Clinical Review & Education

JAMA | Review

Management of Depression in Adults

A Review
Gregory E. Simon, MD, MPH; Nathalie Moise, MD, MS; David C. Mohr, PhD

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IMPORTANCE Approximately 9% of US adults experience major depression each year, with Supplemental content
a lifetime prevalence of approximately 17% for men and 30% for women.
CME at jamacmelookup.com
OBSERVATIONS Major depression is defined by depressed mood, loss of interest in activities, and
associated psychological and somatic symptoms lasting at least 2 weeks. Evaluation should
include structured assessment of severity as well as risk of self-harm, suspected bipolar disorder,
psychotic symptoms, substance use, and co-occurring anxiety disorder. First-line treatments
include specific psychotherapies and antidepressant medications. A network meta-analysis of
randomized clinical trials reported cognitive therapy, behavioral activation, problem-solving
therapy, interpersonal therapy, brief psychodynamic therapy, and mindfulness-based
psychotherapy all had at least medium-sized effects in symptom improvement over usual care
without psychotherapy (standardized mean difference [SMD] ranging from 0.50 [95% CI,
0.20-0.81] to 0.73 [95% CI, 0.52-0.95]). A network meta-analysis of randomized clinical trials
reported 21 antidepressant medications all had small- to medium-sized effects in symptom
improvement over placebo (SMD ranging from 0.23 [95% CI, 0.19-0.28] for fluoxetine to 0.48
[95% CI, 0.41-0.55] for amitriptyline). Psychotherapy combined with antidepressant medication
may be preferred, especially for more severe or chronic depression. A network meta-analysis of
randomized clinical trials reported greater symptom improvement with combined treatment Author Affiliations: Kaiser
Permanente Washington Health
than with psychotherapy alone (SMD, 0.30 [95% CI, 0.14-0.45]) or medication alone (SMD, 0.33
Research Institute, Seattle (Simon);
[95% CI, 0.20-0.47]). When initial antidepressant medication is not effective, second-line Center for Behavioral Cardiovascular
medication treatment includes changing antidepressant medication, adding a second Health, Columbia University Irving
antidepressant, or augmenting with a nonantidepressant medication, which have approximately Medical Center, New York, New York
(Moise); Center for Behavioral
equal likelihood of success based on a network meta-analysis. Collaborative care programs, Intervention Technologies,
including systematic follow-up and outcome assessment, improve treatment effectiveness, with Department of Preventive Medicine,
1 meta-analysis reporting significantly greater symptom improvement compared with usual care Feinberg School of Medicine,
(SMD, 0.42 [95% CI, 0.23-0.61]). Northwestern University, Chicago,
Illinois (Mohr).
CONCLUSIONS AND RELEVANCE Effective first-line depression treatments include specific Corresponding Author: Gregory
forms of psychotherapy and more than 20 antidepressant medications. Close monitoring Simon, MD, MPH, Kaiser Permanente
Washington Health Research
significantly improves the likelihood of treatment success.
Institute, 1730 Minor Ave, #1600,
Seattle, WA 98101 (gregory.e.simon@
JAMA. doi:10.1001/jama.2024.5756 kp.org).
Published online June 10, 2024. Section Editor: Kristin Walter, MD,
Deputy Editor.

I
n 2022, annual prevalence of major depression among US adults 5.62 to 9.48 per 1000 person-years.6 Annual economic burden of
was approximately 7.0% among men and 10.4% among women, depression in the US includes approximately $38 billion due to time
with variation across racial and ethnic groups, ranging from 6.3% missed from work and $43 billion due to decreased productivity at
among Asian people to 9.2% among non-Hispanic White people.1 Life- work.7 Despite 30 years of practice guidelines aiming to improve
time prevalence of depression in the US is approximately 17% for men care, only 18% of people identified with significant symptoms of de-
and 30% for women.2 Risk of depression among young adults in- pression experience a 50% or greater decrease in symptoms after
creased during the COVID-19 pandemic, with a 13.0% increase among 6 months.8 This review summarizes current evidence regarding the
those aged 18 to 24 years and a 9.8% increase among those aged 25 diagnosis and treatment of unipolar depression in adults.
to 34 years.3 A meta-analysis of 83 studies including 41 344 patients
found an overall prevalence of 27.0% (95% CI, 24.0%-29.0%) across
primary care and medical specialty outpatients.4
Methods
Compared with people without significant symptoms of de-
pression, major depression is associated with an 8-fold increase in We searched PubMed from January 2010 through February 2024
risk of suicide,5 and moderate or severe depression symptoms are for relevant English-language systematic reviews and meta-
associated with an increase in all-cause mortality among adults, from analyses regarding 50 specific questions listed in the eAppendix in

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 Clinical Review & Education Review Management of Depression in Adults

Table 1. Screening for Complicating Factors That May Indicate Need for Consultation/Referral
or Affect Management Decisions
Prevalence
among patients
with depression Screening questions or tools Implications for management
Bipolar disorder I 5%24, 25 Screening questions (positive response Specialty consultation or referral
and II requires assessment): generally recommended.
“Do you sometimes have ‘up’ or ‘high’ Antidepressant without mood
periods lasting at least a few days stabilizer can precipitate mania.
when you have lots of energy or feel
speeded up?”
“Has a doctor or professional ever told you
they thought you had bipolar disorder or
manic-depressive illness?”
13-Item Mood Disorder Questionnaire25
includes more detailed questions.
Psychotic NA Screening questions (positive response Specialty consultation or referral
symptoms requires assessment): generally recommended.
“Have you had strange or odd experiences Antidepressant and antipsychotic
lately that you cannot explain?” medication may be indicated.
“Do you hear things that other people
cannot hear or see things that other
people cannot see?”
“Has it seemed like people were talking
about you or taking special notice of you?”
20
Suicidal ideation 5% Score of 2 or 3 on item 9 of PHQ-9 If elevated risk, additional structured
indicates elevated risk.20 risk assessment indicated.
Score of 3 or higher on Columbia Suicide If recent suicidal planning or intent,
Severity Rating Scale22 indicates recent specialty consultation recommended.
suicidal planning and score of 4 or higher If current suicidal intent, safety
indicates recent suicidal intent. planning and urgent consultation or
referral recommended.
Alcohol use 20%32 Score of 4 or higher on AUDIT-C screening Psychotherapy and/or
disorder questionnaire can indicate need for pharmacotherapy specific for alcohol
additional assessment.30 use disorder may be indicated. Abbreviations: AUDIT-C, Alcohol Use
Opioid or other 12%32 “How many times in the past year have you Psychotherapy and/or Disorders Identification Test;
drug use disorder used an illegal drug or used a prescription pharmacotherapy specific for opioid GAD, General Anxiety
medication for nonmedical reasons?”31 use disorder may be indicated. Disorder; NA, not applicable;
Anxiety disorder 40%28 Score of 3 or higher on GAD-219 screening Combined psychotherapy and PHQ-9, Patient Health
questionnaire can indicate need for medication preferred. Some Questionnaire-9.
additional assessment with GAD-7. antidepressants preferred.a a
See Table 3.

the Supplement (eg, depression + screening + systematic review or Association’s Diagnostic and Statistical Manual of Mental Disorders11
meta-analysis). References of identified papers were reviewed and and the World Health Organization’s International Classification of
a search of published articles citing identified papers was per- Diseases and Related Health Problems12 define a major depressive epi-
formed. Of 176 articles retrieved, 110 that reported the largest and sode by depressed mood or loss of interest, accompanied by other
most recent samples are cited in this review, including 51 meta- psychological or somatic symptoms, persisting for most of the day,
analyses, 12 systematic reviews, 15 narrative reviews, 12 random- most days, over 2 weeks or more.
ized clinical trials, 16 cohort studies, and 4 clinical practice guide- The presenting symptoms of depression can vary across care
lines. For meta-analyses comparing treatments, we reported settings and cultures and within individuals over time. In a study of
standardized mean differences (SMDs) for changes in symptom primary care clinics in 15 countries, the percentage of patients with
scores when available and alternative measures, such as odds ra- major depression who initially presented with somatic symptoms,
tios for treatment response (traditionally defined as a 50% or greater such as pain or fatigue, ranged from 45% to 95%.13 However, sys-
decrease in symptom scores9), when SMD was not reported. When tematic assessment identified similar core symptoms of depres-
comparing depression treatments, SMDs of 0.2, 0.5, and 0.8 are usu- sion, both somatic and psychological, across clinical settings, lan-
ally considered small, medium, and large, respectively.10 guages, and cultures.13,14
The US Preventive Services Task Force recommends screening
for depression in primary care settings among adults and adoles-
cents, including during pregnancy and postpartum,15 citing evi-
Discussion
dence regarding the accuracy of screening tools and benefits of or-
Clinical Presentation ganized treatment for those identified by screening.15 However,
The syndrome of depression is defined by symptoms of sad or de- screening for depression that is not linked to effective treatment has
pressed mood and/or loss of interest in usual activities, accompa- no clear benefit.16
nied by other psychological symptoms (difficulty concentrating, feel- The Patient Health Questionnaire (PHQ-9)17,18 accurately iden-
ings of worthlessness or excessive guilt, thoughts of death or suicide) tifies depression across a range of populations and clinical settings.
and somatic symptoms (fatigue, changes in sleep, changes in appe- Compared with a structured research interview, a PHQ-9 score of 10
tite, psychomotor slowing or agitation).11,12 The American Psychiatric or more identifies major depression with sensitivity of approximately

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 Management of Depression in Adults Review Clinical Review & Education

Table 2. First-Line Psychotherapies for Depression

Improvement vs
Typical usual care,a SMD
Psychotherapy formats Key elements Other considerations (95% CI)
Cognitive or cognitive Individual or Identifying and Often effective for anxiety 0.67 (0.56-0.79)
behavioral therapy group, 6 to 16 challenging or symptoms and combined
sessions interrupting negative with behavioral therapy
thoughts (cognitive behavioral
therapy)
Behavioral activation Individual or Increasing the Effective for anxiety 0.73 (0.52-0.95)
group, 6 to 12 engagement in activities symptoms
sessions that are pleasurable or
bring a sense of
accomplishment
Problem-solving Individual or Identifying problems and Effective for anxiety 0.64 (0.40-0.88)
therapy group, 6 to 12 stressors and developing symptoms; specific
sessions strategies to manage them versions tailored for older
adults
Interpersonal therapy 12-16 Focuses on improving Useful for unresolved 0.54 (0.32-0.76)
individual quality of interpersonal grief, social isolation, and
sessions relations and interactions difficult life transitions Abbreviation: SMD, standardized
(eg, divorce, retirement) mean difference.
a
Psychodynamic 20-50 Explores how unconscious Effective for anxiety 0.50 (0.20-0.81) From network meta-analysis30
therapy individual motivations, often disorders including 331 randomized trials and
sessions originating in childhood 34 285 participants. Usual care
experiences, affect
comparison group typically included
emotions, cognitions, and
behaviors primary care treatment, with or
without antidepressant medication,
Mindfulness-based 8 group Uses meditation to bring Includes sessions longer 0.69 (0.45-0.93)
therapy sessions awareness to feelings, than the usual 45-50 min; but no psychotherapy. When
thoughts, and situations to may be effective for comparing depression treatments,
reduce automatic patients who have not SMDs of 0.2, 0.5, and 0.8 are
responses responded to other usually considered small, medium,
psychotherapies
and large, respectively.8

85% and specificity of approximately 85%.17,18 Screening with the first Assessment should also consider co-occurring conditions that
2 items of the PHQ-9 (termed the PHQ-2), reserving the remaining may influence treatment decisions (Table 1). Approximately 40% of
itemsforthosewithscoresof2orgreater,doesnotreducesensitivity.17 people with major depression have clinically significant anxiety,28
PHQ-9 scores of 5 to 9 typically represent mild symptoms of depres- which may be detected through screening questionnaires such as
sion; 10 to 14, moderate symptoms; 15 to 19, moderately severe symp- the PHQ anxiety scale or General Anxiety Disorder-7 scale.19 As dis-
toms; and 20 or more, severe symptoms.19 cussed below, co-occurring anxiety may necessitate a recommen-
dation for psychotherapy and/or selection of specific antidepres-
Assessment and Diagnosis sant medications that are also effective for anxiety29 (Table 2 and
For individuals presenting with depression or those identified by Table 3). Assessment should also include screening for substance
screening, assessment should consider factors that usually require use,31,32 including alcohol use disorder (likely to be present in up to
specialty consultation or referral, including suicidal ideation with plan- 20% of people with major depression), cannabis use disorder (likely
ning or intent, likely bipolar disorder, or psychotic symptoms to be present in up to 12%), or other drug use disorder (likely to be
(Table 1). Approximately 5% of patients treated for depression in pri- present in up to 12%).33 Neither alcohol use disorder nor drug use
mary care report suicidal ideation “more than half the days” or “nearly disorder should preclude diagnosis of depression or delay initia-
every day” in response to item 9 of the PHQ-9, and those patients tion of depression treatment34; co-occurring substance use disor-
have an approximately 1% risk of self-harm or suicide attempt over ders may warrant additional pharmacologic or behavioral treat-
the following 90 days.20 Data from mental health specialty or inpa- ment. Medical conditions, such as chronic pain, may contribute to
tient samples21 suggest that structured assessments, such as the depression35 and depression often amplifies pain or fatigue due
Columbia-Suicide Severity Rating Scale,22 can identify individuals to medical conditions. Some medications, such as corticosteroids
with current or recent suicidal ideation for whom specialty consul- and interferon alfa, may cause or exacerbate depression, although
tation is recommended and those with suicidal planning and intent the causal relationship between β-blocker medications and depres-
for whom urgent consultation or referral is recommended. When sion is not clear.36
same- or next-day specialty consultation is not available, primary care Unless indicated by history or examination, laboratory testing
clinicians can collaborate with patients and caregivers to create a (including thyroid testing37), imaging, or other diagnostic proce-
safety plan or crisis response plan23 that includes steps to reduce dures are not recommended to confirm the diagnosis of depres-
access to lethal means, such as firearms. At least 7% of people treated sion or guide treatment.
for depression in primary care may have unrecognized bipolar dis-
order (type I or II).24,25 For patients with bipolar disorder, mood Treatment
stabilizer medications may be indicated and treatment with antide- Treatment planning should consider severity of depression, pa-
pressants alone can precipitate mania or mood instability. Question- tient preferences, and treatment availability and should address
naires to screen for bipolar disorder may be useful,26 but sensitiv- patients’ concerns, such as fatigue, insomnia, persistent pain, and
ity may be as low as 50% in primary care settings.25,27 current life stressors.

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 Clinical Review & Education Review Management of Depression in Adults

Table 3. First-Line Pharmacotherapy for Depression

Improvement Discontinuation
Usual Additional compared with compared with
AHFS classification/ starting Usual dose approved Common placebo, SMD placebo, OR
generic name dose range indicationsa adverse effectsb Specific precautionsc (95% CI)d (95% CrI)d,e
Selective serotonin reuptake inhibitors
Citalopram 10 mg daily 20-40 mg Dry mouth, May prolong QT 0.24 (0.17-0.31) 0.94 (0.80-1.09)
daily nausea, interval on
somnolence, electrocardiogram
insomnia, sexual
dysfunction
Escitalopram 5 mg daily 10-20 mg Generalized anxiety Headache, 0.29 (0.24-0.35) 0.90 (0.80-1.02)
daily disorder nausea,
insomnia, sexual
dysfunction
Fluoxetine 10 mg daily 20-60 mg Panic disorder, Insomnia, 0.23 (0.19-0.28) 0.88 (0.80-0.96)
daily obsessive- nausea,
compulsive headache,
disorder, diarrhea,
premenstrual nervousness,
dysphoric disorder, tremor, sexual
bulimia dysfunction
Paroxetine 10 mg daily 20-50 mg Panic disorder, Nausea, More anticholinergic, 0.32 (0.28-0.37) 0.95 (0.87-1.03)
daily social anxiety insomnia, avoid in elderly
disorder, dry mouth,
obsessive- headache,
compulsive constipation,
disorder, diarrhea, sexual
generalized anxiety dysfunction,
disorder, tremor
posttraumatic
stress disorder,
premenstrual
dysphoric disorder,
menopausal
vasomotor
symptoms
Sertraline 50 mg daily 100-200 mg Panic disorder, Nausea, 0.27 (0.21-0.34) 0.96 (0.85-1.08)
daily social anxiety diarrhea,
disorder, insomnia, dry
obsessive- mouth, fatigue,
compulsive dizziness, sexual
disorder, dysfunction
posttraumatic
stress disorder,
premenstrual
dysphoric disorder
Other antidepressants
Bupropionf 150 mg 300-450 mg Seasonal affective Dry mouth, May increase risk of 0.25 (0.16-0.33) 0.96 (0.81-1.14)
daily daily disorder, smoking nausea, loss of seizures
cessation appetite,
insomnia,
tremors
Mirtazapine 15 mg at 30-45 mg at Somnolence, 0.37 (0.28-0.45) 0.99 (0.85-1.15)
bedtime bedtime weight gain,
dry mouth,
increased
appetite,
constipation
Selective serotonin and norepinephrine reuptake inhibitors
Duloxetine 30 mg daily 60-120 mg Generalized anxiety Nausea, 0.37 (0.31-0.44) 1.08 (0.96-1.23)
daily disorder, diabetic dry mouth,
peripheral headache,
neuropathic pain, somnolence,
fibromyalgia, fatigue
chronic
musculoskeletal
pain
Venlafaxinef 75 mg daily 150-300 mg Generalized anxiety Headache, May increase blood 0.33 (0.28-0.39) 1.04 (0.93-1.05)
daily disorder, social nausea, pressure
anxiety disorder, insomnia,
panic disorder fatigue,
somnolence,
sexual
dysfunction,
increased
sweating,
nervousness,
dry mouth

(continued)

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 Management of Depression in Adults Review Clinical Review & Education

Table 3. First-Line Pharmacotherapy for Depression (continued)

Improvement Discontinuation
Usual Additional compared with compared with
AHFS classification/ starting Usual dose approved Common placebo, SMD placebo, OR
generic name dose range indicationsa adverse effectsb Specific precautionsc (95% CI)d (95% CrI)d,e
Desvenlafaxine 50 mg daily 50-100 mg Nausea, May increase blood 0.25 (0.15-0.35) 1.08 (0.88-1.33)
daily dry mouth, pressure
dizziness,
insomnia,
increased
sweating,
constipation,
fatigue
Levomilnacipran 20 mg daily 40-120 mg Nausea, sexual 0.27 (0.13-0.40) 1.19 (0.93-1.53)
daily dysfunction
Serotonin modulators
Vortioxetine 5 mg daily 10-20 mg Nausea 0.28 (0.20-0.36) 1.01 (0.86-1.09)
daily
Vilazodone 10 mg daily 20-40 mg Nausea, 0.27 (0.15-0.38) 1.14 (0.88-1.47)
daily diarrhea
Tricyclic antidepressants
Nortriptyline 25 mg at 50-100 mg Dry mouth, More anticholinergic, NAg NAg
bedtime at bedtime somnolence, avoid in elderly
fatigue,
constipation
Desipramine 50 mg daily 100-200 mg Dry mouth, More anticholinergic, NAg NAg
or at daily or at somnolence, avoid in elderly
bedtime bedtime fatigue,
constipation
d
Abbreviations: AHFS, American Hospital Formulary Service; CrI, credible From network meta-analysis40 including 522 randomized trials and 116 477
interval; NA, not applicable; OR, odds ratio; SMD, standardized mean participants. When comparing depression treatments, SMDs of 0.2, 0.5, and
difference. 0.8 are usually considered small, medium, and large, respectively.8
a e
Includes only indications approved by the US Food and Drug Administration. Includes discontinuation for any reason.
Additional off-label indications may be supported by evidence. f
Bupropion and venlafaxine are most often prescribed in once-daily
b
Reported by more than 10% of participants in clinical trials. sustained-release forms.
c g
See text for general precautions regarding precipitation of suicidal ideation or Not included in network meta-analysis.40
behavior.

Efficacy of Psychotherapy and Antidepressant Medication participants40 found 21 different antidepressant medications were
Randomized clinical trials have demonstrated the efficacy of spe- all more efficacious than placebo, with generally similar small to me-
cific types of psychotherapy (Table 2), including cognitive or cogni- dium effects (SMDs ranging from 0.23 [95% CI, 0.19-0.28] for
tive behavioral therapy, behavioral activation, interpersonal fluoxetine to 0.48 [95% CI, 0.41-0.55] for amitriptyline). Those dif-
therapy, problem-solving therapy, short-term psychodynamic psy- ferences correspond to typical response rates of 50% with antide-
chotherapy, and “third-wave” or mindfulness-based therapies.30,38 pressant medication compared with 30% for placebo. The advan-
A network meta-analysis30 including 331 randomized clinical trials tage of antidepressants over placebo varies with depression severity,
and 34 285 participants found all 6 of those specific psychothera- with a meta-analysis of 232 placebo-controlled trials including 73 388
pies similarly more efficacious than usual care without psycho- patients finding only small effect (SMD of approximately 0.15) for
therapy, all with at least medium effect (SMDs ranging from 0.50 patients with mild symptoms of depression and small to medium ef-
[95% CI, 0.20-0.81] for short-term dynamic psychotherapy to 0.73 fect (SMD of approximately 0.38) for those with severe symptoms
[95% CI, 0.52-0.95] for behavioral activation). Those differences of depression.41
correspond to typical response rates of 50% with psychotherapy
compared with 25% without psychotherapy. Nondirective support- Selection of First-Line Treatment
ive counseling, excluding the specific elements in Table 2, has First-line treatment strategies for depression include psycho-
smaller benefit than the specific therapies listed above.30 A meta- therapy, antidepressant medication, or a combination of the 2
analysis of 18 randomized clinical trials including 1913 participants (Box). Randomized clinical trials comparing the efficacy of first-line
with mild depression found specific psychotherapies more effica- treatments have generally found no difference between specific
cious than usual care without psychotherapy with small to medium psychotherapies and antidepressant medications but modestly
effect (SMD, 0.35 [95% CI, 0.23-0.47]).39 greater efficacy for combined medication and psychotherapy over
Similarly, randomized clinical trials demonstrate the efficacy of either alone, especially for more severe or chronic depression.42,43
commonly used antidepressant medications, including selective A network meta-analysis including 101 randomized clinical trials
serotonin reuptake inhibitors (SSRIs), serotonin and norepineph- and 11 901 patients42 reported no difference between psycho-
rine reuptake inhibitors, tricyclic antidepressants, and other newer therapy alone and medication alone (SMD, 0.04 [95% CI, −0.09
antidepressants.40,41 One systematic review and network meta- to 0.16]), but reported combined treatment had a small to medium
analysis including 522 randomized clinical trials and 116 477 effect size compared with psychotherapy alone (SMD, 0.30

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 Clinical Review & Education Review Management of Depression in Adults

Recommendation for or referral to psychotherapy should

Box. Commonly Asked Questions About Depression respect patients’ preferences.53,54 Effective referral often requires
education regarding the components of psychotherapy, assess-
Is psychotherapy or medication more effective for treatment ment of motivation, and addressing reservations or practical barri-
of major depression? ers. When financial barriers, lack of health insurance, and clinician
Research comparing antidepressant medication and specific
shortages preclude access to effective psychotherapy, primary care
psychotherapy for depression has found them equally effective.
Combining medication and psychotherapy is probably more
clinicians can provide brief information regarding elements of
effective than either alone. effective psychotherapies (Table 4). However, brief advice or self-
care resources do not substitute for effective psychotherapy and
Which antidepressant medication is the best first choice?
are not recommended treatments for moderate or more severe
Commonly prescribed antidepressants have similar efficacy but
differ in tolerability and acceptability. Of commonly prescribed
depression.
medications, escitalopram and sertraline rank well for both Meta-analyses have reported that conventional depression
efficacy and acceptability. treatments, both medications and psychotherapy, had medium ef-
fect sizes in people with chronic medical illness55,56 (SMD for anti-
What if first-line depression treatment doesn’t work?
Up to half of people starting antidepressant medication and/or
depressants vs placebo, 0.42 [95% CI, 0.30-0.54]; SMD for psy-
psychotherapy do not improve significantly even with adequate chotherapy vs no psychotherapy, 0.62 [95% CI, 0.52-0.79]), people
treatment. If initial treatment with psychotherapy alone is not who have experienced childhood trauma57 (SMD for antidepres-
effective, adding antidepressant medication should be considered. sants or psychotherapy vs placebo or no psychotherapy, 0.61
If initial treatment with medication is not effective, options include [95% CI, 0.29-0.92]), and those recently bereaved (SMD for psy-
adding psychotherapy, changing medications, or adding a second
chotherapy vs no psychotherapy, 0.35 [95% CI, 0.08-0.62]).58
medication.

Antidepressant Selection and Prescribing

[95% CI, 0.14-0.45]) or medication alone (SMD, 0.33 [95% CI, While antidepressant medications have generally equal efficacy, they
0.20-0.47]). Those differences correspond to typical response vary in frequency of adverse effects40 and in US Food and Drug Ad-
rates of 50% with psychotherapy or medication alone compared ministration approval for treatment of conditions that may be as-
with 65% for combined treatment. Psychotherapy or combined sociated with depression (Table 3). A systematic review and net-
treatment may yield more durable benefit than antidepressant work meta-analysis including 522 randomized clinical trials and
medication alone. A network meta-analysis including 81 random- 116 477 participants reported discontinuation of medication due to
ized clinical trials and 13 722 patients44 reported an odds ratio of adverse effects was modestly lower for citalopram, escitalopram,
1.53 (95% CI, 1.00-2.35) for response sustained through 12 months fluoxetine, sertraline, and vortioxetine compared with other anti-
for psychotherapy alone compared with antidepressant medica- depressants, with odds ratios for discontinuation for any reason of
tion alone and an odds ratio of 2.52 (95% CI, 1.66-3.85) for com- 0.43 to 0.77 compared with placebo (no absolute rates presented).40
bined treatment compared with antidepressant medication alone In that comparison of 21 antidepressants, escitalopram and sertra-
(absolute differences were not reported). No specific symptom line were the 2 medications licensed in the US that ranked in the top
patterns have reliably predicted more favorable response to anti- half for both efficacy and acceptability. Antidepressants with stron-
depressant medications or specific psychotherapies.45,46 ger anticholinergic effects, such as paroxetine, desipramine, and nor-
Based on the efficacy evidence reviewed above, as well as re- triptyline, are not recommended for older patients because of in-
cent evidence-based guidelines47-50 summarized in the Figure, first- creased risk of falls, delirium, and dementia.59 Specific genetic
line treatment depends on depression severity, patient prefer- variations affect the metabolism of antidepressant drugs, and se-
ence, and access to specific treatments. For mild depression (PHQ-9 lection of medication based on pharmacogenomic testing may re-
scores lower than 10), psychotherapies such as cognitive or cogni- duce frequency or intensity of self-reported adverse effects.60,61
tive behavioral therapy, behavioral activation, problem-solving However, antidepressant selection based on pharmacogenomic test-
therapy, interpersonal therapy, or mindfulness-based psycho- ing did not increase the likelihood of a sustained favorable treat-
therapy have moderate benefit, and antidepressant medications are ment response.61,62 Medications may be selected based on associ-
usually not indicated. Exercise, St John’s wort nutritional supple- ated conditions, such as anxiety disorders29 or pain conditions, for
ments, or digital interventions (discussed below) may be helpful. For which antidepressants may be helpful (Table 3); acceptability of an-
moderate depression (PHQ-9 scores 10 to 14), either antidepres- ticipated adverse effects; and cost.
sant medications or specific psychotherapies listed above are rec- Antidepressant medication should usually be initiated at one-
ommended first-line treatments. Combined medication and psy- third to one-half of the usual dose and increased to the lower end
chotherapy may be superior to either treatment alone. For of the usual dosing range in 1 or 2 steps over 1 to 2 weeks (Table 3).
moderately severe or severe depression (PHQ-9 scores 15 or higher), Evidence is mixed regarding the value of higher doses. One system-
combined treatment with psychotherapy and antidepressant medi- atic review and meta-analysis found modest evidence for greater im-
cation is recommended. provement with SSRI antidepressant doses at the upper end of rec-
Treatment decisions should also consider duration of depres- ommended ranges,63 although 2 subsequent larger meta-analyses
sive symptoms and level of impairment. For example, treatment with reported that higher doses did not increase the likelihood of re-
antidepressants51 or psychotherapy52 may be beneficial for pa- sponse and may increase adverse effects.64,65 Less severe adverse
tients with milder symptoms of long duration (sometimes referred effects, such as nausea and headache, often subside over 1 to 2 weeks
to as dysthymia). and improvement in depression may not appear for 2 weeks or more

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 Management of Depression in Adults Review Clinical Review & Education

Figure. Evidence-Based Guideline Recommendations for Initial First-Line Treatment of Depression According to Severity

Mild Moderate Moderately severe Severe

(PHQ-9 score <10) (PHQ-9 score 10-14) (PHQ-9 score 15-19) (PHQ-9 score ≥20)

American College Cognitive behavioral therapy Cognitive behavioral therapy OR second-generation antidepressanta (strong evidence,
of Physicians (2023)50 (conditional recommendation, moderate-certainty evidence)
low-certainty evidence) Cognitive behavioral therapy AND second-generation antidepressant (conditional recommendation,
low-certainty evidence)

American Psychological Psychotherapyb (conditional Psychotherapyc OR second-generation antidepressant (recommendation for use)
Association (2019)48 recommendation for use)

National Institute Guided self-help or group or individual psychotherapyd Cognitive behavioral therapy and antidepressant medication
for Health and Care Cognitive behavioral therapy alone
Excellence (2022)49 Behavioral activation alone
Antidepressant medication alone
Problem-solving therapy alone
Short-term psychodynamic psychotherapy alone
Interpersonal psychotherapy alone

Veterans Affairs and Clinician-guided internet-based Psychotherapye OR antidepressant medication Evidence-based psychotherapyd
Department of Defense cognitive behavioral therapy (strong recommendation) AND antidepressant medication
(2022)47 either alone or with antidepressant (weak recommendation)
medication (weak recommendation)

a d
Includes citalopram, escitalopram, fluoxetine, fluvoxamine, sertraline, Group cognitive or individual cognitive behavioral therapy, behavioral
desvenlafaxine, duloxetine, levomilnacipran, venlafaxine, mirtazapine, activation, or mindfulness and meditation.
nefazodone, trazodone, vilazodone, vortioxetine, and bupropion. e
Acceptance and commitment therapy, behavioral activation, cognitive
b
Cognitive behavioral therapy, interpersonal counseling, problem-solving behavioral therapy, interpersonal therapy, mindfulness-based cognitive therapy,
therapy, and life review therapy. problem-solving therapy, and short-term psychodynamic psychotherapy
c
Behavioral therapy, cognitive therapy, mindfulness-based cognitive therapy, (weak recommendation regarding choice of psychotherapy).
interpersonal therapy, psychodynamic psychotherapies, and supportive
therapy.

after starting an antidepressant medication. Consequently, com- Alternative, Complementary, and Emerging Treatments
munication and encouragement early in treatment are important for As summarized in a 2022 systematic review and practice guideline,72
early adherence. A typical schedule for follow-up visits to measure specific nutritional supplements may be useful adjuncts to antide-
symptom improvement, adjust dose, and manage adverse effects pressant treatment or appropriate treatments for milder depres-
includes initial contact at 2 weeks with subsequent visits every 4 to sion. A meta-analysis of 13 randomized clinical trials including 1233
6 weeks until depression remission or satisfactory treatment re- participants73 reported that omega-3 fatty acid augmentation of an-
sponse. For many patients, follow-up by telephone or online mes- tidepressant medication was modestly more effective than pla-
saging may substitute for in-person visits.66,67 Absence of any ben- cebo augmentation for reducing depression symptoms (SMD, 0.40
efit after 4 weeks of treatment with a dose in the recommended [95% CI, 0.11-0.68]). A meta-analysis of 13 randomized clinical trials
range should prompt consideration of second-line treatment (dis- including 786 participants74 found that probiotic augmentation of
cussed below). antidepressant medication was modestly more effective than pla-
Although antidepressants can decrease preexisting suicidal cebo augmentation for reducing depression symptoms (SMD, 0.36
ideation along with other symptoms of depression,68 all antidepres- [95% CI, 0.24-0.49]). A systematic review and meta-analysis of 18
sants carry a black box warning regarding new onset of suicidal ide- randomized clinical trials including 2922 participants75 found that
ation and behavior after starting antidepressant treatment. A meta- St John’s wort was more effective than placebo among patients with
analysis of 372 placebo-controlled trials including 99 231 patients mild to moderate depression (SMD, 0.49 [95% CI, 0.23-0.74]). None
reported the rate of new-onset suicidal ideation or behavior to be of these nutritional supplements have strong evidence as primary
5.34% higher (95% CI, 0.61%-10.1%) with antidepressants than with treatments for moderate or severe depression.
placebo among patients aged 18 to 25 years with no significant dif- Both acupuncture and structured exercise may augment the
ference in patients aged 25 to 64 years and a 6.34% lower risk with benefits of medication or psychotherapy. A meta-analysis of 16 ran-
antidepressants than placebo in patients aged 65 years and older.69 domized clinical trials including 1958 participants76 reported that
A target trial emulation observational study of SSRI treatment and acupuncture added to antidepressant treatment was modestly more
suicidal risk70 found a similar increase in risk among patients aged effective at reducing depression symptoms than medication alone
25 years or younger. Regardless of age, patients should be advised (SMD, 0.44 [95% CI, 0.33-0.53]). A meta-analysis of 22 random-
that antidepressants can rarely prompt new onset of thoughts of self- ized clinical trials including 1025 participants77 reported that struc-
harm or suicide within a few weeks of starting treatment or increas- tured exercise (primarily aerobic training) added to antidepressant
ing the dose and patients should urgently report any of these symp- medication or psychotherapy was moderately more effective than
toms to their treating clinicians. Clinicians should also monitor medication or psychotherapy alone for reducing depression symp-
patients for emergence of suicidal ideation.71 toms (SMD, 0.62 [95% CI, 0.37-0.86]).

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 Clinical Review & Education Review Management of Depression in Adults

dated digital interventions may be useful as a primary treatment for

Table 4. Brief Counseling Strategies for General Medical Clinicians
mild depression.
Examples of brief advice
Behavioral activation: Setting small, achievable goals for positive activities
scheduling positive can help build motivation and improve mood.
Prognosis and Second-Line Treatments
activities Can we identify one or two positive things you could Among patients starting depression treatment in community prac-
plan over the next week? tice, only 40% to 45% respond within 2 to 3 months of starting first-
When would you do those things? Can we write that line treatment,86-88 reflecting both early treatment discontinua-
down?
tion and unfavorable response to adequate treatment.
Is there anything that might get in the way of doing
these things? How could you manage those? While combined psychotherapy and medication may be rec-
What would help you to get started when the time ommended for first-line treatment, many patients receive only 1 of
comes?
these treatments. Among patients not responding to initial treat-
Cognitive therapy: What are some of the negative or self-critical thoughts
identifying and you can get stuck in? ment with psychotherapy or medication alone, one-third to one-
interrupting negative How can you recognize when you’re getting stuck in half responded favorably to adding psychotherapy to medication,
thoughts those exaggerated or extreme negative thoughts? adding medication to psychotherapy, changing antidepressant medi-
What could help you to interrupt those thoughts or
take away their power?
cation, or adding a second medication.86 Available evidence does
What would help you to take a step back and look at not indicate that changing to an antidepressant of a different type
the evidence about those negative thoughts? or class has greater likelihood of success than changing to a similar
Mindfulness-based Instead of fighting against negative thoughts, it can be medication.89,90
therapy: brief helpful to try just disconnecting from them.
mindfulness exercises You can try to disconnect from negative thoughts by Network meta-analyses43,91 have found alternative second-
focusing on sensations in the present moment – like line treatments have approximately equal likelihood of success, but
your breathing or things you listen to. Some ways you
can do this: selection depends on experience with initial treatment. For indi-
There are lots of mindfulness and meditation exercises viduals who discontinue initial antidepressant treatment due to ad-
on the internet or on apps. You may find you like some
more than others, so try a few. verse effects, either depression-specific psychotherapy or an alter-
Mindfulness practice is often helpful in groups. You native medication less likely to yield similar adverse effects can be
might try searching for a group near you. These groups
can vary in their approach, so it might be worth trying recommended. For patients not responding to initial treatment with
a few.
psychotherapy alone, adding a first-line antidepressant should be
Problem-solving Often when we are depressed, our lives get more
therapy: planning disorganized, which makes us feel even worse. considered. For those not responding to adequate dose and dura-
small, specific steps Try taking a few minutes to plan your day the evening tion of initial antidepressant treatment, options include adding de-
before so you know what to expect and what you may
need to postpone. pression-specific psychotherapy, changing to an alternative antide-
Set 1 to 3 small, achievable goals for the next day. pressant, or augmenting with a second antidepressant (typically
If you aren’t able to achieve those goals, don’t beat
yourself up. Use it as a learning opportunity and see either bupropion or mirtazapine) or with a nonantidepressant medi-
what got in the way. Congratulate yourself for achieving cation (Table 5).
any goals, no matter how small they may seem.
When second-line treatment is ineffective, psychiatry consulta-
Interpersonal There are lots of ways people can support us.
therapy: increasing Sometimes it’s having someone to talk to about tion or referral to mental health specialty care should be considered.
social support problems and other times it may be just doing Third-line treatment options can include an alternative second-line
something with someone who can help give you a sense
of belonging. medication (Table 4) as well as transcranial magnetic stimulation,92,93
Is there someone in your life you feel comfortable
talking with?
intranasal esketamine,94 electroconvulsive therapy,95 or intrave-
Is there someone you’d like to spend a little time with, nous racemic ketamine used off-label.94,96
even if it is something like going for coffee or to
a movie? Meta-analyses97-99 do not support a specific treatment dura-
tion of either antidepressant medication or psychotherapy, but guide-
lines based on expert consensus47,49 recommend varying duration
A 2023 randomized clinical trial78 including 104 participants with of treatment depending on severity and duration of depression. For
moderate to severe depression observed a 42% sustained depres- patients who experience at least 6 months of favorable response to
sive symptom remission rate among those who received a single initial medication treatment during a first episode of depression,
25-mg dose of psilocybin compared with 11% among those who re- gradually tapering and discontinuing medication over 2 to 3 months
ceived an active placebo dose of niacin (adjusted absolute differ- may be considered. For those experiencing a favorable outcome to
ence, 30.3% [95% CI, 13.5%-47.1%]) at day 43 after study drug ad- first-line psychotherapy, a gradual reduction in visit frequency lead-
ministration. Current evidence, however, does not clearly support ing to discontinuation after 4 to 6 months is also reasonable. Taper-
the effectiveness or adequately evaluate the safety of psychedel- ing and discontinuing medication or psychotherapy should include
ics for depression treatment.79-81 discussion of warning signs of relapse and a plan for follow-up as-
Digitalmentalhealthappsandprograms,whendesignedusingevi- sessment a few months after end of treatment. For patients with re-
dence-based psychological strategies and guided by human thera- current or chronic depression, severe symptoms prior to treat-
pistsorcoaches,maybeaseffectiveasface-to-facepsychotherapy.82,83 ment, or need for second-line treatment, treatment lasting several
However, many stand-alone or unguided digital interventions do not years or more and individualized decisions regarding tapering are
include evidence-based content, have high rates of discontinuation, recommended.49 Abrupt discontinuation or rapid tapering of some
and have much smaller effects on symptoms of depression.84,85 Al- antidepressants can precipitate discontinuation symptoms, includ-
though unguided digital interventions are not recommended as pri- ing tinnitus, dizziness, headache, and insomnia. Systematic
mary treatments for moderate or severe depression, guided and vali- reviews100,101 have reported varying prevalence of symptoms after

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 Management of Depression in Adults Review Clinical Review & Education

health care, address gaps in depression care by systematically

Table 5. Second-Line Medication Options for Depression
monitoring treatment adherence and outcomes and then applying
Prescription method Common adverse effects3 evidence-based algorithms to adjust or intensify treatment when
Antidepressant Start second medication NAa symptoms do not improve.87,88 Collaborative care programs also
switch over 2-3 weeks, then
taper first medication facilitate collaboration between primary care clinicians and consult-
over 4-6 weeks
ing psychiatrists and introduce care managers to facilitate system-
Augmenting with Start second medication NAa
bupropion or over 2-3 weeks and atic follow-up. A meta-analysis of 29 randomized clinical trials
mirtazapine continue both including 15 255 patients88 found collaborative or measurement-
Augmenting with based care superior to usual care without systematic follow-up
nonantidepressant
(SMD, 0.42 [95% CI, 0.23-0.61]).Those differences correspond to
Aripiprazole 5 mg daily, increasing Headache, agitation,
after 1 week to 10 mg insomnia, anxiety, weight typical response rates of 40% to 45% in usual care and 60% to
daily gain, nausea, hyperglycemia, 65% in collaborative care programs.
dyslipidemia
Brexpiprazole 0.5 or 1 mg daily, Headache, agitation,
Randomized clinical trials support efficacy of telehealth psy-
increasing after 1 week insomnia, anxiety, weight chotherapy for depression,105,106 with 1 meta-analysis of 155 ran-
to 1 or 2 mg daily gain, nausea, hyperglycemia,
dyslipidemia domized clinical trials of different delivery formats including 15 191
Quetiapine 100 mg at bedtime, Somnolence, weight gain, patients 82 reporting equivalent efficacy of telehealth and in-
increasing weekly as dry mouth, constipation, person cognitive behavioral therapy. The technical capacity for and
tolerated up to 400 mg headache
at bedtime familiarity with telehealth that developed during the COVID-19 pan-
Olanzapine 5 mg at bedtime, Somnolence, weight gain, demic may facilitate access to effective psychotherapy for patients
increasing weekly as dry mouth, constipation, in rural areas and for others unable to access in-person care.
tolerated up to 15 mg tremor, hyperglycemia,
daily dyslipidemia Antidepressant medications and specific psychotherapies for
Buspironeb 15 mg daily, increasing Somnolence, dizziness depression are equally efficacious for Black, Hispanic, and non-
weekly as tolerated up to
15 mg 3 times daily Hispanic White individuals,107,108 but Black and Hispanic patients are
Liothyroninec 25 μg daily with possible Tremors, anxiety less likely to receive effective treatment. For example, data from 6
increase to 50 μg after large health systems indicated that Black and Hispanic patients were
2 weeks
less likely than non-Hispanic White patients to start medication or
Lithiumc 300 mg at bedtime, Tremors, nausea, diarrhea
increasing weekly as psychotherapy following a new depression diagnosis (29.9% and
tolerated to 900 mg at 30.7% vs 39.9%),102 less likely to refill an initial antidepressant pre-
bedtime
scription (61.8% and 60.1% vs 77.0%),103 and less likely to return fol-
Abbreviation: NA, not applicable.
lowing an initial psychotherapy visit (41.3% and 39.6% vs 50.1%).104
a
See Table 3.
Collaborative care programs can reduce racial and ethnic dispari-
b
Approved for treatment of generalized anxiety disorder.
ties in quality and effectiveness of treatment, with 2 systematic
c
Used off-label.
reviews109,110 reporting that collaborative care programs improve
engagement in and effectiveness of depression treatment in Black
antidepressant discontinuation, with rates of 50% or higher when and Hispanic patients.
medications with shorter half-life, especially venlafaxine and par-
oxetine, were tapered over 14 or fewer days. Limitations
This review has limitations. The quality of included studies was not
Practical Considerations formally evaluated and some relevant publications may have been
Depression treatment in community practice often falls short of missed. Regarding some questions, meta-analyses not cited re-
guideline recommendations. For example, data from 6 large health ported different quantitative results. Findings regarding treatment
systems indicated that only 35.7% of 24 251 primary care patients efficacy may not translate to real-world effectiveness. Recommen-
with new diagnoses of depression started antidepressant medica- dations based on meta-analytic evidence may not apply to indi-
tion or psychotherapy within 90 days,102 only 71% of 184 967 pa- vidual patients.
tients starting antidepressant medication for depression in pri-
mary care or mental health specialty care refilled the initial
prescription,103 and only 47.6% of 242 765 patients starting psy-
chotherapy for depression attended a second visit within 45 days.104 Conclusions
A primary care clinician’s role should extend beyond initial diagno- Depression is among the most common conditions treated in pri-
sis, prescription, or referral to ensure the initiation and continua- mary care. Effective first-line treatments include more than 20 an-
tion of effective treatment and improvement in symptoms. tidepressant medications and several specific forms of psycho-
Organized follow-up programs, often called collaborative care therapy. Close monitoring and follow-up improve the likelihood of
in primary care or measurement-based care in specialty mental treatment success.

ARTICLE INFORMATION Conflict of Interest Disclosures: Dr Simon grants from Agency for Healthcare Research and
Accepted for Publication: March 19, 2024. reported receiving grants from National Institute of Quality (AHRQ) and National Heart, Lung, and
Mental Health (NIMH) (U19 MH121738) during the Blood Institute during the conduct of the study and
Published Online: June 10, 2024. conduct of the study. Dr Moise reported receiving grants from National Cancer Institute and Johnson
doi:10.1001/jama.2024.5756

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 Clinical Review & Education Review Management of Depression in Adults

& Johnson outside the submitted work. Dr Mohr meta-analysis: as simple as it gets. J Clin Psychiatry. Psychiatry. 2018;75(9):894-900. doi:10.1001/
reported receiving grants from NIMH during the 2020;81(5):20f13681. doi:10.4088/JCP.20f13681 jamapsychiatry.2018.1776
conduct of the study; personal fees from 11. American Psychiatric Association. Diagnostic 24. O’Donovan C, Alda M. Depression preceding
Boehringer-Ingelheim and Otsuka Pharmaceuticals; and Statistical Manual of Mental Disorders. 5th ed. diagnosis of bipolar disorder. Front Psychiatry.
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Funding/Support: This work was supported by Classification of Diseases and Related Health Unrecognised bipolar disorder among UK primary
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