Clinician Research Summary

Mental Health

Depression

Treatment for Depression After Unsatisfactory Response 

to SSRIs in Adults and Adolescents

Background

Although patients with MDD have a 63-percent response rate 

during 6 to 12 weeks of treatment with second-generation 

antidepressants, 53 percent do not achieve remission.1,2

Up to two-thirds of adult patients will not achieve remission 

with an SSRI.3 SSRIs are a frequently used class of secondgeneration antidepressants.

Clinicians are faced with a number of treatment options (see 

Table 1) after an inadequate response to an SSRI, including 

both monotherapy and combination therapy approaches. 

Monotherapy approaches include: 

 Optimizing the dosage or duration of the current SSRI

 Switching to another SSRI or another antidepressant 

 Switching to a nonpharmacological treatment 

(e.g., psychological therapies or exercise)

Combination therapy approaches include: 

 Adding medications (e.g., augmenting agents, a different 

SSRI, or other antidepressants)

 Switching to another agent (e.g., a different SSRI) and 

adding another medication 

 Adding a nonpharmacological treatment 

 Combinations of these treatments 

1 Gartlehner G, et al. Ann Intern Med. 2011;155:772-85. PMID: 22147715.

2 First-generation antidepressants may include tricyclic antidepressants and 

monoamine oxidase inhibitors. More recently developed second-generation 

antidepressants include SSRIs, selective serotonin and norepinephrine reuptake 

inhibitors, serotonin and norepinephrine reuptake inhibitors, and other secondgeneration antidepressants (bupropion, nefazodone, and trazodone).

3Perahia DG, et al. J Psychiatr Res. 2009;43(5):512-8. PMID: 18707693.

In the studies included in the systematic review, the 

definition of an adequate response to SSRI medications is 

not consistent but generally refers to a 50-percent decrease 

in symptom severity. Remission from depression is defined 

as being free or nearly free of symptoms for the current 

episode. The systematic review evaluated treatment options 

for patients who only had a partial response or who had no 

response to an SSRI medication.

Conclusion

Evidence remains limited to support clinical decisionmaking 

about the available approaches for treating patients with 

MDD who have an inadequate response to SSRIs. For adults 

with MDD, evidence is insufficient to guide decisionmaking 

for comparisons among monotherapies, monotherapies 

versus combination therapies, and comparisons among 

combination therapies with a few exceptions. Adding an 

atypical antipsychotic—risperidone or olanzapine—to 

ongoing SSRI treatment may slightly improve response 

and remission rates when compared with continuing SSRI 

treatment alone. Low-level evidence suggests that comparable 

response and remission rates are obtained from switching to a 

new antidepressant versus combining the new antidepressant 

with pharmacological or nonpharmacological treatment. 

For adolescents with MDD, low-level evidence suggests 

that combining an antidepressant and cognitive behavioral 

therapy (CBT) may be superior to medication alone. 

For adults, most reported adverse effects were consistent 

with those typically associated with antidepressant use. 

Comparative evidence is insufficient to guide decisionmaking 

about adverse effects both in adults and in adolescents.

Research Focus for Clinicians

A systematic review of 44 clinical studies published between January 1980 and April 2011 examined the comparative 

effectiveness, benefits, and adverse effects of interventions for adults and adolescents with major depressive disorder (MDD) 

who have an unsatisfactory response to treatment with a selective serotonin-reuptake inhibitor (SSRI). The review also 

compared recommendations from 27 Clinical Practice Guidelines (CPGs) published from January 2004 to April 2011. The 

findings of this review do not apply to subjects who have a primary diagnosis of bipolar disorder, schizophrenia, or anxiety 

disorder. This summary is provided to inform discussions of options with patients and to assist in decisionmaking along with 

consideration of a patient’s values and preferences and should not be construed to represent clinical recommendations or 

guidelines. The full report is available at www.effectivehealthcare.ahrq.gov/ssri-depression.cfm.
For adults with MDD who have an inadequate 

response to SSRIs: 

Optimizing SSRI therapy or switching monotherapy agents

Evidence is insufficient to determine if differences exist in 

response and remission rates if the current SSRI treatment 

is maintained versus:

 Dose escalation of the current SSRI 

 Switching to a different SSRI 

 Switching to a non-SSRI antidepressant 

 Switching to a psychological intervention (e.g., CBT) 

Monotherapy versus combination therapy: adding 

medications to the existing SSRI or to a new antidepressant 

 Adding risperidone or olanzapine to ongoing SSRI 

treatment may slightly improve response and remission 

rates versus continuing SSRI treatment alone. 

 Evidence is insufficient to determine if there are differences 

in response and remission rates for continuing monotherapy 

with an SSRI versus:

 Adding buspirone 

 Adding other augmenting agents (e.g., lithium or 

mianserin) 

 Adding a non-SSRI antidepressant (clomipramine, 

bupropion, or desipramine) 

 Comparable results were achieved in response and remission 

rates for switching to a new antidepressant versus:

 Combining the new monotherapy with another treatment 

(e.g., a new SSRI, a non-SSRI, or a nonpharmacological 

treatment) 

 Combining the new antidepressant with buspirone 

Monotherapy versus combination therapy: adding 

nonpharmacological treatment

Evidence is insufficient to determine if there are differences 

in response and remission rates for continuing therapy 

with an SSRI versus combining that SSRI with:

 CBT 

 Dialectical behavior therapy 

 Exercise 

(Continued in next column)

For adults with MDD who have an inadequate 

response to SSRIs: (Continued)

Combination therapies

 Evidence is insufficient to determine if there are differences 

in response and remission rates when an SSRI is given in 

combination with another SSRI, another antidepressant, an 

augmenting agent, or CBT. 

Adverse effects in adults with MDD

 In general, most reported adverse effects were consistent 

with those associated with antidepressant use and were 

likely mild to moderate in nature; common adverse effects 

included headaches, dry mouth, dizziness, weight gain, 

sexual dysfunction, and fatigue. 

 In adults with MDD, serious and severe adverse effects (e.g., 

suicidality) were not measured or not reported in most 

studies, so there is insufficient evidence to compare the 

adverse effects of various treatment approaches. 

Adolescents with MDD

 For adolescents with MDD who have an inadequate response 

to SSRIs, adding CBT may be superior to an SSRI alone. 

 In one study on adolescents, there were no significant 

differences in adverse effects for patients on an SSRI or 

venlafaxine with or without CBT, except for an increase in skin 

rashes and cardiovascular events in patients on venlafaxine.

 The FDA has issued a warning about suicidality and 

antidepressant drugs. There is an increased risk of suicidal 

thinking and behavior in children, adolescents, and young adults 

taking antidepressants for MDD and other psychiatric disorders. 

Clinical Bottom Line

Strength of Evidence Scale

High:  High confidence that the evidence reflects the true 

effect. Further research is very unlikely to change 

our confidence in the estimate of effect.

Moderate:  Moderate confidence that the evidence reflects 

the true effect. Further research may change our 

confidence in the estimate of effect and may change 

the estimate.

Low:  Low confidence that the evidence reflects the true 

effect. Further research is likely to change our 

confidence in the estimate of effect and is likely to 

change the estimate.

Insufficient:  Evidence is either unavailable or does not permit 

a conclusion.

Analysis of Clinical Practice Guidelines

Variations among CPGs reflect the great amount of 

uncertainty that exists in the current evidence base. Of 

the 27 CPGs reviewed (January 2004 to April 2011), most 

do not define “inadequate response.” All 27 CPGs provide 

recommendations for patients with MDD, but 7 do not 

provide any recommendations for patients with previous 

inadequate responses to therapy.

When an increase in dose or duration is recommended 

for adults, the change in dose or duration is not 

specified. When switching to a different monotherapy 

agent is recommended, most CPGs do not mention a 

specific antidepressant. When combination therapy is 

recommended, the CPGs are more likely to specify the drug 

to add to the antidepressant, but there is great variability 

in the augmenting agents recommended. For adolescents, 

nonpharmacological interventions are the preferred firstline therapy. However, some CPGs cite research done in 

adult populations as the basis for treatment strategies in 

children and adolescents.
Table 1. Pharmacological and Nonpharmacological Interventions Studied in the Review

SSRIs*  Citalopram (Celexa®)

 Escitalopram (Lexapro®)

 Fluoxetine (Prozac®, Prozac Weekly®, Sarafem®, 

Symbyax®)

 Fluvoxamine (Luvox®, Luvox CR®)

 Paroxetine (Paxil®, Paxil CR®, Pexeva®)

 Sertraline (Zoloft®)

Non-SSRI 

Antidepressants

 Amitriptyline (Amitid®, Amitril®, Elavil®, Endep®, 

Etrafon 2-10, Etrafon 2-25, Etrafon-a, EtrafonForte, Limbitrol®, Limbitrol® DS, Perphenazine®, 

and Triavil 2-10, Triavil 2-25, and Triavil 4-10) 

 Bupropion (Aplenzin®, Wellbutrin®, Wellbutrin SR®, 

Wellbutrin XL®, Zyban®)

 Clomipramine (Anafranil®)

 Desipramine (Norpramin®, Pertofrane®)

 Desvenlafaxine (Pristiq®)

 Doxepin (Sinequan®, Zonalon®)

 Duloxetine (Cymbalta®)

 Imipramine (Janimine®, Presamine®, Tofranil®, 

Tofranil-PM®) 

 Maprotiline (Ludiomil®)

 Mirtazapine (Remeron®, Remeron SolTab®)

 Phenelzine (Nardil®)

 Protriptyline (Vivactil®)

 Selegiline transdermal system (EMSAM®)

 Tranylcypromine (Parnate®)

 Trazodone (Desyrel®, Trialodine®)

 Trimipramine (Surmontil®)

 Venlafaxine (Effexor®, Effexor XR®)

Augmenting and 

Nonantidepressant 

Agents

 Anticonvulsants 

 Antiprogestational agents

 Dopamine agonists

 Psychostimulants

 Sex hormones 

 Thyroid medications

 Other drugs such as buspirone (Buspar®), lithium, 

pindolol, and tryptophan

Atypical Antipsychotics**:

 Aripiprazole (Abilify®) 

 Olanzapine (Zyprexa®)

 Risperidone (Risperdal®) 

 Quetiapine (Seroquel®)

 Ziprasidone (Geodon®)

Nonpharmacological 

Therapies

 Cognitive behavioral therapy

 Exercise

 Interpersonal therapy

 Other psychotherapies

* Concomitant use of selective serotonin-reuptake inhibitors (SSRIs) in patients taking monoamine oxidase inhibitors (MAOIs; e.g., phenelzine 

[Nardil®], selegiline transdermal system [EMSAM®], tranylcypromine [Parnate®]) is contraindicated, as cases of serious and sometimes 

fatal reactions have been reported. These reactions have also been reported in patients who have recently discontinued an SSRI or other 

drugs that interfere with serotonin metabolism and have been started on an MAOI. For additional information, see the U.S. Food and Drug 

Administration (FDA) safety announcements at www.fda.gov.

** Aripiprazole (Abilify®) and quetiapine XR (Seroquel XR®) have been approved by the FDA to be added to an antidepressant to treat adults with 

major depressive disorder. Olanzapine (Zyprexa®) has been approved by the FDA to be added to the SSRI fluoxetine (Prozac®, Prozac Weekly®, 

Sarafem®) to treat adults with treatment-resistant depression.

Gaps in Knowledge

 There is some evidence that suggests that milder 

depression, less family conflict, and the absence of 

suicidal behavior are associated with greater likelihood 

of a positive treatment response in adolescents.

 For adults with dysthymia or subsyndromal symptoms 

who have an inadequate response to SSRIs, there is 

insufficient evidence to evaluate treatment approaches. 

 There is some evidence that suggests that people with 

concurrent anxiety symptoms have less likelihood of 

achieving remission.

Additional Information

 Overall, few studies have evaluated the impact of 

different depressive diagnoses, disease severity, previous 

comorbidities, age, sex, and race on treatment outcomes.

 There is inconsistency between studies in the definition 

of “inadequate response” and in the distinction between 

response and remission.

 More studies are needed on the response and remission 

rates in children and adolescents to treatments 

subsequent to an inadequate SSRI response.

 Evidence is very limited on response and remission rates 

for patients with subsyndromal depression or dysthymia 

who have inadequate responses to an SSRI.
What To Discuss With Your Patients

 The health consequences of depression

 The rate of treatment response following treatment with 

SSRIs and the possibility of treatment-resistant depression

 The various interventions for treating depression after

unsatisfactory response to SSRIs

 Patient preferences regarding cost, nonpharmacological 

treatment, medication type, and potential side effects

 What is known about nonpharmacological interventions 

for treating depression

 Potential drug interactions with medications

 The risk of antidepressants and other medications for 

pregnant or nursing women

 The possibility of severe adverse effects such as 

suicidality and that additional resources or help are 

available from the National Suicide Prevention Lifeline at 

www.suicidepreventionlifeline.org or 1-800-273-8255

Resource for Patients

Treatment Options When Your SSRI Antidepressant Is Not 

Working Well is a free companion to this clinician research 

summary. It covers:

 Background information about 

depression and unsatisfactory 

response to SSRIs

 Descriptions of the types of 

treatments, how they work, and 

potential side effects

 Questions to guide a discussion with 

you about treatment options

AHRQ Pub. No. 12(13)-EHC050-3

July 2013

Ordering Information

For electronic copies of Treatment Options When Your SSRI

Antidepressant Is Not Working Well, this clinician research 

summary, and the full systematic review, visit www.

effectivehealthcare.ahrq.gov/ssri-depression.cfm. To order 

free print copies, call the AHRQ Publications Clearinghouse 

at 800-358-9295. 

Source

The information in this summary is based on Treatment 

for Depression After Unsatisfactory Response to SSRIs,

Comparative Effectiveness Review No. 62, prepared by 

the McMaster University Evidence-based Practice Center 

under Contract No. 290-2007-10060-I for the Agency for 

Healthcare Research and Quality, April 2012. Available at 

www.effectivehealthcare.ahrq.gov/ssri-depression.cfm. This 

summary was prepared by the John M. Eisenberg Center for 

Clinical Decisions and Communications Science at Baylor 

College of Medicine, Houston, TX.