Adjunctive Treatment Options for Patients With Residual Symptoms of Depression

Psychiatric TimesVol 33 No 4
Volume 33
Issue 4

Patients with residual symptoms of depression may continue to experience significant occupational and social impairment. The focus of this article is on the residual burden that so often remains after remission is achieved.

Premiere Date: April 20, 2016
Expiration Date: October 20, 2017

This activity offers CE credits for:
1. Physicians (CME)
2. Other


The focus of this article is on treatment approaches for residual symptoms of depression.


At the end of this CE activity, participants should be able to:

• Recognize the prevalence of residual symptoms of depression after full recovery is achieved according to accepted criteria

• Understand the significant impairments associated with residual symptoms

• Identify the medications that may be used as adjuncts to alleviate the residual symptom burden


This continuing medical education activity is intended for psychiatrists, psychologists, primary care physicians, physician assistants, nurse practitioners, and other health care professionals who seek to improve their care for patients with mental health disorders.


CME Credit (Physicians): This activity has been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint providership of CME Outfitters, LLC, and Psychiatric Times. CME Outfitters, LLC, is accredited by the ACCME to provide continuing medical education for physicians.

CME Outfitters designates this enduring material for a maximum of 1.5 AMA PRA Category 1 Credit™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Note to Nurse Practitioners and Physician Assistants: AANPCP and AAPA accept certificates of participation for educational activities  certified for 1.5 AMA PRA Category 1 Credit™.


It is the policy of CME Outfitters, LLC, to ensure independence, balance, objectivity, and scientific rigor and integrity in all of their CME/CE activities. Faculty must disclose to the participants any relationships with commercial companies whose products or devices may be mentioned in faculty presentations, or with the commercial supporter of this CME/CE activity. CME Outfitters, LLC, has evaluated, identified, and attempted to resolve any potential conflicts of interest through a rigorous content validation procedure, use of evidence-based data/research, and a multidisciplinary peer-review process.

The following information is for participant information only. It is not assumed that these relationships will have a negative impact on the presentations.

Kassandra J. Gibbs, BA, has no disclosures to report.

J. Alexander Bodkin, MD, reports that he is a principal investigator on 2 multisite clinical trials of brexpiprazole augmentation in treatment-resistant depression (TRD) (Otsuka); he is also a consultant for Alkermes (ACK5461 augmentation in TRD) and Otsuka (brexpiprazole augmentation for TRD).

Michael Ziffra, MD, (peer/content reviewer) has no disclosures to report.

Applicable Psychiatric Times staff and CME Outfitters staff have no disclosures to report.


Faculty of this CME/CE activity may include discussion of products or de­vices that are not currently labeled for use by the FDA. The faculty have been informed of their responsibility to disclose to the audience if they will be discussing off-label or investigational uses (any uses not approved by the FDA) of products or devices. CME Outfitters, LLC, and the faculty do not endorse the use of any product outside of the FDA-labeled indications. Medical professionals should not utilize the procedures, products, or diagnosis techniques discussed during this activity without evaluation of their patient for contraindications or dangers of use.

Questions about this activity?

Call us at 877.CME.PROS (877.263.7767)

[[{"type":"media","view_mode":"media_crop","fid":"43305","attributes":{"alt":"Depression-Nomad-Soul/","class":"media-image media-image-right","id":"media_crop_462321371923","media_crop_h":"0","media_crop_image_style":"-1","media_crop_instance":"5683","media_crop_rotate":"0","media_crop_scale_h":"125","media_crop_scale_w":"125","media_crop_w":"0","media_crop_x":"0","media_crop_y":"0","style":"font-size: 13.008px; line-height: 1.538em; float: right;","title":"Nomad-Soul/","typeof":"foaf:Image"}}]]In the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study, 90% of patients treated for depression who met full criteria for remission still displayed residual symptoms.1 Individuals with residual symptoms are at higher risk for relapse and tend to relapse faster than those who are asymptomatic on remission. Moreover, these patients continue to experience significant occupational and social impairment. Clinicians need to be aware of residual symptoms, especially since treatment options are available.

The focus of this article is on the residual burden that so often remains after remission is achieved. We use the term “remission” according to the convention in widest use in the evaluation of antidepressant efficacy in clinical trials, which is a 17-item Hamilton Depression Rating Scale (HAMD-17) score of 7 or less.

Keep in mind that a score of 7 on the HAMD-17 does not indicate the absence of symptoms. For example, a patient with that score could still have obvious depressed mood, conspicuous functional impairment, and passive wishes for death. Thus, remission of an episode of depression may be present by definition, although a significant burden of illness remains. Even with stricter definitions (eg, a score of 5 or lower), clinically significant residual symptoms could still remain. In short, complete freedom from depressive symptoms, which is relatively rare, is not required for a patient to be considered to have achieved remission.

The most commonly identified residual symptoms are low mood, insomnia, difficulty in concentrating, and lassitude. In a 3-year study of 267 depressed patients, Conradi and colleagues2 found that 44% reported cognitive problems, 35% lacked energy, and 39% had sleeping issues during non- depressive episodes. Residual symptoms occurred in 35% to 44% of patients in remission.

The STAR*D study showed insomnia in 94.6% of patients who responded to antidepressant treatment with citalopram. Sad mood (70.8%) and decreased concentration (69.6%) were the other most common residual symptoms reported.3 The prevalence of residual symptoms highlights the need to optimize treatment to reduce the persistent depressive burden.

An SSRI is the first step in treating depression in a patient who requires medication and who has no clear history of effective prior treatment with other classes of antidepressant. However, the rate of robust response to this virtually universal intervention is remarkably low. Remission occurred in only 28% to 31% of patients who were treated with an SSRI given at adequate dosage and duration.4 Considering the frequency and potential severity of major depression, this is a dismayingly low rate of full treatment response.

Typically, clinicians try at least a second SSRI if the first trial is ineffective or poorly tolerated, and patients may undergo multiple SSRI trials before being switched to a different class of antidepressant. Although more research is needed, there is evidence that switching from an SSRI to a non-SSRI antidepressant results in a higher rate of remission than shifting from one SSRI to another SSRI.5 Given the delayed response and the loss of any clinical benefit provided by initial therapy that a switch to a treatment with a different mechanism of action entails, it is reasonable to consider adjunctive pharmacotherapy.

When a patient shows some improvement on a well-tolerated antidepressant medication but a significant illness burden remains, it is usually best to adjust the dosage. If the therapeutic effect remains insufficient after dosage adjustment, any of a wide variety of adjunctive treatments may be tried, depending on specific remaining symptoms.


Antidepressant adjuncts


Bupropion has been shown to brighten mood and ameliorate specific depressive symptoms when combined with serotonin reuptake inhibitor (SRI) antidepressants without a significant increase in adverse effects. It is an effective antidepressant when given as monotherapy and has been shown to improve energy, motivation, and concentration, but its effect is more robust and symptom relief more complete when combined with an SRI.6 Use caution when prescribing this agent to patients who have comorbid anxiety disorders because bupropion may increase anxiety symptoms in some patients.7


An option particularly well suited for patients with decreased appetite and sleep disturbances is the addition of mirtazapine to an SSRI, SNRI, or bupropion regimen. Mirtazapine is effective when combined with an SRI antidepressant, particularly with venlafaxine.8,9 One of the reported benefits has been a reduced adverse-effect profile compared with either SRI or mirtazapine monotherapy, with a specific reduction in sexual adverse effects. Findings also suggest that adjunctive mirtazapine reduces comorbid anxiety symptoms in patients with depressive disorder.10


Off-label use of trazodone can be effective in treating insomnia.11 It has been shown to increase the quality and duration of sleep and to improve daytime functioning.12 Trazodone may also be an effective non-addictive alternative to benzodiazepines for patients with refractory comorbid anxiety symptoms.13 However, daytime sedation may make it intolerable for some patients.

Non-antidepressant adjuncts


Lithium is a long-recognized, although infrequently prescribed, antidepressant adjunct. A drawback is the necessity of continual blood level monitoring, for which the patients must have the resources as well as a vested responsibility in managing this aspect of care. When coupled with an antidepressant, lithium can prevent relapse in patients who show an initial response to therapy.14 Lithium also decreases the risk of suicide, suicidal behavior, and all-cause mortality in persons with mood disorders.15


Once a leading antidepressant augmentation strategy, triiodothyronine (T3) has emerged after a long period of relative neglect as a worthwhile adjunct with relatively few adverse effects and some evidence that it can benefit a subset of patients. A study that compared (T3) with lithium augmentation showed (T3) to be significantly more satisfactory, in part because of its low adverse-effect burden.16 There is no need to monitor blood levels; however, one study noted an increase in anxiety when (T3) was combined with paroxetine.17 Augmentation with up to 50 mg/d of (T3) was effective and safe, although it is unclear what the most effective dosage and duration of treatment are.18

Atypical antipsychotics

In recent years, aripiprazole, olanzapine, and quetiapine have been approved by the FDA as adjuncts in treatment-resistant depression. Although these atypical antipsychotics are well established as effective options for partial responders, drawbacks exist regarding efficacy and tolerability, which differ among specific agents.

Aripiprazole is the most activating agent and addresses 2 of the most common residual symptoms: lassitude and impaired concentration. However, aripiprazole increases the risk of akathisia, which can be treatment-limiting. Nelson and colleagues19 found akathisia to be most frequent in patients under the age of 40 and recommend a lower initial dosage for these patients. Despite the frequency of akathisia (which occurred in 25% of Nelson’s study subjects), aripiprazole is currently the most widely used of the antidepressant adjuncts. The typical dose is between 2 and 10 mg, given in the morning. The activating effects of aripiprazole are specifically helpful in patients who have residual symptoms of apathy, lethargy, and attentional impairment.

Quetiapine is also very widely used as an antidepressant adjunct. It is most useful when sedation is desired or anxiety is prominent. It is the most sedating of the atypical antipsychotics approved for adjunctive use in depression. Quetiapine therapy is most often discontinued because of fatigue.20 Weight gain is also common, with more total weight gained at higher doses, although this effect is milder than that seen with olanzapine. The approved antidepressant dose is 150 to 300 mg given at bedtime; lower doses are often used, with some benefit and less sedation. The sedative effects of quetiapine are specifically helpful in patients who have residual insomnia and anxiety.

Olanzapine is associated with frequent and often marked weight gain as well as increased blood glucose and lipid levels.21 It is FDA approved only for adjunctive use with fluoxetine. However, it is often effective in combination with other antidepressants, although the problem of weight gain reduces its acceptability.


Modafinil, armodafinil, methylphenidate, and amphetamine preparations (lisdexamfetamine is the most studied recently) are stimulants currently used as adjunctive therapy with SSRIs and SNRIs. None are FDA approved for adjunctive treatment of resistant depression, although stimulants are increasingly used to treat residual symptoms of apathy, anergia, fatigue, and impairment of executive function. Findings from a recent study indicate that adjunctive lisdexamfetamine dimesylate reduces symptoms of dysphoric apathy in partial responders to SSRIs and SNRIs.22


Anxiolytic drugs can be an effective adjunct for managing residual or treatment-emergent anxiety and insomnia. Their use was formerly very widespread, yet only alprazolam is FDA approved to treat anxiety symptoms in depressed patients. It is currently the most widely prescribed psychotropic medication.23

As a rule, only limited use of these medications is recommended because of the potential for misuse, diversion, and dependency. Nonetheless, for patients who are well known to the prescriber and are deemed trustworthy in their use of prescribed medication, benzodiazepines have the dramatic advantage of extremely rapid therapeutic effect, and in the context of time-limited use, the risk of dependency is vanishingly small. With higher doses and when consumed with alcohol, there may be adverse effects on the processing of short-term memory.


Pramipexole is an FDA-approved dopamine agonist for the treatment of Parkinson disease and restless leg syndrome. It is an effective, well-tolerated adjunct to treatment with SRI antidepressants.24,25 Evidence of efficacy in bipolar depression is more robust, generally as an adjunct to a mood stabilizer and as monotherapy.26


Buprenorphine is an opioid with low abuse potential that is widely used for the treatment of opiate dependency. Until modern antidepressants replaced them in the mid-1950s, opium and its derivatives had long been recommended for the treatment of symptoms of depression. With the introduction of buprenorphine, a safer opioid became available. Recently, a large multicenter placebo-controlled study showed buprenorphine to be an effective antidepressant adjunct when administered in combination with the opioid antagonist samidorphan, which blocks buprenorphine’s mildly euphoriant effects while still allowing a strong antidepressant effect.27 The combination of buprenorphine and samidorphan is currently under development for potential approval as a novel antidepressant adjunct.


Pharmacological adjuncts may be used to help achieve remission from a depressive episode or to ameliorate the residual symptoms that so often persist in the setting of clinical remission. While adjunctive treatments have been amply studied as interventions in patients with treatment-resistant depression, there is very little empirical literature concerning the use of adjunctive agents to free patients in “remission” from the residual symptoms that often still persist. Well-being, as opposed to recovery from an episode of illness, is not yet accepted as an important outcome to consider in the development of new pharmacotherapies for depression. Therefore, the pharmaceutical industry, which funds the great majority of clinical trials, has not supported investigations of the rate of “wellness” achieved in patients undergoing pharmacotherapy.

However, most prescribing mental health providers see it as their role in depression treatment to help patients achieve the most complete freedom from symptoms. Neither patients nor clinicians are likely to be satisfied with a reduction in the severity of illness to the point that diagnostic criteria are no longer met, or even with improvement to the level of 7 points or less on the HAMD-17, if the patient is left with a residual symptom burden. The shared goal is for the patient to recover to the point of feeling well, to whatever extent that is possible.

Recovery of well-being is not an unrealistic goal in the treatment of depressive disorders. Progress requires extensive research focused on this important, but strikingly neglected, clinical goal.

Although a detailed discussion is beyond the scope of this article, the American Psychiatric Association (APA) recommends a variety of nonpharmacological interventions, such as ECT and transcranial magnetic stimulation. Some of the recommended psychotherapeutic approaches include cognitive-behavioral therapy, behavioral therapy, interpersonal therapy, and psychodynamic psychotherapy. Comparative studies reviewed in the APA practice guidelines for the treatment of MDD found a small but consistent benefit in combined treatment with medication and psychotherapy compared with either modality alone.28 Patients with treatment-resistant depression who have not tried psychotherapy may find it a useful adjunct or alternative to medication.

Overall, we recommend keeping up to date with new literature that pertains to enhancements in the treatment of residual symptoms of depression. An ongoing dialogue with patients should be maintained regarding potential strategies to increase relief and promote well-being when depressive symptoms linger.



Post-tests, credit request forms, and activity evaluations must be completed online at (requires free account activation), and participants can print their certificate or statement of credit immediately (80% pass rate required). This Web site supports all browsers except Internet Explorer for Mac. For complete technical requirements and privacy policy, visit



Need Additional CME Credit?

Check Out These CME Activities-Hurry, Some Expire Soon!

Tips, Cautions, and Successes in Treating Bipolar Patients With Lithium

by Ralph J. Koek, MD Expiration date: April 20, 2016.

Neural Circuitry of Suicidality

by  Lisa Pan, MD Expiration date: May 20, 2016.


Ms Gibbs is a first-year medical student at the University of Vermont School of Medicine in Burlington, VT. Dr Bodkin is Assistant Professor of Psychiatry at Harvard Medical School and Director of the Clinical Psychopharmacology Research Program at McLean Hospital in Belmont, MA.


1. Nierenberg A, Husain M, Rush A, et al. Residual symptoms after remission of major depressive disorder with citalopram and risk of relapse: a STAR-D report. Psychol Med. 2010;40:41-50.

2. Conradi H, Ormel J, de Jonge P. Presence of individual (residual) symptoms during depressive episodes and periods of remission: a 3-year prospective study. Psychol Med. 2011;41:1165-1174.

3. McClintock S, Husain M, Rush A, et al. Residual symptoms in depressed outpatients who respond by 50% but do not remit to antidepressant medication. J Clin Psychopharmacol. 2011;31:180-186.

4. Warden D, Rush AJ, Trivedi MH, et al. The STAR*D project results: comprehensive review of findings. Curr Psychiatry Rep. 2007;9:449-459.

5. Papakostas G, Fava M, Thase M. Treatment of SSRI-resistant depression: a meta-analysis comparing within- versus across-class switches. Biol Psychiatry. 2008;63:699-704.

6. Bodkin J, Lasser R, Wines J, et al. Combining serotonin reuptake inhibitors and bupropion in partial responders to antidepressant monotherapy. J Clin Psychiatry. 1997;58:137-145.

7. Sheehan DV, Davidson J, Manschreck T, Van Wyck Fleet J. Lack of efficacy of a new antidepressant (bupropion) in the treatment of panic disorder with phobias. J Clin Psychopharmacol. 1983;3:28-31.

8. Carpenter LL, Zeljko J, Steven JM, et al. Mirtazapine augmentation in the treatment of refractory depression. J Clin Psychiatry. 1999;60:45-49.

9. Hannan N, Hamzah Z, Akinpeloye HO, et al. Venlafaxine-mirtazapine combination in the treatment of persistent depressive illness (English). J Psychopharmacol (Oxford). 2007;21:161-164.

10. Aydemir O, Deveci A, Taskin E. Mirtazapine combination in treatment-resistant major depressive disorder: a retrospective evaluation of six weeks. Bull Clin Psychopharmacol. 2009;19:347-352.

11. Nierenberg AA, Adler LA, Peselow E, et al. Trazodone for antidepressant-associated insomnia. Am J Psychiatry. 1994;151:1069-1072.

12. Wichniak A, Wierzbicka A, Jernajczyk W. Patients with insomnia and subthreshold depression show marked worsening of insomnia after discontinuation of sleep promoting medication. Prog Neuropsychopharm Biol Psychiatry. 2011;35:1671-1676.

13. Rickels K, Downing R, Schweizer E, Hassman H. Antidepressants for the treatment of generalized anxiety disorder: a placebo-controlled comparison of imipramine, trazodone, and diazepam. Arch Gen Psychiatry. 1993;50:884-895.

14. Bauer M, Bschor T, Kunz D, et al. Double-blind, placebo-controlled trial of the use of lithium to augment antidepressant medication in continuation treatment of unipolar major depression. Am J Psychiatry. 2000;157:1429-1435.

15. Cipriani A, Hawton K, Stockton S, Geddes JR. Lithium in the prevention of suicide in mood disorders: updated system review and meta-analysis. BMJ. 2013;346:f3646.

16. Nierenberg AA, Fava M, Trivedi MH, et al. A comparison of lithium and (T3) augmentation following two failed medication treatments for depression: a STAR*D report. Am J Psychiatry. 2006;163:1519-1530.

17. Appelhof BC, Brouwer JP, Van Dyck R, et al. Triiodothyronine addition to paroxetine in the treatment of major depressive disorder. J Clin Endocrinol Metab. 2004;89:6271-6276.

18. Cooper-Kazaz R, Lerer B. Efficacy and safety of triiodothyronine supplementation in patients with major depressive disorder treated with specific serotonin reuptake inhibitors. Int J Neuropsychopharm. 2008;11:685-699.

19. Nelson JC, Thase ME, Trivedi MH, et al. Safety and tolerability of adjunctive aripiprazole in major depressive disorder: a pooled post hoc analysis (studies CN138-139 and CN138-163). Prim Care Compan J Clin Psychiatry. 2009;11:344-352.

20. Bauer M, El-Khalili N, Datto C, et al. A pooled analysis of two randomized, placebo-controlled studies of extended release quetiapine fumarate adjunctive to antidepressant therapy in patients with major depressive disorder. J Affect Disord. 2010;127:19-30.

21. Kato M, Chang C. Augmentation treatments with second-generation antipsychotics to antidepressants in treatment-resistant depression. CNS Drugs. 2013;27(suppl 1):11-19.

22. Bodkin JA, Mann T, Saxena PP, et al. The effect of adjunctive lisdexamfetamine on residual depressive symptoms in subjects undergoing SRI treatment and displaying persistent dysphoric apathy and retardation. Poster presented at: McLean Hospital Research Day; January 2015; Belmont, MA.

23. Baldessari RJ. Chemotherapy in Psychiatry. New York: Springer-Verlag; 2013.

24. Cassano P, Lattanzi L, Cassano G, et al. Pramipexole in treatment-resistant depression: an extended follow-up. Depress Anxiety. 2004;20:131-138.

25. Cusin C, Lovieno N, Perlis R, et al. A randomized, double-blind, placebo-controlled trial of pramipexole augmentation in treatment-resistant major depressive disorder. J Clin Psychiatry. 2013;74:e636-e641.

26. Goldberg J, Burdick K, Endick C. Preliminary randomized, double-blind, placebo-controlled trial of pramipexole added to mood stabilizers for treatment-resistant bipolar depression. Am J Psychiatry. 2004;161:564-566.

27. Fava M, Memisoglu A, Thase ME, et al. Opioid modulation with buprenorphine/samidorphan as adjunctive treatment for inadequate response to antidepressants: a randomized double-blind placebo-controlled trial. Am J Psychiatry. 2016. [Epub ahead of print.] Accessed February 29, 2016.

28. The American Psychiatric Association Practice Guidelines for the Psychiatric Evaluation of Adults. 3rd ed. Accessed February 29, 2016.

Related Videos
© 2024 MJH Life Sciences

All rights reserved.