]
Fluoxetine HCl [Prozac, Prozac Pulvules, Prozac Weekly, Sarafem, Sarafem Pulvules]
Lamotrigine [Lamictal, Lamictal Chewable Dispersible]
Lithium [Eskalith, Eskalith CR, Lithobid, Lithonate, Lithotabs]
Mirtazapine [Remeron, Remeron SolTab]
Nefazodone HCl [Serzone]
Olanzapine [Zyprexa, Zyprexa Intramuscular, Zyprexa Zydis]
Ondansetron HCl [Zofran, Zofran ODT]
Paroxetine HCl [Paxil, Paxil CR, Pexeva]
Sertraline HCl [Zoloft]
Sildenafil citrate [Viagra]
Trazodone HCl [Desyrel, Desyrel Dividose]
Valproic acid [Depacon, Depakene, Depakote, Depakote ER]
Venlafaxine HCl [Effexor, Effexor XR]
Suggested Reading
Altshuler LL et al: Treatment of depression in women: a summary of the expert consensus guidelines. J Psychiatri
Pract 7(3):185, 2001; Andersson L et al: Implications of antenatal depression and anxiety for obstetric outcome. Obstet
Gynecol 104(3):467, 2004; Malm H et al: Risks associated with selective serotonin reuptake inhibitors in pregnancy.
Obstet Gynecol 106(6):1289; Marcus SM et al: A screening study of antidepressant treatment rates and mood symptoms
in pregnancy. Arch Women Ment Health 8(1):25, 2005; Seyfried LS et al: Postpartum mood disorders. Int Rev
Psychiatry 15(3):231, 2003.
Faculty Disclosure
In adherence to ACCME guidelines, the Audio-Digest Foundation requests all lecturers to disclose any significant financial
relationship with the manufacturer or provider of any commercial product or service discussed. The following has been disclosed:
Dr. Wolkowitz is on the Speakers’ Bureau of Forest Pharmaceuticals, Inc, GlaxoSmithKline, and Pfizer Inc.
Dr. Marcus was recorded at Psychopharmacology Update: From Bench to Bedside in Psychiatric Practice sponsored
by the University of Michigan Medical School, and held on July 8-10, 2005, in Grand Traverse, Michigan. Dr. Wolkowitz
was recorded at the 20th Annual Primary Care Medicine: Principles & Practice, sponsored by the University of California,
San Francisco, School of Medicine, and held on October 19-21, 2005, in San Francisco. The Audio-Digest Foundation
thanks the speakers and the sponsors for their cooperation in the production of this program.
|
