Pharmacologic Treatment of Depression

Heather Kovich, MD, Shiprock-University of New Mexico Family Medicine Residency

Program and Northern Navajo Medical Center, Shiprock, New Mexico
William Kim, MS, MD, Shiprock-University of New Mexico Family Medicine Residency Program, Shiprock, New Mexico
Anthony M. Quaste, PharmD, USPHS, Northern Navajo Medical Center, Shiprock, New Mexico

The prevalence of depression and the use of antidepressant medications have risen steadily in the United States over the
past three decades. Antidepressants are the most commonly prescribed medications for U.S. adults 20 to 59 years of age.
Second-generation antidepressants (e.g., selective serotonin reuptake inhibitors, serotonin-norepinephrine reuptake
inhibitors, serotonin modulators, atypical antidepressants) are first-line therapy for depression. Psychotherapy, including
cognitive behavior therapy and other types of individual and group therapy, is also a first-line treatment. The combination
of medication and psychotherapy is preferred for severe depression. Treatment history, comorbidities, costs, and risk of
adverse effects should be considered when choosing an antidepressant medication. Although many patients use antidepres-
sants indefinitely, few studies have examined safety and effectiveness beyond two years. There is an increased risk of relapse
or recurrence of depressive symptoms when an antidepressant is discontinued, compared with continued use. Gradually
tapering the dosage while concurrently providing cognitive behavior therapy can decrease this risk. High-quality evidence
on antidepressant use in pregnancy is lacking. Depression and use of antidepressants are both associated with preterm birth.
(Am Fam Physician. 2023;​107(2):​173-181. Copyright © 2023 American Academy of Family Physicians.)

The use of antidepressant medications in the United States depressed mood, anhedonia, changes in weight or sleep pat-
has increased fivefold since the introduction of selective sero- terns, fatigue, psychomotor agitation or retardation, feelings
tonin reuptake inhibitors (SSRIs) in the late 1980s.1,2 Between of worthlessness or guilt, impaired concentration, and recur-
2015 and 2018, the percentage of U.S. adults who reported rent thoughts of death.6,8 Clinical trials of antidepressants
taking an antidepressant medication in the past 30 days was often use major depressive episode as an inclusion criterion.
13.2%, compared with 2.4% between 1988 and 1994.1,2 Although most patients with clinician-identified depression
Antidepressants are the most commonly prescribed medi- do not meet diagnostic criteria for a major depressive epi-
cations for U.S. adults 20 to 59 years of age.3 Rates of depres- sode, many are prescribed antidepressants.9
sion and suicide have increased, primarily among those Second-generation antidepressants are the most common
younger than 25 years.4,5 The percentage of adults 18 to 25 medications used to treat depression in the United States.10
years of age reporting a major depressive episode in the past These include SSRIs (e.g., escitalopram, paroxetine), serotonin-
year doubled from 8.8% in 2005 to 17% in 2020. During the norepinephrine reuptake inhibitors (SNRIs;​e.g., duloxe-
same period, rates among adults 26 years and older increased tine [Cymbalta], venlafaxine), serotonin modulators (e.g.,
only slightly from 6.2% to 7.1%.6,7 nefazodone, trazodone), and atypical antidepressants
The definition of a major depressive episode is based on (e.g., bupropion, mirtazapine).
the Diagnostic and Statistical Manual of Mental Disorders,
5th ed., criteria for major depressive disorder.6,8 Five or more Effectiveness
depressive symptoms must be present for at least two weeks, Despite thousands of clinical trials, the effectiveness of anti-
cause distress or functional impairment, and not be due to depressants is not well established. High-quality reviews of
another medical or psychiatric condition. Symptoms include randomized controlled studies show a statistically signifi-
cant improvement in depression with use of antidepressant
See related editorial on page 123. medications.11,12 A 2016 systematic review showed that the
CME This clinical content conforms to AAFP criteria for
number needed to treat for response to treatment or remis-
CME. See CME Quiz on page 127. sion is 9 for tricyclic antidepressants, 7 for SSRIs, and 6 for
Author disclosure:​ No relevant financial relationships. venlafaxine.11 Outcomes of other studies challenge these
Patient information:​A handout on this topic is available
conclusions, with minimal difference in symptoms between
with the online version of this article. placebo and antidepressants, publication bias favoring effec-
tiveness, and pharmaceutical industry sponsorship of most

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 PHARMACOLOGIC TREATMENT OF DEPRESSION

Shared decision-making should be used when choosing

WHAT’S NEW ON THIS TOPIC an initial treatment. Prior treatment and response, comor-
bidities, costs, and risk of adverse effects should be consid-
Pharmacologic Treatment of Depression ered. Pharmacogenetic testing, intended to tailor therapy to
Between 2015 and 2018, the percentage of U.S. adults an individual’s genetic variants, has not shown consistent
who reported taking an antidepressant medication in the benefit in outcomes or cost-effectiveness.21
past 30 days was 13.2%, compared with 2.4% between For the general adult population, treatment should
1988 and 1994. start with a second-generation antidepressant or psycho­
Modest evidence shows that escitalopram, mirtazapine, therapy.10,16,17 If an antidepressant is selected, modest evi-
paroxetine, venlafaxine, and amitriptyline are the most dence shows that escitalopram, mirtazapine, paroxetine,
effective antidepressants for reducing acute depressive venlafaxine, and amitriptyline are most effective in reduc-
symptoms by greater than 50% at eight weeks. ing depressive symptoms by greater than 50% at eight weeks
A 2021 network meta-analysis demonstrated a low risk (odds ratio = 1.19 to 1.96).12
of ventricular arrhythmia or sudden cardiac death in
those taking selective serotonin reuptake inhibitors, Adverse Effects
serotonin-norepinephrine reuptake inhibitors, or tricyclic Nausea and vomiting were the most commonly reported
antidepressants. symptoms leading to antidepressant discontinuation during
Typical symptoms of antidepressant discontinuation clinical trials. Patients taking SNRIs have a higher incidence
syndrome can be described using the FINISH mnemonic of nausea and vomiting than those taking SSRIs.22 Other
(flulike symptoms, insomnia, nausea, imbalance, sensory common adverse effects across drug classes include sexual
disturbances, hyperarousal). adverse effects and weight gain, although these are less likely
with bupropion.22,23
Despite concerns about increased risk of cardiac arrhyth-
clinical trials.11,13,14 A recent national survey of adults with mia with SSRIs, a 2021 network meta-analysis demonstrated
depression revealed that those who used antidepressants a low risk of ventricular arrhythmia or sudden cardiac
had no improvement in health-related quality of life at two death in those taking SSRIs, SNRIs, or tricyclic antidepres-
years of follow-up compared with those who did not use sants.24 QT prolongation can occur with these drug classes;​
antidepressants.15 therefore, caution should be used when combining them
Psychotherapy (e.g., behavior therapy, cognitive therapy, with other medications that cause QT prolongation (e.g.,
cognitive behavior therapy, interpersonal psychotherapy, antiemetics, antiarrhythmics, neuroleptics). Bupropion has
psychodynamic therapy, supportive therapy) is also a first- the lowest risk of QT prolongation in patients at high risk of
line treatment for depression.16,17 The effectiveness of psycho- ventricular arrhythmias. Because of its side effect profile and
therapy is similar to that of antidepressants in the primary potential for beneficial antiplatelet activity, sertraline may be
care setting (relative risk [RR] = 1.03;​95% CI, 0.88 to 1.22).18 preferred for those with ischemic heart disease.25
Evidence for cognitive behavior therapy is more robust than Long-term adverse effects should also be considered when
for other types of therapy.10 The combination of psychother- prescribing antidepressants. Limited-quality evidence,
apy and pharmacotherapy may be more effective than either including a 12-year cohort study, found a correlation
treatment alone for moderate or severe depression and may between SSRI use and falls (hazard ratio [HR] = 1.48;​95% CI,
reduce risk of relapse and recurrence.17,19,20 1.39 to 1.59);​fractures (HR = 1.30;​95% CI, 1.21 to 1.39);​and
all-cause mortality (HR = 1.38; 95% CI, 1.26 to 1.51).26
Selection of Initial Depression Therapy In a review of 21 antidepressants, citalopram, escitalo-
Guidelines from the United Kingdom’s National Institute pram, fluoxetine, sertraline, and vortioxetine (Trintellix)
for Health and Care Excellence recommend against rou- were most tolerated with less discontinuation of treatment
tinely offering medication for mild to moderate depression (odds ratio = 0.43 to 0.77).12 Adverse effects associated with
(defined as a Patient Health Questionnaire-9 score of less antidepressants are summarized in Table 1.23,27-36
than 16). If the patient prefers medication, SSRIs are rec-
ommended. Active monitoring, group exercise, and several Duration of Treatment
types of individual and group therapy are recommended as The treatment of depression is often described in three
management options. For more severe depression, a combi- phases. The acute phase of six to 12 weeks is intended to
nation of individual cognitive behavior therapy and an anti- induce remission of symptoms and aid in recovery of func-
depressant (SSRI or SNRI) is recommended.17 tion. The continuation phase of four to nine months is aimed

174 American Family Physician www.aafp.org/afp Volume 107, Number 2 ◆ February 2023
 PHARMACOLOGIC TREATMENT OF DEPRESSION

SORT:​KEY RECOMMENDATIONS FOR PRACTICE

Evidence
Clinical recommendation rating Comments

In the primary care setting, antidepressant medication and psychotherapy A Network meta-analysis, systematic
should be offered for the treatment of depression.17-20 reviews, clinical practice guidelines

Second-generation antidepressants, including selective serotonin reuptake B Clinical practice guidelines, sys-
inhibitors, serotonin-norepinephrine reuptake inhibitors, serotonin tematic reviews
modulators, and atypical antidepressants, are recommended first-line
medications for the treatment of depression. Choice of medication should
be guided by shared decision-making, with consideration of prior treat-
ment and response, comorbidities, costs, and risk of adverse effects.10,16,17

When antidepressants are discontinued, the risk of relapse or recurrence of A Double-blind randomized con-
depressive symptoms is higher than when treatment is continued.42-44 trolled trial, systematic reviews,
meta-analyses

When discontinuing antidepressants, cognitive behavior therapy should be B Two studies included in larger
used to help prevent relapse and recurrence of depressive symptoms. 56 meta-analysis

Pregnant and postpartum patients should be screened for depression.61 B Systematic reviews of six clinical
trials (n = 11,869) showing decrease
in depressive symptoms in patients
who are screened, even in the
absence of follow-up measures

Fluoxetine and paroxetine should be avoided in older patients. Rec- C Clinical practice guidelines
ommended alternatives include duloxetine (Cymbalta), sertraline, and
escitalopram.77

A = consistent, good-quality patient-oriented evidence;​ B = inconsistent or limited-quality patient-oriented evidence;​ C = consensus, disease-
oriented evidence, usual practice, expert opinion, or case series;​For information about the SORT evidence rating system, go to https://​w ww.aafp.
org/afpsort.

at reducing relapse (return of symptoms). The maintenance adds to a patient’s risk of future episodes, indefinite main-
phase is intended to prevent recurrence (a new episode of tenance treatment is often recommended for patients with
depression) after one year of treatment.10,37 three or more episodes of depression.37
Although up to 75% of patients discontinue antidepres-
sant use within six months, others continue indefinitely.38 Discontinuation
The increase in antidepressant use over the past 30 years The Diagnostic and Statistical Manual of Mental Disorders,
is largely due to longer treatment duration. 39 The longer 5th ed., defines antidepressant discontinuation syndrome as
patients are in the maintenance phase, the less often treat- “a set of symptoms that can occur after an abrupt cessation
ment is reviewed by their primary care physicians.40 Few (or marked reduction in dose) of an antidepressant medica-
studies have evaluated safety and effectiveness beyond two tion that was taken continuously for at least one month.”8
years.41 Effects typically manifest within two to four days and can
Whenever antidepressants are discontinued, there is an last for several months.46 Typical symptoms can be described
increased risk of relapse or recurrence, with the highest risk using the FINISH mnemonic (flulike symptoms, insomnia,
in the first six months.42-44 Compared with antidepressants, nausea, imbalance, sensory disturbances, hyperarousal).47
psychotherapy may have a longer duration of benefit and Patients should be counseled on symptoms that may occur
lower rate of relapse after discontinuation.15 with abrupt cessation of treatment.48
U.S. guidelines do not specify a duration of treatment for Symptoms of antidepressant discontinuation syndrome
antidepressants.10,16 Canadian guidelines recommend at least can be difficult to distinguish from relapse and recurrence.
six months of treatment and two years or more for those at The prevalence of these symptoms varies, but some reviews
higher risk of relapse.45 Because each episode of depression have found that 50% of patients are affected.46 Regardless of

February 2023 ◆ Volume 107, Number 2 www.aafp.org/afp American Family Physician 175
 PHARMACOLOGIC TREATMENT OF DEPRESSION

pharmacologic mechanism, the risk of antidepressant dis- a taper of several months may be needed.51-54 Tapering strate-
continuation syndrome is higher for drugs with a shorter gies are detailed in Table 3.51-53 A dose taper of approximately
half-life (Table 2).49,50 25% every four weeks and a faster taper of 12.5% every two
Despite a lack of head-to-head trials, research shows that weeks are both reasonable strategies. A gradual taper has
a slow medication taper of at least 14 days is best practice;​ been shown to result in as few as 5% of patients experiencing

TABLE 1

Adverse Effects Associated With Antidepressant Medications

Adverse effect Risk Associated medications Time to onset Evidence

Gastrointestinal Odds ratio = 1.55 (95% CI, 1.35 to SSRIs, especially when used Anytime Meta-analysis27
bleeding 1.78) with nonsteroidal anti- during
inflammatory drugs or treatment
antiplatelet drugs;​risk mit-
igated by acid-suppressing
medications

Hepatotoxicity Incidence = 0.5% to 3% Nefazodone, bupropion, Anytime Literature

duloxetine (Cymbalta), during review 28
trazodone treatment

Hyponatremia Incidence = 0.06% to 2.6% SSRIs, SNRIs, mirtazapine, Within the Literature
(sodium < 130 TCAs first month review 29
mEq per L [130
mmol per L])

Osteoporosis Hazard ratio = 1.88 (95% CI, 1.48 to SSRIs, SNRIs Over 10 Prospective
and fractures 2.39) for fragility fracture years cohort30

QT prolongation Dose dependent Citalopram, escitalopram, At initiation Cross-sectional

amitriptyline Typically retrospective
U.S. Food and Drug Admin- dependent studies31,32
istration warns against on coexisting
exceeding recommended risk factors
dose of citalopram (≤ 60
years of age, 40 mg per day;​
> 60 years, 20 mg per day)

Sexual adverse Weighted mean incidence = 40% Trend toward increased risk Within the Meta-analysis33,34
effects (95% CI, 28.3 to 52.6) across obser- with escitalopram and par- first week
vational studies oxetine;​decreased risk with
bupropion

Suicidality Age-related risk Duloxetine, fluoxetine, parox- Not defined Systematic

< 18 years:​odds ratio = 2.39 (95% etine, sertraline, venlafaxine review, meta-
CI, 1.31 to 4.3) analysis of
clinical reports35
≥ 18 years:​odds ratio = 0.81 (95%
CI, 0.51 to 1.2)

Weight gain Rate ratio SSRIs, SNRIs, TCAs​ Over 10 years Population-
(> 5%) 1.21 (95% CI, 1.20 to 1.23) for SSRIs Decreased risk with (highest risk based cohort
bupropion in first two study, system-
1.17 (95% CI, 1.13 to 1.21) for SNRIs years) atic review23,36
1.16 (95% CI, 1.14 to 1.18) for TCAs

SNRI = serotonin-norepinephrine reuptake inhibitor;​SSRI = selective serotonin reuptake inhibitor;​TCA = tricyclic antidepressant.
Information from references 23 and 27-36.

176 American Family Physician www.aafp.org/afp Volume 107, Number 2 ◆ February 2023
 PHARMACOLOGIC TREATMENT OF DEPRESSION

discontinuation symptoms.55 Use of cognitive behavior ther- via breast milk have been documented only in case reports,
apy during the medication taper may help prevent relapse or most commonly with fluoxetine and citalopram. The effects
recurrence.56 are nonspecific and include irritability and decreased feed-
ing. Overall, there is little evidence to support a causal link
Special Populations between antidepressant use in breastfeeding patients and
PREGNANT PATIENTS adverse effects in their infants.73
Approximately 12% of patients in the perinatal period meet
criteria for major depressive disorder.57 Patients with untreated OLDER ADULTS
depression during pregnancy have a higher incidence of Approximately 50% of patients older than 65 years who have
preterm birth and low-birth-weight infants compared with depression report at least a 50% improvement in symptoms
those without depression.58 Treatment of depression has not
been shown to improve these outcomes, and SSRIs may be
independently associated with preterm birth.59,60 TABLE 2
Screening pregnant and postpartum patients for depres-
sion is associated with a 2% to 9% reduction in absolute risk Comparative Risk of Antidepressant
of depression at three to five months, with or without treat- Discontinuation Syndrome for Selected
ment.61 The U.S. Preventive Services Task Force recommends Antidepressants
that clinicians provide or refer pregnant and postpartum Antidepressant Risk*
patients who are at increased risk of perinatal depression to Atypical antidepressant
counseling interventions.62 Bupropion +
For patients taking antidepressants before pregnancy, dis- Mirtazapine +
continuation is more likely to lead to relapse when depression
is severe or recurrent. A meta-analysis showed that discon- Serotonin-norepinephrine reuptake inhibitor
tinuation of antidepressants in patients with mild to moder- Desvenlafaxine (Pristiq) +++
ate depression is not significantly associated with relapse.63 Venlafaxine +++
Patients should continue their antidepressant when, through Duloxetine (Cymbalta) ++
shared decision-making, the risk of relapse is determined to Milnacipran +
be greater than the risk of rare neonatal complications. SSRI
Cohort studies have inconsistently shown a small cor- Fluvoxamine +++
relation between first-trimester SSRI use and cardiac mal- Paroxetine +++
formations (RR = 1.24;​95% CI, 1.11 to 1.37).64-66 SSRI use Citalopram ++
during the third trimester may increase the risk of newborn Escitalopram ++
respiratory distress, tremors, and admission to the neonatal Sertraline ++
intensive care unit.67-69 Discontinuation of SSRIs in the third Fluoxetine +
trimester does not improve these outcomes.70 There are no
data on long-term neurocognitive effects. SSRI/partial 5-HT1A receptor agonist
A U.S. Food and Drug Administration advisory on SSRI use Trazodone ++
during pregnancy and the risk of persistent pulmonary hyper- Vortioxetine (Trintellix) ++
tension in newborns cites conflicting findings;​a causal rela- Vilazodone (Viibryd) +
tionship is unclear.71 A systematic review and meta-analysis Tricyclic antidepressant
found a slightly increased risk of persistent pulmonary Imipramine +++
hypertension in newborns with prenatal exposure to SSRIs Nortriptyline +++
and SNRIs (number needed to harm = 1,000).72 Amitriptyline ++
Clomipramine ++
BREASTFEEDING PATIENTS
Desipramine ++
Antidepressants transfer into breast milk in low concen- Doxepin ++
trations. This transfer is thought to be lower for paroxetine
and sertraline than other antidepressants, producing unde- SSRI = selective serotonin reuptake inhibitor; 5-HT = serotonin.

tectable concentrations in infant plasma. Fluoxetine and *—High risk = +++;​moderate risk = ++;​low risk = +.
venlafaxine produce the highest infant plasma concentra- Information from references 49 and 50.
tions. Potential adverse effects in infants exposed to SSRIs

February 2023 ◆ Volume 107, Number 2 www.aafp.org/afp American Family Physician 177
 PHARMACOLOGIC TREATMENT OF DEPRESSION
TABLE 3

Tapering Strategies for Antidepressant Medications

Strategy Description Example Comments

10% reduc- Reduce dose every four Citalopram:​ Formulated using

tion per week weeks to match 10% 40 mg for four weeks pharmacokinetic data
reduction in serotonin but difficult to precisely
20 mg for four weeks
transporter occupancy implement
19 mg for four weeks
9.1 mg for four weeks
5.4 mg for four weeks
3.4 mg for four weeks
2.3 mg for four weeks
1.5 mg for four weeks
0.8 mg for four weeks
0.37 mg for four weeks

Three- to Reduce dose by 25% Citalopram:​ Easier to accomplish in

four-month every four weeks or by 40 mg for four weeks real-world practice, but
taper 12.5% every two weeks linear dose decrease
30 mg for four weeks may still result in
20 mg for four weeks antidepressant discon-
15 mg for four weeks tinuation syndrome
10 mg for four weeks
7.5 mg for four weeks
5 mg for four weeks
2.5 mg for four weeks

Cross taper Slowly decrease dose Citalopram (current Sertraline (new Exposure to multiple
of the current medica- medication, 40-mg medication):​ serotonergic agents
tion while increasing starting dose):​ has inherent risks
dose of the new 30 mg for four weeks 12.5 mg for four weeks Potential for
medication cytochrome P450–
20 mg for four weeks 18.75 mg for four weeks
mediated drug
15 mg for four weeks 25 mg for four weeks reactions depending
10 mg for four weeks 37.5 mg for four weeks on drug choice
7.5 m
 g for four weeks 50 mg for four weeks Increased pill burden
5 mg for four weeks 75 mg for four weeks and financial strain for
patients
2.5 m
 g for four weeks 100 mg for four weeks

Direct switch Start a new medication Discontinue citalopram, Initiate sertraline, 50 mg May be difficult to
immediately after dis- 20 mg determine if patient-
continuing the current reported adverse
one effects are due to
the new agent or
antidepressant discon-
tinuation syndrome

continues

with antidepressant use.74 Although prior studies showed older patients with dementia-related psychosis. Some drugs
no difference in the effectiveness of antidepressants in older are associated with higher rates of remission compared with
patients, a 2019 network meta-analysis found that response placebo:​quetiapine (RR = 2.38), mirtazapine (RR = 1.90),
rates are significantly higher with quetiapine (RR = 2.09) and and duloxetine (RR = 1.52). In older patients, fall risk should
duloxetine (RR = 1.83) in this population compared with pla- be evaluated and steps taken to mitigate the risk because
cebo.75 Quetiapine includes a U.S. Food and Drug Admin- untreated depression and antidepressant use can both con-
istration boxed warning due to increased mortality risk in tribute to falls.76

178 American Family Physician www.aafp.org/afp Volume 107, Number 2 ◆ February 2023
 PHARMACOLOGIC TREATMENT OF DEPRESSION
TABLE 3 (continued)

Tapering Strategies for Antidepressant Medications

Strategy Description Example Comments

Moderate Current medication is Citalopram (current medication):​ Potential for

switch tapered down, followed 20 mg for four weeks antidepressant discon-
by a washout period of tinuation syndrome
15 mg for four weeks
two or three days due to drug-free period
10 mg for four weeks
New medication is ini- More time-consuming
tiated at a conservative 7.5 mg for four weeks but considered to be
dose, then increased 5 mg for four weeks safer
2.5 mg for four weeks
Discontinue for two- to three-day washout period
Start sertraline:​
25 mg for four weeks
37.5 mg for four weeks
50 mg for four weeks

Conservative Current medication is Same as moderate switch but with longer washout Potential for
switch tapered down, followed period (seven days for most drugs, except those with antidepressant discon-
by a washout period of long half-lives [e.g., fluoxetine]) tinuation syndrome
four or five half-lives due to drug-free period
New medication is ini- Patients must wait
tiated at a conservative longer for treatment
dose, then increased benefit from new
medication

Information from references 51-53.

Because older adults are at greater risk of adverse drug

reactions, initiating treatment at approximately one-half of The Authors
the usual adult starting dose is often recommended. Guide- HEATHER KOVICH, MD, is program director of the
lines recommend sertraline, duloxetine, or escitalopram as Shiprock-University of New Mexico Family Medicine Resi-
good first-line options for older patients.77 Bupropion, mir- dency and a family physician at the Northern Navajo Medical
Center, Shiprock.
tazapine, and venlafaxine are also considered appropriate
because of their favorable side effect profiles. Paroxetine is WILLIAM KIM, MS, MD, is associate program director of
associated with more anticholinergic effects, and fluoxetine the Shiprock-University of New Mexico Family Medicine
Residency.
has a greater risk of agitation and overstimulation;​neither
should be used in older adults.77 Before initiating SSRIs and ANTHONY M. QUASTE, PharmD, USPHS, is a clinical phar-
SNRIs in older adults, clinicians should screen for a history macist at Indian Health Service, Northern Navajo Medical
Center.
of hyponatremia and measure serum sodium level two to
four weeks after initiating therapy.77 Address correspondence to Heather Kovich, MD, Northern
Navajo Medical Center, P.O. Box 160, Hwy 491, Shiprock, NM
87420 (email:​heather.kovich@​ihs.gov). Reprints are not avail-
This article updates previous articles on this topic by Kovich and
able from the authors.
DeJong78;​Adams, et al.79;​and Warner, et al.80

Data Sources:​PubMed searches were completed using key

terms such as depression, antidepressant, and antidepressant
References
1. U.S. Department of Health and Human Services. National Centers for
discontinuation and specific classes of antidepressant medi-
Health Statistics. Health, United States, 2013:​with special feature on
cations (e.g., selective serotonin reuptake inhibitor). Additional
prescription drugs. Accessed April 21, 2022. http://​w ww.cdc.gov/nchs/
terms were added to further refine results. For example, after data/hus/hus13.pdf
an initial search generated a list of common antidepressant 2. Brody DJ, Gu Q. Antidepressant use among adults:​United States, 2015-
adverse effects, each effect was searched separately. The search 2018. NCHS Data Brief. 2020;​(377):1-8.
included meta-analyses, randomized controlled trials, system- 3. Martin CB, Hales CM, Gu Q, et al. Prescription drug use in the United
atic reviews, and clinical trials. The U.S. Preventive Services Task States, 2015-2016. NCHS Data Brief. 2019;​(334):​1-8.
Force recommendations were referenced, and citations from 4. Twenge JM, Cooper AB, Joiner TE, et al. Age, period, and cohort trends
relevant recommendations were examined. Essential Evidence in mood disorder indicators and suicide-related outcomes in a nation-
Plus and the Cochrane database were also searched. Search ally representative dataset, 2005-2017. J Abnorm Psychol. 2019;​1 28(3):​
dates:​February through December 2022. 185-199.

February 2023 ◆ Volume 107, Number 2 www.aafp.org/afp American Family Physician 179
 PHARMACOLOGIC TREATMENT OF DEPRESSION

5. Hedegaard H, Curtin SC, Warner M. Suicide mortality in the United 23. Alonso-Pedrero L, Bes-Rastrollo M, Marti A. Effects of antidepressant
States, 1999-2019. NCHS Data Brief. 2021;​(398):​1-8. and antipsychotic use on weight gain:​a systematic review. Obes Rev.
6. U.S. Department of Health and Human Services, Substance Abuse 2019;​20(12):​1680-1690.
and Mental Health Services Administration. National Survey on Drug 24. Prasitlumkum N, Cheungpasitporn W, Tokavanich N, et al. Antidepres-
Use and Health. 2020 NSDUH detailed tables. January 11, 2022. sants and risk of sudden cardiac death:​a network meta-analysis and
Accessed April 21, 2022. https://​w ww.samhsa.gov/data/report/​2020- systematic review. Med Sci (Basel). 2021;​9(2):​26.
​nsduh-detailed-tables 25. Teply RM, Packard KA, White ND, et al. Treatment of depression in
7. Weinberger AH, Gbedemah M, Martinez AM, et al. Trends in depression patients with concomitant cardiac disease. Prog Cardiovasc Dis. 2016;​
prevalence in the USA from 2005 to 2015:​widening disparities in vul- 58(5):​514-528.
nerable groups. Psychol Med. 2018;​48(8):​1 308-1315. 26. Coupland C, Hill T, Morriss R, et al. Antidepressant use and risk of
8. Diagnostic and Statistical Manual of Mental Disorders. 5th ed. American adverse outcomes in people aged 20-64 years:​cohort study using
Psychiatric Association;​2014. a primary care database. BMC Med. 2018;​16(1):​36.
9. Mojtabai R. Clinician-identified depression in community settings:​con- 27. Jiang HY, Chen HZ, Hu XJ, et al. Use of selective serotonin reuptake
cordance with structured-interview diagnoses. Psychother Psychosom. inhibitors and risk of upper gastrointestinal bleeding:​a systematic
2013;​82(3):​161-169. review and meta-analysis. Clin Gastroenterol Hepatol. 2015;​1 3(1):​
10. Qaseem A, Barry MJ, Kansagara D. Nonpharmacologic versus phar- 42-50.e3.
macologic treatment of adult patients with major depressive disorder:​ 28. Voican CS, Corruble E, Naveau S, et al. Antidepressant-induced liver
a clinical practice guideline from the American College of Physicians. injury:​a review for clinicians. Am J Psychiatry. 2014;​171(4):​404-415.
Ann Intern Med. 2016;​164(5):​350-359.
29. De Picker L, Van Den Eede F, Dumont G, et al. Antidepressants and the
11. Arroll B, Chin WY, Martis W, et al. Antidepressants for treatment of risk of hyponatremia:​a class-by-class review of literature. Psychoso-
depression in primary care:​a systematic review and meta-analysis. matics. 2014;​55(6):​536-547.
J Prim Health Care. 2016;​8(4):​325-334.
30. Moura C, Bernatsky S, Abrahamowicz M, et al. Antidepressant use
12. Cipriani A, Furukawa TA, Salanti G, et al. Comparative efficacy and and 10-year incident fracture risk:​the population-based Canadian
acceptability of 21 antidepressant drugs for the acute treatment of Multicentre Osteoporosis Study (CaMoS). Osteoporos Int. 2014;​25(5):​
adults with major depressive disorder:​a systematic review and network 1473-1481.
meta-analysis. Lancet. 2018;​391(10128):​1 357-1366.
31. U.S. Food and Drug Administration drug safety communication:​revised
13. Stone M, Kalaria S, Richardville K, et al. Components and trends in
recommendations for Celexa (citalopram hydrobromide) related to
treatment effects in randomized placebo-controlled trials in major
a potential risk of abnormal heart rhythms with high doses. March 28,
depressive disorder from 1979-2016. Poster presented at: American
2012. Accessed April 21, 2022. https://​w ww.fda.gov/Drugs/DrugSafety/
Society of Clinical Psychopharmacology Annual Conference;​May 2018;
ucm​297​391.htm
Miami, FL.
32. Castro VM, Clements CC, Murphy SN, et al. QT interval and antide-
14. Turner EH, Cipriani A, Furukawa TA, et al. Selective publication of anti-
pressant use:​a cross sectional study of electronic health records. BMJ.
depressant trials and its influence on apparent efficacy:​updated com-
2013;​3 46:​f288.
parisons and meta-analyses of newer versus older trials. PLoS Med.
2022;​19(1):​e1003886. 33. Reichenpfader U, Gartlehner G, Morgan LC, et al. Sexual dysfunction
associated with second-generation antidepressants in patients with
15. Almohammed OA, Alsalem AA, Almangour AA, et al. Antidepressants
major depressive disorder:​results from a systematic review with net-
and health-related quality of life (HRQoL) for patients with depres-
work meta-analysis. Drug Saf. 2014;​37(1):​19-31.
sion:​analysis of the medical expenditure panel survey from the United
States. PLoS One. 2022;​17(4):​e0265928. 34. Worthington JJ III, Peters PM. Treatment of antidepressant-induced
sexual dysfunction. Drugs Today (Barc). 2003;​39(11):​887-896.
16. American Psychological Association. Clinical practice guideline for
the treatment of depression across three age cohorts. February 2019. 35. Sharma T, Guski LS, Freund N, et al. Suicidality and aggression during
Accessed April 21, 2022. https://​w ww.apa.org/depression-guideline antidepressant treatment:​systematic review and meta-analyses based
17. National Institute for Health and Care Excellence. Depression in adults:​ on clinical study reports. BMJ. 2016;​352:​i65.
treatment and management. June 29, 2022. Accessed August 12, 2022. 36. Gafoor R, Booth HP, Gulliford MC. Antidepressant utilisation and inci-
https://​w ww.nice.org.uk/guidance/ng222 dence of weight gain during 10 years’ follow-up:​population based
18. Cuijpers P, Oud M, Karyotaki E, et al. Psychologic treatment of depres- cohort study. BMJ. 2018;​361:​k1951.
sion compared with pharmacotherapy and combined treatment in pri- 37. Gelenberg AJ, Freeman MP, Markowitz JC, et al. Practice guideline
mary care:​a network meta-analysis. Ann Fam Med. 2021;​19(3):​262-270. for the treatment of patients with major depressive disorder. Third
19. Cuijpers P, Noma H, Karyotaki E, et al. A network meta-analysis of the edition. American Psychiatric Association. October 2010. Accessed
effects of psychotherapies, pharmacotherapies and their combina- August 10, 2022. https://​psychiatryonline.org/pb/assets/raw/sitewide/
tion in the treatment of adult depression. World Psychiatry. 2020;​19(1):​ practice_guidelines/guidelines/mdd.pdf
92-107. 38. Jung WY, Jang SH, Kim SG, et al. Times to discontinue antidepressants
20. Guidi J, Fava GA. Sequential combination of pharmacotherapy and over 6 months in patients with major depressive disorder. Psychiatry
psychotherapy in major depressive disorder:​a systematic review and Investig. 2016;​1 3(4):​4 40-446.
meta-analysis. JAMA Psychiatry. 2021;​78(3):​261-269. 39. McCrea RL, Sammon CJ, Nazareth I, et al. Initiation and duration of
21. Li KX, Loshak H. Pharmacogenomic testing in depression:​a review selective serotonin reuptake inhibitor prescribing over time:​UK cohort
of clinical effectiveness, cost-effectiveness, and guidelines. Canadian study. Br J Psychiatry. 2016;​209(5):​421-426.
Agency for Drugs and Technologies in Health. January 31, 2020. 40. Sinclair JE, Aucott LS, Lawton K, et al. The monitoring of longer term
Updated February 18, 2020. Accessed December 5, 2022. https://​ prescriptions of antidepressants:​observational study in a primary care
www.cadth.ca/pharmacogenomic-testing-depression-review-clinical- setting. Fam Pract. 2014;​31(4):​419-426.
effectiveness-cost-effectiveness-and-guidelines 41. Sim K, Lau WK, Sim J, et al. Prevention of relapse and recurrence in adults
22. Gartlehner G, Gaynes BN, Hansen RA, et al. Comparative benefits and with major depressive disorder:​systematic review and meta-analyses of
harms of second-generation antidepressants:​background paper for controlled trials [published correction appears in Int J Neuropsycho-
the American College of Physicians. Ann Intern Med. 2008;​149(10):​ pharmacol. 2016;​19(10);​pyw031]. Int J Neuropsychopharmacol. 2015;​
734-750. 19(2):​pyv076.

180 American Family Physician www.aafp.org/afp Volume 107, Number 2 ◆ February 2023
 PHARMACOLOGIC TREATMENT OF DEPRESSION

42. Lewis G, Marston L, Duffy L, et al. Maintenance or discontinuation of a systematic review and meta-analysis. J Clin Psychiatry. 2020;​81(4):​
antidepressants in primary care. N Engl J Med. 2021;​385(14):​1 257-1267. 19r13134.
43. Machmutow K, Meister R, Jansen A, et al. Comparative effectiveness 64. Huybrechts KF, Palmsten K, Avorn J, et al. Antidepressant use in preg-
of continuation and maintenance treatments for persistent depressive nancy and the risk of cardiac defects. N Engl J Med. 2014;​370(25):​
disorder in adults. Cochrane Database Syst Rev. 2019;​(5):​CD012855. 2397-2407.
44. Baldessarini RJ, Lau WK, Sim J, et al. Duration of initial antidepressant 65. Bérard A, Zhao JP, Sheehy O. Antidepressant use during pregnancy and
treatment and subsequent relapse of major depression. J Clin Psycho- the risk of major congenital malformations in a cohort of depressed
pharmacol. 2015;​35(1):​75-76. pregnant women:​an updated analysis of the Quebec Pregnancy
45. Kennedy SH, Lam RW, McIntyre RS, et al. Canadian Network for Mood Cohort. BMJ Open. 2017;​7(1):​e013372.
and Anxiety Treatments (CANMAT) 2016 clinical guidelines for the man- 66. Gao SY, Wu QJ, Sun C, et al. Selective serotonin reuptake inhibitor
agement of adults with major depressive disorder:​section 3. Pharma- use during early pregnancy and congenital malformations:​a system-
cological treatments [published correction appears in Can J Psychiatry. atic review and meta-analysis of cohort studies of more than 9 million
2017;​62(5):​356]. Can J Psychiatry. 2016;​61(9):​5 40-560. births. BMC Med. 2018;​16(1):​205.
46. Davies J, Read J. A systematic review into the incidence, severity and 67. McDonagh MS, Matthews A, Phillipi C, et al. Depression drug treat-
duration of antidepressant withdrawal effects:​are guidelines evidence- ment outcomes in pregnancy and the postpartum period:​a systematic
based? Addict Behav. 2019;​97:​1 11-121. review and meta-analysis. Obstet Gynecol. 2014;​1 24(3):​526-534.
47. Bhat V, Kennedy SH. Recognition and management of antidepressant 68. Grigoriadis S, VonderPorten EH, Mamisashvili L, et al. The effect of pre-
discontinuation syndrome. J Psychiatry Neurosci. 2017;​42(4):​E7-E8. natal antidepressant exposure on neonatal adaptation:​a systematic
48. Horowitz MA, Taylor D. Tapering of SSRI treatment to mitigate with- review and meta-analysis. J Clin Psychiatry. 2013;​74(4):​e309-e320.
drawal symptoms. Lancet Psychiatry. 2019;​6(6):​538-546. 69. Nörby U, Forsberg L, Wide K, et al. Neonatal morbidity after maternal
49. Henssler J, Heinz A, Brandt L, et al. Antidepressant withdrawal and use of antidepressant drugs during pregnancy. Pediatrics. 2016;​1 38(5):​
rebound phenomena. Dtsch Arztebl Int. 2019;​1 16(20):​355-361. e20160181.
50. Zwiebel SJ, Viguera AC. Discontinuing antidepressants:​pearls and pit- 70. Warburton W, Hertzman C, Oberlander TF. A register study of the
falls. Cleve Clin J Med. 2022;​89(1):​18-26. impact of stopping third trimester selective serotonin reuptake inhib-
51. Fava GA, Benasi G, Lucente M, et al. Withdrawal symptoms after itor exposure on neonatal health. Acta Psychiatr Scand. 2010;​1 21(6):​
serotonin-noradrenaline reuptake inhibitor discontinuation:​systematic 471-479.
review. Psychother Psychosom. 2018;​87(4):​195-203. 71. U.S. Food and Drug Administration. FDA Drug Safety Communication:​
52. Tint A, Haddad PM, Anderson IM. The effect of rate of antidepressant selective serotonin reuptake inhibitor (SSRI) antidepressant use during
tapering on the incidence of discontinuation symptoms:​a randomised pregnancy and reports of a rare heart and lung condition in newborn
study [published correction appears in J Psychopharmacol. 2009;​23(8):​ babies. December 14, 2011. Accessed April 27, 2022. https://​w ww.fda.
1006]. J Psychopharmacol. 2008;​22(3):​330-332. gov/​drugs/drug-safety-and-availability/fda-drug-safety-communication-
53. Phelps J. Tapering antidepressants:​is 3 months slow enough? Med selective-serotonin-reuptake-inhibitor-ssri-antidepressant-use-during
Hypotheses. 2011;​7 7(6):​1006-1008. 72. Masarwa R, Bar-Oz B, Gorelik E, et al. Prenatal exposure to selective
54. Jefferson JW. Strategies for switching antidepressants to achieve maxi- serotonin reuptake inhibitors and serotonin norepinephrine reuptake
mum efficacy. J Clin Psychiatry. 2008;​69(suppl E1):​14-18. inhibitors and risk for persistent pulmonary hypertension of the new-
born:​a systematic review, meta-analysis, and network meta-analysis.
55. Himei A, Okamura T. Discontinuation syndrome associated with parox-
Am J Obstet Gynecol. 2019;​220(1):​57.e1-57.e13.
etine in depressed patients:​a retrospective analysis of factors involved
in the occurrence of the syndrome. CNS Drugs. 2006;​20(8):​665-672. 73. Schoretsanitis G, Augustin M, Saßmannshausen H, et al. Antidepres-
sants in breast milk;​comparative analysis of excretion ratios. Arch
56. Maund E, Stuart B, Moore M, et al. Managing antidepressant discontin-
Womens Ment Health. 2019;​22(3):​383-390.
uation:​a systematic review. Ann Fam Med. 2019;​17(1):​52-60.
57. Woody CA, Ferrari AJ, Siskind DJ, et al. A systematic review and 74. Gutsmiedl K, Krause M, Bighelli I, et al. How well do elderly patients
meta-regression of the prevalence and incidence of perinatal depres- with major depressive disorder respond to antidepressants:​a systematic
sion. J Affect Disord. 2017;​219:​86-92. review and single-group meta-analysis. BMC Psychiatry. 2020;​20(1):​102.

58. Jarde A, Morais M, Kingston D, et al. Neonatal outcomes in women 75. Krause M, Gutsmiedl K, Bighelli I, et al. Efficacy and tolerability of
with untreated antenatal depression compared with women without pharmacological and non-pharmacological interventions in older
depression:​a systematic review and meta-analysis. JAMA Psychiatry. patients with major depressive disorder:​a systematic review, pairwise
2016;​73(8):​826-837. and network meta-analysis. Eur Neuropsychopharmacol. 2019;​29(9):​
1003-1022.
59. Eke AC, Saccone G, Berghella V. Selective serotonin reuptake inhibi-
tor (SSRI) use during pregnancy and risk of preterm birth:​a systematic 76. van Poelgeest EP, Pronk AC, Rhebergen D, et al. Depression, antidepres-
review and meta-analysis. BJOG. 2016;​1 23(12):​1900-1907. sants and fall risk:​therapeutic dilemmas—a clinical review. Eur Geriatr
Med. 2021;​1 2(3):​585-596.
60. Vlenterie R, van Gelder MMHJ, Anderson HR, et al. Associations
between maternal depression, antidepressant use during pregnancy, 77. Canadian Coalition for Seniors’ Mental Health. Canadian guidelines
and adverse pregnancy outcomes:​an individual participant data on prevention, assessment and treatment of depression among older
meta-analysis. Obstet Gynecol. 2021;​1 38(4):​633-646. adults. Updated June 2021. Accessed August 13, 2022. https://​ccsmh.
ca/wp-content/uploads/2021/06/CCSMH_ ​D epression_​G uidelines_​
61. O’Connor E, Rossom RC, Henninger M, et al. Primary care screening
FINAL_​EN.pdf
for and treatment of depression in pregnant and postpartum women:​
evidence report and systematic review for the US Preventive Services 78. Kovich H, DeJong A. Common questions about the pharmacologic
Task Force. JAMA. 2016;​315(4):​388-406. management of depression in adults. Am Fam Physician. 2015;​92(2):​
62. Curry SJ, Krist AH, Owens DK, et al. Interventions to prevent perinatal 94-100.
depression:​US Preventive Services Task Force recommendation state- 79. Adams SM, Miller KE, Zylstra R. Pharmacologic management of adult
ment. JAMA. 2019;​321(6):​580-587. depression. Am Fam Physician. 2008;​7 7(6):​785-792.
63. Bayrampour H, Kapoor A, Bunka M, et al. The risk of relapse of depres- 80. Warner CH, Bobo W, Warner C, et al. Antidepressant discontinuation
sion during pregnancy after discontinuation of antidepressants:​ syndrome. Am Fam Physician. 2006;​74(3):​4 49-456.

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